Using Brain Imaging to Understand Pain: A Conversation With Karen Davis

Editor’s Note: The first-ever North American Pain School (NAPS) took place June 26-30, 2016, in Montebello, Quebec, Canada. An educational initiative of the International Association for the Study of Pain (IASP); Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); and the Quebec Pain Research Network (QPRN), NAPS brought together leading experts in pain research and management to provide 30 trainees with scientific education, professional development, and networking experiences. Six of the trainees were also selected to serve as PRF-NAPS Correspondents, who provided first-hand reporting from the event, including summaries of scientific sessions and interviews with NAPS’ six visiting faculty members, along with coverage on social media. This is the fifth installment of interviews from the Correspondents, whose work is featured on PRF and on RELIEF, PRF’s new sister site for the general public. See previous interviews here.

Karen Davis, PhD, is a professor in the Department of Surgery and Institute of Medical Science at the University of Toronto, and the Head of the Division of Brain, Imaging, and Behavior-Systems Neuroscience at the Krembil Research Institute, Toronto Western Hospital, University Health Network. Davis is a pain researcher who uses brain imaging to understand how pain affects the brain’s structure and function. Davis sat down with PRF-NAPS Correspondent Erinn Acland, a PhD student at the University of Toronto, to discuss her path to pain research, the challenges of brain imaging, and what she is currently working on. Below is an edited transcript of their conversation. Within the transcript below is also an animated podcast, created by Acland, covering part of the interview with Davis.

How did you become interested in pain research?

It’s an interesting story that goes all the way back to high school. I had a very enthusiastic and influential biology teacher. He was a young guy who would tell us about advances in science. One day he said that somebody had discovered endorphins, which activate opiate receptors in the nervous system and are the body’s way of handling pain. I thought that was really interesting, and that when I got to university I would study the brain and pain, which is exactly what I did.

What happened once you reached university?

I was really lucky. I went to the University of Toronto and in my first-year biology class I took a module taught by a world-renowned neuroscientist named Bruce Pomeranz. At the time, he was making the link between endorphin release and acupuncture analgesia. I approached him and eventually worked in his lab as a summer student for several years. During one of the summers, researchers in his lab told me about one of his previous graduates, named Jonathan Dostrovsky, who was starting up his own lab in Toronto. I ended up doing my graduate studies with him.

https://youtube.com/watch?v=aPmOXaprqrI%3Frel%3D0

When did you know you wanted to be a professor?

Most people might be surprised by my answer that it wasn’t a path I saw myself taking. As a graduate student and as a postdoc, I saw that professors had to spend a lot of time writing grants and in many situations could no longer actually do the experiments themselves. I was an electrophysiologist and I loved recording from neurons, so I couldn’t imagine having to give that up and sit behind a desk just pushing papers. My dream job was to get a position as a research associate running somebody else’s lab, doing the experiments, and the fun stuff that I wanted to do.

It wasn’t until after doing two postdocs that I realized this was a naïve dream because there is very little stability in that kind of career path. I also became aware that it would put me in a situation where I couldn’t necessarily ask the scientific questions I wanted to ask. I realized I needed to have my own lab if I was going to be able to follow up on the questions I was interested in and not somebody else’s questions. So I had to jump in.

You recently did a TED-Ed video where you talked about how pain affects attention. What was your goal with the video?

The goal was to talk about the spectrum of responses and priorities that people place on doing a task or attending to some cognitive demand in the face of dealing with pain. I really wanted to get across the idea that there was a large inter-subject variability: some people can naturally mind wander away from a painful stimulus, while others have very focused attention on the pain. This difference in pain response can affect performance of attention-demanding tasks. We also looked at how the brain responses that we found match behavior.

Did most people fall into the category of either mind wanderer or pain focuser?

Initially we thought it was a bimodal situation. We had people called P types who focused on the pain, so their performance in a task diminished. Then there were A types who focused their attention to the task. Sometimes the performance of the A types improved when we delivered pain, because they said, anecdotally, that the pain made them focus more on getting the task right. However, when you look at the behavioral data, it shows a spectrum. The majority of people are at one end of the spectrum or the other, but there are some people in the middle too.

How do you know whether the results from functional magnetic resonance imaging (fMRI) originate from physical or psychological sources?

The short answer is you don’t know, because when you’re looking at the fMRI response, you’re really looking at the final outcome of whatever is going on in that individual. So the origin of that response is really something you can’t identify with fMRI; you need other techniques to dissect that. But I should note that people talk about a psychological source of pain, but the reality is that everything you’re thinking, feeling and experiencing is in the brain.

We know there are ascending pathways to the brain that have their origin in peripheral nociceptors, and they end in various regions of the brain. We also know there are regions in the brain that are involved in modulation of those signals, and that there are top-down controls. The origin of the top-down pathways are in the same areas where the ascending pathways terminate. For instance, in people with post-stroke pain, the origin of pain is that they’ve had damage in the brain that is generating some signals. It’s no less real than if you stub your toe. Is something any more or less real if the original trigger for the response comes from the periphery or from within the brain? So there is a distinction between physical and psychological sources of pain, but it’s sometimes a distinction that has a negative connotation to it, and I think we need to be very aware of that.

Some question the meaning of fMRI results because this technique provides only an indirect measure of brain activity. What are your thoughts about that?

Certainly fMRI is quite different from placing an electrode into an individual cell and recording action potentials—there is no doubt about that. It is an indirect measure that looks at where neurons are active in the brain by assessing increases in oxygenated blood flow to an area. fMRI only looks at the outcome of brain activity, and many things can lead to that metabolic demand. In recent years, we have been learning more and more about how non-neuronal cells, such as glia, may affect fMRI signals.

We can try to use other complementary methods to validate fMRI results. For instance, when people first started to look at functional connectivity and were unsure whether the ultra-slow frequency responses seen with fMRI were real, they went out and replicated the results using EEG [electroencephalography], and although the frequencies were different, they still found the same network present. So you can use another technique to cross-validate your findings with fMRI, which gives you more confidence in what you’re looking at.

You recently published research on how personality can affect chronic pain. How did that work come about?

I was interested in individual differences and it became clear very early on that in order to study them, we had to take into account all sorts of aspects of the person, including personality. In the early days, we were looking at pain catastrophizing and found that people with high catastrophizing scores can be more sensitive to pain and show a greater response to a painful stimulus in the brain. We then looked at some other aspects related to catastrophizing; some of these are subscales of the pain catastrophizing score, like rumination and helplessness. I was also collaborating with psychologists and they introduced many other questionnaires, for depression and anxiety, for instance. Now we’re interested not only in the negative aspects, like helplessness and rumination, but also in the flip side, like resilience.

What else are you working on now?

We’re working with a number of different patient populations, which are giving us slightly different takes on what could be going on in patients with chronic pain. Some of these studies have a treatment component so we can study why some people respond to treatments and others don’t.

The other thing I’m quite excited about is that we’ve expanded our arsenal of technologies. More and more we’re using the approach of functional connectivity, and we’re now adding magnetoencephalography (MEG), which gives a much greater temporal resolution.

Most recently, we’ve been looking not only at connectivity of regions of the brain, but also the dynamics of what’s going on within an individual area of the brain. So we’re looking not just at how connections to other brain areas might fluctuate, but how the signal within an area of the brain might be in a state of readiness in some people, whereas in other people it might be quite static. In this instance, this variability is called regional BOLD [blood oxygenation level-dependent] variability, which looks at how the BOLD response at resting state fluctuates over a five to ten minute period. If it doesn’t wax and wane very much, people have lower pain thresholds and are more likely to be P types. However, when people have a greater variability in the signal within an area of the brain, they are less sensitive to pain, and those people are more likely to be A types.

Do you have any advice for those just starting out in their careers as pain researchers?

I always say follow your passion because I have many stories of opportunities that I turned down, such as tenure track positions I was offered early on in my postdoctoral work. At the time, some people thought I was crazy to turn down those opportunities to do yet another postdoc, but they were opportunities that were not necessarily right for me.

When accepting a position, you need to consider what kind of research you want to do, what kind of social and academic environment you want to be in, and which city or country you eventually want to live in. However, if you wait for the perfect job, you may never get it. Even if it’s not the perfect job, in the perfect place, and in the perfect environment, maybe you should take it; it could be a stepping-stone to something else.

I really don’t like to give advice about taking jobs or not taking jobs. Follow your passion, because at the end of the day, you’re going to be putting more time into your science than anything else in your life. You have to love it and it has to be a passion. If it becomes a grind that you hate or it’s not a passion, then you should think about something else—and it’s not for everybody. There are many other great ways to contribute to society and to science so you just have to find what fits you.

Are there any specific qualities you look for when hiring?

What I look for has changed over the years. There’s a technical aspect, obviously, because the projects that people predominantly do in my lab are brain imaging studies, so people who come to the lab can’t be afraid of technology. They don’t necessarily have to be a math or physics expert, but they have to be the kind of person who can learn those abilities on their own or with someone else.

Academically, everybody getting into our graduate program has a great CV. Everybody is smart. Many of the faculty at the university even say how we might not have gotten into our own graduate program if the standards were that high when we were applying!

But the first thing I look for is whether they’ve had some exposure to research. It’s quite a commitment to do graduate work or a postdoc. They have to have passion even at this early stage, so if they haven’t had decent exposure to research, I say that they should get some experience, because they may not like what they’re doing in my lab.

Are there any skills that you find particularly important in research?

I look for something that reflects how resilient or perseverant people are because there are many people who get very high marks, but that doesn’t necessarily mean they have the same kind of skills that will be successful in science. One of the most important skills is the ability to rebound after failure. The percentage of success is quite low for grants and scholarships, and experiments often don’t work—lots of things go wrong in the lab. The most successful people in science are the ones that have had a bit of failure; failure is good, because you learn from it. People who have only been highly successful might not have even had the opportunity to test their resilience.

People with other interests, such as in music, art, or sports, have certain skills that are also important in the lab. For instance, an involvement in team sports is good because a lot of research involves working in teams. People who are good at these other interests put in hours and hours perfecting a skill, so they’re not afraid of repetition and hard work. These are all transferable skills that I look for.

What makes a good lab? Is there a formula that is most successful?

I don’t know if there is a formula. One of the successes of my lab over the years has been an overlap between students who are finishing up and new students coming in, so the new students can learn from the previous students and the transition is smoother. The best thing is when the student is new to the lab and somebody else is graduating, so I usually make a party at my house for a graduating PhD student. This shows the new students that people do finish, no matter what stories they hear about how hard it is, and they’re going off to do something great.

Also, having a mix of people in the lab, both culturally and in terms of skill set, has always been really important. Culturally, people learn from each other and have very different ways of thinking about problems, which really helps growth.

But the most important component to a good lab is to make sure potential new students will fit into the lab, not always scientifically, but socially. It’s really exciting in the beginning and really exciting at the end. But in those middle years, it can be a real grind, so if you don’t like going into the lab every day, because maybe you have some friction with somebody in the lab, which happens in every workplace, that just adds to the stress and to the difficulties. If there is a social element to the lab, that really creates a great environment, which helps people get through those tough times.

Thank you so much for speaking with PRF.

Thank you for the opportunity.

Additional Reading

Regional brain signal variability: a novel indicator of pain sensitivity and coping.
Rogachov A, Cheng JC, Erpelding N, Hemington KS, Crawley AP, Davis KD
Pain. 2016 Jul 15.

Abnormal cross-network functional connectivity in chronic pain and its association with clinical symptoms.
Hemington KS, Wu Q, Kucyi A, Inman RD, Davis KD
Brain Struct Funct. 2015 Dec 15.

Individual differences in temporal summation of pain reflects pronociceptive and antinociceptive brain structure and function.
Cheng JC, Erpelding N, Kucyi A, DeSouza DD, Davis KD
J Neurosci. 2015 Jul; 35:9689-9700

The dynamic pain connectome.
Kucyi A, Davis KD
Trends in Neuroscience. 2015 Feb; 38:86-95

Dynamic functional connectivity of the default mode network tracks daydreaming.
Kucyi A, Davis KD
Neuroimage. 2014 Oct 15; 100:471-80.

Enhanced medial prefrontal-default mode network functional connectivity in chronic pain and its association with pain rumination.
Kucyi A, Moayedi M, Weissman-Fogel I, Goldberg MB, Freeman BV, Tenenbaum HC, Davis KD
J Neurosci. 2014 Mar 12; 34(11):3969-75.

Mind wandering away from pain dynamically engages antinociceptive and default mode brain networks.
Kucyi A, Salomons TV, Davis KD
Proc Natl Acad Sci U S A. 2013 Nov 12; 110(46):18692-7.

Neural underpinnings of behavioural strategies that prioritize either cognitive task performance or pain.
Erpelding N, Davis KD
Pain. 2013 Oct; 154:2060-71.

Perceived helplessness is associated with individual differences in the central motor output system.
Salomons TV, Moayedi M, Weissman-Fogel I, Goldberg MB, Freeman BV, Tenenbaum HC, Davis KD
Eur J Neurosci. 2012 May; 35(9):1481-7.