New Study Links Headache Pain to Circadian Rhythms
A recent study published in Headache: The Journal of Head and Face Pain, titled Regulation of Headache Response and Transcriptomic Network by the Trigeminal Ganglion Clock, explores a question many headache specialists and patients have long wondered: why do some headaches strike at the same time each day? The study was awarded the 2025 Basic Science Prize, given to the top three basic science articles published in Headache® in the past year.
As first-place recipients, Dr. Seung-Hee Yoo and Dr. Mark J. Burish will present their findings at the 67th Annual Scientific Meeting in Minneapolis on Thursday, June 19, 2025, at 4 p.m. Their lecture will also be available for AHS members via Education On Demand beginning June 30.
Co-authored by Dr. Mark Burish, Dr. Seung-Hee Yoo, and colleagues, the study provides compelling evidence that the trigeminal ganglion, the primary sensory relay for headache pain, operates on a circadian cycle. This discovery could mark a significant step toward personalized headache treatment based on the time of day.
Dr. Burish explains, "There's a series of genes that turn each other on and off over 24 hours, but they then signal other genes to turn up and down over 24 hours." As he and Dr. Seung-Hee Yoo worked to understand this innate system, they focused on how the circadian rhythm regulates pain responses, particularly in headache disorders. Dr. Seung-Hee Yoo elaborates, "Circadian rhythm is basically your endogenous clock, a built-in clock that tells your body what to do at what time point to maximize your efficiency of physiology." This discovery highlights how these circadian cycles are crucial in headache pain and timing.
Watch the whole discussion with Dr. Seung-Hee Yoo and Dr. Mark Burish:
Headache: The Journal of Head and Face Pain is the official publication of the American Headache Society and serves as a leading source for clinical and basic research in headache medicine. The journal regularly publishes studies that advance our understanding of headache disorders' pathophysiology, diagnosis, and treatment.
In this study, researchers investigated the circadian characteristics of the trigeminal ganglion in a mouse model. Using ex vivo and single-cell cultures, immunohistochemistry, and RNA sequencing, which were measured every 4 hours, they identified vigorous circadian activity in the ganglion. Importantly, mice treated with nitroglycerin to simulate headache pain also showed circadian pain responses — responses that disappeared in genetically arrhythmic mice.
They found that 466 genes in the control group displayed natural circadian rhythms, including core clock genes and pain-related neurotransmitters. However, the nitroglycerin-treated group experienced significant circadian reprogramming, as 331 rhythmic genes lost their pattern, while 584 new genes gained a circadian rhythm.
Pharmacogenomic analysis further revealed that 10 circadian-regulated genes encode proteins targeted by existing treatments for migraine, cluster headache, and trigeminal neuralgia. This opens up the possibility of time-based or "chronotherapeutic" approaches to maximize treatment efficacy.
This study's findings validate what many clinicians have heard from their patients for years: headache attacks can have predictable timing. Biological evidence supports these clinical observations, positioning researchers and practitioners to explore time-of-day treatment strategies more effectively.
The next step is to study how these circadian mechanisms function in humans and whether adjusting medication timing can significantly improve outcomes. As Dr. Burish notes, this research provides a clear direction for what comes next, including developing animal models specifically designed to study circadian headache patterns.
This research represents an exciting advancement in the field of headache medicine. By linking the molecular clock within the trigeminal ganglion to patterns of headache pain, Dr. Mark Burish, Dr. Seung-Hee Yoo, and their team have laid the groundwork for future time-based therapeutic strategies. Their work underscored the significance of incorporating circadian biology into research and clinical care and suggests a future where treatment timing may be as crucial as the treatment itself.
“We are very excited to start this. We have been working together for many years, but we really feel we now have a really great grip on correcting more mechanisms of circadian regulation of headache pain.”
Read the Interview Transcript
Dr. Rashmi Halker Singh
My name is Rashmi Halker Singh. I'm the deputy editor of Headache. It's my pleasure to be joined by two of the recipients of this year's Basic Science Award, Dr. Mark Burish and Dr. Seung-Hee Yoo. They're two of the authors of a recent publication entitled Regulation of Headache Response and Trans Transcriptomic Network by the Trigeminal Ganglion Clock. Welcome to you both. Congratulations on this award as well.
Dr. Seung-Hee Yoo
Thank you.
Dr. Mark Burish
Thank you. We're honored.
Dr. Rashmi Halker Singh
First of all, can you tell me about your paper? Tell me what you did and what prompted you to do this work?
Dr. Mark Burish
So this started just because we've noticed that a few different headache syndromes seem to have a daily rhythm to it — cluster headache, the most well known, but there's some features to migraine and even trigeminal neuralgia. So we were wondering if that had a molecular correlate, a behavioral correlate. There's something that was timing the pain. So, I do a lot of cluster research, Dr. Seung-Hee Yoo does a lot of circadian biology research, and so we combined forces and also worked with a few other people, Amina Pradhan, who does a lot of headache research, and a couple other people who do more transcriptomics.
And so we put this together to try to figure out if the trigeminal ganglion had a circadian rhythm to it. And we found that it did.
Dr. Rashmi Halker Singh
So I think that's really fascinating. It goes along with what we see in clinical practice as well. Our patients are commonly telling us about the timing of their attacks from cluster and also with migraine.
So, share with me what you found from your work. What were the results of your research?
Dr. Seung-Hee Yoo
So I'm a circadian biologist and I studied circadian rhythm my entire career. And circadian rhythm is basically your endogenous clock — a built in clock that you have — to tell your body what to do in what time point to maximize your efficiency of physiology. Because we are all living in the Earth’s 24 hour cycle of day and night.
So our system evolved to adjust our physiology to it. So when we eat, we are ready to digest, when we sleep, our muscles and everybody don't produce energy because we don't need it. So this system is innate. And our curiosity was how this innate clock system is regulating the pain response because various types of pain have circadian rhythm. And me and Mark’s work was really attacking how circadian rhythm is regulating headache pain.
So we decided to look for the headache center trigeminal ganglion and looking [at if the] trigeminal ganglion has innate circadian clock, and if it has circadian clock, how it regulates the pain response. In terms of mouse genetics, molecular and pharmacogenetics, we really dig the mechanism of how circadian clock is regulating pain response. And also in terms of translational direction, we wanted to see that, how all this knowledge can actually help the patient, that when is the best time for taking this specific drug? Because this drug target expresses certain time of the day, peak time.
Dr. Rashmi Halker Singh
So all of that is very fascinating.
And before you share with me, you know, clinical correlations about these things, I think one thing I want to add is this also gives a lot of validity to what our patients are telling us. Right. Because our patients share that they have this time correlation with their attacks, whether it be migraine or whether it be cluster. And now we have some biological basis for that. And I think that really helps to strengthen what their clinical experience is.
So that's really, really fascinating. You shared in your paper and what you just shared right now about, you know, maybe we can take some of these findings and apply this to clinical practice and maybe give our patients some recommendations about, about timing of medications or other things. Can you share some of that with us right now, too?
Dr. Mark Burish
Sure. So in internal medicine, they do this all the time. They give blood pressure medications at certain times of day because blood pressure spikes at different times. So we're trying to bring this over more from a headache side of things. So like Seung-Hee was talking about, there's a series of genes that turn each other on and off over 24 hours, but they then signal other genes to turn up and down over 24 hours. So they are the central clock or the main clock, and then they turn other genes up and down.
So we looked at all the genes that are cycling either in a normal mouse or in the headache mouse. This is from Amina Pradhan's nitroglycerin model. And as you know, if you inject nitroglycerin into a migraine patient, they get migraine, clustering patient, they get cluster. It's a very good human model. But the idea here is if there's a gene there that's cycling, is there a drug that targets the gene? And so we took basically the Venn diagram here between all of the circadian cycling genes and then all of the medications that are guideline approved for cluster headache, migraine or trigeminal neuralgia.
And we found there were about 10 drugs that do target genes that cycle over 24 hours. So this is kind of an initial idea of maybe could we start to study the best time to take these medicines.
Dr. Rashmi Halker Singh
I think that's really fascinating work and sets us up for additional research in this area as well. Do you have any additional thoughts you want to share with our viewers?
Dr. Seung-Hee Yoo
I'm very excited to start this. We have been working together for many years, but we really feel like we now have a really great grip to correct more mechanisms of circadian regulation of headache pain. And we are very excited to do more to understand how we can actually apply this basic knowledge to patient treatment.
Dr. Mark Burish
Yeah, I think like Seung-Hee said, this has given us a very clear direction in what we do next. From an animal side, we've started to create an animal model of circadian headache, and so we're excited for what comes next.
Dr. Rashmi Halker Singh
That's really fascinating. Thank you so much for all the research you're doing.
This was really advancing the science of headache medicine and we really, really appreciate you both and your colleagues.
Dr. Mark Burish
Thank you very much for having us on and again, we're honored to receive this.
Dr. Seung-Hee Yoo
Thank you.