A National Migraine Centre Heads Up Podcast transcript
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Transcript
00:00:00 Welcome to the Heads up podcast, brought to you by the National Migraine Centre, the only UK charity treating headache and migraine. Visit our website to book your appointment with a world-class headache doctor, wherever you are in the UK. There is no need for a referral. You can refer yourself. Our headache specialist doctors are looking forward to helping you soon.
00:00:34 Dr Katy Munro
Welcome everybody to this episode of our Heads Up podcast and this one is a very interesting topic about what’s happening in the brain and what we understand about the science of migraine. It’s something that people do ask me in consultations quite often, and I was at a conference recently where my guest today explained migraine pathophysiology in such a clear way that I’ve invited him to join us.
So, welcome to Doctor Phil Holland, who’s a reader in neuroscience at the Wolfson Sensory, Pain and Regeneration Centre at King’s College London and Phil has done lots of research about migraine and runs a team there. So thank you very much, Phil, for joining me and do you want to just introduce yourself a bit more and tell us about your role and your team?
00:01:31 Dr Phil Holland
Hi Katy and thank you very much for getting me on the Heads Up podcast. I’m going to start by saying I’ve listened to many of your podcasts and it’s an excellent resource. So, people should definitely look back on the library, all of that.
I lead a largely preclinical team, but I do work with clinical neurologists. For example, Professor Peter Goadsby at King’s College London. So we have a translational research programme and my number one interest is, as you said, is what are the mechanisms underlying migraine because we believe that really by only in understanding those mechanisms can we get new targeted treatments. You know probably from listening to these podcasts that a lot of the historical treatments for migraine are adopted from different conditions and that can come with a variety of problems. So really we are trying to do really uncover new targeted therapies and mechanisms that happen in patients and we reverse translate those mechanisms to the bench in the laboratory so that we can understand what’s happening and then hopefully identify new targets that we can go back to the patients. It’s sort of a bench to bedside approach as we like to call it in the translational field. I have a wonderful team of researchers actually and I’m going to take this moment to give a shout out to the Migraine Trust because they fund a couple of my team at the moment and really excellent work they’re doing to fund migraine research.
So I’ve an excellent team of researchers, so young academics who want to build a career in migraine and headache research. And that’s really an important thing, I think, that we sort of train and retain the best people for migraine research and headache research more widely. We have a number of PhD students. So these are the youngest academics who have just graduated from university and are now undertaking a four-year training programme where they’re looking at migraine and headache in detail. Incidentally, I did my PhD with Professor Peter Goadsby, back at University College London. Some time ago, I think 2001, I started that back in UCL, so it’s been a few years of working in the field and then really one of the other things I do because it struck me when I was at university — I went to university in Glasgow as the accent may tell some of you — that actually, I never learned a single thing about migraine or headache. It’s one of the most common neurological conditions, and I studied neuroscience, so the science of the brain. And I never heard the single lecture about headaches or migraine or cluster headache or any of these conditions. So one of the main things we do at King’s now and more generally through for example, this podcast and the British Association for the Study of Headache is that we actually look at migraine and headache education. So teaching the medics at King’s, the physiotherapy students, the pharmacy students and even the neuroscience students and the master students about actually the importance of headaches so that when they go out into the real world, some of whom are going to be clinicians in the future, they really understand from an early point the importance of this disorder.
00:04:35 Dr Katy Munro
I think that’s a really excellent point to be making right at the beginning of this episode because so many times people say to me, oh, you know, is there any research going on and we are aware that education is such a priority throughout the whole of society, I think. Certainly as a GP in training, I didn’t get taught very much about headache and migraine at all. So again, at the National Migraine Centre one of our main goals is to try and raise awareness of the importance of understanding headache and migraine. So I think people will be delighted to hear that there’s been lots of research going on, there’s still lots of research going on.
00:05:15 Dr Phil Holland
Yeah, I think it’s really something that we should be striving to have on the curriculum, certainly for most medical schools because you know, it is one of the most common neurological conditions out there. So if you’re going to be thinking about neurology as a specialist, you’re going to be seeing a lot of these patients. So definitely should be higher up on the agenda than it is and I think, you probably agree with me here, Katy, that that’s probably a wider problem for migraine and headache that we need to have a bigger voice both in policy and finance and funding for research. So that’s something that we’re really vocal about actually.
00:05:48 Dr Katy Munro
Yeah, I think the stigma is real still, isn’t it? And recently at a conference in Barcelona, we had a presentation from one of the European Migraine and Headache Association leaders who’s done a whole study on stigma and a big survey about it and how real that still is. And I think we’re fighting against that as well, aren’t we? It’s not just a headache. It’s much more complicated. I’m just looking at some figures in front of me from your slides. The lifetime prevalence of headache is 90%, so that’s pretty much everybody is going to know what a headache means. But migraine is about 18%.
00:06:32 Dr Phil Holland
Yes, I mean, it obviously — So I’ll just start by saying that there’s a previous wonderful podcast on migraine hormones in women. So you should definitely go back and listen to that if you haven’t done so. But well, the prevalence is about 18%, the prevalence of women is much higher than men. So before puberty, before the onset of puberty, the prevalence is quite similar. But with the onset of obviously the cyclic hormonal changes happening after puberty, it becomes three to four times more common in women than men, and of course then that reduces after the menopause. But obviously again, there’s another podcast on menopause and migraine. So people who have listened to that will know that things get a little bit worse during that phase, or can get worse during that phase before sometimes they settle down later so. So really striking predominantly women, through some of the most productive years of their life, actually, and it’s a major concern. It’s probably no surprise that in my research group, I think, including myself, we only have two men and the majority of the research team are females who are doing this research and are really passionately interested in making new discoveries for this condition.
00:07:46 Dr Katy Munro
So that certainly backs up what I see in clinic, you know the large majority of our patients are female, but of course we also do see some children as well. And I think recognising migraine in children is one of the things I feel quite passionately about. So I’m always asking people, you know, do you have a family history? And also do you have any signs of migraine in your children, any of your descendants showing any signs? Because I think the prevalence is there’s some variability in the figures I read but anything between 7 and 10% of children will experience headache and migraine.
00:08:25 Dr Phil Holland
Yeah. So definitely migraine 100% has a genetic component which I know for example, we might talk about later on some of the things we do in the laboratory or for example, the clinical team we do in the laboratory is that some of you wonderful patients will volunteer to come into a facility and we’ll actually try to trigger a migraine in you by giving you some different triggers that we know work in in migraine patients but don’t work in what we would call healthy controls. So those people who are not susceptible and one of the first things we do with those patients is you screen them for first degree relatives having migraine and that of course is one, so it’s that link between the family. I’m probably one of the unique people here actually because I have a twin sister who gets migraine with aura. But I’ve actually really never suffered a headache in my life actually. And it’s really amazing for me. And I know it sounds strange to say it’s amazing, but some of my team do and I know some family and close people that do. And to see the suffering that that goes along with these attacks. We know it’s more than just a headache and it’s something that I see and I’m passionate about helping with that. But again, people sometimes get surprised when they realise that actually myself, I don’t ever get headaches.
00:09:44 Dr Katy Munro
I’m not wishing it on you. I am a sufferer, I get migraine without aura, but I don’t think it’s compulsory to be helping people with migraine and have migraine yourself, but it certainly does give–
00:09:57 Dr Phil Holland
Definitely not. But you do tend to find that most people in the field are interested because of, as you say, there’s a lack of education and through university and different things that most people come to it through personal interest. And that’s how they actually get into migraine research or clinical work.
00:10:13 Dr Katy Munro
So just before we start talking about the nitty gritty, I wanted to just maybe talk about a little bit of neuroanatomy in a very simple way. Because one of the things that we do as doctors very often as we throw out names of bits of the brain that we’re quite familiar with. So could you just go through some of the main structures or that outline the migraine pathway anatomy perhaps?
00:10:39 Dr Phil Holland
Yes. So you’ll often hear people talking about what we call the trigeminal vascular system. And that obviously sounds relatively complex and it is. But essentially if we think of that as if you think of the head and face and of course, you’ve got the sensory innervation of the face, so the nerves that carry that nociception as we call it, or the pain signal from the head. And of course some of those nerves also innervate the meninges, which are the layers surrounding the brain. The brain itself can’t feel pain. That’s one important thing to say. It’s these areas in meninges and different nerves around the brain that can sense pain signals, and that information then is relayed into your spinal cord. Really the upper spinal cord of the cervical level. And you’ll often hear people talk about the trigeminal cervical complex. And on the way, those nerves go through a structure called the trigeminal ganglion and this is where the sort of cell bodies, the control centres of those nerves live that relay that information.
And that’s really the first point at which the peripheral sensory information goes into your brain or your central nervous system, and from there we have what we call the ascending pathway and that’s where now the signals coming from the periphery are sent to the higher order structure. So deep in your brain areas like the thalamus, this really important control sensor for sensory integration, but also really important in sleep and sleep-wake states. And again, we might talk about some roles of sleep in migraine briefly and then that information is relayed on to the cortex. So, this is the area at the top just underneath your skull. And that’s the area where a lot of the sensory integration goes.
As a researcher, it’s important for me to differentiate between what we call nociception and what you would call pain. So nociception is the physical ability to sense a noxious stimuli or a damaging stimuli and pain then is the conscious perception of that stimuli. So, for example, someone who has had in the past a negative experience or a negative emotional experience associated with pain may have a more painful response to the same level of a nociceptive stimuli. And again, we have to take those things into consideration when we’re thinking about mood, anxiety, and the crosstalk between migraine and different headaches.
00:13:00 Dr Phil Holland
So that’s kind of the ascending pathway. And then if we look at the other end, the brain itself has what we call top-down control. So, it can regulate those ascending pathways and we’re starting to look at areas now like the hypothalamus. The hypothalamus is a really interesting one. It’s a really deep nuclei in the brain involved in hormone release and the reproductive axis, but I like to think of it a little bit like the thermostat of the brain. It’s the part of the brain that balances, for example, your energy intake and output, your response to the light-dark cycle, so night and day, the environment and can change how you behave in response to those external stimuli.
And we know, as we’ll probably come to, that this area is dysregulated in migraine and then those areas going down through the brainstem then. So now into the sort of just above your spinal cord. These areas have a number of different nuclei like the locus coeruleus or the periaqueductal grey, which again can modulate pain processing, not just turning it down but can actually turn up or down pain signalling coming in from the periphery. So, it’s really interesting. Again, you could think of those as like dimmer switches where you could turn up or down the pain signalling in the brain. And we’re probably going to come to this, but we know in migraine that that regulation of these signals is abnormal in migraine patients.
00:14:22 Dr Katy Munro
We do hear that from patients very often, don’t we, and I guess that’s part of the reason why some people with episodic migraine that’s occurring on that sort of fewer than fifteen days in a month. Over time if things are irritating the brain, activating those pathways, we hear that things are getting worse and they may slip into chronic migraine, where they’re getting more and more attacks. And there’s a thing called wind-up, isn’t there, where those pathways become so easily triggered? And I’m very conscious of what you were saying about, you know, the brain controls our response to pain. And we are aware that even if there’s actual no physical damage, sometimes the brain will from previous experiences send us signals that say there’s pain there and that I’m quite fascinated in that. And I know there are some pain-reprocessing programmes out there for patients because pain, anxiety, depression, all of these things that it’s like, you know, there’s no sections of the brain that that’s the depression part, that’s the anxiety part, that’s the pain part. It’s all so interconnected as you’ve described so clearly, with this complex interaction of controls and influence.
00:15:45 Dr Phil Holland
I think it’s very clear from a number of different parts. So first of all, I think it’s clear that we can feel pain in the absence of an injury, as you say, even thinking things like phantom limb pain, where you can experience pain in a limb that’s no longer there because of some change in the nerve structure that’s innervating those areas or nerve damage. So that’s one thing, but of course we can then have a different response to pain. I mean migraine in itself and many of your readers will probably have heard the term allodynia. The point there is it’s an obnoxious response to a non-noxious stimuli, so the stimuli which would not normally be causing a pain response is now and how I try and describe that to my students actually because sometimes they struggle with the concept is to think about — you wouldn’t think about it just now, because I think it’s about -3 outside, but thinking about sunburn where you can actually get, you know, a sensitising stimuli to the skin in the form of sunburn. And now even sort of light touch to that area is perceived by your brain, as being noxious. Of course, it’s not noxious. It’s just a warning signal that there’s some tissue damage there. And therefore it’s a warning signal not to over-stimulate that area.
And if we look at, I suppose, migraine-related photophobia or light aversion as we would call it in the laboratory, actually you know the light bulb is not any brighter. Or there’s not any more lux or lumens coming off from that light source, but the migraine brain is perceiving that as being stronger because, again, these networks are dysregulated. And the way that light information is incorporated into those networks is kind of slightly abnormal compared to the normal condition and therefore it can exacerbate pain, but can in itself create quite an emotive and uncomfortable feeling through the autonomic nervous system in patients so really affecting not just the pain of migraine. As we said, it’s not just a headache. It’s much more than that where you can see this multi-sensory sensitivity.
00:17:48 Dr Katy Munro
Yeah, a few practical examples that patients have told me is and sometimes they say, oh, I can’t put my hair back in a ponytail because that just acts like tension on the hair when they have a migraine attack either coming or in the process can feel painful, whereas at other times they might be able to. And I had a lady the other day who said, oh, I can’t wear my glasses because when I have a migraine attack, it feels too heavy on my face. And there are things like that, obviously it’s not damaging to wear her glasses, but her brain is reacting in a negative way which is part of the allodynia.
00:18:25 Dr Phil Holland
Yeah, there were some wonderful studies done a number of years ago. It was a Belgian colleague, actually, called Professor Jean Shoenen. He did some wonderful work around this, and there’s a process in the brain called habituation and what happens there is repeated stimuli. Once your brain has heard those stimuli and they become not novel and it realises that they’re not dangerous, for example you learn to be able to filter out those signals and ignore. Again, if I was explaining that to my students, I would say, you know, for example, maybe you live near an airport runway or a flight path. When you first move into that house you can hear the aeroplanes going overhead, but after a few weeks that noise is filtered out and you don’t hear it, until maybe you have some friends round for a BBQ or a drink and they’ll say, oh, what’s that and suddenly because your attention’s back on that response, you’ll hear it again.
So that’s the process of habituation, where your brain can filter out what it considers non-important information and Jean Shoenen did, they used visual evoke potential. So light flashes at patients and recording in their brains in their visual cortex and they were able to show that actually migraine patients are not very good at doing that habituation. So filtering out these non-important signals, so you can imagine a situation going back to your wind-up comment, Katy. You know, this constant stimulation that’s not being filtered out properly is causing this wind-up within the brain and these circuits that are already abnormally activated and therefore this is where that sort of vicious cycle is coming from of worsening attacks and more attacks coming.
00:20:00 Dr Katy Munro
That makes a lot of sense. Yeah. So how would you study the brain in your role as a scientist? And obviously, we can’t kind of crack open this. Well, I guess neurosurgeons can crack open the skull, but I’m pretty sure that you’re not doing that, Phil. So what sort of techniques are you using to study the brain?
00:20:21 Dr Phil Holland
Well, actually one of the seminal studies in headache was — we spoke about these meninges earlier, these layers that cover the brain — and one of the seminal studies done really that’s helped us understand headache was actually in humans that were undergoing neurosurgery for another purpose and as part of these patients were awake, so that obviously could do that surgery and look at the areas of stimulation, and these patients when you were moving and mechanically stimulating the meninges were actually reporting painful feelings.
And importantly, they weren’t reporting those feelings on the meninges themselves, but they were reporting them referred to the face. So if you think about, for example, I know in some of the other podcasts you spoke about the different dermatomes of the face. So we have these three branches of the trigeminal nerve: the V1, which is around your eyes; the V2, which is more mid-face, and the V3, which is more jaw.
And the patients, depending on where you stimulate these meninges that surround the brain, were actually reporting pain to their face. So behind their eye, for example classic areas, where migraine patients would report pain. So really what we try and do in a way, as we try and mimic those features, we’re looking at trying to understand, using tools that we call translational tools. So things like EEG where we can record brain activity or brain imaging where we can do deep brain imaging. And trying to understand, so for example my work I’m doing just now, we’re interested in fatigue and why many patients really report this abnormal extreme fatigue with their migraines. And even before the headache. So we’re trying to understand, for example, how the arousal networks in the brain. So these areas that keep us awake and keep us alert, how they might be dysfunctional in migraine. And of course, as Katy says, we can’t do that in patients. We know from neuro-imaging in patients that those structures, the locus coeruleus, for example the hypothalamus, that these structures are abnormally active in patients. And now what we try to do in the benches really is use some different tools to manipulate those structures so that we can understand how they regulate arousal, so fatigue. But how that might have a spillover onto pain processing pathways through different networks, and in doing that we can then look at, for example, which receptors, so how drug molecules might act on those targets and therefore making new therapies, So really trying again as I said at the start to do that bench to bedside or bedside to bench approach where we really take a patient-driven symptom because I think you can do a lot of research or you know, neuroscience is a massive field. You can do a lot of research for fundamental basic principles, but actually, really, we want them to be anchored in a patient phenotype or a patient relevant symptom that we can understand and then obviously ultimately the goal is to take that back to a new therapy for those patients, something that’s targeted and not as we said before, adopted from another disorder.
00:23:23 Dr Katy Munro
Yeah, I think that’s really interesting. And I hear what you’re saying because we get a bit obsessed with migraine headache pain, but actually a lot of my patients are saying that I can deal with the pain, but actually it’s the brain fog or the dizziness, or the fatigue or the other symptoms which we’ll come onto in a bit more detail in a minute, but I think, yeah, we have to think around the whole complexity of migraine and the symptoms it brings.
00:23:54 Dr Phil Holland
Yeah. And I think we’re about to discuss, sorry to come in there, we’re going to discuss this, but actually many of these symptoms do occur before the headache actually. So they’re sort of what we would call the earliest identifiable symptoms of a migraine attack coming in. Some kind occur with the headache or during the headache and the lead up to it. But some of these symptoms actually last in patients, like the brain fog, like some of the fatigue, in between attacks.
And really, I think starting to think now that if we could start to understand them better, we can make such a difference to patients’ lives if we start to look at the non-pain symptoms and again actually just another little plug for the Migraine Trust. We’re just recruiting for a new PhD student, part funded by the Migraine Trust, part funded by King’s and the Medical Research Council, so the UK Government funding body, that’s going to be looking into non-pain symptoms in migraine.
00:24:47 Dr Katy Munro
Excellent. And maybe once you’ve got them up and running, we’ll have to have another podcast on that.
00:24:52 Dr Phil Holland
Yeah, well, they’ll be with us for four years from October this year. So we’ll have them there for some time.
00:25:00 Dr Katy Munro
So one of the theories I know that people sometimes still ask me about is, oh, isn’t migraine, you know, it’s to do with the blood supply to the brain, isn’t it? And it’s to do with changes in the blood vessels. And that theory was held quite a long time ago. That has been largely debunked. Do you want to just explain a little bit about why we think of it more of a as a brain disorder now rather than a blood vessel disorder?
00:25:27 Dr Phil Holland
Yeah, I think it’s probably really good to start at the start and see that the original thought in these meninges and these structures surrounding the brain was that they have nerve fibres. So these sensory fibres, that sense pain transmission around them. And the thought was that as these blood vessels dilated, they stretched the nerves and created this pulsatile pain that was linked to your heart rate or your cardiac output. Now, of course, that theory was strengthened when the triptans came along, because the triptans as well as having a nerve function, which we now think is their main function, of course they had some vasoconstrictive components. And many of you people who are licensing triptans or giving a prescription, will be aware of these cerebrovascular contraindications for triptans and of course, the fact that triptans help with migraine and were vasoconstrictive people thought that was another strength for that argument.
00:26:26 Dr Phil Holland
But we’re starting to understand now that actually the disorder does have a vascular component, but it’s really the neuronals or the nerve cells, and hyperexcitability and hyperactivation of these nerve cells, that is an important path in that. I think one of the key things, and it’s a very recent piece of information. It’s not actually available in the UK yet, but there’s a new drug molecule called lasmitidan that has been developed. It’s like a cousin to the triptans. So it acts on what we would call the serotonin 1F receptor and rather than the 1B1D which the triptans work on. And importantly, that receptor is only on nerve cells, it’s not on blood vessels and in the recent clinical trials that passed right up to phase three now, so this is a licenced therapy in in the US with the FDA for migraine, that that drug was as effective as the triptans in patients. So really showing that if you target the nerve function you’re as effective as drugs. Now it’s not available, I think you can correct me on this, Katy, but it’s not available in the UK or Europe yet from that point of view
I think then really that brings us into talking about things like the neuropeptides or calcitonin gene-related peptide, which many of you will be aware of because we have these new both antibodies that target the system or small molecule antagonists that block the receptor, but again really both of those approaches looking at targeting and blocking or inhibiting CGRP signalling, this calcitonin gene-related peptide. Now of course calcitonin gene-related peptide along with a number of these neuropeptides are vasodilators. So they do have a vasodilator-related role, but they also have quite diverse functions on nerves and again, we’re starting to understand that it’s likely these functions on nerves that are really important for patients. I think we really have to think of these two things as being related to each other and occurring together, but really focusing now on certainly my work on the brain and the nervous system and how that’s involved in migraine-related pain processing and all these other complex features that go along with migraine that really can’t be explained by the vascular theory.
00:28:40 Dr Katy Munro
Yeah, yeah. So when I’m explaining to people about migraine and why they’re getting attacks, we always talk about the genetic background that sets the brain to be more sensitive to change. And that can be internal body changes or it can be external environmental changes and it’s things combining. So it’s never just one thing, is it? Sometimes hear people saying, oh I got told I was just stressed and so that’s it. But it’s such a complex interaction of factors, isn’t it? And you know our sleep-wake cycle is important. Our blood sugar levels are important. So, do you want to just say a word or two about that?
00:29:33 Dr Phil Holland
Yeah, I think I’m often asked by some of our young first year students about this and how I kind of describe it again it shows you maybe a little bit of misspent youth. I describe it as, you know, those kind of penny arcade machines where you drop in your one pence or two pence and it pushes the coins along.
00:29:52 Dr Katy Munro
I love those.
00:29:52 Dr Phil Holland
Of course. Yeah, so you know what you see at the end is that those coins are building up and building up and building up and there’s multiple slots to put those coins in, and that’s a little bit like migraine. One of them might be environmental. One of them might be stress. One of them, you know. Clearly genetics is underlying all of this to make you more susceptible, but you build up this, what we call an allostatic load. So this likelihood of having an attack and eventually when that load becomes strong enough, you tip over the edge and tip into an attack.
And really, the pathway, this one clear thing, the pathway for head pain and that phenotype is very similar in everybody. It’s just that threshold to having an attack that’s much closer to the tipping point in migraine patients. And again there’s probably a genetic risk that puts you higher or lower on that scale depending on the type of what we would call snips or polymorphisms. These little risk variants which all in their self have very little likelihood. They’re all half a percent, 1%, likely, but they add together in patients and make for the same in what we see in patients, which is quite a heterogeneous population. You know, where one patient will tell you that something is definitely their trigger and another patient will tell you that they’re triggered by something else.
And again, that probably speaks to the diversity in therapies that we have that it’s not going to be that one drug fits all or one pill fits all. We really need to understand the breadth of this disorder so that we can have the right treatments that we can then perhaps learn based on your symptoms, so not sort of personalised medicine but stratified medicine. So based on your set of symptoms, we could say well actually it’s more likely that you would respond to this therapy over this therapy and that’s really where we need to get to, I think, in migraine long-term.
00:31:46 Dr Katy Munro
That would be so helpful, wouldn’t it? Because I’m constantly saying, look, nothing works for everybody, but some of these things work really well for some people and not at all for other people and so unfortunately we don’t at the moment have any way of discriminating which one will be good for you. So you just have to pick one that you feel best about trying and give it a go. And that takes time because again, we know that medications take quite a long time. Preventative medications very often we’re saying, you know, maybe keep going for at least three months. And the other thing I am very aware of is that if I’m asking patients about their family history, if they say, oh yes, my mum has it, then and my grandmother and my auntie and my daughter, you get a very strong sense of a family history. But if they say, oh yes, my mum and dad get it, then they are unfortunately very much more likely to have bothersome migraine attacks because the genes on both sides of family seem to make your risk of having migraine attacks worse. But then going forward there is hope because we also hear from patients who say, oh, I used to get it really badly when I was a teenager and then it settled down for twenty years and it was only, when I was in the perimenopause, I started getting problems. So these triggers and the threshold can change right throughout a person’s life, depending on so many different factors that are happening.
00:33:17 Dr Phil Holland
Yeah, I think 100%. There’s another previous podcast. I’m sorry to keep reflecting you all back to these, but there’s one on sleep.
00:33:24 Dr Katy Munro
I’ve already listened to them all, yes.
00:33:28 Dr Phil Holland
I’m sure you’ve all already listened to them all, but if you haven’t, go back and have a quick listen. There’s one on sleep and for example I’ve just done a lovely body of work. We were really interested in why most patients — And when I say most, of course there’ll be some patients listening to this saying, no, I get my attacks in the evening. But if you look at the population level, the majority of patients get their attacks early in the morning and sometimes waking up with those attacks. So we were very interested in this. So we did a study with an app that’s available with an app that’s available, and we looked at when patients were reporting, so over 2 million patients and when they were reporting their attacks, and we see that the peak incidence of attacks, reporting onset, is really from sort of 6 till 10 in the morning. So many patients are waking up with these attacks. So we were very interested in what might be causing that. So we looked at the circadian system, so that’s this circadian meaning about a day, it’s this system that goes again in your hypothalamus, this area deep in the brain that we discussed as being a thermostat. It’s the area that regulates your need to sleep. And of course, we sleep when it’s dark and we’re awake when it’s light. And that’s what the clock does. The light resets the clock.
And we know that in people with migraine, for example, that jet lag or shift work, anything where you change that cycle is detrimental and can actually lead to triggering of attacks, and you’ve got to remember as well in the background that that clock changes over your lifetime. For any of you with young teenagers who are really struggling to get out of bed. It’s not the teenagers being awkward, although they are for most things, because my son’s approaching that age, it’s actually their circadian clock has changed. So now their clock profile is just pushing them to sleep longer and have those lie-ins. And as you get older, the power of that clock weakens. And that’s why then you start sleeping for less and less as you get older. So we’ve got to remember that many of these systems that sort of regulate our brain and our body change across the lifestyle. And migraine probably then follows those patterns. So it’s a really good way to think about what fundamental principles in the brain might underlie this lifetime course of migraine, and therefore again, we can go back and study them and understand the most prominent of which, as we’ve said already, is the hormonal cycle starting with puberty. Because of that massive increase we see in young women during that time.
00:35:53 Dr Katy Munro
Yeah. And of course in the perimenopause there are other factors contributing to disrupting sleep, so maybe hot flushes, night sweats, pressure of career worries, family worries, all those kind of things can disturb people’s sleep. And travel and all. You know, travel is such a big contributory factor if you’re changing time zones and your whole body clock is thrown out of sync there. I always feel a bit guilty about saying to teenagers, you know, you need to try and have a regular routine and go to bed at the same time and wake at the same time.
But then, of course, society says yes, but during the weekday, you have to get up and go to school at 7 o’clock in the morning or whatever, and then at the weekend they try and catch up and have a sort of long lie-in. And it’s very hard in real life, isn’t it, to keep up these systems that we know are quite important in quietening the brain and helping reduce that threshold and to actually practically do that. You know, young mums with a baby that wakes them up every two hours through the night, much more likely to have an irritable brain because of the sleep deprivation.
00:37:03 Dr Phil Holland
Yeah. So we just recently published a study actually in neurology where we looked at actually in meta-analysis of lots of studies that had been published already and looked at what were the factors around sleep that were really impacting migraine and one of the strong things that came from that is it’s not so much sleeping too much or sleeping too little. It’s a change from your regular routine that really predisposes the likelihood that the patients who had that sleep. change were much more likely to then report an attack in the next day or two. And so really again a change from that cycle and I think we often say that the migraine brain likes you to be boring. You know, so it likes you to have that very regular routine. And I know it’s a colloquialism, but that’s where we go.
But it can be difficult to follow those patterns. I spoke a couple of years ago at a meeting in Hull with one of our colleagues, Professor Fayyaz Ahmed.
00:38:01 Dr Katy Munro
Fayaaz.
00:38:02 Dr Phil Holland
Sorry, Fayyaz, I forgot your name there. So we spoke there and there’s this modern thing. If you think about circadian work as well, there’s this modern phenomenon called social jet lag. And it’s kind of similar to what you said where you know Monday to Friday, we are constrained by work. You know, we’ve got certain work times and of course you can have what we call a chronotype. And how we would refer to that in the UK is whether you’re a morning lark or a night owl. So depending on when you’re at your best and your most awake and actually really interestingly, migraine people tend to have more extreme chronotypes than the general population. So they tend to be either more morning larks or more night owls. And that can actually predict when you get your attacks most commonly. So there is a really interesting story there. And of course these people, Monday to Friday, they’re working their set hours. And then I kind of tell the story of on a Friday night, then you come home and you relax and you know, you maybe start watching a movie or something and suddenly you’re eating something at 10 o’clock at night, which is unusual. So you’re starting to change how your body’s signalling, feeding and processing. You may be breaking open a glass of wine. Suddenly it’s now midnight or 1 in the morning, and you’re usually going to bed at 10 or 11 o’clock, and you’ve actually created a two or three hour shift paradigm in your chronotype. So like a jet lag, almost, a social jet lag, and really interestingly for every one hour you change your biological clock, it takes a day for your body to recover from that. So if you fly a six hour, eight hour time zone shift, that’s why by the time you get to the end of your holiday, you’re starting to feel better again. And then you fly home and you get all those feelings again. But it takes a day for every hour that your clock is shifting to realign. So it’s really important.
00:39:59 Dr Katy Munro
Yeah. So that’s really interesting actually. And I like that term social jet lag because we often hear people saying, oh, I’m fine all week. I’m really busy at work and I do this and I do that and then I get migraine attacks at the weekend and that is really what that often, one of the–
00:40:16 Dr Phil Holland
Yeah, I think people used to refer to that as let-down migraine, wasn’t it? And where, you know, it was that relaxation and of course it maybe is. There was a beautiful study from an American colleague who looked at stress and migraine in that way. And one of the real things that come out of that study was it wasn’t necessarily the level of stress, but it was your perception of that stress level. So again, how your brain was responding to that stress that really predicted an upcoming attack so it may be a combination of these things where you know there’s a bit of social jet lag going on. There’s a change in your routine because if you go on, the weekend is way too short, of course, nothing to do with migraine, but the weekend is way too short. Of course. But you know, it’s definitely that difference to the week.
00:41:06 Dr Katy Munro
And of course it could be excitement rather than stress too, couldn’t it? So I often hear from parents that, you know, their children are really looking forward to their friend’s birthday party. And they’re so looking forward to it and they’re really excited. And then because they’re really excited, they’re get a migraine attack on the day and miss the party. And so it’s not just bad stress, it’s also excitement that can control it.
00:41:31 Dr Phil Holland
Yeah, with my son as well, if he’s excited, again his sleep might be affected. It would change your sleep patterns. So any of these things that are having a change in your lifestyle and your usual routine can certainly increase that risk. So it’s definitely something to keep an eye out. Many patients now are looking at migraine diaries or different apps or just keeping an eye on what you might think yourself. Are these precipitating factors that are pushing you towards an attack, so that when you come to see obviously the excellent clinicians here that you would deal with, that actually you can have a conversation around those.
00:42:07 Dr Katy Munro
Yeah. So change is a keyword. So I wanted to go back to something that brings us on very nicely, Phil, to the phases of migraine, because you were saying, you might find that a day or two later you have a migraine attack, you become aware of a migraine attack. But actually let’s just talk about the phases of migraine in particular, so starting off with the premonitory phase or the premonition phase that we sometimes call it so that can be the things that are happening in the sort of 48 hours before a person becomes aware of an attack. So what do we think is happening in the brain at that time?
00:42:48 Dr Phil Holland
Yeah. Yeah. So I think in America, they would refer to these as the prodromal features, we would tend to call them the premonitory, but they’re similar and in their nature really there was one defining study conducted by a neurologist, Nicola Giffin, a number of years ago now. And she asked patients using an electronic diary system to stamp in how they were feeling. And it became really clear that as you see up to 2 to 3 days before an attack, before the headache, patients were starting to report that things weren’t quite right and they were reporting symptoms such as fatigue, neck stiffness, photophobia, excessive yawning. And actually in that study, when they looked at those features, the patients could actually predict their attack with about 70% accuracy based on the presence of those features. So it really stood out that those features are some way disease-defining in terms of what’s happening in an attack.
And what we think is happening now is that actually from those very early phases and some people talk about the premonitory phases being a different phase, but actually we all think in general that it’s just the earliest features that you can identify of the attack. What we think is happening now is that’s the changes starting to occur in these brain networks that are building towards the next attack. So these networks are becoming a little dysregulated.
Some of them that are say involved in fatigue and that’s why we’re looking at fatigue, some that are involved in maybe light processing or mood, and you see these changes and then that leads to the attack. And again, one of the complexities about that is that sometimes people can confuse maybe a premonitory feature with a trigger. So, you know, I have a standing joke with my pharmacology students when I’m doing this lecture that actually one of the premonitory features can be cravings, food cravings. So I often tell them not to worry about eating that bar of chocolate because it’s not that the chocolates are a trigger for your attack. It’s simply that it’s part of the craving and you’re getting the migraine anyway, so you might as well enjoy yourself just now and go for that. I know it’s a little bit of a simplistic way to see it, but it, but it’s true. There was a beautiful study done by Professor Arne May in Germany who showed that, for example, patients who got photophobia — so that’s light aversion — during their premonitory phase were much more likely to say bright lights were a trigger for their attacks.
00:45:22 Dr Katy Munro
Yeah.
00:45:23 Dr Phil Holland
So there’s just that little bit of confusion and it’s really important to try and tease out what’s truly a triggering factor in a patient and what might actually be a symptom of the disease. But again, these symptoms happen a few days before the attack, but can happen right up to and through the attack. And we then sort of move into what we would call for some patients the aura phase. So many patients will report it as visual, but it could be motor or sensory. You know, often the flashing lights or the zigzag pattern in the eyes. And that, of course, from what we know occurs in about 30%, up to about 25 to 30% of patients, the so-called migraine with aura, and again that can happen either before or during the headache phase. And then these patients will tip into the headache phase. Traditionally starting with a lower level pain that will then build over time. And this is again where a lot of the treatment information comes up to treat while mild and before the attack becomes established, before you get that wind-up in the brain that’s going to become much harder to treat.
And sadly, for many patients, actually even with the remission of the pain, whether that’s natural remission or pharmacological or whatever treatment strategy that then after the attack many patients will report feeling washed out and again fatigued and it takes a number of days to be able to recover that normal function. And you put this all on top of patients reporting this overall sort of brain fog that happens, this sort of challenging cognitive state. You can really see that it’s quite a disabling disorder in itself for everyday life, really. And it does impact every aspect of life, from work to social to everything.
00:47:12 Dr Katy Munro
Yeah, yeah, I agree. And you know people who are told, oh, it is just a headache, you know. Yes, there may be a day or two or three of headache, but if you’re not quite right for a couple of days before and you’re not quite right for a couple of days after those three days of the headache or impact phase as I sometimes call it, that’s a lot of time out of your months where you’re not functioning properly and people quite rightly sometimes really worry that they should try and get back to work or they should try and get back to doing what they do, but they struggle through those days. And I think, you know, turning up at work when you’re either in the early stages of a migraine or in the later stages when the headache phase is past you still may not be functioning at 100%. And this is where we find that impact can occur on employers with employees who are coming into work because they feel guilty or they’re getting penalised by attendance policies, you know, absences and things. So it’s so important that it’s better understood.
00:48:26 Dr Phil Holland
I think you made a real comment there and I’ve spoke to a number of patients who have used the word guilty to me, not just in the context of work, but also in the context of having to withdraw from their family, from their children especially. You know, if people have young children and are getting more attacks or anything that they feel guilty about having to withdraw from that activity. And that goes back to the stigma of migraine again that you know, you shouldn’t feel guilty for being unfortunate suffering from this really disabling disorder. But that stigma is still there, and that’s something that we do need to work on more generally in migraine.
00:49:01 Dr Katy Munro
Yeah, yeah, definitely. So I want to throw three words at you. Cortical spreading depression. Shall we talk about cortical spreading depression? Because that’s something which people may have heard about and just to explain a little bit more. So this is about, as I understand it, almost like an electrical process in the brain, isn’t it?
00:49:23 Dr Phil Holland
Yeah. So I think the first thing to say is that you’ll have heard about migraine aura and cortical spreading depression is the presumed underlying mechanism that gives response to aura. The reason I say presume is because to really show that it’s truly a cortical spreading depression, you need to put an electrode in the brain to record that, and of course we can’t do that in healthy human beings. These processes have been recorded in injured human brains as part of the normal monitoring process, so we know they do occur in the human brain. But again, really, it’s been neuroimaging studies in humans that have allowed us to see sort of, not necessarily see the cortical spreading depression, but see the after-effects of that spreading depression on for example blood flow and changes.
So again, using these features, but what we mean by cortical spreading depression is thinking about it as an electrical wave of discharge. So the neurons signal the electrical signals, and what happens is that you get this wave of excitability. And that’s why people will often experience bright lights or flashes, because that’s this excitation wave, often starting in the visual cortex, or why many patients in the brain at the back of your head, why many patients will report these visual phenomena. And again often behind that then, once these nerves have become hyperactive, they go into what we call a bit of a refractory period where they can’t fire properly or signal, and many patients will report black spots or an area of diminished activity behind that wave. The first thing to say is that, because this sounds really terrible and awful, is that actually there’s no real evidence in the healthy migraine brain that these things cause any pathology or any really, you know, adverse effects.
So again, there is of course, and I presume — I didn’t read this — but if you go back to the women and hormones podcast, there is a risk of contraceptives and female with aura and smoking. And there’s this combined risk that’s there. But in terms of the healthy brain, the brain seems to be able to cope with them quite well and retain normal function. Now of course in some people — -and we have a sub-class of patients, quite a rare form of headache called hemiplegic migraine where familial hemiplegic so very genetic form, but we can get sporadic types of that as well, where people will just sporadically develop a mutation that leads to that attack. These patients get really bad aura events, spreading de-polarisations, and these can lead to muscle weakness and really severe symptoms in those patients. But in in terms of general migraine, it tends to be more that we get these visual or motor or sensory sort of deficits or abnormalities that can last, again, they can be quite transient or can last for a few minutes to a few hours. The after-effects of this while it’s being restored. But I think the important thing to say here is that there’s no evidence that they cause any real pathology within the brain because when you think about it, if you hear this sort of brainstorm or electrical discharge in your brain. It can get people quite worried, actually.
00:52:30 Dr Katy Munro
It sounds quite a lot.
00:52:33 Dr Phil Holland
Well, many of the patients, you’ll know this better than me, Katy. Many of the patients that turn up at accident and emergency thinking they’re having a stroke is because they’re having one of these aura events, either because it’s their first aura event or because the symptoms have changed. So it appears slightly different to what they’re used to. You know, it’s a terrible thing in migraine and headache that we say, oh, that’s just my normal headache, but that’s just the normal pain I feel. It really amazes me as a non-headache sufferer when I speak to someone and they tell me how bad it is, and I say, but what about…? Oh, no, no, that’s just my normal headache, I don’t worry about that.
00:53:08 Dr Katy Munro
Yeah, I know what you mean. People are amazingly stoic, putting up with things. I spoke to somebody the other day and she said, oh, yeah, I get headaches and they put me in bed for three days and I get numbness and tingling and weakness down my arm. And I said, oh, I hope you’re getting some good advice. And she said, oh no, I’ve never asked anybody about it. I’m very surprised. You know, people are incredible on what they do put up with. But going back to what you were saying about cortical spreading depression. So this is a wave of activity moving over the brain. So does it go over the whole surface of the brain, or does it vary from attack to attack, and does it explain why? I’m certainly aware that some patients say to me, well, I get tingling in my hand and then it moves up my arm and then it goes further and further. And we also hear people saying, well, my visual changes start in the middle of my vision and then they spread out towards the edge of my visual field. So is that because of cortical spreading depression?
00:54:10 Dr Phil Holland
Yeah, so often what can happen in patients is that these symptoms can be quite reproducible. And as I mentioned then in some patients where the symptoms suddenly change. That’s where the patient gets worried and really thinks maybe, for example, there’s something going on. There was one beautiful study actually where an American colleague, Professor Andrew Charles, published this where he’s a clinician and he actually saw a patient who was an engineer to trade actually. And this patient had actually drawn out the progression of their visual symptoms. And I think they had done this, if I recall correctly, for over one-thousand aura attacks or certainly a few hundred where they had drawn out the progression of the attacks and they were able to image that patient in the scanner in the US and they were able to see that wave of spreading depression moving across the cortex in that patient and map the symptoms to the spread of that wave.
So yes, you can see that actually as that wave will spread across the cortex, it can have that sort of ordering effect on the symptoms that you will see. Now, the human brain is what we call gyrencephalic, and that’s a really complicated word, but think of it of all these folds, it has all these folds that increase the surface area. So, making more area for sensory processing and things and we know that the spreading depression doesn’t cross from one side of the brain to the other. It seems to stick to one side where it occurs and it seems to not spread across the entire cortical surface in the human brain anyway. It certainly seems to be restricted to specific areas, and that’s often why maybe patients will get those recurrent either visual or motor symptoms depending on the area of susceptibility for them. I think the really interesting thing about aura is actually it seems to be more associated with genetics. So if you think of migraine with aura, there seems to be a stronger genetic basis, so there’s much more evidence of it having a genetic component to it. And I like to think of the two as sort of a shared genetic risk. Again, migraine’s comorbid with so many different things. And I think aura is one of those things in susceptible individuals. They just have the susceptibility to trigger things into these attacks.
00:56:24 Dr Katy Munro
So with the medications that we use for migraine, we often say to people, well, that is more helpful in the headache phase. But if we were advising our patients to be migraine detectives and look into those premonitory symptoms that we were talking about or if they get visual aura and they have an awareness that they’re likely to be going into one of their migraine attacks, is it a good idea for them to be jumping in? Can you switch off those processes more easily if you start treating them early, maybe in phase one or phase two?
00:57:00 Dr Phil Holland
Yeah. So there’s certainly the evidence now that treat while mild, for example, before the pain gets established. So the earlier you can treat the pain seems to be obviously the more effective for certain therapies. And that’s probably because some of these therapies are acting in the periphery and because when you then get this wind-up in this central process that’s going abnormal in the brain it’s much harder to get those therapies into those areas to have an effect. Certainly the work we’re doing now, say for example around fatigue, is that pie in the sky idea. You know the real top level aim here is that we can try and stop the migraine process in its track rather than masking the pain as we see it, we’re actually trying to treat the underlying mechanism and therefore stop the progression to the pain.
00:57:47 Dr Katy Munro
Yeah
00:57:48 Dr Phil Holland
We should always caveat with all your patients because you’ll know this better than me, Katy, is that there’s a risk with some medications of medication overuse headache. So you have to have that balance depending on the therapy between treating very early and obviously making sure that it is a proper attack because some of these therapies when used to excess can have again a detrimental effect.
00:58:11 Dr Katy Munro
And I think the worst of those, and we’re always warning patients about it because you can still buy it over the counter is codeine or opioids, you know, often they’re not really treating the migraine in the way that is most helpful and they can lead to much more likelihood of chronic migraine or medication overuse headache developing. They’re addictive. They make the gastric stasis, the emptying of the stomach and moving on of the gut worse. And people still say to me, oh, no, I’ve never been told that before. So I like to mention it in every podcast pretty much just to say keep away from codeine.
00:58:48 Dr Phil Holland
Yes, and it’s not just a case for migraine. In pain more generally from a wider pain and neuroscience perspective, there is a huge problem here with this overuse component and what we call opioid-induced hyperalgesia. So this increase in pain response to excessive use of these compounds so definitely and for migraine 100% I think. Well, I hope that in the UK now we’ve got that message out pretty strongly. But of course there are still problems. It’s something perhaps at the sort of primary care level we may need to, you know, be more vocal for.
00:59:27 Dr Katy Munro
Or even in pharmacies. I think we still need to be constantly reminding people and I still get even GPs and pharmacists saying oh, but what about these products that have codeine in and they are labelled suitable for migraine? And I say, well, I never would recommend them and I really, really recommend that nobody else pushes those to patients with migraine, but.
00:59:52 Dr Phil Holland
Yes. Well, as a scientist, I never recommend medication, but I will tell everyone that they should listen to you, Katy.
01:00:02 Dr Katy Munro
Thank you. So that’s really interesting and I think the other places that people get pains, we’ve talked about head pain and face pain, but a lot of patients say– and I had one the other day — and she said, it wasn’t until my migraine attacks got controlled by the preventive medication I was taking that I realised that my neck and shoulder were better as well. And I’ve been having physio and I’d had all this pain. So is that the cervical part of the cervico-trigeminal pathway? And that’s certainly a common thing we hear about. So what’s happening there?
01:00:40 Dr Phil Holland
So I think, you know, you had a podcast again on dental pain and different things. And of course, when we think about these different pains around the head, we’ve got to think about shared pathways and convergence as we call it. And we know that, for example, some of your cervical nerves. So we’ve got the facial, so the V1 V2 V3 of the trigeminal nerve that we spoke about that go into the spinal cord, but also some of those cervical routes. So there’s higher cervical routes send nerve fibres to the meninges, not as much, but these layers that surround the brain. So there is some layer there.
And if you remember right at the start, I spoke about this ascending pathway. So within this trigeminal cervical complex, we have these neurons that sit there and their job is to signal sensory information to the brain. And they get convergent inputs from the face and head, but also from the neck and shoulders. So that incoming information. So that one neuron, for example, in your spinal cord is signalling to your thalamus or up into your cortex, these areas that integrate pain, saying that it’s getting hyperactivity and that there’s a pain response. It can’t differentiate where that signal’s coming from.
So we get this process called convergence where patients will report often stiffness in the neck or soreness and tenderness in the neck and the muscles around the shoulders. And again, this is sometimes reported as a premonitory feature actually starting before the headache in some patients. And there’s been some beautiful anatomical work done on this by a German neurologist called Thorsten Bach when he worked with Peter Goadsby at UCL a number of years ago and really mapped that pathway of how those nerve sensory fibres from these different areas, the neck and shoulders and the head converge in our spinal cord and go up through our brain stem to our thalamus and can therefore really lead to that convergence. And I’m not an expert in, you know, as a chiropractor or an osteopath or anything but so of course there may be in some cases there may be problems. You know, there may be pinched nerves, there may be things going on. But at a functional biological level, certainly I think a lot of this is probably about that convergence of signal.
01:02:52 Dr Katy Munro
Yeah, I think we are aware sometimes that people’s posture isn’t very good, where a lot of us spend our time looking at our phones or laptops and having our heads full and things. So I think anything that actually does cause a bit of neck spasm or muscle spasms can be helpful to look at that and address it as part of your overall management of a migraine attacks. And of course we also see quite a lot of patients who have hypermobility and even Ehlers-Danlos syndrome, which is a very much a link condition that we see and have their own particular problems with the neck and shoulders sometimes.
01:03:29 Dr Phil Holland
Therapeutically wise, of course, it’s very hard to describe this when you’re not on camera, but things like greater occipital nerve injections or blockade of that, so these are nerves that run up the back of your neck on the musculature there and it’s been shown of course that injection of, say, a local anaesthetic with a steroid mix there can have beneficial effects. And we think what’s happening there from a biological science perspective is that it’s dampening down that sensory information, so allowing the brain to recover and dampening down that sort of allostatic load that we spoke about earlier, on that wind-up that’s happening in the brain. So any of these processes that can dampen down that activity and that incoming information are going to be really beneficial.
01:04:12 Dr Katy Munro
Yeah, some centres I know are doing multiple cranial nerve blocks around the whole of the sort of forehead and just above the ear and around the back of the head with using local anaesthetic. And that seems to be very effective for some people as well. It’s not necessarily available everywhere, but yeah, so blocking those nerves. So we’ve talked a bit about neuropeptides and there’s a multitude of neurochemicals in our brain and also around our body, even our gut is producing neurochemicals. Is there a number that we think are implicated in migraine or are there sort of 3 or are there 30 or do we really not know how many different chemicals are involved?
01:04:56 Dr Phil Holland
Yeah, I’d say there’s a number that we’re currently looking into in migraine. And again, that number will probably grow over time. And I think just to take a step back there, I think it’s really important to know that. So we have our nerves, of course. And these nerves traditionally communicate with what we call neurotransmitters. And these are chemicals that are just passed from one nerve and then act on a receptor on the next nerve and cause that signal to be passed on.
Neuropeptides are slightly different. They’re these sort of molecules within the brain and they can act as neurotransmitters directly so they can activate a nerve, but they can act as what we call neuromodulators so they can have a more distant effect where actually the role is to kind of sensitise the nerves and change the function. So if you think of them, I like to think of them more as these neuromodulators so they can have this wider effect on the brain, not just on nerve cells but on different types of cells that are involved in pain and inflammatory processes and can really again contribute to that wind-up.
The most prominent of which we know of at the moment is calcitonin gene-related peptide, obviously. Studies back, I think it was in 1980s, of course, by Peter Goadsby and colleagues when they were in Australia, were showing that, for example, in patients undergoing a migraine attack, that levels of CGRP increased in the jugular blood. So suggesting that there was this release of calcitonin gene-related peptide during the attack. And there were a number of studies that carried on from that. A couple of the real seminal ones where some work they did themselves where they gave triptans to these patients and showed that in response to triptans where the patients became pain-free, there was a reduction in CGRP. So that suggested that that might be a mechanism and we know now actually that one of the mechanisms of the triptans is to block the release of CGRP.
So that’s how the how they act. And really then one of the most seminal studies by Jes Oleson and colleagues was showing that if you give calcitonin gene-related peptide itself to migraine patients, you can trigger attacks in about 60 odd percent of patients, or 60 plus percent I think it was, of patients can trigger a delayed migraine attack, but it had no effect in healthy controls. So really showing that CGRP is one of the neuropeptides that’s quite integral to the migraine pain pathway. But again, I won’t go into detail because there’s a number of wonderful podcasts talking about these new CGRP therapies that we now have available. But again, as you see, they won’t work for everybody and there’s going to be a number of other neuropeptides, neurotransmitter targets that we’re interested in.
And probably the next in the pipeline in terms of development is what we call PACAP. So it’s pituitary adenylate cyclase-activating polypeptide, and this is a neuropeptide that was discovered in the hypothalamus, remember, going back to that little thermostat area, and actually its role there is about the integration of light into the brain. So how our body responds to light-dark plays an important role in that bit called the superchismatic nucleus, the master clock of the brain. But it turns out actually that it’s also in these trigeminal nerves in these sensory afferents that that are processing pain signals.
And actually just towards the end of last year and presented at the International Headache Society meeting in South Korea, one of the large pharmaceutical companies, I won’t name them for the podcast, they actually reported some phase one clinical data showing that their antibody now against PACAP was effective for migraine. So it had passed the phase two.
For anyone who doesn’t know: phase one clinical trials, they’re like the very early small safety trials. So looking in healthy controls, looking at dosing regimes and for any adverse effects. Phase two now that would be done in migraine patients in a randomised blinded way, but a small number of migrant patients. So I think this study used about ninety patients per dose and compared that to placebo and were able to show this study had an effect. And the natural progression of that going forward, if there’s no adverse side effects that weren’t reported here, is that would then go into a large phase three study and those are the studies that are needed to get regulatory approval for this as a drug that could come to market. So PACAP is probably the next in line in terms of coming to the market and that’s going to be really important.
From a science perspective, actually, I’m really interested in PACAP in terms of cluster headache because anatomically the different systems that are involved in cluster headaches, so the parasympathetic system as we call it, and that’s the system that causes the sort of lacrimation, the rhinorrhoea, the runny nose, the tearing, the feeling of fullness or the facial flushing that some patients report. PACAP is very much involved in that pathway. So I’m really excited about that. It’s probably going to take a while to get clinical trials in cluster headache because it’s a smaller population in terms of migraine, but that will be really exciting from my perspective.
01:10:06 Dr Katy Munro
That really needs more medication. More understanding too, doesn’t it? I’ve recently recorded a public vote on cluster headaches, which —
01:10:13 Dr Phil Holland
100%.
01:10:18 Dr Katy Munro
— maybe people would want to listen into. I’m not quite sure when that’s coming out. Hopefully in March, I’m not quite sure when this one’s coming out, so maybe before or after. Look out for that one, listeners.
01:10:32 Dr Phil Holland
No, cluster headache’s definitely a really important condition and a really disabling condition in its own right for different reasons, but again, slightly less population, so you know it’s the world we live in where it gets less attention, for example, from industry and from pharmaceutical companies because of the size of the market in that way. And then going back to the neuropeptides, one that we and a number of others are working on actually is a neuropeptide called amylin. This is another neuropeptide again.
I wouldn’t quite describe it as a cousin of calcitonin gene-related peptide, but it and calcitonin gene-related peptide share some of the targets that they work on. There’s a bit of crosstalk between the targets that are worked on and this is a peptide that’s involved in that feeling of satiety. So that fullness and control of appetite. So again, linked with food and migraine and appetite and migraine and there’s been a number of studies now.
The Danish colleagues, with some of their American colleagues and others, have again shown that if you target this pathway, you can trigger migraine in migraine patients using this amylin and a lot of the research going on now is trying to understand the crosstalk between amylin and CGRP and whether it could be maybe its own independent target. Or it could be something that you could give with calcitonin gene-related peptide targeted therapies to enhance their effect.
So that’s another exciting one that’s a little bit further behind PACAP in terms of development, but I think will be coming out in the future. And then of course there’s VIP, as we call it, vasoactive intestinal peptide. That’s an interesting one. For a number of years, there have been some studies showing that VIP didn’t provoke migraine in patients, but actually that’s been revisited now and it turns out that it does. And depending on how you dose and give the molecule. But again, that’s quite interesting for cluster headache. I think more generally as well because of the underlying pathways. But it’s again even further down the pipeline, I would say in terms of development.
So I suggest that there’s four or five neuropeptides coming. We are working on one at the moment in our laboratory, and we’re just about to try and get funding to take this forward. So if you’re from the Medical Research Council and you’re listening to this, you should fund that research when it comes in.
01:13:02 Dr Katy Munro
Here, here.
01:12:54 Dr Phil Holland
And this is a neuropeptide that’s really involved in regulating the onset of puberty and reproductive functions in people. And we think that it’s got a really important shared role in the prevalence of migraine in women. So we’re really excited about that one and trying to target the therapy that comes from this high prevalence of women because you may be aware that, for example, there was a meta-analysis a year or two ago now showing, for example, that the triptans aren’t as effective in females as they are in males and have more side effects and more recurrence of attacks. So it’s really important that we also think about therapies that address the prevalence of migraine in terms of looking at actually at therapies that we develop because of the high prevalence in women, not just therapies that work. Because most drug trials, especially early stage one trials happen in healthy males for reasons of not wanting to test drugs on people of childbearing age. So again, that’s an implication for migraine that we need to think about more widely.
01:13:59 Dr Katy Munro
Yeah, that gender difference is really important. And yeah, it’s good to hear that that’s really being thought about and considered. Can I just ask you about amylin a little bit more? So sometimes people worry that if they have migraine, that might lead on to more damage in the brain. And amylin and amyloid have very similar names and amyloid is implicated in dementia, people are terrified about dementia, especially if they’re having brain fog, memory problems with their migraine. “Then am I getting dementia?” They’re not the same thing, are they?
01:14:37 Dr Phil Holland
No, they’re completely different. So actually in my migraine pathway, in terms of my career, I actually stepped out from migraine and I had been at the University of San Francisco with Professor Peter Goadsby. When I finished my PhD in and started to do some research there. And I stepped away from migraine and worked in dementia for five years, looking at Alzheimer’s disease and vascular dementia at Edinburgh University with colleagues there. And during that time I actually worked with amyloid and these different things. And yeah, they’re very different in that way in terms of obviously, amyloid’s this molecule that forms these plaques within the brains of dementia patients. And, you know, a bit of what we call sort of cellular debris in terms of having an effect and can be toxic.
Interestingly, this is not a dementia thing, but it’s not those plaques that are toxic. They think now it’s the soluble forms of amyloid circulating in the brain that cause these problems. But that was something I worked on for a number of years, but very different to amylin. Amylin’s a peptide involved in feeding and regulation of appetite and sort of energy balance. So again, it’s a slight difference, released in your gut often and signalling to the brain, using actually in some way the vagal nerve as well for a bit of that signalling, you’ve probably touched on the vagal nerve in some of your podcasts. So again, very different to amyloid, so there’s no need to worry there.
01:16:01 Dr Katy Munro
That’s really reassuring because you know, it’s something that we do get often asked about. So have we covered everything, Phil, do you think there’s anything else that you’re thinking, well, I wish she’d asked me about this? Now’s your chance. So we’ve covered pretty much a lot of topics.
01:16:20 Dr Phil Holland
Yeah, we’ve covered a lot of topics. I think you know, again while I’m a scientist, I think one of the most important things we can do for migraine is advocacy and pushing the story. So anyone listening to this podcast, who may not be a scientist or may not be a clinician but may have an interest and feel that they could actually contribute to that wider side of policy and advocacy, I think it certainly would be a time to consider getting involved in reaching out and helping with that. For me particularly, I think that there are a number of things we need to do for migraine. So you know, what’s the next big thing we need to do? And I think all of that stems from getting migraine on the map. And so I’ve recently been elected to the European Headache Federation Board. So it’s great to have a UK representative on that and as part of that, we’re really trying to push migraine research and the importance of migraine and a little bit, you know, the stigma as well. I think that’s really important from it. People do misperceive migraine as being simply a headache and that’s not simply true. You know I see people that I’m speaking to that have these attacks and I see the impact that has on their life and really I think if you have a family member, if you know somebody that’s got migraine, you will get this. But not everyone does. So I think it’s really important that we all champion that message.
And without going into this in too much detail, I think one of the problems we have is you can’t listen to — I like football. Traditionally, I’m a Glasgow Celtic fan so I’ve just upset half of Scotland by saying that — when you know you can’t listen to something like a news article in sport where the manager has a headache because of a team selection. Or they’ve given someone a headache because they’ve got a choice to make.
01:18:11 Dr Katy Munro
Yeah.
01:18:11 Dr Phil Holland
And you just wouldn’t see that with any other disease or condition where it’s colloquialized so much. So I think we need to think about the terminology we use. And as I say, getting the message out that for these patients it isn’t just a headache, it’s not something that the patient should be feeling guilty about, and it’s a real condition that, you know, we are making strides to make better but it’s going to take time and there needs to be understanding as we make that timing and in order to fast track that process, we need the government and the healthcare services to step up and fund the new medicines that are available.
01:18:47 Dr Katy Munro
Yeah.
01:18:47 Dr Phil Holland
Because you will understand this, Katy, there’s a problem sometimes at bringing these medicines to market because of cost implications, but also then to fund new research, not just by myself. Of course, I’m happy to receive the money to do the research, but by all the researchers, clinical basic scientists who are really working and pulling in the same direction to try and do this. So that would be my kind of last call that anyone who is listening to this, that is involved in that in some way or feels that they could contribute that they really should think about trying to get involved.
01:19:17 Dr Katy Munro
Yeah, I think our advocacy is so important and I’m hoping to go to the UK Parliament fairly soon to go and run an event there to try and raise awareness among MPs. And that’s been really helpfully spearheaded by Dehenna Davison’s announcement in September that she was suffering from chronic migraine and had to resign from her minister of levelling up post because she’s suffering and she’s been a very loud advocate. Which is wonderful because we do struggle to get people to step forward and say, I have migraine, I suffer from these attacks. You know, it’s something I’ve been aware of for many years that that people keep quiet about it.
But the other thing is there’s a Women’s Health strategy going forward and it was launched quite recently in Parliament. And again, nothing about migraine or headaches. And when you think about it as being migraine as one of the top or the topmost disabling condition for women of reproductive age. You know, we need to start taking this very much more seriously than is currently happening, I think.
01:20:31 Dr Phil Holland
Yeah, 100%. I mean, I think statistics get a bad rap in different things you know and how people use them. But actually you know, there was a really fundamental study that looked at years lost to disability. So the amount of time an individual loses to disability across their lifespan. In young women migraine is the number one cause of years lost to disability and we can’t hide from that fact. That’s there. It’s published. It’s a pan-European study that looked across Europe and it is the number one cause in in young women of disability. And that really is striking. And when you think back to very early, when we spoke about education and teaching and the fact that, you know, really, I think if many other conditions get more coverage, focus and attention, and of course some of them rightfully so, we’re not trying to detract from any of these other conditions. We’re just trying to make sure that migraine has a fair and equitable voice at that level.
01:21:35 Dr Katy Munro
Yeah, I sometimes say to people, you know, let’s try and lose the S so we don’t talk about a headache and migraines because I always get journalists saying, well, what’s the difference between a headache and a migraine? I say it’s a migraine attack. Migraine is the neurological condition, but it gives migraine attacks because you wouldn’t say to me, you know, how are your asthmas? You would say, how’s your asthma attacks? Or how are your epilepsies? Fortunately, I don’t have either of those conditions, but you get the gist. It’s about how we know that asthma is the condition that gives asthma attacks, and I think we need to be really emphasising to people that migraine is a condition that you have. And that you may or may not have migraine attacks throughout your life because of that, but it’s not justified, yeah.
01:22:21 Dr Phil Holland
Yeah, it’s a lifelong disorder with this predisposition. Yep, definitely. It’s this lifelong disorder that can change over your lifestyle and again, then you can have these episodic, recurrent disabling attacks and for some people, when that’s really an interesting question, it’s one that we try to work to. Some people will get one or two attacks occasionally. Some people get three or four attacks a month. But when you really speak to someone, and say I speak to someone who gets migraines and they say to me I get, you know, one, two, three attacks a month, it’s really disabling, it’s really hard. And then we start to talk about these chronic migraine patients. That’s more than fifteen attacks per month, where eight of those are migraines. They really go, wow, you know, these patients exist and they’re suffering and to think that some therapies, for example, we struggle — these therapies are developed but we struggle to make those available to the patients evenly, for example, throughout the UK, for these conditions is really something that needs to be addressed, and it’s something that can be addressed now. It doesn’t need future development, it doesn’t need me doing research for another ten years. We could actually make a change now with the right advocacy and voice for migraine.
01:23:34 Dr Katy Munro
So we all need to shout louder. But that’s really wonderful. Thank you so much, Phil. It’s been a really fascinating episode. I think everybody’s going to have learned a lot. I certainly have. And good luck with all the research.
01:23:47 Dr Phil Holland
Yes, thank you. I’d like to say a big thank you to all my team who obviously I spoke a little bit about earlier on, but without those people that the research just wouldn’t happen, they’re all a wonderful bunch of scientists and clinicians who work with us and do that work at King’s College London. And thank you for inviting me on the podcast. It’s been really great and I hope people have enjoyed discussing a little bit different around the science of migraines, because I know a lot of these podcasts are normally with clinical colleagues. Been really great. Thank you for having me.
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