COMMENTARY

Mindsets Can Make the Difference in Clinical Medicine

; Abraham Verghese, MD; Alia Crum, PhD

Disclosures

November 27, 2019

This transcript has been edited for clarity.

Abraham Verghese, MD: Hello. This is Abraham Verghese, and I want to welcome you to a new episode of "Medicine and the Machine." With me today is my cohost Eric Topol, and we're delighted to have Alia Crum as our special guest. Alia is an assistant professor of psychology at Stanford University who is doing exciting work on mindset and placebo. I've had the pleasure of listening to her before and working alongside her, and we can't wait to get into a meaty discussion with her. Alia, it's such a delight to have you on this podcast.

In Eric's book, Deep Medicine,[1] there's this moment when he says—and you as the reader come to the recognition—that machines have basically eclipsed our human abilities to, for example, process huge amounts of data and to see 2000 patients or images in a row without getting tired. Eric makes the point, using a wonderful graph of machines eclipsing humans, that this is also the moment where humans need to learn to be more human. We need to more powerfully use our presence and our human capacities at the bedside or with the patient, because clearly, when someone is critically ill, there is very much the need for that kind of human connection.

I think that is a perfect segue into the work that you've done all these years, and I wondered if you could tell us a little bit about your career and how you got into this. I know you were a phenomenal athlete, but how did you get into psychology and then to placebo and mindset and so on?

Alia Crum, PhD: Thank you for having me. It's really an honor to have a conversation with you both. I'm deeply passionate about questions around what it means to heal and what makes us human, and the intersection of both of those things: What about what makes us human actually enables us to heal?

I got interested in this work when I was an undergrad at Harvard. I had been a gymnast most of my life and transitioned into ice hockey, where I became a Division I player. I'd seen firsthand the power of our minds to influence our physical state. Any athlete knows that you can be in the exact same physical condition and have a totally different performance depending on the thoughts, ideas, and expectations that are going through your mind. I think a lot of people who have had experiences with injuries, especially athletes, know that there is a limit at which you can push, and we don't really know what that limit is.

When I was a gymnast, I was competing to qualify for nationals and I hurt my ankle in practice a few days before the competition. I was so committed to doing this competition that I did it anyway and qualified. Only after did I learn the fact that I had competed on a broken ankle. I'm not saying that that's a good idea, but it did bring into question: What is pain? And is it really a direct reflection of something physical in the body, or is it also something about our beliefs about our abilities and our capacities? That's how I became interested on a personal level.

I studied psychology at Harvard and took a class on the history of mind-body medicine with Anne Harrington. I remember reading her book and hearing her lectures, and one of the things she said that I found to be quite provocative was that, in many ways, the history of medicine is almost just the history of the placebo effect. We think these great, new, wonderful things are going to dramatically advance the way we treat illness and disease, but we come to find that maybe it isn't the specific ingredients in the bloodletting or the magnetism or the new surgery. It's something else, something about the connection that we have with the person delivering that treatment, or the belief that we have in the body's capacity to heal, that is driving the effects.

I was moved by that, but I was actually more moved by the data that exist on placebo effects. If you look at the past century of clinical trials, we have some evidence showing that just taking a placebo pill under the impression that it's a real medication can lead to substantial benefit, both subjective and objective. We have arguably more data on placebo effects than we do on any treatment in the history of medicine, and yet we have done almost nothing to deliver, deliberately leverage, understand, or capitalize on that power in the formal practice of medicine. That is what got me interested in those questions and ideas.

Studying the Placebo Effect

Verghese: You joined a lab at Harvard that was already studying some of these things?

Crum: Yes. I worked with Ellen Langer, who is a professor of psychology and does a lot of research on mindfulness, more with a Western cognitive flavor (Eastern mindfulness being more than nonjudgmental, deliberate attention). Her mindfulness is more questioning the status quo. Why is high blood pressure designated as 140/90 mm Hg? Why isn't systolic 145? What if systolic is 139? This was more of a cognitive and inquisitive curiosity around mindfulness. She had done a lot of interesting studies looking at the benefits of mindfulness.

I came to one of our lab meetings with a black eye from a head injury from hockey, and she said, "Why are you putting yourself through all of this physical activity? Don't you know that exercise is just a placebo?" I thought that was kind of a ridiculous statement, because exercise is good for you and it's important to stay fit. But having been interested in placebo effects, it got me thinking: What if part of the benefit of physical activity is not just what you are doing objectively, behaviorally, physiologically, but also what you think about that? If you believe that you are getting good exercise, will that actually lead you to get more benefits from the exercise you are doing?

We decided to test that question in her lab. In the formal medical sense, it's pretty easy to run a placebo-controlled trial. You just make a fake pill with sugar or some other inactive substance. But how would you run a placebo-controlled trial with something like behavioral medicine or exercise? Instead, we found people who were getting a lot of exercise but weren't necessarily aware that what they were doing was exercise. We worked with a group of women who were hotel housekeepers, who throughout their daily work were getting a fairly substantial amount of physical activity.[2] But when asked if they exercise regularly, two thirds of them said "no" and about one third of them said, "I get zero exercise on a scale from zero to 10." This was a case where the mindset was not present—it was stripped away.

We randomly assigned these women into two conditions. Half we told, "Your work meets the Surgeon General's requirements for good exercise. You should be receiving these benefits." We found, 4 weeks later, that this group of hotel housekeepers not only saw themselves as more active but actually were getting more benefit. They had reductions in weight and systolic blood pressure compared with the group that was not given that information. This is a way that we can start to test the influence of our mindsets and the ways that we're thinking about the things we're doing, not just on how we feel but also how our bodies are responding.

Warmth Can Drive Benefit

Eric J. Topol, MD: I wonder if I can take that to another dimension. You probably are familiar with the placebo study conducted by Ted Kaptchuk, where the doctors told the patients they were giving them a placebo. There was a pronounced effect, but it was the relationship between the doctor and patient that seemed to be driving the benefit. Can you comment about that?

Crum: Ted Kaptchuk is a mentor and inspiration to me. He's done a lot of extremely important work on the placebo effect, really taking it out of the shadows from something you do to control for extraneous factors to something that should be deliberately looked at.

The study I think you're referring to is one on acupuncture for irritable bowel syndrome.[3] Participants got no treatment; a placebo acupuncture treatment (where it looks like they are inserting a needle at pressure points but they don't actually puncture the skin); or placebo acupuncture from a warm and caring provider who was really empathetic, connected, present, and human. They found that that was where the benefit happened. It wasn't just this sham acupuncture with needles you thought were going in, but it was being in the presence of somebody who seemed like they were caring for you.

Topol: That's the study I was thinking about. It's extraordinary, because getting back to what Abraham was saying about how we can be more human, it's not only the placebo, but trust, presence, and that patient-doctor relationship. It's almost like placebo-squared when you have that.

It's not only the placebo, but trust, presence, and that patient-doctor relationship. It's almost like placebo-squared when you have that.

Crum: Exactly. Abraham and I have a paper in the BMJ[4] where we start to break it down a little more. Essentially, our model helps us understand that placebo effects are not a miraculous response to an inactive substance; rather, there is an understandable and systematic response to several things. First is the body's natural abilities to heal. In a lot of randomized controlled trials, that is seen as a confounder—like you don't know whether this was a placebo, per se, or whether the person just got better over time. True, we don't know that, but that also should not be discounted. The body has a natural ability to heal itself with time in many conditions, and yet we often just overlook it.

But that's not all. There are also patient mindsets, such as "I'm in good hands," or "I'm taking something that is going to help me," or "This isn't going to kill me," or "I'm going to be okay." Mindsets can have an impact by activating, tapping into, and strengthening the body's natural healing systems: the endogenous opiate system, the adaptive immune system, the growth-promoting endocrine system. These systems are all influenced by our brains in some ways, so those mindsets can help prioritize or activate those systems.

But what you are getting at and is critical is that those mindsets don't come out of nowhere. They are not operating in a vacuum. They are influenced; they are set in the social context. They are set by that warm and competent doctor or medical assistant, or whoever it is who comes in and says, "This is going to be okay. I think this is going to really help you." That social context, that human element is what helps shape adaptive mindsets, and those mindsets can work with the body to have these healing effects.

Studying Physician Influence

Verghese: Alia, I've had the pleasure of coming to your lab. You have a room that looks exactly like a clinic room in a physician's office, and you're able to do these amazing studies. The one that fascinates me the most is when you take volunteers who think they are doing a "real" study. You inject a histamine and then measure the wheal and flare response and how it's affected by different things. Could you talk a little bit about that research? Because for me, that was the moment when I could sort of see this visually, and it was really quite an epiphany.

Crum: Thank you. Yes, that was inspired by Ted Kaptchuk's study that we were just talking about. As social psychologists, we know that a lot is going on when you think about that human interaction. What is going through your mind when you interact for the first time with the doctor or provider to make you trust them? We know from work in social psychology that as humans, within microseconds, we're immediately judging people on two things. The first is, does this person have good or bad intentions toward me? Are they warm? But second, does this person have the ability to enact those good intentions? Are they competent? In the clinical space, this has its slightly unique flavor. Essentially, it can be distilled down to: Is this provider competent? Do they get it? Do they get the type of medicine or medical issue that I'm dealing with? But also, are they warm? Do they get me? Do they care about me? Are they going to prioritize me? Do they understand my personal situation in the context of this medicine?

What we wanted to do with this study[5] was to unpack those things and to see systematically what influence those human qualities of warmth and competence were having, if any, on the physiologic progression of a treatment. As you pointed out, we've created our lab rooms to look exactly like the Stanford hospital. Even the chairs are the same. It's essentially what you would think of if you were going to a doctor's office.

We told patients that in order to participate in our research on food preferences, we needed them to undergo a histamine skin prick test, essentially an allergy test. We had 164 patients in this study, and each of them were given a prick of histamine on their forearm. This reliably creates an allergic reaction in everyone, and we can measure the size of that allergic reaction because it increases and eventually decreases over time.

About 6 minutes after applying the histamine, a provider, who is a member of our research team, went in and applied an unscented hand lotion placebo. To half of the participants, she said, "This is an antihistamine cream; it's going to make your rash and irritation go away," essentially setting a positive mindset about this cream. To the other half of participants, she said, "This is a histamine agonist, which might make your rash and irritation worse." Here you have a placebo condition where participants expect positive benefit or a nocebo condition where they expect some potential harm or deterioration. What we're able to do just in that simple design is measure the influence of the expectations or the mindsets that are set on the physiologic response to the histamine. We found that when patients think the cream is going to make their rash better, it does actually get better faster—measured by the size of the allergic reaction—than when they think it's going to get worse.

Now what makes this study interesting—because we've seen placebo response in the context of allergy in other studies—is that we also changed the qualities of our provider along these two lines. In one condition, we ramp up her warmth and competence. She's wearing a white coat, and her badge reads, "Fellow at the Stanford Allergy Center." The room is very clean; everything is done with precision. We also increase her warmth. She looks the patient in their eyes. She calls them by their first name instead of just saying, "Date of birth?" She says, "Where are you from? How are you feeling today?" She makes an attempt to connect with them on a human level.

In another condition, we strip those qualities away from the provider. We take away the warmth and the confidence. She's sort of sterile in her interactions. Instead of looking the patient in their eyes, she's looking into the computer screen taking notes. We also raise some questions about her competence. The badge reads "Student Doctor" (remember that this is perceived warmth and competence). The room is a little messy. And when she puts the blood pressure cuff on to check their blood pressure, she sort of fumbles and puts it on upside down and has to redo it.

So you can see now that we have these two conditions of whether patients expect benefit or expect harm, but also whether they are in the presence of a warm and competent physician, or somebody who's sort of cold and not connected and maybe not as competent as you would hope.

Stripping away those human qualities of warmth and competence in our study took away the entire benefit of those expectations.

We found that that really matters. When the physician is connected and caring and competent, what she says about the cream matters even more. In particular, when she says, "This is going to help," it does. It helps at an increasing and even stronger rate. Then, when she is cold and disconnected, what she says about the cream does not matter at all. She could say it's going to make it worse or make it better. It has no impact. Stripping away those human qualities of warmth and competence in our study took away the entire benefit of those expectations. Whereas having those there was what magnified it, is what made that mindset have an impact on the on the physiology of the patient.

Mindfulness

Topol: Alia, I wanted to get into a study just published that is kind of up your alley. You maybe haven't looked at it yet, but that would be good, because we could get your candid impression.

There is a gene in man called REST, which is related to neuronal activity, so the more you have of it, the less you have neuronal activity. Interestingly, it had been shown that people with dementia have less of this, whereas people who live longer have more of it. Now, there was a report in Nature[6] whereby this relationship of neuronal activity is shown in model organisms. Here is another remarkable relationship between the mind and body that might have been unanticipated. There is a great emphasis on mindfulness and whether such things as meditation and mindfulness could be good for your health. Could you talk about that?

Crum: There is a lot of work on the relationship of mindfulness to health. Now again, mindfulness, as it's typically studied, is a process of nonjudgmental awareness in the present moment. So it's related to practices in meditation and deep breathing, which is confounded with the relaxation response. But essentially, it's all getting at this idea of being present and connected. There is a lot of really good work on that. We don't study mindfulness directly like that in our lab. But I think it's very linked to the idea and the power of mindset in the following way. Essentially, mindsets are our sort of core assumptions about our experience or the nature of something in the world that orient us toward a particular set of expectations, goals, and explanations.

For example, a diagnosis of cancer is a very complex thing to understand, so we humans create simplifying systems to help make sense of that complexity in ways that help simplify and direct our attention and goals. You might have a mindset that cancer is a catastrophe that will damage your life and potentially even cause you to die—all along the way, it will be catastrophic. That mindset, of course, is not necessarily true or false, but it does have an impact. It shapes what we're paying attention to, what we're motivated to do, how we feel and expect to feel, and what our bodies are prepared to do.

But the mindset that cancer is a catastrophe or that diabetes is a death sentence, or whatever it may be, is not the only way to look at things. In fact, there are many other interpretations or assumptions we can make about the same thing. Some people have the mindset that cancer can be an opportunity. That does not mean that it's a good thing, but that going through it can help you recognize a deeper appreciation for life or a deeper connection with others or a revived sense of clarity on the ways you want to live your life.

This is just to point out that our beliefs and thoughts and the cognitive activity that we have in our brains are not a direct reflection of some objective reality. It's an interpretation that is malleable. It's subjective, it is influenced by our cultures and our backgrounds, and it can be changed. Mindfulness—the process of being present, of noticing our thoughts, of being aware and nonjudgmental—helps us to recognize that we have mindsets, that they are a product of our development in cultures, but that they are a choice. That lends us to being able to have more agency in the ways we go about perceiving and interacting with the experiences that we have. How that relates to this gene? I'm not sure.

Topol: You zoomed in on something that's really important, because that ties in with the presence and the mindfulness and all the human qualities that we're not going to see in machines. I'd be getting pretty worried if a machine became mindful. It is really interesting, as we try to understand how we can become more human and differentiate from the ongoing increase in machine capabilities. They're relatively narrow today, but these deep learning, deep neural network algorithms are expected to get more capable over time. It seems like that does call on us for warmth, for mindfulness, for all of these things that are unique attributes of people.

Crum: Without a doubt. All of these advancements in artificial intelligence and machine learning are wonderful. But it also makes us question what it is that makes us human. Going back to this work on placebo response, it's forcing us to recognize that these aspects of the social psychological context of presence, trust, and connection (the psychological aspects that are not reducible to some algorithm around mindset or belief) are not things to be ignored or subtracted, as we have done since the advent of the clinical trial. They are things that need to be addressed in terms of being understood, but they also need to be leveraged. We need to teach people about them. We need to encourage people to figure out ways to leverage them in medicine and healthcare.

I'd appreciate both your takes on this. It seems like we've done so very little of that. What is it going to take to have this be something that we prioritize in our science, our training, and, perhaps most important, that we prioritize in our billing and in the ways we reimburse the ways that we value healthcare?

Teaching the Power of the Placebo and Mindset

Verghese: Alia, I was going to ask you just that. How do we operationalize this? How do you take all that you've learned in these past few years on placebo and mindset, and how do we teach that to medical students? How do we make that come about in the clinic? How do we get patients to adopt it? In a perfect world, how would we take advantage of all that you've taught us?

Crum: I think two things are important. One is continuing to do good, rigorous studies on the power of mindset and the power of being present and being connected in the healthcare relationship. We've done some of this work, as I described today. Ted Kaptchuk and others have done some work.

But there's so much more to do. We need to keep doing that to show that this isn't something that's superfluous. Calling your patient by name is not just a nice thing; it has a demonstrable, measurable physical impact and/or subjective impact on the patient. As a scientist, I'm really passionate about designing studies that show that, because I think that it matters to help understand it.

But the second thing is from a practical standpoint. We need to start training and having a dialogue. Your books and these podcasts are one way to do it, but what is the formal training in medical school or in continuing education? Kari Leibowitz, who's a grad student in our lab, is starting this process. We've recently worked with Stanford primary care clinics, and we've created a training that helps not just physicians but also medical assistants, nurses, and front and back desk staff. It's not so much a training, but more a session much like our discussion today. It helps in recognizing the time being spent or the intention being given, to connecting with the patient from the moment they walk in the door, to what you say about the treatments they are given or about the illness they are being diagnosed with. That's not an afterthought. That's not a "nice to have." That's central to the impact of healing or to the potential of what it means to be a good doctor, a good healthcare system.

We're doing some work on that now, thinking about how best to inform people that this stuff matters. We have a paper where we really break down the elements of warmth and competence,[7] for example. We need to keep doing rigorous research around this, and we need to start weaving in formal education and training. Those are my two beliefs.

Being Mindful of Mindsets

Verghese: That is wonderful. For our listeners, what are some things that we might do to enhance our daily routines or lives that revolve around the mindset that we might adopt in the morning, for example?

Crum: I would start in any context that seems uncertain or troubling by just asking, what is your mindset? What is the core assumption that you have about this thing you're experiencing? Whether you're going through a diagnosis of cancer, for example, or you have recently just been dealing with something that's stressful: What is your assumption about the nature of that stress? Do you view that as something that's going to make you sick and kill you? Or do you view that as something that's going to make you stronger? These are not right or wrong. The ways we view the world are not true or false, but they can be more or less useful.

I have a 15-month-old daughter, and I'm thinking a lot about the ways I am starting to talk about healthy eating with her. Our lab does a lot of work showing that our culture for many years has been saying that you should eat healthy, but it's really not that tasty. So how can I create a mindset that vegetables and fruits actually are delicious and indulgent? These are all mindsets, and we have an incredible ability as humans to be mindful of the mindsets we have and the impact that they're having, and to choose more useful ways of perceiving and thinking about the world.

Verghese: That is a beautiful answer, wouldn't you say, Eric?

Topol: I couldn't agree more. It's just fascinating work that you're doing and it is inspiring to us and to the medical community.

Crum: Great. I hope I can have a follow-up conversation with the two of you, who are so influential, on how we can put some of these ideas into practice or what we as a lab could be doing to have our work be more useful and relatable.

Verghese: Thank you so much for being with us today, Alia. We do look forward to having you back on another podcast of "Medicine and the Machine."

Crum: Thank you.

Eric J. Topol, MD, is one of the top 10 most cited researchers in medicine and frequently writes about technology in healthcare, including in his latest book, Deep Medicine: How Artificial Intelligence Can Make Healthcare Human Again.

Abraham Verghese, MD, is a critically acclaimed best-selling author and a physician with an international reputation for his focus on healing in an era when technology often overwhelms the human side of medicine.

Alia Crum, PhD, has won several awards, including a Thomas Temple Hoopes Prize and the William Harris Prize. Her work has been covered in the Boston Globe, the Wall Street Journal, and New York Times Magazine's 2007 "Year in Ideas," and she presented a 2016 TEDMED talk on the power of placebos.

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