Tying the Research Together to Understand Migraine: An Interview with Gretchen Tietjen

“So many research ideas come from clinical observations. So, having the chance to be a clinician is a real gift that allows you to ponder, wonder, and then start to investigate what is happening with a patient. It may take a while to find someone with the expertise you lack, who is interested or has the time to join the investigation, but I am encouraged by basic science researchers who take a genuine interest in clinical disorders and seek out clinicians with whom to partner.”

Editor’s note: This is the first in a series of interviews with Migraine Science Collaborative editorial board members.

Gretchen Tietjen, MD, is Distinguished University Professor Emerita of Neurology at the University of Toledo. She founded the Department of Neurology in 1999 and led it as an endowed chair through 2019. Specializing in headache medicine and vascular neurology, she directed the Stroke Center for 15 years and the Headache Treatment and Research Center for 23 years. Recently, she was recognized with the American Headache Society’s Lifetime Achievement Award.

Tietjen’s research focuses on the relationship of migraine and stroke, and includes investigation of the vascular biology in migraine, the association of childhood maltreatment and migraine, and the effects of early life stress on vascular and brain biology in a rodent model. While she has retired from clinical practice, Tietjen continues to pursue migraine research.

Here, Tietjen speaks with freelance writer Kayt Sukel to discuss her career path, the overlaps between migraine and stroke, her most surprising findings, and much more. This interview has been edited for clarity and length.

What inspired you to start doing research into migraine and headache?

When I came out of residency in 1989, I was at the University of Michigan and wanted to do a stroke fellowship. The university didn’t have any stroke physicians at the time – or even a stroke unit – so I went to Henry Ford Hospital, which is in Detroit, for stroke fellowship training with Dr. Michael Welch, a stroke and headache medicine specialist, who chaired the neurology department.

Stroke is mostly an inpatient specialty, but I also saw patients in the neurology clinic at Henry Ford, where I noticed that the majority of people coming in to see me were patients with migraine. After a few weeks, I went into Dr. Welch’s office and quite boldly told him, “You know, I didn’t come here to do migraine. I came here to do stroke. Why am I seeing mostly migraine in clinic?”

He told me that if I was interested in stroke, I couldn’t ignore migraine because the two are connected. That got my attention, because no one had ever talked to me about that connection before. Over time, I came to find that the overlaps between stroke and migraine in these patients were very interesting, and I wanted to learn more.

Gretchen Tietjen

Your research has touched on so many different topics. What connects them?

I had been interested in coagulation abnormalities ever since I was a medical student; for some reason, they just captured my interest. Early on, I had written some papers on migraine and stroke, and whether the possible connection between the two might be related to antiphospholipid antibodies [these are antibodies directed against phospholipids, which are lipid molecules in the cell membrane, and make blood more likely to clot].

After focusing my research on that for a while, I surmised that wasn’t the most important link. So, I started looking at other pro-coagulable and inflammatory biomarkers, which can indicate endothelial dysfunction. This eventually led to a paper on the relationship between endothelial dysfunction biomarkers and migraine in pre-menopausal women.

At about the same time, in the early 2000s, I started to investigate early life stress and its association with migraine. I’d see a lot of adults with a history of abusive situations who also had migraine, and I remember wondering if it was just the stress or if something else was going on. I ended up collaborating with the Adverse Childhood Experiences [ACEs] study, which was run through the US Centers for Disease Control and Prevention [CDC], and contributed to a paper on the relationship between frequent headache and ACEs.

I’ve also worked on a study with Dr. Richard Lipton and Dr. Dawn Buse, using data from the American Migraine Prevalence and Prevention study, to show a connection between childhood abuse and migraine, particularly emotional abuse. I found this same link in the Add Health study, which surveyed young adults. In another study, I went back to the women who participated in my migraine biomarker investigation and asked them to complete a 10-point ACE questionnaire. Every biomarker we looked at, particularly CRP [C-reactive protein], had a significant correlation with the ACE score.

Later, I studied an animal model of early life stress, specifically, daily brief periods of separation of the newborn rat pup from the mother for 14 days, and found it led to migraine-like qualities in early adulthood, including cortical excitability, increased sensitivity to touch and light, and increased anxiety-like behaviors.

So, looking back, I think what connects it all is what I saw, day to day, in my clinic. In all of these instances, I was able to take an idea inspired by the patients I was seeing and then try to answer questions about it through epidemiological, clinic-based, and basic research studies. With both migraine and stroke, these overlapping theories and ideas kept coming back around again.

You’ve been interested in the association of migraine with aura and stroke. Can you tell me more about that connection?

I had worked on a bunch of studies that suggested there was a hypercoagulability in migraine. But was that from having the migraine? Or did it cause the migraine? Or both? My original theory was that elevated antiphospholipid antibodies predisposed to stroke and to migraine with aura. But we didn’t find an association of these antibodies with migraine, either with or without aura.

So, I then looked at von Willebrand factor [a blood-clotting protein], which was associated with endothelial activation and increased risk of stroke. We found that von Willebrand factor was associated with migraine and specifically with aura, so maybe increased clotting due to endothelial vascular changes linked migraine with aura and stroke.

When I first read studies showing that patent foramen ovale [PFO, which is a tunnel between the right and left sides of the heart’s upper chambers] was twice as common in persons with migraine with aura, I was fascinated by this. I started thinking maybe it wasn’t so much that migraine with aura caused stroke, but rather that migraine with aura was a marker for ischemia secondary to thrombosis or embolization – something more like a transient ischemic attack [TIA].

We know that ischemia can cause cortical spreading depression [CSD], the process producing aura, and that hypercoagulability could be working together with PFO to increase risk of both CSD/aura and stroke. Further, hypercoagulability might predispose to ischemia-induced aura, no matter what the cause – endothelial dysfunction, inherited or acquired conditions, birth control pills, or a combination of these things. I wonder about the size of the subset of persons with migraine with aura who have ischemia-induced aura.

What are some of the most surprising things you’ve learned over the course of your career?

In my career, there have been a lot of things somewhere in the background that other people looked at but didn’t pick up on in terms of their association with migraine. In my work, I sometimes managed to look at these things and put them together with other findings to bring it back to migraine. Being a vascular neurologist and keeping up with new discoveries in the stroke field often gave me ideas that made me look at my migraine patients from a fresh perspective.

For example, in my migraine clinic I found the first family in the United States with CADASIL [cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy]. CADASIL is now recognized as the most common hereditary small vessel cause of stroke. I recall in 1994 reading an article in Stroke from the first international workshop on CADASIL during the prior year, and I thought immediately of a patient; she was about 40, with atypical migraine aura who had abnormal white matter lesions on MRI but a negative evaluation for multiple sclerosis.

Several siblings had migraine, and her mother with dementia had a similar MRI. I remember thinking that her family had to have CADASIL. I tracked down the French geneticist who coined the term CADASIL at an American Academy of Neurology meeting the following month. She had me send her the MRI scans and blood for DNA from my patient and her whole family. And it turned out the family did have CADASIL. Their DNA, along with that of several European families, led to the discovery of the original CADASIL mutation. It was exciting to read something in a journal, put the pieces together, and then find a connection that not only gave my patient a diagnosis, but furthered the science of the disease.

What else has surprised you?

Finding that endometriosis is associated with migraine was also surprising. I became interested because, as I worked up many of my female migraine patients, they often reported having heavy menstrual periods. I thought maybe they had some kind of bleeding disorder, and as I asked about other gynecological problems, they’d say, “Well, I do have endometriosis.”

I then did two studies in women with migraine compared to those without migraine, and both showed an association of migraine with endometriosis. At about this same time, a researcher in a gynecology clinic published a paper reporting the same association. And then, an NIH research group found overlaps in the genes involved with endometriosis and migraine. The pieces just came together.

There have been other discoveries in my career, like the association of migraine and livedo reticularis [a patchy mottling of the skin] that started with a casual observation in the clinic. But if you just ask enough questions and keep an open mind, you will keep finding things that are interesting.

Speaking of endometriosis, what inspired you to look at this aspect and how it intersects with migraine?

My first boss, Mike Welch, suggested I should look at female hormones in migraine back when I was doing my fellowship at Henry Ford Hospital. I’ve written about that in terms of the risk involved with combined hormonal contraceptives and the increased risk of stroke in those with migraine. But at the time, it just wasn’t exactly what I was interested in. Later, I started noticing overlaps of migraine with stroke, pregnancy, endometriosis, and livedo in so many of my female patients. I wanted to learn if there was a thread there that could tie it all together for me.

The big question for me was always: Why do some people with migraine have no problems other than migraine, but then other people have all of these other conditions? Maybe part of it is genetic. Maybe there is some kind of gene-environment interaction that we don’t fully understand yet. Then, when I learned how many people, unfortunately, encountered early life stress, whether it was a lot of chaos in the home or maltreatment, that was another thing that tied many conditions together with migraine.

The American Headache Society recently honored you with their Lifetime Achievement Award. How does that feel?

There are a lot of other people who are very deserving of the award, but it is nice to be recognized. I wasn’t expecting it.

I am proud of my work, but I would have liked to have done more. I suppose that’s how everyone feels, no matter what they’ve achieved. There are still questions I’d like to get answered, but at this point, I’m probably not the person who will be doing the research. Instead, when I see someone working on something interesting at a meeting, I’ll often go up to them and share my thoughts or ideas about their work.

So, when I can add something, whether it’s pointing someone to a different tool or asking a particular question, I hope they’ll find it interesting and maybe even helpful. People may not take my advice. But when you’ve had a career like mine, and you’ve spent 30 years puzzling over these different things and couldn’t initially see where certain findings fit, and then someone presents something and you say, “I think I know where this might fit now” – it’s a lot of fun to share that.

As you look at the research landscape, what makes you the most hopeful for the future?

There’s been a lot of excellent research for migraine drug development. That makes me incredibly hopeful because there weren’t a lot of treatments for patients when I started out. With new options, I hope that people won’t have to suffer from migraine or be as disabled by it as they’ve been in the past.

There’s more and more research about migraine pathophysiology that will lead to a better understanding and more therapies. Some of the things people have been working on, like cognitive behavioral therapy and mindfulness-based stress reduction therapy, are really interesting – they are therapies I often thought would benefit my own patients.

It’s also exciting to look something up on PubMed and find a new study that links migraine with something else. Today, so many researchers, across different fields, are looking at migraine. This shows there is an expanding interest in migraine research, and as we uncover more connections, we can do more to help our patients. That gives me a lot of hope, too.

I have a feeling that so many conditions that seem to be tied together epidemiologically may not only have common genetics but also common environmental stressors. We could be talking about illness early in life, death of or separation from a parent, or some other kind of adverse event. The more we study these stressors, the more we recognize how they impact physical and mental health. And, more importantly, maybe we can find ways that exposure to early stressors could be addressed to improve or even prevent conditions, including migraine.

What advice do you have for researchers working in the migraine field?

I would tell them that ideas can come from anywhere – and the main place I found my ideas was in the clinic. If you see a patient and something strange stands out about their case, start reading about it. Find out if there’s anything in the literature about it. Then keep that information in the “back pocket” of your brain, because there will be a time when you may find that knowledge useful.

So many research ideas come from clinical observations. So, having the chance to be a clinician is a real gift that allows you to ponder, wonder, and then start to investigate what is happening with a patient. It may take a while to find someone with the expertise you lack, who is interested or has the time to join the investigation, but I am encouraged by basic science researchers who take a genuine interest in clinical disorders and seek out clinicians with whom to partner.

Find people who are interested in the same things you are interested in, even if they are in a different field or have a different skill set, and forge connections. It will give you a chance to learn new things and invite more people to be part of the kinds of conversations and research studies that expand everyone’s horizons so we can, hopefully, do more good for our patients in the long run.

Kayt Sukel is a freelance writer based outside Houston, Texas.