This is the sixth in a series of Forum interviews with PRF’s eight new science advisors for 2014-2015.
M. Catherine Bushnell, PhD, is scientific director of the National Center for Complementary and Integrative Health (previously known as the National Center for Complementary and Alternative Medicine, or NCCAM) at the US National Institutes of Health (NIH), where she oversees a program on the brain’s role in perceiving, modifying, and managing pain. Prior to her appointment at the NIH in 2012, Bushnell was the Harold Griffith Professor of Anesthesia at McGill University in Montreal, Canada. Her research interests include forebrain mechanisms of pain processing, psychological modulation of pain, and neural alterations in chronic pain patients. Her current clinical studies use sensory and physiological testing, and functional MRI and TMS, to explore mechanisms of non-pharmacological modulation of pain in healthy volunteers and chronic pain patients, mechanisms underlying reduced pain perception in yoga practitioners, and neural mechanisms underlying emotional touch. Her lab is also evaluating the effects of environmental factors on brain anatomy and neurotransmission in nociceptive models. Bushnell spoke with Neil Andrews, PRF executive editor, by telephone to discuss how her interest in experimental psychology led to a career in pain research, her current projects, and future challenges for pain research. Below is an edited transcript of their conversation.
How did you become interested in studying pain?
I studied psychology as an undergraduate at the University of Maryland and took a job in a laboratory cleaning rat cages on the weekends. I became very interested in animal behavior, so I went to graduate school in an animal behavior program at American University. At that time, American University had a very strong operant conditioning program led by Charlie Ferster. It was Ferster, along with B.F. Skinner, who wrote the bible of operant conditioning, which at that time was a hot thing in psychology.
As I was studying animal behavior, I kept thinking of the “black box” of the brain. Neuroscience didn’t even exist at the time; there was only experimental psychology, from which many neuroscientists would emerge. It was interesting to understand the environmental factors that led to certain behaviors, but I wanted to understand the underlying neural mechanisms. I was fortunate because, toward the end of graduate school when I was writing my thesis, the NIH was looking for someone to train monkeys, and I said I would do it—this was in Ron Dubner’s pain lab at the National Institute of Dental Research. At the NIH, I was exposed to neurophysiological work, and then I did a post-doc at the National Eye Institute with Mickey Goldberg, a neurologist. We did electrophysiology in awake behaving monkeys to study visual attention mechanisms. So I was able to learn neurophysiology and combine it with my expertise in animal behavior.
After I finished my post-doc, I went back to Ron Dubner’s pain lab and worked there as a staff scientist for five years. Then I moved with my husband, who was also working in the lab, to the University of Montreal. When I went to Montreal, I started doing human studies in addition to animal work. When brain imaging came along, the Montreal Neurological Institute, where I was an adjunct professor, was in the forefront of that area of research, and I had the opportunity to do the first brain imaging study of pain. I went on to do many brain imaging and psychophysics studies in humans, and now I’ve come full circle by combining human brain imaging with rodent imaging and behavioral studies.
Why did you move from McGill back to the NIH [see PRF related story]?
When Ron Dubner was at the NIH, his laboratory was one of the best pain research labs in the world, and it generated some of the most outstanding pain researchers in the field. After Ron left for the University of Maryland, the pain program at the NIH fell apart, and there were various initiatives over the years where people at the NIH tried to decide if they wanted to rebuild it.
Story Landis, at the National Institute of Neurological Disorders and Stroke, was very keen about pain, and that’s why she helped develop the Pain Consortium. But while there were people on the NIH campus who were interested in pain, there wasn’t a coherent program. Josephine Briggs, the director of the NCCAM, was interested in developing an intramural program focused on complementary and alternative medicine with a very strong mechanistic base. Pain and nonpharmacological modulation of pain fit the profile of that program, and she and Story decided to recruit a director of intramural research and give that person enough resources to build a program. I thought this would be an interesting activity toward the end of my career, to have the opportunity to establish a new program, hire young investigators, and get them started, so I came back to the NIH.
What are some of the research projects going on in your lab?
On the animal front, we are looking at the effects of both diet and exercise on the development and maintenance of chronic pain in rats, using an arthritis model of CFA [complete Freund’s adjuvant] injection into the ankle joint. Many exercise studies involve forced exercise where animals are placed on a treadmill, and if they step off the treadmill, they get shocked. The animals will exercise, but it’s also a stressful situation, so it’s hard to distinguish between stress-produced analgesia and the effect of the exercise itself. To more closely approximate exercise that people do, we take the animals out of their cages, put them in a little exercise room for two hours a day, and let them exercise as much as they want; they don’t have to exercise. We have found that with just this two-hour exposure a day to exercise, there is a large beneficial effect on the recovery from pain induced by the arthritic injury, even though the joints are still quite inflamed. This effect appears fairly independent of the amount that the animals run, because we still see it even in the ones that don’t run that much.
We are also interested in the effects of stress on pain. Since we use whole-brain imaging in rats and mice, one issue is whether to anesthetize the animals or restrain them before putting them into a scanner. We are looking at the effects of restraint, and have found that restrained animals have elevated cortisol levels and show stress-produced analgesia. We have also discovered that animals tested in the same room where other animals have previously been stressed exhibit elevated cortisol and stress-produced hyperalgesia. This has many implications for animal testing in general, since animals are taken in and out of testing rooms, and you may not know which animals have been in the room beforehand. Even though the boxes and rooms are cleaned, the animals’ sense of smell is so much more powerful than our own, so these social contagion stress effects are very powerful. This is important when you extrapolate to people living with chronic pain patients or those living with individuals who have other chronic diseases, and the effects that it has on them. A previous study we did at McGill found that when you are in the presence of a person who has pain and you feel empathy for that person, your own pain perception is enhanced.
In human studies, we are using transcranial magnetic stimulation to transiently deactivate brain areas and then study the effects on different types of perception. We are interested in pleasant touch and the role of different cortical areas, including the primary somatosensory cortex, secondary somatosensory cortex, and insular cortex. We showed that transiently deactivating the primary somatosensory cortex alters two-point discrimination and perception of the intensity of brush stroking, but the affective aspects of touch are not altered, which is consistent with what we suspected in the primary somatosensory cortex. We are now looking at regions that are important for affect and emotion.
You have also studied the effects of yoga on pain. Is your lab still working in that area?
Yes. Chantal Villemure in my group has been very interested in yoga. In a previous study, we took normal people who had been practicing yoga for at least six years on a regular basis and compared them to healthy people matched on age, sex, education, other exercise—as many variables we could think of that were important—and we saw dramatic changes. We found from brain anatomy studies that the people practicing yoga had more grey matter in a number of regions; as we get older, we lose grey matter, but we didn’t see that decrease in the yoga practitioners, which suggests that yoga may have a neuroprotective effect. When we looked at pain perception, there was a significant increase in pain tolerance in the yoga practitioners, and there was a change in pain thresholds, too. Using brain anatomy and diffusion tensor imaging to look at the integrity of white matter tracts, we also found that increased size and connectivity within the insular cortex was the most important factor accounting for these changes in pain tolerance.
Chantal believes that a lot of these effects may be related to autonomic factors and stress reduction, and she is doing more detailed studies looking at cortisol and autonomic measures. She is also comparing yoga practitioners to healthy people in terms of their relationship with the expectation of pain. We have data suggesting that most people, when they are expecting pain, which is a stressful situation, show increased autonomic sympathetic activity, whereas in yoga practitioners we see the opposite effect—they can slow their heart rate and relax, and so they have a different relationship with the expectation of pain.
Does the case still need to be made that there is a convincing physiological basis underlying the effects of alternative and complementary treatments on pain in order to legitimize those treatments? Or does the pain field recognize the value of non-pharmacological approaches?
I think the tide is turning. If you look at chronic pain, all of our pharmacological treatments are very marginal; drugs have been approved and have been shown to be more effective than placebo, but the numbers of patients needed to treat in order for one to benefit are very high. People are starting to realize, more and more, that the effects of non-pharmacological interventions such as exercise, reducing anxiety, and changing one’s emotional state and attentional focus have effects on the brain that are just as powerful as clinical doses of opiates or other pharmacological treatments. I think this is becoming more mainstream, and people are starting to believe in it, but really understanding the underlying mechanisms is important for people to fully accept it.
What are some other directions your research is taking?
We are doing more extensive testing of the consequences of chronic pain, including anxiety, depression, and cognitive effects. This is really important because pain is not only about reflex hypersensitivity to being touched; it’s really the emotional, psychological, and cognitive burden of pain that’s hard on people. This is one direction we are going in and that is critical for our field in general.
In our human studies, we are also addressing the mechanisms of placebo analgesia. Do chronic pain patients have the same placebo effects as healthy people, and if so, are the mechanisms different—for instance, are they shifted from opioid-induced mechanisms to non-opioid mechanisms? There have been many mechanistic studies in healthy people, but what we are finding when we look at pain-related brain changes in chronic pain patients is that there are anatomical and functional alterations in the same parts of the brain that are involved in placebo analgesia.
Whether non-pharmacological modulation of pain is due to a placebo effect or whether it depends on sex, emotion, attention, and expectation, and whether these are altered in chronic pain patients, are all important questions we are working on now.
What obstacles do you see hindering pain research?
In terms of translation from animal to clinical studies, there is the issue that the animal studies don’t have the same rigor as they should—for instance, animal studies are not necessarily blinded, or they have very small sample sizes, so the effects may not be real or generalizable. Research is getting more competitive, and so people feel they have to publish these small studies. I think this will be corrected, but it will require a change in funding to allow people to replicate studies and to have larger ones.
Also, the NIH is going to require researchers to include both sexes in their preclinical studies (see PRF related news story). That is also going to cost a lot more because it will require larger sample sizes. The big hindrance is that there is not enough money in research. There are estimates that approximately 80 percent of people getting their PhDs in neuroscience are not going to get classic tenure-type jobs, and they are looking for alternative careers. We have generated many trainees, and neuroscience is one of the most popular undergraduate fields, but, unfortunately, there isn’t enough money for all of those people to do research.
Any advice for young people who do go into research?
You have to follow your heart and your passion. If you are really passionate about something, put a lot of effort into it, and are good at it, then there is always room for the best in any field. But you also have to be realistic and recognize what you are good at. If you don’t have the ability to stay at the top of the field, then I think looking for other paths is important.
Thanks for taking the time to speak to PRF.
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Other Forum Interviews with PRF’s 2014-2015 Science Advisors: