The Trajectory and Significance of Perioperative Changes in Alzheimer’s Disease Biomarkers

When Miles Berger, MD, PhD, received the email to tell him he had been awarded the 2014 IARS Mentored Research Award, he initially thought it was a mistake. Newly on faculty at Duke University Medical Center, he had already applied for several awards and received rejections to all of them. He was beginning to feel discouraged and questioning whether he would find success as a researcher. Fortunately, that IMRA recognition was not a mistake, it gave him renewed confidence in his abilities as a scientist, and supported his research on “The Trajectory and Significance of Perioperative Changes in Alzheimer’s Disease Biomarkers,” taking his research and professional career into novel directions. His findings indicated that there is significant variation in how each patient’s brain responds to anesthesia, implying that cognitive assessments on all older adults before surgery could prove crucial. Now an Associate Professor in Anesthesiology at Duke, Dr. Berger and his research team found that if you didn’t have the time to perform a preoperative, cognitive assessment, you could just look at how much alpha power the patient’s brain produced in response to anesthetics and get a rough prediction of what their cognitive function would be like post-surgery. After they published their results in 2017, their work has been replicated by multiple groups around the world including in Europe and Chile. Dr. Berger went on to be successful in achieving additional grants to support his research around cognitive function after surgery in older adults. Every study Dr. Berger has embarked on since has involved one or more aspects of what he investigated in that initial IMRA-funded study, setting him up with a strong toolbox to succeed as a physician-scientist. Below, he shares his fascination with current brain health research, his dedication to discovering answers to how anesthetics affect cognitive function in older adults, and the impact the initial IMRA-funded research made on his career and research trajectory.

1. What is your current position? How long have you been in this position? What was your role when you were first funded by IARS?

I’m an Associate Professor of Anesthesiology at Duke. Other positions I’ve accumulated over the years include Adjunct Faculty of the Center for Cognitive Neuroscience at Duke, and I am a Senior Fellow of the Duke Center for the Study of Aging and Human Development. I’m also Associate Biomarker Correlator for the Duke UMC Alzheimer’s Disease Research Center or ADRC.

I was an instructor at the time I received it, and I received it in the spring or early spring of 2014. I remember when I got the email saying that I got the grant, and I think I wrote back or called up and said, “Are you sure this isn’t a mistake?” Because I had applied for it once before and I had applied for the FAER MRTG once before. I didn’t get either of those. I applied for both again a second time, and I didn’t get the FAER grant, so I figured I’m probably not going to get this one either, and then I got it! And whoever wrote back said, “That’s really funny. No, you absolutely got it. We didn’t make a mistake. Go celebrate,” or something like that.

2. What was the goal of your initial research project? Was it met?

While I was a resident, a group of colleagues and I did a study where we looked at cerebrospinal fluid (CSF) Biomarkers and Alzheimer’s disease before and after neurosurgical procedures in which a lumbar drain was placed to withdraw CSF just for the surgery. And we had found that there were about threefold increases in CSF levels of Tau, which is a neural injury biomarker. That led me then to propose an IMRA grant to study non-neurosurgical patients to see if CSF Tau rose after other kinds of surgery, and if so, was that correlated with cognitive dysfunction after surgery? Another aim of the study was to see if there were functional MRI activity or connectivity changes that would correlate with the CSF Tau changes.

Our study goal was absolutely met. We enrolled 140 surgical patients on whom we did pre- and post- sterile lumbar punctures to obtain CSF. We did MRI scans before and after surgery on half of them, and cognitive testing before and after surgery on all of them. It succeeded better than I had expected or anticipated, and it even provided data that’s led my life in some novel directions that I had never expected when I wrote the grant.

The basic finding was that no, our hypothesis was wrong. There’s not an increase in CSF Tau after non-neurosurgical or non-ENT, non-cardiac procedure, nor for a variety of other types of surgery. There was no increase in tau in the spinal fluid of these patients, either 24 hours or 6 weeks after surgery. Unlike what we had seen in the neurosurgery patients, and whatever small fluctuation there was in CSF tau levels from before and after, surgery was not associated with the change in cognition up to 6 weeks after surgery. In science we often worry about, what if we get a p-value between point 0.05 and .15, then is it really a negative result, or is it a trend? Were we under powered? What does it mean?

Well, we weren’t just wrong. We were completely wrong. The p-value was close to 1 and all the other statistics showed there was absolutely no association. It didn’t matter how you analyzed the data. So that was fulfilling.

I like to say that my favorite thing about science is it’s the only part of my life where it’s completely acceptable to be wrong as long as I’m totally and completely wrong and not just partially wrong. Every other facet of my life, whether I’m at home or in the OR, it’s usually a problem if I’m wrong. But, in science it’s okay to disprove your hypotheses. And often that’s how paradigms change.

We discovered that the whole thing is much more complicated than we would have conceived of in the first place. That’s really an enjoyable part of science for me. It makes it a fun adventure.

The other thing we did during that study which has led to some of the work my group is doing now is, we started doing some EEG recordings during these cases. I was very influenced by the work of Emery Brown, Patrick Purdon, Oluwaseun Johnson-Akeju and Ken Solt up at MGH. I was heavily influenced by their work, and particularly by their paper in 2014 which showed that in response to both inhaled anesthetics and propofol there’s a very distinctive appearance of both delta power and alpha power in response to both of those kinds of drugs. There’s also a bit more theta power and response in the inhaled anesthetics. But, the interesting thing was when they looked across the human age span, the alpha power essentially disappeared after age 60 to 65 or so. When I first saw that, it rocked me because I knew that’s when delirium and cognitive dysfunction really start to increase in incidence. I thought to myself, “we have got to look at our patients and see, is there an absence of alpha power, a biomarker of either delirium or post-cognitive dysfunction.”

We collected a bunch of data as sort of an ancillary study. This was one of those things that you do when you’re a junior faculty member, and you run around trying to collect all the data you possibly can to find whatever phenotype is out there, and you work really hard and work a lot of hours. We had no funding for this. We just did it out of our extra time, worked extra mornings starting at 5 am, showing up to put EEG caps on patients’ heads before their surgery at 7:30 am. What we found was also very surprising. We found no relationship between the EEG alpha power in older adults and post-cognitive dysfunction, and no relationship between EEG alpha power and delirium. What we did find, unexpectedly, was a very robust correlation between intraoperative alpha power in response to either propofol or inhaled anesthetics and baseline cognitive function.

We had 2 separate cohorts, one that had BIS & Entropy EEG recordings, and one that had full 32-Channel EEG cap recordings, and in both of those cases the frontal alpha power correlated really nicely with pre-operative cognitive function. That really changed how I thought about EEG, and about what anesthetics do to the brain.

A lot of work had been done, showing that there were distinct fingerprints of specific anesthetics. You could tell which drug a patient was getting just by looking at the spectrogram, unless you give a very complicated mixture of drugs, in which case it would look complex. But, each drug on its own produces a very characteristic spectrogram pattern.

I think what that paper made us really realize is that even in folks who didn’t have diagnosed dementia, didn’t have a diagnosed neurologic disease, that there’s significant variation in those patterns. Emory, Patrick, Ken, Seun and colleagues, they had all shown that already as a function of age. But, what we found is that even among folks that are all in the same age band, there was significant variation in how their brains responded to anesthesia, how much alpha power they produce. And that was related to their pre-operative neurocognitive function. That suggested to us something interesting, which is, there was a lot of talk and movement at that time, and still is, saying that we should really be doing cognitive assessments on all older adults before surgery, given that the brain is the target organ of our drugs. It’s the only organ that we’re not monitoring routinely in the OR and it’s not part of the ASA standard monitors to monitor the brain.

There was a lot of discussion back then about how this was going to happen. There’s more than 19 million older Americans who have surgery each year. Are we really going to have 19 million patients undertake hour-long cognitive testing sessions? That didn’t seem very realistic for a healthcare system that’s already over budget or costing too much for the country.

Of course, there are shorter cognitive assessments, and a number of people have done excellent work on those, but our work made us think a little bit differently. It made us think that even if you didn’t have time to do a preoperative cognitive assessment, you could just look at how much alpha power the patient’s brain produced in response to inhaled anesthetic or propofol. The data is not that good, but you could at least get a rough idea of what their cognitive function might be like by looking at their alpha power.

We published that work in 2017, and then fortunately, we’ve seen that work be replicated now independently by several groups all over the world, investigators in Europe and Chile and at MGH and elsewhere.

That’s really influenced our work since then. I was just talking with a friend and colleague yesterday, and we were commenting that still no one knows, to my knowledge, why some people produce more alpha power than others in response to the same anesthetic dose. We can have 2 70-year-olds in 2 ORs, and one of them has robust alpha power, and one of them doesn’t. And they’re both getting point Iso fluorine. I don’t think we know or can point to anything. Okay, this is why this patient has good alpha power. This is why this patient doesn’t. And so that’s led to an R01 Grant that my group has that is designed to answer that question now, to really understand what are the brain correlates or neurologic underpinnings of these altered brain anesthetic response patterns.

We’re using some of the same techniques we used in my IMRA grant, CSF biomarkers, functional and structural neuro imaging, to try to get at that question and understand what’s different about these patients’ brains and potentially even use it as a screening test or as a stress test for the aging brain. Our hope is that this could eventually lead us towards saying, “based on how this patient’s brain responded to anesthesia, they really ought to be seen by neurology, or they ought to get worked up for either Alzheimer’s or something else.” We’re not quite there yet, but that’s where we could see this field leading in the next 5, 10, 20 years. I think that could be a valuable thing, because a lot of anesthesiologists are using friendly EEG monitors just to titrate the anesthetics and we’re not really thinking about it like we’re doing a neurologic stress test today. Most anesthesiologists don’t think that way. Most of them think we’re giving anesthesia so the patient can have their knee replaced, and we need to hurry up and start the case on time. But, this is a different way of thinking about how we can use that data for the patient’s benefit in the longer term, hopefully.

The other point, I would add, is, when I say this, some people say, “there’s nothing you can really do for dementia. So what difference does it make if you tell somebody they’re at risk?” As we’ve seen in the Alzheimer’s disease field, that negative view is starting to crumble. The newer anti-amyloid drugs have a small but nonetheless statistically significant beneficial effect in reducing the slope of cognitive decline in people that are amyloid positive. There’s a couple of those now that have been shown to do that. And I think we’re going to see more and more drugs coming out. They do start to have positive effects on protecting the older brain, and this could potentially be useful to select people before they first have memory deficits.

3. How did your findings impact patient care?

I view myself as a basic scientist who studies humans. I joke sometimes that I study humans as a model for the mice. I don’t think that there is a major change in patient care right now, however, there are several things that we can tell patients now based on our findings that we couldn’t have told them in 2014 and all of those things can reassure patients.

If someone says, “Doc, I hear that a lot of people get confused after surgery. Is it true that anesthesia makes you get Alzheimer’s? Or is it true that anesthesia accelerates the path to Alzheimer’s?” Or, if you had a very informed patient who asked, “is it true that anesthesia accelerates the underlying neuropathologic processes that cause Alzheimer’s?” The answer is a No to each of those. And it’s a pretty clear no, from our CSF Biomarker data, and that wasn’t what we were looking for. We thought we would find a correlation. We looked as hard as we could, but there’s just no correlation there, at least in our hands and in our data. I think this can reassure patients.

Another thing is that we did a nested, randomized, controlled trial within my IMRA award. We enrolled 140 older folks having a major non-cardiac or non-neurologic surgery. We also randomize them to propofol versus an inhaled anesthetic. And then we compare cognitive trajectories over time, from 4 to 6 weeks after surgery in patients who got TIVA versus inhaled agents, and again, we saw no difference. There was no difference in cognition trajectories between groups.

There was no difference in any of the CSF biomarker trajectories we examined, no difference in amyloid levels or amyloid change over time, no differential change in Tau over time. No differential change in phosphorylated tau or ptau 181 over time between anesthetic treatment groups.

There’d been a bunch of basic science studies that at least in vitro suggested that the inhaled agents might enhance the oligomerization or clumping together of these amyloid beta monomers. There are additional studies suggesting that the inhaled agents might be worse for memory function in animals. But our data pretty clearly says at least, in these kinds of patients in this age range, undergoing these kinds of procedures, we see no evidence for that. That’s powerful.

I used to worry back in 2014, what if we had a really sophisticated patient, and they said, I don’t want inhaled anesthetics because isn’t it true that your animal model research has shown that certain inhaled anesthetics accelerate Alzheimer’s disease pathology. I never had a patient who actually said that, but if I had, I would have had to say, “Yes, that’s true. There are a number of studies that do suggest that.” But now we have human data to say, “no, that’s not the case.” I think there’s other reasons that you can decide whether to use an inhaled agent or a propofol total intravenous anesthetic without worrying about if you’re going to have differential effects on cognition or on CSF biomarkers, at least as far as what our data shows. There’s other people here and there who found some different things, and I don’t want to ignore that. But, at least that’s what our data showed in a large cohort of non-cardiac, non-neurologic surgery patients.

The fact that there’s a number of us working on this has raised awareness about the fact that delirium is the most common complication after surgery in older adults, and I’m not sure many people recognized that in 2014. And, I’m not saying this is a result of my work at all. I’m saying it’s the result of the whole field, and especially Dr. Sharon Inouye, Mark Antonio, Wes Ely and a number of others. You know, senior leaders in the delirium field who’ve really helped promote awareness of this. Such that residents now know what delirium is. Nurses are talking about delirium. It’s good to see that there’s more awareness about it.

Even though my IMRA-funded study did not support a role for CSF, Alzheimer’s disease-related biomarker changes in postoperative cognitive dysfunction, it also gave us a lot of samples and a bio repository that we’ve been using for a number of other studies.

One of my mentees, Dr. Mike Devinney at Duke, who’s a junior faculty member here,  and who has been a true, absolute joy to mentor, he just had a very nice paper in Neurology that showed that there is blood-brain barrier dysfunction that occurs after surgery in all older adults essentially but it occurs to a greater extent in patients with delirium. It’s also associated with increased hospital length of stay, independent of its effects on delirium. So now that gives us a biological process that we could actually target to, and at least have a hypothesis that “okay, if we could protect the blood-brain barrier, maybe that would reduce delirium rates.” It’s at least a plausible hypothesis that’s worth testing. And I think we’ll see studies looking at that over the next 10 years.

4. How did your research impact the field of anesthesiology?

The fact that so many people are working on this and there’s so many smart people in the anesthesiology field, even basic neuroscientists with PhDs, studying delirium and studying these topics, it’s really raised awareness. That brings us a lot closer to an ability to care for patients better in the future. That’s not just my work. That’s the whole field.

5. Has your research subject area evolved since the award?

At the time I received the IMRA, there had been a lot of animal model studies, a lot of in- vitro studies suggesting a link between anesthetic exposure or surgical stress and changes in Alzheimer’s disease pathology in mouse models, or Alzheimer’s-like pathology in mouse models as well as a link with cognitive dysfunction or memory dysfunction typically in those animal models.

But one of the things that frustrated me when I was a resident, was reading all these papers and thinking, “Okay, well, that’s really interesting that this happens in mice, but does it happen in people? Because if it happens in people, that’s a huge deal. If it doesn’t happen in people, then okay, it’s a species difference or something different that happens in a lab vs. in actual patients.” The inhaled anesthetics have some other effects in vitro that haven’t been seen in vivo in patients. It wouldn’t be totally surprising if this was that way. The field has really changed in terms of, we’ve seen a real monopoly of studies from many groups, Rob Sanders and many others, looking at these biomarkers both in CSS and plasma before and after surgery, and trying to correlate them with cognitive phenotypes or delirium. We have much more human data now, and we’re getting a much better handle on what the nature of the relationship is between their degenerative disease pathology, anesthesia and surgery and perioperative neurocognitive disorders. We’re filling out that picture much better now than what we had understood in 2014. It’s getting us to a place where now we know biological processes that can be targeted, whether it’s the blood-brain barrier, whether it’s neuro inflammation, etc. There’s things that now you can develop hypotheses, that are biologically based, to test in this field. And I’m hopeful that that means in the next 10 years, we’ll start to see some interventions that are targeted at specific biological mechanisms that will improve outcomes for older adults cognitively and neurologically after surgery.

6. How did the award affect your research/professional trajectory?

The award is responsible in many ways for my research and professional trajectory since then. I mean the IMRA was the first award that I received when I came on faculty as an instructor. One of the challenges about science is that you need grant funding to do it. Typically, no department can support someone forever without them receiving grant funding. I mean, my department’s been wonderful to me, and extremely generous in supporting my time, but nonetheless, that’s always in the hopes of making an investment that’s going to lead to extramural funding and so on. One of the challenges of science is there is no grading system. There’s no honors pass fail. There’s no A, B, C, D, E, F. You either get funded or you don’t. If you don’t get funded after a certain period of time, usually either a department can’t support the person anymore, or the person gets too frustrated and burned out.

It’s hard to keep going when you get rejections. It’s hard for all of us. I hadn’t received a couple awards that I applied for before this, and then this one gave me renewed confidence that maybe I am on the right track. Since then, we published a lot. We’ve been able to get a good amount of NIH funding, and so on. The IMRA really helps launch all of that and helped give me the confidence that I could really do this.

At a more topical or research level, it’s heavily influenced the work I’ve done since then. Every study I’ve done since then has involved one or more aspects of what we did in my IMRA-funded study, meaning other CSF biomarkers, neuro imaging with functional structural MRI intraoperative EEG and cognitive and delirium testing. I can’t think of a study I’ve done since then hasn’t used one of those things in some way. That really set me up with a good toolbox going from molecular and cellular biomarkers up through systems neuroscience, functional MRI activation data to outcome data and with some EEG thrown in as well.

7. How do you feel about having received the IARS Mentored Research Award?

I’m extremely grateful for the IMRA Award. People talk about trajectories and about looking backwards at history. I would like to think that if I hadn’t gotten the IMRA, that I would have gotten something else. But, you never know, there’s no control experiment in life. And at that point, I was really starting to wonder, if this could be a career possibility for me being a primarily researcher anesthesiologist. I’m not sure you’d be interviewing me if I didn’t get the IMRA award, because I’m not sure I would be doing research now if I hadn’t gotten it.

You got to get something to start off and this was the thing that started me off. In addition to, of course, generous departmental support and a great environment here at Duke.

8. What would you like to convey to our donors, the people who made this award possible?

THANK YOU, in all capital letters.

9. What drew you to academic anesthesiology and to your particular area of research?

I was always interested in neuroscience in college. I was an undergrad at Columbia, and they were making a big deal out of Eric Kandel’s work there at the time, and he later won the Nobel Prize for elucidation of basic cellular and molecular mechanisms that underlie memory and that are seen in sea slugs all the way up through humans. So I knew from that, and reading about his work, and working in cellular immunology, that I wanted to do something with neuroscience.

I decided I would do an MD-PhD Program because I wanted to understand clinical applications as well as the science. I wound up joining a lab in graduate school that worked on serotonin receptors and behavior. It was a lab of a guy named Larry Tecott at UCSF who was a psychiatrist, and did an MD-PhD himself as well.

I made a line of transgenic mice as a graduate student that were supposed to have altered behavior and altered serotonin neurochemistry and they didn’t. Instead, they started dying. They were dying as little pups, and, as one colleague told me, “Death is a rather extreme phenotype.”

Through a long series of surprising events, we eventually figured out that they were dying of basically severe diabetes from a defect in pancreatic islet development which was induced by the serotonin receptor transgene that we had inserted into these mice. That led us down a very surprising line of work. We eventually got a paper on the proceedings in the National Academy of Sciences, showing that g protein, coupled receptors, played a key role in pancreatic islet development.

When asked by friends what field I planned to go into, I said, “Well,  neurology or psychiatry, maybe anesthesia.” And I remember one of my friends was totally shocked. He said, “Anesthesia or psychiatry. Those are the 2 most opposite fields, and the 2 most different groups of doctors, in both what they do on a daily basis and personalities and everything that you could possibly imagine.”

I couldn’t fully explain this to him then, but I knew I wanted to be a researcher, and what I learned from graduate school is that these fields, while they seem siloed, these divisions don’t exist. Especially for psychiatry and anesthesiology, we now see all of these studies. Peter Nagele doing work on nitrous oxide as an antidepressant. My friend and colleague, Boris Heifets, who’s studying ketamine and MDMA and rapid antidepressant actions, and we use ketamine pretty often as an anesthetic and nitrous oxide as well. The boundaries aren’t as sharp as they might appear to medical students, and as they appeared to my friend.

Then the other thing that happened to me was my first rotation back in medical school, after finishing my PhD was surgery, and I did it at Highland Hospital in Oakland, California, which is the level-one trauma center for the East Bay and San Francisco, and it is a true inner city emergency department. They see a ton of trauma. They see a ton of gang violence. The experiences I had there, I’ll never forget.

My fiancé at the time, now my wife, told me, despite the fact that I was working really hard, and I had to be there at 4 o’clock in the morning and all kinds of crazy stuff, “You know you seem a lot happier than when you were doing your PhD.” And I was really shocked by that observation I always thought that I really wanted to be a researcher and surgery was boring. It’s just tying knots and things. I had all kinds of bad stereotypes at the time that are false. What I realized is that I really like the immediate gratification of surgery and of anesthesia, and it’s very fulfilling to be able to do something with your hands based on complex thoughts about physiology, and how the body is working, and then to see the body respond to them in real time. It’s very fulfilling to do something with your hands for a patient that really helps their life. I think that’s true for the surgeons. It’s also true for us, because we work with our hands also.

There’s just something intrinsically fulfilling about that in a way that I just never found as a graduate student. As a graduate student, I found it very hard to have a good weekend if nothing worked in the lab all week. I have great admiration for basic scientists who do pure basic science and nothing else. I don’t have the patience that many of them have, and that’s something I learned about myself.

Somebody told me to think about my own reward structure and to think about what I would find rewarding for my career not just on the good days, but on the bad days as well. I realized that I am sort of like a mutual fund. I need some delayed gratification, but I also need some kind of immediate gratification at least once every week or 2. And being an anesthesiologist scientist, provides that for me.

It’s very fulfilling to walk out of the OR and say, “Two people have a brain tumor that’s no longer in their head.” The neurosurgeons did that. I didn’t do that, but I helped them get through it, and know they needed me or one of my colleagues to get them through. They were often scared and we would reassure them, etc. That’s very fulfilling. And then the ability to take a lot of these things into the lab and study them.

There was one other experience that convinced me that I belonged in anesthesia, which is that on my surgery rotation at Highland, I was asked to hold a retractor, as medical students we’re typically asked to hold the retractor during a surgery. While holding the retractor I just happened to glance at the anesthesia machine, and that looked fascinating to me. There were all of these numbers and dials and knobs and physiologic data. I was wearing a sterile gown and gloves, and I sort of wandered over towards the anesthesia side and was looking at things, and then I got in trouble. One of the surgeons was like, “Hey, medical student, what are you doing over there? You’re supposed to be here holding this retractor. Get over here.”

There were a couple more cases where I kept looking over and thinking, that looks really interesting over there, and holding the retractor didn’t interest me that much and eventually it occurred to me, if I’m going to be in this room in my future, I probably belong on that side of the drapes, not this side. Something about all the data and the ability to monitor all of that data in real time and adjust things really appealed to me.

10. What is something that someone would be surprised to learn about you?

I play guitar, not all that well, but I do play guitar, and I was in a rock band in high school. The band was called “Blurred Vision.” We played a mixture of metal, punk, rock and grunge sort of rolled up together, and a little bit of what I would call power pop.

Also, I own a chainsaw and I use it sometimes. My colleagues would feel that this is incongruous of what they think of me. I live in Chapel Hill, North Carolina. We’re fortunate, we have a big, nice yard, over an acre of land.

It’s wonderful living out here. Housing is inexpensive, and there’s beautiful woods and occasionally a tree falls down and it needs to be cut up, or occasionally firewood needs to be cut up, or things like that.

Last year, we had a thunder and lightning storm which knocked down a portion of a large magnolia tree on our property. Thanks to my chainsaw skills, I was able to cut it apart.

There’s a disproportionate number of male anesthesiologists who were Boy Scouts, and who made Eagle Scout, which is the highest rank in Boy Scouts. I have a good friend in my department, Jon Dunkman, who, like me, was an Eagle Scout. I think a lot of us have the same desire to work with one’s hands, leading one to become a surgeon or an anesthesiologist. It is part of the same drive that makes one like to do other things with one’s hands, whether it’s outdoor activities or whether it’s woodworking. The former division chief of neuro-anesthesia at Duke, Cecil Borel, a wonderful man, built a boat in his garage. The boat was what he did to cope with things when he had a rough day in the OR. I believe he’s actually sailed on it. I should look him up and ask.

11. What do you hope for the future of anesthesia research?

If medical specialties were a rock band, we’d be the bass player. We’re in the back, and we’re holding down the groove but nobody really misses us until we’re not there. We’re not the singer that gets all the attention. We’re not the guitar players doing these amazing solos. We’re not the drummer who does drum solos. The bass player, with some exceptions in music, is typically in the background. But, you notice when they’re not there, and it’s kind of the same thing with anesthesia in the sense that patients don’t typically come to us because they want our services. They typically go to a surgeon, and then they get us along for the ride to help keep them alive and get them through the surgery and help make sure they don’t have traumatic memories of the surgery, to make sure they don’t vomit afterwards, to make sure they have good pain control, unconsciousness, etc.

But other than maybe my ICU colleagues or my colleagues in pain medicine for whom patients actually come directly to them because they need their help directly, as an OR anesthesiologist, I’ve never had a patient come and say, I want to have my surgery at Duke, because this person is here at Duke to do my anesthesia. I’ve never really heard that. We are the unsung hero in the OR.

Patients usually don’t remember us as their anesthesiologist, because we give them drugs that make them amnestic before, during, and even a little bit after surgery. So I think of us as kind of a bass player you need us, but we’re not in that highly noticeable role. But, yet, what we do is crucial to getting a patient successfully through surgery, and I think is increasingly going to become essential to their postoperative recovery. I think we’re going to see an ability to manipulate a patient’s physiology in ways that put them on a trajectory towards a successful recovery. We’re not there yet, but if you look at much of the work that’s being done in our field, whether it’s all the work on delirium that Stacie Deiner is doing, Phil Vlisides, others across the country, Rob Sanders and around the world. Or if you look at even the work, like Brice Gaudilliere is doing on the immune response to surgery, and how that predicts recovery, it all suggests that if we understood the process of recovery, both cognitive and physical recovery in better biological, mechanistic terms, we could do things to manipulate that process so that patients would have a better recovery. We’re already doing that in special situations. For example, every transplant surgery, when we give specific immunosuppressants, that’s not part of general anesthesia. That’s not part of analgesia unconsciousness, immobility, and human dynamic stability. It has nothing to do with those, but it has everything to do with making sure that organ graft is successful and the patient has good renal function, after kidney transplant or good cardiac function after heart transplant. Similarly, you’ll see in the future that anesthesiologists will probably be giving other drugs that we don’t have now, and we don’t even know what they would be, or what mechanisms they would hit now.

In the future, 40 years down the line, we will be doing things to modulate the endocrine, immunologic, and nervous system responses to surgery, to promote a better recovery for patients.

It’s hard for anesthesiologists of my age. I’m 45. It’s hard for us to imagine a time when there wasn’t pulse oximetry, and the way you knew the patient was hypoxic, because the surgeon would say, you know the blood is pretty blue here. I can’t imagine that I’ve never been in an OR where they didn’t have a pulse oximeter. I hope that when I’m in my eighties that I’ll have a chance to talk with anesthesia residents who are in the mid-twenties, and they’ll say, “Dr. Berger, is it true that you guys used to give these gas anesthetics and some opioid and some Zofran, without doing anything to promote postoperative recovery trajectories.” And I’ll say, “yes, we did that. We didn’t understand.” I hope we will understand that 40 or 50 years from now.

I have great admiration and respect for Emery Brown. He’s one of my intellectual heroes. There’s one point I must disagree with him on, though, he says that it’s not true that we don’t understand how anesthesia works. He says, “we do understand how it works.” He gave a very nice talk at the Society for Neuroscience meeting last year on how it works using circuit level diagrams. I’m not convinced that we fully understand it. I don’t think we have a full understanding of the molecular mechanism by which the inhaled agents work. He’s right that we understand some of the circuit-level mechanisms, and each year we learn more from new papers about which circuit level mechanisms are engaged, which drugs produce unconsciousness, which produce amnesia, which produce a lack of movement, etc. However, we still don’t have a great understanding of how these drugs interact with individual differences across patients and brains.

I think that’s a major area of research that needs to be worked out.

If you look at psychiatry, there’s a lot of argument about this, but at least to the best of my knowledge, as an outsider to that field, there is data to show that SSRIs work as antidepressants, but they clearly don’t work in everybody.

At least as of the time I was a graduate student, there was no prior measurement that you could take to predict which patient would respond to an SSRI versus a combined serotonin or something else. This is common across many fields of medicine that we try things, and if one drug doesn’t work, we try something else. But understanding the individual differences, and how people respond to these drugs, will teach us a great deal about individual differences or cross-sectional differences in patients’ brains and in their neurocognitive trajectories into the future.

Dr. Bill Young at UCSF and David Warner here at Duke, they are great anesthesiologists, great human beings, wonderful researchers and strong clinicians, and both of them felt strongly, and Bill Young actually wrote about this in an article in Anesthesiology that was essentially, “sapere aude,” which means dare to know in Latin. And his point in using that phrase was that research is really about the dare to know. An intrinsic part of being human is being curious. And it’s using that curiosity in a very harnessed and rigorous way to ask questions and answer them scientifically.

Beyond that his point was that anesthesia research should not be narrowly defined by the study of anesthetic drugs. It should be more broadly defined as the set of research done by anesthesiologists who are limited only by their own imaginations and what they work on.

I had been fortunate to meet Bill Young a couple of times when I was finishing medical school at UCSF and going through the application process for residency. I emailed him after I read that article and told him that I loved the article and the idea, and I completely agreed with it.

I don’t think that our research should be limited at all by narrow, disciplinary lines. In graduate school, this serotonin receptor that was supposed to alter brain neurochemistry and behavior wound up giving us insights into pancreatic islet development that are relevant to the treatment of diabetes and pancreatic islet transplants for diabetes.

The research that anesthesiologists are doing now is not only going to improve anesthesia care, it’s going to improve mental health care. It’s going to improve cardiac care. Anesthesiologists are contributing to a much larger footprint in medicine than the confines of our own specialty, and that’s what I hope it’ll continue to do.

I just hope that the young people coming up, residents and medical students, who are going to be tomorrow’s anesthesiologist scientists, that they’ll be supported and that they will be given the freedom to study what interests them. Because I think that scientists following their own intrinsic curiosity is really how important discoveries are made.

In fact, it’s fortuitous we’re talking about this today. The Nobel Prize in Medicine was announced today to 2 people, Drew Weissman, and Katalin Karikó. Their papers were not published in Science, Nature, or Cell. None of the papers that resulted in that Nobel Prize were published in these top-notch journals, but they were following what they thought was an important line of research. A lot of us are alive today because of that line of research. Millions more people would have died of COVID had they not done that work. And both of them tell stories about how many difficulties they had in their career, because people didn’t think this work was important, etc.

Curiosity-driven science results in untold societal benefits, and I hope we, as a field, can continue to support that. Ongoing research is absolutely essential for the best care possible of tomorrow’s patients. I hope we’ll continue doing that in anesthesiology.