Editor’s note: The second North American Pain School (NAPS) took place June 25-29, 2017, in Montebello, Quebec, Canada. An educational initiative of the International Association for the Study of Pain (IASP) and Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), and presented by the Quebec Pain Research Network (QPRN), NAPS brings together leading experts in pain research and management to provide 30 trainees with scientific education, professional development, and networking experiences. This year’s theme was “Where Does It Hurt and Why: Peripheral and Central Contributions to Pain Throughout the Body.” Six of the trainees were also selected to serve as PRF-NAPS Correspondents, who provided firsthand reporting from the event, including interviews with NAPS’ six visiting faculty members and summaries of scientific sessions, along with coverage on social media. This is the fifth installment of interviews from the Correspondents, whose work is featured on PRF and RELIEF, PRF’s sister site for the general public. See the first, second, third, and fourth installments of NAPS interviews.
Rami Burstein, PhD, is a professor in the Department of Anesthesia at Beth Israel Deaconess Medical Center and John Hedley-Whyte Professor of Anaesthesia at Harvard Medical School, Boston, US. Burstein studies the mechanisms of migraine headache. He sat down with PRF-NAPS Correspondent Michael Lacagnina, a postdoctoral fellow at the University of Texas MD Anderson Cancer Center, Houston, US, to discuss the philosophy that guides his lab, the type of research he thinks young investigators should pursue, and some of the latest thinking on migraine. Below is an edited transcript of their conversation.
What was your path to scientific research?
I began in the field of medicine in Israel. Over time, I realized there was more than one way I could make a real difference in the world: I could treat patients for a living, or I could spend my life trying to push human knowledge forward, in a way that leads to new treatments for patients. The satisfaction of the latter path—of asking questions to which there’s no answer, to discover something that nobody else in the world knows, and to then stand in front of the world and share that knowledge—is really what drove me to become a scientist. I ended up doing both medicine and research, but the second path is much more rewarding—otherwise I wouldn't do what I do. But they go together; they are not mutually exclusive.
How did you get into pain research specifically?
Once I realized I wanted to go into research, I ended up at the University of Minnesota in Minneapolis. They had a fantastic group that was working on the spinal cord, specifically dorsal horn mechanisms of pain. At the time, I thought that the answer to treating pain had to be in the spinal cord, in the first synapse between peripheral and central neurons. It was somewhat naïve, but I thought this would be the only way to intercept the signal before it reaches the cortex and is perceived as pain.
It turns out I was in the right place at the right time. I was lucky enough to discover a new spinal pathway to the brain, called the spinohypothalamic tract, which led to many publications during my PhD program. And my career moved forward from there. I came to Harvard in 1990, and I’ve been here ever since.
Do you have a philosophy or motivating principle for how your lab operates?
There’s an expression in science about research being “bench to bedside.” I truly believe the right way to do science is “bedside to bench.” You work in the clinic to make observations and develop hypotheses, and you push the limits up to the point where the hypotheses are no longer ethically or methodologically testable in humans. Only then do you move back to the bench and animal models, to explore how fundamental your original hypotheses were. If you start instead with benchwork, there’s a high probability your discovery will have zero implications for the clinic.
Take, for example, how we first observed some migraine patients describing their pain by tracing a path on their head that followed their suture lines, even though, of course, they had no idea where these lines were. This allowed us to design the right study with rodents to identify networks of pain fibers that traverse the suture lines and contribute to migraine pain.
The interplay—the back-and-forth between animal and human work—is so critical to stay on the right track. But in the end, humans are the best animal model of pain.
What is the current state of modeling migraine in animals?
In general, there is no animal model of migraine—there never will be. However, there are animal models for distinct aspects of migraine pathophysiology. For instance, we know which pain fibers are activated during migraine. If we activate them transiently, we have a model of the acute headache phase of migraine. If we activate them for weeks, we may have a model of chronic headache, which can turn into a migraine. Or if we want to study migraine aura, we can induce an abnormal wave of cortical spreading depression. From here, we can measure many outcomes associated with migraine: how neurons in the brain are firing, where blood vessels are contracting, and whether the animal is sensitive to light. Do these animals really have migraine? We will never know.
Migraine has a long list of comorbid and complicated associated symptoms, like nausea, vomiting, cognitive impairment, and aphasia. These symptoms are not all captured by simple pain fiber stimulation. And remember, a patient may take 20 years to develop chronic migraine. We don’t have a rat model for 20 years; we have a rat model for 14 days. As a result, it’s not realistic to call these animals a “migraine model.” But they serve to reveal small parts of the larger puzzle.
The title for your talk at NAPS was “I'm Stressed. I Can't Sleep. I'm Too Busy to Eat. Oh, and I Can't Get Rid of My Migraines. By the Way, Can I Make My Finger Hurt Just by Trying?” What does this title mean?
The title was essentially an outline for my talk, which covered, in part, how sleep is slowly taking center stage for understanding migraine. One of the most common triggers of migraine is lack of sleep, or prolonged wakefulness. On the other hand, we know that if patients go to bed with a migraine, normally the pain will be gone by the time they wake up.
So it’s not just the passage of time that makes the migraine go away—when the patient goes to sleep, you think there is a specific process going on that resolves the migraine?
Absolutely. We believe the explanation lies in modulation of neuronal activity in the thalamus—of relay trigeminovascular thalamic neurons. These neurons cycle between two modes of firing, and disruption of this balance is associated with exaggerated pain. We found that these neurons receive innervation from an incredible diversity of neurotransmitters and neuropeptides— dopamine, noradrenaline, histamine, orexin, melanin-concentrating hormone, and so on—which can shift the balance of thalamic firing. During sleep, release of the inhibitory neurotransmitter GABA and elimination of the excitatory neuropeptides in the thalamus could explain how sleep helps resolve migraine pain.
Neuroscientists often say the thalamus is a simple relay station for sensory information, but it’s not that simple. The thalamus is like the conductor of a symphony—it synchronizes activity across cortical structures. But in chronic migraine, there’s a breakdown in how the thalamus controls the flow of information. Think of an orchestra—when the conductor is not functioning, the whole symphony is squeaking. This is a metaphor, but it’s close to what we see when recording from thalamocortical neurons. If we understand how these neurons behave, maybe we can use this knowledge to invent a whole new approach to treatment.
Earlier you mentioned sensitivity to light. Why is this a characteristic of migraine?
Photophobia, or light sensitivity, is fascinating. It’s not associated with most pain conditions. Toothache doesn’t cause photophobia; neither does neuropathic pain, stomach ache, or cancer pain. It seems that only conditions involving the dura, such as migraine, cause sensitivity to light. In 2010, we discovered retinal ganglion cells that terminate on dura-sensitive thalamic neurons in the rat, and these thalamic cells happen to respond much more to light than neurons that don’t receive input from the dura. What’s interesting is that blind patients who suffer from migraine can also experience photophobia. So we think it involves the dura, but we’re still not entirely sure how.
Migraine shows dramatic sex differences. Why is migraine more common in women?
The short answer is: We don’t know. We have a lot of observations but very little knowledge. It is certain that some women get migraine every menstrual cycle, or at other time points when estrogen and progesterone are fluctuating, so hormones must play some role. But we still cannot definitively answer why women get migraines more than men do.
The theme of NAPS this year was peripheral versus central contributions to pain. In your talk, you said that people can’t look at their fingers and make them hurt, arguing that the brain does not have complete control in creating a pain sensation. What are your thoughts on this issue?
Everyone knows that if you bang your finger with a hammer, it hurts. In other words, stimulating a pain fiber drives the pain. The brain, in turn, can modulate pain. Catastrophizing on the finger injury can augment the pain sensation, or by diverting your attention the pain can be minimized. So most people agree the periphery and brain differ as drivers versus modulators of pain.
Now, the debate in the field is whether the brain can be the driver of pain in the absence of any peripheral input. Under acute conditions, I think it’s clear the answer is no. Clinicians have tried for decades to induce pain by stimulating different brain regions. Out of thousands of patients, only a handful have reported pain. For chronic pain, there is evidence that central neurons become sensitized. But again, the question is whether they can serve as the driver of pain without input from the periphery. There is opinion but not hard evidence. For the debate at NAPS, the students need to stick to data, not to opinion.
Do you have any advice for young researchers just starting their careers?
That would take two hours!
Okay, more specifically then: What type of research should young investigators pursue?
It’s pretty clear that everything that is easy has already been done, and what’s left to be done is not easy. So, number one: Don’t look for an easy way to produce science. Don’t just follow the latest trend. You will understand the true meaning of science when you have a question that you know no one in the world can help you answer.
Next, your ability to address these unanswered questions depends on your techniques. If you can invent a technique that answers your difficult question, then you’re a step ahead of everybody. But it’s not easy. For the photophobia study, it took us two years to develop the technique, but only six months to gather all the data once it worked. Your technique is what gives you an edge.
Finally, you can’t ask a question simply because you can answer it. Instead, you have to ask a question because it is important and will make a real difference. When I talk to young scientists and ask them about their research, too often they tell me what they’re doing. I don’t care about the specifics of the study. I only care about the question they are asking.
Additional Reading
Neural mechanism for hypothalamic-mediated autonomic responses to light during migraine.
Noseda R, Lee AJ, Nir RR, Bernstein CA, Kainz VM, Bertisch SM, Buettner C, Borsook D, Burstein R
Proc Natl Acad Sci U S A. 2017 Jul; 114(28):E5683-92.
Melo-Carrillo A, Noseda R, Nir R, Schain A, Stratton J, Strassman AM, Burstein R
J Neurosci. 2017 Jul 26; 37(30):7149-63.
Migraine photophobia originating in cone-driven retinal pathways.
Noseda R, Bernstein CA, Nir R-R, Lee AJ, Fulton AB, Bertisch SM, Hovaguimian A, Cestari DM, Saavedra-Walker R, Borsook D, Doran BL, Buettner C, Burstein R
Brain. 2016 Jul; 139(Pt 7):1971-86.
Migraine: multiple processes, complex pathophysiology
Burstein R, Noseda R, Borsook D
J Neurosci. 2015 Apr; 35(17):6619-29.
Noseda R, Kainz V, Borsook D, Burstein R
PLoS One. 2014 Aug; 9(8):e103929.
Altered placebo and drug labeling changes the outcome of episodic migraine attacks.
Kam-Hansen S, Jakubowski M, Kelley JM, Kirsch I, Hoaglin DC, Kaptchuk TJ, Burstein R
Sci Transl Med. 2014 Jan 8; 6(218):218ra5.
Zhang X, Levy D, Noseda R, Kainz V, Jakubowski M, Burstein R
J Neurosci. 2010 Jun; 30(26):8807-14.
A neural mechanism for exacerbation of headache by light.
Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K, Burstein R
Nat Neurosci. 2010 Feb; 13(2):239-45.
An association between migraine and cutaneous allodynia.
Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH
Ann Neurol. 2000 May; 47(5):614-624.
