Targeting the Circadian System for Migraine Treatment: A Conversation with Yohannes W. Woldeamanuel

“The most important thing is that circadian rhythms are a  strong factor in migraine. Physicians will tell you that the patient is doing everything right in terms of sleep. But the circadian rhythm is not just sleep – don’t just ask about sleep and stop there. There are other areas that are highly interrelated in improving sleep, like eating throughout the day and night, timed light exposure, and timed exercise.” – Yohannes W. Woldeamanuel

Yohannes W. Woldeamanuel, MD, is an assistant professor of neurology at the Mayo Clinic in Phoenix, Arizona, US, where he studies how circadian interventions can help migraine and cancer patients.

Modern life has greatly impacted circadian rhythms. Cross-time-zone travel, night shifts at work, and exposure to blue light at night from digital screens can all contribute to circadian issues. This year, Woldeamanuel published a meta-analysis, now in preprint form, examining how irregular night shifts impact migraine frequency. The research revealed that people with disrupted circadian rhythms reported more migraines. This work is part of a small but growing body of evidence that migraine has a circadian element, and that maintaining a regular schedule over the course of each day could help reduce migraine burden for some patients.

Woldeamanuel recently spoke with Freda Kreier, a freelance science journalist, to talk about the hidden complexities of the circadian system and to share his experience on this new migraine research frontier. The interview has been edited for clarity and length.

How did you become interested in circadian rhythms and migraine?

I used to get very frequent migraine headaches during residency and during my postdoctoral fellowship. I took a lot of medications for my migraines, and I realized it was not working. It became clearer from all of my conversations with patients, and from studies, that lifestyle-based modifications could really offer me a lasting solution. That’s how I started to learn more about circadian medicine and how circadian disruptions are correlated with migraine attacks.

My first study was an observational study that asked patients: Do you do any exercise? Do you go outside in the morning? What time do you do exercise? What are your meal hours? People talk about sleeping like it’s alone in a vacuum. But sleep doesn’t exist on its own. You really must talk about what happens throughout the day.

It became very clear that those who were doing behaviors that have strong circadian cues seemed to be having fewer migraine attacks. That’s especially true of people who do their things in the morning and tend to go to sleep earlier; they have a healthier outcome in terms of migraine. And now, especially since COVID and the lifestyle disruptions it caused, people have started doing more circadian rhythm research. The big cancer classification body has labeled circadian disruption as almost equivalent to daily smoking in terms of cancer risk. We’re increasingly realizing that lifestyle and disease are related, and chronic migraine is one condition where this is true.

Yohannes Woldeamanuel

What is the evidence that circadian rhythms and migraine are connected?

That’s the million-, if not the billion-dollar question. It’s what I’m trying to explore in my research. The headache field doesn’t have a lot of research going on in this area compared to the cancer or diabetes fields; not a lot of us are doing circadian research.

For example, for mealtimes, there’s only one study that showed a connection using an intervention for migraine. One group received a regular breakfast and one group skipped breakfast intentionally. The skipped group had higher migraine burden for 10 weeks. Other than that, there is no study that shows this correlation other than my own ongoing work.

There is indirect evidence from the chronobiology field. Mammals generally have a pain threshold cycle. A human study was only published in 2022, from a French group. They found that if you give the same pain trigger to a participant throughout the whole day, every two hours, there are certain hours where the same trigger will lead to higher pain sensitivity: We have higher thresholds to pain in the afternoon, compared to lower thresholds during the early hours of the morning.

This is especially true for migraine, which has a morning phenotype. If you ask a thousand migraine patients, they’d say their attacks either start in the morning or wake them up from sleep. On top of that, there are very core circadian clock genes that are highly expressed in about 70% of migraine patients, especially those with chronic migraine [see MSC related news story, and a recent preclinical study in preprint form from Woldeamanuel and colleagues]. In addition, the suprachiasmatic nucleus – the master regulator of the circadian cycle – is also involved in migraine attacks. And, the choroid plexus and glymphatic system, both of which have a bidirectional relationship with the central circadian network, are also implicated in migraine pathophysiology.

So when you consider all of these findings, and then people tell you that if they miss the morning light, if they skip their meal, if they don’t sleep well and then they get migraine, everything adds up to give you evidence of a circadian connection.

If circadian rhythms and migraine are connected, how can we use this knowledge to treat patients?

That is exactly what I’m trying to do. I have two clinical trials looking at whether we can develop a protocol to personalize circadian rhythm research to help patients [see here and here].

The study has a baseline period where we follow patient behaviors on a day-to-day basis for four weeks. We also collect MRI scans and blood markers. Then we look for behaviors to target. So somebody may say they exercise every day, but then they’ll tell you they only exercise in the evening, at 7 p.m. That’s like taking an espresso shot at night. Or they may say they eat during almost the whole 24-hour day, deep into the night. That’s not how our body is designed; we are hard-wired to eat during the day and fast during the night. Snacking is going to disrupt that cycle and interrupt exercise and sleep. We then have one-on-one discussions, trying to find which areas are the easiest to work on and build better habits.

Do these lifestyle changes help?

It’s a preliminary result, but yes, they work. I need to replicate this work in a larger, multi-center clinical trial, which requires a lot of funding. And I need to show more biological evidence – changes in genes, proteomics, and melatonin – to support positive patient-reported outcomes.

How do patients react when you suggest these treatment options?

The type of patients I recommend for my circadian rhythm research have experienced migraine for decades; the median is 12 years of almost daily migraine. They’ll tell you that they have tried everything in terms of medication and they really want to see if there are non-drug options out there for them. When you start those conversations, you’ll find that there are areas that really need huge improvement.

With these types of patients, we try to build coping skills. Learning to cope is more effective than avoiding triggers, whether it’s light or movement. Lifestyle changes are not a magic pill that works on day one. It’s not an acute intervention, like a triptan. It’s an intervention that works through time. But once it starts to work, you can predict or control your migraine attacks.

You also work on exercise and migraine. Tell me about that.

I did a study comparing the impact of strength training intensity to cardio and daily medications like amitriptyline on migraine burden. Strength training performance outperformed all of them in reducing migraine burden. There’s something about the muscles that secretes these myokines and exerkines that can reach the trigeminal ganglion and even cross into the brain to modulate migraine pain. Another group from Portugal had a similar study showing that exercise can reduce migraine frequency.

My protocol involves a strong component of muscle conditioning – mostly of the upper body and the posterior chain muscles. Slowly strengthening the upper shoulders and neck muscles three days per week at the minimum – that’s the protocol – really helps in terms of migraine improvement.

What do you most want people to know about circadian rhythms and migraine?

The most important thing is that circadian rhythms are a  strong factor in migraine. Physicians will tell you that the patient is doing everything right in terms of sleep. But the circadian rhythm is not just sleep – don’t just ask about sleep and stop there. There are other areas that I talked about that are highly interrelated in improving sleep, like when you eat, timed light exposure, and timed exercise.

Once you know what’s interrupting your patient’s circadian rhythms, then you can start to intervene at the easiest point. It’s about giving patients a self-management protocol and giving them control.

And no matter which drug you take, if your circadian health is poor, you are not going to stop migraine; this is very clear. Drugs are no substitute for a healthy lifestyle. Patients on a migraine drug should not use it as an excuse to disrupt their sleep or skip exercise. At the end of the day, circadian health is key, and not only for migraine. So we can use the circadian rhythm as a one-stop shop intervention for different health conditions.

Freda Kreier is a science journalist based in Corvallis, Oregon.

Image credit: ID 378877427 | Circadian Clock © Ihor Lukianenko | Dreamstime.com