People Who Have Never Had a Headache: What Explains It? A Conversation with Isa Amalie Olofsson and Thomas Folkmann Hansen

“The biggest criticism we get about our work is that being free from headache could be explained by memory failure – that this should be a phenotype of people who have a bad memory and just don’t remember ever having a headache. And yes, there’s probably a small proportion of people who can’t remember having a headache, but I have a hard time believing it’s just memory. There must be something more to it than that.” –Thomas Folkmann Hansen

Isa Amalie Olofsson, MD, PhD, and Thomas Folkmann Hansen, PhD, from the Danish Headache Center at Copenhagen University Hospital in Denmark, are taking a unique approach to headache research: Focusing on people who report they have never experienced a headache – even when they are sick, stressed, or hungover.

In this Migraine Science Collaborative interview, Olofsson and Hansen chat with Lincoln Tracy, PhD, a researcher and writer from Melbourne, Australia, about how they started this line of research, what they have learned about individuals who are headache free, and more. The interview has been edited for clarity and length.

How did the idea of researching people who report being completely free from headache first come about?

Hansen: I came into headache research from psychiatry, and one of the things that fascinates me about this field is the continuum of headache. At one end, you can have a very severe headache that is inherited and monogenic [involving a single gene], and then it slides down to something that’s less severe but still devastating for people who have it. You can slide even further down into a tension-type headache, which most people have experienced, and then there’s anecdotal evidence about people who have never had a headache before, meaning they don’t know what a headache is.

When Isa started her PhD with our research group, we were curious to look at the clinically relevant headache-free phenotype within a broader population to see how many people claim to be free from headache, and whether this is actually true.

Olofsson: Other researchers at the Danish Headache Center had previously looked at headache frequency at a population level, and about 4% of people had claimed they’d never experienced a headache before. This really helped us to start asking questions at the beginning of my PhD.

How can looking at people who are free from headache enhance our understanding of people at the other end of the spectrum who experience severe headache and migraine?

Olofsson: This is something we have a lot of discussions about with our group – asking whether there is something special about these people that protects them against headache or whether they are just people who are free from headache risk factors, as there are potentially many environmental risk factors that we don’t really know a lot about. That was one of the reasons we did our recent genetic study, which identified a locus in a gene called ADARB2 that was associated specifically with complete freedom from headache and not with any primary headache disorders, to see if there is anything special about headache-free people or whether they lack all the genes known to contribute to migraine risk.

Thomas Folkmann Hansen

Isa Amalie Olofsson

You initially started this research in a cohort of blood donors. Why did you choose this particular population?

Olofsson: Thomas had already worked with the Danish Blood Donor Study and shown that blood donors experience headache at a similar rate to the rest of the population. So it was an accessible population that allowed us to send the initial survey to a large number of people. But it also made sense to recruit this phenotype as blood donors are known to be quite healthy.

Hansen: Exactly. Blood donors in Denmark are volunteers, so it turns out they are relatively representative of the broader population, with the exception of people from the very high and very low end of the socioeconomic spectrum. This approach would usually cause problems with the healthy donor effect [blood donors are often healthier than the general population because of the criteria they must meet in order to donate blood], but in our case, it was an advantage, as we wanted to recruit healthy individuals without over-selecting super-healthy people who may be more resilient to headache.

What have you learned from the four papers you’ve published on this topic? Is there any evidence to support the idea that people who are free from headache  have certain protective mechanisms or do not have risk factors?

Olofsson: Most of the studies have shown there’s no specific lifestyle factors that contribute to being free from headache. Initially, we thought people who were free from headache were simply super healthy, but the population-based study didn’t show any major difference in sociodemographic characteristics.

We then found that people who were free from headache reported similar pain sensitivity to people who had experienced headache, so there didn’t seem to be anything there, either. And then, when we used nitric oxide to induce headaches, they developed headaches at the same rate as the controls.

Together, these studies show that people who are headache free have the ability to get a headache, and support the hypothesis that there is a threshold you need to cross in order to experience a headache.

Hansen: But it’s important to remember that Isa started out with a completely open field, as there had been little to no research in this space prior to these studies. Even though the studies didn’t identify a whole lot of major differences, it’s okay, because we can start excluding a lot of things. That helps us narrow down to identifying the headache-free phenotype.

So what does, in fact, contribute to the headache-free phenotype, given the results you’ve had so far?

Olofsson: There are probably several subgroups of people along the spectrum Thomas described earlier. I think there are some people who have been lucky and haven’t experienced enough migraine or headache triggers, and maybe also have some genetic factors that make them less vulnerable. And I hope this is the case, because it would be really cool if that turned out to be true.

Hansen: Another hypothesis relates to the arterial vasodilation that is associated with headache. Imagine that while everyone gets this vasodilation, there’s something different about the nerve fibers around the arteries in people who get headaches versus people who are free from headache. I think this is a possibility, because people who are headache free can describe experiencing some kind of pressure that could be, but isn’t, a headache. This would be an interesting hypothesis to follow, and there’s a reasonable amount of evidence to support testing it.

Do you have plans to continue this line of research?

Hansen: We’ve been quite inspired by this work, so if we can get more funding, we’re definitely keen to continue working in this space. Isa and I are exploring two different directions. I’m keen to investigate potential sex differences in those who are headache free. A lot of our work to date has been done in men, so we need to address this in women, too, and that is why we are now investigating menstrual migraine, and how headache and migraine experiences vary throughout the menstrual cycle, as this is something else we don’t really know about. These will be completely different studies, as they have to run for at least 30 days.

Olofsson: And then I’m curious to explore why we get headaches in the first place, and why some specific groups of people experience headaches and others don’t – such as when one monozygotic twin is diagnosed with a headache disorder, but the other isn’t. We also have gene expression data we collected during the pain sensitivity and headache induction studies that we’ve yet to analyze.

What role, if any, could hormones play in the headache-free phenotype?

Hansen: This is one of our key research questions at the moment, and I know there are other people who are also looking into the association between hormones and migraine. I believe hormones do play a part here.

Some of our colleagues from the Danish Headache Center just published a paper on cluster headache – the only headache disorder to affect more men than women – which showed there is a shift in steroid hormone levels in people with cluster headache. So there’s definitely something going on, and I feel a similar thing happens in menstrual migraine, and in women whose migraines disappear during pregnancy but come right back after they give birth. There’s a blinking neon sign pointing towards hormones, but it’s not as simple as saying estrogen goes up or down like what was hypothesized 50-odd years ago.

How have other researchers and clinicians reacted to your approach of looking at people who are free from headache, rather than focusing on people at the other end of the spectrum?

Olofsson: The response has been great, despite the lack of positive results we’ve published. When we present on the project, there’s always a mix of people who are really curious about it and feel it’s a fun or interesting way to approach studying headache. But there are also people who don’t believe there’s anything substantial to what we’re looking at.

Hansen: The biggest criticism we get about our work is that being free from headache could be explained by memory failure – that this should be a phenotype of people who have a bad memory and just don’t remember ever having a headache. And yes, there’s probably a small proportion of people who can’t remember having a headache, but I have a hard time believing it’s just memory. There must be something more to it than that.

Olofsson: I agree with that point. As a clinician, when people tell me they’ve never experienced a headache, I believe them just as much as I believe a patient who tells me about their severe headaches. There’s no reason for me to think one is forgetting something and the other is not.

Is there anything else you would like to say about this line of research?

Olofsson: I think our most recent article shows there is something genetic going on in this population. I would like to see someone replicate this finding, and to be able to understand what the ADARB2 gene does inside the brain, and whether it is important in headache development. This leads to a pretty obvious next step in doing cell-based studies and exploring potential changes in the genes and neurons.

Lincoln Tracy, PhD, is a researcher and freelance writer based in Melbourne, Australia. Follow him on X (formerly Twitter) @lincolntracy. 

Image credit: 123RF Stock Photo.

References
Compensated hypogonadism identified in males with cluster headache: A prospective case-controlled study.
Petersen et al.
Ann Neurol. 2024 June;95(6):1149-61.

Genome-wide association study reveals a locus in ADARB2 for complete freedom from headache in Danish Blood Donors.
Olofsson et al.
Commun Biol. 2024 May 27;7(1):646.

Headache provocation by nitric oxide in men who have never experienced a headache.
Olofsson et al.
Cephalalgia. 2022 Jun;42(7):598-607.

Pain sensitivity in men who have never experienced a headache: an observer blinded case control study.
Olofsson et al.
J Headache Pain. 2021 Nov 8;22(1):134.

Prevalence and socio-demographic characteristics of persons who have never had a headache among healthy voluntary blood donors – a population-based study.
Olofsson et al.
Cephalalgia. 2020 Sep;40(10):1055-62.