Understanding the Pathophysiology of Headache Disorders: An Interview with Philip Holland

“It’s a very exciting time for headache research. We’ve had a very exciting time recently in terms of the development of new therapies that have made it to the clinic. I think that, equally, we can be hopeful for what’s coming in the future. Headache research and management are in good hands. We’re in a place where we still have potential to make a great difference. We should keep working hard and keep doing that.” – Philip Holland

Philip Holland, PhD, is Reader in Neuroscience, and principal investigator of the Headache Group at King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Wolfson Sensory Pain and Regeneration Centre (SPaRC). He also recently became president-elect of the European Headache Federation (EHF) – he will be just the second basic scientist to become president of EHF. He also serves as a Migraine Science Collaborative editorial board member.

Dr. Holland’s research focuses on the underpinning biology of headaches, and his group works closely with clinical colleagues to enable a full translational program of research at King’s College London. For this MSC interview, he spoke over Zoom with Neil Andrews, a science journalist and the executive editor of MSC, to discuss his path to the migraine field, some of the projects he’s working on now, and his interests outside of science. What follows is an edited transcript of their conversation.

How did you get into the migraine field?

I actually wanted to be a vet at first. I was really interested in agriculture and grew up in a farming community in the countryside. I then found a passion for neuroscience and became interested in how the brain works, and how, at that point, we knew little about it – there was so much more to discover. So my undergraduate degree in Glasgow was in neuroscience.

When I finished that degree, I looked for PhD opportunities, and I came across an advert from Professor Peter Goadsby, who was advertising for a PhD project down in London. I applied and flew to London for an interview at the Institute of Neurology, which was part of University College London; it was my first time ever in London, coming from the countryside. I’m glad to say that they must have liked something about me because I was offered the position. I eventually moved to UCSF in San Francisco for postdoctoral work.

At that time, as a scientist, it was quite difficult to maintain a career in headache. So when I moved back to the UK, I actually stepped away from headache for a period of time and was very interested in neurovascular coupling – how blood vessels and nerves work together within the brain. I took up a role looking at Alzheimer’s disease and vascular dementia at the University of Edinburgh. I was there for about five years.

Then, an opportunity arose to move to King’s College London, where I am now, to start a preclinical headache laboratory; I’d always kept an interest in headache and had projects running in the background. I jumped at the chance and moved to London again, where I developed the laboratory that I lead now, looking at the underpinning mechanisms of migraine and other headache disorders. I work very closely with clinical colleagues, including Professor Goadsby, who is here at King’s and leads a translational human research program.

Philip Holland

Tell me more about your lab: What are the goals and what are the specific questions you are addressing now?

I’ve got a great team of people in the lab, and they’re all interested in slightly different areas of migraine and cluster headache. But a lot of our research now focuses on understanding the underpinning biology of headache disorders.

For example, in the context of migraine, we’ve been very interested in the rhythmic expression of attacks: Why do patients get attacks at certain times of the day or certain times of the year? We’ve been investigating how our own internal biological clocks, the circadian rhythms that regulate our behavioral patterns, influence attack onset. We’ve shown that attacks are much more likely to occur in the early morning, and we want to understand what’s causing this internal variation in attack susceptibility, to see if we could harness that as a potential new way to treat migraine.

More recently, we’ve become very interested in the premonitory symptoms of migraine. Many patients with migraine report, up to a couple of days before the onset of the headache, symptoms like fatigue, irritability, or a stiff neck, many of which are very bothersome and disabling for individuals with migraine. We’re trying to understand the biology of these early symptoms of the attack that happen before the pain. It would be great if we could figure out how to stop the attack from happening or from progressing to the headache pain condition by treating symptoms during the premonitory phase.

Tell me more about the circadian rhythm research.

The circadian project is a really interesting one because it’s been a combination of preclinical research and clinical research – looking at patients and what they report. For example, we worked collaboratively with the Migraine Buddy app and were able to access data from over 1.5 million patients and ask when they reported their migraine attacks. That showed that the attacks were happening very early in the morning.

That’s led us to the idea that perhaps we should be thinking about chronotherapy in migraine – treating patients at particular times. If patients are more likely to have their attacks early in the morning, then we need to think about a therapeutic window to maximize a treatment effect at that time, rather than later in the day or when the attack has already happened. We’ve been doing some work in this area and have some interesting results suggesting that late-evening dosing with the new gepant drugs may be a very beneficial way to increase their efficacy.

This has also made us look at the side effect profiles of these drugs. For example, some drugs might cause sleepiness, and so taking them in the evening before bedtime may be an advantage for the patient. Quite interestingly, one of the outcomes from this and some meta-analysis work we did around sleep and migraine was that we found it wasn’t sleeping too much or sleeping too little that predisposed individuals to having an attack. Instead, it appears that it’s more a change in your regular sleep pattern that has a major impact on the likelihood of having an attack.

We always say that the migraine brain likes you to be boring, that it likes routines, and so this work really speaks to that. It’s a piece of biological evidence that tells us that if you disrupt those routines, in this case, by changing your regular sleep pattern, it could lead to problems. So, for example, if you’re up early working Monday to Friday, you should really try to get up at the same time on the weekends so that you don’t increase your susceptibility of having weekend attacks. So keeping consistent sleep patterns can have a major influence on people’s attacks.

Let’s switch gears and look at the migraine field a bit more broadly. How would you characterize the current state of knowledge about the pathophysiological mechanisms of migraine? Do we mostly know what’s going on? Do we partly know? Do we only dimly know?

I think we can safely say that we now have a very good handle on migraine pain and headache; we understand the pathophysiology of that, and we’ve had success in developing drugs that can target the pain.

But what we’re starting to understand now is that migraine is much more than a pain condition, and we are less certain about the non-pain symptoms. For example, what’s the role of the premonitory symptoms that we are working on? How are these features associated with migraine – is it cause or effect? That’s the area that I think has the most potential for developing our understanding of migraine pathophysiology.

Are there particular research approaches, such as genetics or neuroimaging, that look particularly promising to you?

I think genetics, certainly in the past, held significant promise. The migraine field is actually way ahead of many other areas in terms of genetic research, the trials and the genome-wide association data we’ve generated. However, ultimately, when you ask the question if it has led to translation in terms of new therapies and targets, at the moment the answer is not really, or not convincingly.

Neuroimaging is certainly exciting. It’s exciting from my perspective because it’s a translational tool where we can understand changes in the human brain and reverse translate that to the bench to look at what the mechanisms are behind those changes, so that we then have a better understanding of what’s going on in the human brain. That’s really one of the most promising areas that we have in migraine.

I think there is a strong place for human models as well. We’re in a situation now where we’re getting much more access to brain organoids and human tissue from migraine patients. That, in itself, will enhance our research going forward as this area grows.

If I ask you to look towards the future, what do you think the understanding of the pathophysiological mechanisms of migraine will look like, say, 10 years from now? Where do you think we’ll be?

Earlier I mentioned the non-pain symptoms of migraine, and I think we’ll start to understand more about the biology of the disease by focusing on those symptoms.

It would also be wonderful to be in a position in 10 years’ time where, based on the biological phenotypes or the individual symptoms of a patient, we could perhaps look at personalized approaches. So based on, say, a chronotype, which I mentioned earlier, or a select array of features and symptoms that a patient shows, we could start to predict which therapies are more likely to work or not work in each individual.

That’s certainly where I would like to see us in 10 years, because then we would be able to broaden access to therapies. At the moment, we simply don’t know which patients the drugs will work for and which ones the drugs won’t work for. If we could predict that, we would be able to open up access to those people who are most likely to benefit from a drug and have relief.

Is personalized medicine actually a realistic goal a decade from now? Because people have been talking about personalized medicine for a long time but we’re still not there yet.

With advances in AI and big data, we’re in a position now where we can take advantage of those data sets to start to look at predictors of drug response. It’s very early stages, and so maybe 10 years is too soon to really have a conclusive impact. But I would like to think that in 10 years, we’ll be much closer towards understanding this.

Earlier you mentioned working with clinical colleagues and translational research. What is it like to work with clinical colleagues? Is it a challenge? What makes for a successful collaboration?

I think successful collaboration always comes down to joint interest and having a passion to move understanding of the disease forward. I’m very lucky in that a lot of my work is with Professor Goadsby, who everyone knows in the field and who was integral in developing the new CGRP-targeted therapies. There are a lot of things in clinical studies that are different from what we do in the laboratory, so these collaborations are not easy to do. But if you have the right team of people around you, and the drive to answer those questions and fundamentally improve how we understand headache mechanisms, these collaborations can be really rewarding.

But we should also include patients. For example, I work very closely in the UK with the Migraine Trust, a leading patient organization. I think this is an area where we’ve still got a way to go but, more and more, we’re incorporating the perspective of people living with migraine. Many of the large funders here, like the Wellcome Trust and the European Research Council, expect that you have patient engagement and involvement in your research.

Let’s help readers to get to know you a little bit more on a personal level. When you’re not doing science, what are you doing? Any interesting hobbies? How are you spending your free time?

If you ask anyone in the headache field who knows me, they’ll tell you that I’m out running somewhere. It doesn’t matter whether I’m here at home or going to a meeting –you’ll always find me with my trainers in my suitcase and out early in the morning getting a few miles in. I really think keeping fit and healthy, and having that as a release sometimes – your own space away from work, away from everything else where you can either think or not think, depending on what you need – is really helpful. Beyond running, a lot of my time is taken up with my teenage son, helping his athletics and his football club. So family and running are my two key things outside of science.

Are you a long-distance runner?

Yes. The longer and the muddier, the better.

Do you do races?

I do races now and again. Certainly there’s a couple of races each year I do without fail because they’re really part of the calendar that I like to take part in. It’s not just the race itself, but also the environment that surrounds the race. We go as a club and enjoy a weekend away. And I get time to relax and enjoy the beautiful scenery, for example, down on the Devon coast in the southwest of England. But I prefer running to racing. I like to just zone out and think about the run, and the mud, and the trees. That’s why I love trail running or fell running, as we would call it in the UK. So the muddier, the hillier, the more countryside, the better.

Here’s another one: If you could have dinner with a scientist, living or dead, is there a particular scientist that you would invite who you would most like to have a discussion with? This could be someone in the migraine field or outside of it.

I was privileged when I entered the migraine field that I got to speak to a number of amazing scientists and people who have recently retired, like Professor Jes Olesen, who I really hold as an exemplar in the migraine field – an amazing man and a wonderful mind. I really enjoyed discussions with him. As I mentioned, I’ve worked very closely with Professor Goadsby and others. But I’m quite interested in physics, so I would have liked to sit down with Stephen Hawking and have a discussion – we might as well have a theory of migraine as well as his theory of everything.

Is there anything else you might like to mention that I haven’t asked you about, or that you might like to reiterate?

It’s a very exciting time for headache research. We’ve had a very exciting time recently in terms of the development of new therapies that have made it to the clinic. I think that, equally, we can be hopeful for what’s coming in the future. Headache research and management are in good hands. We’re in a place where we still have potential to make a great difference. We should keep working hard and keep doing that.

Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative.

Image credit: ID 119821073 | Brain © Anton Chervov | Dreamstime.com