If you are anything like me, you might be a little exasperated that we don’t have a clear answer for how to cure and indeed prevent all forms of headache by now. After all, if we can trace back their origins deep into our evolutionary history, in this day and age – 50 years after we put men on the moon with no more technology than is currently contained within your mobile phone – why have we not solved this headache business? The answer is complicated, by some things that we can see and some things that we can’t.
Let’s first think about the things we can see. We know a lot about headaches – how they present, what is happening in the body during their course, how people experience them. Medical, clinical and molecular science enquiry has grown up around the issue so that we have a better understanding now than ever before about the molecules like CGRP that might have an influence, right up to physical processes like cortical spreading depolarisation. Sure, there’ve been false starts and avenues that turned into dead ends (MSG, anyone?) but treatments to interact with these levels have been born and have been successfully deployed in the past. But science, like lots of other things, such as running a business for example, suffers from the aperture problem, with people only focused on a tiny pixel of the overall picture. That can give you a really false impression of what the whole picture looks like. For example, if you were to look a square centimetre of your face in a photo, would you be able to identify yourself? You might not even think that square came from a face – it could just as well come from a paper bag (entirely preferable in my case). But if you zoom out, it begins to become apparent that you are looking at a face and that that face is yours.
In the investigation of headache it is really important that we do this kind of zooming out; sense checking our purpose in a way. We must get our molecular scientists, together with our physiologists, flow dynamists (who look at what makes blood flow in a turbulent or smooth way), computer scientists, statisticians, clinicians, neuroscientists, psychologists, physiotherapists and indeed patients involved in our next stage of enquiry. This interdisciplinary approach is the future. It will ensure that we ask the right questions and interpret the answers in the realm of human experience and reality. We can also borrow from other disciplines. One of the great tickle points of my life has been following a story that has seeped into a load of other fields, including migraine.
The rhythm of life is a powerful beat
It all started with a Columbian neuroscientist called Rodolfo Llinás and his team at New York University in the late 1990s. Having spent years working on how single neurons talk to each other in various parts of the brain and looking at how neurotransmitters are released in the giant squid synapse, he then changed his focus. He is a brilliant example of how to change the scale that you are working on.
Magnetoencephalography (MEG)
This is a technique that marries the best qualities of functional imaging, allowing you to know where something is happening, with the brilliant specificity in time that physiological recording like electroencephalography (EEG) gives us so that we also know when something is happening.
What the MEG machine does is detect and decode the magnetic fields that our brains are generating. Wherever there is an electrical current, and our brains are full of those, there will be a magnetic field associated with it. It is the principal of electromagnetism as discovered by Michael Faraday, an English scientist way back in 1831. Google him. He looks like your quintessential mad scientist (based on historical pictures of scientists, I often thought I wasn’t going to make it unless I was somewhat bald, with copious facial hair and wore a frock coat) but he utterly changed the game around energy, our understanding of it and how we can harness it. Not only are we surrounded by exemplars of his theories in our daily lives (every time we switch an electrical appliance on, for example) but his work was also the basis of transcranial magnetic stimulation (TMS) and MEG.
Rodolfo zoomed out his lens from looking at these almost microscopic properties to investigate how neurons communicate across the brain. Using MEG, he realised that in Parkinson’s patients, he was seeing a pattern of activity coming from the motor cortex (the bit that makes us move) in exact synchronicity with the twitch that his patients exhibited: about three twitches a second. But he also saw this pattern in another place in the brain, namely the thalamus, which sits underneath the cortex. There are connections from the thalamus to every bit of the cortex and back again and so these ‘thalamocortical loops’ are involved in everything that we do. As Rodolfo was interested in a movement disorder (Parkinson’s disease) he tracked the motor thalamocortical loop and noticed that the thalamus set the pace for what happens in the cortex. It turns out that abnormal rhythms can happen in any of the thalamocortical loops, affecting any function, and that this symptom is apparent in a wide variety of brain-based disorders. The thalamus generates the signal to the cortex based on the input it is getting from elsewhere, so it is not necessarily the cause of the problem, but its reaction to it potentiates the symptoms.
This knowledge gives us an incredible opportunity. If the screwy signals coming from the thalamus cause the symptoms through their action on the cortex then can we play with those? In the early days, Daniel Jeanmonod, a neurosurgeon from Zurich, destroyed little areas of the thalamus thought to be involved in the motor loop in Parkinson’s patients on the proviso that no signals are better than screwy signals. However, the side effects were massive; it was just too hard to be that precise 20 years ago and it’s not like these neurons looked any different to any others. A major advance was made when Daniel started to put electrodes into the area to ‘listen’ for the abnormal signals, and then he could destroy the area that was sending those out. Outcomes were better, twitching decreased or ceased, but it was still fraught with risk.
But what if instead of destroying an area, we could actually set the pace of the neural firing from this very slow rate to a more normal faster rate? We can do it with the heart when the natural pacemaker of the electrical activity that causes heart contractions fails, and now we can with the brain, too. It’s called deep brain stimulation and can have value in a variety of disorders, including motor disorders like Parkinson’s and dystonia (where all of the muscles are tensed up), obsessive compulsive disorder, Tourette’s syndrome, tinnitus, migraine and cluster headache. The effects are instant and striking. The battery for the pacemaker is fitted under the skin in the chest and if you switch off the stimulator by passing a magnetic field over it, the symptoms instantly return. You can even have a stimulator in both sides of the brain controlling your symptoms on both sides of the body. It really is life-changing.
Having these slow signals coming from the thalamus means that the area of cortex, the eye of the storm, that it feeds is getting very abnormal inputs, making it act irrationally. Even worse, instead of the cortex receiving constant steady input, it is now receiving bursts of activity in an on/off fashion. The usual way the cortex tamps down on activity breaks down, meaning that the area becomes overactivated, setting up a wave of excitation radiating out from the eye of the storm. As we saw in Chapter 6, this description sounds very like the wave of excitation we see at the beginning of the migraine attack, followed closely by the wave of depressed activity. In the case of migraine, we still don’t know for sure where the cause of the thalamocortical effect lies – there could be a number of reasons, as we have discussed. It could be that the overactive visual cortex of the migraineur feeds back to the thalamus, which tries to correct this with slower signals back to the cortex. Regardless, Thalamocortical Dysrhythmia, as Rodolfo Llinás called it, is certainly complicit in the migraine experience.
This means that for those whom medicine doesn’t help, there is another way. Deep brain stimulation to reset the communication pathway between the thalamus and the cortex is a credible last resort and shows some good efficacy. There is positive progress here for cluster headache, too. It seems more certain that it is regions of the hypothalamus that are to blame here, and these regions then project to the thalamus. Harith Akram, a neurosurgeon from University College London, has identified a good area of stimulation is an area in which the trigeminal and other areas involved in pain perception meet with the hypothalamus, towards the back side of the hypothalamus. In 2017, he reported a 30 per cent reduction in pain, so with even greater precision afforded by advances in neurosurgical techniques and our understanding of the underlying neuroscience, this option can only become more credible.
The magnet and the mind
There are ways that we can play with the activity of the outermost layer of the brain that is responsible for actioning the symptoms we can see and this has had some importance, particularly for people who experience migraine. I’ve mentioned already that transcranial magnetic stimulation (TMS) can be used to briefly and reversibly switch on an area of neurons inside the brain. This involves holding a magnetic coil that discharges a magnetic pulse to the skull. It just feels like a tap on your head but it passes really easily through the skull into the brain tissue below. Through Michael Faraday’s electromagnetic induction, this magnetic pulse induces an electrical current in the brain and this causes action potentials to happen. In the lab, I can use this to work out not just what an area of your brain is doing but also when it is talking to other regions. Various treatments have resulted that the patient can use at home either as a preventive measure against migraine attack or as soon as the migraine experience starts.
The most popular form of treatment being recommended at the moment is to deliver two pulses 30 seconds apart using a device the patient holds to the back of their head. I’ve worked with TMS for 25 years, so you’re going to have to forgive me for being a little sceptical. The kinds of protocols we use in the lab are much more precise, both with respect to where we deliver pulses in the brain and how powerful they are. They have to be, in order to find out anything at all, because the brain really sees what I am doing with my TMS coil as a bit of nuisance noise. Holding a device imprecisely to the back of the head and tickling the brain with a couple of pulses, each with mere milliseconds of effect in the brain and expecting it to kick-start the area into a more synchronous activity seems like a bit of a leap to me. Having said all of that, there has been a randomised controlled trial. Of the included 164 people who experience migraine with aura, 39 per cent of patients were pain-free two hours after treatment in comparison with 22 per cent after placebo treatment. Results also showed that 29 per cent had no recurrence or need for any further treatment after 24 hours in comparison with 16 per cent of people who had the placebo treatment. There may be something there. The use of TMS doesn’t preclude any other treatments though and so it could be used as another combat tool in the box.
Scale has also been important in the development of a different non-drug intervention, this time focusing on manipulating the activity of a nerve that is quite accessible on either side of the neck. The vagus nerve is the tenth cranial nerve, and you have one on each side of your body. Need your heart to beat faster? No problem. Need your blood vessels to dilate or contract? That’s your vagus nerve too. It also tells your brain what it has done through sensory feedback and carries pain signals from the nociceptors or pain receptors up to the brain. Knowing this, transcutaneous vagal nerve stimulation (tVNS) has been developed to interact with this rather peripheral node in the pain network. Electrical currents are released from a device the size of a mobile phone that is held to the neck for about 90 seconds, and the stimulation of the vagus nerve seems to modulate the firing rate of the pain neurons in the trigeminal pathway. This then has a knock-on effect for how our brains perceive pain, by increasing the inhibition that damps down the pain response. This treatment seems to have good efficacy, particularly in people who suffer from cluster headaches and who can’t tolerate injected sumatriptan and in whom oral sumatriptan has no effect.
What’s good for the goose may not be good for the gander
Another thing that we can see is the variability between all of us; we have to start including this knowledge in how we decide how efficacious our treatments are at an individual level. When drugs are put through clinical trials, the smallest amount of variability is preferable so that we can get the cleanest possible answer as to whether the drug works or not, and whether or not it is safe. But we only get to this stage after a number of other steps. Funding has to be secured to develop the drug, either from the national research councils or from the pharma industry. Once a drug has reached the point at which it can be administered, it is then required, by law, to be tested in two animal models, usually rodents and dogs, before it can get to human clinical trials. Now, I have known many humans who have acted like rats and dogs, but as a comparative physiologist, I know that they are entirely different. If the drug fails in curing these animals of whatever illness has been inflicted upon them to test the drug, then the science goes back to the drawing board. But what if the drug would have worked in humans, and doesn’t work in animals because their physiology is different? And, on top of that, there are many examples of drugs working in animals that have no effect or even dire consequences in humans.
Shouldn’t we find a better way of testing drugs meant for humans by replacing the need for animals at this stage? Not only would we do better science, perhaps arriving at answers much more quickly than the animal detour allowed us to, but we would get to not inflict all manner of illness on our fellow custodians of the planet. I am happy to report that great strides are being made on the science side of this issue. In my post-doctoral years I was funded by a wonderful charity called Animal Free Research UK, which support scientists young and old to find alternatives to animal testing. Before the advent of TMS, the kinds of questions we were answering would have been addressed using lesions to monkey brains. That certainly wasn’t my bag, so I was honoured to be part of the constructive solution, finding a credible and valid alternative to this practice.
The next step is to change the law that requires animal testing before clinical trials and prove that we can have as much confidence in the human-based replacement as we would in the animal model. Who knows what useful treatments we have missed out on because they didn’t work on animals? Scientific discovery is hard enough without creating blind alleys for ourselves along the way.
The clinical trials themselves are another issue. There has been much concern recently that many are done with men, because the cyclical nature of the release of female hormones muddies the waters somewhat. To determine if this is a real phenomenon, Geert Labots from Leiden in the Netherlands looked at 38 drugs (and the 185,000+ people who participated in their trials) that had been approved by the FDA in the USA to see if there was any difference there. Sure enough, in Phase 1 trials, where scientists are trying to investigate side effects and what happens to the drug in the body, there was a difference, with only 22 per cent of participants being female. These studies tend to be small, involving only 20–50 people, but nevertheless the possibility of progressing to Phase 2 is contingent upon these results. Phase 2 includes more than 100 people and finds out more about side effects and how well the treatment works. Phase 3 could include thousands of people and is randomised; this is where the new drug is compared with the standard treatment to see if it infers any advantage at all. Phases 2 and 3 had a much better gender divide, approaching parity between the sexes. The lynchpin is Phase 1 though, so this factor is certainly something to think about in the future.
And it is not just what sex you are that makes a difference. If you are a night owl or an early bird, you should modulate when you take your drugs. For example, if you have high blood pressure, taking your medication at night will have a maximal and lasting effect on the system that controls blood pressure, the renin–angiotension–aldosterone system that activates during night-time sleep. This is called chronotherapy (from the Greek khronos- meaning ‘time’); the right dose of the right drug at the right time leads to a more effective outcome and often then requires smaller doses.
The dosage of drugs is currently the same for every adult no matter what size you are or how fast your metabolism is. And don’t even get me started on co-morbidities. If you suffer from headache but you also have an arrhythmia and a pain in your big toe, we don’t tend to put these things together as being causative of each other (such as gout caused by circulatory problems). Most of this time, our various aches and pains are pretty random, especially as we get older, but sometimes, pulling the lens out of the condition that the patient presents with will help diagnose a headache as not just a headache for headache’s sake, but a circulatory problem that could be best tackled some other manner. In the same way as thinking about the individual’s circadian rhythm for optimal treatment, putting together information from different fields leads to a treatment that is more personalised and effective.
So what about the things that we can’t really see? How do we put all our lives together into some kind of narrative that will illuminate the factor or factors that are causing you to get headaches? If there was ever a time to poke around in the wardrobe of your life, this would be it. Take every piece out, see if the moths have got to it. If they have, recycle it; take what you have learned and let it go. Even if the moths haven’t enjoyed the fabric, are you really going to wear it again? As you will probably know, the best way to do this is to keep a diary. This doesn’t have to be a Dear Diary diary, but merely a record of your day. What you ate, how much exercise you got in and when you did it, what you drank, how you felt at different points in the day, what emotional pressures you had on you – that kind of thing. People tend to only do this when they feel awful, but it is so important to have the contrast with when you felt well. You need to look at all of the factors that affect your health, both physical and mental. And just like Kate Blackmore, the paediatric ENT surgeon we met in Chapter 3, we can become detectives but in this case of our own lives. We all have triggers, some of which we can watch out for and manage, such as dehydration, posture or flashy lights. There are some, though, as we have seen, that we won’t know about and the first thing we notice are the symptoms of headache. Knowing that your headache doesn’t just live in your head, that its effect and often its cause happens in your body, or your behaviour, should help you be more holistic in your approach.
Pain means something, take it seriously.