Dedication

To my parents, who let me fly,

and to Kathy, who keeps me grounded

Prologue
Molehills Out of Mountains

Pleasure is oft a visitant; but pain clings cruelly to us.

—John Keats, Endymion, 1818

In the spring of 2021, I was riding an e-bike up a steep mountain road in western Montana. I was happy and high as a kite.

About an hour earlier, I had taken a large dose of psilocybin, delivered by way of dried, psychedelic mushrooms supplied by friends. I’d taken mushrooms before, as a young person—a common dalliance at Grateful Dead shows or backyard parties in my teens and twenties. But in the thirty or so intervening years, my life had become one that did not really make room for tripping. I was (and remain) a professional journalist with a long reporting history, most of it at the New York Times. More recently I cofounded a digital science magazine, and this work has kept me busy and mostly garden-variety in my indulgences.

Still, excitement over the potential therapeutic effects of psychedelics had been swirling for a while and, at the time of that journey up the mountain, I needed therapeutics. I was battling cluster headaches, and they are, in a word, awful.

I cannot explain the pain of a cluster headache, and it would be ludicrous to even try. At the same time, the pain is so extraordinary that I sometimes want to try. It is something superlative, supernatural. A tourist would take pictures of it, as a towering monument or new world wonder. I want you to take in its bigness with me, to stand together in the shadow of its mass.

But how? Writers and thinkers have spent hundreds of years trying to communicate pain, fumbling for clever or cutting words to describe its imprimatur on the psyche and the soul. St. Augustine1 called pain “the greatest evil.” Canadian sociologist2 Arthur Frank described pain as the “black hole into which language seems to disappear.” The endeavor is a literary cliché and the feedstock for countless moody meditations—sociological, journalistic, anthropological, poetic, medical, and pop-psychological parables steeped in metaphor and existential angst.

Pain—has an Element of Blank—

It cannot recollect

When it begun—or if there were

A time when it was not—

It has no Future—but itself—

Its Infinite contain

Its Past—enlightened to perceive

New Periods—of Pain.

That’s pretty good—or is it? Does it bridge a gap, or speak only to those who already know? I think it’s the latter, and if Emily Dickinson3 could not nail it, what hope have I here? I might ask you to imagine the most physically painful thing you’ve known—a broken bone, a slipped disc, a wicked burn, a kidney stone—and then invite you to relocate that pain, stretched over time and firing at its peak, to the inside of your head. A childbirth in your skull. Can you feel that? If you’ve experienced a cluster headache, I know you can feel it. If you haven’t—and if you don’t have migraines, either, because those are their own dark valleys of head pain—how can I bring you there?

Maybe I could tell you about the research. Some studies call my disorder4 “suicide headache,” while others suggest5 that it is among the worst pain disorders known to human beings. Further downstream,6 in the swirling soup of low-budget self-help websites, you can find clickbaity articles that sort humanity’s most painful conditions—shingles, sciatica, gout—into lists. You’ll very often7 see cluster headache at or near the top.

It sometimes helps to describe the spastic, ancillary symptoms a single cluster attack delivers—the need to move, to moan, to rock and rub. I might point8 you to ghoulish online videos of cluster headache patients in the throes of an attack—an emerging genre, but hard to watch and, well, weird and probably distancing. And the same would be true, I suspect, if I told you about my own contortions: of writhing on the bathroom floor; of spittle and drool; of fingertips ground furiously into the scalp in a futile attempt to soothe whatever shrieking complex of anatomy is tearing at the right side of my head. It is white-hot, blinding but invisible, frantic but elephantine—all earthly things gathered up in a piercing nuclear bundle behind the eyeball. This also sounds weird, I know. All I can say is that in my shoes, you’d likely feel the same.

Or would you?

Pain is so hopelessly subjective, so personal, so inaccessible, that despite numerous attempts to develop an objective measure of pain, the best we still have in this third decade of the twenty-first century is the so-called visual analog scale, that spectrum of colored cartoon faces, ranked from grimace to grin and from 1 to 10, on the wall of your doctor’s office. A person’s moans or gesticulations can certainly indicate that they are in pain, but the rest of us can’t really measure that pain or know its contours. Might they be exaggerating? The question prosecutes silently from the ether.

A swollen limb, a discolored spot, or an open wound can certainly help to speak for our pain. An MRI’d tumor, or the x-rayed shadow of a break, a tear, or a rupture—these can make a case for us, at the very least giving other people something to see and, with luck, relate to their own memories of painful things. They make our pain tangible. Those unlucky enough to have hidden physical pain, untraceable to an apparent injury and invisible to focused wavelengths of light and magnetism, have only their words—and the pain scale.

I sense my cluster pain as a 10, but really, it’s an 11 or, truly, a 75. There is no cartoon face to describe it. But can I really know you’d feel the same? If I could unzip that pain vestment, that hairshirt, and allow you to slip it on, to feel it against your own skin, would your cartoon face be crimson and sad? Maybe I am weak and you’d wear that pain suit lightly, as an amber-hued 5. I can’t know.

Scientists in the last ten or fifteen years have occasionally declared objective measures of pain at hand. They claim to have located the “fingerprint of pain”9 or the “signature of pain” using functional magnetic resonance imaging (fMRI) or some other flashlight peering into our skulls. But those studies, such that they are, have not led to anything clinically useful. More recently, researchers10 are turning to artificial intelligence and machine learning as potentially objective pain-measurement tools,11 mostly based on vast databases of facial expressions that the AI is trained to interpret. (What could possibly go wrong?) And for unconscious patients12 who can’t describe their own pain, clinicians have tools like the Critical Care Pain Observation Tool, which attempts to make a guess based on breathing, facial movements, and other observed behaviors.

But it’s all just poetry in the end—like trying to describe the color of an atom, or the texture of gravity, or the shape of sadness. We can’t see it directly, and no meter can truly read it. There are no dials to calibrate, no blinking lights. We cannot dip a litmus strip under our tongues and watch the acidity of our pain—because pain is surely acidic—turn the paper red. We can only tell stories about our pain, and hope that somewhere in the fog that separates each of us from the other, a glimmer of insight will break through. Can I create that connection for you? Can anyone illuminate their pain for another person?

Probably not. “Whatever pain achieves,13 it achieves in part through its unsharability, and it ensures this unsharability through its resistance to language,” wrote the Harvard essayist and author Elaine Scarry in her book The Body in Pain. She goes on to cite Virginia Woolf, the patron saint of every artist struggling to paint pictures of shadowy illness: “The merest schoolgirl,14 when she falls in love, has Shakespeare or Keats to speak her mind for her, but let a sufferer try to describe a pain in his head to a doctor and language at once runs dry,” Woolf wrote in her 1926 essay “On Being Ill.” “He is forced to coin words himself, and, taking his pain in one hand, and a lump of pure sound in the other . . . crush them together that a brand-new word in the end drops out.

“Probably,” Woolf added, “it will be something laughable.”

I suspect that Woolf is right. Still, I will try.

I took a megadose of psychedelic mushrooms that spring day because I was having cluster attacks and they wouldn’t stop. For me they came several times a day, and then again whenever I fell asleep at night: violent and swift crescendos of pain that only an injection of sumatriptan, which targets serotonin receptors in the head, could really stop. I was being ground down by the relentless injections, self-administered into an abdomen bruised and pockmarked by previous jabs, and overuse of the medication was likely driving an endless cycle of rebound attacks. Given this unappealing tableau, why not shrooms? It would be just one more in a menagerie of drugs I’ve explored over the decades. Over-the-counter medications like aspirin and ibuprofen couldn’t touch these things—an eyedropper for an inferno. The many prescriptions I’d been given had mostly negligible effects—possibly helpful sometimes, but just as often not—and virtually all were off-label concoctions with harsh side effects that were developed for other conditions. What, I frequently wondered, is behind this ferocious, recurrent pain in my head? And why the poverty of purpose-built treatments? Cluster headache is uncommon, I’ll grant you, but people living with migraine are legion. Can it really be that hard?

In this netherworld of sanctioned chemical exploration, I was quite willing to go to unsanctioned—and even illegal—ends if it had some promise and I thought I could get my hands on the stuff without jeopardizing my livelihood (or life). Pain makes us psychonauts.

So, as my perceptions began to warble and warp, as they do on mushrooms, and as the edges of my vision started to undulate, I felt alive and hopeful that I was zipping up that dirt road, wind in my hair, toward a new salve. Another headache always loomed—unless this time . . . maybe not? I allowed myself to think it as I navigated an ill-advised, psychedelic, but wholly ecstatic path, where undulating fields of yellow balsam root flowers cascaded down the steep slope to my left, and armies climbed the grassy mountain wall to my right. Surely this multitude of golden florets, turning toward me like a crowd to a king, were here to celebrate my triumph? To cheer and pop champagne as I broke through the finish ribbon and crossed over from that old life of being haunted by this angry visitor, to a crisp new life of blue skies and rainbows and, well, surely other annoying problems—but not these fucking headaches.

“I’d first like to thank my wife, Kath, who stood by me on this long journey—I couldn’t have done it without you, babe! [Crowd cheers.] And of course, my friends Eric and Heather, who nurtured this psychedelic prescription into being. Genius! Keep rockin’, dudes! [Laughter.] But really, I’m so just humbled by all of you here, and this is—sorry, I don’t usually cry—this is just a tremendous honor, so thank you, thank you!”

A searing headache came the next day. Maybe I’d done it wrong? Taken too little mushroom? Taken too much? Taken it at the wrong time? Taken it during the harvest moon instead of the waning gibbous? Such are the vexing and deeply pharmaceutical questions of a person dealing with unexplained, recurring head pain. Everyone’s journey varies, of course, and this one is uniquely mine. But there are good odds, if you’re reading this book, that it’s something like your journey too. Or if not your journey, then it is surely that of someone you know. And yes, I will concede: In a world troubled by all manner of disease and unrest, it can seem absurd to bemoan headaches, of all things. Suck it up, right? There are worse fates.

But this implication of malingering—one that we half believe ourselves—is what makes the headache odyssey, and really any passage with chronic or recurring pain, a frequently lonely one. In researching this book, I met swashbuckling and deeply competitive scientists pushing into uncharted parts of the nervous system in a hunt for headache’s headwaters and the downstream generation of pain. They are a small, odd, and sometimes belittled subset within neuroscience and neurology, and while there really ought to be more of them, I am humbled by their obsessions and fascinated by the previously hidden biological axioms they are starting to uncover. I can offer readers who need it this amulet of optimism: there has never been a better time to have a headache.

Still, it’s the fellow headache sufferers I’ve spoken to who touched me the most. In them I witnessed some of the most dignified and relentless displays of perseverance and resolve, even amid bouts of intractable pain and the inevitable quagmires of depression and even self-harm that so often accompany debilitating forms of cephalalgia—the fancy term, derived from the Greek, for head pain. Many of these folks are far worse off than me, and they are sucking it up this very minute, right in front of us: smiling across the counter despite a sleepless night of wrenching pain; making that presentation through a half-medicated ache behind the eye; taking that final exam through the dopey haze of an off-label drug the doctor insisted would help, but really doesn’t; and probably doing their very best, day after day, year after year—sometimes for their entire lives—trying not to trouble you with it too much. It’s just a headache.

*  *  *

This is not a textbook. I am not a scientist nor an academic. What I offer you here is a sweeping and, I hope, accessible and (sometimes) entertaining look at the curious history and long-running scientific struggle to understand, diagnose, and treat headache disorders. For readers who live with them, I hope it is informative and affirming. If it’s someone you love who is unlucky, I hope the book opens new avenues of understanding. And if you know nothing of headaches, you’re in for a ride. The human body is a weird, wonderful thing, but arguably no more so than inside the dense garden of synapses we call a brain—that metabolic crucible where every photon, sonic wave, scent molecule, and tactile input gathered by your sensory antennae is collected and turned. Whether you’re asleep or awake, an endless stream of chemical and electrical communiqués, dispatched from organs, vessels, tissues, and glands at the far reaches of your inner anatomical kingdom are also received, recorded, and answered here. The seat of headache may well be somewhere near the center of this ancient neural hum—a critical breakdown in normal signal processing that can manifest as great pain. The hunt for headache’s origins, then, is not some narrow quest; it traverses the nervous system itself.

On this front, we are in an age of great flowering, and scientists have shaken off decades of presumption to identify new molecular culprits of headache attacks. This means that the long history of relying on hand-me-down preventative drugs designed for other disorders appears to be ending, and pharmaceutical companies are churning out new treatments that go directly after those complicit molecules. Meanwhile, research labs are hunting for yet more consequential targets—perhaps even the Higgs boson of headache, the cephalalgial God particle behind the storms in our skulls.

At the same time, public funding for basic headache research is minuscule in relation to its burden on society, and scientists are uncomfortably beholden to the whims of the pharmaceutical industry. It’s also surprising, despite punctuated moments of innovation, how little we still know about the nature of head pain, such that even top researchers disagree—sometimes bitterly—over what exactly is going on during a headache. They can’t even agree on what it is that’s hurting.

Most of the research in this vein is devoted to migraine, and so too are many of the narrative threads I’ve assembled here. It is, by a wide margin, the most widely debilitating among what are known as primary headaches—meaning the head pain and accompanying battery of other neurological effects that constitute disorders unto themselves, rather than symptoms of some other underlying disease. As far as we know, they are headaches all the way down, and generally outside the reach—again, by a wide margin—of over-the-counter painkillers. Migraine is also radically different from my own affliction, cluster headache, in how it presents itself. Still, it seems certain15 that there are biological affinities between migraine and other forms of severe, idiopathic head pain, including mine. Such headache disorders fall into more than twenty different varieties, but many of them no doubt share common physiological characteristics. What we learn about migraine will inevitably shed some light on related afflictions.

I should also note that this book, while sometimes about me, is frequently about others like me—and very often about women, who represent the majority of migraine patients. While every disorder can make a case for itself as being understudied and underfunded, there is little question that migraine’s cultural framing as a “woman’s disease” has played a role in slowing the advance of headache science writ large. It’s not everything, of course. Men get migraines and other headache disorders too—and they are overrepresented among cluster patients. Also, as with many things where the brain is involved, the underlying mechanics of head pain are simply hard to pin down, and researchers have sometimes labored under theories that turned out to be wrong. It happens.

But when you consider the amount of time and productivity lost to a collection of disorders that render more than a billion people around the world wholly disabled for hours or days at a time, at a cost of tens of billions of dollars per year, it can be surprising that the community of researchers interested in exploring its biological mechanisms is so small.

In the end, it’s probably the word itself.

Migraine, in its most salient sense, is a “headache.” Cluster too. Trigeminal autonomic cephalalgia, hemicrania continua, thunderclap, hypnic, nummular, and a forest of other disorders—they all have a rich array of neurobiological symptoms, but they are all headaches. Attach to a disease a word so diffuse and nonspecific, and you’ve likely established a permanent beachhead for social misunderstanding. It’s a peculiar thing, after all, to have a condition so painful and debilitating share a name with something so ho-hum and unremarkable that virtually everyone on Earth can say they’ve experienced it. The word slips easily into idiomatic veins that signal a mere annoyance, an inconvenience, a catalyst for excuse making. In the cultural kiln where popular wisdom and scientific curiosity are forged, this linguistic alchemy transforms a neurobiological disease into the sniffles.

And yet, as anyone with these things can tell you, there are headaches, and then there are headaches. The pages ahead are about those distinctions too. They matter.

For all these caveats and qualifications, though, this book is mostly another imperfect attempt to describe what words always fail to do; to paint what none of us will ever see; and to ascribe a logic to what science still cannot fully understand.

This is, at its heart, a story about pain.

Chapter 1
A Beautiful Disease

I was disappointed when the doctor came back and told me that I didn’t have a brain tumor—that they’d checked the CAT scan and nothing was found. I can’t imagine anybody else other than cluster [headache] people being disappointed to be told that they don’t have a brain tumor, but I was completely lost. You know it’s not something simple. And it’s not something that’s going to kill me like a brain tumor. So, what the hell is it?

—Bob Wold, cluster headache patient and founder of Clusterbusters, Chicago

I stared at the ceiling as I lay prone on a gurney in eastern Denmark. As one of the oldest and most prominent headache research facilities in the world, the Dansk Hovedpinecenter, or Danish Headache Center—and particularly its Human Migraine Research Unit—specializes in the use of human test subjects. In late 2021, I volunteered to take part in one of the center’s many human provocation studies, which is to say: they were looking to give me a headache.

Lanfranco Pellesi, a boyish postdoctoral researcher at the facility, tightened a compression strap around my right bicep to surface a suitable vein for the cannula, and we chatted as he worked. Growing up in Italy, Pellesi said, he’d been fascinated by American Indian culture—his explanation for the tattoo tracking down his inner right arm: a colorful indigenous motif evocative of the fletching at the nock-end of an arrow. I asked him why he was now here in Denmark, trying to give people head pain.

I had often thought headache researchers must be burdened with head pain themselves, or at least someone dear to them was. I’ve found that to be true in some cases, but not so for Pellesi. He’d toyed with other specialties, he told me, making half-hearted gestures toward worthy areas like toxicology or pharmacology. But he wasn’t moved. “In Italy I completed my medical degree, and then I started—I wanted to do something in research. I wanted to find something . . . wonderful in the nervous system,” he told me. “So, I started to plan something with near-death experiences.”

This got my attention. Was there some mysterious, sensory link between that murky life-death boundary and headaches? It was a flight of fancy, of course, but captive there on the gurney, and perhaps a bit jet-lagged, it made an odd sense to me. There had been times in my life, particularly when the headaches first began in my early twenties and I had not yet been diagnosed, when I was sure that the excruciating pain was a sign of looming death—a tumor or a farewell seizure of some kind. Other times, when that siren of pain in my temple would reach what seemed an impossible pitch, I thought I might be approaching the edge of something, some border beyond which human pain could no longer become worse, and where some downy, comforting place of sweet release awaited.

I’d also spent too many years reading discordant threads of subreddit poetry and Facebook prose from sad people attempting to articulate their head pain—and, I admit, very privately cultivating my own rhapsodic venerations for how they made me feel. This had me highly attuned to any new corollary that might offer an echo or insight into what was going on in my brain. If my experimental sherpa for the day had once considered devoting his life to that vaporous existential border, then I was well primed to believe that there were tendrils of fate leading him there—a cosmic synchronicity connecting life, death, and headache.

Pellesi laughed as I half-heartedly plumbed this connection with him. It wasn’t quite so profound as all that, he told me. There was too little to grasp in the realm of near-death experiences, too little concrete science for a young researcher. He was eager for something challenging, a problem to crack, but one that had broad implications in the world. At some point, he alighted on the rich, mysterious, and surprisingly contentious subject of pain—and specifically, headaches. “It’s a very difficult topic, because it’s so difficult to understand what’s going on,” he told me.

Scientists look for problems to solve, and as a scientific problem, Pellesi said, headache disorders were “beautiful.”

It was refreshing to hear such a thing. I had already learned by that time, through my many conversations with headache scientists, that serious headache disorders like migraine, for example, or cluster headache (my affliction) were largely considered a research backwater. Tens of millions of people in the United States have them, but for reasons both scientific and cultural, they are remarkably understudied. Even today, many researchers, medical students, and clinicians of all sorts will admit when pressed that a headache specialization is often viewed as a province for flunkies and underachievers in neuroscience circles—a redoubt for those without the chops to study more rare and life-threatening neurological diseases.

It’s an unfair characterization. Migraines, clusters, and other primary headache disorders are as marvelously complex as they are widespread. The World Health Organization1 estimates that 40 percent of the global population—about 3.1 billion people—experiences some form of headache disorder. Most of these are the familiar tension-type headache that, while sometimes quite serious and debilitating, can often be managed with over-the-counter medications and perhaps some adjustments in lifestyle. (If you have tension-type headache, please read on, because the fortunes and failings of migraine science have implications for nearly all headache disorders.)

As much as 15 percent2 of humanity—or 1.2 billion people—experiences more wrenching and debilitating bouts of migraine—including anywhere from3 3 to 10 percent of children and teenagers. That amounts to roughly 50 million people in the United States alone. Most people experience migraines during their nominally productive years—from young adulthood through late middle age. Women experience migraine at far higher rates than men, at a ratio of about three to one, while men are more likely to experience cluster headache—a rarer condition affecting less that 1 percent of the population, but still roughly as common as more familiar diseases like multiple sclerosis.

While all of these numbers can be fuzzy, given variability in data collection and quality across the literature and across jurisdictions, it is quite safe to say that at least a billion people grapple with recurrent, severe headache disorders that can interfere with work, hinder learning, foreclose on ambition, exacerbate or even cause depression, and otherwise grind down the unlucky. With cluster headache, the primary symptom is mind-bending pain. It comes on fast and escalates quickly. In the case of migraines, the process is often more gradual. They can be preceded by subtle autonomic symptoms hours or even days before an attack: constipation, food cravings, frequent yawning, stiffness in the neck, or increased thirst and urination, among other signs that an inner storm is taking shape. As the attack draws nearer, some patients experience sensory or motor function disturbances, known as the aura, which is frequently followed or accompanied by acute sensitivity to light and sound, nausea, and severe head pain. Roughly a third of migraineurs experience the aura. For most others, the pain—commonly but not always one-sided, and more diffuse than the concentrated pain of cluster headache—is the first sign that something is going wrong. There are also rarer varieties, sometimes called silent migraine, that deliver the aura, nausea, dizziness, and light and sound sensitivity, but no pain. (Neurologists prefer the term “migraine aura without headache” over “silent migraine,” as a way of acknowledging that these nonpainful symptoms are not silent.) Some patients have been diagnosed with both cluster headache and migraine headache, or some other combination of head-pain disorders. Theirs is a cruel fate.

There is endless speculation and scholarship on environmental insults or biological processes that seem to trigger these bouts—foods, alcohol, scents, stress, menstrual cycles. Some of these are more definitive and easier to avoid or plan for than others, if they have relevance for the patient at all. Clusters are marked by a certain rhythm, often arriving at specific times of year, and occurring at or near the same times of day or night—features that point to involvement of the hypothalamus, our internal clock. Emerging evidence4 suggests that migraine, too, may have important circadian aspects. This varies from patient to patient, of course, and as every headache sufferer knows, perfectly reliable patterns are elusive. Indeed, it’s the unpredictability that is often the most vexing aspect for many people. You may be on a walk or at a restaurant, at home watching a movie, or taking the kids to soccer. You may be delivering a speech before a large crowd, cooking dinner for a friend, or simply lazing alone on a hammock staring at the sky. You may even be sound asleep when it happens. At any moment it can appear, creeping in like a shadow in some cases, ambushing like a predator in others.

Once it has gained hold, it can thrash inside the head for hours or even days. Left untreated, the assailant grows tired or bored on its own, slipping off as mysteriously as it arrived. A person can usually carry on capably from there, but always with a mix of exhaustion and foreboding: the exact time and place will remain unknown, but another attack is dead certain.

The toll of all this is significant. Global health researchers often attempt to compare the burden of different diseases using something called the DALY, or “disability adjusted life-years.” It was first conceptualized in 1990 as part of a World Bank–commissioned study of the world’s health problems, and has since become an institutionalized metric in the global health field. The DALY has its critics, but it is one way of placing the wide gamut of human affliction on a single impact-scale, so that the social and economic costs of different diseases and accidents can be measured and compared. DALYs are a time-based measure derived by combining a couple of other acronyms: years of life lost due to premature mortality, or YLLs, and years of healthy life lost due to disability, or YLDs. DALYs are calculated as the sum of these; one DALY represents the loss of one year of full health. (For disorders that don’t generally result in death, including migraine, the YLL figure would be zero.) It sounds very abstract and complicated, but as the World Health Organization puts it, “Using DALYs, the burden of diseases that cause premature death but little disability (such as drowning or measles), can be compared to that of diseases that do not cause death but do cause disability (such as cataracts causing blindness).”

Think of it this way: If a disease, a disorder, or an injury is associated with a lot of DALYs around the world, it’s considered a bigger burden than one associated with fewer DALYs.

The DALY is enshrined in what is today a multinational endeavor called the Global Burden of Diseases, Injuries, and Risk Factors Study, described as “the single largest5 and most detailed scientific effort ever conducted to quantify levels and trends in health.” It is managed by the Institute for Health Metrics and Evaluation at the University of Washington, with support from the Bill & Melinda Gates Foundation. According to the 2020 Global Burden of Disease6 study, published in the journal The Lancet, headache disorders are associated with a significant number of DALYs among people aged twenty-five to forty-nine, ranking them at number five among 369 diseases or injuries across 204 countries and territories—a few notches below accidents, HIV/AIDS, and heart disease, and well above conditions like stroke, diabetes, and drug- and alcohol-use disorders. For the cohort aged ten to twenty-four, headache disorders rank second, just behind road accidents. “The prominent position of headache disorders in the DALY rankings in the 10–24-year and 25–49-year age groups,” the authors noted, “has received little attention in global health policy debates.”

This struck me as an almost humorous understatement.

A more recent report,7 published in The Lancet Neurology in March 2024, looked specifically at the global burden of disorders that affect the nervous system. The analysis ranked roughly three dozen such disorders, ranging from Down syndrome and multiple sclerosis to traumatic brain injury, Parkinson’s disease, epilepsy, and dementia. Globally, the neurological condition delivering the greatest burden was stroke, followed by neonatal encephalopathy—a broad term encapsulating a range of brain dysfunctions in newborns. Migraine was number three.

The study also broke down disease burden by region. Virtually everywhere—rich region or poor region, global south and global north—stroke was still the highest-ranking disorder in terms of DALYs. Neonatal encephalopathy, however, was much further down the scale in many regions, mostly based on aggregate GDP. Migraine, meanwhile, remained a highly disabling disorder virtually everywhere. In Australasia, which roughly encompasses Australia, New Zealand, and neighboring islands of the Pacific, migraine was ranked number one, just ahead of stroke. So too in Western Europe. In regions of Latin America, it was either the second or third most cumulatively disabling disorder. In South Asia it was third, and in North Africa it was number two—the same as in high-income North America.

By these measures, migraine—and one must assume other, less common headache disorders—are a wildly underappreciated scourge, quietly stripping billions of people of days, weeks, and even years when they might otherwise have been productive, nurturing, and creative participants in the hum of humanity. If that sounds overstated, consider this: by these same DALY metrics,8 the World Health Organization has historically described a day lived with severe, continuous migraine to be as disabling as a day lived with dementia, quadriplegia, or acute psychosis—and more disabling than paraplegia, angina, rheumatoid arthritis, and even blindness.

Perhaps your eyes are rolling now. Mine did too when I first encountered these data. It seems a grotesque attempt to steal sympathy, to acquire a bit of unearned capital—pinching coins from a blind man’s cup. But if I let it turn for a bit, sit with the idea, think about the people I’ve known who’ve had a terrible bout of migraine, consider my own head pain, I start to concede that there may be a useful nugget of truth buried in the actuarial arithmetic. The analogies broker something real. Cluster headache is too rare to be singled out in studies like this one, but during a typical attack, a person is entirely handicapped. “I’ve actually had patients who’ve had an attack during the consultation. You can’t continue talking to them,” said Paul Rolan, an Australian clinical pharmacologist at the University of Adelaide. “They’re totally disabled.”

Could I add up the hours that I’d spent incapacitated in this way, over thirty or so years? Might I include the in-betweens, the periods of low-level dread that come with knowing another attack is always near? What would be the sum? How many DALYs have I lost? I would never bother to find out—and in most moments, I hate thinking about it this way. It still feels hyperbolic. Setting aside those cursed with a chronic form of headache, in which the pain never remits, even the worst headache tends to end, either by way of medication or, for reasons we can’t explain, spontaneously on its own. It might have laid you low for a spell, sure, but it’s gone now, right? Yes, of course, it will come back again, but there will be a respite, an interlude. It returns. It departs. It has a mind of its own. It decides when to visit and shriek, and when to leave with a quiet promise. We’ll brush it off each time, heed the cues, avoid making a fuss. It’s just a headache.

I kept my head pain mostly to myself for the last thirty years, but once I’d decided to write publicly about it, the keystone questions I aimed to explore were infused with a mix of genuine curiosity and withering disbelief: What have scientists been doing to understand and address these disorders? We’ve had some luck in identifying chemical compounds that can sometimes curb migraine and cluster pain when it arrives, but they have a lot of side effects, don’t work at all for many people, and until very recently, these were invariably off-label medications developed for other disorders. Even if you could find a medication that quelled an individual bout of grinding head pain, the next bout remained a near certainty. The bigger questions for me were these: What sets these pain bouts in motion in the first place, and why are they so hard to prevent?

These would strike a neuroscientist as facile concerns. The brain is a wildly complex organ, after all, to say nothing of the latticework of nerves, blood vessels, and other anatomy that work together to connect the brain to the rest of the body. But from the perspective of a person with a headache disorder, the problem can seem exceedingly simple: I experience violent pain inside my head and it keeps coming back. Why?

Sure, we haven’t been able to cure the common cold either, but we know quite a lot about rhinoviruses, which cause that familiar inflammation in the membranes lining your upper respiratory system—principally the nose and throat. And we’ve developed some nifty medications that can help to alleviate symptoms. We can even articulate why the problem of the common cold is so hard to crack: there are some 160 different strains9 of rhinovirus circulating, for example, making a cure-all a mathematical conundrum. A lot of science has gone into colds.

The era of Covid-19—which has been closely linked10 to a variety of headache symptoms—has also demonstrated that humanity can snap quickly in response to an emerging pathogen and begin producing, within the space of a year, an evolving suite of effective vaccines. No, they aren’t perfect, and no, they aren’t very good at preventing infection, but they have, without question, dampened the virus’s ability to fully overcome most people’s immune systems. It’s hard to parse exact numbers, but it’s certain that millions of people were spared the grave in a feat of science that was, yes, messy and poorly communicated, but also remarkable. (For those of you inclined to wonder whether scientists had an inadvertent hand in creating the pandemic in the first place, I share your yen for definitive answers. Science, as these pages will attest, is nothing if not a fallible human enterprise.)

Human brains are arguably more difficult to study closely than external pathogens. But the basic mechanics of migraine and cluster attacks still struck me as something that should be at least as describable as a rhinovirus giving me a cold. It’s pain, right? Something inside your head must be getting twisted, pinched, pulled, pressed, or poked in the wrong way. You stub your toe, you smash your elbow, you break a bone, and you feel pain. Even internally, if you develop an ulcer, or a tumor, or even just a cramp, there are errant, injured tissues setting off that familiar brain-body signal loop that we call pain—tissues we can identify and locate and address. Depending on the severity of the injury or stimulus, that signal might simply nudge us—Hey, did you feel that? That burner is still warm, so be careful—or it might scream: Your leg is not supposed to bend like that! Get help immediately!

But you don’t need to go very far into the headache literature to realize that while the field is accelerating quickly, the precise cause and choreography of these attacks remain mysterious. We’re not even quite sure, after centuries of investigation, where the pain is coming from.

*  *  *

As the eighteenth century was ending, Erasmus Darwin, grandfather to the naturalist and evolutionary theorist Charles, began publishing the fruits of a twenty-year project on the human mind and body. Among other things, he was perplexed by headaches, and he wondered whether strapping a patient to a grindstone and setting it awhirl just might cure them.

Darwin called his work Zoonomia; or the Laws of Organic Life, and over its more than one thousand pages, published originally in two volumes between 1794 and 1796, and occasionally updated in newer editions until his death in 1802, the British philosopher, Enlightenment poet, and experimentally zesty physician sorted the vast menagerie of planetary life into “classes, orders, genera, and species.” By comparing all of these, he hoped to “unravel the theory of diseases”—including a vague constellation of symptoms assembled under the Latin term “hemicrania.”

The word was distilled originally from the Greek hēmikrania, which translates as “half” (hēmi) and “skull” (kranion). If you have migraines, you may already know—or can at least quickly recognize—the lexical pedigree here: the condition frequently delivers pain to just one side of the head.

Etymologies suggest11 that over time, the Greek and Latin terms were absorbed into recipient languages like French, and later English, such that hēmikrania lost its leading hē and emerged, simply, as “migraine.” Darwin used a further English vulgarization, “megrim,” which was common at the time, and whose meaning was somewhat more varied—analogous in some instances with migraine, but also incorporating notions of vertigo, low spirits, and even flights of fancy and caprice. But what’s important is that these terms sought to capture a recurring, typically one-sided, unexplained aching of the head—one that has plagued the human animal for most of recorded history.

Medical explanations for these mysterious disorders have a long and colorful lineage, but Darwin’s primary fascination was with what he called “fibrous motions,” which included the swishing and sloshing of the blood. All disease, he reckoned, could be traced to “the disordered motions of the fibers of the body.” The plight of megrim was no exception, and while he noted a variety of potential causes and cures (a rotten tooth was very often responsible; fatigue in others; and one should never underestimate the power of leeches, or even electric shock, to set things right), Darwin also suggested that the underlying mechanics might well be vascular: too much blood, or perhaps too little, was flowing into the head.

The rough contours12 of this idea predated Darwin by at least a century, though it was often mixed up with the pre-Enlightenment notion that all human disease derived from an imbalance in the four bodily “humors”—black bile, yellow bile, phlegm, and, of course, blood. But Darwin was much more concerned with the kinetics of our internal anatomy, and this extended to his discussions with his contemporary and friend, the British canal engineer James Brindley. In the third edition13 of Zoonomia, published in 1801, Darwin described a visit the engineer had made to a local millwright who’d alighted on what seemed to be a peculiar remedy for insomnia. Brindley had “more than once seen the experiment of a man extending himself across the large stone of a corn-mill,” Darwin wrote, “and that by gradually letting the stone whirl, the man fell asleep before the stone had gained full velocity.”

From the orbit of a gristmill to the gravitational push-and-pull of the sun and moon, the influence of motion both on and within the body and its potential role in human disease intrigued Darwin repeatedly throughout Zoonomia—enough so that he wondered whether a purpose-built contraption, designed to “compress the brain” by mechanically spinning a patient around a horizontal axis, could be used to treat other conditions. “This might be done by suspending a bed, so as to whirl the patient around with his head most distant from the center of rotation, as if he lay across a mill-stone,” he wrote. “. . . For this purpose, a perpendicular shaft armed with iron gudgeons might have one end pass into the floor, and the other into a beam in the ceiling, with a horizontal arm, to which a small bed may be readily suspended. By thus whirling the patient with increasing velocity, speed might be produced, and probably the violence of the actions of the heart and arteries might be diminished in inflammatory fevers.”

While Darwin never14 saw his human centrifuge come to life, his friend, the mechanical engineer and power-unit eponym James Watt, did produce drawings of a “rotative couch” informed by Darwin’s ideas. Patients could be seated or stretched out prone during the ordeal.

From a twenty-first-century vantage, this can all seem absurd. But Darwin, like many of his contemporaries, did grasp that the abiding and harmonious rhythm of our internal anatomy was central to human health, and that disturbances in that intersystemic rhythm might be linked to disease, which is not altogether untrue. It also made some sense, in that light, for Darwin to wonder whether disturbances in our rhythmic blood-tides could be involved in the mysterious disease he called hemicrania. Darwin noted that other doctors of the time claimed that by compressing certain arteries serving the neck, they could produce a kind of “apoplectic state” in a patient, similar to one produced by aggressively whirling a patient around. “By the compression of the two subclavian arteries, a greater quantity of blood will be circulated through the head,” Darwin noted, “whence the patient soon complains of drowsiness and vertigo: and that hence different species of headaches are soon removed.”

Darwin couldn’t help but think that his spinning contraption might achieve the same effect. “Would such a circulating bed,”15 he wondered, “remove any kind of headache?”

Inspired by Darwin’s musings16 on the subject, a trio of American military doctors would take up that question roughly 150 years later, in a research paper published in 1948 in the Archives of Neurology & Psychiatry. Working at the joint Aero Medical Laboratory in Dayton, Ohio, the researchers recruited eleven subjects, nine men and two women, some of whom suffered from headache already, and others who had their head pain artificially induced by exposure to histamine—a neurotransmitter long known to trigger migraines in some people. (Still others were subjected to nonheadache pain while spinning, principally in the form of radiant heat applied to the arm.)

Each subject eventually took a turn in an enormous centrifuge, which rotated them at speeds that would have felt, as the rotation pressed against them, something like two to four times that of conventional earthbound gravity. Did those experiencing pain at the outset see it quieted by the spin? Quite often, the investigators suggested, they did—though the small sample size should strain anyone’s faith in the results.

Nonetheless, “the human centrifuge,” the study declared, “is a useful tool in the analysis of vascular mechanisms in headache.”

*  *  *

At various points in researching what I thought would be simple questions about headache disorders, from quirky historical episodes to modern pharmaceutical innovations, I turned to Andrew Charles, the Meyer and Renee Luskin Chair in Migraine and Headache Studies at UCLA, director of the UCLA Goldberg Migraine Program, and former president of the American Headache Society. Charles is a modest and cautious thinker with a shy smile and a mop of sandy brown hair that belies his thirty-year career in neurology. When I asked him what exactly is going on inside the head during a migraine or cluster attack, his response was characteristically cautious: “I mean, I like to really stay grounded in what we know, which isn’t a lot. But we do know some.”

Unlike other diseases, laboratory animals that might provide a reasonable proxy for studying human headaches have been hard to develop, and most of what we know comes from limited but creative human studies. It’s been a slow and methodical process, usually involving necessarily small groups of volunteers, some with migraines or clusters, some without, and a targeted research question. Many of our current insights come from what we’ve been able to observe through carefully timed imaging of these volunteers while attacks are in progress, Charles explained, or from what we’ve been able to detect by extracting blood and tracing the ebb and flow of certain chemicals as the pain and related symptomology of a migraine unfolds.

These probative approaches are challenging, as they rely on a narrow population of people who represent the experimental trifecta: A primary headache condition, time on their hands, and a twisted willingness to undergo analysis, including, in some cases, while experiencing a spontaneous headache, or one that has been chemically induced. Given that my experiment in Pellesi’s lab only sought to learn if a headache could be generated, I knew that I would only need to signal that it was happening before being given an injection of sumatriptan to shut it down. I am aware17 that some cluster patients have, in fact, submitted to brain scans during an actual attack—often induced but, in rare instances, organic18—though the number is quite small. This is toughness.

Given all this, I suppose I shouldn’t be surprised that scientific advance on primary headache disorders has seemed slow. As one 2023 study spearheaded by the University of Southern California’s Keck School of Medicine in Los Angeles put it: “Imaging patients19 during migraine presents with several practical and ethical challenges, one of which is the exacerbation of participant suffering from migraine due to visual and auditory stimuli during MRI.” As a result, the study added, imaging data from patients in the throes of a migraine is limited.

That’s not to say it doesn’t exist, however, and researchers have inarguably learned a great deal in the last three decades. What they have discerned, according to Charles, is that headache disorders like migraines and cluster involve a complex interplay of cranial anatomy. “What we know in humans, through functional imaging studies, is that certain regions of the brain light up during migraine attacks or cluster attacks. And so, we know that there is activation and inhibition of different brain regions that correlate with the symptoms of migraine or cluster. Something turns those regions on,” Charles told me during a visit to the UCLA Goldberg Migraine Program, a research lab that he oversees. “We don’t know what it is, but fundamentally, we do know that the experience of pain in these circumstances—and other symptoms—is correlated with the abnormal activation of brain regions.”

The second thing we know, Charles suggested—and this is only in the last few decades—is that there are elevations of certain brain chemicals during an attack, and that those chemical levels return to some baseline level, either through spontaneous remission or through treatment with a drug. Remarkably, Charles20 is also quick to note that despite ongoing debate, and despite Darwin and whole centuries of correlated scientific assumption, there is still no good evidence21 that blood vessel dilation—in the head or anywhere else—is a necessary or even sufficient condition for the experience of primary headache pain.

This struck me as both odd and marvelous. I think most of us imagine throbbing blood vessels as the salient characteristic of a headache, no matter the variety—a subjective experience typically attributed to sensory nerves in the head detecting the distention of cranial arteries during systole, or the contraction phase of your beating heart. And yet, studies attempting22 to match the timing of each perceived throb during a headache with each contraction of the heart in volunteers have mostly failed to establish a conclusive relationship. Indeed, while the caveats and nuances to all this would run to hundreds of thousands of peer-reviewed pages, if one were to boil down existing knowledge of primary headache mechanics, these three statements would more or less cover it: (1) key parts of the brain seem to be involved; (2) certain neurochemicals seem to be important; and (3) we still aren’t entirely sure about the role of blood vessels in the whole matter.

As to what sets a headache in motion, which components matter more or less than others in generating various symptoms, including the lacerating pain, and whether removing any particular domino, or combination of dominos, in the cascade of an attack might provide a universal solution—well, all of that also remains unknown. “Everybody has the hardware to have a headache,” is how Emmanuelle Schindler put it to me. She’s an assistant professor at Yale School of Medicine and medical director for the Headache Center of Excellence there. She does a lot of cutting-edge research into psilocybin and other psychedelic compounds as potential headache treatments—fertile terrain that speaks to the conviction that certain neurotransmitters and receptors play key roles in the dance of head pain. I met her at her home on a tree-shrouded cul-de-sac in southern Connecticut. A cuckoo clock on the wall called out as we spoke. “If you hit anyone on the head, or if people get a hangover, they’ll have a headache, because everyone has the hardware,” she said. “But everyone’s software is a little bit different.”

When any person’s software—which might be thought of as running to billions of lines of code—is prone to glitching on its own, absent that thunk on the head or that dehydrating binge the night before, debugging things has proven to be a formidable challenge. Indeed, for much of medical history, headache disorders have often carried suggestions of user error.

In past eras, and even more modern ones, migraines were frequently attributed, for example, to certain personality types—high achievers among the men, or overworriers among the women. The historical literature on cluster headache, meanwhile—and even some scholarship that might be reasonably called contemporary—is replete with what were supposed to be clinically meaningful descriptions of patients’ physical attributes. The trope of lionlike features has always been, for me, among the most laughable: “Individuals who suffer23 from cluster headaches are often described as ‘leonine’ in appearance,” wrote Marilyn J. Connors, an osteopath in the Department of Family Practice at the Scripps Clinic Medical Group in La Mesa, California, in 1995. Such patients were also described as having “particularly masculine body habitus, including tall stature, thick skin folds, coarse facial skin with telangiectasias, broad chin, and well-chiseled lower lip.” (“Telangiectasis” is a fancy way to say “spider veins.”)

While the disease is still thought to skew statistically toward men, these sorts of observational assumptions almost certainly kept women with cluster headache disorders from being properly identified for decades. And for those with migraine, the cultural distillations24 could be withering. Physicians often25 linked headache in female patients with percolating strains of “hysteria” in the Victorian era and beyond. And as recently as 2016,26 the New York Times felt the need to run a health feature making the case that “Women’s Emotions Do Not Cause Their Migraines.” While clinical reliance on such presumptions is much harder to find today, our lingering inability to fully crack the algorithm of primary headache disorders—that mysterious, conditional, if-then loop that governs when and why they happen at all—guarantees that such pat explanations linger.

“I told Dr. Clay27 that I was diagnosed [with cluster headache] by a neurologist in Atlanta 15 years ago,” wrote Karen Mann, a Virginia pastor, farmer, and former athlete, in Please See Me, an online journal devoted to health care narratives. It was published in 2020, and the encounter had unfolded about a decade prior, she told me in an interview. She knew what she had. She had battled cluster headache for years. With its distinct set of symptoms and characteristics, which are unusually uniform across the patient base, clusters are incredibly easy to spot and diagnose. Mann had gone through the standard litany of medications, with middling success, and had recently enjoyed a few years of remission—also not uncommon—before the headaches resurfaced at forty. She’d moved since her previous bout, and “Dr. Clay” (a pseudonym) was her new primary care doctor.

“I gave him a list of which medications worked and which did not, highlighting the need to start these meds soon if there was a chance of them working,” Mann wrote. Her goal, she later told me, was to project calm, and to manage this new doctor’s possible assumptions about her, or about people whose primary trouble is pain. She did not want him to see her cry. “Narcotics are not at all effective for cluster headaches,” she wrote, knowing that the doctor might well suspect a drug seeker, “and I did not ask for them.”

Dr. Clay listened, Mann told me—or more accurately, he sat opposite her while she spoke. And when she was finished, he dismissed her. “I don’t think cluster headache is what is going on here. Perhaps you are just stressed,” he said. “Have you tried taking some aspirin?”

Mann’s outrage was palpable even upon the second telling. What you have, Dr. Clay seemed to say, is just a headache.

This is not to suggest that there haven’t always been compassionate doctors committed to discovering and understanding and treating their headache patients. There were and are. But in ways that can seem unique to headache disorders, physician encounters can still be typified by hurried, dated, and frequently ill-informed recommendations—even as promising scientific and pharmaceutical advances are made outside the exam room.

About thirty-five years ago, drugs known as the triptans hit the market and sparked a revolution. For a significant percentage of patients, they can quell the grinding pain of a migraine in a couple of hours—and even faster for cluster patients, if taken by injection rather than in pill form. In keeping with the notion that migraine and similar headache disorders were a disorder of the vasculature, scientists have long presumed these drugs worked because they trigger the constriction of engorged blood vessels in certain pain-sensitive tissues between the skull and brain, known as the meninges. For many clinicians, the idea that dilated meningeal blood vessels are somehow irritating or activating surrounding pain-sensitive tissue remains the default explanation for why headaches hurt—and for why the triptans, which selectively target and constrict those engorged blood vessels, are so good at shutting down the pain. Others question that and regard vasoconstriction and vasodilation as mere epiphenomena—extras milling about in the background of headache’s key dramatis personae.

Whatever their salient mechanism, the triptans have always been imperfect remedies. For starters, the efficacy rate of the triptans in relieving migraine pain varies widely, from as low as 30 percent28 in some analyses to as high as 70 percent in others.29 The truth is likely somewhere in between, but it’s clear that they don’t work for everyone. Further, the vascular action of the triptans can make them unsuitable for patients with heart-related comorbidities like hypertension—a sizable population. They are also what’s known as an abortive medication—specifically designed to stop an individual headache that’s already underway, rather than preventing the process that results in head pain from unfolding at all. In most cases, the triptans should be taken sparingly, lest they start to cause terrible headaches. And yet, because migraines and clusters are often typified by repeated attacks, sometimes occurring day after day in the former, and even multiple times per day in the latter, many patients overuse the triptans out of desperation, and become ensnared in a vicious cycle.

The elusive thing, the Holy Grail for patients, doctors, and scientists invested in this space, has always been a safe and effective preventive drug—something that would, for a high percentage of patients, stop whatever it is that’s causing these cyclic storms from starting in the first place. For most of human history, that’s proven elusive—and from one angle, it’s not surprising. If scientists can’t be sure what bits of anatomy are drivers and which are supporting players, which activated neurons are pointing toward the root of the disease, and which are merely downstream participants in an attack already underway, it can be very difficult to develop effective drugs. What part of the anatomy, after all, should be targeted?

A promising and recent candidate is called calcitonin gene-related peptide, or CGRP—a neuropeptide first described in the 1980s. Among other things, it is a key chemical messenger in the nervous system’s pain communication pathway. It took three decades for that discovery to wend its way through animal testing, preclinical human experiments, and pharmaceutical company drug development and trials. But in September 2018, an injectable solution designed to prevent CGRP from binding to its neural receptors—a monoclonal antibody called erenumab and sold under the brand name Aimovig—was first approved by the FDA. It had been nearly sixty years since a drug had been purpose-built to prevent migraines—the last being methysergide, an effective but ultimately noxious migraine drug first marketed in the late 1950s under the brand names Deseril and Sansert. Because long-term use30 was linked to a litany of risky side effects, including hallucinations, vision problems, and, most serious, scarring of kidney, heart, and other tissues, methysergide was ultimately discontinued31 in many countries, including the United States.

By June 2019, the FDA had approved the drug company Eli Lilly’s CGRP inhibitor—which binds to CGRP itself to prevent uptake—for the prevention of cluster headache too. Mere months later, after weeks of imperfectly managing excruciating headache pain with lousy drugs and haggling with insurance carriers, I stood in my kitchen—then in Western Massachusetts—hiked down my trousers, and administered three separate injections of the CGRP inhibitor, as prescribed, into my right butt cheek. Alongside a slight burning sensation, I felt a rush of hope and a measure of gratitude that some two hundred years after Erasmus Darwin dreamed of spinning people like me on a millstone, things were finally getting a bit more sophisticated.

Can I say that the CGRP therapy worked for me that first go around? I think so. My attacks abated shortly after—though it’s characteristic of cluster headache to go into periods of remission anyway. In 2020, my wife and I relocated to Montana, and during the 2021 bout that had me tripping on mushrooms and desperately pedaling up a mountainside, the injections seemed to have no effect—perhaps, I reasoned at the time, because I’d taken them too late in the cycle. In 2023, however, I’m quite sure I stopped an oncoming period of clusters before it ever got off the ground by relying on aging CGRP syringes that I have kept in my refrigerator long past their expiry date. Indisputably applying brakes on a bout has never happened for me in thirty years of battling these attacks, and given early tussles with a new doctor in nearby Missoula, who didn’t want to prescribe the expensive remedy, I have hoarded the syringes whenever I can. Headache people hoard meds.

Three years after32 the CGRP inhibitors hit pharmacy shelves, the most coveted prize in neuroscience, the $1.5 million Brain Prize, went to four scientists33 who, often working independently of one another, helped to usher in this new class of CGRP medications. The innovation has helped to nudge a more nuanced understanding of migraines and clusters as true neurobiological disorders—by-products of a still uncertain signaling malfunction in the brain and/or surrounding anatomy. “I’m humbled34 by the emails that we get from patients whose lives have been changed by these medicines,” one of those researchers, Peter Goadsby, told The Guardian at the time.

All of this said, these are not miracle cures. While there’s every indication so far that the new treatments are safe, the long-term side-effects of repeated, prolonged CGRP inhibition are still unknown. More pointedly, some patients have begun to note that, as with so many other drugs that have come before, the effectiveness of the CGRP cocktails can wane over time as patients’ bodies and brains adapt and realize some spirited will to pain. And even while the CGRP blockers continue to prove effective for large numbers of people, for others they have simply been another in a long line of pharmaceutical heartbreaks. Perhaps these disorders are so complex, so multifactorial, and so idiosyncratic that no perfect remedy will ever be found. Perhaps advanced genomic studies will help doctors better identify which patients will respond to which medications so that therapies can be more tailored to our individuated anatomies. Or maybe there is some more fundamental, more universally effective molecular target still hiding in the darkness of our skulls.

This was what Pellesi and his fellow researchers in Denmark were after. This was not an imaging study, but one designed to see if a certain cellular mechanism, triggered by the infusion of a chemical known to activate that mechanism, was somehow intrinsic to the formation of a headache. So, with the cannula in place and an infusion pump attached, Pellesi administered into my bloodstream a carefully measured dose of . . . well, something. By trial design, I could not know what at the time. Even Pellesi was blinded. But the study hinged on a chemical compound called levcromakalim.

As the active isomer of the chemical cromakalim, levcromakalim—pronounced lev-kro-MACK-uh-lim—was originally studied for a variety of ailments, including the treatment of gastric ulcers and preventing cardiomyopathy. Development of the drug35 was eventually abandoned in the United States, however, because monkeys developed heart lesions under prolonged use—though it has more recently been resurrected for use as an investigational drug in the study of head-pain pathogenesis.

I lay down for the trial on two separate days, one week apart. On the first day, I would receive an infusion of either levcromakalim or a saline solution—the precise cocktail selected at random elsewhere in the facility and delivered to Pellesi without labeling. On the second day, I would receive whatever I had not on the first day.

This investigation, which was focused specifically on patients with cluster headache, followed an earlier experiment36 that, while exceedingly small in sample size, had delivered some interesting results. For that study, published in the journal Brain in 2019, researchers at the Danish Headache Center, working under the direction of Danish-Azerbaijani neurologist and neuroscientist Messoud Ashina, had recruited sixteen patients aged eighteen to forty-nine who suffered between one and five migraine attacks a month. The subjects were randomly allocated either 0.05 milligrams of levcromakalim or a placebo on two separate days, between late May and late November of 2017. The goal, again, was to see whether levcromakalim might bring on a migraine—or at least that was the proximate goal.

The real insight, should these brave migrainauts be provoked into a pain that they had undoubtedly spent much of their lives trying to avoid, involved certain molecule-specific gates, or channels, found on the membranes of many types of human cells. Levcromakalim can open those channels, allowing potassium ions to flow out of the cell—a key step, among other things, in managing the ever-undulating electrical charges that facilitate communication from one neuron to another.

If this also precipitated a migraine, it might well suggest that those potassium gates play some key role in the complex and still poorly understood cascade of physiological changes intrinsic to a migraine attack. And if that were true, could those channels represent a novel target for drugmakers? It remains a speculative question. Lots of other substances have long been known to provoke migraine attacks in a laboratory setting. Exposure to nitroglycerin, another potent vasodilator, or the neurotransmitter histamine, which was used by those military doctors back in Dayton in the 1940s, can reliably induce headaches in migraine patients, though neither have led to useful treatments.

But in a field of science so historically bereft of paradigm-shifting successes—and one that now seemed to be brimming with new and hopeful scientific activity—the questions being probed by the team in Denmark were titillating. So, too, were the initial results: every single one of the participants in that 2019 study developed a migraine.

Ashina, Pellesi, and the team at the Human Migraine Research Unit were now wondering whether opening those same cellular channels might induce an attack in cluster patients like me. It was a somewhat more nuanced question. Clusters like mine—technically called episodic cluster headache—come in groups (hence the word “clusters”). I might go months, even a year or more, without any attacks. Then suddenly, they will come, hitting me with bouts of pain two, three, four times a day, every day, for two or three months, only to suddenly stop as mysteriously as they’d arrived. How might levcromakalim affect someone who was in the middle of a cluster period? And would it be different if the patient was, like me in the fall of 2021, in remission—that long period of calm between bouts? (A less common form of cluster headache is chronic, and the sufferer never gets a break.)

These sorts of questions are catnip for certain scientists. “If you’re a migraineur, you’re always a migraineur, meaning if I take someone who hasn’t had a migraine for three months, and I give them an infusion of nitroglycerin experimentally, I can trigger their attack,” Peter Goadsby, one of the 2021 Brain Prize recipients, told me. Goadsby has bounced around, with appointments at Kings College London and the University of California, San Francisco, among others, and he is currently a professor of neurology at the David Geffen School of Medicine at UCLA.

Goadsby is a lucid, colorful speaker, originally from Australia, and his ability to command an audience has won him both admiration from those advocating for more research funding for headache and the ire of some colleagues who see him as having sharp elbows and a tendency to siphon spotlight. But his contributions to modern headache science are inarguable, and his pronounced fixation on these disorders—which he has never experienced himself—can be infectious. We were speaking a month or so after I’d returned from Denmark.

“If [a patient had a migraine] last week, I’ll trigger their attack. If they had it two months ago, I’m still going to trigger an attack—by 80 percent chance,” he said. “And if you’re in a bad bout of cluster [headache], you know, 90 percent chance—and that would be on an unlucky day—to trigger an attack with nitroglycerin.”

But if you’re not currently in a cluster headache bout? There’s the rub.

“Zero. Forget it. Nothing. Zip, boom,” Goadsby said—clearly delighting in the puzzle of it all. “So, something is switching, and I think it’s a switch in the brain—it’s the only sort of way you can think about it—that turns you on and turns you off. If you could understand either what turns it on or turns it off, then cluster is a place where you could get to a cure faster, I think. Because clearly, clearly episodic cluster patients are cured between attacks. Not by anything I do, but by the process. If I understood that, I’d cure the whole lot of them, because it’s there. It has to be there.”

But where? Versions of that question have bedeviled patients and puzzled physicians since headache prescriptions, aimed at driving out the evil spirits, were first described on ancient Mesopotamian papyri—contributing, perhaps, to our complicated relationship with one another’s pain. As a culture, we still frequently attribute unexplained pain to psychological, rather than physical origins. We also continue to discount research into pain disorders, including migraines, that are experienced disproportionately by women—to the detriment of everyone. Our scientific dialectic, for good or ill, still favors, and even rewards, paradigm stasis over innovation and discovery. And many headache doctors and advocates argue that our leading scientific funding institutions still give short shrift to common diseases that, while not necessarily terminal, nonetheless deliver decades of misery to the afflicted.

How much more basic knowledge might we have accumulated—not just related to migraine and cluster headache, but on the nature of pain itself, and the basic structures and functioning of the human sensory and nervous systems—had we been paying more attention to these incredibly widespread disorders? “This is, like, 30 percent of the population probably has this, where you basically are firing off things in your brain, or your occipital cortex is producing a perception, even a hallucination,” Charles told me over coffee on the UCLA campus. “That’s incredibly interesting from a neuroscientific perspective. And yet people just don’t seem to engage with it. It’s sort of like, ‘yeah, okay.’

“Something so common as migraine is likely just skating on the surface of normal brain physiology,” he added. “So, it likely has a lot to teach us about the normal functioning of the nervous system.”

*  *  *

The Danish Headache Center (DHC) resides in a frosty white, two-story facility at the Glostrup outpost of Denmark’s largest public and teaching hospital, the Rigshospitalet. The center is omnivorous in its investigational appetites, including explorations of in vitro and in vivo headache models, human genetics, and epidemiology, as well as biochemical and imaging studies. An engineered hushedness prevails over the Scandinavian aesthetic of the center, which was designed with input from migraine patients—many of whom experience acute sensitivity to light and sound during an attack. Sound-dampening floors, neutral colors, and a soothing reliance on natural light prevail.

At the north end of the second floor, artfully framed canvases painted by headache patients attempt to evoke the soul of a migraine. In one, bolts of electricity float about a disembodied head, a hammer tapping at the temple while incandescent dots float nearby, hinting at visual disturbances. In another, the head of a downward-looking man appears to be splitting along a fault line through the middle of his skull, while a red-faced woman nearby throws her head back in agony. Around them both float smaller, two-faced figures: on the one side, a blank stare; on the other, the figure weeps.

I was drawn to Copenhagen in part because of the DHC’s emphasis on human provocation studies in headache, which intrigued me. The region is also one of the most productive and influential hubs for headache research in the world. It likes to describe itself in promotional materials as “the world’s largest interdisciplinary center for research and treatment of headache diseases,” though this sort of peacocking is as common in medical research as it is difficult to accurately measure.

Still, influential headache research emanating from Denmark dates back at least a half century, and really began to accelerate with the work of Jes Olesen, who established the Copenhagen Acute Migraine Clinic in 1976. Olesen, another of the 2021 Brain Prize recipients, was intensely curious about the mysterious pathophysiology of headache disorders, and he shepherded the growth and consolidation of that early clinic under the DHC name in 2001. Originally dispersed across several different locations on the Rigshospitalet Glostrup campus, the DHC moved into its custom-built home in 2018. It now sees roughly nine thousand patients per year, in addition to conducting primary research into the pathogenesis of headache disorders.

As a comparatively small country, Denmark—which has approximately 230 neurologists37—cannot approximate the sheer volume of research being generated in the United States, which is estimated to have something on the order of sixteen thousand neurologists, according to a 2020 estimate by the market consultancy KPMG.38 (The latest data from the Bureau of Labor Statistics cites a smaller figure: just over nine thousand.39) Obviously, not all of those neurologists are doing primary research, and an even smaller subset—too small, given the burden of these disorders—are devoted to headache. Headache research is also conducted by a wide range of specialists, from neurologists and other neuroscientists to geneticists, molecular biologists, pharmacologists, and others.

Even so, scientific insights born of the Glostrup group, along with Gentofte Hospital at the University of Copenhagen and the wider Rigshospitalet, are frequently cited as among the discipline’s most influential. Together they accounted for the second-largest portion of the one-hundred most influential papers in headache science, according to one 2017 analysis.40 Olesen appears as first author most frequently on that list—tied with Richard B. Lipton of the Albert Einstein College of Medicine in New York.

Speaking in his office in Glostrup, Olesen, a wiry and wizened doctor, bald but for the laurel wreath of snow-white hair encircling his head, relaxes confidently in his chair, legs crossed and striking an almost stereotypically professorial figure. Anthony Hopkins could portray him, I think, in a movie. Or perhaps Larry David. Olesen characterized the landscape of basic headache research and medicine when he first took an interest in the topic in the early 1970s as forbidding. “Those were days when you couldn’t measure anything abnormal,” he said. “Nothing. EET is normal. Scanning is normal. Everything is normal.” I asked him if he thought many doctors at the time still suspected that these disorders were in large part psychological—all in our heads, so to speak. “Yeah, sure, all in your head,” he said, “but also it was considered to be almost impossible to break the code. Because, you know, what can you do? You can’t do an EET, you can’t do a scan, you can’t do blood—blood was normal even during the attacks, and so on. No clear chemistry abnormalities, you know, how can you get to grips with such a disorder, you know, and people just didn’t know what to do.”

As I lingered around this facility and talked with its researchers about neuropeptides and potassium channels, about cellular signaling and the trigeminovascular system, it was easy to think that so much has changed. Olesen continues to conduct his own research at the DHC, turning his attentions in later years to the hunt for clear genetic markers to migraine—an elusive and long-running effort—but the facility is now directed by his colleague and DHC cofounder, Rigmor Højland Jensen.

Ashina, meanwhile—an expressive and ambitious émigré from Azerbaijan with his own well-established reputation in the field—directs the DHC’s Human Migraine Research Unit. His conviction that cellular potassium channels, technically called KATP channels, might well represent a new, more root-level target for preventing migraines and clusters, is palpable.

“All the roads go to Rome,” he told me in his blended Turkic-Germanic accent. He was explaining his quest to nudge upward the number of headache volunteers who might have an attack induced by certain chemical triggers. If one experimental substance triggers 60 percent of trial participants, as was the case with CGRP in early experiments, and another induces an attack in 85 percent of volunteers, as is frequently the case with substances like nitroglycerin, it suggests that you’re tiptoeing closer and closer to some converging pathway, some common biological mechanism that is necessary for all, or at least most, headache attacks. You reach 100 percent the further downstream you go, Ashina told me, pointing to his 2019 study by way of example.

“The question is, if you are so successful at inducing attacks,” he said, his eyes drawing wide and voice modulating to a tone of playful suspense, “what would happen if we developed drugs counteracting this mechanism?” Ashina considers this work the most important of his life. “For me personally, it’s my major—one of my highlights of my career,” he said. “Because this kind of data—it’s not every day that you get this kind of data.”

Years of further exploration stand in the way of confirming Ashina’s suspicions around KATP channels, and not every scientist I’ve spoken with—particularly many of Ashina’s American counterparts in neurology and neuroscience—is as enthusiastic about this line of research as he is. We have long known of substances that have a very high probability of provoking attacks, after all, and until recently, few of them elucidated promising structural targets for drugmakers. But to the extent that scientists are probing the dark contours of headache pathogenesis at all, it’s hard for me to find fault in any particular quest. Let no stone go unturned.

I was thinking about that 100 percent number, and Ashina’s infectious hunt for the universal head-pain pathway, as I lazed in my peekaboo hospital gown helping them search for answers. The results would not be published until late 2023, but at the time I was just happy to be contributing in a small and maybe even weird way, to the furtherance of headache science. In all, forty-one cluster headache volunteers participated in the levcromakalim/KATP channel study at the Danish Headache Center. Seventeen were known to have chronic cluster headache, without remission; ten had episodic cluster headache that was in an active period; and fifteen had episodic cluster headache that was in remission.

I was one of those fifteen.

Chapter 2
The Night of the Train

It’s the constant roller coaster, because you get your hopes up when you try a new medication, like, this is the one that’s going to cure me, right? And then it doesn’t work. And then you’re back at ground zero again, and you try another and think, well, this is the one. And then that doesn’t work. You’re back at ground zero again. And all throughout that process, you’re continually getting worse. And I did—it did affect me tremendously, I mean, to the point where I attempted suicide.

—Jaime Sanders, aka the Migraine Diva, Fredericksburg, Virginia

On a warm evening in the autumn of 2006—some fifteen years before I would find myself skulking around a Danish headache clinic—I no longer cared if I lived or died. I didn’t want to die, exactly. I just had no opinion on the matter, a feeling that washed over me at various other times over thirty years of ingesting, injecting, or inhaling a veritable potpourri of prescription headache remedies alongside a freelance pharmacopeia of “natural” supplements, illegal drugs, and gray-market, choose-your-own-adventure chemical recipes.

So, I was drugged up that night, to be sure, and also a bit self-loathing. I’ve deployed vast stores of mental and emotional energy ensuring that very few people could ever really see and understand just how miserable these cluster attacks were making me. I was embarrassed by it, and I was quite sure I wouldn’t be believed if I dwelled on it at all. Like all headache sufferers, I had no wound to display, no visible mark of disease. So, I’d be quietly thought an exaggerator—a fabulist who conjures disease from discomfort, or seeks sympathy for mild suffering. Maybe, I thought that night, that’s who I am.

Some people were aware, of course—close friends and family. But even with them I avoided talking about it too much, lest it come to define me. And I would move mountains to ensure that no one would ever see me in the ugly throes of an actual episode, much less believe that I could ever arrive at a place so dark that I’d be willing to gamble anything to make it stop. And yet I know that at some crucial point on that particular evening, as I was pacing madly around the kitchen of my one-bedroom apartment in Queens, slapping that side of my head where a lacerating pain was once again growing in intensity behind my right eyeball, the mix of panic and anger that I usually felt in such moments gave way to mental detachment.

I had a supply of ostensibly therapeutic prescription pills and instructions on how to use them. For days before I’d performed the ritual pill-taking: 160 milligrams three times a day; take with food; drink plenty of fluids to offset the common side effect of severe constipation. But as the pain inside my head grew, again, over the course of just a few minutes, from prickly and faint to ferocious and frantic, something snapped. The guarded optimism that keeps patients following the program printed on the side of an amber pill bottle—that delicate faith that there is an answer; that someone knows something about what’s happening to you; that this pharmaceutical ritual, performed as described, must have delivered results for someone, and so it just might work for you—that was all gone. I no longer believed. The doctors didn’t have the answers, and their carefully measured milligrams of hope couldn’t touch the beast inside my head. I was on my own.

Cluster headache is the rarest among the three most common primary headache disorders, according to the most recent edition of the International Classification of Headache Disorders1 (ICHD-3)—a diagnostic compendium published and periodically revised by the London-based International Headache Society. Tension-type headaches are the most common, even if most people aren’t aware of the name or diagnosis, and roughly three-quarters2 of the general population will experience one at some point in their lives. They’re typically bilateral (felt on both sides) and described as a tightening or a pressure—like a band or a vise around the head. Life can be miserable for chronic sufferers, but they are generally considered less disabling than the other primary headaches—migraine being perhaps the most familiar to the average person.

As with virtually all headaches, tension headaches were once thought to be psychogenic in nature—that is, they were products of the mind or the emotions. That bit of medical and cultural presumption has long dogged people with primary headache disorders, and modern culture still retains the residue. It’s all in your head, right? This despite the fact that headache disorders of this sort are quite obviously neurobiological in origin—as much so as epilepsy or multiple sclerosis or any other disease that is easier for onlookers to see. All of which is to say: something very mechanical, very real, is going awry inside the skull.

“Migraine is essentially a disorder of the way the brain regulates its sensory environment,” the neuroscientist Peter Goadsby told me. “The brain gets light, the same as you, but it overinterprets it. It hears a sound, like you do—the same sound—and overinterprets it. It gets a smell, same as you do, and overinterprets it. . . . I think the whole thing is about how the brain doesn’t handle—control—what’s coming in.”

Not everyone agrees with Goadsby, but it’s indisputable that migraine pain is often (though not always) accompanied by other neurological disturbances that further implicate the nervous system—impaired vision, nausea, dizziness, sound and light sensitivity, and a host of other impacts. Some migraineurs even report losing cognitive function, like the ability to read,3 as part of their migraine choreography. And, of course, there’s the characteristic pain: boring, typically one-sided, lasting for hours, and sometimes for days, driving many of the afflicted—overwhelmingly women, by a greater than three-to-one ratio among adults—to seek stillness, darkness, and solitude.

Precisely what kicks off a migraine, or even what exactly is hurting inside the head, is still a mystery, and even top researchers in the field vehemently disagree on some of these baseline questions.

Cluster headache falls into a family of far more rare headache disorders called trigeminal autonomic cephalalgias—with cluster being the most common among them, impacting less than 1 percent of the general population, and three times more men than women. And, of course, there are myriad and imperfectly parsed subdivisions to all these categories: There is episodic cluster (mine), but also chronic cluster (blessedly not). Some migraine sufferers experience aura, and some don’t. Some folks have infrequent tension headache, others have the frequent variety, and so forth. And there are countless other primary headache disorders that plague still smaller populations. These include everything from “cough headache” and “posttraumatic headache” to “exercise headache” and even “sex headache,” wherein the sufferer is thrown into bitter agony at or near the point of orgasm. As with all the primary headaches, no one really knows why.

In my case, the malady is called a “cluster” because of its peculiar temporal aspect: These excruciating headaches, when they come, arrive in bouts, or clusters, surfacing suddenly for an hour or two several times a day—or just as likely at night—and often, though not always, at the same time of day or night, for at least a couple of months each year. There’s also a seasonal periodicity for many patients, with the bouts seeming to come at roughly the same time of year, only to disappear without a trace for long stretches. (For chronic patients, these episodic respites never come.) The tick-tock nature of it all suggests involvement of the hypothalamus, the tiny region at the base of the brain that, among other things, governs the autonomic nervous system and regulates things like body temperature, hormone production, metabolism, and assorted circadian functions. One of the telltale signs of a cluster attack, aside from the frantic behavior of the patient, is a suite of accompanying symptoms arising from activation of the autonomic nervous system, which is not under voluntary control. These include ptosis, or the drooping of the eyelid; miosis, or pronounced constriction of the pupil; lacrimation, or excessive tear production; nasal congestion and runniness; facial sweating; and even perceptible swelling around the eye. Virtually all of these occur on just one side of the head—the one feeling the pain.

Again, scientists still don’t know precisely how the hypothalamus is involved, but these symptoms would seem to strongly implicate a prominent role for it, and PET and MRI studies consistently show activation of the hypothalamus during episodes of cluster headache. The research also sometimes describes cluster headache as delivering some of the worst pain known to humankind, and while neither I nor anyone can pretend to know the pain of others, I can verify that each attack is a wretched thing. At onset, a knot of pain rises deep inside my head, invariably sensed behind my right eyeball. It then swiftly clicks up through the intensity scale, racing past the dull ache you might get from staring at the screen too long, leapfrogging over that doozy you had the morning after your brother’s wedding, skipping past the agonizing-but-fleeting stab of an ice-cream headache, and arriving, within a matter of minutes, at a pain so piercing and sustained that it cannot be tolerated sitting still. Each arrival—always with little warning and ratcheting up quickly to a scream—is an emergency.

For nearly all cluster patients, alcohol is anathema during periods when the headaches are coming, given its near dead-certainty to bring on an attack. (As with other substances known to trigger head pain in a clinical setting, the precise physiological mechanisms at work are unclear.) For a modest percentage of people with cluster headaches, meanwhile, the most familiar components of cannabis—cannabidiol (CBD), as well as tetrahydrocannabinol (THC), which is what gets you high—can sometimes help4 to reduce the number of attacks. I had been a marijuana dabbler since high school—not a stoner, per se, but also not opposed in any way to weed—and the weak evidence for its efficacy in headaches was enough to make me want to try. So, as the attacks came on that fall, I combined small doses of cannabis with a variegated menu of over-the-counter supplements recommended to me by self-help forums online: an imperfect admixture of magnesium, vitamin D, inhaled capsaicin—yes, the stuff of hot peppers snorted up the nose has long been suggested, without great evidence, as a potential cluster headache remedy—and other nonpharmaceutical nutrients. And then, of course, atop all of this were the official prescriptions—the front-line, first-order, textbook-sanctioned medications for headaches like mine. These included prednisone (a powerful steroid), an antiseizure drug called topiramate, and a calcium-channel blocker known as verapamil—none of them originally developed to treat headaches.

I also had needles—precious, precious needles.

These were miniature glass syringes, preloaded, two each, into double-barreled plastic cartridges about half the size of a pack of cigarettes. Each vial contained 0.5 milliliters of sumatriptan succinate, a member of the triptan family, exquisitely designed to seek out, bind to, and activate serotonin 5-HT1 receptors in the central nervous system. This has a variety of molecular-level effects, and while modern medicine still cannot fully articulate why, one by-product when delivered by injection is the very rapid silencing of cluster headache pain, usually in a matter of five to ten minutes for a great number of patients—myself among them.

The cartridges were a distinctive color of blue, and I would often wonder how much time and treasure GlaxoSmithKline, the British pharmaceutical company that made them, had spent getting to that color. It was a winsome, autumn-sky blue that, over time, I could spot with raptor-like precision through a single squinted eye while clawing—neck cocked to shoulder in a sympathetic pain response—through a tangle of toiletries in a Dopp kit. Did someone dream up that blue? Some product designers? Did focus groups nudge things this way or that until the marketing team arrived at this plastic azure? It was genius. Or maybe just incidental? I didn’t know. But it was a blue that said, I’ve got you, and I heard it and believed it—grateful to the point of reverence for a ration that the American medical system, and GSK’s own mercenary grip, had made absurdly difficult to get.

When the time came, my doctor instructed, I needed only to insert the accompanying “pen”—a pale gray plastic tube—into one of the blue cartridge chambers, turn, and withdraw. A button—also happy-day blue—sat atop the injector pen. The other end was to be pressed firmly against some fatty bit of skin. Depressing the trigger would release a tensioned spring, catapulting the short needle straight down into the flesh. Over the years I would come to favor the belly as my target, but any suitably soft, fleshy area, I was told, would do just fine. The injections were somewhat idiotproof—not unlike an Epipen used to treat a severe allergic reaction—and subcutaneous, meaning I’d insert the needle and disperse the liquid only as deep as the tissue layer between the skin and the muscle. This would trigger a physiological response more swiftly than an oral medication—a boon for cluster patients who would otherwise be left writhing on the floor for an hour or more while waiting for a capsule or tablet to wend its way through the digestive system and into the bloodstream.

Inhalers had also been developed as something of an intermediate option for delivering sumatriptan, based on the notion that access to the bloodstream could be gained a bit more quickly via the nasal passages, though even a lightly congested nose—something that commonly accompanies a cluster headache—could easily blunt that pathway. I found them useless.

High-flow oxygen inhaled through a non-rebreather mask at a rate of something like ten to fifteen liters per minute is really the only other remedy that can quickly abort a cluster attack for some patients, though no one quite knows why. Some experts still speculate that the constriction of the blood vessels, which occurs with deep draws of oxygen, is the central mode of action. Other researchers5 have suggested that oxygen may trigger a class of receptors found throughout the body—including the central nervous system. The receptors respond to naturally occurring molecules of adenosine, a nucleoside that, among other things, can influence the perception of pain.

Whatever its mechanism of action, I’d read enough patient testimony online to know that those who used it found it immensely helpful, and I understood it to be far less noxious than repeated sumatriptan injections. So, in my early days with cluster—and even at various waypoints over the last thirty years—I was intensely curious. From my research I knew that finding a doctor who would prescribe something that had never really been properly studied as a remedy, under controlled settings, was unlikely, as would be getting any insurance company to cover it. The alternative, frequently shared in the online cluster headache kibbutzim, was to obtain a tank of industrial oxygen from a welding supplier and make a go of it yourself—potential impurities and other risks notwithstanding. I did not relish the idea of presenting at work, or anywhere out in the world, with an oxygen tank in tow, but I did explore this avenue precisely once, during that terrible season in 2006, with a mask purchased online and a small tank obtained from a nearby warehouse in the vicinity of the bridge to Rikers Island. I felt vaguely criminal in the enterprise, knowing that I planned to inhale the stuff rather than bind metal with it, but I pressed ahead, guided by baroque online instructions from fellow travelers. When the next attack came, I tried it to no avail—almost certainly because I did not purchase the right kind of mask, or was clumsy at controlling the flow rate. In the rising crescendo of pain, I was also quick to surrender and reach for an injection.

Those beautiful injections! They were my panic button. My escape hatch. They were a protective talisman—an arsenal of silver bullets neatly arrayed in my backpack, ready to dispatch the beast when it returned. During months when my headaches would mysteriously fade away, I stored whatever cartridges I might have, like a trusted revolver, in a shoebox under the bed, or stashed high on a closet shelf. I’d return to that shoebox now and then, touching it to make sure it was real, even opening it sometimes to lay eyes on the calming blue. During the months when the headaches came daily, sometimes hourly, I would jealously count those blue injections like a Scrooge, worrying over their limited number, wondering whether they’d last.

As much as I cherished these injections, sumatriptan is intended6 only as an “abortive,” designed not to prevent headaches, but to stop a single episode in its tracks. Taken too frequently, it can cause a cycle of even more severe rebound headaches,7 wherein the hapless user chases one dose after another of a drug that both stops, but then later starts, mind-numbing pain. In short, it is intended mostly for sparing use—the ax behind the glass.

Being still somewhat new to the headache therapeutics marketplace of 2006, and still locked down by a GSK patent, the drug—and the injections in particular—was also still wildly expensive, costing hundreds of dollars per unit at the time. Insurance companies would typically cover only a precious few per month. To make the medicine last, I would eventually learn to discard the spring-loaded injector pen altogether, choosing instead to pry the glass vials out of their pretty blue cartridges and then ration that 0.5 milliliters, sticking the needle into my belly manually and then gently pressing the rubber plunger down with a cotton swab, administering just a half, maybe a third of the elixir. Against all tenets of medical hygiene, I would then slip the used syringe and its remaining liquid back into the blue cartridge for use again later, when the next emergency struck.

I was lucky that most of the time, the partial payload was enough, and within a few minutes I would feel a tingle, first in my legs. In another sixty seconds, the sensation would rush upward along my back, onward to the nape of my neck, and ultimately into my head, where it registered as a slight tickle behind the ears. It was heroin-esque and euphoric in its way—a swift and wonderfully prickly dissipation of a pain that would have otherwise set me rocking wildly back and forth in agony. On a few occasions, I wept as the pain left me, often out of pure weariness, but also sometimes out of sadness and frustration. I also think those tears had shades of joy—joy that science and commerce, however bluntly and inelegantly and stingily and unevenly, had conspired to give me, if only for this one moment, a way out of a nightmare.

And yet. And yet . . .

I was in trouble. This particular bout of headaches had flared up at the end of August, and my doctor, who would show me the ultimate kindness by hoarding for me the free samples of sumatriptan injectables handed out to him by drug company representatives, had nonetheless failed to convince my insurance company that one or two injections per month were incommensurate with the documented nature of cluster headaches. And despite my own schemes to make the injections last, I was down to just one cartridge, with more than a week left before a prescribed refill.

This had me arranging to work from home whenever I could so that I could bear down and ride out the headaches privately. For me they tended to last at most a couple of hours, often less, with several hours of calm in between. Working from home, I could be at the computer for reasonable stretches, stepping away as needed to face down the demon alone. As is the case with many primary headache patients—and cluster headache patients in particular—hiding the attacks was extremely important to me, and I was blessed to be able to conceal them from most of my colleagues.

This is, after all, not a pain that can be talked through or endured in polite, professional company. Untreated, a cluster headache gives rise to rapid pacing, rocking, stomping, and other grotesque contortions—ugly grunts, involuntary tears and outward flows of nasal mucus, and ritualized head slapping and other forms of manic self-harm which, aside from being personally torturous, would cause great worry to onlookers. Today, some brave cluster patients have allowed themselves to be filmed during an attack, and to have their contortions published on YouTube and other websites. A collection published8 by BBC News in 2017 provides an accessible overview, if you are curious, but I’ve personally not been able to watch such things—and back in 2006, these representations were rare, if they existed at all. That was fine with me; I simply did not want to be seen like that, particularly by co-workers. After witnessing such a spastic display, they might offer polite expressions of worry and sympathy, sure. But despite my assurances that I’m fine and can continue to be productive and even thrive in my work, I’d forever worry that I’d been privately marked a weak link. An injured calf. Dead weight.

Was my worried mind wrong? Maybe so. But on that autumn evening in 2006, I was keeping that last syringe in its pale blue casing, saving it for a moment when I could not hide, when I had to be present. I was getting hit with clusters two or three times a day at that point, and in desperation, I was leaning doubly hard into whatever preventive meds—the prednisone, the verapamil, the topiramate—I had on hand. In some cases, these were pills obtained through a current prescription. Others were leftovers from previous bouts and previous doctor visits, hoarded detritus that could nearly always be found in the back of my medicine cabinet, rattling around in the bottom of a backpack, or stashed into drawers around my apartment. Nothing seemed to be working, and I’d taken to experimenting with my own combinations—and more precariously, my own dosages, edging ever upward in a clumsy attempt to stop the next attack.

It was a Sisyphean strategy. Topiramate, discovered in 1979, was developed to treat epilepsy, but some doctors observed that patients frequently reported an unrelated decrease in migraine headaches, and so its off-label use for migraine and even cluster headache treatment grew. It made me stupid, and occasionally uncoordinated and dizzy, but it did nothing for my headaches that I could discern. Still, if I had it on hand, I would take it. Any port in a storm.

Corticosteroids like prednisone, meanwhile, do have powerful anti-inflammatory and immune-suppressing properties, and they can have near-miraculous effects on a whole host of miseries, including causing cluster headaches to temporarily vanish. The problem is that steroids are also famously toxic. When taken at the sort of high doses needed to control clusters, prolonged use can cause muscle wasting, osteoporosis, glaucoma, cataracts, “steroid dementia syndrome,” and a host of other diminishing returns. It gave me predictable relief from the attacks when maxed out at eighty milligrams per day, but the prescribed course at that level was always necessarily short, and as the dosage was tapered down over the subsequent ten or so days, the attacks would start breaking through again. That night in 2006, I was at the end of the taper.

At that time, verapamil was still the most common frontline approach to cluster headaches—though it was never developed as such. Its key characteristic is the ability to block the movement of calcium ions into cells, principally those of the heart and the arteries. The influx of calcium molecules into the smooth muscle cells of the blood vessels has the effect of augmenting their tone and rigidity, which in turn ratchets up blood pressure. Blocking this calcium-signaling process has the opposite effect, slackening vascular tone and, in turn, decreasing overall blood pressure. That’s why verapamil is approved and marketed, among other things, as a treatment for hypertension. But interfering with calcium channel signaling can have a variety of other, unapproved, off-label effects that, over the years, doctors have nonetheless found useful—including in the treatment of migraine and, in my case, cluster headaches.

Given the prevailing view that primary headaches were, at their root, vascular diseases, it made some sense that verapamil might be efficacious. And in any case, it has fewer potential side effects than prednisone—chiefly constipation—and it can be taken as a preventive for longer periods of time. In most cases at the outset of treatment, doctors recommend that daily doses of verapamil be paired with the steroid, the latter being used to cease the bouts of pain while the former builds up in the system as the primary pain blockade. It’s not perfect and does not work for everyone. In many cases, headache patients need to take obscenely high doses of verapamil to elicit any sort of relief—so high that baseline and ongoing cardiac monitoring is sometimes necessary while taking it. If it does work, however, it can be well worth the risk for people who otherwise would be cycling through repeated bouts of gnawing head pain.

It worked for me sometimes, somewhat. Not always. Or did it at all? It was impossible, really, to know, given the many chemicals I was ingesting and the mysterious tendency for repeated cluster bouts to suddenly vanish on their own. Was it the verapamil? Something else? Or were the headaches just done with me for now? It didn’t much matter. In my misery, I would venture nearly any potential avenue to relief, and so I took the verapamil—first as prescribed at 80 milligrams three times daily, then, as per the typical regimen, ratcheting up by 80 or so milligrams until a therapeutic dose was reached—usually about 480 milligrams a day. By that night in September, though, I’d abandoned any sequenced approach and was already self-experimenting, out of sheer desperation, with far higher doses of 960 milligrams or more.

At some point, I stopped counting milligrams at all.

*  *  *

“Stress” is a tricky word when it comes to head pain—particularly migraine. It taps into decades of overly simplistic diagnostic tropes that, absent any other solution, simply encouraged the headache sufferer to relax more, to not worry so much. At the same time, stress is a chemical and hormonal event—a wash of adrenaline and cortisol, courtesy of the adrenal gland. In that sense, stress can be like any other headache-triggering input, whether it’s a laboratory-introduced exposure to nitroglycerin, a celebratory glass of red wine—rich in tannins, flavonoids, and other chemicals—or a waft of strong perfume that slips into the olfactory system and somehow activates the trigeminal nerve, which delivers sensory information from the face and head to the brain. In those genetically prone to it, a looming performance, a family crisis, or other stressor sets in motion a poorly understood neurochemical event cascade too—very often resulting in terrible head pain. Some good evidence suggests that for many migraine patients, the migraine-production machinery is set in motion in the twenty-four or so hours after a stressful event has passed, leading to what is sometimes called9 a let-down headache. The problem with all this is that migraine attacks can just as often come on with no discernible pattern or exposure at all.

Stress is rarely associated with the incidence of cluster headache attacks, though I tried for years to test the idea, keeping notes and spreadsheets to document any potential pattern in what I might be feeling or experiencing at any given time at the onset of each cycle. Aside from the imperfect but inarguable rhythmicity of individual attacks—they can reliably yank me out of a sound sleep, for example, and strike with some predictability between 9 a.m. and 11 a.m.—I have never been able to personally connect stress to the onset of an attack, or series of attacks.

That’s not to say that in the autumn of 2006 I wasn’t subject to the ordinary trials of maintaining a reasonably ordered adult existence and a midstage career. But my life to that point, and in the aggregate, had been no more or less weighty or put-upon than that of the collective mean. I had been divorced for years. I was advancing in my career as a journalist, albeit with an undertow of restlessness. And by most accounts I would have been considered both established and well paid—at least in the impoverished context of my fast-eroding profession. In sum, I had an average assortment of bills to pay, relationships to nurture, breakups to navigate, hopes to pursue, and failures to mull. But none of this ever seemed to coincide with the emergence—or the retreat—of these painful bouts. The shadow of a cluster period was as likely to sweep over me in the middle of an otherwise Zen-like vacation in the mountains of Oregon as it was in the throes of an investigation10 into the safety of nuclear power plants in the United States. (I had wicked bouts during both events.) Many of my most demonstrably stressful periods, when I might be crashing on deadlines, or traveling relentlessly, or watching a cherished relationship curdle, were entirely headache free.

If anything, individual attacks seemed more aligned with my most relaxed moments, and for many patients—including me—it is quite common11 for the most severe and excruciating cluster attacks to come, night after night, just a couple hours after blissfully falling asleep. This widely recognized characteristic of cluster headache is one of the stronger signals suggesting a role for the hypothalamus,12 the brain’s biological clock and the neural structure regulating, among other things, sleep-wake cycles.

In 2006 I was covering a variety of topics related to the dark side of the still-youthful internet for the New York Times: Nigerian internet fraudsters, identity theft rings, the rise of blogs, and the treadmill sagas of customers attempting to cancel their AOL accounts. It was a varied and exciting beat, and I was doing reasonably well in what would have been my eighth year at the paper, having started there just out of graduate school in 1998 as a producer for the fledgling website nytimes-dot-com—at the time housed a few blocks away from the paper’s headquarters, in a glassy office building known as the Hippodrome Center.

The building had been named for the famed theater that had occupied the same corner at Sixth Avenue and Forty-Third Street until 1939, and somewhere along the way that first summer, I’d learned that the magician Harry Houdini had performed in 1918 at the Hippodrome Theater, famously making an elephant13 disappear on the stage. When the pain became unbearable during my Hippodrome days, I would slip into a bathroom stall to ride it out, rocking rhythmically back and forth astride the toilet (the one in the corner if I could get it), and quietly reciting plaintive abracadabras of my own, hoping to make the beast in my head, like Houdini’s elephant, disappear.

By then I was already accustomed to the attacks, which had begun in my early twenties. I wonder sometimes if my dalliances in drugs and booze and cigarettes as a young person played a role in the headaches—were a trigger somehow, a key that unlocked something in my brain that, had I the good sense to avoid it, might have spared me decades of anguish. Recent research offers14 some compelling if inconclusive evidence that nicotine might act as just such a chemical “on switch” for cluster headache, irrevocably changing some aspect of certain brains that are genetically primed for it. But even here, the data paints a confounding picture: some cluster patients have never smoked, and few find relief by quitting.

I was invited in the late summer of 1998 to leave the Hippodrome and come over to the mothership on Forty-Second Street, and in the ensuing years I drifted like a Zelig from desk to desk—a reliable scribe and editor with promise, but also a love-hate relationship with the spotlight and a habit, as often as not, of gravitating to the edges of the action, rather than to the center of it.

I would go on to write a smattering of front-page stories—a prison profile of a young identity thief, an investigation into underground websites trading in stolen credit card information, the debut of electronic voting in the United States—but even with these I felt as though I was keeping my job, along with my relationships and any sense of real ambition, at arm’s length. In my heart I wanted all the things—a rich journalistic career, foreign assignments, the minor celebrity that comes with it all. But as the headaches continued, I became more exhausted than anything else. The menagerie of prescription drugs could help me manage, but I frequently shrunk from opportunities within the paper, feeling more like a lurker, a dabbler—dipping a toe into potential oceans of success when the headaches vanished for a time, only to withdraw and seek out a quiet corner of the operation to cling to while the pain took over.

It’s a familiar refrain among migraine and cluster headache patients: the struggle to manage a life, to self-realize, to rise to opportunity amid the persistent and largely unpredictable threat of debilitating pain, and to escape the wretched tether of whatever interventions we cling to. “I have seen doctors, neurologists, heart doctors, nutritionists, naturopaths, psychologists in two countries,” one migraine sufferer, Emily Walding, told me in a wrenching email message. Emily, a thirtyish music label executive, is originally from the UK and now living in Canada. She first started having migraines at the age of eight, and she was never the same.

“The migraines seemed to come out of nowhere. I still to this day don’t know what caused them, I can only presume hormonal changes in my body. One day I was a healthy, normal child and the next minute, I was a child with a medical condition. I was home-schooling myself and I spent a lot of time in bed in tears.

“I have vivid memories of the pain—a pain which has changed and evolved over time. But at this age, up to my early twenties, it was excruciating,” she said. “I would go blind in both eyes in the center of my vision. I would be sick—boy would I spend a lot of time being sick—until I didn’t have the strength to be sick anymore. I would cry, looking to my parents for help but they were as shocked as I was that they offered little relief.”

At one point, she was sent to an optician and given glasses as a purported remedy.

“I took more painkillers than a child should. I was missing so much time from school that my parents were getting called in. . . . I’ve had parts of me cut out and tested on. I’ve lost more days in bed than I care to count. . . . My condition is currently, with a working-from-home lifestyle, manageable. But I am very much that girl who is one minute a healthy, hard-working, high-flying career girl, and the next minute, needs hospitalization and critical care.

“It’s something which I still struggle to come to terms with,” she added. “Even typing this it feels like I am writing about someone else.”

Joel McCleary, a former treasurer for the Democratic National Committee and a White House assistant during the Carter administration, shared his history battling cluster headaches, which came on in his forties—uncharacteristically late in life. “I called it the freight train effect,” he told me. “I would I get a little tingle, and then before I realized it—they just came on so fast. I’ll be at a dinner table or something, and I’d just have to get up and go right—I mean, it would interrupt a lot of things in life. And of course, then it started changing my behavior, because I think it destroyed my marriage—my second marriage.”

I asked him how. “Well, because I’d be sitting there and all of a sudden I’d be howling on the floor or, you know, jumping out of a car and it’s—it’s hard to, if you live within a family context. . . . It’s not easy for people to live with somebody with a cluster headache.”

*  *  *

A different sort of train came for me that fall. I was deep into an investigation into a mortgage fraud scheme for the paper, and through it all, I was experiencing uncontrollable headaches. Whatever relief I’d obtained through the high pulse of steroids my doctor had prescribed was now wearing off and the attacks were breaking through. Between phone calls and emails I was ingesting high doses of magnesium; inhaling up my nose regular squirts of water and capsaicin; popping calcium-channel blockers like candy; and practically mainlining caffeine, which sometimes seemed to abort an individual headache if taken quickly, but also, probably, helped to make the headaches worse overall. It was, as with most of my bouts with cluster headache up to that point, a chaotic time marked by repeated attacks of excruciating pain and long, miserable nights spent craving and yet dutifully avoiding sleep for fear of triggering that regulating blob in the center of my brain into another nighttime spasm. I was physically fatigued and medicating myself with absurd tides of chemical experimentation and excess.

We put the story to bed that evening, and it would run15 on the front page the following day. I tried to feel a sense of pride for my role in pulling it together, but as the shadows grew long over the low-rise walkups and brownstones that stretched out from my fire-escape view, I mostly felt defeated. Somehow, everything always came back down to these headaches. I might be able to still an individual attack, but another attack would soon return, and then another, and another. I also felt ashamed that something so banal, so common, and so inconsequential as “headaches” was bringing me to my knees.

I knew intellectually that I ought not feel this way. My reading of bizarre case studies in dusty library stacks, and intelligence gathered from bleary-eyed forays into internet bulletin boards, made clear that the pain of a cluster headache was a category difference, and that anyone who suspected otherwise was simply blessed by their ignorance. But when you get worn down enough, the broad and supportive perspective—that vital and sustaining span of intellectual scaffolding—seems to just crumble beneath you. You’re too tired to find the solace, too blurred and blinkered to mount the counterargument, too blank to register one more redemptive spark.

I was brushing my teeth when I heard my freight train. That’s what I remember.

It was probably eight or nine o’clock at night, though I’m not certain of the time. I was standing in front of the narrow, whitewashed vanity, staring into the drain as I brushed. I was about two hours removed from the last attack. I can’t be sure, but by my subsequent reckoning I had probably swallowed well over 1,500 milligrams, perhaps more, of verapamil over the course of the day, alongside numerous other substances. I remember off-handedly reasoning—perhaps not precisely on that day, but at some point in the fullness of my mangled attempts at disorder management—that some studies had suggested daily doses as high as 960 milligrams of verapamil might be required to control recalcitrant clusters. This was considered worryingly high, though, requiring some degree of careful physician oversight and monitoring of vitals.

But I wasn’t thinking about caution anymore. I’d long ago blown past caution. I just wanted the attacks to stop. I needed the attacks to stop. I had these pills, and I was going to take them until the attacks stopped.

The noise started as a low rush—like the thick, displaced air of a distant but fast-approaching engine. It wasn’t the familiar rattle-and-hum of the elevated N line, which passed a few blocks to the west of my windows, but the gathering storm of a locomotive. I recall thinking little of it at first, and I continued my brushing routine, staring thousands of miles across the emptiness into the sink’s black drain hole. If I was having higher-level thoughts—contemplating the next day’s A1 laurels, for example, or worrying that we’d gotten the details right—I don’t remember them. All I can conjure is that train, far away at first, and then gathering in intensity, rising to a roar, as if for all the world I was straddling the tracks.

At some point the sound moved from the background of my consciousness to the electric center, and I remember snapping my gaze upward, into the mirror. In the ages of a millisecond, I took in my face, my cheeks—now bloated and flabby with the lipid deposits left behind by the steroids—and then the darkened circles under my eyes, and then the eyes themselves. I locked on them, the train now thundering, and stared at someone I failed to recognize. Did I smile at myself in that moment too? I imagine, sometimes, that I did.

I took a jerky, spastic step or two to the left—a lunge, really—toward the door and the narrow corridor outside the bathroom. I was conscious that something was going wrong, and that I needed to get somewhere, to be prone, but the details are lost. My memory grows murkier from here, but I recall the darkness of the hallway, a crack of lamplight spilling out from the bedroom just a few feet ahead, and the floor rising unevenly beneath me, as if I were now at sea, the whole apartment now listing in a gale, heaving hard to the portside and taking me with it.

Then blackness.

I would later calculate that two hours had passed before I regained consciousness, face down on the hardwood in my bedroom. Verapamil toxicity16 is serious stuff, and I’d pushed the limits. The admixture of other things I was taking—the steroids, the cannabis, the caffeine, the anti-seizure medication, the magnesium capsules, the vitamin D supplements—almost certainly played a role too. But at root, I had very likely crippled too many of the cells in the smooth muscles of my heart and blood vessels—blocked their ability to take in those calcium molecules. Absent these,17 the electrical signals that govern circulation, that contract the heart, go weak, even silent.

With my cheek pressed to the floor, I could, with great effort, shift my head and pan my gaze enough to gather that I’d tumbled several feet forward before fully collapsing. I could see the toothbrush on the hallway carpet. I could see that my bedside lamp was now on the floor, still lit. But my hands, my legs—everything was pressed fast and immovable to the floor, paralyzed by a heart rate that I would later understand to have been made deadly low, unable to pump sufficient blood to my limbs to even make them move.

Over the subsequent hour, I would somehow shimmy myself, one wormlike lurch after another, across the few feet separating me from the bed, stopping and blacking out again at regular intervals. I have no recollection of eventually heaving myself into the bed—and I also have no recollection of even considering more urgent action, like, perhaps, calling 911. I can’t explain it, exactly, save to say that I felt vaguely happy and unworried in those drifts of consciousness, maybe a little intrigued? Mostly I felt weirdly at peace, satisfied that I’d managed to reach deep into the molecular soup of this malfunctioning body and fuck things up good and hard. I went in there and kicked over tables and broke things, showed the inner corpus that I had power too. I could touch things in there—big, systemic things. Don’t mess with me.

I woke the following morning to blood on the pillow. The skin was split just above the outer corner of my left eye, and the wound now sat atop a throbbing, golf ball-sized knot on my temple. I remember none of the climactic impact, but I’d clearly landed like a rag doll, floppy armed and unaware of a freefall.

I understood what had happened. I knew I’d crossed a line. I even knew, if I’m honest, that I crossed it deliberately, maybe even a little hopefully, but at the very least without a care. And after calling into the newspaper and letting my editor know that I’d again be working from home that day, before I’d even righted the lamp or tended to the dried blood on my head, I registered an abiding sense of thanks—not because I’d survived a reckless overdose, but because I had finally slept through the night without a headache.

Chapter 3
Holes in the Head

What could I have done? Would I have settled for things that I’ve settled for, you know, in my life, had it not been for migraine? Who are the people that would have been in my life that are no longer in my life because of migraine? It affects your entire being physically and emotionally and psychologically. It envelops your life and those around you. You’re existing, you’re not living.

—Kathleen J. O’Shea, author of So Much More Than a Headache, Rochester, New York

A display case in a conference room at the Diamond Headache Clinic in Chicago is brimming with memorabilia and assorted curios from headache’s colorful past. On one shelf, a collection of nineteenth- and early-twentieth-century medicinal relics promise relief in the form of potions, pills, balms, and wafers. In a tall box depicting an American Indian holding up a fistful of vegetation, Dr. Simmons’ Squaw Vine Compound—12 percent alcohol—offers “relief of diseases peculiar to women, and derangements arising from disorder of the female organs.” Nearby, a box of Penslar’s Headache Powder, which contains acetanilide, suggests the product be dissolved “in a little water.” If the headache persisted, the customer was advised to “consult a physician or an oculist.” DeWitt’s Headache Tablets, wrapped in faded yellow paper stamped with the assertion that they contain no cocaine or morphine, are also acetanilide-based—a full “245 Grains.” The chemical, used in varnishes, rubber production, and assorted industrial dyes, was also used as an early analgesic. It was largely discontinued for that purpose on its own due to its side effects, including a condition where methemoglobin is present in high levels in the blood, inhibiting the transport of oxygen. It is still sometimes used today in the synthesis of more advanced drugs.

On another shelf, a graying ceramic bust stares out with blank eyes from behind the glass, a grid etched into its bald head with the magical arithmetic of a phrenologist. Above the eyes, the numbers 24, 25, and 26 indicate brain regions for perceiving size, weight, and color. Higher up, and nearer the center of the forehead, other numbers—34, 35—indicate the seats for perceiving comparison and causality. Lower numbers adorn the back and sides of the head, where the provinces of personality and emotion reside. A practitioner of the pseudoscience would have drawn conclusions about patients by palpating the contours of their scalps, noting the location of each bump and divot, and consulting this numeric road map.

As I looked at the sculpture I thought of Charles Lutwidge Dodgson, better known as Lewis Carroll, the author of the “Alice in Wonderland” stories. I’d read that Carroll was known1 to have suffered from a headache disorder, likely migraine, and some historians have wondered whether aspects of the Wonderland tales were inspired by his migrainous aura. He is also known to have at least once visited a phrenologist, in 1852 at the age of twenty. The expert’s report advised: “Do not stress the brain too much at [a] time, because it is not firmly knit yet. Upon the whole, a good head.”

The Diamond clinic has a colorful past of its own. One of the earliest clinics established specifically for the treatment of headache disorders, it was founded in 1974 by Seymour Diamond, an internist who was also one of the key officers leading headache medicine’s professional society, then called the American Association for the Study of Headache. It was an interdisciplinary organization that included a wide variety of practitioners outside of neurology, but internal schisms were already brewing at the time the clinic opened. Diamond would eventually be ousted from his leadership role at AASH—in part because the organization was perceived as being insufficiently scientific at a time when younger and more experimentally ambitious neurologists were entering the field. Today, the American Headache Society, as the organization is now known, is dominated by neurologists with a heavy, albeit not exclusive, emphasis on research and academic work, while the National Headache Foundation, which Diamond founded in 1970, as well as the Diamond Research and Education Foundation, established in 1987, emphasize patient-facing initiatives, interdisciplinary professional education, headache support groups, and some underwriting of clinical research.

Seymour Diamond,2 who titled his autobiography The Headache Godfather, died in 2019, and the clinic is now overseen by his daughter, Merle Diamond, also an internist, with an early specialty in emergency medicine. The brand has expanded to several regional locations, but the Chicago outpatient suite is the nerve center. In her office, adorned with sports memorabilia from the University of Michigan, where she studied as an undergraduate, Diamond admits that the divisions sewn between her father and his allies, and the upstart generation of striving neurologists, were deep, and a residue of acrimony still lingers. Some peacemaking has unfolded in recent years, but Diamond is not alone in mentioning to me a sense of tribal segregation—often measured in how many members are willing to cross lines and attend the other group’s annual gatherings. “Our conferences are different than their conferences,” Diamond tells me. “We reach out to, you know, psychiatrists, pediatricians, OB-GYNs. I like to think of us as the home family conference, because we really try to make headache something attractive and fun for people to do, as opposed to heavy science.”

(Diamond says she makes a point to attend the AHS science meetings whenever she can.)

Arguably the most distinguishing feature of the Diamond Headache Clinic is its inpatient facility, a sprawling, forty-three-bed ward housed nearby, on the ninth floor of Ascension Saint Joseph–Chicago Hospital in the city’s Lincoln Park neighborhood. Patients with intractable migraines, clusters, and other headache disorders travel from around the country to seek help at the unit, which, like the outpatient clinic, offers the usual battery of pharmacological treatments, including the new CGRP medications—and everything else under the sun: acupuncture, biofeedback, Botox injections (a longstanding migraine therapy with a mixed reputation for efficacy,3 though some clinicians and patients swear by it), “medical foods,” physical and psychological therapies, migraine elimination diets, nerve blocks, and more. They also provide various IV infusion treatments—including histamine.

Histamine is a key chemical messenger, or neurotransmitter, released naturally by the human immune system. We tend to associate it with allergies, for good reason: when the body detects a foreign allergenic protein—the inhalation of pollen, for example, or the ingestion of certain compounds in foods—the immune system disperses histamine in response. This can cause all sorts of reactions, from itchy skin and a racing heart to the widening of blood vessels—alarm bells indicating that something is not right. Histamine can also cause blood vessels in our brain to expand, and experimental researchers have long known it to be an effective trigger of headaches in many human test subjects.

From its beginnings in the 1940s, histamine therapy has reckoned that if the chemical is an established headache trigger, it might well explain headache conditions writ large. Sufferers are having an allergic reaction to some unknown stimulant, the thinking goes, and in response, their bodies release histamine and develop a grinding headache. At the Diamond clinic, inpatients who opt for it will receive multiple drip-bag infusions of histamine, titrated upward gradually, as a way of training the body not to overreact to this natural neurotransmitter. “I don’t remember exactly how many bags it is, but it’s around twenty-six bags of IV solution with a very low dose of histamine in the solution,” Bob Wold told me. Wold managed a family construction business in the Chicago area for most of his career, and he is also a longtime cluster headache patient. He’s become something of a guru within an online community of “clusterheads,” as they’re known, who experiment widely with, and share insights on, a whole ecosystem of standard, alternative, and sometimes illegal substances in search of relief. Psilocybin is their primary fixation, but Wold was also instrumental in pushing drug company Eli Lilly to seek FDA approval for a CGRP cocktail aimed specifically at cluster. When he was first experiencing cluster attacks in the 1980s, there was no such therapy, and he sought help at the Diamond clinic.

“What they’re trying to do is build up a tolerance in your system for histamine. They think that histamine is the main trigger for starting the attack,” Wold continued. “So, they try to desensitize your body to histamine. And you can kind of control it yourself. You’re walking around for two weeks with an IV hanging from, you know, a little wheeled cart.” Wold says it worked for him the first time, breaking a vicious cycle of attacks that wouldn’t seem to stop. When the headaches returned months later, he tried it a second and then a third time, to somewhat more middling effects. The fourth time didn’t work at all.

There’s little conclusive evidence that it does for anyone. Few studies have rigorously tested it under controlled conditions, and many insurance companies, though not all, consider it an experimental treatment and ineligible for coverage. More than one researcher I spoke with—prominent figures among the AHS’s deeply science-focused membership—likened it to quackery, and it is not listed in the American Academy of Neurology’s evidence-based guidelines for primary headaches. The insurance firm Aetna’s4 policy on the treatment, last reviewed in September 2023, states simply: “Its effectiveness has not been established by randomized controlled studies.”

The company does not cover it.

Numerous patients who have had the histamine treatments—which are usually aimed at cluster headache, though there is some literature describing its use for migraine too—told me that they helped, though I would reckon that just as many told me it didn’t. But whatever its efficacy, I have to admit that the therapy has always struck me as a bit strange. It seems like a throwback to some dusty age of medicine, when we were still probing scalps or spinning volunteers in centrifuges—blunt therapies based on blind hunches and anecdotes, or on nothing at all. At the same time, while we are remarkably similar creatures at the macrolevel, when we zoom in on our individual genetic details, the variations in how, whether, why, and for how long a drug or other intervention might work become vast. This is one of the main reasons why a drug that seems helpful to 50 percent of patients—which amounts to a coin toss for anyone taking it—can be considered a smash hit for a drug therapy. Hitting 60 percent is downright miraculous.

Similarly, what works for one person today may not always work, which will force them to seek out a new remedy from a well of options that necessarily shrinks with every change. This is, of course, the natural way with many medications—but it is particularly true for headache sufferers, many of whom obtain great relief from a drug, only to see its effectiveness diminish over time. To those who don’t understand, this can often feed the perception that a migraineur is a drug seeker or a drama queen, predisposed to say that nothing works because they don’t want it to. But the relationship between diseases and the chemical or biological remedies we develop to fight them are rarely static. Instead, they are exquisitely fluid—a constant dance of manipulation and adaptation.

There are many reasons for this. As we age, for example, our metabolism naturally changes, which can impact how drugs are absorbed, distributed, and eliminated, potentially leading to changes in medication effectiveness over time. What we eat and drink can influence medication efficacy—and those combinations are not always fully understood, even by doctors. Many medications work by targeting protein receptors on the surfaces of cells, stimulating or blocking them to enhance or mute a particular process or signal that, at the right levels, can be therapeutic. But receptors can become desensitized with repeated chemical stimulation, and our cells can compensate for blocked receptors by expressing more of the relevant messenger molecule, so that the effect of the drug weakens over time. Enzymes in our livers, which break down many of the traditional medications we take, can become more efficient over time, clearing the drug from our systems more quickly, and reducing the efficacy of a drug that seemed potent at first. Our neurons are also remarkably plastic, and changes in synaptic strength can occur with long-term exposure to certain drugs, resulting in alterations to neurotransmitter release, receptor expression, and intracellular signaling. We can even develop what’s known as cross-tolerance, where the cellular adaptations we develop in response to one drug can make us resistant to other drugs we’ve never taken.

Any doctor, if nudged, will say their practice includes a small population of attention seekers and hypochondriacs who linger at the margins where no remedy could ever work, and where an unarticulated mental turmoil creates insatiable appetites for help. We can’t usually know for certain who they are, and we ought not worry over it either. They deserve compassion and treatment regardless of whatever field distortion is driving them. But the larger province of edge cases, where all remedies eventually fail, and where the hopeless and the desperate gather, is mostly made up of people who would prefer to be anywhere but here, staring out the window of a Chicago hospital ward with an IV dripping maybes and why-nots into their veins. Their desperation should speak loudly to anyone who is really paying attention.

In this sense, the long history of diagnosing and treating headache disorders is unsurprisingly replete with the weird and the wacky. And while researchers are prying open new molecular secrets, and pharmaceutical companies are translating those insights into a new generation of highly targeted therapies, a lot of people remain out of luck. Maybe their uninformed doctor isn’t comfortable prescribing a newfangled remedy, or maybe their insurance won’t cover it. Or maybe their genetics simply relegated them to the wrong side of the therapeutic lottery, such that they’re not among the lucky 50 or 60 percent of people who seem to respond to this or that new headache treatment. Even as so-called nonresponders, they will be in the company of millions of similarly hapless patients willing to try just about anything to make it all stop.

“They’ll point to something that we do, histamine or whatever, that they think is voodoo,” said Konrad Kothmann, the chief operations and finance officer for the Diamond Headache Clinic. “Without a lot of solutions, though, I think you have to try everything in your toolbox.”

*  *  *

In chapter 465 of the late-nineteenth-century dramatic novel Uarda: A Romance of Ancient Egypt, a heroic surgeon called Nebsecht is dying in a tent. He had recently rescued the novel’s title character, Uarda, from a burning palace, and he was badly injured. As Nebsecht contemplated his imminent demise, Uarda and his longtime friend, Pentaur, stood watch.

What unfolds is a comically protracted death scene, with the wounded physician alternating between quiet delirium and fits of mania—jerking up repeatedly from his stupor to deliver feverish soliloquies on life and biology. Among other things, he held forth on the brain: “Now I know what the organ is that thinks,” he declared. “The heart! What is the heart? A ram’s heart or a man’s heart, they serve the same end; they turn the wheel of animal life, they both beat quicker in terror or in joy, for we feel fear or pleasure just as animals do. But Thought, the divine power that flies to the infinite, and enables us to form and prove our opinions, has its seat here—Here in the brain, behind the brow!”

Pentaur worries aloud that Nebsecht might be heading into a great nothingness—a particularly cruel fate for an ancient Egyptian. But Nebsecht is more confident, and after mounting one more speech about the orderliness of nature, he exclaims, “My head! When the pain is in my head I cannot think.”

With all the bubbly melodrama of a midafternoon soap, Nebsecht then succumbs. His last words, delivered in what one imagines were descending, breathy whispers: “If only I could prove—could prove—”

Just what Nebsecht hoped to prove seems lost to the ages, as is any definitive sense that the novel’s author, Georg Ebers, was informed by his own real-life anthropological work when he focused Nebsecht’s deathbed obsessions on the head and the brain. What’s certain is that a mere four years before publishing the first edition of Uarda in 1877, Ebers—a German Egyptologist and prolific writer of antiquity-period fiction—had purchased a rare medical document while traveling near the site of ancient Thebes. It contained what is often characterized as one of the earliest written references to migraine.

Dated to around61550 BCE, during the reign of Amenhotep I, the Ebers Papyrus (Ebers named the artifact after himself) is actually a scroll running to about sixty-six feet in length,7 with over one hundred columns of text describing various remedies for all manner of diseases and injuries. For what some readers have guessed might be rheumatoid arthritis8 in the shoulders or fingers, the document recommends forcing patients to vomit “by means of fish with beer,” and then bandaging their fingers with bottle gourd. To expel pain in “all the limbs of a man,” one twentieth century medical historian described9 the papyrus’s ancient healers recommending equal parts of honey, the mineral malachite, ammi (a flowering plant), styrax (a shrub), and what is translated as “dog’s excrement.” These are presumably mixed into a paste and applied to the patient’s face. “Do not lay hands on him,” the textbook reportedly advised.

As is often the case in Egyptology, the document’s place in the history of headache varies from account to account, and from one scholar to another. The scroll itself10 is a mix of magical and sometimes remarkably empirical thinking, and modern headache specialists have noted its sophisticated descriptions of the circulatory and nervous systems. For his part, Ebers produced a two-volume facsimile of the scroll—complete with a hieroglyph-to-Latin glossary attributed to his colleague, the librarian and Egyptologist Ludwig Stern—in 1875, just two years before publishing the fictional tragedy of Uarda and Nebsecht.

I wanted very much to believe that Ebers was inspired by this ancient medical corpus when he saddled his protagonist with deathbed meditations on physiology and the brain, but given that11 a full translation of the papyrus would not be published until 1890, it seems unlikely.

Two of the most recent medical histories focused on head pain, Mervyn J. Eadie’s 2012 Headache Through the Centuries and Katherine Foxhall’s 2019 Migraine: A History, each provide only a passing reference to the Ebers document, noting the difficulty in saying with any confidence that migraines were what the ancient Egyptian physicians thought they were treating—though it is roughly translated as a “disease of one-half of the head.” Is that a reference to migraine? It can be difficult to discern, in part because the treatments are often the same for everything. Foxhall, a social and medical historian and now a local Green Party politician in the UK, points out that the instruction12 to anoint an aching head with “the skull of catfish, fried in oil or fat for four days was the same as was indicated for a thorn in the side, in order to draw the thorn out of the wound.”

Other researchers are less skeptical, even if they raise questions about whether translations of the Ebers text have mishandled the headache passages—including the remedy of fried catfish oil. One theory, for example, holds that the term “fried” might have been used poetically by the Egyptian scribes, who had in mind a species of catfish that would have been familiar to residents of the ancient Nile River Valley—one capable of delivering an electric shock. “With the patient having a severe migraine attack, why would the Egyptian healer want to take time out to fry up in [an] oil medium the head of dead fish which is already naturally oily anyway?” asked Rosalind Park in a chapter of the 2010 paperback13 Pharmacy and Medicine in Ancient Egypt: Proceedings of the Conferences Held in Cairo (2007) and Manchester (2008). Park posits that “fried” in this context may well have described an early form of electrotherapy, in which the high-voltage zap of a catfish is used as an abortive, or at least a counterirritant—and “applied to the migraine sufferer’s head (once every) 4 days.”

Many headache patients today will no doubt recognize some resonance here with a modern category of medical devices used for therapeutic migraine treatment at home. These units are designed to deliver electromagnetic impulses to certain branches of the trigeminal nerve, the cranial structure responsible for the head and face, among other functions, or to the vagus nerve—a major communications pathway governing unconscious functions like breathing, heart rate, and digestion—as it passes through the neck. Other devices, applied to the back of the head, deliver a mild electrical current to the occipital cortex, a region at the back of the brain that is primarily responsible for processing visual information. Going by trade names like Cefaly and gammaCore (Catfish is apparently still available), these devices have been shown to help reduce the frequency and intensity of migraine attacks in some patients, and many fans swear by them. Still, as with nearly all remedies for head pain, real-world experience seems to vary.

Whether or not the ancient Egyptians were, indeed, early adopters of neuromodulation for the treatment of headaches is hard to pin down. What’s clear is that the Eber Papyrus’s description of a distinctly unilateral “disease of the head”—one of the most indelible characteristics of migraine and other primary headaches—rarely escapes mention in works tracing the history of these disorders, even if the document’s importance on the topic is sometimes overstated.

Other histories sometimes attribute entirely different migraine or headache treatments to the Ebers Papyrus, including one involving a clay figurine in the shape of a crocodile. According to this prescription, the reptile sculpture must have its mouth stuffed with curative herbs before being placed atop the patient’s head, where it is secured with a linen cloth. A former president14 of the American Headache Society recounted this ancient remedy and attributed it to the Ebers scroll as recently as 2005, in a textbook on migraines. That citation echoes15 one made in an earlier paper, dated 2003, suggesting that the crocodile treatment—also attributed to the Ebers Papyrus—may have “relieved the headache by collapsing distended vessels which were causing the pain.”

Setting aside whether an effigial crocodile strapped to the skull might help with a headache, Lutz Popko, a modern-era translator of the Ebers Papyrus and a lecturer at the Egyptological Institute of the University of Leipzig, noted in a 2018 essay in the Bulletin of the History of Medicine that the remedy never really appears in the Ebers document at all. Rather, it springs16 from a specimen of somewhat later vintage called the Chester Beatty V Papyrus, which is held in the British Museum. It dates to 1200 BCE.

Despite these misattributions, there seems little reason to doubt that the human animal has been dogged by excruciating, migraine-like head pain for a very long time—though precisely why and for how long remains a mystery. Several researchers, for example, have wondered why migraine hasn’t simply been relegated to the evolutionary dustbin—a disabling, pain-generating burr in our genetic source code that, over millennia of self-correction and fitness-favoring, should have been long ago bred out of the species. It’s a compelling question, particularly given evidence that the portion of the population experiencing migraine and other headache disorders appears to be remarkably stable, neither ebbing nor flowing very much over time, and with only small variations across ethnicities and geographies.

This stability suggests that migraine and other idiopathic headache disorders are strongly influenced by innate genetic and neurobiological mechanisms, rather than being primarily driven by external environmental exposures. Migraine in particular has a significant hereditary component, with studies showing that individuals with a family history of migraine are at higher risk of having the disorder themselves.

Elizabeth Loder, an associate professor of neurology at Harvard Medical School, chief of the Division of Headache and Pain in the Department of Neurology at the Brigham and Women’s Faulkner Hospitals in Boston, and the head of research for the British Medical Journal—a true giant in modern headache science—surveyed several potential explanations for migraine’s genetic persistence more than two decades ago. Might the disorder be part of a latent defense mechanism, Loder wondered, with the pain possibly driving a self-preserving retreat away from trouble and into solitude? Could it be that evolution’s natural favoring of quick and reactive nervous systems also delivered a few negative by-products that, while debilitating to certain individuals, weren’t enough by themselves to force a species-wide adaptation? Maybe migraine is protective against some still-unidentified pathogen, or perhaps the disorder is newer than we think, and we just haven’t had time to shed the trait?

It’s even possible, Loder speculated, that migraine—and I would throw in cluster headaches here myself—persists due to an inherent and inescapable communication conflict between the most primitive, most fixed parts of the primordial brain stem, and the more plasticky, more recently evolved structures like the neocortex—the largest and most advanced part of the cerebral cortex. “To draw an analogy17 to the computer world,” Loder writes, “such a mismatch between older and newer structures might be seen as akin to the difficulties that occur when one attempts to use the latest printer or fax machine with an older and less advanced central processing unit.”

I had similar conversations with Paul Rolan, the Australian clinical pharmacologist at the University of Adelaide. Rolan was among the early pharmaceutical researchers working on triptans in the 1980s, and he remains fascinated by the still-hidden blueprint that allows for idiopathic human head pain. “The records from ancient history seem to indicate these conditions have been with us unchanged, and yet there doesn’t appear to be anything similar in animals,” he told me. “I’ve never seen one of my pets lie in its bed with its paw over its head, sort of not working well. And the real question is why we got this, because first of all, it’s largely a young person’s condition. And usually, diseases that impair the productivity of your breeding population . . . have a winning disadvantage and tend to die out. So why is this so prevalent?”

Loder also notes in her monograph that Charles Darwin, the wellspring of modern evolutionary theory and the grandson of Erasmus, suffered from wrenching headaches himself. In his nineteenth-century journals, documenting his wanderings aboard the HMS Beagle, the younger Darwin recounted several local remedies shared with him during a bad bout in Buenos Aires, Argentina. They were probably at least as effective as a clay crocodile tied to the head: “A common practice is to bind an orange-leaf or a bit of black plaster to each temple,” Darwin noted, “and a still more general plan is to split a bean into halves, moisten them, and place one on each temple, where they will easily adhere.

“It is not thought proper ever to remove the beans or plaster, but to allow them to drop off,” he added, “and sometimes, if a man with patches on his head is asked, what is the matter? he will answer, ‘I had a headache the day before yesterday.’”

It has been easy for me at times to develop a jaundiced view of the headache’s distillation in the culture. Any pain disorder will do that to you, I’m sure, but pain in the brain breeds a special sort of cynicism, and I have to believe that it’s not uncommon to lose your sense of humor, even your sense of perspective, when the thrashing has got the better of you. Still, if the pain and associated symptoms of migraine and cluster headache often feel like heavy drags on the momentum of life, their lively presence across the span of time can be a compensatory joyride. What else can be said of Charles Darwin wearing wet beans on his temples?

*  *  *

Headache histories sometimes reach much further back than the Ebers Papyrus. Trepanation, for example, also known as trephining, or trepanning, is the practice of surgically drilling or boring into the skull for some presumed medical purpose, and it is thought to extend deep into human cultural history. Skulls with evidence of bore holes date at least as far back as the late Paleolithic period,18 roughly twelve thousand years ago, and specimens bearing what appear to be clear examples of a survived form of the procedure, discovered in France in the late nineteenth century, date back about three-quarters that distance, or about nine thousand years.

Writing in his 2012 book A Hole in the Head: More Tales in the History of Neuroscience, the late Charles G. Gross—one of the founders of cognitive neuroscience—describes the work of Paul Broca, the nineteenth-century French physician and anthropologist best known for his work studying an area of the brain’s frontal lobe, today called Broca’s area, that is linked to speech production and language processing. Broca, Gross tells us, was also fascinated by ancient surgical skull mining, though his conviction that ancient surgeons had been able to perform such procedures without killing their patients, based on a fossilized skull recovered in Peru, was initially met with skepticism by his colleagues. But Broca’s interpretation was ultimately supported by the discovery at a Neolithic gravesite in France of multiple skulls bearing similarly carved holes—along with the bone disks that would have been removed during the procedure.

“Although a few19 of the discs had been chiseled out after death, in most cases it was clear from the scar formation at the wound’s edge that the interval between surgery and death must have been years,” Gross noted. “Trephined skulls were found of both genders and of all ages. Virtually none of the skull holes in this sample were accidental, pathological, or traumatic. . . . These findings finally established that Neolithic man could carry out survival trephination but left unresolved the motivation for this operation.”

On occasion, historians of headache have ventured a guess. Writing in the Journal of Neurology in 2009, for example, researchers from Athens University and the Athens Naval Hospital noted—somewhat off-handedly—that “the first evidence20 of treatment interventions to relieve patients probably of headaches came with the discovery of 9,000-year-old Neolithic skulls that showed trepanation.”

The word “probably” is doing a great deal of work here, and the researchers offer no evidence for their assertion—but the presumption that trepanation had some role in historical headache therapy reaches at least as far back as the seventeenth-century British doctor and father of neurology, Thomas Willis. He introduced21 the term “neurology” in his influential 1664 tome Cerebri Anatome (Anatomy of the Brain), and two decades later, in The London Practice of Physick (1685), he related that a contemporary,22 William Harvey, had once attempted to convince a patient to submit to the procedure. “There remains yet another surgical operation, extoll’d by many for an obstinate Head-ach, but tried as yet by none (that I know) to wit, the opening of the skull with a trepand iron near the place of the pain,” Willis wrote. “Our famous Harvey endeavor’d to persuade a Lady of great quality to this, who was troubled with a terrible and inveterate Headache, promising her a Cure thereby; but neither she nor any other has been content to admit to the administration.”

Whether doctors in subsequent centuries had better luck pressing their headache patients into skull surgery is unclear, though in the late nineteenth century, a short paper23 in the British Medical Journal, written by Scottish physician Alexander Haig, did describe a treatment for headaches that persist “with little change hour after hour, day after day, even week after week, or month after month.” It involved “opening the skull and membranes” to let the pressure out—though Haig seemed to assume such pain was from a tumor or other growth.

Katherine Foxhall suggests that trepanation’s understanding as an ancient headache remedy gained its firmest purchase in the early twentieth century, by way of the London physician Sir Thomas Lauder Brunton. Foxhall describes Brunton’s 1902 lecture, which was published24 in the Journal of Mental Science, as a mix of “neurological theory25 and armchair anthropology [ranging] over subjects including premonitions, telepathy, hypnotism, hallucinations, and epileptic and migrainous aura.” As part of this, Brunton asserted in his lecture that some of these perforated, prehistoric skulls almost certainly belonged to migraine patients:

Some authorities26 have supposed that these openings in the skull have been made for the purposes of priestcraft, and that the priests, by pressing hard on the brain through the opening in the skull, were able to induce epileptic fits in the patient, and then announce that he was possessed by a spirit, and in a fit condition to give oracular responses. It is possible that the openings in the skulls may have subserved this purpose, but to any sufferer from sick headache the first idea that suggests itself is that the holes were made at the request of the sufferers in order to “let the headache out,” for when the pain of headache becomes almost unbearably severe, an instinctive desire sometimes arises either to strike the place violently in the hope of relieving the pain, or to wish that some operation could be done to remove the pain.

This notion would be repeated in subsequent decades by other experts. Foxhall traces it forward to the American physician William Osler in 1913, and then to a Dr. Thomas Wilson Parry, whose own fascination with trepanation was extensive, and who argued in a December 1931 issue of The Lancet27 that the sheer number of trepanned Neolithic skulls suggested that at least some of them had to belong to migraine sufferers.

As Foxhall notes,28 there are documented—albeit rare and extreme—cases of twentieth-century experimentation with trepanation as a headache treatment. But she and others also argue strongly that there is scant evidence that skull drilling was ever a common practice in the treatment of head pain, neither in the near nor distant past—though some scholars have gone digging elsewhere to support the notion. The Greek god Hephaestus29—overseer of metalworking, fire, and fine arts—has been described by neurosurgeons, for example, as the performer of the first craniotomy; he relieved Zeus of a grinding headache by cracking open his skull. (The “headache” turned out to be Zeus’s daughter, Athena, emerging fully formed from Zeus’s head.) And in his book A Hole in the Head, Gross notes that a Chinese historical novel dating to the Ming dynasty, and set between first and second centuries CE, carries a fictionalized interaction between the military commander Cao Cao and the renowned physician Hua Tuo (both are actual historical figures).

In the novel, Hua Tuo explains to Cao Cao, who is being tortured by a throbbing headache, that he suffers from a buildup of intracranial fluid and air, and that the good doctor could open Cao Cao’s skull “with a cleaver” to set things right. In the story,30 Hua Tuo is sent to prison for this suggestion, and Cao Cao dies days later.

Despite such tantalizing tidbits, Foxhall characterizes most associations of headache and trepanation as fanciful, perhaps even irresponsible speculation on the part of experts—though it should be noted that the idea lingers across the culture, sometimes in high places. A cursory internet search will easily find the trepanation fable repeated on the patient-facing websites of ordinary neurology clinics, including—at least as of this writing—one belonging31 to Optimum Neurology of Bala Cynwyd, Pennsylvania, a tony suburb of Philadelphia. Here, the practice is described as having arisen in direct response to headaches. Researchers in neurology and neurosurgery from Johns Hopkins and Indiana Universitys, meanwhile, repeated the ancient-skull conjecture in a 2011 paper32 published in the Journal of Neurosurgery. And in 2014, doctors in the department of neurological surgery at Rutgers University did the same: “Whereas the earliest documented descriptions of headache only date back 4,000 years, its treatment may be traced back to the trepanation of Neolithic skulls 9,000 years ago,” they write. “It is believed33 that trepanation was used to treat headaches by giving evil spirits a physical route to leave the ailing head.”

Historical evidence notwithstanding, I am primed to accept trepanation as part of head pain’s long origin story. Anyone who has experienced the pain of a cluster attack will have at least contemplated an act of self-violence commensurate with trepanation, and it takes little coaxing to imagine that some ancient healers might have guessed that a hole in the head could bring relief. It’s also easy to imagine that at least a few miserable patients, in all their agonies, would have welcomed such a therapeutic Grand Guignol, whether the grisly excavation was carried out by gouging stone or hand drill. When there is a terror unfolding inside the skull, how crazy is it to think that another terror might let it out?

*  *  *

Fast-forward a few thousand years, from the late Paleolithic–early Neolithic periods to the cusp of the common era, and the history of the headache gets a bit less murky. Works attributed to the Greek physician Hippocrates, for example, and dating to the final centuries before the common era, are thought to include a clear description of a migrainous aura: “He seemed to see34 something shining before him like a light, usually in part of the right eye,” Hippocrates noted, “at the end of a moment, a violent pain supervened in the right temple, then in all the head and neck. Vomiting, when it became possible, was able to divert the pain and render it more moderate.”

A few hundred years later, evidence that ancient doctors were treating patients for recurrent headaches becomes unmistakable. Several works35 describe that second-century Chinese physician Hua Tuo as treating Cao Cao’s persistent struggle with tou feng, or headache—not with a skull-cracking cleaver, but with delicate acupuncture, for example. (Interestingly, some encyclopedic entries for Hua Tuo speculate that Cao Cao had the court physician put to death “in a fit of rage, perhaps triggered by his headaches,” although the basis for this is unclear.) And descriptions of recurring head-pain disorders—distinct from the occasional headaches we all get—seem unequivocal in the work of other early Greek physicians, including the second-century surgeon Aelius Galenus, or simply Galen. He is credited with coining the term “hemicrania” to describe a pain disorder affecting half the head.

Things progressed by way of the Greek physician Aretaeus of Cappadocia, who toiled around the same time as Galen, albeit in a different part of the expansive Roman Empire—quite likely in what is modern-day Turkey. He is generally credited as being the first to divide headaches into distinct categories, including forms that were sudden and acute (he called these “Cephalalgia”), and others that were more droning and chronic (dubbed “Cephalaea”). Aretaeus also had a category for “an illness by no means mild” that ravaged just one half of the head: “It occasions36 unseemingly and dreadful symptoms,” he noted, including “spasm and distortion of the countenance, . . . nausea; vomiting of bilious matters, [and] collapse of the patient.”

Aretaeus also described this headache disorder in ways that will strike most anyone with migraine as familiar: These were bouts of head pain involving “much torpor, heaviness of the head, anxiety, and weariness,” Aretaeus wrote—and patients were inclined to “flee the light,” because “the darkness soothes their disease.” These sufferers could not bear “to look upon or hear anything disagreeable,” the Cappadocian added, and “their sense of smell is vitiated.”

Medical explanations for headaches in the early Roman empire, as with other diseases at the time, had coalesced around the Hippocratic theory of the four humors, with good health depending on keeping them in balance. But treatment of specific symptoms was as enterprising and animated as in any other era. Galen, not to be outdone by his Egyptian forebears, was reportedly fond of applying a torpedo fish—another electrogenic species, this one of the ray family—to the heads of headache suffers, perhaps as a counterirritant. (The torpedo fish37 was also thought to be useful by Galen and his contemporaries in the treatment of gout and prolapsed anus.) Aretaeus, meanwhile, favored other common remedies of the time, including bloodletting, cupping, blistering, and where all else failed—and in a vague fidelity with trepanation—cauterization of the scalp.

In his own words:

Consequently,38 you have to shave off the hair (which yet on its own is good for the head) and cauterize superficially down to the muscles. If you wish to cauterize down to the bone, carry it out at a site where there are no muscles. For if you burn muscles, you will provoke cramps. Some physicians incise down to the bone on the forehead along the border of the hair. They abrade or chisel the bone down to the diploe and let flesh grow over the place. Others perforate the bone down to the meninges. These are hazardous treatments. You have to apply them when the headache persists after all that has been done; the patient keeps courage, and the body is vigorous.

(It wasn’t quite trepanation, of course, but the impulse to treat head pain by strip-mining the human skull seems to have been far from unusual.)

Aretaeus called his one-sided head pain disorder “heterocrania,” and while Galen’s coinage would be the one to eventually morph into the word “migraine,” the former physician is usually credited with what might be the earliest and most detailed description of the very common disorder we all know by that name. Still, researchers and historians continue to quibble over how extensively the headache diagnoses of the ancients correspond to those that emerged post-Enlightenment.

What’s clear is that for roughly one thousand years following these bits of second-century insight, headache science, as with all medicine, was somewhat static—which is not to say headache sufferers stopped describing their disorders. Caelius Aurelianus,39 a fifth-century Roman physician from what is now Algeria, wrote about hemicrania, as well as something he dubbed “crotophon,” which, according to British neurologist J. M. S. Pearce, involved “a pounding or hammering” in the head, accompanied by vertigo, burning eyes, nausea, and vomiting. Aurelianus also described “lachrymation, noises in the ears, and deafness,” Pearce notes.

Meanwhile, the Persian scholar and physician Ibn Sina (often called Avicenna in the West), whose life straddled the tenth and eleventh centuries CE, described headaches that were “not concomitant with fever, but with epistaxis, vomiting, . . . confusion, and visual hallucinations.” From his environs at the intersecting corners of modern-day Uzbekistan, Tajikistan, Kazakhstan, and Kyrgyzstan, Ibn Sina’s encyclopedic medical writing, which would prove to be among the most influential in the medieval world, synthesized and expanded upon traditions from both East and West. His work40 also carried a sophisticated identification of headache’s headwaters: “Headache originates,” he wrote, “from brain tissue, meninges, vessels, or the extra-cranial extension of meninges.”

Of course, Ibn Sina also suggested that headaches were linked to as many as sixteen types of imbalances in the bodily humors, suggesting, perhaps, that a belief in the humors didn’t necessarily preclude a capacity to make other, more salient scientific observations. What’s clear is that this ironclad idea of the humors, alongside varying and sporadic religious diktats prohibiting or limiting the educational dissection of human cadavers, would conspire to slow medical advancement until the earliest stirrings of the scientific revolution in sixteenth-century Europe. Even so, these dusty tomes from the post-Classical and Medieval periods do suggest that gnawing, recurring head pain was as real for the ancients as it is for millions of people today. It also seems to underscore a notion that sometimes gets lost in modern distillations of the headache: that prior to the twentieth century, unexplained head pain was considered a consequential matter—a mysterious and even baffling affliction that warranted serious medical consideration, accumulating documentation, and frequently dramatic interventions. Andrew Charles has suggested that the rise of Freudian psychology, professional misogyny, and other factors likely contributed to the decreased status of headache disorders as an object of both scientific and social concern.

On a more personal level—and allowing that the details may be open to interpretation—I’m inclined to see these ancient meditations as clear evidence, at the very least, that headaches have a storied pedigree. How not to feel a sense of kinship with afflicted souls who sought comfort in a slippery fish electrocution? If I had the opportunity in the throes of an otherwise untreatable cluster attack, I would welcome a torpedo fish even now.

*  *  *

Thomas Willis, that seventeenth-century British physician and anatomist whose colleague had sought to drill holes in his patients’ heads, was not exclusively or even predominantly focused on head pain. But he did carry forward the study of the disease in parsing its various manifestations. These categories typically hinged on whether the pain was unrelenting and chronic, intermittent but cyclic, or something more unpredictable and uncertain. Given that it was understood, even in his time, that the brain itself is not capable of feeling pain, Willis suspected that the characteristic ache of a headache must be arising from the fleshy structures of the meninges surrounding it. At the same time,41 Willis is often credited with the notion that migraine was likely a vascular disease, with pain brought on by dilated cranial blood vessels.

Willis also helped to codify what appeared to be common “triggers” among patients, from diet to atmospheric changes, as well as the curious stages of a migraine attack, including a vivid description of what now would be called the “prodrome” phase, wherein recognized neurobiological changes—irritability, difficulty sleeping, yawning, confusion, and strong food cravings, among others—can occur hours or even days before the onset of pain.

Writing of one patient,42 Willis described a

beautiful and young woman, indued with a slender habit of body, and a hot blood, being obnoxious to an hereditary headach, was wont to be afflicted with frequent and wandering fits of it, to wit, some upon every light occasion, and some of their own accord. On the day before the coming of the spontaneous fit of this disease, growing very hungry in the evening, she eat a most plentiful supper, with an hungry, I may say a greedy appetite; presaging by this sign, that the pain of the head would most certainly follow the next morning; and the event never failed this augury. For as soon as she awaked, being afflicted by a most sharp torment, thorow the whole forepart of her head, she was troubled also with vomiting, sometimes of an acid, and as it were a vitriolock, humor, and sometimes of a cholerick and highly bitterish; hence according to this sign this headach is thought to arise from the vice of the stomach.

Cluster headache, being a rarer condition than migraine, has proven harder to identify amid the fog of disorders described in aged medical texts. Some researchers believe they see a description of a cluster attack in work dating to the Byzantine era, including that of Oribasius, a fourth-century medical writer and personal physician to the Roman emperor Julian the Apostate, and that of Aetius Amidenus, a fifth- and sixth-century medical scribe. Paulus Aeginita’s seven-book medical compendium43 from the late seventh century is cited by the same researchers for its description of a “headach [that] proceeds from exposure to heat,” and where “the eyes of such persons are red.”

Whether that’s a cluster headache is highly debatable, and it would take many centuries for a less equivocal description of the disorder to emerge—the first being attributed most commonly to the seventeenth-century Dutch surgeon Nicolaes Tulp. Europe at this time was in the throes of a great scientific awakening, marked by rapid advances in mathematics, physics, astronomy, chemistry, and biology—not to mention art. Tulp himself is perhaps best known as the central subject of Rembrandt’s 1632 masterpiece entitled The Anatomy Lesson of Dr. Nicolaes Tulp. The painting depicts the physician hovering over a pale cadaver, his colleagues leaning in with rapt attention as Tulp tugs at the exposed sinews of the corpse’s dissected arm with a pair of forceps.

Roughly a decade later, Tulp would publish his Observationes Medicae, which included numerous case studies of patients struggling with headache disorders, including one by the name of Isaak van Halmaal. It seems that van Halmaal, “in the beginning of the summer season,” Tulp wrote,44 “was afflicted with a very severe headache, occurring, and disappearing daily on fixed hours, with such an intensity that he often assured me that he could not bear the pain anymore or he would succumb shortly. For rarely it lasted longer than two hours. And the rest of the day there was no fever, nor indisposition of the urine, nor any infirmity of the pulse.” Writing in the journal Cephalalgia in 1993, the Dutch neuroscientist P. J. Koehler noted the absence of some other clear cluster headache markers in Tulp’s account of van Halmaal, including unilateral head pain and the signature red, watery eyes that come with an attack. But anyone who suffers from cluster headaches—and indeed, anyone who has witnessed one unfolding—will readily recognize the affliction in Tulp’s description.

A century later,45 in 1745, another Dutch physician, Gerhard van Swieten, would offer an even more definitive account of episodic cluster headache:

A healthy, robust man of middle age was, each day, at the same hour troubled by pain above the orbit of the left eye, where the nerve leaves through the bony frontal opening; after a short time, the left eye began to redden and tears to flow; then he felt as if his eye was protruding from its orbit with so much pain that he became mad. After a few hours, all this evil ceased and nothing in the eye appeared at all changed.

Now, in the twenty-first century, I can think of no better description of a cluster headache than this. As the eighteenth century gave way to the nineteenth, a pair of competing theories about the pathophysiology of headaches began to take shape.

Chapter 4
Blood vs. Brains

The verapamil dialed back the intensity a little bit, but it didn’t last. It maybe got two or three weeks of lower intensity but not no headaches. And then the intensity just jumped right back up . . . Is it ever gonna go away? That was just psychologically awful.

—Karen Mann, rural Virginia

Samuel Tissot was not a fan of masturbation. The eighteenth-century Swiss physician wrote an entire medical textbook on the matter, in which he argued that semen was a precious commodity that “physicians of every age have unanimously admitted that the loss of one ounce of it enfeebles more than fifty ounces of blood.” Tissot thought gout, rheumatism, memory loss, blurred vision, and other ailments could be tied to jacking off—and his admonitions weren’t just for men. He claimed to cure an eighteen-year-old girl of drowsiness and general swelling after “advising her of the danger of this practice.” It’s unclear what sort of fluid loss would have accounted for her ordeal.

Among the maladies tied to masturbation, Tissot also mentioned headache—a disorder for which he is arguably better known. His famous treatise on nerves and nervous disorders included a lengthy chapter devoted to migraines, and he is widely considered—his views on masturbation notwithstanding—to be among the classical authorities on headaches. He was convinced that they were linked to the stomach, gall bladder, or uterus.

This was not an unreasonable speculation. There are clear associations between migraine and gastrointestinal upset, and, many doctors and patients will insist, between certain dietary triggers and the onset of migraine. Some research today1 even distinguishes a separate condition, abdominal migraine, in which the locus of pain is in the belly and not the head.

The precise nature2 of this “gut-brain axis,” as the bidirectional relationship between the gastrointestinal and central nervous systems is sometimes called, remains unclear even now. But Tissot was attuned to the idea that the body’s distinct networks of organs and conduits—the gut and its metabolic plumbing, the heart and its tidal blood vessels, the brain and its emissary nerves—were animated by a fundamental interdependency, a vital hum of electrical and chemical interaction that was, at the time, still invisible from view. A disturbance in that system—or “the disordered motions of the fibers,” as Erasmus Darwin put it—could be at the root of many illnesses.

Scientific interest in the role and function of the nerves and brain were ascendant in the late 1700s, and terms like “sick headache” were gaining currency in the literature—a means of capturing head pain accompanied by this menagerie of visceral and sensory symptoms. It was also a time of increased commerce, wealth, and trade, and as inflows of previously unavailable spices, sweets, and spirits began to circulate through the emergent economies of the West, medical experts of the day seemed to take notice. The subject of dietary triggers3 remains a topic of heated debate even today, but observational links between food and bouts of migraine had been noted for hundreds of years, and in the bustle of the Industrial Revolution, they gave rise to a fertile subgenre of professional menu recommendations and dietary admonitions. Katherine Foxhall recounts4 the scolding of one John Fothergill, a Quaker physician from Yorkshire, for example, who pointed the finger in 1778 at “melted butter, fatty meats, and black pepper.” All of these being key ingredients in one popular indulgence of the time, Fothergill considered meat pies “as fertile a cause of [sick headache] as anything I know.”

Fatty foods5 and black pepper6—or its key constituent, the natural alkaloid compound piperine—have been shown in recent years to be effective vasodilators, so it shouldn’t be surprising that scientific preoccupations with food triggers would help to fuel theories that migraine and related headaches were primarily diseases of the vasculature: if you eat these things, it might cause the blood vessels in your head to expand and rub some nerves the wrong way.

Fothergill wouldn’t have put it quite that way, of course, but Foxhall identifies this period as the dawn of an emergent blame-the-victimism among the scientific and medical establishment—one that increasingly tied migraine to overindulgence, sedentary lifestyles, or simple frailty. “Fothergill’s writing,7 particularly when viewed in the context of concern about the nation’s health,” Foxhall writes, “illustrates how nervous theories about migraine, which updated old humoral ideas about a sympathetic relationship between different parts of the body, could be allied with the concept of disease as attributable to failings of individual character, as well as to one’s constitution.”

This is inescapably true—and such perceptions and judgments persist to this day. But it’s also possible to spot the more sophisticated, underlying idea, imperfectly articulated but percolating just the same, that there was some connection between the onset of a migraine and the way the brain was processing inputs—be it a meal, a lack of sleep, a puff of perfume, or emotional stress. This might be8 typified in the observations of the nineteenth-century French physician Henri Labarraque, who, Foxhall notes, argued that migraine “was a disorder of the nervous system in the head, which came in several varieties, provoked by a sympathetic transmission of irritation from the eyes, stomach, or sinuses.” To avoid a bout, Labarraque recommended foregoing coffee and tight clothing, while favoring “white meats, fish, green vegetables, and water.” And in a nod to his ancient forebears, Labarraque thought relief could be found in bleeding, induced vomiting, and the application of a mixed plaster—one historically composed of honey, leaven, and bits of snakes and other animal flesh—to the stomach.

One frequently overlooked figure in the annals of headache history, Elizabeth Garrett Anderson, was similarly convinced, by the end of the nineteenth century, that migraine and related headaches were tied to a disordered processing of central nervous system inputs. Anderson was a pioneering physician and suffragist best known as the first woman to qualify as a physician and surgeon in Britain—achievements she made despite being largely barred, like most women of the time, from clinical dissection rooms where cadaver studies were flourishing, and from the surgical theaters that were opening up new medical vistas. While she established herself in countless areas, including founding the London School of Medicine for Women and becoming the first female mayor in Britain’s history—in Adelburgh on the North Sea coast—it was her exclusion from hands-on anatomical training that drove her to focus her doctoral thesis on a topic that she thought was within reach: headaches.

“I had to find a subject which could be well-studied without post-mortem observations, of which I can have but very few in either private or dispensary practice,” she wrote with palpable ire. “And I wished to take a large subject, one that demanded some insight into the harmony that exists between the main physiological functions.”

While she completed her medical education in London, as a woman, Anderson faced significant obstacles in obtaining a medical degree there. She turned instead to the University of Paris, where she successfully presented her doctoral thesis—written and defended in French—to a committee presided over by the French brain anatomist Paul Broca in 1870. In her thesis,9 which would not be translated to English until nearly a century later, Anderson provided a keen synopsis of migraine’s clinical presentation, as well as its clear hereditary aspects. In seeking out the origin of the disease, she also urged her contemporaries to stop obsessing over points of input—be it foods landing in the gut or scents wafting up the nose—and instead focus on the anatomical network designed to process the signals delivered through these portals: the central nervous system.

From a second translation10 of her thesis, published in 1999:

One finds few patients who do not attribute their attacks to some imprudence in eating, to constipation or to other digestive upsets; and one cannot deny that the initial cause in many of these attacks is found in the digestive organs and that the medical remedies for these unhealthy conditions succeed in diminishing the attacks. But this does not prove that the origin of migraine is to be found in the stomach, any more than puerperal madness proves that the causes of true madness are to be found in abnormal conditions of the uterus. The primary cause of these morbid phenomena should be looked for outside the exciting causes, and if it can be demonstrated that these are numerous, it is certain that the true cause is outside them. However great the influence of an upset digestive system, other well-defined agents are equally capable of provoking migraines. A strong light is one, but it can scarcely be said that this has any influence on the digestive system. Emotion, anxiety, excitement caused by public speaking can also bring on attacks. It is more logical to assume a direct effect on the nervous system than an indirect effect on the digestion.

From her late-nineteenth-century vantage, Anderson also seemed to grasp that the malfunctioning response of the central nervous system in headache patients, which she attributed to the poor “nutritional condition of the nerves,” was unlikely to be repaired or cured. Rather, this was a genetic predisposition that could be only imperfectly managed—in large part by avoiding the stimuli that seemed to trigger the attacks. “As has already11 been shown,” she wrote, “the pathological characteristics make all treatment directed against the symptoms very difficult. Also, the healing of migraine is seldom more than partial. It is impossible, in most cases, to augment the nutritive activity of the tissues beyond their congenital or inherent type.”

Anderson was, of course, not the first to argue that a true understanding of the pathophysiology of migraine—our ability to map its choreography and deduce its prime mover—could be found only in the nervous system. But this idea remained one part of a binary debate that, while tracing its roots back centuries, would animate the late-Victorian period and persist, with some waxing and waning, well into the modern era. In this case, the question hinged on whether recurring headache pain was primarily vascular in nature—a malady of the blood vessels, as Willis and Darwin and many others believed—or, as Anderson and others would have argued, a disorder of the brain and its constituent anatomy.

While dozens of researchers would have helped to nurture and carry this division out of the late nineteenth century and beyond, the two camps are almost always represented, at least in English-language literature, by two key figures: Edward Liveing and Peter Wallwork Latham. Both were British physicians trained in Cambridge, and both published12 comprehensive theories on the origins of migraine and related headaches in the early 1870s: On Nervous or Sick-Headache, Its Varieties and Treatment (Latham), and On Megrim, Sick-Headache and Some Allied Disorders (Liveing).

There’s little doubt that from the rearview mirror of modern medicine, the legacies and contributions of both men have been collapsed into just-so stories that provide a neat evolutionary arc. Framed as a decades-long struggle for the primacy of two competing theories of headaches, the two doctors make for easy foundational pillars, both because they were contemporaries who critiqued each other’s theories, and because the anatomical fiefdoms where they planted their flags can, in an oblique way, be seen as representing a debate that lingers within headache medicine even today. Zoomed in, the arc from then to now is bumpier, with myriad other disagreements, innumerable wrong turns, and some very accidental correct ones. As a 2012 reanalysis13 of the Liveing-Latham narrative put it, history is often written “to serve contemporary ends.”14

Still, the two men are key characters in the origin story that modern neurology has been writing for itself in the last couple of decades, making Liveing and Latham notable on those grounds alone. One, after all, is now often viewed as being on the wrong side of history—a catalyst for convictions that modern headache refused to abandon for far too long. The other, meanwhile, is held up as prescient, his ideas ahead of their time and vindicated by latter-day experiments into cranial anatomy.

Latham championed the so-called vascular theory of migraine. While there was an inescapable role for the nervous system even here—Latham reckoned that some admixture of fatigue or depression reduced the brain’s ability to manage the excitable reflexes of the sympathetic nervous system—it was the resulting action on the cerebral blood vessels that set the cascade of symptoms in motion, including the pain. A key role of the sympathetic nervous system, our fight-or-flight regulator, is to prepare the body for a threat by, among many other things, constricting blood vessels to increase blood pressure. Normally this includes reducing blood flow to less consequential anatomy so that more can be driven to the brain, heart, and muscles. But in migraineurs, Latham reckoned, the sympathetic nervous system overresponds, constricting cerebral arteries and generating what many patients experienced as an aura. At some point, the sympathetic nervous system would grow weary and, out of necessity, go into a state of overrelaxation, allowing cerebral arteries to dilate and swell with increased blood flow—too much, Latham thought—and a perceptibly pulsing headache was born.

In his book Headache: Through the Centuries, Eadie, an emeritus professor of clinical neurology and neuropharmacology at the University of Queensland in Brisbane, Australia, points out that despite Latham’s modern association with a vascular hypothesis framed in opposition to a neurogenic one, the physician always15 considered migraine to be, for the most part, a nervous system disorder.

But Latham’s preoccupation with blood flow was nonetheless in keeping with the broader vascular hypothesis of migraine, which posited that the most salient aspects of the disease—the aura and the subsequent pain—could be attributed to vascular composure. The vascular theory proposed that the migraine aura was associated with vasoconstriction, while the subsequent headache was associated with ensuing vasodilation and cerebral hyperperfusion—a flood of blood. Subsequent decades of research would remain mostly preoccupied with the cerebral vasculature, both in the hunt for more detailed and evidence-based descriptions of how migraines unfold and why they hurt, and in efforts to develop medications that could provide relief. Gain control of those blood vessels, the thinking went, and you gain control of the disease.

Liveing had a different take. He saw similarities between migraine and any number of established episodic brain disorders, chiefly epilepsy and its characteristic seizures. According to Eadie, he also saw reverberating echoes in all manner of involuntary tics of the body, from hiccups and sneezing to myoclonic jerks—the sudden twitch that sometimes happens when you’re falling asleep, or the startle response to a sudden noise. Within the constellation of central and peripheral nervous system phenomena, according to Eadie, Liveing saw a natural home for migraines, which he considered to be the result of what he called “nerve storms.”

For Liveing, the migrainous “seizure” arose somewhere in the three-inch span of anatomy between two egg-shaped structures located deep within the middle brain, where a good deal of sensory information is relayed, and the lower end of the brain stem. Disturbances in those eggs would account for migraine’s common visual auras, by this theory, while disorder at the bottom of the brain stem, where vomiting and other key autonomic functions are regulated, would account for the gastrointestinal upset so many migraineurs experience. Most important: while Liveing did not dispute that vascular disturbances could sometimes be associated with migraine attacks, he considered these to be epiphenomena—by-products of the primary problem.

It was as good an explanation as any, according to Eadie—even if it failed to account for other key aspects of migraine. This included impacts on speech that can sometimes occur as part of the aural phase—a symptom that would likely involve a part of the brain that Frenchman Paul Broca had already lent his name to years prior, and which fell outside Liveing’s proposed choreography. More to the point, there was no central role here for cranial blood flow—an omission that seemed to run counter to centuries of scientific description.

Still, both Liveing’s and Latham’s theories were well-known among their contemporaries, who would have understood them as astute contributors to a swirling ecosystem of hypotheses that were already leaning in one direction or the other. And while neither man bothered much with migraines after issuing their grand unifying theories, the vascular and “nerve storm” concepts drifted into the early twentieth century, with the latter seeming to gain more purchase, at least at the outset. This was in large part owing to William Gowers, the British neurologist whose Manual of Diseases of the Nervous System (1888) underscored the likely neuronal action of migraine, even as it critiqued Liveing’s “nerve storm” coinage, which Gowers called “a somewhat inapt metaphor.”

Metaphors notwithstanding, Gowers’s Manual embraced the idea that migraine shared characteristics with epileptic seizure, and while this remains a debatable notion even today, his conviction that only the neural anatomy, rather than the vascular, could fully explain the suite of symptoms attending a migraine attack, was influential. “Migraine is essentially a derangement of nerve-cells of the brain,” Gowers declared in the second volume of his opus. The book’s place as one of the foundational texts of early-twentieth-century neurology seemed to promise a starring role for the central nervous system in primary research.

It didn’t quite happen that way.

*  *  *

Andrew Charles, the UCLA neurologist and former president of the American Headache Society, likes to talk about Thomas Kuhn. He mentions him in his own mentoring seminars, and he dropped the reference more than once as we strolled across the UCLA campus in late 2021, and over longish Zoom discussions before and after.

Kuhn was an American historian and philosopher of science best known for his 1962 book The Structure of Scientific Revolutions. It was and remains both influential and critiqued, but the book’s greatest contribution to the popular nomenclature is inarguably the idea of paradigm shifts in science. According to Kuhn, scientific progress does not proceed in a linear and cumulative fashion, as traditional accounts of scientific history would have portrayed it. Instead, scientific development is characterized by periods of “normal science,” where researchers operate within an established paradigm, interrupted by “scientific revolutions” that breed paradigm shifts.

In periods of normal science, scientists conduct research that is primarily guided by the accepted theories, methods, and assumptions of their field. They focus their attentions on puzzles and questions that fit neatly within this framework—a sort of Overton window for scientific inquiry—and mostly remain blind to anything outside of it. Consensus is the engine, and while marginal disagreements bubble up as a matter of course, scientists toiling within the prevailing consensus don’t question its fundamental assumptions. The stasis is powerful, but anomalies can arise that defy the explanatory power of the existing paradigm, and if these anomalies accumulate in large enough number, consensus may find itself in crisis and, quite possibly, a paradigm shift can occur.

This is a pat summation, of course—and Kuhn was not without his critics, some of whom pointed out that he leaned too heavily into affirming historic case studies, like the Copernican revolution and the shift from Newtonian to Einsteinian physics, while overlooking less deterministic examples from other areas of science that have tended to unfold with more continuity. But there’s little doubt that Kuhn ignited expansive new realms of scholarly discourse and interpretation—and his spotlight on the pivotal role of scientist in-groups, bound by a mutual paradigm, unleashed a new generation of sociologists keen to study the human dynamics of scientific knowledge making. This new discipline saw academics bringing an anthropological lens to scientific disciplines, which were no longer viewed as inevitable by-products of objective enlightenment but as deeply human communities governed and driven, like any other community, by cultural customs, rules, biases, and blind spots. The notion that prevailing theories have a way of occluding competing ones, and that research (and funding) tends to have a herding aspect—also seemed to describe an axiom that many academics already recognized: outlier science, they might say, risks an impoverished anonymity.

Charles points to another more recent example of Kuhnian dynamics at work: Alzheimer’s. For decades, the field of Alzheimer’s research and drug development had been dominated by the idea that the accumulation of amyloid-beta peptides in the brain is the primary culprit behind the cascade of neuronal dysfunction, synaptic loss, and ultimately the neurodegeneration that is characteristic of the disease. First proposed in the early 1990s, the amyloid cascade hypothesis formed the prevailing paradigm for subsequent Alzheimer’s research—even as critics16 began questioning its explanatory power, given that not all individuals with amyloid plaques develop Alzheimer’s disease, and some individuals with significant amyloid pathology do not show clinical symptoms of the disease at all. Clinical trials targeting amyloid also showed limited success in effectively treating or reversing Alzheimer’s symptoms, raising further questions17 about the central role of amyloid in the disease process.

Whether the amyloid hypothesis18 still holds promise is a matter of ongoing debate, but some critics have argued19 that its dominance over the field meant that researchers were essentially captured by an idea for decades. Their reputations—and a good deal of capital—were invested in the prevailing paradigm, leaving alternative and potentially promising theories to wither. “Perhaps because of those heavy commitments and the near lock that the amyloid hypothesis had on public attention,” a 2022 analysis in the digital science magazine Qunata speculated, “some researchers faced pressure to accept it even after its unsuccessful track record was clear.”

Matters were not helped20 when a 2022 investigation by Science magazine revealed that a foundational amyloid paper published in 2006, and scores of other papers spawned in its wake, may well have used falsified imaging data. If the theory is ultimately abandoned, it will have likely been a nearly thirty-year journey down a blind alley—a wrong turn that will have consumed billions of public and private pharmaceutical dollars before setting a new course.

It’s an instructive example to Charles, who views his own discipline’s stubborn adherence to a particular theory of headache pathophysiology as a case study that Kuhn would have appreciated. “The real example of the dogma that fits perfectly with this kind of Kuhn model is the vascular hypothesis of migraine,” he told me. “The fundamental tenet of that is that it’s the dilation of blood vessels that is responsible for pain, or headache. And there’s so much incredibly obvious evidence that that’s not the case. And yet, even still, it’s still being taught in medical school. And so, I mean, part of that is, it sort of belies an unwillingness to be skeptical about, you know, an extraordinarily complex problem.”

Charles is not alone in chastising his profession for becoming stuck for too long in a conceptual rut. But if the “normal science” that unfolded over most of the twentieth century kept headache researchers focused on cranial vasculature, there were some compelling reasons for it.

*  *  *

From the time of Gowers through the first three decades of the twentieth century, little in the way of new theories of headache pathogenesis emerged. Eadie mentions21 that variations on both the vascular and neuronal theories were circulating, with the latter seeming to hold the most purchase among neurologists. Allergies and defective vision were also sometimes invoked as proximate causes, without much in the way of corroboration. And Sigmund Freud—a migraine sufferer himself—eventually became inspired22 to offer his own psychodynamic interpretations of the disorder, albeit after self-medicating in the fashion of the day: “I was suffering23 from migraine, the third attack this week, by the way, although I am otherwise in excellent health,” he wrote in an 1885 letter to his wife Martha. “I took some cocaine, watched the migraine vanish at once, went on writing my paper as well as a letter to Professor Mendel, but I was so wound up that I had to go on working and writing and couldn’t get to sleep before four in the morning.” (As the funk musician24 Rick James once put it, “Cocaine is a hell of a drug.”)

A more effective drug—and one less likely to result in an amped-up work binge—was gaining attention around the same time: ergotamine. While known25 for its various medicinal properties since the Middle Ages, ergot is the name for a type of fungus that infects certain grains, particularly rye. The fungus produces ergotamine among other alkaloids—lysergic acid diethylamide, or LSD, is another—that can have profound physical and psychoactive effects on humans, and it was the culprit in various food-borne epidemics of ergotism in the Middle Ages, which afflicted victims with impaired blood circulation, gangrene, convulsions, hallucinations, seizures, and, for tens of thousands, ultimately death.

But the isolation of ergotamine26 alkaloid from ergot by Swiss biochemist Arthur Stoll in 1918 was an important moment in the history of headache science. Though they couldn’t have fully understood why it worked, ergotamine—a potent vasoconstrictor—gave obvious relief to many patients in the throes of migraine pain, and it would eventually be marketed in pill form as the very first migraine remedy in the 1920s, by the pharmaceutical company Sandoz. It was known then under the brand name Gynergen.

A synthesized derivative of ergotamine, called dihydroergotamine, or DHE, would arrive in the 1940s, deliverable chiefly through inhaled nasal spray or, more effectively, by injection or IV. Both ergotamine and DHE would be the only medications specifically marketed to abort headache attacks for generations—and they are still around. Novel methods27 of administration of ergotamine and derivatives are also being explored, though they remain in various phases of clinical trial.

Ergot-based preparations have always carried some suboptimal risks, however, including acute vascular spasm and thrombosis at high doses, and even at normal doses, it can lead to stomach and circulation problems. As with sumatriptan, frequent use is discouraged, not least because it is potentially habit-forming—despite the extremely common side effect of nausea and vomiting—and several countries28 have begun to ban common brands like Sandoz’s Cafergot, a caffeine-ergotamine preparation, because the benefits have not been found to exceed the risks. (I used DHE as recently as 2015, when nothing else seemed to be working. It was helpful but required self-administration of several injections, along with antiemetic suppositories to control the urge to retch.)

In the long arc of headache medicine, what ergotamine and DHE were truly good for, however, was reinforcing the idea researchers should be looking to the blood vessels of the head in their hunt for explanations of the migrainous cascade. And no one would contribute more to entrenching that notion for much of the twentieth century than Harold George Wolff.

Chapter 5
Pillar to Post

I’ve had patients break down and cry, just saying, “You’re the first person to believe me . . .” That’s a terrible indictment, because you know, it doesn’t need any fancy tests. It’s such a characteristic history. And so, I teach our medical students and I say, look, I want you to pay attention for the next ten minutes. There’s a condition that you may or may not see in your life, but it’ll be devastating to your patient if you miss it.

—Paul Rolan, MD, clinical pharmacologist, University of Adelaide, Australia

The first doctor I ever brought my cluster headaches to, in the early 2000s, drove a red Corvette and looked for all the world like the actor Wilford Brimley, right down to the luxurious mustache: a walrus bristle for the ages. His clinic was near my apartment in Queens, and while he didn’t specialize in headaches, and his penchant for locker-room banter ought to have set off red flags, I viewed him as a miracle worker and dear friend for his willingness to slip me pharma samples—and to try anything that might work. I’d sought out a neurologist at the time, but the wait to see one with any sort of headache specialization, even in New York City, was a month and a half. My attacks were very likely to have gone back into hiding by then, and I’d found in this man—I’ll call him Dr. Wilford Brimley—someone who didn’t really study headaches, but was willing to get creative with prescribing. He would also pick up the phone if nothing seemed to be working.

I stayed with him throughout the aughts, through that wretched time in 2006, and even after leaving the New York Times and taking a position in 2007 at National Geographic magazine in Washington, DC. Despite the distance, I would still make panicked journeys by car, up across the eastern seaboard from my apartment in the U-Street corridor to the outer edges of Queens—a five-hour trip—to see him. I can only say that headache patients will often cling to those we perceive as helpful. Better that than to be cast back into a dark sea in search of some new safe harbor. And better that than having to win over some new medical ally with our boring stories of torment.

But my doctor was in his own trouble then. He’d intimated once before that he was facing a legal comeuppance, but he was nonspecific. He’d “fucked up,” he once put it. My mind reeled at the time, speculating a bit on what he might have done—peddled drugs? Embezzled cash? In my position, I didn’t really care. He would speak into a dictation machine and routinely misdiagnose me—even after seeing me for years—with migraine rather than cluster headache. He would seem to forget the details of my condition, often beginning our sessions by asking me, “Are you having a headache now?”—a laughable query. If this doctor did not know that a person cannot sit still through a cluster headache, that rocking and pacing and pounding in agony are telltale signs, that I’d more than once drawn blood from my own scalp while trying to scratch the pain away—if he could still ask this question, what hope was there?

At the same time, he was open to my corrections and reminders. He would seem to take the bits of scientific literature I’d printed out for him—new studies, new theories, hints at new or alternative dosages for the same old middling drugs—and at least pretend to scan them. But more than anything, he seemed to be sincere when he asked, “Tommy” (he called me Tommy, without prompting). “Tommy, what can I do to help you? I don’t believe in suffering.” I remember that line specifically, turning it over in my head as I walked home. I’m not suffering, I thought. People are starving, ravaged by war and pestilence. I have everything. I have fucking headaches, man. I don’t suffer!

By hoarding the medications he gave me—refilling the prescriptions again and again, long after a bout with clusters had subsided and I was pain free—I didn’t need to trouble him much. My stockpile could usually accommodate the next bout, months down the line, assuming it didn’t last too long and I stayed on top of it by touching base with him once or twice a year.

On more than one occasion, my doctor would complain on my behalf to insurers who would not cover this medication or that—usually the sumatriptan injections, which were the only things that reliably worked to stop an attack. My insurers were rarely persuaded, but I gladly shelled out hundreds of dollars from my own pocket for a single cartridge, sometimes a thousand dollars or more for a small collection. But Dr. Wilford Brimley had my back, I thought, and so I stuck with the guy, knowing the potential gauntlet that would accompany a change in doctors: waiting for a new intake appointment, re-explaining years of history and learned experience, navigating suggestions to relax more, or being forced to start over with old drugs that never worked. It would have taken a lot for me to initiate a breakup.

In the end, he broke up with me. Sort of. I saw him one last time, after a desperate drive up from Washington, DC, to Queens in 2008. A year later, after I’d left National Geographic and returned to the New York Times, I received a letter at our home in the Hudson Valley. It notified me that my doctor had left medical practice and that my records had been transferred elsewhere—I don’t even recall where. I was in remission from my headaches then, so it wasn’t an emergency, but I was nonetheless distraught. His office number had already been cut. I searched the internet to see if I could find an email address or cell phone for him—some avenue to share a last thought. To say thanks?

I learned1 in my subsequent searching that he was accused of being a very bad doctor. His license2 had been suspended in the late 1990s by New York’s Department of Health for engaging in a sexual relationship—consensual, by all accounts—with a patient he was prescribing medication to. Then, according to a lawsuit against both him and the Flushing Hospital Medical Center where he once had admitting privileges, he was accused of nearly a decade of harassing behavior—inappropriate sexual comments, touching, and other acts of relentless, unwanted, and very unrequited pursuit of female nurses and pharmaceutical representatives. In 2009, a jury awarded $15 million in damages in a suit leveled against both the doctor and the hospital—one of the largest penalties ever awarded for a sexual harassment case in the United States to that date. A newspaper account3 mentioned his mustache. “We would say, ‘koo koo kachoo,’” one witness to the behavior was quoted as saying, “after the Beatles song, ‘I Am the Walrus.’”

I had never really bothered, until that point, to do a background check on Dr. Wilford Brimley. Didn’t look up his license, didn’t search for his name. But it was all right there, out in the open. I guess I’d just found my bunker, my refuge, in an okay doctor who would see me quickly, consider my suggestions, and prescribe what was the standard, albeit imperfect protocol for cluster headache. He might not have even known what those were, but I knew the bleak landscape of headache medicine. What else was anyone further up the professional food chain going to do for me?

The penalties, I would later learn, were significantly reduced, but Dr. Wilford Brimley was ruined and my lifeline was cut.

*  *  *

By almost any account, primary headaches are poorly managed diseases. Migraine is particularly so, even for those with unfettered access to the full complement of health care options. For them, the voyage from the initial onset of migraine to a clear diagnosis can often feel like a Kafkaesque gauntlet of different doctors and, possibly, a neurologist or two. Only if they are lucky will they encounter a specialist with training in headache science.

They’ll also cycle through a litany of prescription drugs, various lifestyle alterations, diet changes, and, when those don’t work well, a few “alternative” treatments—chiropractic, acupuncture, curative teas, supplements like feverfew and magnesium, and a kaleidoscope of homeopathic tinctures. “I was probably twenty-five,” Amy Oringel told me about the very first time she was able to see someone who specialized in headache diagnosis and treatment, which would have been in the mid-1990s. “That was the first time,” she recalled, “where someone looked at me and said, ‘Oh! You’re one of X million people who get this.’”

Now in her early fifties and a communications consultant for a risk management firm in New York City, Oringel seemed, at least in our conversation, a strong, friendly, and ebullient personality with little apparent patience for nonsense. She had sought me out in the summer of 2021, after reading an article I’d published in the Times on emerging research into migraines and clusters. She was tired, she intimated, of hiding. “I really do feel seen,” she said in an initial email exchange about the article, “in part because the world is falling apart, and because I’m turning 50 this fall, I’ve hit a wall and made a conscious decision to stop shrugging off my health when talking to family, friends, [and] work colleagues.”

During a subsequent video meeting, her eyes, framed in concentric circles by a bob of brown hair and then, more narrowly, by a pair of tortoiseshell spectacles, frequently grew wide with what seemed like genuine excitement at the opportunity to speak intellectually, peer-to-peer and at length, about headaches.

Oringel had been coping with undiagnosed migraine disorder for roughly a decade prior to visiting the Headache Institute at St. Luke’s Roosevelt Hospital Center on Manhattan’s Upper West Side. Although the number of such specialty clinics has grown over time, they remain something of a rarity—and they were far more so even in the waning decades of the twentieth century. “I remember feeling—I was so excited, I couldn’t even stand it,” she told me. “And when I got there, they said, I mean, obviously, in those days, nothing’s covered. Nothing. God, I remember this so well. It’s $1,200 just to walk in the door. This is before anyone’s done anything to help you. And, you know, I have a privileged upbringing to a certain extent, for sure. But I was twenty-five. And I remember standing outside the hospital and telling my then boyfriend, now husband, and crying—and I’m like, not much of a crier—and being like, these people are in this building, and they can help me!”

They certainly tried. But what unfolded over the ensuing years for Oringel is not remotely uncommon. While her headaches and accompanying symptoms varied in intensity and frequency over the years, waning significantly during her two pregnancies only to return with a vengeance, they dominated her life. She experienced nausea, vomiting, and even occasional blackouts. And then there was the pain:

“At their worst, I was—I could not live,” she told me. “I could not live. I could not live. I was completely down for the count and couldn’t do anything. And then I couldn’t plan my—it’s the same story everyone has: You can’t make plans. You cancel plans. You can’t go anywhere. I couldn’t fly. I couldn’t go to the movies. I couldn’t travel. I couldn’t be, like, in motion. I mean, there’s so much of my world that really, as I got older, just closed right in.”

As the bouts continued, she bounced from drug to drug and doctor to doctor. She was placed on beta blockers initially, to ill effect. “I basically went to sleep for like three months and didn’t wake up,” she told me. “So, I wanted to change that up.” Next came topiramate, an anticonvulsant. That helped intermittently, she said, and while it didn’t have the stupefying effect it has on many other people, including me (many in the headache community call it “dope-a-max,” a play on Janssen Pharmaceutical’s familiar brand name version of the drug, Topamax), it provoked profound weight loss in Oringel. “I’m five feet tall, and I weighed about ninety-six pounds. This is after having my kids. And when you live in the suburbs, and you weigh ninety-six pounds, you have people come up to you and say things like, ‘So, what’s your secret? How did you, you know—the baby? You had the baby and all of a sudden you’re so skinny! How’d you do it?’

“Meanwhile, I’m like—I was sickly. I was not a well person.”

At various points Oringel was prescribed gabapentin, another anti-convulsant and nerve pain medication. She also tried Botox—the brand name for the protein derived from the Clostridium botulinum bacteria, known as botulinum. Most people will4 recognize it as the wellspring of the deadly condition botulism, and its exquisite ability to cause rapid muscle paralysis makes it among the most toxic substances in the world. Most people will also recognize it as a popular cosmetic treatment when injected in controlled amounts into the face—those same paralyzing properties doing wonders for wrinkles (albeit at the sometimes-unsettling expense of facial mobility). It also appears to help some patients with recurring headaches, but for Oringel it wasn’t effective. “I passed out on the table,” she said. “It didn’t do anything.”

For a period of time, her doctors also tried aripiprazole, a so-called atypical antipsychotic drug that acts on specific dopamine and serotonin receptors within the central nervous system. The drug—an uncommon albeit not unheard-of tool for migraine5—was developed and approved for the treatment of schizophrenia and bipolar disorder. A common side effect is tremors. “So, one day I wake up and I’m like, Oh, great. Now I think I have some kind of palsy,” Oringel said.

She was also introduced to the triptans, which helped somewhat reliably to mute individual headaches, though often enough, and in the absence of anything that could effectively prevent the attacks from coming on in the first place, at increasingly diminishing returns. “Forgive me, it was kind of a mindfuck,” she said of the triptan she was prescribed—and on which she still relies—sumatriptan. “Because you take it, and you’re gonna feel better,” she said, “but then you know you’re getting one the next day. And then you’re in the cycle.”

This will be familiar to many headache patients, this life of funhouse mirrors, where each new doctor and each new intervention offers a tickle of hope, even optimism, only to warp and warble and contort into something at best uncertain, middling, and half-effective, and at worst a new, unwelcome misery to complement the existing ones.

In her late thirties, with her two children in middle school, Oringel thought she needed to detoxify. Having ingested an alphabet soup of pharmaceuticals, none of which had been developed for her disease, she decided to explore nonpharmaceutical therapies like biofeedback, guided meditation, and acupuncture. She also sought out the blandishments of a tony wellness retreat near her home, which emphasized “slow medicine” and a vague admixture of “integrated wellness” and “psychospiritual counseling.” The cost for a consultation with the facility’s founder was $1,000, and she was given what she described as a massive tome of questions.

“I was ecstatic,” she told me. “I’m like, Oh, my gosh, I’m gonna talk about my migraines! And it’s so exciting. And I gave it to him. And when we were—he was kind of giving me his analysis of what he saw in terms of my data and my responses. And then he said: ‘You have to cut out dairy.’”

For a potent drumbeat, Oringel’s expression grew flat.

“I lost my mind,” she said. “I was like, are you serious? I’m paying you $1,000 to tell me to stop eating dairy? Like, I was just freaking out. And he goes, ‘Amy, I have to be honest, you’re having kind of a heroin-addict-esque reaction to me saying you can’t have dairy.’

“It just made such an impression on me,” she confessed, her gaze slipping somewhere off-screen, as if reliving a distant defeat. “I felt, just, so at the end of my rope, because I’m going out on a limb, paying this guy to try and tell me, to finally give me some good advice. And instead, I’m feeling kind of judged and weird. And I knew in my head that this was an absolute waste of time, because, well, I’m not cutting out dairy. That’s just not going to help you. I mean, it’s just not going to help. That’s absurd. If I had a nickel for every time someone told me to cut out gluten!”

For all of this, Oringel remained open to trying anything. She stuck with the wellness retreat for a couple of years, scrupulously following a regimen of meditation and other self-calming techniques. They were “not not helpful,” as she put it. They offered other health benefits, to be sure. And maybe, in some way that’s impossible to pin down in the fog that separates biology and chemistry from consciousness and conditioning, they might have sometimes interrupted the circuitry of a migraine attack. But as with so many remedies, be they chemical or spiritual, the headaches ultimately proved to be the mightier force, seeming for all the world to learn and adapt and mutate around each new defense, eventually finding Oringel hiding behind this pharmaceutical wall, or that lifestyle adjustment, and attacking her once more. “The fact that a lot of us go through all of this, and there’s no conversation around it, and there’s no one to say, ‘Oh, my god, me too!’” Oringel said, “it’s just bananas.”

The new drugs aimed at blocking or inhibiting the neuropeptide CGRP arrived in 2018, and Oringel was among the first in line. She participated in an early trial of one such drug and was prescribed the first official medication to successfully navigate the Food and Drug Administration’s approval gauntlet: Aimovig, codeveloped and marketed by Amgen and Novartis. The drug, a self-administered injection taken once per month, was highly effective, Oringel said, at least at the outset. “The first six months were heavenly,” she told me. Since then, its effectiveness has waxed and waned.

This is not unusual for some patients taking the new therapies, which continue to be refined and expanded, with new CGRP blockers and inhibitors following Aimovig—in both injectable and oral formulations—in rapid succession in the 2010s and 2020s. A modest but significant percentage of patients, perhaps around 20 percent, are considered super responders to CGRP—their lifelong, personal narratives of disabling, unexplained, recurrent head pain being completely rewritten in ways that would have been wholly unheard of just a few short years ago. It’s not been quite that for Oringel, but it does seem to help. Often. Sometimes.

Still, even when its effectiveness seems less than perfect, and even though some days the pain just breaks through anyway, she insists that she isn’t disappointed; indeed, she says she’s elated that the market for purpose-built migraine therapeutics is finally getting off the ground. “I actually have had this conversation with my husband where I’m like, it really is a great time to have migraines,” she told me. “I really feel like I’ve grown up alongside the field to a certain extent. You know, like, when I started out when I was a teenager, no one would—you know my primary care doctor didn’t even mention it . . . So, from that perspective, I’m oddly grateful. And the fact that people are talking about it, I mean, it’s just been such a thing.”

Oringel’s sense of joy derived from seeing headaches given sustained and fruitful scientific and clinical attention is something that I heard from multiple people with migraines and clusters—even those for whom the CGRP class of medications have so far proven ineffective.

This isn’t surprising when considered against the historical tableau of poor disease management and pharmaceutical meandering that has long typified the migraine experience. Some research6 has suggested that migraine patients spend an average of seven years navigating a skein of primary care physicians, emergency rooms, and other waypoints in the health care labyrinth before receiving an accurate diagnosis. (They are often miscategorized as suffering from sinusitis.) Cluster patients can face similarly long diagnostic roads. A systematic review7 of the literature, published in the journal Neurological Sciences in 2019, suggested that while the time frames are narrowing, the mean time to a correct diagnosis for cluster patients in the United States is between 6.6 and 8.9 years—despite the unambiguous and uniform constellation of symptoms. An earlier study8 estimated that nearly half of all cluster patients wander the corridors of the health care system for at least five years before a doctor correctly recognizes their plight, during which they often undergo invasive procedures at the hands of well-meaning but misguided ENT specialists, dental surgeons, and other practitioners attacking the disease from all the wrong angles. Similar journeys unfold for patients in countries all over the globe. “Delays in diagnosis,9 misdiagnosis and mismanagement of [cluster headache] are a widespread problem,” the 2019 study concluded, “and have been reported in many countries with well-developed health services, including several European countries, Japan and in the USA.”

Meanwhile, even with an accurate diagnosis, newly designated primary headache patients are often at the beginning of a long, zigzagging journey through a pharmacological forest, as their doctors and neurologists mix and match potential remedies in a hunt for some combination that might bring even a small measure of relief. One of the most enduring aspects of clinical migraine treatment is that, even within the stable collection of known neurological symptoms, the disease’s precise presentation can vary widely from one individual to the next. This not only complicates diagnosis, but also makes treatment highly individualized; what works for one person might do absolutely nothing for another. Even more vexing: medications that have worked in the past will often stop working somewhere down the line, requiring both patient and caregiver to go back to the drawing board.

One upshot of this is that headache sufferers will have experienced a wide array of different and typically imperfect medications on their treatment journeys—and they will often be on multiple drugs at once. Indeed, while studies are somewhat limited on this front, what research has been done suggests that people living with primary headache, if they seek and find help at all for their disorders, are often on lists of medications comparable to that of elderly populations—even though headache disorders tend to be at their worst in the years between puberty and late-middle age. One 2018 cross-sectional observational study10 from Italy, for example, analyzed the prevalence of “polypharmacy,” or the use of multiple medications, among three hundred patients diagnosed with primary headache. The mean age of those included in the analysis was just under forty-three, with the youngest participants being in their late twenties, and the oldest in their midfifties. The average patient was taking at least four medications. Nominal polypharmacy, which the researchers defined as the use of five or more medications, was found in more than 40 percent of those included. Among those who experienced fifteen or more days with headache per month for a period of three months or more—defined as chronic, as opposed to episodic headache patients—the rate of polypharmacy was nearly 60 percent. About three-quarters of patients were using medications in an acute context—that is, they were trying to stamp out an individual headache attack, with 30 percent of episodic sufferers and nearly 65 percent of chronic patients taking some combination of drugs on a preventative basis.

“Patients with primary headaches, mainly young adults, are exposed to high polypharmacy, comparable to that of the elderly,” the researchers concluded—adding that the potential for worrying drug interactions, as well as the risk of rebound pain from overuse of medication, was unusually high in this population. It also suggests that a large percentage of primary headache patients, along with their doctors, have been listing from pillar to post in search of an intervention, or combination of interventions, that will work.

Indeed, it had long been considered axiomatic11 within clinical headache treatment circles that the medications traditionally prescribed for migraine prevention are, at best, effective for about half of all patients—and for these responders, the drugs work only about half the time. That might even be somewhat optimistic. A separate study12 spearheaded by researchers with the Applied Neurophysiology and Pain Unit at Bari Aldo Moro University, in Bari, Italy, examined a decade’s worth of data for migraine patients treated at a single headache center between 2009 and 2019. After screening for various edge cases, the researchers alighted on 1,100 cases of diagnosed migraine with aura, migraine without aura, or chronic migraine. They then traced the various prescribed interventions and follow-up visits for each to see how well the remedies performed. While there are sure to be idiosyncrasies specific to headache treatment in Italy, versus, say, treatment in the United States, the analysis examined most of the common medications prescribed for migraine patients across the developed world. These included the gamut of anti-epileptics, calcium-channel blockers, beta blockers, and antidepressants, among other drugs. The results weren’t heartening.

Overall, only about 12 percent of the 1,100 patients included in the study saw a reduction in the frequency of their headaches of 50 percent or more, and large numbers of patients—discouraged by poor results and miserable side effects—simply bailed on treatment altogether. This is remarkably common across surveys and studies worldwide.

The historical difficulty in finding reliable pathways to relief for many patients creates frustration all around—so much so that several clinicians admitted to me that some of their colleagues in neurology prefer to avoid headache patients anywhere they can. Physicians pick up this disposition toward headache patient avoidance early on in medical school—and even within neurological subspecialties. In some instances, it’s a matter of perceived helplessness: Most doctors, after all, genuinely want to heal their patients, or at least get negative symptoms under some sort of control. For many common conditions, there are clear road maps to get there, with tried-and-true lifestyle adjustments and pharmaceutical interventions that can turn the tables on an otherwise debilitating disease burden for a significant percentage of patients. That doesn’t necessarily mean a cure, of course, but it does mean that for many people living with persistent disorders—from allergies and asthma to diabetes, depression, cardiovascular disease, and even many cancers—modern medicine has offered a measure of power over, and predictability to, the burden of disease.

This trajectory tends to be muddier for headache patients, particularly those with migraine, which, while well described in its broadest contours, remains incredibly idiosyncratic and neurobiologically variegated from one patient to the next. Add these complexities to the vagaries of pursuing and managing a career in clinical neurology, and it can be little wonder that some doctors come to view a headache specialty as singularly unrewarding. One survey of care providers, published in 2015, concluded that “headache medicine specialists13 have one of the highest rates of burnout compared to other physician specialists.” That burnout rate was twice that of working adults in all fields, and while many of the reasons skew toward the mundane and the general—dissatisfaction with the practice environment, difficulties with insurance companies, government regulations, and the like—another key factor was the sheer complexity of helping individual headache patients.

“We became14 headache medicine specialists with great enthusiasm and idealism to reduce the burden of headache and suffering where headache is so often unappreciated, misdiagnosed, and inappropriately treated,” the authors wrote. “Although the practice of headache medicine can be personally meaningful and fulfilling,” they added, “the field can be especially stressful and demanding.” Why? In part, they noted, because “we spend long hours with patients who may have the most challenging chronic and sometimes intractable headaches and comorbidities.”

Many neurologists say that because of the field’s reputation as a thankless treadmill, headache disorders are frequently viewed as a trivial choice for specialization. Migraine, by this view, is attractive only to the most mediocre and unambitious scientists and clinicians, or those otherwise not cut out for the truly maverick science needed by other diseases of the brain and nervous system, like epilepsy or Parkinson’s disease. This was reflected in numerous conversations I had with clinicians and scientists working at the top of the field, as well as with medical residents pursuing a neurology specialty.

“Yeah, I think the more glamorous ones, maybe, get more attention,” said Monica Sarkar, now a medical resident at the Ohio State University Wexner Medical Center. She was describing the basic neurology education she received during medical school, and the diseases that merited special attention. She recalled deep dives on conditions like myasthenia, an autoimmune disease-causing muscle weakness, or the degenerative brain disease Parkinson’s. The average medical student15 gets about three hours of training on headaches, according to one early study. “It’s more commonplace,” Sarkar said of migraines. “Everyone knows someone with headaches, or they’ve experienced migraine or whatever . . . I feel like we got so much teaching about other things, which are important, too, but way less common. So I was surprised by that.”

The sentiment spans generations of neurologists—and even crosses borders. In a conversation with two young scientists working at the Danish Headache Center, Anja Sofie Petersen and Agneta Snoer, I asked whether a headache specialization was considered a respectable career choice within neurology. “In essence, you have a pecking order in neurology, and I think that movement disorders are at the top,” Snoer began. “Yeah, they consider themselves rock stars,” Petersen added. Below that you’ll find stroke specializations and maybe cardiovascular neurology, followed by epilepsy, neuro-oncology, multiple sclerosis, and a host of other disorder specializations, they seemed to agree. “And then right at the end, just below or maybe ranked with dementia: headaches,” Snoer said.

I commented that dementia research struck me as pretty respectable, right? “Yeah, so we’re below dementia,” Snoer said upon reconsidering. “That was just my opinion.”

Back in the United States, Amaal Starling, a neurologist and researcher at the Mayo Clinic campus in Phoenix, Arizona, says she sensed the same thing. “It is crazy, right? But it’s the stigma of migraine, even within the physician community, even within the neurology community, that migraine is like soft neurology, it’s not real neurology, it’s not real science,” she said. She pointed to the stereotype of a female migraine patient, the “hysterical woman lying in the dark room with her hand on her head, who just wants to get out of housework and taking care of the kids and working.” Those stereotypes bleed into the scientific community, Starling told me, such that during her residency, after she applied to and was accepted for a headache medicine fellowship, she was met with dismay by her peers. “I had so many people who came to me, like attendings, who said to me, ‘Oh, you know, you’re so smart, Amaal. Why are you wasting your career on headache medicine?’”

In a conversation months later, another neurologist and researcher intimated the same thing. “There’s no question that people who go into neuroscience research have been and are still told, ‘Do not do that. There’s no money there. And it’s kind of embarrassing—and it’s not really science.’ So why would you do it?” Christopher Gottschalk told me during a visit to his offices at Yale New Haven Hospital. Gottschalk is a professor of neurology at the Yale School of Medicine. He established the first headache medicine program at the school.

Even Peter Goadsby, perhaps the most recognizable figure in headache science today, says he would eventually come to learn that his chosen research interest, which he fell into in his native Australia, was looked down upon. “It did dawn on me after a while, as I went to other places, that headache was not considered a respectable pastime,” he told me. “It was kind of soft, you know, nonsense, BS, basically crazy people, la-la-la. There were no specific treatments, if you go back before the triptans, and it wasn’t considered a respectable pastime. I didn’t realize that because I grew up in a cocoon that said this is important, and we can do biology. And we were doing that. And the first couple of times I interacted with people outside the cocoon, I thought, well, you people are crazy. But then I realized that I was the crazy one, like I was the one from Mars, and that they’re all from Earth.”

That’s stigma at work, Goadsby said. “It makes it hard to discuss something and get it out, if the field is broadly considered to be not really a serious thing.”

It’s little wonder, given these sorts of pressures, that there is a structural shortage of expertise in headache medicine relative to its burden. One 2020 study16 put the number of headache specialists accredited by the United Council for Neurologic Subspecialties at 564—for a population of migraine, cluster, and other headache patients that numbers in the tens of millions. The UCNS is not part of the much larger American Board of Medical Specialties, which recognizes certification only through the American Board of Psychiatry and Neurology. The board offers certification in epilepsy treatment, brain injury, vascular neurology, and pain medicine, among others; there is no headache subspecialty. The UCNS was formed17 in 2003 to fill that void. (A 2019 letter18 appealing to institutional department chairs, chief medical officers, and other credentialing and hiring committees, imploring them to recognize UCNS as a legitimate certifying body, suggests that it is still fighting for recognition.)

The UCNS database, as of early 2024, listed about seven hundred diplomaed headache specialists, though this seems to include certifications in Canada and Australia. Most of these specialists are concentrated on the coasts. New York has sixty-seven certified headache specialists, and California has seventy-two. Alaska and Wyoming have no specialists. In Montana, where I now live, there is one.

All of this means that much of the diagnostic and treatment burden will necessarily shift to primary care physicians—which is fine. For roughly 70 percent19 of migraine patients, this is precisely where they turn. A primary provider can capably manage most headache patients if they stay up on the literature and, ideally, get some specialized training on new treatment modalities. Both the American Headache Society, in concert with the American Academy of Neurology, publishes detailed guidelines and position statements on standards of care that are regularly updated as new treatments emerge. And both the AHS and the National Headache Foundation are among professional organizations that offer doctor-facing educational programming in headache medicine, but it’s up to individual doctors to seek out these opportunities and to stay informed. It’s hard to know how many do, but one 2016 survey20—not strictly scientific, but probably suggestive of something—found that only about 28 percent of primary care physicians polled were familiar with standard American Academy of Neurology guidelines on preventative migraine treatment. I can promise without consulting any data that far fewer would have a clue about cluster headache.

This often means that patients are receiving substandard or even wholly inappropriate treatments. A 2023 study,21 for example, estimated that roughly 20 percent of migraine patients had been prescribed opioids for their head pain. This despite neurological consensus statements and guidelines that expressly advise against opioids as a treatment option—in part because it’s so addictive, but mostly22 because it tends to make the condition much worse. And given the middling efficacy of many recommended migraine interventions, patient adherence to various drug regimens can often be quite low. Why bother with a battery of pills, after all, that make you fuzzy-headed or bloated, or that raise your blood pressure or give you a mild case of the shakes, if the odds of that crucial payoff—an end to the pain—are at best even? A large percentage of headache patients will simply give up and attempt to deal with the disorder by structuring, and often curtailing, their lives in other ways: locking bedroom doors, skipping family and work events, turning down career opportunities, calling in sick, powering through pain where they can, or even going on disability when it gets bad enough.

“A mild effect of current preventive treatments on headache frequency and disability emerged from the present data,” the researchers from Bari, Italy, concluded in what struck me as an almost comical understatement. “The number of patients lost to follow-up or who dropped out because of adverse events was large,” the researchers noted, “and confirms that the preventive approach to migraine treatment is currently inefficacious and unwelcome.”

Gottschalk treated me for a brief stint in 2015, when the usual remedies I’d leaned into, including prednisone and a constipating calcium-channel blocker, had ceased to work. My wife’s family lived nearby the Yale campus in New Haven, Connecticut, and being aware of his work from my late-night doom-scrolling through online headache literature and cluster forums, I reached out in desperation. He prescribed the dihydroergotamine (DHE) injections, which seemed to help. But I was also aware of some promising cluster headache clinical trials happening at the time, involving a pharmaceutical company and an experimental antibody designed to regulate a neuropeptide called CGRP. I perceived Gottschalk as having a fair amount of truck in the world of headache science and patient advocacy, and I attempted to enroll in one of the clinical trial hubs near my then home in Massachusetts by dropping Gottschalk’s name in a direct appeal to the principal investigator. It didn’t help, and my emails were ignored.

I wondered if it came off as a crass move, too thirsty. Managing how the medical world perceives you becomes a matter of high art when you know that each new interaction is informed primarily by two things: (1) the doctor’s present state of knowledge specific to your condition; and (2) the thousands of patient interactions that preceded you. You have control over neither of these, but in a culture structured around for-profit care, the imperatives of economy and expediency dictate that you will be sized up quickly and placed in a frame: talk too much about medications you’d like to try, and you might be perceived as drug seeking. Contradict an uninformed physician with up-to-date literature in the wrong way, using the wrong tone, and you risk insulting a fragile ego—and being treated accordingly. When a doctor’s framing of you works, all is well. When it doesn’t, you may need to push a bit, advocate for a new framing. In some cases that will come, but pushing also carries a risk. Do it too hard, or in the wrong way, and it can become its own sort of framing—you’re a complainer, a malcontent, an attention seeker, or some other more damning assessment that can be impossible to escape.

Studies and my own reporting make it obvious that women struggle with this dynamic more than men. Nearly every female migraine patient I spoke with described negative interactions with a doctor at one point or another in their attempts to find effective care. And research has repeatedly shown that women’s pain—regardless of source—is a routinely harder “sell” in the context of a doctor’s office or an emergency room. (Millions of primary headache patients23 visit emergency rooms annually.) A 2022 analysis24 published in the Journal of the American Heart Association, for example, sourced data from the National Hospital Ambulatory Medical Care Survey between 2014 and 2018 focusing on emergency department visits by adults aged eighteen to fifty-five years presenting with chest pain. The analysis, which covered more than 29 million emergency room visits during the sample period, found that women were less likely than men to receive urgent triage (19.1 percent vs. 23 percent), receive electrocardiography (74.2 percent vs. 78.8 percent), or be admitted to the hospital than men (12.4 percent vs. 17.9 percent). After adjusting for various factors, men were also attended to more swiftly.

It’s not a new phenomenon,25 and pain seems to be a key catalyst for gendered judgments—not just in doctor’s offices, but across the culture. A pair of 2021 psychological experiments,26 for example, found significant differences in how participants perceived female vs. male pain. In one test, volunteers were shown video clips of people experiencing shoulder pain. (Remarkably,27 this is a real research database developed by McMaster University and the University of British Columbia; it includes recordings of the spontaneous facial expressions made by real patients experiencing shoulder pain as they performed a series of range-of-motion movements.) The volunteers routinely estimated female patients’ pain to be less than that of the male patients depicted in the clips. In a second experiment reported in the same paper, volunteers recruited online were shown clips from the same database, and then asked to imagine they were doctors who needed to prescribe either pain medication or psychotherapy. Women were more often recommended for the latter.

Not surprisingly, some studies have found that depression can be roughly twice as frequent among people with migraine compared to the general population28—particularly when the headaches are chronic. Precisely which way those comorbidities flow, of course, is difficult to tease out: are people depressed because they have chronic head pain, or is chronic head pain somehow an occasional by-product of depression?

Whatever the answer, the combination can be inherently disabling,29 and the locus of the pain—that is, inside the head—seems to matter a great deal. Consider, for example, a retrospective analysis30 published in 2021 in the Journal of Pain Research, which looked at suicide attempts in U.S. veterans with chronic head-pain disorders. In that study, researchers with the Department of Neurology at the Columbia VA Healthcare System in Columbia, South Carolina, examined Veterans Health Administration data for millions of patients diagnosed with chronic pain of the head, neck, back, and other regions of the body. After adjusting for a variety of demographic and psychiatric factors, the researchers concluded that veterans with chronic headache have a higher risk of suicide attempts than those with other types of chronic pain. Women with chronic headache, they found, were at a higher risk than men.

Although research is far more limited, studies have suggested that people living with cluster headache specifically may have three times higher odds of lifetime depression compared to the general population.31 The disorder has been given a variety of names over the years, from histamine headache and red migraine to Horton’s headache (named for American physician Bayard T. Horton, who described clusters in detail in the 1930s), and even the “erythroprosopalgia of Bing”—a nod to the early 20th century Swiss neurologist Paul Robert Bing, by way of compounding Greek: erythros (red); prosopon (face); and algos (pain).

The name “suicide headache” sums it up just fine.

*  *  *

Dr. Wilford Brimley told me he worked at a car dealership when I reached him in the summer of 2022. It had been well over a decade since I’d last spoken to him, and I had tracked him down, with some effort, as I got into the weeds of this book. I wanted to close that loop somehow, to hear a note of regret or penitence from him, maybe, and to gauge how much he remembered, or ever really knew, about cluster headaches. It was a selfish enterprise, on my part—and arguably callous to the ordeals of the women he’d harassed. And yet I couldn’t shake the need, despite the despicable things he’d done to others, to thank him for what he’d done for me. I accept your judgments for that. I share them.

When I reached him by phone, he was as I remembered: thoughtful in turns, but blustering and overconfident in others, and always speaking with the rapid-fire, street-tough cadence of outer-borough New York: Goodfellas with a stethoscope—or at least he used to be. We didn’t discuss his career ruin or his earlier bad acts, beyond him saying that it had cost him a great deal, including his family, and that he felt lucky to have found a new partner and a relatively quiet way to live out the rest of his life. He’d be in his eighties now, I’d guess, or near it.

When I asked him about his approach to my headache disorder, it was clear that the specifics of our interactions had made less of an impression on him than they had on me. As always, he remembered my problem as migraine. He also said he tended to treat headache patients on his own, as a primary care doctor and an internist, rather than immediately refer them to a neurologist. “Nowadays there’s more of an inclination to refer everyone to see a specialist, but that’s not why I got into medicine,” he said. “You’ve got a problem, I want to try and treat it—and migraine intrigued me. I had some patients, mostly women, so I’d go to an annual conference in the city, in Manhattan.”

These were educational conferences, he explained. “They’d catch you up on the latest research, the latest medications, the latest imaging, the latest theories on causes—was it hormones? Was it diet-related? Was it moon rays?” He was trying to be funny, and I could sense the ends of his handlebar mustache turning up with a see-what-I-did-there smile. “Whatever the fuck it was—who knows? But I would learn things. I wasn’t an expert of course, but if you had migraine, and I could treat you, I would treat you. I wanted to try and treat you, anyway.”

I decided not to get into the whole cluster/migraine distinction. They are so wildly different in their presentation, and it seemed completely beside the point so many years on. But before we hung up, I did ask him about the time he mentioned suffering to me—that people shouldn’t suffer. It was a loaded question, given everything else he’d done. But it also had made an impression on me at a time, in my late twenties and early thirties, when I now think I probably was suffering. “Well, on the one hand, people need pain—it’s an important part of our life experience. It reminds you that you’re alive. I’m someone who believes that you need trouble sometimes so that you appreciate the good stuff,” he told me without any detectable note of self-awareness. “But I don’t believe people should suffer—and that’s what’s happening with a lot of headache patients—and a lot of people with chronic pain. They’re suffering. No one should suffer. There’s no benefit in suffering.”

A day later, he called to leave a voice mail, saying he’d done some research online and that he’d found an organization I should look into for my book. It was something called the Mayo Clinic, “M-A-Y-O”—he spelled it out, assuming I was unaware. “Looks like they’re doing some interesting stuff there.”

I do think he meant well.

Chapter 6
Painful Thrusts

I get ocular migraines, so they’re behind my eyes. And I can’t do anything when it’s bad. Like, even like the smallest light or the lightest noise sets me off. I wear sunglasses everywhere. It’s just, like, constant. I can barely open my eyes. And its just stabbing pain, like throbbing pain from behind my eyes. And I just feel so much pressure in my brain. Like, I really feel like my brain is gonna explode.

—Emma Haggett, college student and migraine patient, Edmonton, Alberta, Canada

In the spring of 1947, a traveling circus arrived for an extended stay in New York. One of the performers, a trapeze artist, suffered from headaches and sought out treatment, which eventually led her to Dr. Harold Wolff. By that time, Wolff was an established icon within neuroscience, known for his appetite for experimentation and his conviction that diseases of the mind were not distinct from those of the body—that the former could readily manifest in the latter. Simply looking at a person in the throes of a bout, or assembling accounts of self-reported symptomology, diets, and other behaviors, was not enough for Wolff, who notably suffered from migraine himself. He wanted to get inside the head—and inside the person—to discover what bits of cranial anatomy, and what bits of a patient’s life and temperament, were conspiring to create the pain.

Among other things, Wolff is responsible1 for one of the earliest attempts to establish the now well-known hereditability of migraine by obsessively tracing the family trees of patients. (Numbers vary,2 but modern population studies have shown that migraineurs are far more likely than the general population—perhaps fourfold—to have a first-degree relative who also has the disorder. Interestingly, migraine3 with aura appears more heritable than migraine without.) Wolff was also keen to put anecdotal remedies—however strange—to empirical test. So, when this trapeze artist reported to Wolff that her headaches could sometimes be relieved when her job required her to stand on her head, the researcher’s curiosity was piqued. He went to the circus himself to observe this head-standing behavior, and returned to the lab the next day asking his colleagues to consider what might happen inside the skull when a person is inverted. He also sent his collaborators to the circus to observe and ask the upturned acrobats questions of their own. One researcher reported finding another headache sufferer among them, who confirmed that he, too, often found some relief while upside down. Wolff had heard enough.

“He . . . had all of us,4 as well as some patients, stand on our heads,” his lab assistant would later recall. “We had a sturdy tilt table for the purpose. Prompt and vigorous vasoconstriction took place at the head-end of the body which diminished the pain if you had a headache, and occasionally terminated it.” (Erasmus Darwin would no doubt have felt vindicated.)

It was just one more data point in a rich headache dossier that Wolff had compiled in the preceding decades. Having studied for a time at the Conditioned Reflex Laboratory in Russia, under experimental neurologist Ivan Pavlov, and later with psychiatrist Adolph Meyer at Johns Hopkins, Wolff eventually ended up with dual appointments at Cornell University Medical College and New York Hospital, where he would remain until his death in 1962. These early influences5 contributed to his interest in percolating debates about the divide between functional and organic disease—or disease that can be clearly attributed to some corporeal source vs. that with no apparent somatic aspect. Was migraine a product of the body or of the mind? Wolff, influenced by predecessors, considered this binary view of human disease too simplistic. “His interest was6 in moving beyond the typical Cartesian mind/body divide to understand how psyche, personality, and biology could simultaneously contribute to nervous disorders,” as Joanna Kempner puts it in her 2014 book Not Tonight: Migraine and the Politics of Gender and Health.

To that end, Wolff was a keen collector of detailed patient case studies—comprised not just of headache symptoms but family life, careers, upbringing, emotional tendencies, and other factors—which he and his team mined for meaningful patterns. Wolff was sure he’d found some, identifying personalities uniquely prone to migraines: “The elaboration7 of a pattern of meticulous perfectionism for dealing with feelings of insecurity begins early in childhood,” he was quoted as saying by his longtime research associate, Helen Goodell, in a lecture given after Wolff’s death in 1962. “The individual with migraine aims to gain approval by doing more than and better than his fellows through ‘application’ and ‘hard work,’ and to gain security by holding to a stable environment and a given system of excellent performance, even at high cost of energy. This brings increasing responsibility and admiration, but gains little love, and greater resentment at the pace he feels obliged to maintain. Then the tension associated with repeated frustration, sustained resentment, and growing anxiety is often followed by prostrating fatigue, the setting in which the migraine attack occurs.”

To paraphrase: Wolff seemed to think that migraine patients were well admired but relentlessly competitive high achievers who were a bit fussy, control-freakish, and prone to frustration. That Wolff himself suffered from migraines almost certainly contributed to this typology, and other descriptions8 of his temperament by students and peers lends credence to the idea that his notion of the migraine personality was to some extent autobiographical.

At the same time, Kempner notes that these personality traits—brilliant, competitive, overachieving—were almost always used to describe men. Kempner, a sociologist at Rutgers University who studies medicine, science, gender, and inequality, is one of those researchers presumably unleashed by the Kuhnian microscope. As a migraine patient herself, she has taken a deep interest in deconstructing the culture of headache science and the paradigms that have historically dictated what is understood as “known” in the field. For female migraineurs, she argues, Wolff had distinct impressions:

Wolff described9 the migrainous woman as unwilling to accept the female role, particularly in sexual relations. He described 80 percent of his female sample as sexually dissatisfied. “Orgasm was seldom attained, and the sex act was accepted, as at best, a reasonable marital duty. In several instances, it was deemed frankly unpleasant and was resented.” Furthermore, the migrainous woman was sometimes “reluctant to accept . . . the consequences of maternity.” In contrast, Wolff reported that his male patients were sexually well-adjusted, even if their sex drive occasionally suffered “as an accompaniment of ambition and hard application to work.” Three of Wolff’s male patients did experience “sexual maladjustment,” but Wolff pointed out that they had “vigorous sex drive[s, but] . . . were married to sexually indifferent or frigid wives. Women, it seems, were always the source of sexual problems.

Wolff’s attempts to find patterns to explain patients’ head pain in their personality traits were not entirely unusual in an era when Freudian psychology was capturing popular attention. Even in previous eras, doctors were quick to spot any indication of stress and nervousness in a patient and ascribe to it a certain explanatory power. It’s also worth noting that even within today’s more sophisticated, neuronal paradigm of headache, there remains plenty of room for stress, fear, worry, and other states of mind to play a role in tripping whatever wire separates bodily homeostasis from a trigeminal short circuit in any individual. These trip wires vary widely among patients; for some it may well be exceeding some threshold of stress, while for others it’s a scent or some ingested molecule.

It’s possible, albeit entirely unproven, that it all begins with the hypothalamus, the conductor leading the body’s internal orchestra. Responsible for maintaining the soft, steady music of our autonomic nervous system, the hypothalamus, through a mix of direct action or hormonal release, governs everything from body temperature and blood pressure to hunger and thirst, digestion, sleep-wake cycles, and mood. For reasons we don’t fully understand, some event, some signal arising in an invisible half moment between a systemic tick and its following tock, might be throwing the symphony into disarray. Just what precipitates the upheaval is hard to say; often it can seem to be some combination of factors in a single person, or sometimes nothing identifiable at all. What seems clear is that by some genetic predisposition that remains invisible to us, the neural latticework designed to interpret, modulate, and respond to stimuli is prone to going haywire in some people, causing a cascade of changes that very often results in head pain.

Wolff would eventually become convinced that the pain was due to dilated blood vessels in the membranous layers surrounding the brain—and he also thought patients prone to orchestral breakdown shared common traits that were more visible to the naked eye. As with the ruddy, leonine features ascribed to cluster headache patients, the midcentury retreat into migraine personality types, while understandable from the point of view of scientists and doctors struggling to explain what remained unexplainable, was always little more than nostrums filling a void. But Wolff’s work and influence, alongside a simultaneous rise in the fields of psychology and psychosomatic medicine, helped to disperse those nostrums into the wider culture—and into the prevailing paradigm within which other headache scientists and clinicians toiled.

In a lush, 1945 newspaper spread appearing in the Pittsburgh Sun-Telegraph, to take just one example, science journalist Gobind Behari Lal—who had won the Pulitzer Prize just eight years prior—reported on the latest findings regarding the female migraine personality. The package is anchored by a large image of an elegant and begowned middle-aged white woman seated in a Victorian-era armchair. Teams of hand-drawn and intentionally cartoonish baphomets come at her head from both sides armed with whips, horns, hammers, drills, and drums. One attacks her right temple with a jackhammer. Another approaches from the left with what appear to be two kitchen box graters. The title of the piece: “Beauty Is a Headache.”

In this telling, migrainous women are not so much frigid as they are clever and cute, with an abiding tendency to fret. “Women who are most easy on the eyes, charming, dazzlingly intelligent and highly sensitive,” Lal reports, “are the very ones who are particularly prone to attacks of migraine headache.” This, the journalist noted, was according to Prof. Walter C. Alvarez, on the staff of the Mayo Clinic in Rochester, Minnesota. Described as a “widely experienced and keenly observant physician,” Alvarez is quoted as saying, “Yes, I can often recognize the migrainous woman the minute I see her. This is very helpful diagnostically, because often she is rather sensitive about her handicap.”

Alvarez added: “Most of these women tend to be petite, and with nice figures.”

From our advantaged view of things seventy years later, it can seem almost too easy to assail past eras of scientific ignorance. They labored, after all, in the myopia of their cultural and historical moment—as do we all. At the same time, it can be hard not to marvel at certain empirical blind spots that ought not have been there by the middle of the twentieth century. As Kempner and others have pointed out, for example, such “observations” frequently suffered from first-order selection biases, with scientists basing them on the narrow and comparatively well-heeled slice of the population they had access to in their clientele. “Women who have everything are apt to have migraine,” declared the subhead of the 1945 Sun-Telegraph article.

Forgivable or not, the residue of these facile taxonomies has been hard to scrape off the patient-doctor relationship ever since—particularly for women, and even more so for women with migraines. “So, I didn’t have any of the warning signs,” Kathy O’Shea told me when I asked her about the first time she could remember getting a migraine. It was 1976, O’Shea was fourteen, and her memories are vivid: “My brother and I were off at some—we were up on the St. Lawrence River camping with my family, and we’d been over at the rec center watching, of all things, a Charlie Chaplin film, and we were sitting there on these uncomfortable seats and all of a sudden, I mean, truly out of nowhere—like, I know we always talk in metaphors when we talk about migraine, but it was just like a knife had gone through my head and I couldn’t function.”

It was the beginning of a devastating period for O’Shea, who had been active and involved in school sports for most of her life to that point. When the migraines began, however, all that shut down. Her first visit to a neurologist was devastating. “He thought that it was psychological,” she tells me. “I just remember very distinctly the first consultation, and he said to me, ‘Do you want your mother to leave the room, so you could talk to me more about what’s really going on at home?’ And I thought, what? My mother was like my best friend, first of all, and there’s nothing I can tell you that’s going to shed any light on this. So, he really was quite dismissive. And he threw me on a lot of medications that were, of course, for other things, and most of them made me very ill.”

O’Shea, a professor of English at Monroe Community College in Rochester, New York, wrote a book10 about migraines, published in 2020, that mines the world of literature—from Jane Austen to Joan Didion, and from Emily Dickinson to Oliver Sacks—for meaningful distillations of migraine and its lingering stigmas. While she eventually found a compassionate neurologist who alighted on a combination of therapies that worked well for her, his retirement a few years ago sent O’Shea, now in her sixties, back into the marketplace for a headache specialist. When she found one in 2018, it did not go well. “I started to get kind of emotional,” O’Shea says of a visit to this new doctor—a woman—who suggested that her prior care was all wrong and that she needed to be sent to an inpatient clinic to start over. “She didn’t back off of it. I mean, she wasn’t compassionate at all,” O’Shea said. “She just was like, ‘I’ll send you to a clinic and, you know, they’ll make you go through withdrawal from all your medications.’ It was almost like she was implying that I was some kind of addict.”

It might be overstating things to draw a line between these experiences and the wisdom of mid-twentieth-century headache researchers, but it can also be hard not to. Alvarez did seem more willing to grant charitable traits to his female patients than Wolff—he described them as being “above the average in intelligence,” for example, and “quick in understanding.” With a creepy self-assurance, Dr. Alvarez also suggested that migraine was somehow correlated with the women that men found most attractive. “Many a lovelorn male has complained that a good-looking woman gave him plenty of headaches,” the wink-wink introduction of the 1945 article on Alvarez’s theories began. “But now it turns out that it is the beauty herself who is most susceptible to the aggravating misery of the head.”

If only, he lamented, they could learn to chill out: “They get so tense over thinking of doing something,” he complained to Lal, “that they can get a headache even before they get started.” Other experts of the era, including O. Spurgeon English and Edward Weiss of Temple University, co-authors of one of the first books on psychosomatic medicine, signaled that the roots of a female migraine patient’s problems could be traced to childhood: “When a little girl does not receive enough affection from her mother, or someone else to whom she is attached,” Lal writes in describing the English-Weiss hypothesis, “she stores up a hidden hostility which, during her later years, causes such migraine attacks.” These observations were not “haphazard,” the article was keen to note, but a “constitutional pattern; a physical and temperamental make-up which is the basis of nearly all migraine cases.” And for the woman experiencing frequent attacks, Dr. Alvarez’s diagnosis was simple: She was “overworking or worrying or fretting or otherwise using her brain wrongly.”

Alvarez, a Wolff admirer,11 retired from medical practice in 195112 and took up writing a widely syndicated newspaper column on a variety of health issues—becoming known at one time as “America’s favorite doctor.” He frequently opined13 on migraines here, including in one column published in 1965—twenty years after the Lal interview—in which he described a letter he’d received from a woman suffering from repeated headache bouts:

Recently her doctor sent her to the hospital where she wasted several hundred dollars on a general examination. As usual, nothing wrong was found. I must have seen a few thousand women whose doctors thought that by giving a very thorough examination they could surely find the “cause” of the migraine, but I never saw a cause found in this way. . . . I have no interest in examining a woman with migraine. I want to talk to her for an hour and learn why she is unhappy, worried, or unable to make up her mind about something. If I can help her to solve her problem, I may be able to “cure” her migraine overnight.

Many women will attest that this clinical mindset persists—a cul-de-sac of diagnostic nonsense where physicians and scientists have toiled for decades. That framing probably contributed to the comparatively low social status of headache science itself, driving research interest—and research dollars—toward other subspecialities that were less freighted with perceptions of female hysteria. I once asked Peter Goadsby, the UCLA–King’s College London scientist, why headache research seems to drag and sputter—an interesting finding here, a promising breakthrough there, but little in the way of sustained investigation and discovery—despite the potentially massive social and economic benefits that might accrue from better treatments. “It’s like having one of those huge A380 planes and trying to get it to take off,” he told me, referring to the massive double-decker aircraft developed by Airbus, capable of carrying nearly nine hundred passengers. “You need all four engines up to speed, pushing pretty hard to get three hundred tons off the ground. But once you get them gliding, get a little bit of lift, you’re going to get some momentum. At the moment, we’re on the runway, but we’ve got a fully-laden A380 and boy oh boy, that’s gonna take some, you know, some gas to get off the ground.”

I abused the metaphor and asked what was really keeping that plane on the tarmac.

“Too many female passengers,” he said.

Still, the notion of the “migraine personality” was just one of two blind alleys the profession spent an inordinate amount of time exploring in the middle years of the twentieth century, and where Wolff was a key influencer. The other was his fixation on cranial vasculature.

*  *  *

In the late 1920s,14 Wolff and his collaborators reported stronger blood vessel pulsations in the heads of live cats after injecting them with histamine. When fellow researchers established a few years later that histamine was also an effective experimental headache trigger in humans, Wolff and his collaborators sought to test the idea that cranial vasculature played a key role in human migraine pain. In one key experiment, Wolff and his team rigged up a system in which a needle was inserted into the cerebrospinal fluid space between the brains and skulls of volunteers, while tambours—small drums with pressure-sensitive diaphragms—were placed on the skin over the temple, roughly where one branch of the carotid artery ends. Both probes were connected to rubber tubing terminating in elastic walls, to which mirrors were attached. A narrow beam of light was cast on the mirrors, which would reflect into a nearby slit camera attached to a rolling scroll of bromide paper.

After a histamine injection, the volunteers described their symptoms—including, in some cases, the onset of head pain. Air pressure changes within the engineered tubing, caused by dilating blood vessels distending the skin of the temple or sending sympathetic waves through the meningeal fluid, caused the elastic at the tube ends to flex, the attached mirrors to move, and the reflected light to bend and make its imprint through the camera onto the rolling bromide. The stronger the pulsation, the longer the imprint—and the results seemed unmistakable: as the histamine dilated the blood vessels in the head, those prone to migraines reported a throbbing pain—“the painful thrusts of each cardiac systole,” as Goodell put it.

Wolff and his colleague John Graham repeated this setup15 a few years later with the addition of an important component: ergotamine. Earlier experiments had shown that administration of ergotamine, a potent vasoconstrictor, could effectively quell the pain of a headache, but Wolff and Graham wanted to trace the course of its effects as it was happening—to etch it into the bromide paper for all to see. They recruited sixteen volunteers with migraine who would submit to a combined thirty-two chemically induced migraine attacks, with additional, less-complete observations made in six volunteers who had a total of twenty combined attacks. They also recruited forty-six control volunteers from healthy patients or workers at New York Hospital. All subjects were described as resting “comfortably on a couch” during the ordeal. “This was a far cry from the modern pressure gauges and transducers for recording pulsations,” Goodell recalled, “but in that old-fashioned but ingenious way, both intracranial and temporal artery pulsations could be recorded quite satisfactorily.”

Those who developed head pain during the experiment were asked to describe the intensity of the pain as it changed by writing down a series of plus marks each time the pain grew or slackened, with ten plus marks indicating extreme pain. Timers were used to clock intervals between pulsations recorded on the bromide, and blood pressure readings were taken at regular intervals. In some cases, skin temperature was recorded at the ear, temple, and cheek. When the ergotamine was injected intravenously, the researchers tracked the changes.

Wolff and Graham would report that in twenty cases, the introduction of ergotamine was followed by a decrease in recorded pulsations—once by 84 percent, but on average by 50 percent—and often very quickly. Most crucially: “This marked decrease in the amplitude of the temporal or occipital pulsations bore a close relation to the decline in the intensity of the headache,” the two researchers reported. “In sixteen of the twenty experiments the amplitude of pulsations declined with the diminishing intensity of the headache. If the amplitude of pulsations decreased slowly, headache likewise diminished slowly. If the amplitude dropped precipitously, the headache was ended promptly.”

Wolff and Graham reported other interesting results. Compressing the common carotid artery in a patient during an attack also seemed to provide a reduction in pain, for example. And in the other direction, they inserted a syringe filled with sodium chloride into the temporal carotid artery of migraine-prone volunteers, and then, just above the insertion site, pressed a finger into the temple to compress the artery further upstream. Pushing the plunger on the syringe and filling the blood vessel with additional liquid caused the artery to “visibly distend,” the researchers reported, adding: “In each of several trials such distention was accompanied by severe pain referred to the temporal region.” Go figure.

These studies would spark what many historians consider a crucial paradigm shift in the study of headaches. Not only did they seem to prove that the pain that migraineurs had been reporting for centuries was very real, and indeed, almost mechanical in nature. They also seemed to suggest that whatever else might be going on, engorged cranial blood vessels were clearly responsible for that pain—and ergotamine, which could effectively constrict those blood vessels, seemed a reliable way to turn it off.

These findings were not incompatible with the percolating theories of the migraine personality, of course. While the internal wiring of some people made them prone to this sort of short circuit, important aspects of preventing attacks continued to be thought of as within their control: Don’t stress too much. Don’t eat the wrong things. Relax more. Confront your childhood demons. Kempner seems16 to delight in listing some of Dr. Alvarez’s more colorful assertions about migrainous women, which distilled readily into a 1960s culture where Mad Men–esque pharmaceutical marketing was ascendant and the psychologizing of medical problems with no clear cause was a booming industry. Migraine patients were “petite [and] full-breasted,” for example, but also full of “unusual sensitiveness,” “nervous tension,” and “easy fatigability,” according to Alvarez. And even though it was clear that the pain and accompanying symptoms were biological in nature, prevailing wisdom held that the best prevention—for men and women—was to get a grip. “A person with migraine17 deals with his life situations in a manner which rapidly depletes his reserve of energy,” argued Dr. Arnold P. Friedman, who studied headaches at the Montefiore Medical Center in the Bronx, in a 1964 interview with U.S. News and World Report. “This sets a pattern of function which the limited physiological capacity of the individual is unable to stabilize, resulting in cranial vascular changes which produce headache.” (The reporter’s next question: “Does this weakness show up in childhood?”)

Ten years later,18 a newspaper article covering the work of one of the pioneers of biofeedback therapy, Dr. Elmer Green of the Menninger Foundation in Topeka, Kansas, seemed to fully marry the vascular and psychosomatic theories for migraine: “A migraine is caused by improper blood flow in the head. But . . . the patient could learn to control what’s called the ‘vascular tension.’ Presto, the headache is gone.”

This isn’t to suggest that biofeedback therapies cannot be helpful to migraineurs. While by no means universal, there is almost certainly a stress component to the triggering of symptoms for many patients, and it makes sense that learning to consciously control some of the autonomic features of stress—heart rate and blood pressure, for example—might be useful. At the same time, it’s rare that a moment of stress will immediately trigger the migraine process, and some patients and researchers trace long delays: a stressful event occurs, and then only hours or days later does the breakdown in cerebral signaling make itself known. Others suggest that it is the time of relaxation after a stressful event—often called the “let-down” period—that provokes the attack.

Many patients report19 that biofeedback can be helpful in at least dampening the severity or frequency of attacks—though some researchers have argued that the same20 might well be achieved by learning more ordinary (and less expensive) relaxation techniques. A recent review21 of the evidence for various psychological interventions in migraine conducted by the influential Cochrane group found that there was little empirical evidence to support the efficacy of biofeedback or other psychology-based self-help techniques. Looking at the broad evidence base for several psychological interventions—including cognitive behavioral therapy, which focuses on teaching patients to control thoughts and behaviors; relaxation therapies involving either exercise or machine-based biofeedback; or a variety of other mind-over-body treatments—the Cochrane researchers concluded that the quality of most studies in the area was distressingly low.

Whatever the reality, if any headache patients can find relief by simply adjusting their mindsets, I say godspeed. Relief being such a fickle visitor, never trusted to stay, each of us must coax it back in our own way. But it’s also inarguable that for most people, this is no more plausible or practical a solution than meditating your way out of cancer or thinking yourself out of heart disease. And it’s fortunate that as scientists began to probe more deeply into the biochemical aspects of human physiology, the diagnostic framing that implicated headache patients’ personalities and pinned the pain solely on cranial vasculature began to break down. A couple of key developments were behind this.

The first was the identification of serotonin. Technically known as 5-hydroxytryptamine, or 5-HT, which describes its chemical structure, this key neurotransmitter was first identified in the 1930s, during cellular studies in the guts of frogs, mollusks, and rabbits. The Italian scientist22 credited with its discovery, Vittorio Erspamer, dubbed the substance enteramine, after those gut cells (“entero” is from the Greek root for “intestine”). Later, when researchers23 at the Cleveland Clinic found the same monoamine in beef serum in 1948, they noted its effectiveness, among other things, at modifying the tone of blood vessels. Their coinage—a conflation of “serum” and “tone”—was serotonin, and that’s the name that stuck. Despite its well-known role in nervous system function, the vast majority of serotonin is, indeed, located in our guts, where it helps to regulate bowel movements and related functions. In the brain, though, it’s thought to regulate mood, modulate pain perception, and is often referred to as the body’s natural “feel-good” chemical. Most modern antidepressants seek in varying ways to control its presence in the brain.

The neurotransmitter quickly became an object of intense scientific interest, including among researchers studying migraine. Wolff himself,24 along with colleagues, reported in the mid-1950s that perivascular injections of serotonin could trigger migraine-like headaches in the lab—albeit in patients25 submerged in hot water. Other researchers26 reported the opposite: that intravenous administration of serotonin—in a lab exercise with too many risks to ever be commercially therapeutic—nevertheless seemed to ease migraine symptoms. (Interestingly, Wolff’s studies at this time were also thought to have discovered actual tissue injury in areas of the head associated with headache pain, although to date,27 no conclusive evidence of this exists.)

In 1961,28 a group of Italian researchers working out of the University of Florence observed that during migraine attacks, the main metabolite of serotonin, 5-hydroxyindoleacetic acid, was elevated in the urine samples of test subjects, while other studies of the era had shown that plasma concentrations of serotonin seemed closely tied to the waxing and waning of migraine, with higher levels during attacks and lower levels when things returned to normal. Just what role serotonin was playing in migraine formation was unclear, but its apparent status as a key molecule in the process did not escape the notice of the Swiss pharmaceutical company Sandoz, which was searching for a drug that could target those 5-HT receptors. It had found one in methysergide, a synthesized ergotamine derivative that entered the 1960s as a revolution in migraine treatment, particularly because it wasn’t designed to stop a bout of pain, but rather prevent the attacks from coming at all—and it was quite good at that, showing efficacy rates of 50 percent or more. The presumption, of course, was that serotonin, which has a role in vasoconstriction, was likely regulating cranial blood vessel tone. If methysergide could modulate serotonin levels, then vessels in the meninges or other pain-sensitive anatomy of the head would not become dilated, leaving nearby nerves untroubled and the patient pain free.

Links to a litany of problems associated with long-term methysergide use, which is somewhat promiscuous in the types of 5-HT receptors it binds to, also began to surface in the late 1960s. These included the formation of scar tissue in the area behind the stomach and intestines, fibrotic thickening of cardiac valves, and assorted fibrotic plaques—worrying collateral damage that had researchers and pharmaceutical companies eager to find alternatives.

Among these researchers was Patrick Humphrey, who in 1972 had been tasked by his employer, the UK-based Glaxo, to find a new antimigraine drug. He immediately focused29 on serotonin regulation, hoping to identify a chemical compound that was as effective as methysergide, but more discerning in its targeting of 5-HT receptor types. In many ways, the team was toiling in darkness. Only a couple of serotonin receptors had by that time been fully described, and Humphrey could not have known that at least fourteen individualized subtypes spanning across distinct 5-HT receptor families would eventually be discovered. Blocking one type of serotonin receptor or stimulating another—particularly from Humphrey’s place of imperfect knowledge—is somewhat like toying with a vast chemical switchboard, completing or cutting signaling pathways that would have unknown downstream effects. Pull this plug and some crucial neuronal conversation might be silenced; insert a plug elsewhere and you might facilitate a sinister plot among conspiratorial molecules. I’ve also sometimes30 thought of it as akin to a standup bit the comedian Steven Wright used to do, in which he described a light switch in his house that didn’t seem to do anything. “Every so often, I would flick it on and off just to check,” the joke went. “Yesterday, I got a call from a woman in Madagascar. She said, ‘Cut it out.’”

Building on research out of India and Australia, Humphrey and his team began hunting for new 5-HT receptors in anesthetized dogs, among other animals, and eventually they found one. Today it is known as 5-HT1B, and it is associated with a range of neurotransmitters that play a role in mood regulation, memory, aggression, stress sensitivity, and anxiety, among other functions. Interestingly, methysergide seemed in this case to be acting as an agonist—stimulating rather than blocking the 5-HT1 receptor, which Humphrey and his colleagues had found present on cranial blood vessels. If they could develop a serotonin analog that would do precisely that but leave other 5-HT receptors alone, perhaps they could achieve the desired vasoconstrictive effects, precisely in the part of the head where it mattered, without other unwanted serotonergic cross talk being unleashed body-wide. In the end, his team of chemists were able to develop just such an analog, and it worked—to Humphrey’s own apparent surprise. “We knew that 5-HT231 receptor activation leads to all sorts of undesirable things such as platelet aggregation and bronchial constriction, among others,” Humphrey wrote in 2007, more than thirty-five years after his experiments first began. The 5-HT3 receptors, the team also knew, can cause neurons to become more electrically active, and they wanted to avoid those as well. “So, we set out to make an analog of 5-HT that would selectively stimulate the 5-HT1 receptor,” Humphrey wrote—adding with some restraint: “To some extent we were lucky that it did not stimulate all these other 5-HT receptor types that were identified later at the molecular level.”

Humphrey and his colleagues ran tests in dogs, and then in cats, tracing the effects of their new serotonin analog on the vasculature throughout the bodies of these animal models. Unlike ergotamine, the molecule’s action appeared to be remarkably specific, with “no effect on vascular beds supplying the kidneys, adrenals, the heart, or the brain,” he noted.

Getting from cats and dogs to humans was somewhat tricky, because the locus of action for their experimental molecule, at least in the cat, was in specialized vascular connections in the animal’s neck. This did appear to be particularly meaningful for pain in the human head, and Humphrey was worried that he and his team would have trouble convincing clinicians, based solely on these early animal results, to conduct trials of their drug. A variety of theories was offered to help bridge that gap, but Humphrey credits something called the “carotid shunt” theory of migraine, which suggested that anomalies in the blood flow through the carotid arteries, which supply blood to the brain, may somehow contribute to the onset of migraine attacks. It was mostly bald speculation, and most scientists dismissed the notion. It’s unclear from Humphrey’s own writings whether he even believed it himself. Still, it provided the shred of plausibility he needed to nudge experimental use of Glaxo’s prototype in humans. Small trials in Germany, and then in the United States, showed that the company’s new drug, which they would call sumatriptan—my eventual saving grace—was highly effective. Results, published by an international study group32 in the New England Journal of Medicine in 1991, showed that roughly 80 percent of trial participants experienced a marked reduction in migraine pain within an hour—although frequently much faster. “We conclude that a single 6-mg dose of sumatriptan given subcutaneously,” they wrote, “is a highly effective, rapid-acting, and well-tolerated treatment for migraine attacks.”

The UK and parts of Europe had already approved sumatriptan in 1991, but in late 1992—three days after the Christmas holiday—U.S. regulators gave the nod33 to a 6 mg injection of sumatriptan, branded as Imitrex, for the treatment of acute migraine. It was an almost eerily pinpointed medication, capable of providing swift relief for the pain of a migraine, but effectively useless for any other kind of pain in the body—or even other pain disorders in the head, like common tension-type headache. Humphrey and his team had done something extraordinary: identifying a serotonin receptor so highly specialized in its function that it seemed intimately involved in the production of migraine pain—and almost nothing else. Debates would quickly ensue34 over where, precisely, the salient action of sumatriptan was taking place, but those were academic questions; what mattered to patients was that it worked.

For Glaxo, it was a huge pharmaceutical hit, and the press went wild—sometimes declaring that migraine would be eradicated altogether. “Glaxo is gearing up35 to launch what could be its next blockbuster,” the Associated Press declared in a March 1993 dispatch, “an injectable medicine that cures migraine headaches.” (It does not cure migraine headaches.) A Knight-Ridder syndicated story in April the same year declared in a headline: “New Miracle Drug Giving Hope to Migraine Sufferers.” The piece36 profiled forty-two-year-old Susan Simon of Miami, who put herself on the waiting list at her local pharmacy months earlier. “It’ll mean I don’t have to go and sit in the emergency room for a couple of hours to get a narcotic shot for relief,” Simon said.

Approval for use in the acute treatment of cluster headache would soon follow, as did other migraine formulations aside from injection, including oral and nasal-spray preparations. And of course, other companies came out with their own triptan drugs—including zolmitriptan (Zomig) from AstraZeneca; rizatriptan, marketed as Maxalt by Merck; and naratriptan, another Glaxo triptan sold as Amerge. The frenzy would become familiar to all Americans, with Glaxo Wellcome (the new name arising from a merger in 1995) flooding magazines, newspapers, radio, and television programming with the very first direct-to-consumer advertising for a migraine medication. Its competitors quickly followed suit, such that in 1998, AdAge magazine37 was predicting a market-wide ad spend among all triptan makers of roughly $120 million—or roughly a quarter-billion dollars today. Old Imitrex ads38 from the late 1990s still minister to the nostalgic on YouTube, often featuring a shadowy woman in black-and-white breaking through dark glass into a world of color and light—often one inhabited by a child giggling with delight that Mom can now skip through a dandelion field or go fly a kite.

At the outset, the triptans were outlandishly expensive and out of reach. The injections frequently retailed from $35 to $75 each; a reasonable month’s supply might run to $1,000 or more, and insurers were slow to offer coverage. Indeed, despite their seemingly unprecedented efficacy, at least one study39 analyzing triptan prescriptions among Medicaid recipients between 1993 and 2013 seemed to show that use of the drugs expanded substantially over their first ten years before falling off a cliff in the early 2000s. That trend would not recover until 2009—the year Glaxo’s patent on sumatriptan expired, and the analysis suggested that insurance cost-containment policies had prevented thousands of patients with migraine from obtaining a relatively safe and effective abortive remedy for nearly twenty years. Even among those lucky enough to get their hands on triptans, the stinginess of insurance coverage surely birthed millions of underbed shoeboxes and overstuffed bathroom-drawer arsenals filled with expired triptans that promised better than even odds of pain relief, however temporary.

In his 2007 retrospective on the discovery of sumatriptan, Humphrey acknowledges that the success of the triptans came about almost by accident, given that the animating force behind Glaxo’s quest, when it began in the 1970s, was to find something that could constrict meningeal blood vessels—the assumption being that this was necessary to curb the pain of a migraine headache. By the time the triptans were hitting the market, scientists were already raising questions about that bedrock notion, given emerging evidence that sumatriptan’s salient effects might well be somewhere in the nervous system instead. Did it work because it was acting directly on the blood vessel tone, or did it work in the neural anatomy of the head—or even inside the brain itself? Writing nearly twenty years after sumatriptan hit the market, Humphrey was still unsure. “We do not know whether40 the vasoconstrictor action is just important, or whether it is essential for terminating a migraine attack,” he wrote. “We do not know the role central 5-HT receptor activation plays in terminating migraine. [And] most of the triptans seem to be able to get into the brain, but whether that is how they act is another matter; it is not obvious to me that sumatriptan works in this way. Although there is the possibility that during a migraine attack, there may be localized changes in the permeability of the blood-brain barrier.”

These mysteries continue to animate fierce disagreement among researchers even today—and while Wolff retains his reputation as a founding father of modern headache research, the sumatriptan conundrum soon had neuroscientists questioning whether the profession had held too long to the vascular explanation—and unable to think outside of that box for too long. “His narrowness is evident41 in a high degree of obsession, a desire to be on top and to win, and from an intellectual point of view, his dogmatism and ultra-focus on the vascular theory of migraine,” wrote British neurologist Joseph Norman Blau in an essay about Wolff in the journal Cephalalgia in 2004. “If, as Gowers wrote in 1888, the cranial vessel caliber variations are a secondary manifestation of neuronal activity, then Wolff retarded progress in the understanding of migraine by at least 30 years—even to the present day.”

For his part, Andrew Charles points back to Kuhn: “The real example of the dogma that fits perfectly with this kind of Kuhnian model is the vascular hypothesis of migraine—that it’s the dilation of blood vessels that is responsible for pain, or headache,” he said. “There’s just so much incredible evidence that that’s not the case, and yet it’s still being taught in medical school.” Charles can become animated on the topic, arguing scientists and practitioners are too quick to become comfortable with an explanation that only seems to make sense, and despite little, or at best, very conflicting evidence. The result, he argues, is that other explanatory avenues remain unexplored—and underfunded. “There’s this smug acceptance that we know what’s happening,” Charles told me, “much more so, I think, than in other disorders. And I think that’s something that really has held us back.”

I heard that a lot in my discussions with headache scientists, though it is by no means a universal conviction. Some researchers I spoke with considered it laughable to even entertain the idea that vasodilation and vasoconstriction aren’t central drivers of migraine and cluster disorders. Others, as you’ve come to know by now—and will learn more intimately ahead—consider this to be a conviction rooted in nothing.

Fair enough. The mysteries abide.

For my part, I’ve mostly felt blessed to have matriculated into a condition at precisely the moment in the early 1990s when a drug like sumatriptan was shaking everything up—though it would take more than a decade before I ever got my hands on it. The trickle-down nature of therapeutics in the American health care system tends to work that way: profit drives not just remarkable innovation, but access to care itself. I don’t have the answers for this, and complaints about the structure and even the morality of America’s unique and, some would say, broken health care apparatus is beyond the scope of this book. What I can say is that, as with everything else, the triptans simply never worked for some people. No one can say why. They are also contraindicated for use in a wide array of patients, including those with a history of heart attack or chest pain (angina). People with a history of strokes should also avoid it, as should those with uncontrolled high blood pressure or severe liver issues. These exceptions account for a lot of patients, and even for those who can take them, the triptans have always been maddeningly conditional for many people, including me. When my cluster attacks came, their number always exceeded the number of triptan doses I could reasonably afford or even safely take. That meant I often had to decide which bouts to abort, and which to ride out in agony.

Still, this was exponentially better than nothing, and I can say without reservation that my life would have been very different without the triptans—and I expect I am not alone in saying that. What I hadn’t fully realized, as I began chasing and hoarding those beautiful blue injections, was that at precisely the same time Humphrey was nudging Glaxo’s abortive to market, a few other scientists, scattered around the globe, were eyeing a new molecule: CGRP. It would eventually prove even more divisive, expensive, and, some would argue, more consequential for headache medicine than the triptans—though it would take another three decades to get there.

Chapter 7
The Malingerers

I wasn’t contemplating suicide, but I was very morose. I—it wasn’t that I was going to do anything. But I felt my life was running out, like I was at the end of the road where, you know, I said it to the doctor, and he put me on antidepressants to just alleviate the situation which did help. But that was one of the black times, if you like, where I just thought, this thing is not ending. I’m not coping with this anymore.

—John Dennis, 73, cluster sufferer for 55 years, Ireland

Will Erwin had already had a tough go of it before the headaches started. The son of well-to-do Houstonians with deep roots in the community, Will loved the outdoors, frequently joining his parents and two siblings for quail and pheasant hunts at the Hawkeye Hunting Club, near the thick beech stands of Sabine National Forest at the east edge of Texas. Other times, he’d travel with his father on fishing trips to the Bahamas. As a child, Will was a budding entrepreneur, making cash by selling Pokemon cards and Beanie Babies online. In his teens, he took up skydiving. But he was also troubled on and off by depression, visiting psychiatrists during his middle and high school years before seeming to turn a corner and enrolling at Texas Christian University in Fort Worth, about four hours north of Houston. He majored in business—though computers were his true passion.

While home on break from TCU, he told his parents that he’d sought help for sinus problems. They took him to an ear, nose, and throat specialist who noticed that Will, then twenty-two, was dragging a foot. The ENT recommended a neurologist.

Tests revealed a nonmalignant, golf-ball-size brain tumor in the rear of Will’s head. Jimmy Erwin, Will’s father and a long-time executive with the Chicago Title Insurance Company’s commercial services division in Houston, ensured that his son saw a nationally recognized surgeon in Indiana, who removed the tumor without incident. His mother, Pam, a local community leader, says that was when the headaches started. “They told Jimmy that had nothing to do with the headaches,” she told me over lunch with the couple at a French brasserie on Houston’s near-west side in 2021, “which I never believed.”

I told the Erwins I’d never heard of such a connection between brain tumors, or even brain surgery, and the onset of a true primary headache condition. “The brain is a weird thing,” Jimmy said.

Will’s headaches worsened, and after an initial diagnosis of migraine, his doctors alighted on the real problem: Will had cluster headaches. Whether his ordeal with the brain tumor had anything to do with their onset is impossible to know, and from what I’ve come to understand about the location of the surgery and the pathophysiology of clusters, it seems likely it was an unfortunate coincidence. What is clear is that Will’s headache symptoms were unmistakable: excruciating, one-sided bouts of head pain that came in waves for weeks or months at a time, with brief stretches of remission in between. These respites were not long for Will, and the grinding cycles of pain prevented him from returning to school.

Like most cluster patients, Will threw himself into online headache research. He plugged into a community1 called Clusterbusters, and befriended one of its leaders, Bob Wold, the Chicago construction company owner who, more than a decade earlier, had turned to the Diamond Headache Clinic and its unusual IV infusions of histamine for his own cluster headaches. The group’s forums2 were percolating at the time with news that Harvard researchers had taken an interest in the effectiveness of psilocybin as a treatment in cluster headache patients—largely prompted by forum participants.

Clusterbusters had grown out of sporadic online testimonials that began surfacing in the 1990s, in which one cluster headache patient, and then a growing chorus of others, reported some efficacy in curbing their bouts with LSD. The Clusterbuster forums diversified into a meeting place for sharing a whole range of prescription and anecdotal treatments—triptans, calcium-channel blockers, caffeine, herbs, vitamins. But its core was patient-driven self-experimentation with psychedelics, along with a wide ecosystem of derivatives, analogs, and cousin molecules found in all manner of fungi, seeds, and plants. Many of these substances and formulations were (and remain) illegal in most jurisdictions, but accessible enough to the highly motivated and desperate. Over time, and after years of comparing notes, many users coalesced around a specific treatment approach involving sequenced, high doses of psilocybin. Done correctly, and with proper preparation, it seemed to break—or bust—a cluster headache cycle for many patients. Done regularly, some users said, it could even extend the remission periods. The Harvard researchers were paying attention, and they began speaking to Wold and others.

According to Pam and Jimmy, Will was eager to explore this therapeutic avenue, and he convinced them to finance his journey to Boston. He was taken into the care of John Halpern, then a professor of psychiatry at Harvard with a keen interest in the potentially therapeutic effect of various psychoactive compounds, including LSD, psilocybin, MDMA, and others. Will underwent a variety of treatments in the subsequent year—some of it under Halpern, some of it under other doctors, and some of it on his own. The Erwins still refer to the doctor as “Will’s angel.”

His parents couldn’t fully keep track of what therapies Will was trying, but they recalled some. In addition to traditional medications, Will tried psilocybin, various herbal concoctions, and, when he was able to obtain them, opioids. (He might not have known that using opioids can become a driver of migraines and clusters.) Will also sometimes used sumatriptan injections, according to Pam, as well as inhalable oxygen, which could sometimes—sometimes—ease a headache when it came on. She also recalled Will receiving testosterone injections, though she couldn’t say when, or from whom. He twice had a deep brain stimulator device implanted—typically a procedure of last resort for patients who are unable to get relief any other way. “I don’t think any of it worked,” Pam said. “I really don’t.”

Amid the afternoon din of clinking forks and plates, and the cheerful hum of lunchtime chatter, Jimmy gazed for a moment at some half distance between himself and the crisp white tablecloth. He then uttered the lament of millions of headache patients: “He tried all that stuff,” he said. “It would work for a while, and then . . .”

I finished his sentence for him: “. . . it would stop working.”

On Christmas Eve of 2009, Will called Bob Wold. The headaches were coming more frequently, Will told him, and he was growing despondent. Wold had already heard through Halpern that Will left the Boston facility where he’d been getting treatment and checked into a hotel. Halpern, who’d been working with Wold and other leaders in the Clusterbusters community for his studies of psilocybin and other alternative remedies, had asked Wold to talk to the young man. When they spoke that night, Will said he was desperate, feeling hopeless. I asked Wold if he could remember whether cluster headaches were Will’s primary torment, or if he spoke of other demons too. “It was the clusters,” Wold said unequivocally. “I mean, it drove him out of school. He could find nothing that would work. He was going through multiple attacks a day.”

Not long before their phone call, Will had his second brain stimulator inserted. The device is designed to deliver a small electrical current to the neural tract connecting the trigeminal nerve to the brain stem. The goal is to interrupt key pain signals. “It didn’t work,” Wold said, “and I’m sure that whoever put that in told him that this is probably the last, best effort to find something that’s going to help you. And it didn’t help him, so he’d had enough of it.”

Jimmy and Pam stayed in close touch with both Will and Halpern by phone during his time in Boston. With Will, the conversations were rarely cheery, but at some point in early 2010, they recalled a tone change. Jimmy says his son, by then twenty-four, sounded overly drugged, slurring. Pam would ask frequently in her phone calls whether Will wanted her to come up to Massachusetts, and he always said no. In mid-May that year, however, he said yes. Pam took a flight the next day and met Will at the hotel he’d been staying in on Tremont Street, directly across from Boston’s centuries-old cemetery, the Granary Burying Ground. His room was a mess, she told me, and Will had stopped bathing. Pam booked a room for herself and began making a plan to try to coax her son out of this funk.

On Sunday, May 16, Pam suggested that she and Will go for a walk through the sprawling green space of Boston Common. It was a bluebird spring day, she recalled, and the area was alive with shoppers and tourists and other unhurried residents of weekend Boston. The fresh air would do him some good, and having never been to Boston herself, Pam was keen to explore. But Will was adamant: he wasn’t in the mood, and he wanted to stay in his room.

Not long after, Pam went out for some air on her own. Somewhere along the way, Will called and asked her to pick up a prescription for him from the CVS near the hotel. She said she would, and she began making her way to the pharmacy on Washington Street, enjoying the midafternoon sun. She obtained the prescription and headed back to the hotel. When she turned the corner onto Tremont Street, the yellow tape was already in place.

Will’s body landed in front of Tremont Temple Baptist Church, which was next door to the nineteen-story Nine Zero hotel. Reports would later say he’d jumped from the hotel’s roof, though details are sketchy, and I did not have the heart to press Pam for them. One or two online sources suggest that a crowd of people gathered and gawked. Some reportedly took pictures. A post3 on a Boston-area web forum relayed the account of one eyewitness, who noted that before the police and other first responders arrived, the hotel concierge had thrown a sheet (mostly) over Will’s body. “All I could see was a leg and the top of his head,” the witness said.

Pam didn’t know what had happened at first. She saw the commotion and immediately went up to Will’s room to deliver the prescription, but he wasn’t there. She tried his cell phone, but he wouldn’t pick up. “Then I knew,” she said.

A week later,4 a Boston Herald columnist told the story of a woman identified only as Kathy. She’d been on Tremont Street that day, and she saw Will take his life. She thought at first that it was a prank by the way he’d landed—a dummy thrown out the window by college kids. When she drew near, she understood it was not a prank. Kathy was outraged at the gawkers, but more pointedly struck by the detachment of the moment: the bustle of Boston carrying on with its business; the insistence of her husband, waiting in the car nearby, that they needn’t stick around; the nonchalance of the firefighters, who used their hoses to wash Will’s blood off the sidewalk and into the gutter, where it gathered into a meandering stream that slipped silently down the drain at the corner.

Her account made me think of W. H. Auden’s poetic ode to Landscape with the Fall of Icarus, the sixteenth-century painting commonly attributed to Pieter Bruegel. In the image, Icarus, the allegorical Greek figure who flew too close to the sun with wings of wax, is a minor player; only his legs can be seen protruding from the sea in a tiny corner of the frame—the last moment of his fall before he descends into the depths and drowns. The rest of the painting is a vast study in pastoral ordinariness: a ship sails by in the harbor; a farmer continues plowing his field; a nearby shepherd looks skyward and away from Icarus’s fall; a fisherman reaches out over the water with his pole, seemingly oblivious to the unfolding tragedy. “About suffering they were never wrong,” Auden wrote, “The old Masters: how well they understood / Its human position; how it takes place / While someone else is eating or opening a window or just walking dully along.”

Kathy had come forward, she said, because she wanted the boy’s mother, if she was out there somewhere, to know that Will was not alone in those final moments, and that she’d prayed for him. “How could someone that young reach a point of such despair that death seemed the only answer?” she asked. “I do not know.”

*  *  *

Even if we could somehow measure pain—put it in a bottle and then inject 30 ml of Excruciating PainTM into ten volunteers—everyone would react differently. Some would curl into a ball. Some might pace and rock. Some might bang their heads against the wall, while others would just grit their teeth and squint through the ordeal. And as that dose of pain fades, each person would recover in their own way. Some would bounce back readily, their constitution allowing them to move quickly past traumatic experiences. Others might feel exhausted and need a nap. Over repeated experiments, the brains of some volunteers might begin registering this pain data in different ways. Some might store the experience in the Dread & Worry folder, which can become overfull and, in time, bring great disorder to the algorithm of their personhood. Other brains might write these pain experiences, at least initially, to the Enemies & Adversaries partition, resigning to fight on. But for every volunteer, each bout of great pain will inevitably overwrite a few bytes of joy from the internal hard drive. Sometimes, over years, there are no joy bytes left.

“I have suffered from debilitating migraines for eleven years,” a man named David Grier told me in the summer of 2021. I’d written an essay5 in the New York Times about headaches, and he’d reached out by email. He described being treated for those eleven years at the Jefferson Headache Center in Philadelphia—one of the oldest headache research and treatment facilities in the United States. The care had helped somewhat, but despite receiving “every treatment, preventative, injection, and gadget known to neurology,” his migraines at the time had spiraled out of control. He lamented that modern medicine had made so little progress on his crippling condition, and that more resources weren’t being focused on it. “I can tell you that even under what’s perhaps among the best care in the country,” Grier said, “once a month I wonder where I can get a gun to put in my mouth.”

Such raw revelations were guardedly shared with me by many of the headache patients I’ve spoken to, surfacing over time as we talked. I would guess they sensed in me a fellow traveler, and slowly offered a view of themselves that they would normally endeavor to keep hidden from strangers. One cluster headache patient I interviewed, a Philadelphia-based nursing student named Rachel Weinberg, described one of her first bouts with cluster attack—back when she wasn’t even sure what it was. “It’s the one I remember because I was driving, okay?” she began, adding that she was accompanied by a co-worker, and they were probably transporting turtles.

In telling the tale, Weinberg exuded an amused matter-of-factness that many care providers told me is common among cluster patients. Maybe it’s because, unlike migraineurs who can go days and even weeks enduring grinding head pain, most cluster patients—at least those with the episodic variety—know the bouts will end. Sooner or later, they can be reasonably sure, they will have at least a few months of pain-free normalcy. Maybe in this way, their cache of joy-bytes is more slowly depleted.

“I was driving with some kind of animal in the back of a van,” Weinberg told me. “It was not my car. It belonged to the clinic where I worked and I was driving an animal to the vet—maybe it was like turtles or something, to have an X-ray if they were pregnant, or you know, if they had eggs and we wanted to see how many eggs were in them, and they needed to get x-rayed. So, I was driving with my co-worker, and I got a headache while I was driving. It was like a twenty-minute drive. And I just got unlucky that it happened to hit me in that twenty-minute span. And I remember it—so, like, it was memorable because I was in the car, and I wasn’t alone. And I didn’t know what to do.”

The pain was excruciating, but rather than say anything, she squeezed her right eye shut in response to the stabbing pain in her temple, gripped the wheel, and pushed through the short drive to deliver the turtles. Only then did she seek out a quiet place to ride out the remainder of the bout. Why didn’t she ask the co-worker to drive, or explain what was happening and pull over, given the enormity of her anguish? Had she developed a stabbing pain in her abdomen or in her chest, she conceded, she would have immediately raised an alarm. But there was something about it being a headache.

“I don’t know if it’s embarrassment or what, but I—I want to pretend it’s not there,” she told me, her bright brown eyes searching for the right words to explain a reflex that she didn’t fully understand. “I don’t want to show it to other people. So, if I’m like, you know, with people that I don’t know very well—and this was someone who I didn’t know super well, we were working together, we weren’t very good friends yet. And so, you know, I didn’t want—I didn’t want to show that I was in pain. So, I just kind of like, went with it.

“It can be sort of hard to say I’m having a headache,” Weinberg added, “and for people to understand what that means.”

There is undoubtedly a stigma attached to any sort of unattributed pain. A first instance of acute but hidden pain can raise alarms—Is it a tumor? Maybe a burst appendix? But if the pain lingers, comes and goes, renders you likely to miss events and cancel plans even though you look perfectly fine, an undertow of skepticism forms. It’s rarely mentioned aloud, of course, but below the surface, there’s a steady tug. This is particularly true for headaches—for some obvious reasons.

A 2024 analysis6 by researchers working out of several U.S.- and Denmark-based institutions—including the Danish Headache Center—examined the prevalence of the word “headache” in a dataset of more than one million articles and summaries published by roughly three dozen major media organizations between 1998 and 2017. (The open-source dataset,7 called Newsroom, is maintained by Cornell University.) The researchers coded each use of the term as being either medical or metaphorical: “A year later, he got a call from Dr. Barry D. Pressman, chairman of the imaging department,” begins one example of medical usage from a 2009 AOL.com article, “who asked whether Biggles, 51, had experienced any headaches, blurred vision, or hair loss.” In contrast, a 2016 CNN report on internal squabbling at Fox News noted that while ratings weren’t suffering, “the tension between the two stars is a source of intrigue and sometimes a cause of headaches for Fox News chief Roger Ailes.”

One goal of the analysis was to determine the extent to which the term “headache,” which by dint of bad luck happens to be the name of several neurological disorders—some quite serious—is also used in a colloquial sense, to mean an annoyance. The study found that usage was split down the middle, with metaphorical usage being roughly as frequent as medical usage in the popular press. “Migraine” was far less likely to be used metaphorically, but even here, dozens of examples surfaced: “For more than a year, a lawsuit filed by Brooke Melton’s family has caused major migraines for General Motors,” reported the Associated Press in 2014.

The study concluded, somewhat obliquely, that “the way headaches are portrayed in the media and society can lead to the trivialization of the condition and the stigmatization of individuals who experience headache.” That’s almost certainly true—though it’s hard to imagine what might be done about it. As a writer, I’m reluctant to endorse coercive language policing on just about any front, and I’m certain that at times I must have exclaimed “What a headache!” without a care or thought, to refer to some nonclinical conundrum. The fluidity and poetry of language, after all, is a virtue, and we dip into metaphorical use of medical terms as a matter of course. A favorite football team, when the stakes are high, can give an invested fan a heart attack or a stroke when its players miss a pass or drop the ball. (I am from Cleveland; I know.) An overbearing boss can be a pain in the neck (or elsewhere). It would be difficult to argue that these somehow participate in the diminution of heart disease or high blood pressure, or the trivialization of swollen thyroid glands. We can be deaf to criticism, blind to our own faults, and prone to getting cold feet. Modern usage may argue for more sensitive uses of “blind” and “deaf” to avoid unintended ableism, but surely there is room for both empathy and metaphor even here—just as cold feet, an idiom for changing your mind at the last minute, ought not be bothersome to someone with Raynaud’s syndrome. I have known people who are prone to spastic leg movements in their sleep. They are sometimes diagnosed as having periodic limb movement disorder, or what’s occasionally called jimmy legs. I don’t think any of them are ill served by our cultural aversion to knee-jerk reactions.

Goadsby said something similar in one of our conversations. “I don’t think the words are important. I think the things that people think that word means are important. I think it’s widely understood now, for example, that depression can be a very serious problem. I think that’s an understood thing. But if I said to you, ‘Oh look, it looks a bit depressed,’ I could use it in a more trivial way without demeaning people who have serious depression, because I think that word has made its transition in the consciousness. I would use that as a good example that the words aren’t as important as what people take them to mean when you use them. Because English is like that. I’m less worried about the words than I am about what people read behind them.”

One of Goadsby’s stated missions is to imbue “headache” with deeper and more varied shades of meaning, so that its gravity can be felt in the right contexts. “When I talk to colleagues, I want them to see brain scans, I want them to see biology, I want them to see receptor pharmacology,” he said. “I want them to think about migraine first in terms of the anatomy and physiology and disturbed function. If you want to start thinking about all the emotional stuff, that’s great, you know—I’m not decrying having a broad view of what’s going on. But if you don’t start thinking that it’s serious in its manifestations in biology, it will never be taken too seriously.

“One of my contributions as a scientist, to helping with that,” he added, “is to make it a more concrete thing.”

Whether that tactic can actually make a difference is a matter of some debate, and it remains hard not to see how the banality of the term “headache” still works against millions of sufferers. “Migraine” can offer a less generic badge of legitimacy to those who can claim it, but it has never been able to fully dissociate itself from the flimsier connotations of “headache,” its parent disorder. One of my favorite recent examples of this comes from the Showtime dramedy Shameless. Midway through the first season, the craven lead character, Frank Gallagher, sits and fidgets in the waiting area of an overcrowded Chicago health clinic. He pretends to flip through a magazine while scanning his fellow patients, including the man in a cervical collar seated next to him. “What do you get for that?” Frank asks in confidence. The man is confused, but viewers, who’ve already come to understand Frank as a drunk and a con man, know exactly what he’s asking: What sort of disability compensation is the man getting for faking his neck injury? The man’s answer—“$674 per month”—prompts Frank to chuckle. “That’s what I get!” he declares. And then, demonstrating his ability to move his own head and neck freely about, adds: “But look, I can do this!”

Satisfied that his own insurance scam was superior, Frank turns his attention to a woman in a full body cast, standing on crutches near the door. He shuffles up alongside her and, feigning another flip through a magazine, then leans in and says, “While I admire your commitment, I gotta tell you, it’s a bit over the top.” The woman responds in untranslated Hungarian, but Frank wants her to know: “I told them I get migraines,” he says, holding back laughter. “Genius, huh?” he adds. “Try proving I don’t have them!”

The joke is pushed a beat or two further when Frank finally gets inside to see the clinic’s physician, who drags on a cigarette while conducting the exam. She tells Frank to drop his pants. “I don’t see how that has any bearings on my migraines,” Frank says. “Me neither,” she responds, “but it’s on the state form.”

Another pop-culture reference that will resonate for many readers is the famous migraine—or infamous migraine, depending on your perspective—experienced by the professional basketball star Scottie Pippen. It came on during Game 7 of the 1990 NBA Eastern Conference finals against the Detroit Pistons. Pippen played terribly for the Chicago Bulls that night, leaving the game after a heroic forty-two minutes with a grinding migraine. In that time, he had scored just two points, grabbed four rebounds, and dished out two assists. His shooting was notably poor, making only one out of ten field goal attempts. (His career shooting average8 was just under 50 percent—on par with his superstar teammate,9 Michael Jordan.)

“All I remember10 is my eyesight kept getting worse and worse,” Pippen writes in his 2021 memoir, Unguarded. “I could make out my teammates but couldn’t tell how far away they were or read the numbers on the 24-second clock. During every time-out, I put a towel with ice around my head, hoping the pain would magically go away. It never did.”

The press, particularly in Chicago, was withering. Tribune sportswriter11 Bernie Linciome, for example, complained mercilessly about the Bulls’ many failures during that game, before turning to Pippen: “And there was, more mysteriously, Scottie Pippen’s headache, unadvertised by any swelling or bandage, rather only by Pippen’s word for it.” The sentiment echoed the callous assessments and eyerolls known to migraineurs everywhere—You look fine. Why are you being so dramatic?—and Pippen would be haunted by “the migraine” for the rest of his career, occasionally fielding audible jeers from fans: “Got a headache, Scottie?!”12 When the widely acclaimed ESPN documentary film The Last Dance was released in 2020, thirty years after that fateful game, “the migraine” would surface again. As they chronicled the Chicago Bulls dynasty of the 1990s and interviewed many of the now-retired players, the filmmakers inevitably asked Michael Jordan about the famous headache. The camera captures Jordan smirking—his eyes open wide in an expression of bemused “no comment.” Writing for ESPN shortly after the film’s debut, sportswriter Zach Lowe crystallizes the moment: “Whatever Jordan13 meant with that look, he and the filmmakers had to know the impression it would give: that Jordan still doesn’t quite buy the severity of Pippen’s migraine, or the notion that any migraine—any malady at all—could impact his own performance in a big game.”

Joanna Kempner uses a single word14 to capture these cultural distillations of head pain: malingering.

A person complaining of ambiguous symptoms puts his or her credibility on the line. In the absence of an objective test that can prove the existence of a disease, the onus is on the individual to find a way to be rescued from any taint of malingering. I mean malingering here not in its narrow usage, which is limited to the exaggeration or feigning of illness, but in a broader sense suggested by its etymology, which comes from the French word malinger, a word formed from the prefix mal—“Wrongly, improperly”—plus haingre—“Weak.” That is, malingering extends not just to the person who is consciously faking his or her symptoms, but to the person who ought to be fine, but is in some way “improperly weak.” The malingerer, therefore, includes those who are disabled by the kinds of everyday ailments that the rest of us seem to cope with on a regular basis.

That illness and disease are often the basis for stigma and prejudice in the world is hardly a novel insight—and it’s worth noting15 that some sociologists have described steep declines in this sort of stigmatization in recent years, as populations become more comfortable with previously taboo topics, from clinical depression and other mental illnesses to HIV/AIDS, herpes, breast cancer, colorectal cancer, obesity, substance use disorders, and many others. Some of this is attributed to the rise of advocacy organizations lobbying on behalf of various disease groups, and migraine and cluster headache advocacy is ascendent. In addition to the work done by professional organizations like the American Headache Society and the National Migraine Foundation, patient-driven groups like the Alliance for Headache Disorders Advocacy (AHDA),16 the Coalition for Headache and Migraine Patients (CHAMP),17 and Clusterbusters are working to dispel stigma and unite patients online and in person. The Migraine World Summit18 hosts annual interviews with leading researchers to discuss diagnoses and treatments in plain language for patient audiences, and the annual Miles for Migraine19 sponsors run and walk fundraising events across the country.

The medicalization of disease, in which a disorder gains new legitimacy when the medical profession can describe its underlying mechanisms, or develop a chemical agent or other therapy to treat it, is sometimes thought to play a role in the reduction of stigma as well. When something mechanistic is broken and can be repaired, this thinking goes, cultural response to a disorder loses its edge. Blame and disapproval shift away from the person carrying the disease and toward the underlying misfortune—which is seen as beyond their control. Not everyone thinks it’s quite so pat,20 however, and there’s ample evidence to suggest that in our increasingly information-rich and medically sophisticated world, biases persist—and in some cases remain impervious to these forces. One study21 that captures this nicely was published in the American Sociological Review in September 2023. Spearheaded by University of Michigan sociologist Rachel Kahn Best, the researchers compiled a corpus of media references to a wide array of health conditions across three categories: behavioral disorders, such as depression or anorexia; infectious diseases, such as malaria or syphilis; and chronic conditions, like multiple sclerosis, inflammatory bowel disease, or migraine. In total they examined 4.7 million news articles published between 1980 and 2018, and culled from seventeen national and regional U.S. newspapers, two wire services (the Associated Press and Reuters), two news magazines (Newsweek and U.S. News and World Report), and transcripts from ABC News, CBS News, Fox News, MSNBC, NBC News, and the NPR program All Things Considered.

The researchers used a variety of tools to eliminate false references—for example, capturing uses of the word “depression” to refer to mental illness, but setting aside references to a financial crisis—and to develop an algorithmic model that could quantify semantic relationships between different disease terms, based on how they were contextualized or discussed across the wide universe of news articles. These associations were then tested against two stigma variables—“judgment” and “disgust”—distilled from existing categories in the field of stigma theory. It all sounds very complex, but you may imagine it as something like a three-dimensional map of an artificial solar system, with each stigma variable playing the role of an organizing sun: Insert “judgment” at the center, and the collection of diseases, weighted this way or that by the way they are written or talked about, distribute themselves around the gravitational pull of the prejudicial sun-star. Diseases that share certain relevant nuances and shades of meaning might cluster around each other, as planets and moons, and hold a tight orbit around “judgment.” Others will more loosely organize, or settle into more distant and oblique circuits. Substitute “disgust” as the central star, and the semantic realignment begins anew.

This is, of course, an oversimplification—and it elides many of the ways that these interpretations derive from a whole complex of social and even evolutionary conditioning patterns and theories, which the University of Michigan study discusses. Norm enforcement, for example, is thought to be deeply embedded in human culture, which favors predictability and punishes deviation. Contagion avoidance—a natural reflex of the primordial mind—can also color the ways we think and talk about disease, even when the threat of infection is not immediate or present. It can also color how we interpret and process diseases that aren’t contagious at all.

None of these bits of sociological theory have complete explanatory power on their own, but collectively they attempt to get at a sort of linguistic alchemy that most of us know is real. It’s the vast cauldron where fear, survival, tribalism, and other primitive human reflexes blend and chemically interact. Dip a disease into the vat, and it can be transformed into an object of sympathy or scorn—or somewhere in between.

For a slice of the news corpus dated 2010 to 2018, the University of Michigan researchers ascribed scores based on how tightly or loosely diseases coalesced around the dimensions of stigma in their analysis. Plotted along the two different stigma axes, from low to high, the results were frequently intuitive: Ranked on a “disgust” scale, infectious diseases as a group had the highest scores—with herpes leading the pack. Behavioral disorders like obsessive-compulsive disorder and schizophrenia tended to fare better—though in some cases they outranked infectious diseases: anorexia, for example, had a higher disgust score than chlamydia. Chronic conditions—the largest group—stretched out across most of the scale, with eczema at the high end, roughly aligned with hepatitis and pneumonia among infectious diseases, and dyslexia registering the lowest “disgust score” among all 106 diseases and disorders modeled.

When the stigma axis was changed to “judgment,” things shifted around. Behavioral disorders clustered at the high end, with depression, bulimia, drug addiction, and alcoholism taking the top four slots. Infectious diseases were in the middle of the scale, with all the sexually transmitted diseases earning the highest judgment scores in that disease category. The chronic disorders again distributed across most of the scale, with Parkinson’s, multiple sclerosis, and amyotrophic lateral sclerosis (ALS) earning the least amount of judgment. And here’s the interesting thing: topping out the list of seventy-nine chronic conditions with the highest judgment score was migraine.

The researchers don’t dwell on this curious artifact, but it is suggestive of something that millions of migraine patients—and I would argue that this extends to anyone with a primary headache disorder—know in their bones. Migraine had a higher judgment score than cirrhosis, obesity, and chronic fatigue syndrome among chronic disorders, and was ranked roughly on par with hepatitis among infectious diseases. It had a higher judgment score than chlamydia.

When analyzed temporally over the whole corpus of news articles, the researchers were able to see steep declines in stigma scores attached to certain disorders—particularly among mental health conditions and certain infectious diseases. Advocacy seemed to play a small but inconclusive role in these shifts, and the “medicalization” of disease—such as migraine’s transition from a psychosomatic condition to a neurobiological one—seemed to have no effect on stigma at all.

These findings only seemed to underscore what certain clinicians and patient groups have been arguing for a long time. Writing in the journal Headache22 in 2020, Robert Shapiro, a neurologist and professor at the University of Vermont, and one of the early drivers behind the nascent headache advocacy movement, argued that unlike almost any other noncommunicable affliction, migraineurs put enormous amounts of energy into hiding their disorders—and how that works to harden stereotypes. “People with migraine fiercely guard against its discovery,” he wrote. “The concealment of migraine is virtually a diagnostic trait of the disease. But it also follows that concealment undermines the credibility of people living with migraine; hiding it magnifies the dissonance between their claims of experiencing pain and the unmet expectations of those observing their behavior. ‘You just don’t look like you’re in pain.’ Intractable migraine presents a double bind to the person experiencing it; both its disclosure and its concealment are unacceptable. Hiding migraine deepens its isolation and compounds stigma, particularly self-stigma. People with migraine ‘feel involuntarily isolated from life’ and ‘struggle to avoid being doubted.’ It is often said that migraine is a lonely disease.”

Why does any of this matter? In practical terms, people with highly stigmatized conditions are likely to endure additional psychological burdens that can contribute to, or even create, comorbidities like depression. They are also statistically more likely to delay diagnosis and treatment. All of this has a cost in terms of lost productivity and economic output, compounding health care expenditures, and even increased incidence of substance abuse and self-harm. But stigma can also have a self-reinforcing nature that reaches across whole cultures, dictating what societies deem worthy of study or economic expenditure, and what they don’t. Sometimes these judgments align with the social burden of a particular disease, but very often there is a deep disconnect.

“It is, thus far, an invisible disease,”23 the Mayo Clinic’s Amaal Starling explained to the hosts of the syndicated radio program On Point in the spring of 2022. They were discussing migraines. “There are no objective biomarkers. So, there’s this question in the back of some people’s mind, whether it’s the lay public, or even, maybe even some physicians, like, is it really real? And actually, even people who live with migraine—it’s invisible because they hide it. They even sometimes will refuse the diagnosis, and they, unfortunately, suffer in isolation.”

*  *  *

During the week between my two experimental infusions at the Danish Headache Center, I rented a small flat in central Copenhagen, near Assistens Cemetery. This is where many notable Danes have been laid to rest, and I took some time that September to visit the monuments, which were shrouded in manicured stands of mature poplars and willows. The grave of Niels Bohr, one of the twentieth century’s leading figures in theoretical physics, is marked by a gray stone pillar with an owl perched on top. Hans Christian Andersen, the author who gave us The Little Mermaid and The Ugly Duckling, among other treasured stories, resides here too. But it felt most appropriate to my mission that Danish philosopher Søren Kierkegaard, who thought suffering was where life’s meaning is forged, occupied his own leafy corner of the park. In the Kierkegaardian tradition, suffering is redemptive—the feedstock of enlightenment—and rather than wallow in its insults and pains, the sufferer should embrace its power to transform. “Even the heaviest24 suffering cannot be heavier than a mountain,” he once wrote. “And thus, if the sufferer believes that his suffering is beneficial to him—yes, then he moves mountains. In order to move a mountain, you must get under it.”

For me, this idea mingles readily with other strains of insight I’ve gathered in my wanderings through headache science. The notion, for example, that migraine and similar headaches ought to have been bred out of the species by now, and that it might have some beneficial aspect that keeps it entrenched on the genetic code, is difficult to shake. Too many people have experienced it for too long, this thinking goes, for it to be an imperfection that is still working its way out, so what’s keeping it present in so many people? It’s not hard to imagine that an acutely sensitive nervous system, attuned and highly responsive to sounds, sights, smells, and threats, would be valuable to our primitive forebears on the predatory savannah: eat or be eaten, hunt or be hunted. Maybe the desirability of these triggerable, keenly attentive senses meant that our internal wiring would evolve to a razor’s edge, forever spring-loaded, but prone, in some of us, to errant firing under the wrong conditions. It’s a bug, but not life-threatening on its own—and so not consequential enough to outweigh the benefits of an exquisitely prepared nervous system.

I also thought of Kierkegaard when I first presented my arm to Lanfranco Pellesi at the DHC for my initial dose of levcromakalim. His interest in near-death experiences and his migration from there to pain, and from pain to headaches, seemed like such an obvious trajectory, one that followed an almost inevitable path. I asked how he made sense of that progression. “I think probably it links to the problem of consciousness—where it is, where it is not.”

There has always been some resonance for me, I think, in contemplating a connection, however tenuous, between the seat of consciousness—that unknowable location of the life force—and the uniqueness of head pain specifically. This is a thought train that will be familiar to anyone who has spent years dealing with serious headaches, and students of these disorders have held forth on this idea far more eloquently than me. The neurologist25 Oliver Sacks rhapsodized in the 1992 revision of his book Migraine that migraines offered “countless familiar analogies in human and animal functioning, a model which illuminates the entire range of psychophysiological reactions, by reminding us, again and again, of the absolute continuity of mind and body.”

More recently, Joanna Kempner put it this way:

Headaches strike a central feature of personhood [and] the head is an area of particular cultural sensitivity in which to experience pain. In a modern Western landscape fundamentally shaped by the Cartesian dictum ‘I think, therefore I am,’ the head is often considered the center of personality. The head houses the brain and can be used to describe the seat of the faculty or reason, as in “she calculated it in her head,” or as a metaphor for mental ability or aptitude: “He has a good head for strategy.” The head is also used to indicate authority; a person who leads or is in charge is referred to as the “head of an organization,” and political leaders are often called “heads of state.” The “head of the household” sits at the “head of the table.” The head is so essential in Western understandings of personhood that an individual’s existence or job is often reduced to the synecdoche of the head: “it cost him his head.”

Even before Pellesi nudged the notion, this is something I’d both pondered and struggled to fully articulate even for myself. Why does a severe headache—from the grind of a migraine and its kaleidoscopic sensory symptoms, to the searing cluster attack that throws a person into fits of rocking and pacing—why do these feel so categorically different from any other kind of physical anguish? As a runner I’ve had grim surgeries performed on my knee, and more recently (and extensively) on my ankle. In the latter case, absent the caress of opioids, the pain in the days immediately following the procedure was extraordinary. And yet it always had a remoteness to it—a geographical distance across the expanse of the body that made it less of a threat. It was menacing, to be sure, but it was also “down there,” while I remained “up here.” Excruciating pain in the head, though—deep inside the very nub of the self—always seemed to collapse that sense of separation.

There are some physiological aspects to pain generation that ally with this sensibility. Virtually every other part of the body capable of feeling pain passes its noxious signals through the spinal cord. You accidentally place your finger on a red-hot stove burner, and nociceptors activate. These nerve endings are found in your skin and throughout the body, inside and out, and are uniquely designed to detect tissue damage from mechanical insults (a thorn tearing your skin, or the tendons in your ankle twisting the wrong way); thermal threats (a hot burner); or chemical hazards (think stomach acid slipping out of your stomach and causing heartburn). In this case, nociceptors in your finger generate an electrical signal that travels along the axon and, in a series of synaptic hops from one neuron to another, neurotransmitters carry that signal toward the dorsal horn of the spinal cord. Second-order neurons in the spine modulate that signal—amplifying it if the stimuli remains, for example, or inhibiting it if the threat has receded—and then send the message upward to the thalamus, the brain’s relay station for most sensory and motor signals. The thalamus then distributes the signals to the appropriate parts of the brain, where they mingle with billions of other ongoing signals and bits of stored data—other events unfolding immediately around you, distant memories, emotional states—and then the brain responds. It will very likely send an immediate motor signal down a descending pathway, causing you to jerk your hand away before you can even think about it. It will also provide you with the sensation of pain, perceived at the site of the incident. Its intensity will be determined by a complex mix of factors: the temperature of the burner; the amount of tissue damage; whether you’ve been dumb enough to put your finger on a hot burner before; whether you were feeling sad or happy at the moment you did this dumb thing; and even whether you are being intensely distracted in that moment by, say, a cat video on TikTok.

When operating normally, the whole complex of pain sensation and processing—a biopsychosocial phenomenon without which we would never survive—is a fine-tuned system. No two people will likely experience pain in the same way, given the unique, cumulative cache of data stored in each brain, and the many variations in our individual anatomies. You may have more or fewer nociceptors than I do, for example, or mine might be better at transporting certain messenger molecules. But everyone will benefit from the efficiency and expediency of nociception—and most people are going to get a sharp bite from that burner.

Still, the process of nociception described here, which governs virtually everything from a stubbed toe to a tummyache, and a stab wound to a strained muscle, doesn’t work quite the same way in the head. Sensory signals from the head and face primarily travel through the trigeminal nerve, while the glossopharyngeal nerve and the vagus nerve transmit sensory signals from the ears, throat, and certain parts of the neck. They all plug directly into the brain stem—making them, at least anatomically, distinct from every other pain-sensitive tissue of the body. Whether or not that offers the pain arising in these regions a distinct quality or aspect might well be a psychological question, or even a philosophical one. But rob that pain of one other crucial aspect—tissue damage—and it begins to acquire an almost apparitional character.

Talk to people who have experienced excruciating head pain—not on the surface, not on the scalp, and not from a punch to the nose, an infection in the ear, or an ill-advised chili pepper, but spontaneous pain deep inside the head—and the struggle to articulate its uniqueness, to identify a useful metaphor, begins. The pain is nowhere and everywhere, innate but foreign. It’s a mirror reflecting a mirror, an infinite echo that recedes unto itself but never leaves. When the pain gets that close to the line that divides me from everything else, or even crosses it, where is the pain anymore? Where is it in relation to me? I sometimes liken this conundrum to the experience of a 360-degree photograph, that wonder of the digital age that allows you to pan around an image’s frozen, spherical moment in all directions. You see them sometimes in virtual tours of homes for sale, or in Google’s “street view” function. Click and drag the image, and it’s as if you are in some snow-globe version of that captive scene, able to peer not just left and right, but skyward and downward, in a hunt for all the details hiding at the periphery. The illusion breaks down, though, when you pan too far inward, to that place where the gaze of the lens could not reach because it cannot turn on itself. Here you’ll typically see a distortion—a shadow cut in half, maybe, or pixels that don’t line up. To me, this is where the details of head pain often seem to reside—in that unphotographable nadir that I can never turn far enough to see, its existence implied only by a gap.

It’s clumsy and imperfect, I know. This type of pain, the one that invades the seat of the self, evades words. “It does so, in part, because it shuts down and then vandalizes brain space, inhibits and even lays waste to the parts of consciousness that think and shape and speak,” writes Andrew Levy, a professor of English at Butler University in Indiana and the author of the 2010 book A Brain Wider Than the Sky: A Migraine Diary. “But it also does so because of pain’s social contract: Pain is the surest thing in the world to the person feeling it, and the least sure thing to the person hearing about it, and that’s a bad deal all around.”

*  *  *

I can’t know if Will Erwin ever thought in these terms, or if he ever pondered the asymmetry between a disorder that loomed over him like a tyrant—controlling everything and stealing what it wanted in broad daylight—and a world that seems to stand by and shrug. Maybe he had other demons that provoked his decision to end things. Maybe those other things would have been manageable had it not been for the grinding pain in his skull, which turned on, and then off, and then on again without respite or explanation. Or maybe it was simply the pain. Maybe it had become everything.

What I can say with great certainty—without ever having known him—is that he would have intuited a universe of social and systemic cues, over his twenty-four short years, that told him the pain he was going through, in the grand scheme of things, was trivial. That there are bigger problems in the world, that there are far more important diseases to address, that society’s priorities naturally—understandably, even—rest elsewhere.

The epic spasms in his skull were rare and weird, sure, but they were also probably something like what we all experience, right? We all get headaches, and I’m sure yours are a drag, but maybe try drinking more water? Is it possible you’re being oversensitive, Will?

Jimmy and Pam launched the Will Erwin Headache Research Foundation in 2014. It’s funded largely through donations and an annual golf tournament organized by Jimmy, who said the idea for the foundation came to him in a dream—and a message from God—after Will died. The Foundation, in collaboration with the Memorial Hermann Health System and the University of Texas Health Science Center at the McGovern Medical School in Houston, gave rise to the Will Erwin Headache Research Center, which opened in 2016. It is headed up by neurologist Mark Burish, who has taken a special interest in cluster headache. As part of an ongoing observational trial, he and his collaborators are currently building a national database of cluster patients in a hunt for genetic and epidemiological patterns. They are also focusing on studying the relationship between the body’s circadian rhythms and pain.

I asked Burish, in a visit to his offices in Houston, what the argument might be for more research funding into cluster headaches. The population with migraines is exponentially larger, and researchers looking into them have complained bitterly to me that public funding for basic migraine research is paltry relative to its social burden. How could anyone possibly make the case for cluster research when the disease affects less than 1 percent of the population? He told me that there’s a disconnect happening. Diseases like multiple sclerosis, and even Parkinson’s, receive huge amounts of public funding, despite the fact that they impact roughly the same proportion of the population as cluster headache. I countered that Parkinson’s and multiple sclerosis are arguably more debilitating—and terminal: they’ll eventually kill you.

“It comes down, in that sense, to how do you value quality of life?” he responded. “They’re all terrible diseases. I’m not trying to compare, I’m just saying that cluster headache—it affects your life in the sense that there are certain jobs you may never be able to do if you can’t treat those headaches effectively. Or you may not be able to work for long stretches of time. And that affects your personal life, that affects your work life, it affects everything you do if you—if you can’t do the normal stuff that you want to do. This is truly a disruptive disease.”

Burish added that he understood that in a world of finite resources, hard decisions need to be made. But he also suggested that there’s something else at work—something that prevents money from flowing toward cluster, and toward migraine and other headaches too—that reaches beyond the quality of the science and the severity of the disease. “There is just so little going into it that almost no research can be done. Like, it will only move exceptionally slowly when you only have two or three people doing studies on that every year with that amount of funding. So, it’s just—there’s no way for it to even take off.”

Did Will think about this at all? This sad, underfunded research cul de sac? I couldn’t help but wonder. I know I used to—though I tended to gravitate to the conclusion that it was all just bad luck. There are all kinds of orphan diseases out there—rare but terrible, debilitating disorders, that also struggle for attention and research. It’s a numbers game, and with so few cluster patients out there, it seemed destined to languish in empirical obscurity.

At the same time, knowing that there must be mechanistic similarities between migraine and clusters, knowing that the universe of pathways and processes capable of generating pain inside the head is narrow and presumably knowable, it can feel irksome to think that migraine, too, struggles for basic research funding. Could stigma be behind that as well? It seemed absurd to me. Science is science. But there are researchers in the headache field who are convinced, in their bones, that this is exactly what’s going on.

“We have collectively, the advocacy community in this space, never had enough sharp-edged reporting in high-profile media,” Shapiro told me in one of several interviews. He is well-known as a gadfly in the headache community—and he has become a burr in the side of funding decision-makers at the National Institutes of Health (NIH), part of the U.S. Department of Health and Human Services. He is convinced that society’s approach to headache disorders, both broadly within the culture, and specifically among public health and funding agencies, borders on the inhumane—a socially acceptable callousness that would be worthy of investigation and headlines, were it any other disease. “The stories that we tell, I think, are newsworthy—and they’re egregious, and they’re fact-based,” he said. “And I think they can be crafted into a well-supported story about how there is systematic—and intentional, to the degree that people even think about it—neglect of a very large percentage of a very large number of Americans who are disabled by disorders which are disparaged.”

If that’s even remotely true, Will Erwin deserved better.

Chapter 8
Awakenings (and Cats)

I have been to over ten neurologists, multiple ENTs, a hematologist, rheumatologist, and countless other doctors. I have had numerous CT scans, MRIs, my tonsils and adenoids removed, my wisdom teeth removed, two sinus surgeries, a spinal tap, and probably countless more tests that I can’t even remember. I have also exhausted many medication options. The only thing that temporarily diminished my pain was Emgality, a CGRP self-administered injection. Emgality eventually stopped working.

—Brianna Bartol, speech pathologist and migraine patient, Suffolk, New York

A BBC film crew visited the Danish Headache Center during my time there. They were making1 a promotional video—a service of the BBC’s commercial StoryWorks division—about headache medicine at the behest of the Lundbeck Foundation, the charitable arm of the Danish pharmaceutical giant Lundbeck. Messoud Ashina was on deck for an interview, and he was shifting in his chair beneath the lights as the crew went about their preparations. Ashina is fully bald, a bit round but not fat, and his face at rest is almost Buddha-like, save for a mischievous half smile that creeps in when he’s about to make a joke, or begin a Socratic interrogation of one of his postdocs. He wore a long white laboratory coat, white pants, and black sneakers. Over his right shoulder, on the distant conference room wall, the filmmakers had hung a poster they’d found in a storage room, diagramming the human muscular system. They thought it provided a more medical-looking backdrop than the plain conference room wall, but they eventually took it down.

I lingered behind the cameras as the operator tweaked the framing, and Ashina chatted with me amid the bustle. He mentioned that some of his migraine patients had asked him to stop wearing striped shirts, because the pattern somehow caused them “an unpleasant feeling.” (A good-natured joke was there to be made, but I held my tongue.) “They are afraid they will get an aura,” he added.

Alcohol is often problematic, too, Ashina said. I noted that this was definitely true for cluster headaches, which of course he knew. A single sip of alcohol is virtually guaranteed to bring on a swift attack when a cluster headache patient is in a cycle. Miraculously, when the cycle ends after a few months, that trigger evaporates and alcohol has no effect. Migraineurs who are sensitive to alcohol have told me that they never get that sort of break—though Ashina offered a countervailing anecdote: “Some years ago, one of my patients returned,” he said. She’d left his care five years earlier but had come back. “She said, ‘Messoud, don’t you recognize me?’” He didn’t, but the patient said she remembered Ashina well. “You know, you gave me fantastic advice,” the patient explained. “I was complaining that I can’t go to parties, because I always get a migraine from alcohol, from wine. And you advised me to drink vodka, not wine, just straight vodka—not too much, but just for fun, you know.” The film crew laughed, and Ashina flashed his half smile.

“And she did it!” he exclaimed with comic enthusiasm, “and she was very happy with that—but I said don’t put it on the Facebook, that your doctor advised you to drink vodka.”

The interviewer explained to Ashina that she would ask him a series of questions, but that her voice would not be part of the final promotional video, so he would need to repeat the question in setting up his answer. “So, if I say, ‘What are you working with here at the Danish Headache Center?’ you would start your answer with ‘Here at the Danish Headache Center . . . ,’” she explained. The producer also mentioned that they had a script, but Ashina didn’t want to follow it, so they pressed ahead. “Can you tell us what you are working with here at the Danish Headache Center?” the interviewer asked. Ashina responded with a rambling description of the facility, which sees patients in a clinical setting, but also does research—including his own research, which is multidisciplinary, and onward. When he finished, they asked him to try again, but to keep it focused on the research, coaxing him toward the scripted answer they were after. “You don’t want to hear about the clinical part?” he asked. Not right away, they said. Ashina tried a shorter version of his original answer, but forgot to say “Here at the Danish Headache Center . . .” at the top. The third time was a charm: “Here at the Danish Headache Center, we investigate mechanisms underlying migraine, and my focus is experimental models, where we induce migraine attacks to explore the signaling pathways responsible.”

The center was getting a lot of attention at this time. It had been announced the preceding spring that its founder, Jes Olesen, was one of four scientists awarded the 2021 Brain Prize, a newish award, now in its fourteenth year, bestowed on researchers in neuroscience. Winners share a prize of 10 million Danish kroner, or about $1.5 million—the largest such prize in the field. It is administered by Lundbeck, Denmark’s largest private funder of basic neuroscience research in the country. The foundation distributes over $70 million in research grants to a variety of fields in the medical and natural sciences, about half of which is aimed specifically at brain science. It also owns a 70 percent stake in the commercial part of the Lundbeck empire, a decades-old enterprise that focuses largely on drug development for brain diseases, including depression, schizophrenia, Alzheimer’s, Parkinson’s, and migraine. “Research by the four laureates of the Brain Prize, on the role of CGRP in migraine pathophysiology, laid down the foundation of new, migraine-specific preventive medications,” Ashina says in the final version of the video. A backing track of xylophonic bleep-bloop music evoked “science” and “discovery” as interstitial shots of researchers at the DHC seeing patients or running experiments panned in and out.

The lavish ad was just one part of a massive PR push—much of it funded by Lundbeck—in the days leading up to a gilded award ceremony planned for the following month. The goal was to draw attention to both the Brain Prize and to the work of headache scientists. Both camps had something like an inferiority complex, and I was asked several times by a Lundbeck representative, and even by one of the scientists being honored, how they might get the press to pay more attention to them. I was sympathetic. The foundation seems generally interested in doing good in the world, and the unusual arrangement, in which the nonprofit owns and drives the commercial enterprise, clearly translated into a lot of money being given away for basic research in some important fields. “The board of directors wanted to invest in something that was like the Nobel Prize in the brain field,” Jesper Sloth Møller, then the head of media relations for Lundbeck and now representing the Rigshospitalet, told me in a phone call after I’d returned to the United States. “And yet it’s not the Nobel Prize. It’s never going to be because, you know, there’s nothing bigger than that,” he added. “But you know, it’s a very narrow and focused prize, and very prestigious for brain research. So, this is the ambition with it. In neuroscience, neuroscience communities across the world, we want people to recognize this prize. That it’s the biggest one.”

Multiple materials were prepared for the awards gala and ancillary promotional channels, including a short documentary film profiling the four awardees: the DHC’s Jes Olesen; Swedish researcher Lars Edvinsson of Lund University; UCLA’s Peter Goadsby; and Harvard neuroscientist Michael Moskowitz. The movie features each scientist interviewed or filmed in their natural habitats—Goadsby in his blazer, speaking in front of a wall of books in his office, or typing at his computer, for example; or Moskowitz in a blue cotton oxford, carrying a basket of apples or playing with his grandchildren in a leafy New England backyard. Olesen—posed in a brown leather chair in what appears to be his home library—sits square and open legged toward the camera, his plaid shorts showing what one attendee described to me as far too much naked thigh. (Upon viewing for myself, I had to agree.)

Aging family photographs of the men as youngsters, or as students, panned in and out as they talked about their upbringings and how they found their way into medicine. Edvinsson was the son of a petrol station attendant. Moskowitz’s father was a doctor. All but Goadsby had become involved in headache research in the 1970s, when the field was still comparatively primitive. Goadsby came along in the 1980s, when explorations of neurotransmitters and the key physical structures thought to be involved in migraines were coming into view.

As the short film’s orchestral soundtrack rises toward a crescendo, Moskowitz paraphrases the German philosopher Arthur Schopenhauer’s three phases of truth: “First, it is ridiculed, then it’s violently opposed. And then it is accepted as being obvious and self-evident.” (He would repeat this line to me in an interview.) Edvinsson advised all researchers to “do good work and trust the data.” Goadsby offered that “there is light at the end of a very dark tunnel” for people with migraine.

An accompanying information pack describes in more detail how the four scientists, working separately and sometimes in collaboration, each played a role in driving a revolutionary line of research. “An international group of four neuroscientists have discovered a key mechanism that causes migraine, a condition that affects more than a billion people and which according to the World Health Organization is one of the most prevalent and disabling diseases,” the brochure declares. “Their research paved the way to the development of an entirely new class of migraine-specific drugs called CGRP antagonists which help provide long-term prevention of migraine attacks.”

I asked Møller, Lundbeck’s media director, how this luxe and tidy narrative came together, and how he and his team were able to pluck a clean arc out of four decades of science unfolding on different continents. It was a nightmare, he said. The four researchers bickered endlessly over how the story should be told, and how their individual contributions ought to be portrayed. Olesen didn’t even believe, in the beginning, that CGRP had any significant role in migraine, Møller said. “I think Lars thinks that Jes is trying to steal the story sometimes,” he added. Goadsby and Olesen, meanwhile, bear old grudges. “They are not really friends.”

I told him I’d gotten tastes of this in my discussions with some of these scientists—a hint of disdain toward a particular study, or an eye roll when I mentioned the name of a rival. “Yeah, you got this all along,” Møller said of Lundbeck’s own story-building exercise. “You will never get the same story. You will get bits and pieces, and then you can just put them together and try to find some compromise that they can agree on.”

*  *  *

The neuropeptide that would eventually be dubbed calcitonin gene-related peptide, or CGRP, was first described2 in the early 1980s by Michael Rosenfeld and colleagues at the University of California. The two decades prior had seen a blossoming in biochemistry and molecular biology with the arrival of novel detection techniques like radioimmunoassay, a highly sensitive laboratory test that uses tiny amounts of radioactive materials to measure substances like hormones or drugs in the blood or other fluids. High-performance liquid chromatography revolutionized the ability to separate, identify, and quantify individual components in complex mixtures of biological samples. And the ability to clone DNA sequences and manipulate genes in the laboratory, which first emerged in the 1970s, was also allowing researchers to identify and characterize the genes encoding various peptides.

Based on its location and distribution throughout the body, the University of California researchers, writing in the journal Nature, reckoned that CGRP likely had key roles in appetite, modulation of the autonomic and endocrine systems, and crucially, nociception. Headache researchers almost immediately perked up—and in the narrative constructed by the Brain Prize, they would have owed their antennae to Michael Moskowitz.

Moskowitz was just finishing up medical school at Tufts University when a paper published out of Brookhaven National Laboratory in Upton, New York, ushered in a new era of Parkinson’s disease treatment. The paper,3 written by pathologist and researcher George Cotzias and colleagues in 1967, described a successful dosing protocol for treating Parkinson’s patients with a then-experimental drug called levodopa, or L-Dopa. Levodopa is a naturally produced chemical in the body and a key building block for several important neurotransmitters, including dopamine. In the brain, L-Dopa is converted into dopamine, which plays a major role in movement, motivation, and reward. It remains the most used drug to treat Parkinson’s today.

L-dopa had been a chemical of interest for decades before that, but it wasn’t until the 1950s that its role as a neurotransmitter in the brain was established by the Swedish researcher Arvid Carlsson. His work4 revealed particularly high levels of dopamine in certain areas of the brain that are critical to movement. In animal studies, he demonstrated that reducing the levels of dopamine would diminish motor control in ways that were evocative of Parkinson’s. Administering levodopa, meanwhile, seemed to alleviate the symptoms.

Other researchers began experimenting with L-Dopa in human Parkinson’s patients. The chemical showed promise, but concerns lingered over the potential for toxicity at the high doses necessary. Cotzias and his colleagues found a way around that, using graduated oral doses, increased slowly over time, that proved therapeutic and tolerable. “The most important5 immediate prospect in our field,” Cotzias said in accepting a Lasker Award in 1969, “is that distinguished scientists from many disciplines may now join as equal partners in the struggle against deterioration of the human brain.”

(L-Dopa wasn’t just useful in treating Parkinson’s, and many readers will more readily recall its starring role in the 1990 film Awakenings, a fictionalized interpretation of neurologist Oliver Sacks’s 1973 book by the same name. The book chronicled Sacks’s own experience at New York’s Beth Abraham Hospital treating patients afflicted by encephalitis lethargica, which in some patients induced a state of catatonia—awake, but entirely motionless and unable to speak. Taking a cue from brimming investigations into Parkinson’s treatments, Sacks and his colleagues were able to “awaken” many of these patients, at least temporarily, using L-Dopa.)

When Moskowitz moved on from Tufts to Yale New Haven hospital to begin his residency, he worked under one of Cotzias’s frequent collaborators, Melvin Van Woert, who would regale the younger doctor with stories from his Parkinson’s research. Moskowitz recalled being transfixed by L-Dopa’s narrative arc. “It was the most elegant history of uncovering the basic science of a disease, and then modifying it,” he told me. Moskowitz described it as one of the key moments in his own career trajectory, which would eventually lead him to the study of migraines. “The bottom line was, you know, they found a pathway,” he said. “They found a transmitter. They found in Parkinson’s the transmitter was depleted. They developed an animal model, and to some extent a human model. And then they replaced the missing transmitter with a precursor and cured the disease. And I said, ‘Man,’—and this was in ’68. I started my neurology in ’71—and I said, ‘if this is, you know, what the future is, not only do I want to be there, but I want to find a disease in neurology where I could play along similar lines—find some logic behind it that allows for that progression of events.”

Moskowitz began that hunt in earnest, initially by working with his mentor to investigate the connection between certain neurological diseases and catecholamines, a class of transmitter that includes norepinephrine, epinephrine, and dopamine. He described himself as the “library gopher” for the project, and he spent his time digging up research and assembling dossiers devoted to each disease. One folder he labeled “migraine.”

“It was a huge folder,” he told me. “It was twice the size of any other folder. And at the end, when it came to writing the article, there was nothing I could say that was coherent about migraine. So, when the article was published, I threw all the other folders out for all the other diseases, kept the one on migraine in my drawer, and every time I opened the desk drawer, there was this big file with all this information that I couldn’t quite put together.”

Most of the literature in that migraine folder, by way of Wolff and his acolytes, concerned itself with cranial blood vessels—their dilation, the resulting pain, their constriction, and the subsequent relief. But that didn’t make sense to Moskowitz. He knew, for example, that balloon catheters were routinely used to dilate blood vessels. “You really have to crank up that balloon in order to get pain,” he said. “The normal constriction and dilation of blood vessels, by itself, generally doesn’t cause pain.” He also thought that the unilateral aspects of migraine—the pain that often impacts just one side of the head—robbed the vascular theory of head pain of its explanatory power. “If you think about it, the blood from the heart is going to go to both sides of the head,” he explained. “Whatever was happening on one side should happen on the other. So, this unilateral head pain was also another clue to me, that there had to be another explanation—and whenever you think about something happening on one side of the body and not the other, of course, you think of nerves.”

Moskowitz brought that folder with him when he joined the joint Harvard-MIT’s Health Sciences and Technology program in 1975. Just four years later,6 he and colleagues wrote a paper that shook things up. Published in the journal The Lancet in 1979, Moskowitz and his co-authors theorized—based mostly on hunches, he will admit today—that the key anatomical structures involved in the pain of a headache were (1) the trigeminal nerves, also called the fifth cranial nerves, which carry sensory information from both sides of the upper face and forehead to the brain stem; (2) the vasculature of the meninges; and (3) the brain. Moskowitz’s proposition was that the headache phase of migraine developed due to the abnormal release of vasoactive neurotransmitters from trigeminal nerve endings surrounding cranial blood vessels. The brain errantly interprets this activation as injury, and pain ensues. Moskowitz thought the key neuropeptide in this process might be neurokinin 1, also known as Substance P, which had been known since the 1930s—though he wasn’t sure. It was also unclear what set the whole migraine process in motion. Still, the articulation of their broad hypothesis would prove prescient. “The abnormal release of substance P or as yet unidentified peptides or other transmitters from the fifth cranial nerve,” the 1979 paper posited, “may explain both the hemicranial pain and the vasodilation which are characteristic of the headache of migraine.”

Moskowitz and his colleagues would go on to describe this signaling pathway in greater detail—largely through research using cats, which were a popular research model at the time. Cats, it would seem, played a significant role in early- and mid-twentieth-century headache research, and I suspect a whole book could be written on their contribution, however unwilling it must have been. I asked Moskowitz why cats made good research subjects. He seemed worried about the line of questioning, but I was genuinely curious. I have no aversion to the humane use of animals for research purposes, and I suspect we would be a good deal more ignorant and unhealthy as a species if we’d not drafted certain animals into our empirical enterprise. “Well, because they were big,” Moskowitz told me. “You know, they were large, okay? We knew where the ganglia was. And the setups at that time, you know, people weren’t doing that much rat research, or mouse research for that matter. So, it was convenient, and they were being sold, and they were probably not the healthiest. They were stray cats.”

In time, Moskowitz said, cats would be supplanted by rats, which happened to impact a research grant proposal he’d submitted to the NIH later in his career. “Probably in the mid-’80s, it started to become unfashionable to use cats,” he told me. “And so my grant comes back, and it says, ‘The science is great, but we’re really quite concerned that you’re proposing this work in the cat.’” Moskowitz, chuckling, recalled having a quick fix: “By that time, fortunately, the find-and-replace function had been invented. So, I replaced the C with an R, and that was that.”

The grant was funded.

In 1983,7 Moskowitz and his colleagues published a paper that is generally credited with coining the term “trigeminovascular system,” which gave the world of headache science a concise conceptual framework for understanding the pathogenesis of primary head pain—and perhaps a nudge to start looking at other key signaling molecules that might be involved. As it turned out, researchers elsewhere in the world were already doing that.

Working out of Lund University in Sweden in the mid-1970s, Lars Edvinsson helped to identify8 the first neuropeptide within the intracranial vasculature, known as vasoactive intestinal polypeptide, or VIP. Originally from the industrial city of Malmö, Edvinsson seemed drawn to the brain and structures surrounding it from his earliest days in medical school. Biographies frequently mention9 that he temporarily suspended his medical studies during his second year so that he could devote his full attention to studying vascular receptors, cranial innervation, cerebral circulation, and the autonomic nerves in the head. He completed his MD and PhD in 1980, and it would take only three years for him to start laying down a case for CGRP’s critical function in this complex, and possibly even in the production of migraine pain. Soon after its discovery, Edvinsson and collaborators added CGRP to the growing list of neuropeptides they were examining in isolated tissues taken from a variety of species, including cats, cows, and guinea pigs, as well as humans. They found plenty of it in trigeminal sensory nerves on cranial arteries, and later experiments would validate its role as a potent vasodilator. In March 1985, Edvinsson was lead author on a review paper that took stock of the brain research landscape and the growing list of newly identified neuropeptides. In an almost casual aside,10 Edvinsson noted that CGRP might be “of considerable importance in the regulation of cerebral blood flow and the migraine syndrome.”

Across the globe, Peter Goadsby was working as a young researcher under the mentorship of James Lance, a neurologist at Australia’s University of New South Wales with a global reputation in the field of migraine research. In the summer of 1985, Goadsby traveled to Sweden to attend an international neuroscience conference, where he watched Edvinsson present on trigeminal innervation and the roles of neuropeptides like CGRP and Substance P in the still newly described trigeminovascular system. Goadsby was hooked. “I thought, well, this is what we need,” he told me. “We need to think about what it is the trigeminal system uses for talking to other nerves.”

After Edvinsson’s talk, Goadsby asked him to have a chat over coffee. “It was the twenty-first of June 1985, midsummer,” Goadsby said. Sensing that I might be skeptical of his specificity, he continued: “I’m not making it up. It’s easy to remember. I was a much younger guy, and I’d never been in Sweden in summer and it weirds you out, because it can be two o’clock in the morning and the sun’s out.”

It was a busy time for headaches. That same year, Jes Olesen had convened a meeting of international headache specialists with a goal of developing a more unified and global classification system for headaches. Prior to that point, the diagnostic criteria for migraines, clusters, tension headaches, and a whole constellation of other primary headache disorders was something of an international hodgepodge, with neurologists and neuroscientists in different countries relying on varying definitions and treatment protocols. Olesen, who had already11 published some of the earliest imaging studies of cerebral blood flow during migraine attacks, spearheaded efforts to refine things, establishing the International Headache Society’s first classification of headaches in 1988. Today it is the de facto source for describing and characterizing the wide gamut of primary headaches, as well as secondary headaches attributed to trauma or substance abuse, for example, and even facial neuropathies.

In Goadsby’s telling, he proposed to Edvinsson over that midsummer coffee in 1985 that migraine would be an interesting phenomenon to explore with regard to signaling pathways in the trigeminovascular system, and a collaboration was born. They immediately turned to cats.

I couldn’t help being intrigued by this again—in part because years ago, I had come across a blog post that included a video of a cat doing something funny under the headline “Cats Are Science!” My wife and I still utter that phrase when our cat is curiously unable to resist the allure of a new cardboard box, or when she stares at you long enough that it goes from being cute, to weird, to so unnerving that you must look away. Cats are science—though I hadn’t realized how much so until I started talking to scientists about headaches.

“Their brains have undulations—ups and downs,” Goadsby told me, by way of explanation. “If you’ve ever seen a human brain, it’s got those peaks and troughs. It looks sort of like little lines, line tracks, yeah? It undulates. The sulci and gyri, they’re called. If you look at a rat brain, it’s smooth. It’s called lissencephalic, because it’s smooth. Cat brains, monkey brains, human brains are gyrencephalic. They undulate.” Among other things, a gyrencephalic brain has a greater surface area than a smooth lissencephalic brain, enabling more cognitive and functional complexity without a corresponding increase in overall brain size.

Goadsby mentioned that his mentor, Jim Lance, had also done frequent experimentation in cats because their nervous systems are much more similar to the human nervous system than those of, say, rodents. “Just go online, look at a rat brain and look at a cat brain,” he said, “and then look at a human brain and tell me which one looks like what.” Again, I didn’t express any sort of opposition to his cat research, but when given the chance, Goadsby seemed keen to press a case. “The things the cat protection people used to do are just really . . .” He paused, and then he told a story: “To get the cat supplier in the UK to stop supplying us, the cat protection people found where his mother was buried, dug up the grave, took the body, and threatened that if he didn’t stop supplying us with cats, he would never get his mother’s body back.”

I have not been able to independently verify this story, but to my surprise, it seems that digging up the graves of relatives is a tactic that animal rights activists have deployed more than once. I found reference to a farm in Staffordshire, for example, that bred guinea pigs for research. It was forced to shutter after repeated acts of intimidation from animal rights groups, which included digging up and holding hostage the remains of Gladys Hammond, the mother-in-law of one of the farm owners. (The activists were sentenced12 to twelve years in prison in 2006.) In Switzerland in 2009, vandals attacked the family burial plot of Daniel Vasella, then the chief executive of the pharmaceutical giant Novartis. They absconded13 with the ashes of Vasella’s dead mother, and threatened to flush her down the toilet. (They also set fire to his vacation home in Austria.)

If you ask Goadsby why he doesn’t use cats in research anymore, he will give two reasons. One is that the cultivated genetics of rodent models are much more sophisticated and useful today. “Society is not in love with rats,” he added. The other: “Because the cat people will try and blow you up or steal your mum’s body.”

Goadsby and Edvinsson14 inserted cannulae into the external jugular veins of anesthetized cats. Through these and other experiments in human volunteers, the pair were able to demonstrate some foundational notions regarding CGRP in migraine. In cats, electrical stimulation of various trigeminovascular structures, including the superior sagittal sinus, a large venous channel located within the dura mater, triggered release of CGRP into the cranial circulation. A similar release15 was documented in human volunteers, who had their jugular veins tapped during a migraine attack—and the pair would go on16 to show similar neuropeptide changes in cluster patients. With Glaxo’s sumatriptan hitting the market during this time, Goadsby and Edvinsson were also curious to test its impacts on CGRP levels. They showed that the drug seemed to reduce CGRP—suggesting that whatever was going on during a migraine attack, CGRP was in the thick of it. Homing in on that molecule, Goadsby and Edvinsson were convinced, could lead to novel headache therapies.

“It was not just luck,” Goadsby told me, “it was a good idea.”

Researchers in the UK17 would eventually identify the receptor for CGRP in 1998, but it remained unclear whether CGRP was circulating as an ancillary phenomenon to migraine, or whether it was directly involved in the production of pain. Olesen and other researchers,18 working out of Glostrup Hospital, seemed to conclusively demonstrate the latter in a 2002 paper in the journal Cephalalgia. The double-blind, crossover study involved twelve migraine patients who were given intravenous CGRP infusions for twenty minutes. Two patients would ultimately be excluded for technical reasons, but the results seemed unequivocal: All participants developed a migraine headache after the infusion, compared to just one in the placebo group. “Our study suggests that the increase in CGRP observed during spontaneous migraine attacks may play a causative role,” Olesen and his colleagues wrote.

If you’re following along, you can quickly guess what hypothesis the researchers wanted to test next: if CGPR could turn on a headache, would suppressing CGRP shut one down? It was an enticing question, though Edvinsson and Goadsby have publicly lamented that they seemed alone in their fixation on CGRP, and that headache researchers elsewhere remained errantly focused on Substance P. The pair had demonstrated19 as far back as 1990 that while CGRP levels were elevated in patients experiencing a migraine, Substance P levels seemed unaltered, but it didn’t seem to matter. Looking back on those days in a 2019 editorial, Goadsby and Edvinsson could hardly contain their resentment: “For a decade20 we tried to convince our headache-interested colleagues that CGRP was important,” they wrote, “largely in vain.”

Whether or not that’s fair is hard to say—in part because the early case for Substance P seemed strong. Multiple animal studies21 had shown that receptor antagonists for the molecule could successfully modulate pain signaling, and in tests of other agents that seemed effective in animal studies—principally nonsteroidal anti-inflammatory drugs—the analgesic effect carried over into humans. The expectation that Substance P would simply follow suit was natural. But as failures22 for Substance P antagonists mounted, CGRP enthusiasts seemed keen for their fellow investigators to move on. Animal models, after all, are imperfect proxies for humans, and what is physiologically true for a cat or a rat doesn’t always turn out to be true in us. In 2001, Goadsby teamed up with Arne May, a prominent headache researcher at the University of Regensburg in Germany, to assert that it was time to give up on Substance P interventions. “These are highly effective23 in animal models of dural inflammation,” they noted, but they had “failed to demonstrate any effect in acute migraine.”

The story would turn out differently for CGRP.

*  *  *

After finishing her undergraduate degree in human and animal physiology, Cen Xu, a native of China’s Jiangsu province, not far from Shanghai, decided to pause her schooling and take a job as a live-in research assistant at a mental health facility. Her parents—one a college professor and electrical engineer, the other a teacher—were upset by her decision, but Xu says she wasn’t ready for graduate school; she needed time and experience. Her dormitory at the facility was directly across the courtyard from the ward housing the patients, and she recalled dark nights listening to the lonely wails of residents struggling with schizophrenia and other disorders, who were not well cared for. It was the early 1980s, and drug treatments were bleak, Xu told me in a series of interviews not long after the Brain Prize was announced. It was a formative experience, and one that compelled her, after finishing a PhD in pharmacology at Illinois State University and a postdoctoral appointment at the University of Illinois College of Medicine, to forgo an academic life and instead seek a scientific role in the pharmaceutical industry. “It was rough, it was rough,” she said of her time working at the mental health facility. “This was first time I actually got exposed to the medication limitations.”

If the Brain Prize honored the research scientists who built the case for CGRP as an important target molecule in headache pain, Xu has been heralded as the industry researcher who managed to take that insight and turn it into the first marketable CGRP therapy—amid stiff competition. By the late 2000s, numerous pharmaceutical companies were chasing a CGRP antagonist that would prove safe and effective enough to pass muster with the FDA, and Xu was leading the charge at California-based Amgen. When the company’s first-past-the-post therapy cleared that FDA hurdle in 2018, it made Xu something of a star. The CGRP inhibitor,24 brand-named Aimovig, was named one of Time magazine’s top inventions of 2018, and Xu was honored with numerous industry accolades—including a lifetime achievement award25 from the National Headache Foundation. But all the fanfare belied what was a really a long and frustrating slog.

Xu’s first role in the industry was as a drug discovery scientist with Bristol Myers Squibb, which she joined in 1998. CGRP fever was already in the air. Drug companies had been watching the growing stream of research on the neuropeptide throughout the 1980s and ’90s, but in the absence of a known receptor, Xu says no one was willing to waste millions on developing a new drug to block it. Once that receptor was identified, commercial interest began ramping up—and Xu was delighted by the challenge. “I’m a pharmacologist,” she told me, “and I really liked the receptor pharmacology.”

Xu started going to migraine scientific meetings around 2000—just as competitors like SmithKline Beecham in the UK, and Boehringer Ingelheim of Germany, were developing and patenting the earliest molecules capable of blocking that tricky receptor. Boehringer Ingelheim,26 for example, showed in 2000 that its experimental molecule, code-named BIBN4096BS, could inhibit the effects of CGRP in marmoset monkeys. Four years later, Jes Olesen and colleagues would demonstrate similar effects in humans. The international, multicenter, double-blind, randomized clinical trial of the same Boehringer antagonist showed that more than 60 percent of the cohort receiving the CGRP blockade experienced marked relief—many in two hours or less. The results of the trial27 were published in the New England Journal of Medicine in 2004, and from there the race was truly on. “That was the real driver home,” Xu said. “This was the last piece.”

The concoction used in Olesen’s trial was mostly proof-of-concept. It was delivered intravenously and did not have a high level of bioavailability. To get something that could eventually sit on pharmacy shelves, most companies immediately set about working on small-molecule drugs—the garden variety sort of medication we’re all familiar with, from ibuprofen to prescription antidepressants. In short: they wanted a pill—and that made sense. Small-molecule drugs are low-mass chemical compounds that can easily enter cells because of their small size. They can be administered orally, and pharmaceutical companies favor developing them because they are easily mass-produced, have longer shelf lives, and are relatively simple to distribute.

For the following four years, drug companies tucked into their laboratories and attempted to synthesize a CGRP antagonist. At Bristol Myers Squibb,28 Xu and her colleagues would patent several new molecules that looked promising—though the competition was fierce. “There were probably five to six small molecules that eventually came on board during that period of time,” she said, “but then there was this big plot twist.”

Merck was trialing at least two molecules of its own, one code-named MK-3207, and another dubbed MK-0974, or telcagepant. Both seemed to work at least as well as the triptans, and the company was sailing through Phase I and Phase II trials, each involving larger cohorts of volunteers who were closely monitored to establish dose, safety, and potential side effects. Merck was leading the pack. “I’m pleased to tell you29 about a new program this year, MK-0974, which utilizes a new mechanism for the treatment of migraine,” Peter Kim, president of Merck’s research laboratory, enthused in a 2006 presentation to shareholders. The drug was proving safe and effective, Kim said, adding that the company planned to push ahead to Phase III trials, with a goal of filing a new drug application with the FDA by 2009.

They ended up backtracking that year instead. Reports of liver problems began to surface in a few early trial participants, and the company abandoned MK-3207 altogether. It also delayed plans to submit telcagepant for FDA review, though it remained hopeful that it might still carry it across the finish line. Two years later,30 however, with Phase III trials underway, Merck announced in a quarterly earnings call that it was applying the brakes on telcagepant, too. A postmortem31 written by Yale’s Christopher Gottschalk in 2016 noted that “a small number of participants developed elevated liver function tests” during the trial.

Alongside kidney damage, gastrointestinal disturbances, and allergic reactions, liver toxicity is a significant concern with small-molecule drugs, due to their metabolism in the liver. And this problem was dogging everyone in the industry. “Drug-induced liver injury may be viewed as an acceptable risk in relation to the benefits of a drug, particularly for those who treat potentially life-threatening illnesses,” Gottschalk noted. “In the case of migraine, however, which is a highly disabling but not life-threatening illness, there is very little tolerance for even transient laboratory abnormalities due to medical therapy.”

Xu called it a sad moment for the field. In 2006, in the middle of the CGRP marathon, she had left Bristol Meyers Squibb to join the California-based biopharmaceutical company Amgen in 2006. Amgen was already busy32 exploring GGRP antagonists when she arrived, but the failure of telcagepant just five years later seemed to drive home a grim reality for the entire industry: despite thirty years of promising bench science, more than a decade of pharma tinkering, and tens of millions of dollars of investment, it seemed the industry had found itself in a blind alley of its own. “The biology was so intriguing—you cannot get any better than this,” Xu said, “but we were just stumbled by the feasibility. You cannot find a good molecule.”

Looking back,33 some of the concern over liver toxicity might have been overblown, but the demise of Merck’s molecule seemed to deflate wider enthusiasm for CGRP as a useful migraine target. Xu recalled attending a meeting of headache scientists at the time of the Merck failure. A researcher was pounding his fist on the podium, telling industry representatives that they needed to step up. “I remember sitting down there feeling, as an industry—feeling almost shame that we couldn’t deliver.”

Amgen wasn’t a traditional pharmaceutical company, however. They were formed in 1980 as one of the earliest biopharmaceutical companies, meaning they were less interested in small-molecule chemical synthesis: they built therapeutic products derived from living organisms or their cells. That’s not entirely novel, of course. Vaccines have long exploited live organisms to therapeutic effect. But as the broader field of biopharma exploded in the 1980s, companies began developing all manner of therapeutic proteins—including monoclonal antibodies, or mAbs.

At the heart of mAb development is the identification of a target—some molecular structure involved in the progression of a disease or disorder. This target could be a traditional antigen—a foreign invader that the immune system naturally combats—or it might be a component of the body’s own cellular machinery, like a receptor involved in signaling pathways. Drug developers have numerous means of developing antibodies to inhibit that target; an early technique involved the immune cells of a mouse, which are coaxed into producing the desired antibody. Scientists can then fuse these antibody-producing mouse cells with special cells that divide indefinitely in the lab—also known as immortal cells. Cancer cells have this feature, and they often play a role in the development of therapeutic mAbs. The process effectively combines the longevity and rapid growth characteristics of the cancer cells with the very specific antibody-producing capability of the immune cells. The result is a tireless antibody factory known as a hybridoma—a cell line that can be cultivated indefinitely, and dedicated to producing just one type of antibody.

Nowadays, scientists produce mAbs in ways far more sophisticated than this, but the goal is always the same: a comparatively fat, single-minded protein with a high affinity for a very specific target in the body. Compared to traditional medications, a monoclonal antibody is significantly more complicated and expensive to develop and manufacture. Owing to their large size and complex structure, they also can’t be delivered orally; they’d be degraded by the digestive system before they could exert their therapeutic effect. That means they must be delivered either by a health care professional as an in-clinic infusion, or self-injected at home. And because they involve living organisms, mAbs need to be kept cold. In practice, all of that can make mAbs a suboptimal and wildly more expensive therapy than a simple pill—and it makes sense that drugmakers would chase a chemical compound first.

Still, there are upsides to mAbs: compared to traditional medications, they are significantly more selective of their targets, resulting in fewer side effects. If a traditional medication is like mortar fire, a mAb is a laser-guided missile. A monoclonal antibody also tends to have a longer half-life in the body than a small-molecule drug, allowing for less frequent dosing and higher preventative potential. And in the context of the flagging CGRP race, one other advantage to mAbs stood out: they aren’t typically metabolized in the liver. Under the direction of Cen Xu, Amgen wagered that a monoclonal antibody might get CGRP therapies onto pharmacy shelves where small-molecule chemical concoctions had not—and they would eventually do just that with patented molecule AMG-334, otherwise known as erenumab (the “mab” at the ends of these names is for “monoclonal antibody,” as per scientific naming convention). Dubbed Aimovig for the commercial market, the novel medication cleared FDA approval on May 17, 2018.

Getting to that point was not a smooth ride, Xu says. Skeptics in headache science told her and her team that a mAb could never work, because the molecules were too big to penetrate the blood-brain barrier. And Amgen, following the lead of the small-molecule aspirants in targeting the CGRP receptor, had chosen a tough road for itself. In the context of drug development, targeting a receptor is more of a high-wire act than going after the molecule that binds to it—known as the ligand. And because of its complexity, targeting the CGRP receptor was particularly tricky.

Not surprisingly, competitors working in parallel with Xu’s team had all gone after the ligand, and while the race to take a migraine mAb to market first was exceedingly tight, the confetti and champagne for that achievement would ultimately go to Amgen. Xu recalls that on the day of the FDA’s procedural deadline for rendering a decision, she repeatedly hustled back and forth from her offices in Building 29, the science hub on Amgen’s leafy Thousand Oaks, California, campus, to Building 37, the business center of the company where Amgen executives were fielding phone calls from federal regulators with last-minute questions. “Hey, have they approved it? Have they approved yet?” she would ask anxiously. Her colleagues would gently wave her away: “No, we’re still on the phone with the FDA, don’t bother us, it’ll get done,” Xu recalls. But when 2 p.m. Pacific Time rolled around—5 p.m. in Washington, DC—she started remembering two decades of false starts. “The anxiety starts to build up,” she said.

In our Zoom call, I asked Cen Xu how the good news finally reached her, and she recalled hearing a scream down the hall just after 4 p.m. in California. She and other researchers spilled into the hallways, where elated hugs and high fives ensued. Other scientists involved in the long journey were at a dinner meeting in Boston, and the two teams connected over Facetime to raise a toast, Xu told me. She then started to cry. “I mean, it is a dream for someone in my function, right? I chose to join the industry to make something meaningful for the patients,” she said, smiling against her tears. But then you realize how hard it is—that 99.9 percent of the people who are scientists will never have a chance to make a drug—a real drug.”

*  *  *

As of this writing, three other mAb therapies for migraine have joined Aimovig: Ajovy from Teva Pharmaceuticals, Emgality from Eli Lilly, and Vyepti from Lundbeck. (The last must be administered via IV in a clinical setting.) The industry has also pushed past the small-molecule liver toxicity barrier to introduce several new oral medications, collectively called gepants, that also target the CGRP molecule. These include Ubrelvy (ubrogepant), approved on December 23, 2019; Nurtec ODT (rimegepant sulfate), approved on February 27, 2020; Qulipta (atogepant), approved on September 28, 2021; and Zavzpret (zavegepant) approved on March 10, 2023. Depending on the drug, these can be prescribed to quell an individual headache or to help prevent them from coming back. Some claim to do both. And the gepants have been joined by another new drug class, called the ditans.34 Currently only one such drug, Eli Lilly’s lasmiditan, sold as Reyvow, has been approved for use in the United States. Unlike gepants, ditans works by targeting a very specific serotonin receptor subtype known as 5-HT1F. The drug causes pronounced drowsiness, which precludes operating machinery or driving a car for eight hours after taking it, but it has the distinct ability to curb migraine pain while not affecting the blood vessels. What, I can’t help but wonder, would Harold Wolff think about this?

Driven in part by the merry band of psychedelic experimenters at Clusterbusters, and through the tireless advocacy of Bob Wold, Eli Lilly agreed to trial its mAb, galcanezumab, for use in cluster headache too. FDA approval came in September 2018, and while the dosage is different from that in migraine, it remains the only FDA-approved medication specifically developed to treat cluster headaches. (Thanks, Bob.)

Meanwhile, the amount of money and hype swirling through all this science is staggering. Whoopi Goldberg and Khloé Kardashian now peddle for Nurtec, and Pfizer brought in popstar Lady Gaga to croon for the drug after it acquired35 Biohaven Pharmaceuticals in 2022 for $11.6 billion. Tennis superstar Serena Williams appears in ads for Ubrelvy, which was acquired36 by AbbVie pharmaceuticals when it purchased Allergan in 2023 for a breathtaking $63 billion.

Part of the advertising dump is reflective of the cost to develop and distribute these drugs in the first place. Novartis, which teamed up with Amgen in 2015 after the biotech company looked like it had a winner in Aimovig, for example, claims to have spent37 nearly $1 billion on helping to develop and commercialize that one drug alone. These stratospheric costs are reflected in the price tag at the pharmacy window: The current cost of the Ajovy is about $640 for a once-monthly dose, or just under $2,000 for the quarterly dose. Patients and insurance companies can expect to dole out over $7,000 for an average user who needs continual management. A single dose of Emgality for migraine is going for between $600 and $700, and one eight-dose blister pack of the oral medication Nurtec retails for about $1,000. This means that these remedies remain very much out of reach for many patients, and most insurance companies today restrict their use by requiring evidence that two other existing remedies—the old off-label ones with the nasty side effects—have been tried without success first. And yet, over the coming decade, the market38 for CGRP inhibiting medications is expected to boom just the same, with sales predicted to reach nearly three-quarters of a billion dollars by 2030.

The arrival of CGRP medications has led to some nasty turf battles. Novartis sued Amgen over what it characterized as an attempt to back out of its 2015 collaboration, and Amgen then countersued. (They settled39 in 2022.) Teva Pharmaceuticals sued Eli Lilly shortly after both companies’ mAbs were approved, claiming that Lilly had violated its patents. Teva won an initial jury verdict worth $177 million, but a Massachusetts federal judge40 overturned that decision in the fall of 2023, and Teva ultimately dropped the suit. Many of the primary care and internist practitioners I spoke with also complained that neurology’s scientific societies initially sought to have prescribing restrictions placed on the new CGRP therapies, such that only credentialed neurologists and headache specialists could make them available to patients. Resounding pushback from nonneurologist physician groups forced an about-face on that front—although some insurance companies still require that the prescription be written by a neurologist.

Was it all worth it? Efficacy data for the CGRP meds is fickle, with some studies touting41 response rates of 70 percent or higher, while others are closer42 to that coin toss where most drugs top out. “One thing about the practice of headache medicine and migraine treatment is that it’s not a one-size-fits-all option,” said the Mayo Clinic’s Amaal Starling. “Even the new class of medications with the CGRP monoclonal antibodies—that still doesn’t work in everyone,” she added. “Patients always ask me, ‘You know, which medication is the best, Dr. Starling?’ And honestly, I tell them every preventive medication that we have, whether it’s a device, whether it’s an injection, whether it’s an oral medication, they all have about a 50 percent chance in working.”

Numerous reports and several neurologists I spoke with describe “super-responder” patients who see significant—even miraculous—results43 from the CGRP inhibitors. The tales are evocative of the L-Dopa awakenings three generations ago, with patients emerging into a world of relationships and interactions that for years, sometimes decades, they’ve mostly viewed from inside a glass box. And yet there is emerging evidence44 that some patients are experiencing waning efficacy over time. The short-term side effect profile for these drugs remains quite good, compared to so many drugs that have come before, although it remains impossible to say what that might look like another five or ten years out. Given that CGRP plays numerous roles in the body that are unrelated to pain signaling, some physicians have urged caution45 in prescribing them in certain patient populations. One potential complication46 that did not surface in clinical trials, but which appears to be emerging in postmarketing use, is an association with alopecia, or hair loss. Virtually all of the CGRP medications—whether a mAb or a gepant—are seeing increasing numbers47 in the FDA’s Adverse Events Reporting System. Scientists are tracking48 these reports.

For now, though, the risks seem small, and in March 2024, the American Headache Society issued a strong statement arguing that enough evidence is now in hand to suggest that these remedies ought to be top-tier options for headache treatment. “The CGRP-targeting therapies49 should be considered as a first-line approach for migraine prevention along with previous first-line treatments,” the organization insisted, “without a requirement for prior failure of other classes of migraine preventive treatment.”

Whether insurers will be convinced anytime soon is hard to say, but it’s clear that the CGRP molecule is playing an important role in the pain-signaling pathways of some headache sufferers, an insight that may be considered the most significant scientific development since the arrival of sumatriptan—or arguably an even bigger one, given that the triptans might well have been a happy accident: a medication that worked for reasons that we understood incorrectly at the time. Then again, we don’t really know precisely where these CGRP inhibitors are doing their job, or what specific role CGRP is playing in head-pain generation either. There’s lots of competing speculation, but little in the way of scientific consensus—even as other neuropeptides50 are being explored.

“I do believe51 that CGRP is important,” said Anja Sofie Petersen, a clinical scientist at the Danish Headache Center, during a recent online debate. At the same time, she said, this history of migraine and cluster treatment has always proceeded from a place of ignorance. Some antidepressant or calcium-channel blocker seemed to have a side benefit of helping, a little, with migraines, and so doctors just went with it, even though no one knew why they had that effect. The new therapies may be purpose-built to target CGRP, but we still can’t really explain why they help some people and not others. “It doesn’t mean we have a mechanistic answer at the moment,” she said. “We don’t know why they work.”

When I shared that last sentiment with Andrew Charles of UCLA, he objected. “We do know why they work,” he insisted, “by blocking the effects of CGRP. We don’t know how CGRP release is triggered, or where in the nervous system it is having its primary effects,” he conceded. “But we now have an opportunity to investigate this systematically. We aren’t just shooting in the dark.”

*  *  *

Messoud Ashina and his colleagues at the Danish Headache Center still believe that KATP channels are a worthy target for further exploration and, quite possibly, drug development. Writing in the open-access journal Frontiers in Molecular Neuroscience in June 2023, five members of the Glostrup group characterized the KATP channel mechanism in superlative terms: “Opening of the channel52 using levcromakalim is the most potent headache and migraine trigger ever tested,” they wrote—adding that these channels may well be the “unifying mechanism for signaling pathways.”

I’d like to believe such a thing exists, but it remains mere speculation at this stage—and at least one experimental study of a KATP channel blocker failed to have any effect on a headache induced by levcromakalim. That study,53 published by Ashina and others at the DHC in 2020, reasoned that a more selective blocker was needed.

The results of the infusion experiment I participated in at the DHC—the one aimed at cluster headache—were published in December 2023. They were more of a mixed bag than the migraine study. In my group—episodic but in remission—only one of the fifteen volunteers receiving the active infusion got a headache, which was to be expected. It is very rare for an experimental chemical to trigger a cluster headache in a patient in remission, even though those same substances can trigger an attack in mere seconds when the patient is in a cluster period—one of the most peculiar aspects of the disease. (I was not the unlucky volunteer in my group to be given a headache.) Only five, or 29 percent, of the chronic cluster headache patients saw a headache triggered by levcromakalim, compared to none receiving the placebo. Six of the ten episodic volunteers who were in an active headache phase, or 60 percent, responded to the potassium channel opener, compared to one receiving the placebo.

Clearly KATP channels are doing something here, but is it really the linchpin they think it is—the quark or lepton upon which every headache disorder is built? I probably won’t live long enough to know for sure. Maybe you will.

During my final days at the DHC, Thien P. Do, a clinical scientist working under Ashina, was preparing a paper that seemed to show something intriguing. A group of staff and associated researchers at the DHC had squeezed into Messoud Ashina’s office to hear Do present his findings, and to try to poke holes in it. The study—a randomized, double-blind, placebo-controlled, parallel trial—aimed to test whether a migraine could be artificially provoked if CGRP were taken out of the picture. They evaluated this by pretreating some participants with erenumab (Aimovig), and then administering cilostazol, another known vasodilator and migraine trigger. As it turned out, a high percentage of patients who received the cilostazol were triggered into migraine, even when CGRP had been inhibited, suggesting that while pain signaling pathways can be facilitated by CGRP, the neurotransmitter is not necessary to complete the connection and make your head hurt.

Ashina gently nudged Do on some of the particulars, and encouraged him to simplify the study’s overall message, because the results, by his estimation, were important enough to warrant publication in a high-impact journal. He suggested starting with Science Translational Medicine, or The Lancet Neurology. The paper was eventually published54 in the December 2023 issue of the journal Brain—and a follow-up analysis,55 published in the January 2024 issue of Cephalalgia, showed similar results using levcromakalim as a trigger. This seemed to suggest that alternative signaling pathways leading to migraine attacks might be able to bypass the CGRP receptor pathway entirely. “The induction of migraine attacks via opening of KATP channels appears independent of CGRP receptor activation,” Do and his co-authors wrote in the 2024 paper.

That’s a powerful assertion to make against the backdrop of multi-million-dollar ad campaigns for CGRP inhibitors, particularly given that some scientists speculate that these artificially triggered headaches—while very real—may be only mimicking a process that is spontaneously accomplished in the body by CGRP. In conversation in the spring of 2024, Andrew Charles used an analogy that many Californians would understand: we know that heavy rain can naturally trigger a mudslide, but triggering one with dynamite instead doesn’t mean that heavy rain isn’t important, or even crucial. At the same time, we already know that CGRP isn’t necessary for the generation of a migraine attack by virtue of the fact that suppressing CGRP in some migraine patients does absolutely nothing. It’s quite likely—and it wouldn’t be unusual to think so—that there is some idiosyncrasy across patients in terms of which molecular components and pathways are needed to wind up the headache process. CGRP may play a big role for me but have very little to do with someone else’s attacks.

Whether those various headache-potentiating pathways eventually converge at some common point that science might one day discover and target is an open question, but I sense that is precisely what drives the Danish group. It certainly seemed to be the point that Do was trying to drive home in his presentation that day: “Migraine is not a CGRP-dependent disorder.” he said. “CGRP is just another potential trigger like many other things, and in the end, it is not the one, true Holy Grail.”

Chapter 9
Feast, Famine, and the NIH

I did try the Emgality, and I had horrible migraines—while I was on Emgality. It definitely was not the medication for me. I have tried the Reyvow. I’ve tried Aimovig. I am now on Nurtec, with very little to no success. I’ve probably been on 90 percent of the medications out there. The triptans do not work for me whatsoever.

—Terri Dean-Alexander, founder, Migraine Support Group, Pennsylvania

A breathtaking moment came for Robert Shapiro in December 2019. He was meeting with decision-makers at the National Institute for Neurological Disorder and Stroke (NINDS), the division within the National Institutes of Health that most often weighs funding requests from scientists doing research in the headache space. Shapiro, a Vermont-based research clinician and the founding president of the Alliance for Headache Disorders Advocacy (AHDA), an umbrella organization of advocacy groups, had traveled to NIH headquarters in Bethesda, Maryland, to urge the agency to do more to nurture headache science. He was joined on-site by a smattering of fellow clinicians, scientists, and patient advocates, while others dialed in from afar. Among those representing NINDS were its director, Walter Koroshetz, and Michael Oshinsky, who at the time was program director for pain and migraine. As of late 2024, he had been elevated to director of the NINDS Office of Preclinical Pain Research, which oversees NIH’s portfolio of pain science grants.

The years preceding the meeting had been busy for pain disorders: The new CGRP medications had just come to market, the International Association for the Study of Pain had recently updated its definitions of pain for the first time in nearly two generations; and the NIH was ramping up its brand-new Helping to End Addiction Long-term,1 or HEAL initiative, which aimed to boost research into addiction and pain in response to the opioid crisis. The meeting began with a slide presentation by Oshinsky, who was eager to show how much the agency had been doing to support migraine research. As Shapiro tells it, the presentation got derailed as discussions and crosstalk over the data ensued.

Headache advocates had spent considerable time and effort over the preceding two decades making a case on Capitol Hill that migraine’s social and economic burdens were substantial, and that public funding for basic research was minuscule relative to that burden. They’d had some success on that front: on multiple occasions, Shapiro and his allies had convinced congressional appropriations committees to include language in their budget reports urging the NIH to use the money it is allocated—$47 billion in 2024—to proactively solicit and underwrite foundational headache science. “Research on these disorders, to date, has not received funding commensurate with their prevalence or their costs to the economy,” the Senate Appropriations Committee stated in its fiscal 2009 report.2 “Therefore, the Committee strongly urges the NINDS to solicit grant applications in this area; encourage new investigators with career training and transition awards; provide fair peer review by headache scientists of submitted headache research grant applications; and collaborate with the research community to develop ‘Headache Disorders Research Benchmarks.’” The 2019 House appropriations committee report3 noted that “in 2016, 36 million Americans experienced a migraine attack, 12 million suffered from chronic daily headaches, and millions further were affected by cluster headaches, post-traumatic headaches, or other disabling headache disorders”—the best estimates at the time. Given this, House members encouraged the NIH to “prioritize fundamental, translational, and clinical research on headache disorders.”

As the 2019 meeting wore on, Shapiro grew frustrated. While maintaining an active practice in Vermont, he had invested enormous time and energy attempting to engage with Oshinsky and Koroshetz, as well as the latter’s predecessor, Story Landis. He’d written letters, asked for meetings, solicited support from lawmakers, written journal articles, and otherwise agitated for increased NIH attention and support for headache science since the mid-2000s. But the agency, by Shapiro’s reckoning—while giving lip service to the issue—had been largely unresponsive to these efforts. As the 2019 meeting wore on, Shapiro wanted to know what it would take for the agency to budge, and he put the question directly to NINDS director Walter Koroshetz: “Look, Walter, we’ve had fifteen separate report language statements describing the sentiment of Congress that this is an area that needs specific funding attention,” Shapiro recalls saying—but before he could finish, Koroshetz weighed in: “That doesn’t matter.”

In a conversation in the spring of 2024, I asked Shapiro how he reacted in that moment. He demonstrated by slowly sliding down in his chair, his jaw agape. It was a bit of humorous theater, which I interpreted to signal a mixture of disbelief, exhaustion, and maybe even a bit of surrender. The relentless marshaling of advocates, all the Capitol Hill meetings, the letter-writing campaigns, successfully nudging members of Congress, year after year, to urge the NIH to breathe life into headache science—if none of that mattered, then what had he been doing? Shapiro was not a creature of Washington, and he’d learned the advocacy game from scratch, taking cues from other disease groups like the Epilepsy Foundation and studying the mysterious levers of influence that citizens can use to inch an agenda forward in the bureaucratic labyrinth of Capitol Hill. He screwed up sometimes, misreading a statute, or wrongly accusing the NIH of giving dismissively poor scores to headache research grants. But the funding shortfall was real, Shapiro believed, and he and his fellow agitators had convinced Congress of this. If the word of Congress didn’t matter to the NIH, what did?

I attempted to contact Koroshetz to corroborate Shapiro’s recollection, and to probe what exactly he might have meant by that statement—It doesn’t matter. The NIH is a massive operation, and I knew enough about the agency to understand that it had the unenviable task of reviewing more than fifty thousand research grant proposals annually and deciding which ones to fund. (In 2023, the agency was able to make about eleven thousand applicants happy—a rate of about 20 percent.) Koroshetz never responded to my queries, although Shapiro’s story was corroborated to me by others in attendance that day. “I was completely shocked,” Peter Goadsby told me in an email message. He’d dialed into that meeting and kept detailed notes. “I thought, as crazy as politicians may be, that Congress was in charge.”

The language included in these budget committee reports isn’t included in the final appropriations bills, so it doesn’t carry the force of law. Still, it’s supposed to be taken seriously, and this “report language,” in the parlance of the Capitol, is an important part of the budgetary process, providing guidance, clarification, and to some extent instructions on how Congress would like to see taxpayer money used at the agencies receiving it. As a 2023 report4 from the Congressional Research Service put it: “Agencies are generally expected to comply with a report’s directives.”

In the estimation of Shapiro, Goadsby, and numerous other scientists I’ve spoken with, the NIH has never really heeded congressional sentiment on headache science. No “Headache Disorders Research Benchmarks” have ever been established, and while funding in the migraine and headache categories has inched upward in recent years, it remains wildly incommensurate with any realistic measure of its social and economic burden. In mulling all this, I was reminded of the radio appearance5 that Goadsby had made in early 2022, where he talked about a migraineur struggling to work. “If she loses her job, that’s a bad economic outcome,” he said. “Setting aside the individual, reduced economic activity is bad for the country altogether, and migraineurs are just perfectly placed—you make them well, and what they do is they work, they spend money, they go to the shops, they do the business, which turns the country over. Migraine affects people from the age of eighteen to sixty-five. News bulletin: they’re the taxpayers. So, if you want society to function, then looking after people with migraine is in the interest of society.”

A 2023 study6 by a team of Denmark economists seemed to offer empirical support for this idea. While the sample size was small and many of the researchers reported receiving support from, or serving as advisors to, pharmaceutical companies, the analysis—published in the peer reviewed journal BMC Neurology—did seem to suggest that treating migraine sufferers with the new crop of CGRP-inhibiting therapies had broad socioeconomic benefits, both in terms of avoided health care costs and increased economic activity. For sufferers of chronic migraine alone, the researchers estimated that curbing the disorder kicks as much as $14,000 per patient back into a country’s GDP. Assuming the incidence7 of chronic migraine is roughly 1 percent in the United States, that would come to a little over a $3 million windfall for the economy. The benefits for those with more episodic forms of migraine were commensurately smaller, but not by much: around $11,000 for high-frequency episodic migraine, and $10,500 for low-frequency episodic migraine. The kicker is that there are a lot more of these people out there missing work, utilizing health care, and otherwise operating at far less than 100 percent capacity. Extrapolate the study’s figures to roughly the 50 million Americans with all forms of migraine, and you end up boosting GDP by over $1 trillion. Even if you assume the CGRP therapies are effective for half of all patients, you still get a $500 billion economic bump.

These sorts of observations contribute to Shapiro’s frustration. The NIH is being given taxpayer money, he insists. Taxpayers elect members of Congress to represent them in deciding how the money that comes out of their paychecks is spent. Some 50 million of those taxpayers and voters have migraine or cluster headache. Millions more have other headache disorders. Ignoring Congress on this front, Shapiro suggests, is ignoring the will of a huge percentage of the American populace—people with real skin in the game.

“It’s not legal contempt of Congress,” Shapiro said, “but it’s clearly contempt for the intent of appropriators.”

*  *  *

Kevin Gilmore worked as an air traffic controller at the Minneapolis Air Route Traffic Control Center in Farmington, Minnesota, for almost thirty-five years. The facility—known by its call sign ZMP—is a key player in the vast network of the nation’s airspace system, overseeing flight corridors that stretch over Minnesota, Wisconsin, Iowa, North Dakota, South Dakota, and bits of neighboring territories. Controllers like Gilmore, attuned to their radar screens and managing the never-ending crackle of radio communications between towers and pilots, are the conductors of the skies, ensuring the smooth flow of millions of flights each year across their domain. For most of Gilmore’s time at ZMP, he also had cluster headaches.

“I couldn’t come clean to management about them because that would’ve been the end of my career,” he told me in an email message. “They would’ve taken away my medical certification to work traffic and I couldn’t let that happen, so I kept quiet about them.” The work was exacting but characterized by frequent breaks—ninety or 120 minutes were spent in the “on position,” followed by a break of thirty minutes or an hour, to prevent mental and visual fatigue. “I spent many breaks in a stall in the men’s room,” he told me, “rocking as we do with my head in my hands praying the headache would go away in time for me to return to the control room. Those prayers weren’t always answered.”

He’d been accustomed to hiding. In a subsequent interview he recalled the onset of cluster headache during his senior year at Thomas Jefferson High School in Bloomington, Minnesota, in 1975. The attacks were short-lived back then—a sudden stab of pain behind the eye lasting fifteen minutes or so, before vanishing. He was frightened by it, not knowing what was happening, but he was also embarrassed. In a balcony above the school’s gymnasium, he found a safe place to hide during an attack. “I’d go there because there were very few people, and I’d just let this thing pass.” The headaches would surface again in the Navy, during a tour in the Philippines, where he was a radar operator. The attacks lasted longer this time, and he self-diagnosed them as sinus headaches, though decongestants didn’t help. A crewmate suggested he should have his adenoid glands removed.

Gilmore saw doctors intermittently after starting work at ZMP in 1985, but he would not receive a diagnosis of cluster headache until the early 1990s. He was eventually prescribed a high dose of prednisone, which would be tapered down slowly, and a new product called Imitrex, which he took in the form of a nasal spray. These helped dramatically in the beginning, but there were problems. He could not reveal that he was taking these medications, nor that had been diagnosed with a headache disorder, without risking his job. The headaches themselves would have been a nonstarter, Gilmore said, and the amount of prednisone needed to stop the attacks was far beyond what was permitted by FAA guidelines. He was fine, of course—the medications did not alter his ability to work; they were not narcotics, and they did not alter his perceptions. They simply drove back the pain when it came. Still, it would have been moot.

At one point in the early 2000s, Gilmore emailed a physician working for a private service that his union had hired—a benefit aimed at pilots, air traffic controllers, and others in related fields who must maintain medical certification to continue in their jobs. The consultations were confidential and would not appear on his FAA record. Gilmore confided in the doctor, who then took his case, anonymously, to FAA brass. “Here’s the situation,” the doctor told FAA officials, according to Gilmore. “I have a controller out here who’s trying to work with me. He wants to come forward and tell you his situation, which can be managed, but he’s afraid to, for fear of losing his job.” The response from FAA leadership was clear: “He will be terminated if we find this out.”

Gilmore stayed underground, as he put it, until the attacks began increasing in frequency and severity in 2004. The pain of the attacks was reaching new heights, and staying at its peak far longer, sometimes three hours or more. The sumatriptan started to fail, and he felt things spinning out of control. At one point, his wife, Tammy, came home to find him writhing and screaming on the floor of the garage as the pain thrashed inside his skull. He could no longer keep it a secret.

Gilmore had taken up blogging about his life, and he pointed me to a 2004 entry8 where he recounts a long bike ride and an unwelcome reckoning. “Along the way, my mind kept returning to my situation at work and I was working through several different scenarios in my head trying to decide what to do,” he wrote. “. . . I needed to approach management and level with them about my troubles. It could cost me my medical certificate to be a controller, but I had to do this for my peace of mind. I’m hoping the loss of my medical will only be temporary and that we’ll be able to work out a solution where I’m able to take myself off the boards when it becomes necessary to work through the headaches.”

He wrote a letter to his bosses that night, stating that while he’d reported that he had headaches of unknown variety during a routine physical early in his career, he ultimately decided to stop talking about it with the FAA. From that letter:

Sometime several years later I was diagnosed with cluster headaches, but I failed to continue to volunteer that information during my yearly physical. I continued down this path alone without confiding as I now know I should have. I’d like to come clean to the FAA so l can continue to be a controller not fearing my next headache cycle. During the headache cycle, I’d like to stop working live traffic and medicate the headaches with prednisone and Imitrex and do assistant duties until the headaches have ceased.

All of my employee evaluations show me to be a model employee and an excellent controller. I have a sick leave balance of nearly 900 hours which is considerably more than nearly all the other controllers I work with. I love my job and I would like for nothing more than to get this out in the open and know that I can continue to control except for when the headaches occur. I’m very fit and take pride in myself for staying in shape. I typically ride my bicycle 300 to 500 miles a week during the summer months. I feel I have many, many good years to continue being an asset to the FAA and I respectfully request that you allow me to do so.

Working quietly with ZMP’s manager and the facility flight surgeon, Gilmore managed to keep his job. His medical certificate would be revoked the moment a cluster period came on, but he was not permitted to stay at the facility. Instead, he would use his accumulated sick time to ride out the headache period, however long it lasted. When the headaches stopped coming, he could return to work and have his certificate restored. He was forbidden from medicating on the job, but at least he could keep it. “I was a good controller,” Gilmore said. “And they enjoyed having me there. So, it was in their best interest to keep me on board as well.”

This scenario worked until it didn’t. As can often happen with this shapeshifting disorder, Gilmore’s cluster periods began to morph. He’d get a few attacks out of nowhere, and then they’d strangely go silent for a few weeks, before resurfacing again in a full-blown bout. “I thought, what do I do now?” Gilmore told me. “I mean, do I go back to the flight surgeon and tell him that okay, these headaches are back again? Because my fear was that he was going to say, ‘No, we’re not doing this anymore. You’re going to need to retire. I’m not going to keep rescinding your medical certificate and giving it back.’” In those final years, Gilmore says he went back underground, choosing to medicate quietly on the job as necessary. In his final year, he’d acquired medical-grade oxygen, and he kept a tank in his car. If an attack came, he’d use his next break to hustle to the parking lot and inhale deeply until it passed.

Gilmore would retire in September 2015—released from a charade that had dogged him for three decades. Writing in his journal earlier that year, as he was experiencing the worst bout of his life, he contemplated his dilemma: “Doctors know little about what causes cluster headaches because there’s been so little money directed toward the study of them,” he wrote. “Pharmaceutical companies are reluctant to expend resources developing drugs to treat them because of how few people would benefit. Without enough people to make it worth their while, and provide a recovery of their investment, I understand why there’s very little research being done about them.”

He’d been hearing talk of some newfangled drugs, CGRP or something like that, but they were still years off, and he’d become curious about the possibility of trying psilocybin or cannabis—though it would have been risky while still on the job. “I’m desperate for relief as I write this and would no doubt entertain that avenue for help, but I’ll need to wait until I’m retired,” he wrote. “I’ve already pushed enough on the boundaries of what’s permissible.”

*  *  *

Researchers have been calculating the social and economic toll of headache disorders around the globe for more than two decades. One early analysis,9 for example, pegged migraine-related losses in the United States at roughly $13 billion per year. A more updated accounting,10 from 2018, suggested that direct and indirect costs—including expenses associated with health care utilization, absenteeism, and short- and long-term disability—now stood at $28 billion. (By comparison,11 epilepsy, which affects about 3.5 million people in the U.S., incurred roughly $13.4 billion in direct health care costs in 2019.) A 2020 study out of Australia12 projected roughly $44 billion in lost GDP over the next decade due to migraine alone in that country. In China, a 2019 analysis13 put the annual cost at 331.7 billion yen, or $47.8 billion. Cluster headache, the disorder affecting Gilmore and me, is nowhere near as costly on a population basis, given its comparative rarity, but a 2018 analysis14 estimated direct costs due to cluster were on the order of $2.8 billion per year. That’s for a disorder impacting just 0.1 percent of the population. A 2022 analysis15 out of Denmark, which probably has fewer than six thousand cluster patients all told, estimated that disability and absenteeism related to the disorder ran to about $100 million annually.

These numbers seemed plain to Shapiro from the beginning. Before arriving as a neurology resident at Johns Hopkins, his education was prestigious and varied—an undergrad degree in biology, and a PhD in anatomy from the University of Pennsylvania—but his interests leaned toward autonomic disorders. These would be diseases like autonomic neuropathy, which involves damage to the autonomic nerves resulting in a variety of symptoms, depending on which organs are affected, from problems with blood pressure regulation, heart rate, bowel and bladder function, and sweating. “There weren’t a lot of people doing it,” Shapiro told me. “So there seemed like a great opportunity to study this.”

He stayed on at Hopkins as a faculty member to help establish a clinic specializing in this area, but soon discovered that the practice was filling up with people whom no one else wanted to see—principally people who had headaches. “There was some back pain, some carpal tunnel syndrome,” he said, “but headache, headache, headache, headache.” Shapiro’s curiosity was piqued. Given many of the accompanying symptoms he was seeing in headache patients—sweating, nausea, abdominal pain—he saw a role for the autonomic nervous system, which keeps heart rate, blood pressure, digestion, respiratory rate, temperature, and other key bodily functions humming along without conscious control. “I happened to casually say to somebody in the clinic, ‘You know, you could think about migraine as being a headache disorder with dysautonomia, or you can think about a dysautonomia with headache. Isn’t that interesting?’ And within a matter of weeks, my clinic was all migraine, because I was the only person who had really uttered anything of interest about it.”

When he relocated to the University of Vermont in the early 2000s, to help build out a program on headache disorders, he was struck by the lack of good options for this sizable population. “I had these patients who had disabling migraine, or even disabling cluster headache, but principally migraines—it’s a hundred times more prevalent—and the drugs that were available were terrible,” Shapiro told me. “They just were terrible. And they worked at a very modest and meager level. They were borrowed from other FDA approvals for other indications. And they were rife with side effects, which made people miserable. And, you know, patient after patient I’d have to say, ‘Look, well, you know, this is what we got.’ And it made me feel very bad. For a doctor, that was really inadequate.”

In some sense, Shapiro’s happenstantial foray into headache science was probably fortuitous; sometimes it takes an outsider to stumble into a situation and recognize that what has been regarded as normal for decades may not be normal at all. The strain on health care resources, the sheer size of the population struggling with headaches, the toll it was taking on their personal and professional lives, and the opportunity cost for the wider economy—these struck Shapiro as incongruous. “I thought, there must be somebody out there who’s doing something to change this, you know, there must be a lot of money that people are rustling up.” But when he started digging into the numbers at the National Institutes of Health, the largest public funder of biomedical research on the planet, he was dumbstruck. “Migraine was getting the least amount of money, relative to its burden, and no one had really done the math,” he said. “So, I started doing the math and start publishing some papers about that.”

It was the beginning of a decades-long crusade that has earned Shapiro the devotion of thousands of headache sufferers (one patient I interviewed called Shapiro “a god”) and the admiration of many clinical and scientific colleagues. It has also earned him the ire of various federal agencies. Shapiro—a professorial figure with a receding bush of gray hair, round, owl-eyed glasses, and a slight L.L.Beanish aspect—quickly struck me as someone with a stubborn streak and an almost prosecutorial appetite for understanding the minutiae of bureaucracy to strategic advantage. He’s polite, articulate, and exceedingly well prepared for an argument—Bob’s done the reading. Not surprisingly, tales of dispute between government apparatchiks and Shapiro are easy to come by.

In a 2014 NINDS interagency meeting16 on pain disorders, for example, then director Story Landis interrupted a slide presentation being given by Rene Etcheberrigaray, deputy director of the NIH’s Center for Scientific Review (CSR)—the agency’s primary screening funnel for tens of thousands of grant applications. CSR assigns grant proposals to the appropriate NIH division—the National Institute on Aging, for example, or the NINDS—as well as to study sections made up of volunteer peer reviewers with relevant expertise. Etcheberrigaray’s presentation had been prompted by repeated complaints from pain researchers, including those in the headache field, that their applications weren’t getting a fair shake at NINDS, so he’d singled out migraine for analysis. As he stood at the podium, about two dozen stakeholders—agency representatives, research scientists, clinicians—looked on from microphoned seats around a large conference table, while a smattering of onlookers watched from tiered seating on both sides. One of Etcheberrigaray’s slides—a grouped bar chart—appeared to show that proposals targeting migraine earned better scores from CSR peer reviewers than the average application across all disease categories—something that Shapiro and others had long complained was not the case.

I have sometimes thought that a person might need a PhD to understand the traditional grant scoring system at NIH and NINDS, and aspects of it are already being overhauled under the administration of President Donald J. Trump. Indeed, even before the 2024 election, the NIH had announced17 planned reforms aimed at improving parts of the grant review and scoring process. Still, some version of the ranking system will likely persist, and traditionally, it has worked like this: Reviewers assign scores ranging from 1 (exceptional) to 9 (poor), with the average of these scores determining the proposal’s preliminary ranking. The most promising proposals—that is, those with the lowest scores—are then discussed further in periodic meetings, or rounds, where scores can be adjusted based on collective deliberation. The final scores are then converted into percentile rankings, 0 to 99, relative to all other applications reviewed by that study section in the previous three rounds. NINDS sets a percentile cutoff point—the 15th percentile, for example, or the 20th—and this determines which grant applications hit pay dirt: Scores below this “payline,” as it’s known, will win. Scores above the payline lose—though NINDS can exercise some discretion here if it chooses. The payline also varies annually, depending on NINDS’s available budget, the pool of applications received, and other factors. Etcheberrigaray’s chart seemed to suggest that a lot of headache research projects were scoring quite well compared to the average proposal inside the payline, and many more were just a hair’s breadth above it. Landis laughed and flipped on her microphone.

“So, I’m sure that the headache community is not going to believe those data,” Landis said during that 2014 meeting, chuckling to sporadic murmurs. Rami Burstein, the prominent neuroscientist and headache researcher from Harvard, was seated across the broad table. He inquired about the data being shown. “Well, we just heard about specific areas,” Landis replied, “where, in general, pain applicants who put in pain grants feel that their grants are not reviewed in the right study sections, or they go to sections where there are more popular scientists. And for whatever set of reasons, we picked out the headache grants for this analysis. And I remember getting horribly beaten up by—” She leaned into her neighbor, Linda Porter, director of NINDS’s Office of Pain Policy and Planning, to help jog her memory. Porter offered up Bob Shapiro, and Landis said yes. “—Shapiro, but also the investigator from UCSF who is no longer . . .” Both Porter and Burstein offered up the other name: Peter Goadsby. “Yes!” Landis declared. “At our meeting—horrible!”

Etcheberrigaray, sensing tension, tried to temper things. “I don’t want to tell you that we don’t have any problems, and—” Landis interrupted again. “No, no, I just . . . but they believe that nobody gets funded, right?” she protested amid more nervous laughter. “And you have obviously gotten funded,” she told Burstein directly, “so it’s not nobody. Anyway, sorry.” She clicked off her mic but continued to bicker with Burstein inaudibly while Etcheberrigaray fiddled at the podium. Burstein asked Etcheberrigaray to share the slide, and he agreed—though he suggested that he could deliver more robust data on how headache grants are scored if given a bit more time. Landis interjected again: “No, no, no this is fine,” she said with a wide grin. “And would you send it to Bob Shapiro, please?”

It seemed mostly a lighthearted moment of professional teasing, albeit one marbled with perceptible resentment. For Shapiro, who was not there, it was telling. “So, Story immediately makes this issue personal and directed at me,” he told me in an email message. Shapiro found it remarkable that instead of looking at this data and concluding that too many strong headache grants were going unfunded, Landis used the moment to mock him at a high-level meeting on pain science—and to point out that he was wrong about how CSR reviewers were scoring headache grants. “In fact, I was wrong about that—happily so. But I couldn’t have known this before the analysis because success rates for NIH grants by topic area are not public knowledge,” he said. “In any event, these data indicated that headache grant proposals actually were high enough quality, that study sections were providing fair enough assessments, but that NINDS was not doing what it could to fund them.”

Shapiro’s willingness to spar for a cause is not limited to the NIH. He also has found it unconscionable that the list of disorders for which the Social Security Administration distributes disability benefits, colloquially called the “blue book,” does not contain an entry for migraine or other headache disorders.

The process for applying for Social Security Disability Insurance, or SSDI, is an arduous one, and the agency’s premiere criterion18 for eligibility is blunt: “You must have a disability that affects your ability to work for a year or more, or will result in death.” In practice, patients seeking SSDI must map out a highly documented case for themselves, matching or exceeding a remarkably detailed exposition of symptoms and accompanying impairments contained in the blue book. Section 11, subsection 9, part A, for example, refers to Multiple Sclerosis that is characterized by one of two varieties of physical limitation, each of which is further described in numbered lists and glossaries. Skipping to section 11.00D1 offers further clarification in the form of an FAQ: “What do we mean by disorganization of motor function?” The answer is exacting:

Disorganization of motor function means interference, due to your neurological disorder, with movement of two extremities; i.e., the lower extremities, or upper extremities (including fingers, wrists, hands, arms, and shoulders). By two extremities we mean both lower extremities, or both upper extremities, or one upper extremity and one lower extremity. All listings in this body system, except for 11.02 (Epilepsy), 11.10 (Amyotrophic lateral sclerosis), and 11.20 (Coma and persistent vegetative state), include criteria for disorganization of motor function that results in an extreme limitation in your ability to: Stand up from a seated position; or Balance while standing or walking; or Use the upper extremities (including fingers, wrists, hands, arms, and shoulders).

Patients with disorders that don’t appear in the blue book are instructed to compare their disability to the most similar disorder that is in the blue book; in the case of migraine, applicants are usually pointed to epilepsy, which the SSDI office considers the most closely analogous disorder. According to Shapiro, when the office had announced plans in 2016 to update the blue book (officially titled “Disability Evaluation Under Social Security”), thousands of headache patients and advocates left comments urging the administration to include migraine as a category. That did not happen, so Shapiro filed a Freedom of Information Act request, or FOIA, seeking documentation of the agency’s deliberation process. He wanted to know how (or whether) they considered adding migraine at all.

The issue devolved into a lawsuit, filed by Shapiro in 2019. He claimed the agency had illegally charged him nearly $3,000 in processing fees while refusing to deliver all but two irrelevant documents out of over 1,300 it had found in response to his request. (The SSA said the rest of the documents were privileged and private.) The agency countered that Shapiro’s request was overly broad and that on taking a second look, they’d located not just 1,300, but 1,581,644 responsive pages that filled his loose criteria. It would require precisely 193.311 hours to review them at a cost of about $7 million. A U.S. District Court in Vermont eventually issued a mixed decision,19 agreeing with Shapiro that he was owed his processing fee back because the agency waived its right to charge one when it did not respond to the initial FOIA request in the requisite twenty days. The court agreed with the SSA, however, that Shapiro’s request was overly and onerously broad. In March of 2022 the court awarded Shapiro $10,262.75 in attorney fees, $444.50 in costs, and $2,908.00 as reimbursement for his initial FOIA fee.

Since then, the SSA has appealed the fee reimbursement—almost certainly because it and every other federal agency, which regularly flout the statutory requirement to respond to an FOIA request within twenty days, saw a potential disaster in the making. (The Reporters Committee for Freedom of the Press filed an amicus brief20 in support of Shapiro.) The appeal was still pending in the spring of 2024, and whether and how the migraine issue was discussed internally at the SSA remains unclear. The agency now has a detailed policy interpretation ruling21 on its website describing SSDI claims involving headache disorders. It still describes epilepsy as the benchmark—something Shapiro calls an “an apples-to-Buicks comparison.”

I must admit I was not entirely sold on this particular crusade—or at least I felt compelled to play devil’s advocate. Estimates put the number of chronic migraine sufferers in the United States at anywhere from 3 million on the low end to 7 million at the high end—the latter being roughly the number of people already enrolled in SSDI in any given year. Even if just a fraction of those patients had an intractable form of the disorder, the increased draw on the Social Security piggy bank could still be substantial, I suggested. Shapiro seemed to misunderstand my argument at first, insisting that there was a presumption of chicanery buried in it. “I think the premise that people are malingering, that we need to protect the public from these cheaters who are pretending to be disabled, is itself a smear—and it’s not actually based on evidence,” he said. His point nudged me to imagine Frank Gallagher, that fictional character from Shameless played with exquisite repugnancy by actor William H. Macy, gleefully tormenting SSDI case managers with his “migraines.” Try proving I don’t have them!

But I wasn’t thinking of the Frank Gallaghers of the world. I was thinking about the roughly 50 million Americans with migraine disorders. Could the SSA support even a tiny slice of truly disabled migraineurs? Shapiro was unsympathetic to this too. Disabled migraine sufferers have paid into this insurance system just like anyone else, he argued, and to deny them benefits—and even refuse to recognize the disorder at all—is an affront. Indeed, part of the reason for his FOIA in the first place, he told me, was a suspicion—maybe an unfounded one, he concedes, but not implausible—that federal decision-making here is driven only by dollars and cents. He wants to know if there are documents tucked away inside the Social Security Administration showing that agency officials recognize migraine’s legitimate place in the blue book, but blanch at adding it for fear of a solvency crisis.

“If it turns out that it’s a cost-benefit analysis determining whether or not people are discriminated against,” Shapiro said, “well, that’s a way bigger case than my little FOIA. A way, way bigger case.”

*  *  *

If you visit the NIH’s Research Portfolio Online Reporting Tool (RePORT in the relentlessly glib parlance of government acronyms), you can get a quick sense of how the agency likes to dole out cash—and it has a lot to dole out. In fiscal year 2022,22 the NIH provided $33.3 billion for 58,300 new or ongoing research projects. NIH largesse23 supports more than three hundred thousand full- and part-time research positions, both in the United States and internationally, according to one analysis, and it can play an outsized role in the fortunes of scientific disciplines. Historically, its twenty-seven ICs, or institutes and centers—these range from the National Cancer Institute and the National Institute on Drug Abuse to the National Institute on Dental and Craniofacial Research—enjoy a high degree of autonomy in deciding what to fund and how to fund it. That level of independence is important, the NIH has long argued,24 to ensure that “applications receive fair, independent, expert, and timely scientific reviews—free from inappropriate influences.”

Whether Congress is an “inappropriate influence” is an interesting question. When the NIH itself sees fit, the agency has mechanisms for ginning up science in certain areas it considers a priority, generally by posting public expressions of interest, or requests for applications in a specific area. Sometimes these come with a specific dollar amount carved out—an obvious carrot at the end of NIH’s stick. Other times the announcements amount to mere encouragement to scientists working in one field or another to submit proposals. These solicitations usually arise as part of internal planning and management at the NIH. A 2019 Congressional Research Service Report25 suggests that lawmakers have historically avoided saddling the NIH and its ICs with requests that specific dollar amounts be spent on selected disease areas, fields of research, or mechanisms of funding, preferring to defer to the agency’s scientific expertise.

That has started to change, however, and Congress has seemed more willing over the last fifteen years to attach dollar amounts to certain NIH endeavors in its appropriations language. In 2023, for example, Congress used appropriations report language to specify a dollar amount of funding for certain programs or lines of research within the National Cancer Institute, as well as the National Institute on Drug Abuse. It has also continued to include somewhat more vague language directing the agency, according to a 2023 CRS analysis,26 “to prioritize certain programs or areas of research, as well as statements expressing the opinion or concerns of Congress regarding NIH.”

It’s my sense that the many bits of language that headache advocates have managed to nudge into congressional reports fall into this latter category, and in the big scheme of things, it’s possible they don’t really matter. Short of a specified dollar sign, these statements seem to operate as a courtesy to the headache community—and other disorder advocates—without a tremendous amount of force. In addition to headache disorders, for example, the 2009 Senate appropriations committee report27 includes comparatively anodyne expressions of encouragement for NINDS to take more interest in dystonia, a neurological movement disorder, and Duchenne and Becker muscular dystrophy, among other disorders. The 2019 House report28 mentions numerous and frequently rare disorders, from amyloidosis (a rare disease affecting the organs) and Angelman syndrome (an uncommon genetic disorder of the nervous system), to trisomy 3 (a chromosomal anomaly causing, among other things, facial abnormalities and developmental delays) and valley fever (a lung infection caused by the fungus Coccidioides).

A vivid counterexample might be Alzheimer’s research. For years, NIH funding for research into Alzheimer’s disease and dementia was flatlined—not unlike that for headache research. And from 2001 to 2013, congressional appropriators gave the NIH similarly broad encouragement in their report language, urging the agency to pay more attention to the disease and to increase research funding devoted to it—quite like the entreaties for migraine. The language got a bit tougher in 2014, basically saying that while Congress didn’t want to tell the National Institute on Aging how to do things, it expected that “a significant portion of the recommended increase for NIA should be directed to research on Alzheimer’s.” If the earlier language was a suggestion, the 2014 message was more like a visit from one of Tony Soprano’s more convincing capos. Ya gotta nice thing going here, NIH, and, uhhh, you know, we’d hate to see something happen to it, that’s all.

By 2016, in what Congressional researchers called “a significant departure from past precedent,” the explanatory statement accompanying the budget included instructions from Tony Soprano himself: the NIH was told to set aside a specific amount of money for Alzheimer’s. One need only look at NIH’s historical funding trends, available online,29 to see that the agency knew when to hop to: Funding for Alzheimer’s research hovered between $450 million and $500 million annually from 2008 to 2015, and then it shot up, ballooning to a billion dollars in 2016, and increasing by several hundred million every year since. The estimated amount of funding that would go to Alzheimer’s for 2024, still unsettled at the time of this writing, was more than $3.5 billion—nearly eight times more than it had been prior to Congress getting tough.

The scientific community took notice: “Such a dramatic increase in research funding for a disease has no precedent at NIH aside from the War on Cancer, an effort launched in 1971, and an explosion of AIDS funding in the late 1980s,” wrote journalist Jocelyn Kaiser for Science magazine in 2018. The effect was a frenzy in the research trenches, with talented scientists who had not studied Alzheimer’s before seeing a ripe opportunity to dive into a new problem with substantial funding support. “Nearly everyone I know is putting the words ‘Alzheimer’s disease’ in their grants,” one scientist told Kaiser, “in an effort to tap into the money.”

Has that dramatically changed things for Alzheimer’s? Not yet, but it would arguably take longer with fewer researchers devoted to the task. Shapiro likes to point to the Alzheimer’s example as evidence that NIH can have an extraordinary influence on what goes under a microscope around the world, if it chooses to do so—though he doesn’t seem to acknowledge that the agency needed to be muscled into it by Congress. And in fact, congressional interest in the topic was spurred by the National Alzheimer’s Project Act, which was signed into law in January 2011. That legislation directs the Department of Health and Human Services, which oversees the NIH, to “be responsible for the creation and maintenance of an integrated national plan to overcome Alzheimer’s; provide information and coordination of Alzheimer’s research and services across all federal agencies; and accelerate the development of treatments that would prevent, halt, or reverse the course of Alzheimer’s.”

The NIH’s commitment to incentivizing Alzheimer’s science, in other words, isn’t really a choice; it’s the law of the land. Supporting migraine research, by comparison, remains a polite congressional suggestion. And to pull back the curtain on report language a bit more: When members of Congress seek to have certain language added to an appropriations report, their staffers typically send the proposed text to the targeted agency for review and discussion first. As a result, the statements that appear in the final reports are sometimes quite different than what was requested, and much will depend on how vigorously the agency pushes back, and how committed Congress members are to the topic at hand. Not only does that mean these prescriptive bromides have an air of collaborative theater, but according to Shapiro, “NIH institute directors have two chances to kill report language—at the appropriations staff level (‘catch and kill’), and by ignoring the final language altogether.”

The haggling that goes on at this level is not typically made public, although Shapiro has been privy to some of the closed-door negotiations. Ahead of fiscal year 2022, for example, he and hundreds of volunteer advocates, as part of their annual Headache on the Hill event,30 successfully convinced a bipartisan group of legislators to support report language emphasizing the outsized burden of headache disorders, and directing NINDS to do two important things: set aside a specific amount of funds from the HEAL initiative for headache research; and raise the payline so that more good headache grants are funded. In a letter co-signed by forty-two members of Congress, and co-authored by U.S. Representatives Madeleine Dean, a Democrat, and Brian Fitzpatrick, a Republican, both of Pennsylvania, along with Republican David McKinley of West Virginia and Democrat Peter Welch of Vermont, the chairs of the House appropriations subcommittee were urged to include the following paragraph in the final budget report:

Headache Disorders—The Committee expects NIH to consider the burden of a disease when setting priorities and developing strategic plans across its Institutes and Centers. Migraine is the 2nd leading cause of US and global disability, affecting more than 17 percent of Americans. Annual NIH analyses over the past decade have shown that headache disorders research has consistently received the least funding among the nation’s most burdensome diseases. The statutory language providing authority for Helping End Addiction Long-Term (HEAL) Initiative appropriations specifically cites the necessity of attending to disease burden in prioritizing HEAL research programs. The Committee therefore provides $50,000,000 of the appropriations designated under the HEAL Initiative to fund fundamental, translational, clinical, and social science research on headache disorders, including migraine, post-traumatic headache, analgesic/opioid-mediated headache, trigeminal autonomic cephalalgias, intracranial hypo/hypertension, toxic/airborne exposure related headache disorders, and infectious/post-infectious related headache disorders. Amounts appropriated in this Act (including the amendments made by this Act) shall be used to supplement, not supplant, current funding for headache disorders research at the NIH. Further, the Committee strongly urges NIH to shift the funding payline to the 25th percentile for all headache disorders grant proposal submissions, in accordance with the testimony of NIH Director Francis Collins that such a funding payline shift does not compromise research quality, but that it would incentivize talented investigators to pursue research in this area.

It had Shapiro’s fingerprints all over it, and the NIH pushed back hard, disputing most of the points made in the statement. Then, at the invitation of congressional staff, Shapiro wrote a letter defending the language, which was subsequently shared with NIH. The agency tore that apart, too, insisting that Shapiro had it all wrong.

In the end, no headache language was included in the fiscal 2022 report. Shapiro called the NIH’s arguments “gaslighting.” At the following year’s Headache on the Hill event, Shapiro and other AHDA advocates lobbied lawmakers to request a Government Accountability Office investigation of the NIH’s research funding relative to disease burden, particularly for headache disorders. No legislators were willing to sign on to that. The last appropriations report to include language on headache was in 2020.

There are times when I’ve thought that it must be a difficult thing indeed to be on the receiving end of a Shapiro-led pressure campaign; he’s the proverbial dog with a bone. At the same time, I understand the point that he and so many other headache researchers have made to me over the course of my reporting this book. For all the success of the triptans, and all the glamour of the CGRP inhibitors, they are useful but narrow and imperfect innovations separated by literal generations—and only a few evolutionary hops, as it were, from Darwin’s human centrifuge or his grandson’s temple beans. The bang-for-your-buck case for increasing fundamental migraine research seems so obvious, so easy, and so necessary, that it strikes many researchers as strange that the NIH wouldn’t make it a priority, even without a shove from Tony Soprano.

“The NIH themselves have stated that disease funding should be congruent with disease burden,” the Mayo Clinic’s Amaal Starling told me. Critics argue that the agency is clearly not doing that—and the evidence comes from the NIH’s own analyses, which includes a scatterplot chart that has launched a thousand disputes:

A chart from the NIH’s Report on NIH Funding vs. Global Burden of Disease (https://report.nih.gov/report-nih-funding-vs-global-burden-disease). Selected diseases highlighted by the author.

The chart shows where a variety of diseases and disorders sit on a matrix of disease burden relative to NIH funding. Burden is calculated using the 2017 Global Burden of Disease Study and its disability adjusted life-years, or DALY metric. Diseases with a lot of associated DALYs—that is, a high global burden—tend toward the right. They will also be nudged higher or lower on the chart relative to the amount of NIH money spend on them in 2017: the higher they are, the more funding they received. Migraine and headache are lonely planets toward the bottom right of the chart, signaling substantial burden but low funding.

“If someone is a career scientist whose career is going to depend on NIH funding, and you are starting to go down that road, you’re not going to go for the pot of money that is $24 million,” Starling told me. “You’re gonna go for the pot of money that’s $200 million. So, we’re not attracting those individuals, those bright scientists into the field. Also, when you have these diseases that have high funding, those are the ones that are thought to be the ‘important’ diseases. And so, ‘importance’ is being set up at the top, and that stigma then trickles down.”

The migraine pot was actually $40 million by the time we spoke, and settled out at close to $50 million in 2024, which is clearly progress. At the same time, advocates will point out that hepatitis C, which has a much smaller burden, has enjoyed an average of $100 million annually for the last fifteen years. Infertility science was supported just north of $70 million annually until 2016, when it saw speedy growth—possibly spurred31 by the NIH lifting some previously restricted lines of research. The estimated outlay for infertility research in 2024 was pegged at just under $200 million. Tuberculosis was estimated at $635 million in 2024, and ALS, also known as Lou Gehrig’s disease, was expected to be $220 million. No one would argue that these disorders do not deserve attention and support. But it’s curious to many in the headache community that migraine remains so underfunded by comparison. Indeed, among disorders with the highest burden, in terms of DALYs, migraine and headache disorders are the lowest funded of them all, with the possible exception of psoriasis. (That should attract more funding, too, of course.)

“The NIH, for reasons that you can’t immediately understand, has persistently, for fifteen years, chosen the wrong path, when it’s constantly being directed towards the right path,” Shapiro says. “Why it does that? I can speculate, I have my own biases, but I suspect it is because there’s intrinsic stigma towards these diseases as being inconsequential.”

Migraine and other headache disorders weren’t even included as distinct disease categories in the agency’s own tracking until the Alliance for Headache Disorders Advocacy successfully lobbied for it in 2007. It was one of Shapiro’s earliest wins, and its presence on the infamous scatterplot has given the research and patient advocacy communities a cudgel in its interactions with the NIH. But does the chart really provide evidence of bias? It’s hard to say. The agency has long believed that DALYs and other comparisons of disease burden are inherently blunt tools providing only limited and perhaps even skewed insight. “NIH believes32 that there is no comprehensive, standard approach for measuring burden across diseases,” the agency has stated. “For the most part, measures of public health burden are designed to detect changes in one disease or condition (or a small subset of related conditions) over time or between populations.”

There are other, more practical considerations at play, according to Michael Oshinsky, who directs the Office of Preclinical Pain Research at NINDS. “NIH doesn’t allocate funds based on burden of disease, meaning allocated before the proposals come in,” he told me. “They don’t say, ‘Oh, we have such a burden of this disease, we need to allocate X amount of dollars.’” In practical terms, that would be unworkable, Oshinsky suggested, because if that money is earmarked for a specific disease, and too few grant proposals come in to consume it, the money is lost.

Oshinsky clarified that NINDS, like other institutes and centers at NIH, does have the ability to make such carve-outs, or to otherwise press a thumb to the funding scale in favor of a particular disorder, but for NINDS specifically, this is very rarely done, and usually at the very direct behest of Congress. (Think Tony Soprano.) “At NINDS, we are payline-driven,” he explained. “The institute is literally responsible for hundreds of neurological disorders, hundreds of them, and we get about $2.4 billion a year. And the vast majority of the work is investigator initiated, meaning there’s researchers out there that want to do research in a particular area, and they put their applications in, and if they come in under the payline—the payline at this current time is the 14th percentile—then they get funded, they just get funded. And this idea of epilepsy, or Parkinson’s, or, you know, ataxias, or movement disorders in general, just having allocations, and they fall on the graph of the DALYs because of that, is a mistake in understanding how the system works.”

Oshinsky is animated in our conversation, almost exasperated. I got the sense that he’d grown weary of the complaints from certain headache advocates, who he characterized as mostly nonscientists. He pointed to Rami Burstein at Harvard, or pain neurobiologist Gregory Dussor at the University of Texas at Dallas, or pediatric psychologist Scott Powers, who studies pediatric migraine at Cincinnati Children’s Hospital, as researchers who routinely have headache grants funded. “If you speak to the individuals who don’t apply for grants, or mainly the advocacy groups that are run by coalitions who aren’t submitting grants, they will say, ‘Well, you know, how come there are so few grants? There’s so little funding.’”

Oshinsky also argues that he and his colleagues have made elaborate attempts to help headache researchers get a leg up. He pointed, for example, to an expansive effort in which NINDS collaborated with the headache research community to develop common data elements, or CDEs. These are standardized, precisely defined terms that can be used to collect and report research and trial data across different studies and researchers in the field, making it easier to compare results, replicate findings, and aggregate information for more significant research insights. It also helps researchers working in a particular area to streamline study design, because some of the baseline and even supplementary information that’s needed for a successful trial or other research project is already largely mapped out and available at the NINDS website. “Sounds really helpful, right?” Oshinsky said. He was setting up a punch line: “They’ve been cited zero times.” His annoyance was palpable.

For the most part, Oshinsky—a former NIH-funded researcher and faculty member at the Thomas Jefferson University’s Department of Neurology for more than a dozen years—feels that the complaints from the headache community are unfounded. He argues that when the agency expresses a special interest in soliciting migraine grant proposals, headache researchers are slow to respond. “If I told the community, I have, you know, $500 million available, I’m still gonna get the same number of applications,” he said.

Clearly there is a communication breakdown here, and one starts to get the sense that it’s at least a little bit personal in both directions. Oshinsky couldn’t tell me basic information, like what percentage of all grant applications in the headache area get funded. (He suggested I submit an FOIA request for that.) But he did intimate that headache researchers do themselves no favors by taking a hostile approach to the agency. “I’ve spoken to all the names that you’ve mentioned many, many times, and I have to tell you, they were my colleagues, and I still consider them my colleagues. I don’t know if they consider me their colleague, but I consider them my colleagues, right?” His sardonic tone made me chuckle. “You can laugh, but to me it was like, night and day, from certain members of the community,” Oshinsky said. He was talking about the moment he left academia and took a seat between the research community and NIH’s pot of gold. “You know, for fourteen years, they interacted with me like X. And then three months later, it was like Y.”

That’s unfortunate, Oshinsky suggested, because the agency really is there to help. “You shouldn’t have the perception that there is a higher level of scrutiny, or that a lower percentage of migraine grants are funded, that’s just not the case,” he told me.

“That’s one-hundred percent untrue?” I asked.

“I didn’t say that,” Oshinsky replied.

Ninety percent untrue?

“I don’t have the data in front of me, but it is not my perception. I have been at this for almost eight years, and I have to tell you, I have looked. They’re really getting a fair shake. They really, really are.”

This would never satisfy Shapiro and many of his fellow researchers. To them it’s a chicken-and-egg problem: If you make the money available, new researchers will enter the field, grant proposals will swell, and the field will finally flourish in a way it never has before. The science will accelerate, genetic markers will be illuminated, and new remedies—perhaps even a cure—will sooner be uncovered. Christopher Gottschalk, the Yale neurologist, described the complaint that there aren’t enough headache grants being submitted to the NIH as specious. “That’s a self-fulfilling prophecy,” he said. “The people at NIH say there’s no good research? Well, no kidding. That’s because you don’t fund it.”

Oshinsky, on the other hand, argues that certain headache researchers too quickly fold up their arms and complain about burdens of disease when a grant isn’t funded, rather than engaging in good-faith communications with agency personnel who want to help and bear no grudges. Acquiring a grant from the NIH is incredibly competitive, and the fact is that most grant applications fall short, regardless of the field. Persistence, Oshinsky told me more than once, is a virtue.

“This idea that because there’s a burden of the illness you should fund my grant, you know—first and foremost it’s the quality of the science to answer the question that’s posed,” Oshinsky reiterated. “I think you’ll agree, Tom, that that’s what it should be evaluated on, right? If you have a science project that’s not going to lead to useful data, meaning moving the field forward, then it’s not worth funding it no matter how much the burden of the illness, right? Because the scientific questions need to be answered.”

For whatever reason, headache scientists insist that the status quo has ensured that advances in addressing these disorders come far more slowly than they should. That, they say, leaves the proverbial A380 of migraine that Goadsby talked about—the one grounded by air traffic controllers at the NIH because it has too many female passengers—glued to the tarmac. It also ensures that trained pilots are hard to come by, Shapiro suggested, using the airplane image in a slightly different way. “The problem is that the NIH has not taken the steps that are proven to be effective at making the field more attractive, and to ensure that there are enough investigators. That’s the fundamental problem,” he said. “They shift the blame back to this tiny group of investigators, but if you put all the NIH-funded investigators on a plane and it crashed, the entire field would disappear. And that’s very unhealthy. It’s a bad analogy, but it’s an unhealthy thing for a disease that has this level of impact.”

*  *  *

Might things improve under a newly energized Trump administration? Perhaps. Even before the 2024 election, a reformation33 of the nation’s prominent health agencies, which earned the ire34 of critics who viewed various Covid-era public health policies as draconian and contradictory, was a high priority for both Trump and his pick to run the Department of Health and Human Services, Robert F. Kennedy Jr. Proposals for modernizing35 the NIH in particular—in part by breaking down its siloed structure, encouraging more cross-disciplinary science, and bringing all the agency’s operations under fresh congressional review—suggest that at least some of its more hidebound practices face a shake-up. That certainly seemed to be top of mind for Jay Bhattacharya, the Stanford physician and economist that Trump tapped to take over the NIH, which operates under the umbrella of HHS. “We will reform36 American scientific institutions so that they are worthy of trust again,” Bhattacharya declared on social media at the time of his nomination, “and will deploy the fruits of excellent science to make America healthy again.”

Kennedy has also expressed deep skepticism about modern medicine and the pharmaceutical industry in particular—not all of it unfounded in my view. At the same time, he has repeatedly argued that Americans are wildly over-medicated compared to other rich nations—though the data on that is somewhat inconclusive. Americans certainly spend more on medications, given the higher costs for everything in our fractured health care system. But several studies have shown37 that drug utilization rates don’t really vary all that much among wealthy countries—and when measuring daily dosage amounts,38 American drug consumption might well be lower than in many comparable nations.

Whatever the vagaries of all this, I tend to think that many things can be simultaneously true: The pharmaceutical industry can be inarguably driven by profits, even if individual scientists working within its sphere are motivated by a passion for basic science and a genuine desire to help people. Consumers the world over are almost certainly being sold on unnecessary pharmaceutical solutions, and many others will be harmed39 by medications that were too hastily moved to market and given insufficient regulatory oversight. But in any given year, thousands, sometimes millions of patients, might also see their lives transformed for the better—sometimes markedly so40—by a Big Pharma innovation. (Kennedy, who infamously recommended41 cod liver oil as a remedy for measles in early 2025, might well disagree.)

Amidst these cross-cutting realities, the question of whether an administration keen on reforming federal science will provide the sort of attention and funding the headache community seeks remains an open one. It might well go in the other direction: Even before Kennedy’s Senate confirmation vote in early 2025, the NIH announced42 steep reductions in the amount of grant money the agency would provide to research institutions for so-called indirect costs—things like equipment, lab space, and other administrative expenses. Proponents heralded the move as ensuring that more taxpayer dollars are spent on pure science, but many critics suggested43 that the move would result in a net reduction in basic biomedical research. Lawsuits aimed at blocking the cuts44 quickly followed.

However that pans out, I couldn’t possibly adjudicate who has the better argument over headache’s historical place in the NIH funding labyrinth—though it’s hard not to have a soft spot for Shapiro’s passion and commitment. For two decades, he’s been picking fights on behalf of tens of millions of headache patients at no personal gain for himself, simply because he felt it was the right thing to do. He’s stepped back from day-to-day management of the advocacy group he founded, but he continues to press the case45 that migraine and other headache disorders are objects of irrational prejudice. I’m with him on that. There’s little doubt stigma plays a role in how headache gets talked about everywhere, such that an eye will surely roll from time to time even inside the vast machinery of the NIH. But attributing headache’s position on the agency’s scatterplot to pure prejudice or bias, or locating this in the minds of NIH’s rainmakers writ large—well, these are powerful claims.

I brought the burden-of-disease question, among other queries, to former NINDS director Story Landis. She’d left the NIH over seven years prior, so her perspective would have been frozen in time, animated by people and politics that have long since turned over. And yet, she seemed to have played such an archnemesis for Shapiro in his early advocacy efforts—the Grendel to his Beowulf, the Voldemort to his Potter—that I yearned for her take.

Landis is a neurobiologist by training, with a decorated career on the faculties of both Harvard and Case Western Reserve Universities before joining the NIH in 1995. We connected over Zoom from her home on the coast of Maine, north of Portland, where she and her husband escaped after retirement. Her cozy fleece and unfussy bob of white hair signaled her New England roots, and for most of our conversation, she wore her spectacles on the top of her head. “When I left the NIH I thought that I didn’t want to stay in Bethesda, because it would be much too easy for people to email me or to phone me or to catch me in the grocery market and come and ask me to do something,” she told me as we got acquainted. “So, it just worked out really well. I finished up the fiscal year and I disappeared.”

I asked her about migraine and burden.

“There must be countless disease groups making that argument for their disease,” she said, pointing to spinal muscular atrophy as one example. “It’s a genetic mutation in the SMA gene and kids who get it die,” she said. “If you have type one SMA, you die within a year of birth; for SMA type two, you might live to be ten, but you’re probably in a wheelchair the last five years—it’s a horrible disease and more prevalent than you would think. And we were spending no money on it. Zippo. And there was a very effective woman, Loren Eng, who ran the SMA Foundation, and she lobbied with Congress and so the amount of money that NINDS was spending on it went up.”

Her story confused me at first, because it seemed to argue that Bob Shapiro and his allies were following the right script, but somehow weren’t “effective.” Landis then added that the SMA Foundation parlayed NIH support into further advances by lobbying the drug industry to take an interest. “And now there are three treatments,” she said, “but here’s another disease that—I mean, headache? SMA is a rare disease, but one that’s lethal for babies, which is horrible.” I started to realize we were talking about “burden” in different ways. I was thinking of it in the abstract, actuarial, and difficult-to-truly-fathom DALY sense. Landis was using it in the way most of us normally do: Is this disease deadly? Will it kill children? Now that’s burden.

The pharmaceutical angle is a contentious one. I’ve heard some stakeholders argue that headache researchers get plenty of support from drug companies for their work and as such, they are less needful of public funding—but this argument rankles scientists. While it’s true that drugmakers can spend lavishly when they see an opportunity to make a drug, that dries up fast when that opportunity is exhausted. “Because there’s so little public funding for headache research, headache researchers are almost entirely dependent on pharma money,” Joanna Kempner, the Rutgers sociologist, told me. “I’ve been in this business for long enough that I witnessed what happened when the triptans were patented, and then when triptans went off patent. The first professional headache conference I attended was in 2001. It was an American Headache Society meeting held in conjunction with an International Headache Congress in Manhattan. And Imitrex was still on patent. The other triptans were on patent. And the conference was huge. The pharmaceutical booths were overwhelming. I had not expected such an immense display. And then I think by 2008 or 2009—I’d have to go back to my records—I went to a conference in Philadelphia, and there were no booths. There were hardly any booths to be seen. And I could hear doctors just kind of shaking, you know, saying like, ‘Well, there’s nothing here,” and just being really disappointed by how little investment there was by the pharmaceutical industry.

“Those booths,” she added, “pay for a lot.”

So do the patents—at least for as long as they last. Most familiar drugs46 are awarded a twenty-year patent from the U.S. Patent and Trademark Office, which legally bars other companies from manufacturing or selling the protected innovation. Biologics like the new CGRP monoclonal antibodies receive similar patent periods, though their trajectory through the patent system is comparatively more complex given their derivation from living organisms. In either case, companies are incentivized to patent promising new therapies early, before they are fully tested in trials, such that the period in which a drugmaker can profit from its innovation is often shorter, given the time it can take to earn the FDA’s blessing and get the drug onto pharmacy shelves. Companies can and do deploy various strategies to extend their market dominance, sometimes by making minor tweaks47 to a formulation and re-patenting it as “new,” or even by paying would-be generics makers to forego entering the market for a period of time after a patent expires—a practice known48 as pay-to-delay. The FDA itself also offers avenues for extending or complementing marketplace protection through a designation known as “market exclusivity.” This is an FDA-granted status49 that bars the agency from approving duplicate or even sometimes similar innovations for varying periods—usually anywhere from three to seven years, depending on the program. It’s often used to incentivize pharmaceutical investment in specialized areas that might not otherwise be a profitable target, such as certain pediatric drugs, or therapies aimed at rare diseases and disorders. (The latter category of so-called orphan drugs targets diseases affecting fewer than 200,000 people in the United States—and, alas, cluster headache, which affects a little over 300,000 Americans, does not make the cut.)

In practice, all of this means that when a company manages to get a hot new therapy to market, it will spend lavishly during its protected tenure to earn back its investment and turn a profit by ensuring that pharmacies stock it and doctors prescribe it. Toward that end, and in addition to traditional marketing, they will subsidize conferences, sponsor physician events, relentlessly hand out samples, and otherwise drop windfalls of cash and attention on whatever branch of medicine is most likely to circulate the shiny new therapy. But when those various market protections are exhausted and the moratorium on cheaper and more varied generic versions is lifted, that largesse quickly evaporates. That’s precisely what happened to headache specialist meetings when the triptan patents began to expire: On patent you get medical conferences that feel like Davos—or even Burning Man; off patent you get Meeting Room A/B at the Toledo Holiday Inn.

The booths are back, at least for now, with the arrival of the CGRP inhibitors, but it seems likely that this too could ebb if avenues for novel therapies dry up and patents begin to expire. The lack of devoted and concerted funding from the NIH, some scientists say, leaves the field uniquely vulnerable to boom-bust cycles that depend too heavily on the whims of industry, and that slows progress. Indeed, many point out that the NIH’s fingerprints are hard to find on the few innovative therapies that have managed to emerge. “NIH has had little or nothing to do with any of the migraine-specific therapies, including the triptans,” Andrew Charles told me. “The reason that I think it is important to acknowledge the industry contribution here is that it has made our field uniquely beholden to them.” In a follow-up email, he added: “Since there has never been much NIH funding, we as academics have had to turn to industry for support, which is inherently problematic.”

I sensed that Landis would agree with this, and she even conceded that $40 million—NIH’s rough spending on migraine at the moment—is “not a lot of money.” So, what’s holding the field back? I asked. She suggested it was a multivariate problem. For starters, when she was running NINDS, it was her sense that headache scientists were simply proposing lackluster research projects. NIH makes it clear that the quality of the science is a key factor in weighing the merits of a grant proposal, she said. So too is the likelihood, in the estimation of peer reviewers, that a project will yield results. The experience of the investigator making the proposal, or the odds of a breakthrough versus an incremental bit of insight, are additional factors. The agency is also less interested in drug development per se than in research that seeks to uncover underlying biological mechanisms and processes, and Landis suggested that headache researchers had been poorly conditioned by industry to focus on pills and shots, rather than foundational science. “It was never that I didn’t want to fund pain research, or headache research,” Landis said. “It was that, in general, the science was not doing as well as it needed to get funded within the payline.”

She also suggested that other disease groups have managed to gin up substantial support from rich benefactors. “If you look at Parkinson’s disease, for example—a prevalent, devastating neurodegenerative disease—if you look at the sources of funding, there is a huge amount of private money that goes into funding Parkinson’s research. Sergei Brin, who set up Google, has Parkinson’s in his family. Andy Grove had Parkinson’s, and so a lot of private money went into Parkinson’s—the Michael J. Fox Foundation. So, what difference does that make? It means that there’s a lot of money supporting a significant body of research, which then can be harvested and written up for an NIH grant. So, there’s just money floating around in that topic area, and that’s never been true for headache.” I wondered why there wasn’t a bigger celebrity movement on this front. Why were Lady Gaga and Whoopi Goldberg taking money from pharmaceutical companies to shill for a migraine pill, rather than helping to fund an independent nonprofit headache research center in the hunt for a cure?

Still, it felt like a dodge, and I finally asked Landis bluntly: Do you think all this burden-of-migraine stuff is overblown? She offered that she herself has struggled with migraine. They started when she was a teenager. She got them every six weeks or so, and sometimes they were terrible. She didn’t know what the triggers were, and the pain could be bad enough to send her into a dark room for hours. Calcium-channel blockers helped, but she recalled running out of them at one point, which unleashed a torrent of pain. “I thought I was going to die,” she said.

Despite all this, she told me, she just carried on: “I don’t think I ever thought ‘Oh my god, I have migraines, and somebody should be doing something about this.’”

Chapter 10
The Blind Men and the Elephant

I get very anxious during a migraine. My brain won’t shut off and it’s like I have to talk to myself continually to breathe and relax. If I let any emotion out or cry, the pain increases immensely. Sometimes, I am fighting the migraine for days. It comes and goes. I start to feel better and back it appears. The last seven years, going through menopause, have probably been the hardest yet. I was getting between twelve and fifteen a month. I have had a wonderful break now. I have no idea why.

—Cindy Vos, mother, grandmother, and musician, Illinois

There are only so many structures that could conceivably hurt inside the head—or so we are told. Most of us learned in school, for example, that the brain itself is insensate—that it does not have pain receptors of its own. It’s a characteristic that has, in fact, facilitated many delicate neurosurgeries, because they can be performed while a patient is awake. A brain surgeon can mechanically poke or electrically stimulate certain brain areas, and a patient can be asked about the effects. In an individual patient, this helps to identify precise locations in the brain governing important speech, motor, and sensory functions, so a surgeon can avoid them when plotting a strategy for removing a tumor, for example.

This also means that while working on conscious patients, neurosurgeons often have access to other cranial structures, including the membranous layers between the skull and the brain known as the meninges. Depending on what bits of those tissues are nudged, patients frequently report pain, often severe, that is not unlike the pain of a migraine or cluster headache—though our evidence base for determining precisely what cranial tissues are nociceptive, and how they relate to the pain that is perceived in a primary headache, is surprisingly small. For decades,1 the most direct knowledge came from Harold Wolff and his colleague Bronson Ray, who in 1940 studied thirty patients undergoing craniotomies while awake. They documented numerous nociceptive sites in the dura mater—the outermost of the three meningeal layers—and they recorded where in the head patients reported feeling the sensation. Such investigations have reportedly happened only twice in the subsequent eighty years—once in 1971 and again in the 2010s, in an analysis spearheaded by researchers in France.

The French researchers,2 who published their findings in the journal Brain in 2018, recruited three neurosurgeons to report painful events in awake craniotomies, all performed for tumor removals, between 2010 and 2017. While it would have been unethical to intentionally induce pain in a patient undergoing a delicate procedure, the surgeons and patients agreed to note when an incidental poke or touch registered as pain. The surgeons recorded the location of the incidents by placing a mark on a cross-sectional drawing of cranial anatomy. They could add details if desired. The patients placed their corresponding pain marks on simple line drawings of the head—one facing to the side, the other facing forward. Most of the pain sensations seemed to register near the ophthalmic branch of the trigeminal nerve, and the patients’ marks were often placed on the temple, or around the eyes.

In the end, fifty-three patients reported a total of ninety-three painful events—many of them originating in areas of the dura mater, as Wolff and Ray had shown. The French researchers also reported that contact with lower layers of the meninges, previously thought to lack substantive nociception, also generated acute pain. So, too, did cerebral distal vessels—which are, in fact, inside the brain.

These nociceptive moments were perceived on the same side of the head where the surgery was being performed, though rarely anywhere near where contact was made—a phenomenon known as referred pain. The site of a nociceptive event in our bodies is not always the location where pain is perceived, and there are classic examples. A familiar one is associated with heart attack, which can be perceived as pain in the left arm or shoulder. The proximate reason3 is that the heart and certain areas of the arm send pain signals through nerve fibers that merge onto the same spinal segments. When a heart attack occurs, this confluence of signaling pathways can sometimes make it difficult for the brain to distinguish the precise location of distress. Sometimes it interprets it as coming from the left arm.

Whether this is a beneficial feature of our complex nervous system or a wrinkle in the body’s matrix is an open question. Some theories suggest that referred pain offers protection by sounding a distant alarm as a stand-in for internal structures where a noxious event might go unnoticed. Or maybe it’s just a by-product of expedient physiological adaptation, in which multiple structures share common signaling pathways out of evolutionary efficiency. Whatever the reason, it would explain why a painful headache typically feels concentrated in structures that aren’t in any way being abused: trigeminal axons carrying afferent signals from, say, the meninges and from the forehead, eventually converge before sending those signals onward down a common pathway to your brain. Your brain’s somatosensory cortex, not quite knowing where the signal is coming from, decides it’s your eye, or your temple, that’s experiencing the insult.

This doesn’t necessarily mean that we know for certain that meningeal tissues are the source of headache pain—and studies like this one seem to both confirm and confound that hypothesis, not least because it identified a few nociceptive culprits beyond the dura mater. Indeed, researchers continue to disagree over whether the meninges are important to headache pain at all—and even the conviction that the brain itself is insensate. On that last point, it can be hard to know which arguments are sincere and which are simply exploiting the fact that no matter how much evidence seems to be pointing in one direction, absent incontrovertible proof, we might still be proven wrong. But the disagreement can be found in high quarters.

Harvard’s Michael Moskowitz, for example, laid out in an interview what I took to be axiomatic: “I went back to the writings of the 1930s, 1920s. And they were brilliant,” he told me, recounting his early years exploring head pain. “They had thought, you know, very, very clearly about what structures within the head would cause pain when stimulated. And it turns out that they’re very few. The brain itself is insensate, as you know. So, it’s just really the connective tissue coverings, the so-called meninges.” But when I made the same assertion while chatting with Andrew Charles in early 2024, he immediately interjected: “No. No. So, that’s actually not true.”

I was dumbfounded and I protested. The idea that the brain can’t feel pain is arguably the most elementary assumption in all of headache science, I told him. It falls off the lips of prominent neurology researchers, it is imprinted in medical textbooks, and it remains a popular gee-whiz sprinkle on hundreds of migraine wellness blogs. But no, Charles insisted. Lesions in the thalamus, he pointed out, are known to produce pain—including headache. And other studies have shown that the periaqueductal gray—a critical region in the midbrain involved in modulating pain and orchestrating the body’s response to threats, among other functions—might well generate pain when disturbed. By way of proof, he sent me a paper4 from 1987, which reported on fifteen previously headache-free patients who had electrodes implanted in the periaqueductal gray between 1977 and 1982. All of them developed excruciating head pain that resembled migraine—either immediately or within a few days of implantation. “These data suggest that perturbation of brain may generate head pain,” the authors concluded.

(The phrase “perturbation of brain” remains my greatest reward in researching this book.)

Charles pointed to other disturbing evidence: “Even primates—and this is horrible that people would even do this. These are the pain guys doing this,” he said with a nervous chuckle. “If they stimulate in the periaqueductal gray, the primates go nuts, they go absolutely—like screaming in pain.” I did not investigate this line of research further.

“This notion that the brain is painless is part of the whole thing that came around in the thirties and forties, that it was only the meninges that were capable of generating pain, and the brain parenchyma couldn’t,” Charles said. (The parenchyma constitutes the functional meat of the brain, the stuff that does the thinking and signal processing, the gray and white matter. It excludes support structures like blood vessels.) “But that has really been challenged by a significant amount of data.” In a follow-up email, I sent him a link to a 2022 educational video5 featuring Rebecca Price, PhD, a program manager for the National Institute of Neurological Disorders and Stroke—the main NIH division responsible for reviewing grant applications in neuroscience. It was called Truth or Myth: The Brain Does Not Feel Pain. Price, whose graduate research focused on pain perception in humans, cleared up the matter succinctly: “This is actually true,” she said, explaining that the pain of a headache is coming from nociceptive tissues surrounding the brain, not from the brain itself.

Is this wrong? I asked Charles in an email message.

“Yes, this is wrong,” he wrote back, “and annoyingly patronizing.”

You can see my predicament, but let’s agree unequivocally on these few convictions: There’s little question—or maybe a few questions, sure, but also a lot of assertions—that the trigeminal nerve is a central player in the pain-signaling pathway of migraine, cluster, or similar headache disorders. (Or maybe not? One 2013 study6 found that stimulation of the first cervical nerve root in the neck produced pain around the eye, prompting the authors to speculate that neck nerves might well be as important, or perhaps even more so, than the trigeminal nerve.) And it seems highly likely—or so I believe most of the time—that it is the meninges, specifically the dura mater, where the nociceptive event is unfolding. Probably?

*  *  *

The International Association for the Study of Pain disseminates definitions, classifications, consensus statements, and other guidelines that help shape the understanding and treatment of pain. In 2020, the group revised its definition of “pain” for the first time in more than forty years, describing it as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”

The original definition, which described pain as an “unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage,” was often criticized for placing undue emphasis on tissue injury alone, as well as on an individual’s ability to describe their pain—a highly subjective and, as Virginia Woolf would have argued, impossible task.

This change came on the heels of another update, issued in 2017, that established a third silo for categorizing human pain, distinct from the two that had prevailed prior to that date. Before then, we had nociceptive and neuropathic pain. The former describes pain arising from actual or threatened damage to nonneural tissue, signaled by the activation of nociceptors. It’s what protected you when you settled your hand onto that hot stove while watching that cat video. Neuropathic pain, on the other hand, is “caused by a lesion or disease of the somatosensory nervous system”—that is to say, damage or disorder in the nerves themselves. Many disorders are associated with neuropathic pain, with one prominent example being diabetes, which can cause direct damage to nerves and induce pain without the need for those pain-monitoring nociceptors.

These two categories captured many of the forms of pain we humans experience, but they elided several painful conditions that had no apparent connection to tissue damage, real or threatened, and no evidence of disease or lesion in the nerves. That prompted the adoption of the third category: nociplastic pain. This type of pain describes a glitch in nociceptive processing, wherein the central nervous system itself becomes the source of pain, somehow bungling the perception or handling of nociceptive signals in the absence of injury, and where no damage to the somatosensory system is present. Fibromyalgia, a condition characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory, and mood issues is now thought to be a nociplastic disorder, for example.

The concept of nociplastic pain seems to have evolved out of a line of thinking that emerged in the late 1980s—spearheaded by Clifford J. Woolf, a professor of neurology and neurobiology at Harvard Medical School and director of the F. M. Kirby Neurobiology Center at Boston Children’s Hospital. At its heart, Woolf’s research established the idea of central sensitization, a condition of the central nervous system characterized by an increased, even hyperactive response to normal inputs, resulting in the amplification of pain signals and often contributing to chronic pain states. You might think of it as your brain stuck in a perpetual state of vigilance: highly reactive, with a reduced threshold for sensing pain, and a reduced ability to send inhibitory signals that, in the absence of threat, would calm things down. The effect in patients is such that even a light touch can be perceived as painful. This concept revolutionized the understanding of pain and the many ways the body is capable of manifesting unpleasant sensations. It also laid the groundwork for understanding how the body’s pain-processing mechanisms can become altered in such a way that pain persists, or is exaggerated, even in the absence of clear physical causes. Central sensitization is one of many underlying mechanisms of nociplastic pain, though it can be associated with nociceptive pain too.

While the idea of central sensitization is generally associated with chronic pain conditions, there are clear signs that migraine attacks can involve an episodic or transient form of central nervous system sensitization. Many migraine patients report symptoms of allodynia, for example, where even a light touch or temperature change becomes painful during an attack. Light and sound sensitivity, detecting scents that aren’t present, and other common migraine symptoms also hint at an overactive central nervous system. Once the attack subsides, this heightened sensitivity also diminishes, and the nervous system returns to its baseline state.

Recent research7 also suggests that chronic migraine—or at least some aspects of it—may be classified as nociplastic pain. A 2015 systematic review, for example, compared pressure pain thresholds in healthy individuals, tension-type headache patients, and migraine sufferers, identifying several nociplastic pain characteristics. And a July 2023 paper,8 co-authored by researchers in the United States and France, argued that “preclinical research on migraine mechanisms should be further developed considering the crucial role of central, nociplastic states in the triggering and maintenance of primary headaches.” In other words, scientists ought to be paying more attention to the brain if they want to find the origin of primary headache.

At the same time, establishing the precise and distinct roles of the central nervous system and key anatomy outside of it in primary headache disorders is a quest that, if pursued, will take you down some of the most fractious corridors of headache science today. What aspects of these attacks are governed by cerebral processes, and which are functions of other structures? Is one side or the other a necessary component, or merely a sufficient one to kick off or maintain an attack? Is one a driver, and the other a participant? Does it all begin in the brain, or somewhere else?

Put these questions to enough scientists, and you’ll quickly learn that the true nature of these headaches is still something of a shadow—wholly unseeable on its own, except as implied by other things.

*  *  *

An old Buddhist parable9 tells the story of a group of blind men and an elephant. Variations on the story have been told and retold for centuries and across cultures, some involving just six blind men, others involving many more. But the central narrative always has the sightless men being led, typically at the king’s behest, to a courtyard where they meet an elephant—a creature they’d heard much about, but never encountered. As they each lay hands on the beast, they begin to make assertions about the essence of an elephant. Those who touched the elephant’s belly concluded that the animal is like a wall, or a granary, depending on which version of the tale you’re reading. Another, grasping a tusk, decides that an elephant is like a spear (or a plowshare in older texts). The animal’s great ears convince some of the inquisitors that an elephant must be like a fan, or a winnowing basket, while those encountering the animal’s mighty legs and feet decide that it is like a pillar, or a tree. The trunk, of course, implies to its tactile inquisitors that an elephant is long and flexible, as a plow pole, or a snake.

In some iterations of the tale, the men compare notes and, after becoming suspicious of one another’s descriptions of the elephant, the gloves come off. Others have the men eventually hearing each other out—or learning upon a full description from a sighted visitor that each of them had only partial information. The nineteenth-century American poet10 John Godfrey Saxe put the parable to rhyme in 1873. Its last verse:

And so these men of Indostan

Disputed loud and long,

Each in his own opinion

Exceeding stiff and strong.

Though each was partly in the right,

They all were in the wrong!

I couldn’t help but think of this allegory while watching an online debate mounted by the Danish Headache Center and the University of Copenhagen in the spring of 2022. The proposition was simple:11 “Migraine attacks are of peripheral origin”—which is to say, the key processes for initiating (and by extension, treating) a migraine attack lay in the blood vessels and other anatomy outside the brain and central nervous system. Arguing in favor was Thien P. Do, the researcher who had argued that “migraine is not a CGRP disease.” Do exudes a confidence that belies his youth—perhaps a function of working in the orbit of Jes Olesen and Messoud Ashina, who believe strongly that migraine and other primary headaches are best understood as diseases that are triggered, and effectively treated, outside the brain. This conviction, according to Do, rests on three pillars of evidence: First, we have known for decades—from the craniotomy studies of Wolff and Ray in the 1940s, to the seven-year French exercise in poking and prodding the meningeal layers—that only very specific structures in the head are nociceptive. These sites of pain, Do argues, are all outside the brain.

Secondly, Do and his colleagues remain convinced that vasodilation is a key component of migraine pathophysiology—a view that other scientists, including Andrew Charles and Peter Goadsby at UCLA, frequently dispute. Too much research, they say, has suggested that while vasoactivity can be associated with a migraine attack, it’s not a necessary condition for generating migraine pain. From Do’s perspective, however, the strong association is all that matters. Vasodilation in the pain-sensitive structures of the meninges has historically been thought to accompany migraine, Do would argue, and most of the substances we know of that are helpful in stopping attacks have vasoconstrictive properties. In this light, whether vasodilation is a necessary or sufficient condition for a headache is immaterial. The strong association implies that cranial vasculature should continue to command scientific and therapeutic interest—and it too resides outside the brain.

None of this, of course, speaks to what kicks the whole process off. What turns the headache machinery on in the first place, and should we be looking for that switch inside the brain? Do and like-minded researchers say no, for a simple reason: “We can actually provoke attacks by purely peripheral mechanisms,” he argued during the videotaped debate—part of the inaugural International Conference on Advances in Migraine Sciences, held at the University of Copenhagen in March 2022. The affair skews heavily European, and the issues discussed frequently underscored the competitive appetites of the Danish group, who are eager to push past CGRP and uncover more consequential targets—outside the brain.

Do pointed to CGRP’s ability to provoke an attack as a supporting line of evidence. In experimental conditions, the neuropeptide is delivered intravenously, and the molecules are too big to pass through the blood-brain barrier. Whatever their mechanism for provoking an attack, Do suggested, it’s obviously happening outside the brain—and the same can be said, he added, of the remedies we’ve identified thus far that provide at least some relief: virtually all of them are thought to constrict blood vessels in the meninges. “So again: peripheral anatomy, peripheral triggers, peripheral treatments,” Do insisted. “So, if you ask me where migraine attacks originate from, it’s not in there,” he declared, pointing to the giant screen behind him, which was showing a purple-hued picture of a brain. “It’s outside of the brain.”

At the outset of the debate, the audience was polled. Before any presentations were made, sentiment among the crowd—mostly comprised of other neuroscience researchers and medical students—seemed to heavily support the leading proposition, with 65 percent agreeing that migraine is not a brain disorder, versus 35 percent who disagreed. It was against this popular conviction that another DHC researcher, Anders Hougaard, mounted his contrary case.

“I like my opponent and colleague here very much, and you know I want to be gentle on him,” Hougaard began. “But I also have to present you with some really hard and cold facts. And I have to remind you that the question here is, what is the origin of migraine attacks? When do migraine attacks begin? It’s not where does the pain comes from.”

Hougaard argued that focusing on the pain phase of a migraine misses the forest for the trees. Yes, it’s the symptom that most troubles migraine patients, but the pain phase comes on the heels of a well-documented succession of symptoms reaching back hours, or even a day or more, before the migraine begins. These include symptoms like yawning, excessive thirst, unexplained mood changes, heightened sensitivity to sounds and light, and other premonitory symptoms—experienced by as many as two-thirds of patients. At least a third of migraineurs also experience the visual disturbances and other symptoms associated with the aura. Many researchers are convinced that the aura arises as a result of cortical spreading depression—a wave of depolarization that sweeps across the brain’s cortex, followed by a period of inhibition. First discovered by the Brazilian neurophysiologist Aristides Leão in the 1940s, this excitatory wave is akin to the domino effect, where the depolarization of one neuron leads to the subsequent depolarization of neighboring neurons, creating a wave that can travel across the cortex at a pace of two to five millimeters per minute. Following this wave of excitement, the affected neurons enter a period of suppressed activity lasting minutes to hours, which is thought to contribute to the neurological symptoms experienced during a migraine aura. The process has become a cornerstone in understanding the pathophysiology of other neurological conditions, including stroke, epilepsy, and traumatic brain injury. But for researchers like Hougaard, it’s CSD’s association with aura that implicates the brain in migraine.

“These symptoms—where do they originate?” Hougaard asked. “From a blood vessel, or peripheral nerve? No, definitely not. They originate from the brain. And we can discuss whether this is the hypothalamus, or the limbic system, or the basal ganglia. We don’t know for sure, but it’s certainly in the brain.” A rich trove of literature supports this idea, Hougaard argued, including PET scans during induced premonitory phases of migraine in volunteers, which have shown increased activity in the hypothalamus and other brain structures. One study in particular,12 which performed functional MRI imaging on seven volunteers every day for thirty days—an effort to uncover precisely when these premonitory symptoms begin—showed increased hypothalamic activity up to two days before a migraine attack surfaced. Spearheaded by Laura Schulte of University Medical Center in Hamburg, Germany, the study seemed to strongly implicate the brain as the engine of migraine, revving up, reliably and inexplicably, about forty-eight hours before a headache came on.

“All in all, it’s clear that the first event of spontaneous migraine happens in the [central nervous system],” Hougaard said. “This may give rise to premonitory symptoms, to aura symptoms, in some cases leading to no symptoms at all in some patients. And subsequently, the CNS orchestrates an activation of the trigeminovascular system in a very specific way, causing activation of peripheral nociceptors, release of neuropeptides, vasodilation—all of this causes pain. These painful signals, of course, go back to the CNS and it’s perceived as pain.”

In a paper copublished13 by Do and Hougaard after the event, Hougaard went on to emphasize that even the presumption that migraine pain arises from nociception in the meninges—or any other peripheral structure—is wholly unproven even today. “It is possible that the pain of migraine originates from peripheral structures, although there is no firm evidence to support this,” he noted. Vasodilation, too, seems not to be the cause of pain in migraine—given that multiple studies have shown that inducing strong vasodilation of cephalic arteries caused little pain in volunteers. There is also no demonstrated correlation between how much vasodilation is occurring and the degree of an induced headache, and even sumatriptan—that most famous and presumed vasoconstrictor, has been shown to provide pain relief without constriction of the dilated intracerebral arteries.

When the audience was polled after both scientists concluded their remarks, it was clear that Hougaard had the better argument. Seventy-one percent now thought migraine was, in its most fundamental sense, a disorder of the central nervous system—of the brain. It might activate pain-sensitive tissues and signaling structures in the periphery—but it all starts in the brain. Support for Do’s argument that the seat of migraine lay at the periphery had declined to just 29 percent.

A subsequent discussion was held among the panelists and the audience, after which the sentiment became even more lopsided: 76 percent favored the brain.

It’s an interpretation of headache genesis that I personally have found most convincing—even if the underlying dispute often feels hopelessly academic. If it’s possible to silence the pain of a migraine, or, analogously, a cluster attack, by targeting molecules at the periphery, who cares where the whole thing gets started?

At the same time, passions on the matter can run deep. Peter Goadsby—by virtue of his avuncular demeanor and appetite for transfixing conference audiences—is probably most responsible for propagating the notion that the brain is the key player in migraines and clusters. For him, there’s simply no more-elegant explanation, and he points to other symptoms of migraine that are clearly mediated by the brain. Altered vision, aversion to bright lights and sounds, olfactory hallucinations, increased pain sensitivity and decreased pain inhibition—all of these are functions of the central nervous system going awry. From his perspective, there’s also no reason to think that nociception cannot be something that the brain is generating on its own—a hallucination pain—or that is arising from activation of structures in the brain, and not outside.

But even if the pain is somehow coming from the periphery, it doesn’t make sense to Goadsby to blame blood flow in the meninges. “I’m quite satisfied with the idea that the pain could be coming from some nerves that are outside, in the dura, in the blood vessels in the head,” he told me during a visit to the UCLA Goldberg Migraine Program offices. “But it’s not because they’re dilated.” His insistence derives from the fact that there can be no other purpose for the nerves surrounding the blood vessels of the dura except as some sort of warning system, protective of the brain. If they were designed to somehow perceive or respond to the shape and tone of our cranial blood vessels themselves, it would make little evolutionary sense—and we’d likely all go mad. In the same way that the brain ignores all kinds of inputs though the process of sensory adaptation—you don’t generally notice that you’re wearing clothes, for example, even though the nerves in your skin are working as they should—we ought never perceive the blood vessels in the meninges, Goadsby insists, except possibly in an emergency that’s protective of the brain. In a migraine or cluster attack, there is no emergency, but the brain is perceiving one anyway. “This is a warning, a protective system,” he insists. “Now, what if it doesn’t work properly? What’s going to be the consequence of not working properly? Pain.”

Goadsby admits that his is not the mainstream view. “If you had to contrast the views of migraine in the world, that’s the kind of contrasting view. It’s the degree to which you think there is—that it’s necessary for there to be a peripheral initiator or promoter of the process. I don’t think it’s necessary.”

Speaking with Ashina in his office at the Glostrup facility, the neurologist was adamant that searching for answers in the brain would ultimately prove fruitless. He and others across the pond from their U.S. counterparts think Goadsby and his ilk are out on a limb, and that they only get attention for the brain-centric theory because they are loud and talk a good game. “The central nervous system, for me, it’s just a part of this—part of the pain matrix. But it is not, it is not a generator, okay? It’s just there. It is a center receiving the complex inputs. And all these inputs are, let’s say, extrapolated and transferred in different ways. And by having a repetitive condition, you can have some changes, you know, in terms of your limbic system, how it reacts, but that’s it.”

He pointed by way of explanation to the big-molecule CGRP remedies that Goadsby’s own research helped to bring about. “You give a molecule sized like that”—he holds up a fist to indicate its girth—“you know it doesn’t cross the blood-brain barrier. And it works in migraine? I mean, how many data do you have for pro central?” He was implying that there’s very little. “And how many data have you against central—you know, as a genesis? It’s unbelievable.”

I asked him why discussion of migraine as a central nervous system disorder carries weight within the profession at all if its evidence base was so wanting. “I mean, it’s just because some people are very well articulated, and they go around and talk about that. And many people, you know, they just fall on their knees, you know—of having somebody who is a real guru in this field and saying—well, I mean, this is becoming a buzzword—the hypothalamus, the premonitory symptoms, the prodromes. But basically, when you look at the hardcore science, we are not yet there.”

It was clear to me he was talking about Goadsby, and those sentiments were echoed with less circumspection by Jes Olesen, who shared the lucrative Brain Prize in neuroscience with the Australian researcher. Olesen was withering in his contempt for the idea that the brain ought to be blamed for migraines—and our conversation illuminated a grand divide between the Danish researchers and their American counterparts. Olesen described the latter as mostly dim acolytes of a brash Aussie with a bad idea. I had to do very little coaxing:

“There’s been a movement of about, let’s say, for the last twenty years, spearheaded by Peter Goadsby,” Olesen began. “You may have talked to him. He is a very charismatic person, extremely charismatic. I like him very much. We’re good friends, actually. But we also disagree on a lot.”

What do you disagree on? I asked.

“Well, I disagree on his very one-eyed view of things. And that’s—on the other hand, that’s his strength, because he makes things so simple. And he’s so convincing that he gets a lot of followers. And especially in the U.S., he has been able to more or less dominate the thinking. And it’s partly because there’s a lot of what you can call ‘lesser minds’ in the field of headache. It’s true that there’s a lot of people who are not really good scientists who are in the field, or in the field or headache, and they’re just doing drug trials and they write case reports and this sort of thing, but they’re not doing real science. And that’s the great majority. And those kinds of people who can convince—if you have a charismatic personality, and if you have a very simplistic way of explaining things, and I think that’s what has happened, you know, that Peter had such enormous influence. Because it was just so simple what he was telling people.”

Is it wrong?

“It’s clearly wrong. It’s been clear from very beginning that he was wrong.”

About?

“About migraine and the brain. It’s not all in the brain.”

So, you’re talking about . . .

“The best reason why he’s been wrong all the time is that we can induce migraine attacks with peptide signaling molecules—you obviously heard about the CGRP, you’re deep into that by now I suppose. So, the whole thing was partly based at least on our demonstration that we could induce a migraine attack when we gave it as an infusion to migraine patients. But CGRP does not penetrate the blood-brain barrier. So, we already knew twenty-five years ago that we could induce a migraine attack outside of the blood-brain barrier.”

I found myself nodding. It made so much sense. If you can generate a migraine from outside the brain, and you can treat it with molecules that never get into the brain, how could it possibly be a disease of the brain? And yet, as I contemplated the dissonance of awarding a million-dollar Brain Prize to scientists who completely disagree over the role of the brain in the disorder they study, I remained unable to decide which side had the better argument. Part of the problem is that while we have been successful for decades at identifying substances that can artificially provoke a migraine or a cluster attack in an experiment, we can’t really accept this as evidence that the disorder is strictly generated in the periphery. Hougaard made this case during the 2022 discussion at the University of Copenhagen, suggesting that these chemical triggers may be simply setting in motion something that, in a spontaneous attack, the brain would have initiated. “I truly believe that these induce genuine migraine attacks that share the pathophysiology of spontaneous migraines,” Hougaard said, “but they may mimic what the CNS does in the spontaneous attacks. So, just like cortical spreading depression may lead to trigeminovascular activation and CGRP release, if you give the CGRP directly, you bypass this initial mechanism and work downstream, so to say. You go directly to the attack.” He also mentioned that in patients who typically experience aura as part of their migraine attacks, artificially inducing a headache using CGRP produces the pain but not the aura. “It seems that using these mechanisms bypasses the initial spontaneous mechanisms,” Hougaard argued.

I found myself nodding at this too. The brain, after all, must be the key culprit in any scenario: if Goadsby and his like-minded colleagues are correct, it’s the thing that spins up a headache attack in the first place. And if Ashina and Olesen are right, the brain must still be playing a role by errantly responding to an exogenous stimulus, or at least propelling the symptoms of the attack along by failing to downregulate the pain in the absence of any threat. If it were merely responding normally to dilated blood vessels in the meninges, then that response should be normal for most everyone, and it’s clear that is not the case.

In a 2012 perspective paper14 published in the journal Cephalalgia, Charles argued strongly that headache is not a vascular disease—and he pointed to evidence that Olesen himself had generated. Olesen’s study,15 published in the Annals of Neurology in 1990, seemed to show that the pain phase of a migraine attack could begin during a period of reduced blood flow. Further, while the pain might continue as the blood flow increased, the accompanying vascular dilation sometimes persisted even after the pain of an attack was gone. Other studies16 have shown vasodilation in response to common headache triggers like nitroglycerin, but in some cases the pain didn’t come on until after the blood vessels had returned to baseline tone. Olesen and Ashina themselves17 co-authored a study in 2008 showing that another important neuropeptide, called vasoactive intestinal peptide, or VIP, could cause marked dilation in the cranial arteries in twelve volunteers with migraine. And yet, none of them developed a headache. “Put simply,” Charles wrote, “there is no correlation between blood flow changes and headache.”

I repeatedly asked Charles in our conversations how it could be that throbbing blood vessels in the head maintained such purchase on headache science for so long, if in fact it was not true. So many of the experimental substances that we use to induce headaches are thought of as vasodilators. And drugs that have any sort of efficacy against migraine and cluster headache symptoms are thought to be vasoconstrictors. How could there not be a connection? The problem, he said, is that no one has ever convincingly shown that blood vessel tone has any real association with migraine. He argued as much in a 2013 commentary18 for The Lancet Neurology, which summarized extensive imaging work done by the Demark group19 in patients experiencing spontaneous—that is, not artificially induced—migraine attacks. They found no association between migraine pain and blood vessel tone in any of the extra- and intracranial structures observed. Constriction and dilation just didn’t seem to matter.

It’s also worth noting, Charles, told me, that CGRP is a multifaceted neuropeptide. “You have to keep in mind that there’s CGRP receptors all over the brain, in the cerebellum, in the vestibular system,” he told me. While it’s certainly true that CGRP has a role in managing blood vessel tone, it can bind to receptors that do all kinds of things that we don’t fully understand. “It’s kind of just trying to get to what is the fundamental mechanism, rather than sort of an epiphenomenon. And that’s really how I view the vascular changes, is that they may be a reflection of what’s going on at a basic level, but they’re not the cause—the vasculature isn’t the causative element.”

That matters, he said, because it dictates which systems and processes we should be looking at when trying to find that causative element. “Regardless of what theory you believe in, the ultimate kind of practical consequence is thinking about what you’re going to target to try and most effectively get somebody better.”

It’s clear to me that both sides in this debate are interested in doing that—though my nonexpert view tends toward the brain. I couldn’t possibly say how; I know far less about all this than these experts. Maybe it’s autonomously generating a pain sensation in response to a nociceptive signal that was never delivered, firing up communication pathways designed for acute, life-threatening events in the tissues surrounding the brain, even though everything is really just fine. Or maybe there is some event unfolding in the dura mater—not necessarily vasodilation, per se, but something—that nudges surrounding nociceptive fibers to send a signal to the brain, and then the brain overreacts. A 2016 paper20 out of the University of Texas at Dallas seemed to get at this possibility, arguing that the chemical conversation between cranial blood vessels and surrounding neurons is not exclusively about vascular tone—and that’s true. “Blood vessels are more than just a conduit for blood that can contract and dilate; they are comprised of a variety of cell types that generate numerous molecules and mediators important for intra- and intercellular processes,” the authors noted. “Endothelial cells mediate immune cell recruitment and downstream inflammatory signaling pathways, which may be critical to the pathophysiology of migraine. They also express a variety of channels and receptors . . . thought to be involved in the detection of noxious stimuli, and along with neurons, endothelial cells may potentiate the responses to noxious stimuli. Any of these processes may be critical for the development of a migraine attack regardless of whether vasodilation is present.”

The pathophysiology of cluster headache is probably less contentious, but only by virtue of its comparative rarity. It also has the benefit of at least one seemingly clear link to a specific structure in the central nervous system: the hypothalamus. The neural structure’s pivotal role in maintaining the body’s circadian rhythms and cluster headaches’ close association with time and season are hard to ignore. Another curious bit of evidence implicating the brain is the trigeminovascular system itself. Its intimate role in primary headache has been presumed for decades, given its chief function of delivering pain, touch, temperature, and other sensory information from the upper-front area of the face and head to the brain.

And yet, in 2002,21 Goadsby and Manjit Matharu—both neurologists with University College London at the time—reported on a fifty-nine-year-old man with refractory cluster headache on the left side of his head. The patient went on to have the left trigeminal sensory root severed in a surgical attempt to bring him some relief. Remarkably, it did not work. His attacks didn’t seem to last quite as long, but they kept coming with the same frequency—several times a day—and the pain remained excruciating. “With complete section of the left trigeminal sensory root,” the authors wrote, “the brain would perceive neither vasodilatation nor a peripheral neural inflammatory process.”

If the brain wasn’t receiving signals from cranial blood vessels or any other anatomy up there—indeed, it could not receive those signals because the connection had been cut—where was the pain coming from?

*  *  *

Anja Sofie Petersen is one of a very small number of researchers in the world whose primary research focus is cluster headache. During the same 2022 conference in Copenhagen that debated the central versus peripheral nature of migraine, Petersen took up the defense of another motion: migraine and cluster headache are two distinct disorders. She likened them22 to tigers and lions. “Both have a mouth and nose, and they look fairly similar,” she argued. “They have an ear, which is also fairly similar. They have yellow, frightening eyes. But when you zoom out, you see that one is a lion and one is a tiger. So, they look alike, but they are clearly different animals. They live on different continents, they have different lifestyles, one lives in packs one lives alone. So, similarities are ok, but they are still different.”

The clinical presentation of the two disorders are wildly different, Petersen argued. One is highly prevalent within the population, for example, while the other is incredibly rare. The sex distributions are mirror images of each other, with migraine affecting women more than men by roughly a three-to-one ratio; cluster favors men by the same degree. Other differences include the very distinct temporal patterns, and what patients do when they are in an attack. Migraine patients lie still in a dark, quiet room. Cluster patients pace and bang their heads. The triptans are useful for both, but they seem to respond differently to most interventions, whether traditional drugs or the new monoclonal antibodies—and the substances we use to experimentally provoke an attack seem to do so at differing rates between the two disorders. Genomic studies have been much more successful in identifying chromosomal loci that appear associated with migraine than they have for cluster, and different brain regions seems to light up during cluster vs. migraine attacks. They do seem to share the obvious involvement of the trigeminovascular system, the network of nerve fibers that connects the trigeminal ganglion to blood vessels in the brain and surrounding tissues, although the precise signaling molecules and pathways seem to vary. And for both types of headaches, far too little is known about the underlying pathophysiology to be able to link them as a common disorder. Petersen concluded her arguments with a Venn diagram, listing the many differences in each circle, with one lonely characteristic occupying the space where they overlapped: headache.

Arguing against the motion was Kuan-Po Peng, a clinical scientist at University Medical Center Hamburg-Eppendorf in Germany. From Peng’s perspective, the two disorders ought not be thought of as residents of distinct circles overlapping in a Venn diagram, but as occupants of a spectrum. Cluster symptoms tend to be clearly distinguishable from migraine, of course, but when you zoom in on individual patients, there is some variation. A small but nonzero number of cluster patients, Peng argued, report symptoms that are evocative of migraines—even experiencing something like an aura. Some migraineurs experience autonomic symptoms like runny noses and drooping eyelids that are characteristic of cluster headaches. Mapping the clinical choreography of attacks—the subtle non-nociceptive cues, the attack, the comedown—often looks similar, such that an individual cluster attack might be viewed as a highly accelerated migraine attack; a cascade of symptoms that in one disorder unfolds over days, and in the other is compressed into mere hours. There is a distinction in cluster headaches that something in the brain clearly turns the disorder off, indistinguishable from a light switch, such that the patient is effectively cured until the brain flips that switch back on months, or even years, later. To Peng, that only means that a brain switch likely exists in both diseases; cluster is just telling us more clearly that a switch is there.

These are not new arguments. A paper23 co-authored in 2007 by the University of Vermont’s Robert Shapiro also took note of the symptomatic outlier patients who seem to present with blends of both types of headache—reflections, the authors suggested, of some protean disorder with shared pathogenic mechanisms that were still invisible to us. They pointed to a statement made by an earlier researcher, John R. Graham—a colleague of Harold Wolff and a giant in the field who speculated similarly: “I should like to suggest for your consideration that the difference between cluster headache and classical and common migraine may be matters of timing and intensity,” Graham said. The similarities were numerous, he thought, but the areas of difference—which once seemed black-and-white—“all begin to fade a little into gray, as more transitional forms in each group are seen.”

In the debate, Peng tried to turn Petersen’s lion-and-tiger analogy against her, pointing out that that the two animals share 98 percent of their DNA. A tiger and a mosquito are distinct, he said, but a lion and a tiger are both cats. The small crowd attending the debate didn’t buy this, however, and they sided conclusively with Petersen. These are not the same disease.

*  *  *

I had met with Petersen over coffee at the Danish Headache Center a year earlier. We were joined by Agneta Snoer, then a departmental researcher at the clinic who has since joined the Danish pharmaceutical company Lundbeck as a senior medical specialist, and Rigmor Højland Jensen, who cofounded the DHC in 2001 and is now the director of the facility. Jensen is a veteran headache researcher, but Snoer and Petersen are rising in the field, and I couldn’t help but notice that while the sex distribution of migraine and cluster leaned heavily toward women in the former and men in the latter, the sex breakdown among researchers studying these disorders at the DHC seemed the exact opposite: The women had their lenses trained on clusters, while the men dominated migraine science. “I hadn’t ever thought about it until just now. Maybe it’s equipment-based,” Petersen quipped.

Whatever it was, I was compelled to ask, as I often do, why they got into headache science in the first place—and clusters in particular. For Snoer it was a happy accident: Jensen had come into some grant funding and was in need of a PhD student, and Snoer was finishing up a neurology residency and was looking for a “hardcore” problem to sink her teeth into. For Petersen, it was watching her father struggle for years with cluster headaches.

I also asked them about the brain, the periphery, and the rancorous divisions that seem to animate the European perspective on headache relative to the American view. “I think you should remember that we are researchers from the Danish center, and we are, of course, influenced by the professors here,” Petersen said with a wry smile. “The notion here has been that it’s a combined disorder, you can’t have a migraine without the vasculature—you can’t have it. It’s not only a central disorder, it’s a combination—a bad combination of the peripheral and the central and the communication is off. That would be our notion here.” That’s not to say that the old way of thinking about these headaches, as vascular disorders, retains any currency.

“That would completely ignore the cyclic pattern of cluster headache,” Snoer said. “It would ignore all the pre-attack symptoms that you see.”

Petersen agreed: “Also, the prodromal phase of migraine, and the aura phase of migraine, is of course, central.”

Snoer: “You can’t have one without the other.”

Petersen: “But a lot of the big ones in the wide world are not fond of peripheral involvement.”

She was talking about the church of Goadsby again. He seemed to lurk in every room of the DHC, occupying just a bit of headspace in everyone, lingering in the subtext of intermittent eye rolls and winks—if not emerging outright in polite but pointed observations on the wrongness of his views. It wasn’t bitterness, so to speak, but more of an ambient, animating force—a catalyst invigorating their belief in an alternative or more anatomically diverse explanation, as well as their commitment to finding therapeutic targets outside the brain. Even in the United States, where the brain’s starring role is more widely accepted, fault lines can be drawn between West Coast researchers like Goadsby and Andrew Charles, who favor the primacy of the brain, and East Coast giants like Rami Burstein, a Harvard neuroscientist with a global reputation in the field who has joined24 his European counterparts in emphasizing the role of the periphery in generating pain. (Goadsby does seem special in his ability to both inspire and irk fellow academics. “I don’t trust Goadsby as far as I can throw him,” one well-established American researcher told me.)

Does the bickering matter? Most of it is good-natured, after all, and competing hypotheses are the engine of science itself, particularly when so many essential questions remain entirely unanswered—perhaps even unanswerable in our technological moment. We’d need better instruments with far higher resolutions and sensitivities, futuristic nano-transmitters and AI-imaging machines, to be able to trace a stepwise molecular process that, for all the world and as far as we’re able to tell, just seems to turn itself on for no particular reason. We know neither where that point of ignition exists, nor why the few medications we’ve developed to mute the symptoms seem to work for some patients. It’s all just highly educated guessing—and almost everyone would concede that structures both inside and outside the brain are being recruited in the creation of migraine or cluster attacks. It’s just not clear which structures matter more than others.

At the same time, the competing schools of thought vie for primacy because money, reputations, and research trajectories are at stake, and grand convictions held too tightly can sometimes elide incremental advances that don’t quite fit the narrative. Cen Xu, the Amgen researcher whose team was first to break the code and deliver a commercial CGRP inhibitor, crystallized this reality. For the better part of two decades, her team was attempting to take the foundational insights arising from the work of Moskowitz, Goadsby, Edvinsson, and Olesen, and turn it into something therapeutic that the company could get onto pharmacy shelves. But when early failures with small molecules hit a dead end and her team began toying with large-molecule antibodies instead, she received pushback from familiar quarters. If you’re talking to someone like Peter Goadsby, she said, “they will tell you migraine is a brain disease.” That meant pharmaceutical researchers exploring the use of monoclonal antibodies to deliver CGRP therapies were wasting their time; the molecules would be too big to get into the brain, where they were most likely to be therapeutic. “They would be very strong about saying, ‘Don’t mess with this—you have to get in the brain,’” Xu told me. “So, they would tell me that an antibody is a dead end, based on the biology, right?”

Disagreements over this notion would sometimes become tense at scientific conferences, Xu said, where the brain-centric framing was becoming dominant. She recalled attending a meeting many years ago, where she, Olesen, and Henri Doods, a biologist with the German pharmaceutical company Boehringer Ingelheim, were listening to a panelist arguing that drug companies needed to focus on the brain. (She couldn’t recall the speaker, or at least wouldn’t say; she used the term “opinion leader.”) Doods, who was the project leader chasing Boehringer Ingelheim’s own CGRP molecule, became visibly upset, according to Xu. “We don’t need the CNS!” he exclaimed.

Plenty of evidence from the literature on CGRP action and inhibition in laboratory settings had suggested to Xu this might be true. “This is the skill that you probably only have when you are in the pharmaceutical industry,” she told me. “To understand—to deduct back and say, ‘Wait, but all the action that they have had, the majority is not coming from the CNS.’ Therefore, I’m pretty sure an antibody could work.”

In the end, Xu was right—maybe. A common retort to the success of the monoclonal antibody therapies is that a small amount is getting through the blood-brain barrier, and that this might still be the location where the magic is happening. Others suggest that the locus of action might well be in the hypothalamus, which is a part of the central nervous system, but outside of the blood-brain barrier. Still others argue that our understanding of the blood-brain barrier itself remains primitive, such that no one can really answer these questions. The Danish researchers I spoke to scoffed at these ideas.

Where does that leave us? Xu suggests most researchers are coming around to the idea that all of this anatomy matters. “There is clearly acknowledgment that the CNS is not the only contributor—though you know, they still believe the CNS is playing a very important role, which I agree with, obviously.” She quoted a quip that Goadsby likes to toss around among colleagues: “You can’t feel pain without a brain.” That’s always true, Xu said. But the cause of it all, that trip wire that sets attacks in motion in the first place, remains entirely hidden—as do, really, any unequivocal descriptions of a headache’s complete choreography.

It’s a bit like the field of plate tectonics, where the movement of the earth’s vast, lithospheric slabs and the occurrence of earthquakes are governed by complex processes we cannot fully observe or understand. Incredible advances have been made in describing the structural interactions and dependencies that dictate how, when, and where these massive plates will groan and shift across the semifluid asthenosphere on which they float. We see and understand parts of what’s going on, and different researchers focusing on different aspects of these phenomena make guesses, even assertions, about the true nature of the system. But no one can really say how it all works—not in a way that would provide full explanatory and predictive power. Yes, there are strange tributaries25 of science that suggest some animals can sense an oncoming earthquake—particularly cows, sheep, and dogs. And canine companions26 can purportedly be trained to alert that a migraine is forming, long before it’s even noticed in that animal’s owner. But these strike me as curiosities at best. Accurately predicting the timing, location, and magnitude of an earthquake—or a migraine—is for some future scientific innovation, as is the ultimate prize:27 preventing them from happening at all.

In the spring of 2024, I went back to Andrew Charles of UCLA again so he could help me parse the whole peripheral-central debate, and the dispute over blood vessels and head pain. You spend enough time alone with this stuff and it all starts to feel like fun house mirrors. “People ask, ‘Is it the peripheral or the central nervous system?’ And my answer is, yes,” Charles told me. “And that’s the same thing with the vascular—of course there are vascular changes. Really, the argument is about the extent to which the vascular changes are important, and/or primary, in terms of causing the symptoms, versus just being—I wouldn’t call it an epiphenomenon, but a related or not-causative phenomenon, or associated phenomenon.” I reminded him that in earlier conversations he had referred to vascular changes as epiphenomena. He said he misspoke.

Charles’s main argument is that digging your heels too deeply into one conviction not only reaches beyond the evidence—because in fact, no one really knows the answers to these questions—but it also makes it harder to spot new evidence or ask new questions. “These are all questions where people take this, this sort of binary position, when that’s just overly simplistic,” he said. “And ultimately, if you do take a binary position, that ends up being detrimental to progress, honestly. And I think my point with the vascular hypothesis was that this fixation with the vasculature actually held back progress in the field.”

*  *  *

Back at the DHC, I asked Petersen, Snoer, and Jensen some of my lodestar questions. What hurts when I’m having a cluster attack? There was a very long pause, and Jensen chuckled. Petersen eventually offered the frontal cortex, one of the key parts of the brain where pain is evaluated and modulated. But that’s not what hurts, I insisted. Animated crosstalk about vasculature and the trigeminal nerve and other fractured bits of anatomy ensued, with Jensen concluding that it’s “probably the extracranial, extracerebral vasculature that is pain sensitive.”

What causes all that in the first place, I asked? Another pause.

“We don’t really know why cluster headache is here,” Petersen said. “But maybe it’s a threshold disease.” She was referring to some unknown, genetically determined trigger in a cluster patient’s nervous system, or perhaps elsewhere, that is provoked into disorder by exposure to certain stimuli. If we could figure out a way to raise the reactive threshold, she suggested, maybe the attacks would never develop.

“That’s the genetic part of the story,” Jensen offered. “You’re born with this threshold.” Add in some indeterminate mix of internal and external environmental variables, and the combination leaves some unlucky people with a “threshold” that can be quite high for long periods, but for some unknown reason, that threshold drops. Migraine is often described in similar terms, although this lowered threshold for activating an intense pain-signaling loop—one that warns of dangers that are not there, that describes tissue injury that has not occurred, that cries wolf—is permanent.

“It’s multifactorial,” Jensen said. “There is a genetic component, and there is a threshold, to my mind.” The solution is to discover a drug or a device—maybe one day a gene therapy—that can permanently, or at least sustainedly, raise that threshold. “That’s my dream, and our dream.”

Snoer nodded. “Yeah,” she said. “That would be the best.”

Epilogue
Our Many Forking Paths

It took a long time for me to just come to terms that this is my journey to understand, and as much as my heart and mind just would love for family, friends, co-workers, everyone to understand what this is, like, they’re just not going to understand it, and they don’t have to, and some won’t. Some just will never be able to comprehend it.

—Nicole Christianson, highway worker and cluster patient, Montana

The mouse had a microchip glued to its skull. A USB port reached up from the microchip like a mohawk, and a cable, plugged into the port, extended to the top of the animal’s clear plastic enclosure, a little larger than a standard home terrarium. The cable connected to a small monitor and a microcontroller, which is in turn connected to a central server. Signals and data can travel in both directions, mouse to controller, and controller to mouse. The animal moved about freely, eating, drinking, burrowing in bits of bedding, and amber graphs on the digital monitor populated with waveforms. Identical enclosures with similarly outfitted mice were lined up on steel shelves running the length of the windowless room, the size of a small office. The room was dimmed, but the luminance, along with temperature and humidity, changed slowly over time, to evoke natural cycles of day and night.

I wasn’t taking shrooms, but I wish I had been. I was in the lab at the UCLA Goldberg Migraine program, where Andrew Charles and neurophysiologist Guido Faas are developing what they hope will be a better mouse model for migraine. The chips on the animals’ heads have a variety of sensors that can measure, constantly over weeks and months, temperature, motion, and blood flow, among other things—a Fitbit for lab mice that are also genetically engineered to express special light-responsive proteins in excitatory cells of the cortex. A blue light on the underside of the chip, pressed to a rodent’s thin, translucent skull, can trigger parts of the brain where these proteins, called channelrhodopsins, respond by activating or inhibiting certain neurons. It all sounds very Frankensteinian, but in the context of animal models of disease, it’s a rather promising advance. The entire apparatus, which the group is seeking to patent,1 obviates more invasive study techniques that would usually require anesthetizing the animal, or otherwise restricting its movement—imperfect analogs for studying physiological processes that are ideally viewed in a natural, low-stress state over long periods of time.

While no one can know how stressful it might be for a mouse to spend its days tethered to wires ascending to its sky (or living in the confines of a terrarium, for that matter), I would probably choose this fate over other laboratory options—and the research team is now developing a wireless version of the skullcap, which would provide an even less invasive study experience. The insights the mouse provides are indisputably sci-fi. The scientists, for example, can use the blue light to provoke a cortical spreading depression, or CSD—that wave of neural depolarization that is known to sweep across the brains of many migraine patients as a precursor to pain. During a CSD event, there is a massive release of excitatory neurotransmitters, changes in ion concentrations across neuronal membranes, and subsequent, temporary inhibition of neuronal activity. In the Goldberg lab, researchers can trigger this phenomenon at will, allowing them to study its real-time relationship to various autonomic processes, like changes in temperature and blood volume, as well as reflexive or voluntary movements in the animal itself.

Video cameras trained on each enclosure also run continuously, so that the researchers can observe the mouse’s external behaviors relative to the physiological processes unfolding inside its head. All of that data—the continuous hum of a mouse’s baseline neurovascular activity; changes in that hum triggered by controlled stimuli; and the precisely correlated movements and behaviors of the mouse as it scurries and builds (they have colorful Legos to play with)—all of that is now being used to train an AI system to look for patterns that humans would almost certainly miss. “The stuff that we’re seeing is just mind-blowing,” Charles told me in the spring of 2024. The technology, which is being developed by an embryonic corporate entity they’ve dubbed Neureflect, is already able to detect when a mouse is in REM sleep simply by looking at it. The AI has seen enough, learned enough about what REM looks like in a sleeping mouse, that streaming data from the skull chip’s sensors is no longer needed. It looks at the animal, and it knows. “It’s seeing things that we can’t see with the eye,” Charles says. “We have no idea how it’s actually telling that, because it just looks to us that the mouse is asleep. But we know now that the video, or the AI that is receiving the video, can tell when the mouse is in REM sleep just by looking at it.”

In practical terms, Charles and Faas think the technology they’re building could have a variety of applications. Faas imagines turning Neureflect into a lab for hire, in which the equipment—which is cheap to manufacture and highly mobile—and the personnel are brought into a pharmaceutical company on contract to conduct research into specific experimental drugs. “We now have a system to look at a whole slew of chemicals in a fully functioning model and try to find the chemicals that would be interesting to make into a drug,” he told me. Charles, meanwhile, already sees potential new avenues for insight into cluster headache, which has a powerful sleep-cycle component. He also imagines a future where your laptop camera, or even a wireless fixed camera in your home, could detect the storm of a brewing migraine attack hours before you do, simply by looking at you. It sounded disturbingly Orwellian to me, but Charles noted that the video stream can be instantly tokenized by the computer digesting it—turning it into bits of data that cannot, by its very design, be reconstructed, while still delivering the relevant SOS: an attack is coming. It’s like a migraine-sniffing dog without the shedding and the appetite.

Will such a day ever come? I don’t know. What’s clear is that with or without NIH funding, there is a lot of interesting science happening—at least for now. Lundbeck, the Danish pharmaceutical giant, for example, announced in early 2024 that it was pushing ahead with additional trials—which so far have been promising—of an experimental monoclonal antibody that targets pituitary adenylate cyclase-activating polypeptide, or PACAP. Like CGRP, PACAP is a neuropeptide and signaling molecule that influences a variety of physiological processes, including hormone release, modulation of immune responses, stress response, pain perception, and regulation of circadian rhythms, among other things. It seems to have a clear role in migraine pathogenesis, as my experimental interrogators Lanfranco Pellesi and Messoud Ashina reported in early 2024.2 Charles thinks it will likely have broad implications for cluster headache, too. Amgen and Alder Biopharmaceuticals have been chasing their own PACAP inhibitors.

Vertex Pharmaceuticals, a Boston-based, multinational company investigating nonaddictive alternatives to opioids, is currently trialing a highly selective drug code named VX-548, which targets the NaV1.8 sodium channel—a key player in the transmission of pain signals within the peripheral nervous system. In randomized, double-blind, placebo-controlled studies of postoperative volunteers who had just completed bunion removal or abdominoplasty surgery—also known as a tummy tuck—the drug showed high efficacy in curbing pain over placebo, with few side effects. Drugs targeting the sodium channel have a long history in the off-label treatment of migraine—the anti-epileptic drug topiramate is one—though comparative lack of receptor precision comes with lots of unwanted side effects, including impaired cognitive function, weight gain, sleepiness, and dizziness. (This is the drug dubbed dope-a-max.) But with Vertex announcing plans to seek FDA approval for VX-548 as a postoperative medication in mid-2024, headache researchers are perking up to the possibility that sodium channels might well be worth a closer look.

The field of neuromodulation has been advancing alongside the arrival of CGRP inhibitors, with several devices now on the market. For intractable headache disorders, implanted devices3 that deliver electrical signals directly to certain nerves thought to be involved in migraine attacks have been available for some time, but a crop of noninvasive therapies that work on similar principles—and that can be administered by patients themselves—have been cleared by the FDA for use in the United States. These include devices like Cefaly, a diamond shaped device that is affixed to the forehead to deliver mild electrical stimulation to the supratrochlear and supraorbital branches of the trigeminal nerve, which together enervate the skin of the forehead and upper eyelid, among other facial structures. A similar device, called Relivion, claims to stimulate4 “the six nerve branches of the occipital and trigeminal nerves simultaneously” by wrapping around the entire head, with electrodes on both the front and back.

No one knows precisely why devices like these might be therapeutic for some people, and it was originally thought that they might block pain signals ascending the nervous system toward the brain, although this hasn’t been supported by the research. They also appear to be only about as effective as most everything else in the headache space, in that roughly 50 percent of people find them to be useful about half the time. The upside is that these devices tend to have few side effects, and while the Relivion device requires a prescription, Cefaly is available over the counter. The downside is cost. As of 2024, Relivion has an introductory price of $200, and then $75 a month after that. A Cefaly device goes for $300 to $400 with ongoing charges for fresh electrodes. Neither device is covered by insurance.

That’s true for most neuromodulators on the market. The SAVI Dual device, which is shaped a bit like an airplane pillow, cradles the base of the skull to deliver a pulse of magnetic energy that may interrupt abnormal electrical activity associated with migraine. It can be prescribed only by a physician, is not covered by insurance, and runs for about $350 a month. The gammaCore device looks for all the world to me like a Taser. It’s got two metal contacts on the top that are held against the vagus nerve in the neck, and when activated, it sends “proprietary gentle electrical energy”5 into the nerve to send “messages to the brain” (the company’s words). It is used for cluster and migraine, as well as rarer headache conditions like hemicrania continua and paroxysmal hemicrania. It also requires a prescription, and runs for about $200 a month, though the company has offered some programs to help offset that cost.

Exploration on this front is legion, although it’s hard to tell how useful these devices really are. Many clinicians I spoke with, when asked about their overall efficacy, responded with what I’d characterize as “meh.” Still, device makers seem keenly aware that there is a hunger out there for almost anything that holds promise, and some doctors told me they expect to see the field of neuromodulation—already a $5 billion market—continue to improve and expand. “From my perspective, the headache stuff is kind of in the first generation where these things don’t really work that well,” Mark Burish, who runs the Will Erwin Headache Research Center in Houston, told me. “They do something, but don’t really work that well. I’m hoping that there is a second generation that’s much more effective.” (Burish and colleagues at UTHealth Houston are spearheading some interesting studies6 into circadian aspects of headache disorders using mice, and he is actively recruiting7 for a clinical trial of megadoses of Vitamin D3 as a potential cluster headache preventative—a notion arising8 from headache’s fertile online forums.)

One interesting device that has managed to secure limited insurance coverage is the Nerivio, which is manufactured by Israel-based bio-electronics company Theranica. In early 2024, the company announced that it had cleared evidentiary hurdles with Highmark Inc., a Blue Cross and Blue Shield–affiliated health insurance organization covering about seven million members in Pennsylvania, Delaware, West Virginia, New York, and Ohio. At the moment, that makes it the only neuromodulation device for the treatment of migraine that is expressly covered as part of a commercial health insurance policy in the United States. The Nerivio, a “remote electrical neuromodulation” device, attaches to the upper arm, and purportedly works by stimulating nociceptive nerve fibers, delivering signals to pain-regulating parts of the brain stem. This, in turn, activates pain inhibitory responses that flow down descending nervous pathways, easing the pain of a migraine. The patient can control the device, which requires a prescription, with a smartphone.

Does it work? A 2019 randomized,9 double-blinded, and placebo-controlled trial involving 252 migraine patients showed some reduction in pain in 66 percent of patients within two hours. About 37 percent reported being pain free within that same window. A real-world follow-up analysis,10 which reviewed data collected from the apps of users, also seemed to show decent results.

If psilocybin and other recreational drugs pique your interest, websites like shroomery.org, bluelight.org, and, of course, clusterbusters.org, are gateways to self-reported citizen science. (Advance at your own risk.) And Yale University’s Emmanuelle Schindler alongside Christopher Gottschalk are continuing to probe11 the therapeutic effects of psilocybin in small exploratory trials. Their curiosity here makes some sense. Psychedelics like psilocybin and lysergic acid diethylamide (LSD) are chemically and pharmacologically similar to medications that have long been known to have effects on both migraine and cluster, including dihydroergotamine (DHE) and methysergide. These all bind to and activate 5-HT2A receptors, and some evidence suggests that subpsychedelic doses might be therapeutic. Whether this will lead to anything clinically useful will not be known for years.

Genetic studies are continuing apace,12 and while some specific mutations have been linked to certain rarer forms of migraine, the hunt for meaningful loci in common forms of the disease has turned up a whole raft of players, which is both promising and muddy. Given that there are likely multiple neurobiological pathways that can lead to migraine and cluster pain, the hope is that further genetic insights will help determine which patients are likely to respond to certain therapies, reducing the frequently long gauntlet of trial and error.

Newer forms of injectable botulinum toxin are in the research pipeline, as are histamine receptor modulators,13 oxytocin receptor agonists, and selective blockers of cyclooxygenase-2, or COX-2, which plays a key role in the production of prostaglandins—compounds in the body responsible for inflammation, pain, and fever. The adventurous can also readily explore a carnival of esoteric folk remedies with varying reputations and murky efficacy profiles, from acupuncture and aromatherapy, to daith piercing, which passes a ring or stud through the innermost cartilage fold of the ear, known as the crus of the helix. It’s gaining in popularity,14 and it certainly looks hip, but your therapeutic mileage may vary.

*  *  *

A 1941 short story15 by the Argentine novelist Jorges Luis Borges is often thought to have prefigured, by many decades, modern cosmological theories of quantum physics. The story turns on acts of espionage and murder, but the true narrative catalyst is a mystical novel that branches into countless parallel outcomes—each choice, each gamble of will or happenstance bifurcating new narrative pathways. “I leave to various future times, but not to all, my garden of forking paths,” the fictional author of this strange book writes. This line gave Borges his own story’s title, “The Garden of Forking Paths,” and readers have rhapsodized over its uncanny resemblance to the “many worlds” interpretation of quantum physics, which theorizes that every quantum event branches off into a separate universe for each possible outcome, leading to a vast, possibly infinite, number of parallel universes.

It strikes me as an apt metaphor for so many things in this weird world of headache. Modern scientists lament the fixations of their predecessors—and even some contemporaries—on explanatory theories they think are wrong, because those fixations banish swifter progress to some other, luckier dimension. For those of us bound to this timeline, there have been opportunity costs, they might say. The decision to fund this disorder over another, the accident of a serotonin agonist that worked even though we couldn’t have known why, the tragic leap of a tormented young man from a Boston tower giving rise to a research center in his name—narrative fibers branching off at fixed moments of chance or purpose. Even the kaleidoscope of neuropeptides and pain-signaling pathways inside our brains and outside our brains, converging and diverging in seemingly infinite combinations—they’re an Escheresque labyrinth, where nociceptive messages travel in mysterious, overlapping trajectories to arrive at pain. Headache disorders, like the fractious scientific quest to understand them; our quixotic desire to imbue them with meaning amid cultural indifference; and even our attempts to grapple with who we might have been, had our timeline been different: each one of these is a garden of forking paths.

“The most painful thing to me, aside from my physical pain, is the incredible feeling of loss migraines have brought me,” a young woman named Emma Haggett wrote to me in an email message in late 2020. Haggett reached out after I solicited input from migraine sufferers on a Facebook group devoted to the disorder. We later met on Zoom.

Haggett had an easy smile, with an oval face, careful makeup, and long, straight blond hair reminiscent of The Brady Bunch era. She seemed both shy and confident, describing a middle-class upbringing in suburban Alberta, Canada, that was idyllic for a time, but slowly marked by a creep of recurring head pain that began around puberty and worsened in her later teens—something she thought might have been related to concussions she sustained playing competitive soccer. She wasn’t sure.

As she matriculated to university, she took an interest in human geography, with plans to start a secondary degree in social work after that. But her visions for herself—indeed, her image of herself—was being distorted by the relentless visitation of pain. Few medications seemed to help, leaving visits to the emergency room as a frequent last resort. Her professors seemed mostly unsympathetic, she told me, and her athletic drive—once a source of joy and release—was being neutered by the pain. The percolating social life she tried to cultivate was being stifled by attacks, too, forcing cancelled plans and bouts of depression. She was needled by friends and acquaintances for being lazy, or boring, or lacking a personality—all the while knowing that the pain, and the imperfect medications, were numbing access to who she really was.

Her story isn’t unusual. It’s a bit like mine, but not perfectly. She might resemble you or someone you know. And yes, it’s impossible to escape the bind of culture and context, which necessarily, or at least inevitably, locates her ordeal in the shadow of bigger, more important things—real problems.

“I know I am smart, but my schoolwork does not mirror it. I know I am social, a good daughter, a good friend, but I worry my life does not mirror this either,” Haggett wrote in that email. “I guess the loss I feel is the loss of what I could have been, or could be, or could do, without migraines.”

*  *  *

In late 2024, I set about reconnecting with the many headache patients I’d spoken to for this book. In some cases, two or more years had passed, and I wanted to know how they were doing. Kevin Gilmore, the retired air traffic controller, told me he had enjoyed his longest reprieve from cluster attacks since he was a teenager, only to see them return in 2023. He believes nightly cannabis gummies have played a role in his respite, and he has begun treating individual clusters with a psilocybin regimen—2.8 grams of dried mushroom taken three times, five days apart. “I’m not keen on the high, but it was effective,” he told me.

Rachel Weinberg, who suffered a cluster attack while transporting those (possibly) pregnant turtles, has found an oxygen supplier near Philadelphia who rents her a tank and regulator at a monthly rate of $25 per month. It’s an effective abortive for many patients—though insurance coverage remains uneven16 despite a decade or more of advocates lobbying federal regulators to reconsider its status as a Medicare-approved treatment. Weinberg covers the cost herself. “I keep it at my house even when I’m not in cycle,” she said, “because I don’t want to be without it when it sneaks up on me.”

Amy Oringel, the New York communication consultant, continues her fractious path, finding astonishing relief for her migraine disorder in a clinical trial for Vyepti, the IV-delivered CGRP blocker, only to see its effectiveness wane after a year. “I am forever amazed at how, as a person of incredible privilege who can see any doctor and receive ‘the best’ care, I’m still cast aside and/or not given the appropriate attention as a person with a chronic illness,” she admitted to me in an email—adding summarily, “It still sucks.”

Karen Mann, the Virginia farmer and pastor who struggled to communicate with a dismissive doctor, continues to grapple with cluster headache. She experiments with a high-fat, low-carbohydrate ketogenic diet during bouts, which she believes helps. Emgality injections—the same CGRP inhibitor that I have used with some success—worked for a time, but then stopped altogether. She has since switched to a competing brand, Ajovy, which she says is not perfect but is better than nothing. In contrast, Emily Walding, the British music label executive, told me that Ajovy has provided “life-changing relief” for her since she began taking it in April 2024.

In a recent update, Emma Haggett, the Alberta student searching for herself amid the maze of migraine, told me that after extensive negotiation with her insurers, she managed to acquire approval for Ajovy, too, which gave her more than a year of miraculous relief. But by mid-2024, that miracle had begun to evaporate, and the migraine attacks returned. “I recently left my job of three years working with chronically unhoused individuals to pursue further education,” she shared. “My new schedule is quite flexible, and definitely less stressful, which has been beneficial in establishing a routine to manage my migraines and avoid triggers.” She’s back to Botox injections, and hoping to try the new class of oral CGRP medications called gepants.

It’s a mixed bag, in other words—though these patients, like me, are the lucky ones by any measure. While data are somewhat limited, there is plenty of evidence17 to suggest that migraine and other headache disorders do not discriminate by race, nationality, or income. And yet the same disparities and barriers that govern health care access generally are clearly at play among headache sufferers too. The incidence of migraine across racial groups is roughly equivalent in the United States, for example, and yet African American and Hispanic patients are anywhere from 25 to 50 percent less likely to receive18 a migraine diagnosis compared to their white counterparts. Along those same lines, most of the research into headache disorders, along with modern therapies that are now arising from that research, remains siloed19 in the affluent world. And wherever headache disorders exist, geography is still destiny. Expertise and scientific interest in headache research and treatment, such that it exists at all, remains clustered in a few major population areas globally, leaving large numbers of patients outside the reach, sometimes by hundreds or even thousands of miles, of anyone who has ever studied headache disorders. The fact also remains that among aspirant doctors interested in a neurology specialty, most still gravitate away from, or are dissuaded from considering, headache medicine. Based on current population levels, the incidence of migraine, and patterns of health care use, a recent study20 estimated that nearly four thousand headache medicine specialists are needed to provide basic care for those most affected by migraine in the United States. To date,21 there are still fewer than seven hundred such specialists.

I asked Andrew Charles whether he thought things might change in any meaningful way as the second Trump administration sets about reforming government science. He said he remained pessimistic about funding for research and clinical care in general, adding that “since headache medicine is always at the bottom of the list, I’m sure it will suffer.” He also pointed22 to Trump’s own history of characterizing the traumatic brain injuries of American soldiers as little more than “headaches.” This, Charles said, “bodes very poorly for [Trump’s] consideration of disabling but nonlethal disorders.”

On the upside, Charles suggests that a new generation of neurology students are taking a less jaundiced view of headache disorders and the science underlying them. In late 2024, he told me that five of the nine second-year neurology residents he supervises at UCLA have expressed an interest in pursuing headache medicine. It’s a small datapoint, and I admit that I had trouble finding evidence of similar trends elsewhere. Still, Charles took heart: “This was unheard of even a few years ago,” he said. “While the young folks are getting on board, there is still remarkable resistance in the old guard of neurology. But generational change is coming.”

Will they be the ones to finally crack the headache code? Maybe so—and if they do, I hope to live long enough to see it—though I’ll feel lucky regardless. Compared to many other primary headache patients, I’m fine—and more so as I age. By the time these words are released into the world, I will have crossed the still plausibly youngish threshold of fifty-five and begun my slide toward the unequivocal oldishness of sixty. That brings with it some inevitable changes in, among other things, hormone levels, brain function, even vascular responsiveness—all of which might play a role in reducing the frequency of cluster attacks in some older patients. Mine do come less often now, and I can enjoy years between cluster periods. My last full bout was during that fateful spring and summer of 2021, when I was eating magic mushrooms and stabbing my stomach with sumatriptan. A single headache attack came on a couple years later, but it was either a fluke, or the expired Emgality injections hushed the neurological storm formation, which might have delivered months of misery, before it could fully take hold. I like to believe it’s the latter, of course: that there’s something out there, something gifted to me, that can halt the Promethean torture that unfolds periodically, unpredictably, inside my head. But I can’t be sure, even as another bout—maybe tomorrow, maybe years from now—remains a dead certainty.

I will still seek out and touch my arsenal of blue injections tonight, I promise you.

*  *  *

In November 2024 I contacted Paula Dumas, a tireless advocate involved in numerous information and advocacy organizations devoted to migraine and other headache disorders. Among them is Migraine Again,23 a web portal that promises to “empower you to suffer less and live more until there’s a cure,” and the annual Migraine World Summit,24 which distills the expertise of the world’s leading headache scientists into accessible interviews and discussions that patients can then use to inform themselves (and often their own doctors).

We chatted casually at first, comparing notes on some of the professional rivalries and colorful characters that populate this remote corner of science and medicine. And given Dumas’s stature in the headache community, I’d thought she might ask what I had gleaned from my own conversations with leading doctors and researchers in this space. Instead, she put me on my heels: “What do you think you learned,” she asked, “that has helped you to understand your own experience with headaches?”

I stumbled to respond cogently, suggesting that a personal reconciliation with my own headache disorder was probably a prerequisite for even considering a book project, rather than something that I needed or sought in undertaking it. I also hadn’t experienced the worst of what cluster headaches can inflict on a person, and of course there are bigger problems, I said.

These were obvious deflections, and I was surprised, even a bit ashamed, to hear myself still uttering—to someone who obviously knew and understood better—the very diminutives that have freighted sufferers, stymied science, and curdled cultural attitudes toward headache for decades. I still felt the urge, it seemed, to apologize for, and to minimize, my own experience with head pain.

Gathering myself, I then offered her an intellectualized version of this realization. I ruminated a bit on the sociology of pain and accumulating evidence that bias is at work here, and that there really might be something unique about the way that debilitating head pain has been studied (or understudied), treated (or undertreated), and interpreted (or dismissed), over the great arc of modern medicine. Perhaps, I suggested, a reckoning was overdue.

It felt right to say these things, but if I’m being sincere, this too was something of an academic smokescreen. It was still an effort at abstraction, a way to distance myself from the gravity of the question—or really, from the gravity of an honest answer, which I never gave.

No, what I’d really meant to say—what I was still unready, even then, to say aloud—was that this fury that has lived inside my head for the last thirty-odd years, and the fury that resides in the skulls of millions of others, is not ordinary. It is larger than its conventions, and weightier than its name.

“It is not just a headache”—is what I meant to say. That is the lesson. And it is a very, very big deal.

Acknowledgments

This book is the result of hundreds of conversations, and none were more important, nor as humbling, as those with fellow headache sufferers and/or their families. Many of them took hours out of their days to speak of their personal struggles, their journeys into dark places as they grappled with debilitating pain, and among those who managed it, their discovery of inner strength and resilience—all shared with a nosy stranger. Some responded to solicitations from me in topical Facebook groups. Others approached me independently after hearing about this project, and still others wrote to me to express a simple note of kinship and good luck. Much as I’d have liked to, I could not include everyone in the preceding narrative, but I’d like to thank all of them here: Lisa Auerbach, Brianna Bartol, Johnny-Ray Bradford, Anne Bruker, Faith Robin Buchin, Stephanie Bull, Imogene Cancellare, Blake Chaffee, Nicole Christianson, Dawn Cooper, Sarah Cribb, Katie Crosby, Ashley Dahl, Kristen Day, Terri Dean-Alexander, John Dennis, Sarah Diers, Megan Dundas, Cindy Eckstein, Pam and Jimmy Erwin, Whitney Fauth, Alicia Friedman, David Gaier, Shira Gertsman, Marla Gibson, Kevin Gilmore, Jessica Granese, Emma Haggett, Marisa Hoffman, Natalie Houghton McNair, Michelle Jean, Dawn Jones-Pickett, Paula Kamen, Emily Kandel, Melissa Keefe, Carla Klowers, Anestis Kozakis, Judy Lebrun, Rebecca Limestall, Christa Lowery, Karen Mann, Joel McCleary, Ann McCulloch, Tracy McCune, Katie O’Rourke, Kathy O’Shea, Amy Oringel, Amy Pakula, Georgia Raines, Patrick Rennich, Vanessa Rice, Amy Rochlin, Jennifer Royer, Jaime Sanders, Emma Schaanning, Stuty Sharma, Cynthia Soucy, Sarah Stetler, Cindy Vos, Emily Walding, Rachel Weinberg, Natali William, Bob Wold, and Jason Yankowitz. I am deeply grateful to all of you for your input and time. You taught me more than you can possibly know.

My initial agent at the Stuart Krichevsky Literary Agency, Ross Harris, hounded me for years for a book idea, until I finally relented; I am grateful for his persistence. My former editor, Alexander Littlefield, was an early and enthusiastic champion of this project, and while we parted ways early in the process, his faith buoyed my own—as did that of his fellow editor at the time, Olivia Bartz. The baton of faith and encouragement was taken up by my new agent, Mackenzie Brady Watson, and HarperCollins/Mariner editor Ivy Givens. I’m indebted to both for helping me to get this across the finish line.

Frankie Schembri, a talented young science journalist, assisted with some early research for this book, and in my navigations around Copenhagen, I’d have frequently been lost without the assistance (and companionship) of Lars Krøldrup. Retired neurologist Jim Wolf, and fact-checker Fatimah Jadwat, eased my worried mind at many stages. And to a particular friend, colleague, and coconspirator over the last ten years: Your advice in all things related to book writing and your limitless enthusiasm for supporting other writers were and are indispensable. Thank you.

I’d like to shout out my extended family, including my brilliant nieces, Charissa Newkirk, a resident physician, and Anna-Corinne McGhee, a director of pharmacy, who helped bridge the gaps in my understanding of the many physiological and biological concepts and processes explored here. My mother (a retired nurse) and my sister Deborah (a genius), helped to copyedit early drafts, as did my scientist wife, Kathy, whose support and patience makes everything possible. My in-laws, Dr. Norman and Anna Marieb, provided a place to stay on a few trips to New Haven for research, but more than that, they offered a quiet moral support that never wavered. And my dear friend, the author Patrick O’Keeffe, did me the favor of never asking why the book was taking so long, offering only his personal refrain: “Keep going.” I’m blessed to have this deep bench of talent, expertise, and kindness in my corner.

I have been lucky enough to have two primary care physicians—Pierre Rouzier at the University of Massachusetts, Amherst, and Blythe Kaufmann Belzer with Providence Medical Group in Missoula, Montana—who took the time to learn about this bizarre thing called cluster headache. I’m indebted to them both—as I am to my generous neighbors, Tyler and Sadie McKay, who stepped up at a moment in the manuscript process that in many ways made all the difference, and my friends Eric Rudnick and Heather Mahr, who offered a medicinal lifeline when all else had failed.

I’m also grateful to the dozens of scientists, doctors, researchers, medical students, therapists, and other professionals who offered time, insight, and access for this book. I am particularly grateful to Dr. Andrew C. Charles of UCLA, who was not only a source but a ready and willing sounding board as I tried to understand the many different strains of scientific disagreement over the precise cause and choreography of primary headache disorders, and why those points of disagreement matter in the long search—arguably too long—for new remedies. Dr. Robert Shapiro of the University of Vermont is every headache patient’s most tireless advocate; he can never be thanked enough. I also owe a special debt of gratitude to Messoud Ashina and the rest of the team at the Danish Headache Center in Copenhagen and its Human Migraine Research Unit. Not only did they allow me to participate in one of their trials, but they made an inordinate amount of time available to me—over several days—to ask questions and plumb some of the most persistent and vexing mysteries in headache science. Finally, the work of Rutgers sociologist Joanna Kempner was a guiding light for me long before the notion of writing a book about headache disorders ever percolated into my consciousness. If you haven’t read her books, put this one down and seek them out.

*  *  *

The nineteenth-century British poet Lord Byron is commonly, perhaps apocryphally, quoted as saying that “the great art of life is sensation, to feel that we exist—even in pain.” The provenance of the quote notwithstanding, I have found it useful in my wanderings. So, to everyone who knew something about my strange and private ordeal; to partners and friends who were close enough over the years to witness the dark parts; and to all those, named and unnamed here, who assisted me in this attempt to forge art (or at least this book) from so many stories of pain—I am forever grateful.

Or as another cluster headache sufferer once put it: “From the bottom of my hypothalamus to the tips of my trigeminal autonomic system, I thank you.”

Further Reading

The following book suggestions are not so much about managing or treating headache disorders. Everyone’s path will vary on that front, and it is beyond the scope of this book—and my own expertise—to be prescriptive. That said, if you’re curious to know more about the history, science, and cultural distillation of headache, I can wholeheartedly recommend the following titles. Some are mentioned elsewhere in these pages—and in many cases, I even interviewed the authors. Others were part of my research, and still others have simply been on my personal reading list over the years. I believe they are all worth your time.

All in My Head: An Epic Quest to Cure an Unrelenting, Totally Unreasonable, and Only Slightly Enlightening Headache (Da Capo, 2005)

Journalist Paula Kamen takes readers on a raucous journey as she seeks relief in everything from surgery and Botox injections to Lithuanian holy water. Along the way, she discovers a new empathy for sufferers of chronic and recurrent pain writ large.

The Body in Pain: The Making and Unmaking of the World (Oxford University Press, 1987)

Arguably one of the most influential explorations of the physical experience of pain and its profound implications on human culture and politics, by American essayist and Harvard professor of literature Elaine Scarry. Here she examines how pain destroys language and reality for the sufferer, and is also manipulated in contexts like torture and war to exert power and affirm political ideologies.

A Brain Wider Than the Sky: A Migraine Diary (Simon and Schuster, 2009)

From Andrew Levy, the Edna Cooper Chair in English and director of the Writer’s Studio at Butler University in Indianapolis, a personal account and cultural history of migraine headache. This deeply literary work is a beautiful, poignant, erudite read, and one that many migraine patients keep on their shelves.

Cluster Headache: Mechanisms and Management (Oxford University Press, 1980)

Now more of a historical curio, the book is still a treasure trove for anyone interested in the evolving medical perceptions of cluster headache, authored by physician-researcher Lee Kudrow—the father, as it happens, of the actress Lisa Kudrow. He is considered a foundational figure in the modern history of headache medicine.

The Headache Godfather: The Story of Dr. Seymour Diamond and How He Revolutionized the Treatment of Headaches (Skyhorse, 2016)

Inarguably a hagiographic take on Diamond’s contributions to headache medicine, self-authored alongside journalist Charlie Morey, the book nonetheless reveals a man who was certain that both headache disorders and headache medicine were woefully lacking serious professional attention.

Headache: Through the Centuries (Oxford University Press, 2012)

An indispensable overview of medical approaches to headache disorders across time, written by Australian migraine researcher Mervyn Eadie. Although the prose can be a bit dense, it is an astute and highly researched history chronicling the disorder from ancient times to the modern day, and unpacking the myriad ways societies have interpreted headaches, from mythological and religious views in antiquity to the scientific paradigms that emerged with the advent of Western medicine.

The History of Pain (Harvard University Press, 1998)

Written by Roselyne Rey, a former research fellow at the Centre National de la Recherche Scientifique in Paris who specializes in the history of medicine, this is another sweeping exploration of how pain has been understood, expressed, and treated across cultures and eras.

Migraine: A History (Johns Hopkins University Press, 2019)

An indispensable and deeply researched account of migraine from the Middle Ages to the modern day, from historian Katherine Foxhall. Aimed primarily at physicians and scholars of the medical humanities, but well within the reach of nonspecialist readers with an interest in the subject of migraine.

Migraine, Revised Edition (University of California Press, 1992)

The late neurologist Oliver Sacks’s comprehensive exploration of the neurological and experiential aspects of migraines, blending clinical case studies with historical, cultural, and scientific insights. A foundational read for anyone interested in late-twentieth-century interpretations of the disorder.

Not Tonight: Migraine and the Politics of Gender and Health (University of Chicago, 2014)

From sociologist Joanna Kempner, a learned but entirely accessible, highly insightful, and quite often witty exploration of migraine headache and its attending science, with a special emphasis on the deeply gendered social values that govern how we talk about (and treat) people in pain.

Pain: A Political History (Johns Hopkins University Press, 2014)

Here, Princeton historian Keith Wailoo delves into the shifting cultural and political landscapes surrounding pain in America, exploring how debates over its treatment have been shaped by broader social values and policy battles. From opioids to health care reform, Wailoo examines the ways pain has been understood, contested, and managed in different eras, revealing its profound implications for medicine and society.

Pain and Profits: The History of the Headache and Its Remedies in America (Rutgers University Press, 2004)

An examination of headache treatment in the United States from the nineteenth century to modern times, by historian Jan R. McTavish. Here we get an alternative view of headache as a cash cow identified somewhat lately (and cynically) by the pharmaceutical industry. While readers may not always agree with its framing (I didn’t), it remains an important book for understanding the complex relationship between health care and the commercial sector—particularly in the United States.

Pathophysiology of Headaches: From Molecule to Man (Springer, 2015)

A detailed exploration of the biological mechanisms underlying various headache disorders, from migraines to cluster headaches, by neurologist Messoud Ashina and professor of pharmacology Pierangelo Geppetti. This comprehensive work—technical, but within reach of curious lay readers—bridges molecular research and clinical insights, providing a deep understanding of how these conditions arise and affect patients on both physiological and personal levels.

Psychedelic Outlaws: The Movement Revolutionizing Modern Medicine (Hachette, 2024)

Another compelling book from sociologist Joanna Kempner, this time unpacking the rise of a group of internet-based citizen scientists who take experimental psilocybin treatments of cluster headache into their own hands. Along the way, they nudge research scientists to pay attention, as Kempner exposes the repressiveness of our public health system.

So Much More Than a Headache: Understanding Migraine Through Literature (Kent State University Press, 2020)

Despite Virginia Woolf’s observation that “language runs dry” when trying to describe a headache, this compelling anthology of excerpts, poems, and even a short play helps to convey the emotional experience of headache disorders—an experience often colored by the doubt and dismissiveness of the culture that surrounds them. Edited by literature professor Kathleen J. O’Shea.

The Song of Our Scars: The Untold Story of Pain (Basic Books, 2022)

A riveting exploration, by Boston-based physician Haider Warraich, of modern medicine’s inability to fully (and honestly) grapple with the concept of pain—as much a cultural experience, he argues, as a physical one.

The Story of Pain: From Prayer to Painkillers (Oxford University Press, 2014)

An interdisciplinary exploration of the human experience of pain across history, by historian Joanna Bourke. The book delves into the ever-evolving ways in which societies understand, interpret, and manage pain—from ancient times to the modern era.

Why We Hurt: The Natural History of Pain (Harvest, 2001)

While now a bit outdated, this book, by American neurosurgeon Frank Vertosick, combines medical insights with personal narratives—often related to his own experience with grinding migraine headache—to explain how pain serves as a critical warning system for the body, and why it is so vexingly difficult to address.

Notes

Prologue: Molehills Out of Mountains

1. St. Augustine: “The Soliloquies,” Soliloq. i, 12, Online Library of Liberty, accessed March 9, 2024, https://oll.libertyfund.org/titles/cleveland-the-soliloquies#lf0579_label_134.

2. Canadian sociologist: Joost Haan, Migraine, Words and Fiction (Newcastle upon Tyne, UK: Cambridge Scholars Publishing, 2022).

3. and if Emily Dickinson: “Conversations: Emily Dickinson and William Styron,” Lapham’s Quarterly, accessed March 12, 2024, https://www.laphamsquarterly.org/conversations/emily-dickinson-william-styron.

4. Some studies call my disorder: John Fletcher, “Why Cluster Headaches Are Called ‘Suicide Headaches,’” Journal of Neurology & Stroke 3, no. 3 (2015), https://doi.org/10.15406/jnsk.2015.03.00092.

5. while others suggest: Mark J. Burish et al., “Cluster Headache Is One of the Most Intensely Painful Human Conditions: Results from the International Cluster Headache Questionnaire,” Headache 61, no. 1 (2021): 117–24, https://doi.org/10.1111/head.14021.

6. Further downstream: Chelsea Ritschel, “These Are the Worst Pains Humans Can Experience: From Kidney Stones to Cracked Ribs,” Yahoo!Life, accessed April 22, 2022, https://sports.yahoo.com/worst-pains-humans-experience-kidney-173153594.html.

7. You’ll very often: Gary Ogden, “The NHS Has Revealed the 20 Worst Pains Known to Man,” ShortList, last modified June 16, 2017, accessed April 22, 2022, https://www.shortlist.com/news/the-nhs-has-revealed-the-worst-ten-pains-known-to-humans.

8. I might point: Hilde Vollan, “Cluster Headache Attack,” YouTube, video, October 5, 2013, accessed April 22, 2022, https://www.youtube.com/watch?v=wRXnzhbhpHU.

9. “fingerprint of pain”: Tor D. Wager et al., “An fMRI-Based Neurologic Signature of Physical Pain,” New England Journal of Medicine 368, no. 15 (2013): 1388–97, accessed April 22, 2022, https://doi.org/10.1056/NEJMoa1204471.

10. More recently, researchers: Gioacchino D. De Sario et al., “Using AI to Detect Pain Through Facial Expressions: A Review,” Bioengineering 10, no. 5 (2023): 548, https://doi.org/10.3390/bioengineering10050548.

11. pain-measurement tools: “AI Pain Recognition System Could Help Detect Patients’ Pain Before, During and After Surgery,” American Society of Anesthesiologists, October 13, 2013, accessed February 25, 2024, https://www.asahq.org/about-asa/newsroom/news-releases/2023/10/ai-pain-recognition-system.

12. And for unconscious patients: “Critical Care Pain Observation Tool (CPOT),” MDCalc, accessed February 25, 2024, https://www.mdcalc.com/calc/2144/critical-care-pain-observation-tool-cpot.

13. “Whatever pain achieves”: Elaine Scarry, The Body in Pain: The Making and Unmaking of the World (New York: Oxford University Press, 1985), p. 4.

14. “The merest schoolgirl”: Virginia Woolf, “On Being Ill,” Woolf Online, accessed April 21, 2022, https://bit.ly/woolf_pain.

15. Still, it seems certain: Mohammad Al-Mahdi Al-Karagholi et al., “Debate: Are Cluster Headache and Migraine Distinct Headache Disorders?,” Journal of Headache and Pain 23, no. 1 (2022): 151, https://doi.org/10.1186/s10194-022-01504-x.

Chapter 1: A Beautiful Disease

1. The World Health Organization: “Migraine and Other Headache Disorders,” World Health Organization, n.d., accessed January 26, 2025, https://www.who.int/news-room/fact-sheets/detail/headache-disorders.

2. As much as 15 percent: Timothy J. Steiner and Lars Jacob Stovner, “Global Epidemiology of Migraine and Its Implications for Public Health and Health Policy,” Nature Reviews Neurology 19, no. 2 (2023): 109–17, https://doi.org/10.1038/s41582-022-00763-1.

3. including anywhere from: Nick Peter Barnes, “Migraine Headache in Children,” BMJ Clinical Evidence 2015 (June 5, 2015): 0318.

4. Emerging evidence: Mark J. Burish, Zheng Chen, and Seung-Hee Yoo, “Emerging Relevance of Circadian Rhythms in Headaches and Neuropathic Pain,” Acta Physiologica (Oxford, England) 225, no. 1 (2019): e13161, https://doi.org/10.1111/apha.13161.

5. “the single largest”: “Global Burden of Disease (GBD),” University of Washington, Institute for Health Metrics and Evaluation, accessed April 7, 2024, https://www.healthdata.org/research-analysis/gbd.

6. 2020 Global Burden of Disease: Cristiana Abbafati et al., “Global Burden of 369 Diseases and Injuries in 204 Countries and Territories, 1990–2019: A Systematic Analysis for the Global Burden of Disease Study 2019,” The Lancet 396, no. 10258 (2020): 1204–22, https://doi.org/10.1016/S0140-6736(20)30925-9.

7. A more recent report: Jaimie D Steinmetz et al., “Global, Regional, and National Burden of Disorders Affecting the Nervous System, 1990–2021: A Systematic Analysis for the Global Burden of Disease Study 2021,” The Lancet Neurology 23, no. 4 (2024): 344–81, https://doi.org/10.1016/S1474-4422(24)00038-3.

8. by these same DALY metrics: Rowan H Harwood, Avan Aihie Sayer, and Miriam Hirschfeld, “Current and Future Worldwide Prevalence of Dependency, Its Relationship to Total Population, and Dependency Ratios,” Bulletin of the World Health Organization, 2004.

9. 160 different strains: Angus Chen, “Why Haven’t We Cured the Common Cold Yet?,” Scientific American, September 4, 2018, https://www.scientificamerican.com/article/why-havent-we-cured-the-common-cold-yet/.

10. which has been closely linked: Mehmet Selim Gel et al., “Changes in Retinal Nerve Fiber Layer Thickness May Be the Cause of Post–COVID-19 Headaches,” Neurological Research 46, no. 7 (2024): 634–43, https://doi.org/10.1080/01616412.2024.2340875.

11. Etymologies suggest: Marco A. Pescador Ruschel and Orlando De Jesus, “Migraine Headache,” in StatPearls (Treasure Island, FL: StatPearls Publishing, 2024), http://www.ncbi.nlm.nih.gov/books/NBK560787/.

12. The rough contours: Goadsby et al., “Pathophysiology of Migraine: A Disorder of Sensory Processing.”

13. In the third edition: Erasmus Darwin, Zoonomia ; or, The Laws of Organic Life, 3rd ed., 1801, accessed January 27, 2025, https://www.google.com/books/edition/Zoonomia_Or_The_Laws_of_Organic_Life/.

14. While Darwin never: Wade, “Guest Editorial: Erasmus Darwin (1731–1802),” 648.

15. “Would such a circulating bed”: Darwin, Zoonomia, 281.

16. Inspired by Darwin’s musings: E. Charles Kunkle et al., “Studies on Headache: Analysis of Vascular Mechanisms in Headache by Use of the Human Centrifuge, with Observations on Pain Perception Under Increased Positive G,” Archives of Neurology & Psychiatry 60, no. 3 (1948).

17. I am aware: Arne May et al., “Hypothalamic Activation in Cluster Headache Attacks,” The Lancet 352, no. 9124 (1998): 275–78, https://doi.org/10.1016/S0140-6736(98)02470-2.

18. but, in rare instances, organic: T. Sprenger et al., “Specific Hypothalamic Activation During a Spontaneous Cluster Headache Attack,” Neurology 62, no. 3 (2004): 516–17, https://doi.org/10.1212/WNL.62.3.516.

19. “Imaging patients”: Wilson J Xu et al., “Structural MRI in Migraine: A Review of Migraine Vascular and Structural Changes in Brain Parenchyma,” Journal of Central Nervous System Disease 15 (April 14, 2023): 11795735231167868, https://doi.org/10.1177/11795735231167868.

20. Remarkably, Charles: Andrew Charles, “Migraine Is Not Primarily a Vascular Disorder,” Cephalalgia 32, no. 5 (2012): 431–32.

21. still no good evidence: Blaine Jacobs and Gregory Dussor, “Neurovascular Contributions to Migraine: Moving beyond Vasodilation,” Neuroscience 338 (June 14, 2016): 130–44.

22. studies attempting: Andrew H. Ahn, “On the Temporal Relationship Between Throbbing Migraine Pain and Arterial Pulse,” Headache: The Journal of Head and Face Pain 50, no. 9 (2010): 1507–10, https://doi.org/10.1111/j.1526-4610.2010.01765.x.

23. “Individuals who suffer”: Marilyn J. Connors, “Cluster Headache: A Review,” Journal of the American Osteopathic Association 95, no. 9 (1995): 533–39.

24. the cultural distillations: Sophie Edelstein, “The Male Treatment of the Female Migraine: Historicizing Migraine Attacks Through a Multifaceted Framework of Sexism,” n.d.

25. Physicians often: Joanna Leslie Kempner, Not Tonight: Migraine and the Politics of Gender and Health (Chicago: University of Chicago Press, 2014), 33.

26. And as recently as 2016: JoAnna Klein, “Women’s Emotions Do Not Cause Their Migraines,” New York Times, April 6, 2016, sec. Health, https://www.nytimes.com/2016/04/07/health/debunking-migraine-misconceptions.html.

27. “I told Dr. Clay”: Karen Mann, “A Woman’s Pain,” Please See Me, no. 6 (November 20, 2020), accessed March 1, 2022, https://pleaseseeme.com/issue-6/nonfiction/a-womans-pain-karen-mann/.

28. from as low as 30 percent: Mengyuan Hou et al., “Efficacy of Triptans for the Treatment of Acute Migraines: A Quantitative Comparison Based on the Dose-Effect and Time-Course Characteristics,” European Journal of Clinical Pharmacology 75, no. 10 (2019): 1369–78, https://doi.org/10.1007/s00228-019-02748-4.

29. 70 percent in others: Julie Corliss, “Which Migraine Medications Are Most Helpful?,” Harvard Medical School, Harvard Health Publishing, February 5, 2024, https://www.health.harvard.edu/blog/which-migraine-medications-are-most-helpful-202402053014.

30. Because long-term use: John R. Graham et al., “Fibrotic Disorders Associated with Methysergide Therapy for Headache,” New England Journal of Medicine 274, no. 7 (1966): 359–68, https://doi.org/10.1056/NEJM196602172740701.

31. methysergide was ultimately discontinued: Glen D. Solomon, “Preventing Migraine: The Old and the New,” Cleveland Clinic Journal of Medicine 87, no. 4 (2020): 219–21, https://doi.org/10.3949/ccjm.87a.19147.

32. Three years after: Philippa Roxby, “Prize-Winning Migraine Experts Hope for a Cure,” BBC, March 4, 2021, https://www.bbc.com/ news/health-56281065.

33. four scientists: “The Brain Prize: 2021 Migraine,” The Lundbeck Foundation, accessed February 3, 2024, https://lundbeckfonden.com/the-brain-prize/migraine-2021.

34. “I’m humbled: Linda Geddes, “Scientists Who Discovered Migraine Mechanism Win £1.1m Brain Prize,” The Guardian, March 4, 2021, sec. Science, https://www.theguardian.com/science/2021/mar/04/scientists-discovered-migraine-mechanism-win-brain-prize.

35. Development of the drug: U.S. Department of Health & Human Services, National Institutes of Health, National Center for Advancing Translational Science, “Levcromakalim,” accessed February 6, 2022, https://drugs.ncats.io/drug/RW7PN4BLDJ.

36. an earlier experiment: Mohammad Al-Mahdi Al-Karagholi et al., “Opening of ATP-Sensitive Potassium Channels Causes Migraine Attacks: A New Target for the Treatment of Migraine,” Brain 142, no. 9 (2019): 2644–54, https://doi.org/10.1093/brain/awz199.

37. approximately 230 neurologists: Gunhild Waldemar, “Denmark,” Practical Neurology 7, no. 4 (2007): 272–74, https://doi.org/10.1136/jnnp.2007.124248.

38. market consultancy KPMG: “Neurology Physician Practice M&A Overview,” accessed January 27, 2025, https://web.archive.org/web/20230323132630/https://corporatefinance.kpmg.us/insights/2020/neurology-ma-overview.html.

39. just over nine thousand: “Neurologists,” Bureau of Labor Statistics, accessed January 27, 2025, https://www.bls.gov/oes/2023/may/oes291217.htm.

40. one 2017 analysis: Kang Min Park et al., “Top-100 Cited Articles on Headache Disorders: A Bibliometric Analysis,” Clinical Neurology and Neurosurgery 157 (June 1, 2017): 40–45, https://doi.org/10.1016/j.clineuro.2017.03.022.

Chapter 2: The Night of the Train

1. International Classification of Headache Disorders: Jes Olesen, “The International Classification of Headache Disorders: History and Future Perspectives,” Cephalalgia 44, no. 1 (2024): 03331024231214731, https://doi.org/10.1177/03331024231214731.

2. roughly three-quarters: Sara C. Crystal and Matthew S. Robbins, “Epidemiology of Tension-Type Headache,” Current Pain and Headache Reports 14, no. 6 (2010): 449–54, https://doi.org/10.1007/s11916-010-0146-2.

3. like the ability to read: Eva Wiseman, “Why Is Chronic Pain Still So Misunderstood?,” British Vogue, April 3, 2022, https://www.vogue.co.uk/arts-and-lifestyle/article/what-is-chronic-pain.

4. can sometimes help: Bryson C. Lochte et al., “The Use of Cannabis for Headache Disorders,” Cannabis and Cannabinoid Research 2, no. 1 (2017): 61–71, https://doi.org/10.1089/can.2016.0033.

5. Other researchers: Peter J. Goadsby, “The Vascular Theory of Migraine—A Great Story Wrecked by the Facts,” Brain 132, no. 1 (2009): 6–7, https://doi.org/10.1093/brain/awn321.

6. sumatriptan is intended: Christopher J. Derry, Sheena Derry, and R. Andrew Moore, “Sumatriptan (Oral Route of Administration) for Acute Migraine Attacks in Adults,” Cochrane Database of Systematic Reviews, no. 2 (2012), https://doi.org/10.1002/14651858.CD008615.pub2.

7. severe rebound headaches: S. Evers et al., “Sumatriptan and Ergotamine Overuse and Drug-Induced Headache: A Clinicoepidemiologic Study,” Clinical Neuropharmacology 22, no. 4 (1999): 201–6.

8. A collection published: “Cluster Headaches: ‘Like Someone Is Grabbing Your Face,’” BBC News, YouTube, video, May 6, 2017, accessed March 1, 2022, https://www.youtube.com/watch?v=OO5oDaG45kE.

9. sometimes called: Richard B. Lipton et al., “Reduction in Perceived Stress as a Migraine Trigger: Testing the ‘Let-down Headache’ Hypothesis,” Neurology 82, no. 16 (2014): 1395–1401, https://doi.org/10.1212/wnl.0000000000000332.

10. in the throes of an investigation: Tom Zeller Jr., “Nuclear Agency Is Criticized as Too Close to Its Industry,” New York Times, May 7, 2011, accessed November 11, 2024, https://www.nytimes.com/2011/05/08/business/energy-environment/08nrc.html.

11. it is quite common: “Cluster Headache,” Mayo Clinic, accessed March 5, 2022, https://www.mayoclinic.org/diseases-conditions/cluster-headache/symptoms-causes/syc-20352080.

12. a role for the hypothalamus: Ilse F. de Coo et al., “Chronobiology and Sleep in Cluster Headache,” Headache: The Journal of Head and Face Pain 59, no. 7 (2019): 1032–41, https://doi.org/10.1111/head.13567.

13. famously making an elephant: “The Vanishing Elephant,” Houdini: His Life and His Art (website), accessed April 22, 2022, https://www.thegreatharryhoudini.com/vanishingelephant.html.

14. Recent research offers: Todd D. Rozen, “Linking Cigarette Smoking/Tobacco Exposure and Cluster Headache: A Pathogenesis Theory,” Headache: The Journal of Head and Face Pain 58, no. 7 (2018): 1096–1112, https://doi.org/10.1111/head.13338.

15. it would run: John Leland and Tom Zeller Jr., “Mortgage Suit Says ‘Trust Us’ Led to Fleecing,” New York Times, September 28, 2006, sec. U.S., https://www.nytimes.com/2006/09/28/us/28martinsville.html.

16. Verapamil toxicity: “Calcium Channel Antagonist Toxicity,” California Poison Control System (CPCS), accessed April 22, 2022, https://calpoison.org/calcium-channel-antagonist-toxicity.

17. Absent these: Claire J. Fearnley, H. Llewelyn Roderick, and Martin D. Bootman, “Calcium Signaling in Cardiac Myocytes,” Cold Spring Harbor Perspectives in Biology 3, no. 11 (2011): a004242, https://doi.org/10.1101/cshperspect.a004242.

Chapter 3: Holes in the Head

1. I’d read that Carroll was known: T. J. Murray, “The Neurology of Alice in Wonderland,” Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 9, no. 4 (1982): 453–57, https://doi.org/10.1017/S0317167100044395.

2. Seymour Diamond: Seymour Diamond and Charlie Morey, The Headache Godfather: The Story of Dr. Seymour Diamond and How He Revolutionized the Treatment of Headaches (New York: Skyhorse Publishing, 2015).

3. mixed reputation for efficacy: Clare P. Herd et al., “Botulinum Toxins for the Prevention of Migraine in Adults,” Cochrane Database of Systematic Reviews 2018, no. 6, accessed March 20, 2024, https://doi.org/10.1002/14651858.CD011616.pub2.

4. The insurance firm Aetna’s: “Histamine Desensitization Therapy for Intractable Headaches,” Medical Clinical Policy Bulletin no. 0647, Aetna, accessed February 23, 2024, https://www.aetna.com/cpb/medical/data/600_699/0647.html.

5. In chapter 46: Georg Ebers, Uarda : A Romance of Ancient Egypt, chapter 46, trans. Clara Bell, Project Gutenberg, https://www.gutenberg.org/cache/epub/5449/pg5449-images.html#link2HCH0046, accessed December 15, 2024.

6. dated to around: Lutz Popko, “Some Notes on Papyrus Ebers, Ancient Egyptian Treatments of Migraine, and a Crocodile on the Patient’s Head,” Bulletin of the History of Medicine, accessed January 27, 2025, https://doi.org/10.1353/bhm.2018.0030.

7. about sixty-six feet in length: Aleksandra Hallmann-Mikołajczak, “[Ebers Papyrus. The Book of Medical Knowledge of the 16th Century B.C. Egyptians],” Archiwum Historii i Filozofii Medycyny 67, no. 1 (2004): 5–14.

8. might be rheumatoid arthritis: “Papyrus Ebers,” Universitätsbibliothek Leipzig, accessed March 17, 2022, https://papyrusebers.de/en/.

9. one twentieth century medical historian described: “Animal Substances in Materia Medica: A Study In The Persistence Of The Primitive,” Journal of the History of Medicine and Allied Sciences, 1946: 153.

10. The scroll itself: Seymour Diamond and Mary A. Franklin, Headache Through the Ages (Professional Communications Inc., 2005).

11. but given that: “Ebers Papyrus: Catalog Description,” National Archives, Wellcome Collection, n.d., https://bit.ly/3SlgJOk.

12. the instruction: Katherine Foxhall, Migraine: A History (Baltimore: Johns Hopkins University Press, 2019), 27.

13. 2010 paperback: Rosalind Park, “Ancient Egyptian Headaches: Ichthyo- or Electrotherapy?,” in Pharmacy and Medicine in Ancient Egypt: Proceedings of the Conferences Held in Cairo (2007) and Manchester (2008), ed. Jenefer Cockitt and A. Rosalie David (Oxford, UK: Archaeopress, 2010).

14. A former president: Stephen D. Silberstein, M. Alan Stiles, and William B. Young, eds., Atlas of Migraine and Other Headaches, 1st ed. (New York: CRC Press, 2005).

15. That citation echoes: Carlos M. Villalón et al., “Migraine: Pathophysiology, Pharmacology, Treatment and Future Trends,” Current Vascular Pharmacology 1, no. 1 (2003): 71–84, https://doi.org/10.2174/1570161033386826.

16. Rather, it springs: Lutz Popko, “Some Notes on Papyrus Ebers, Ancient Egyptian Treatments of Migraine, and a Crocodile on the Patient’s Head,” Bulletin of the History of Medicine 92, no. 2 (2018): 352–67, https://doi.org/10.1353/bhm.2018.0030.

17. “To draw an analogy”: Elizabeth Loder, “What Is the Evolutionary Advantage of Migraine?,” Cephalalgia 22, no. 8 (2002): 624–32, https://doi.org/10.1046/j.1468-2982.2002.00437.x.

18. late Paleolithic period: Charles G. Gross, “A Hole in the Head: A History of Trepanation,” The MIT Press Reader, accessed March 20, 2022, https://thereader.mitpress.mit.edu/hole-in-the-head-trepanation/.

19. “Although a few”: Gross, “A Hole in the Head.”

20. “the first evidence”: Emmanouil Magiorkinis et al., “Headaches in Antiquity and During the Early Scientific Era,” Journal of Neurology 256, no. 8 (2009): 1215–20, https://doi.org/10.1007/s00415-009-5085-7.

21. Willis introduced: Thomas Willis, Cerebri anatome : cui accessit nervorum descriptio et usus (Londini : typis Ja. Flesher, impensis Jo. Martyn & Ja. Allestry apud insigne Campanae in Coemeterio D. Pauli, 1664), http://archive.org/details/cerebrianatomecu00will.

22. he related that a contemporary: Thomas Willis, The London Practice of Physick, or The Whole Practical Part of Physick, 1685, Google Books, accessed March 20, 2022, https://www.google.co.uk/books/edition/The_London_Practice_of_Physick_Or_The_Wh/iZ6Qnh_helkC.

23. a short paper: Alexander Haig, “The Treatment of Headaches,” British Medical Journal 2 (November 4, 1899): 1246–47, https://babel.hathitrust.org/cgi/pt?id=msu.31293108189964&seq=1298.

24. which was published: “Hallucinations and Allied Mental Phenomena / by Sir Lauder Brunton. | Wellcome Collection,” accessed March 20, 2022, https://wellcomecollection.org/works/ehd56s2c/items.

25. “neurological theory”: Katherine Foxhall, “Drilling Holes in the Skull Was Never a Migraine Cure—Here’s Why It Was Long Thought to Be,” The Conversation, March 6, 2018, accessed March 20, 2022, https://theconversation.com/drilling-holes-in-the-skull-was-never-a-migraine-cure-heres-why-it-was-long-thought-to-be-90782.

26. Some authoritites: Sir Thomas Lauder Brunton, “Hallucinations and Allied Mental Phenomena,” 1910, Wellcome Collection, https://wellcomecollection.org/works/ehd56s2c/items?canvas=43&query=have+supposed: 29.

27. issue of The Lancet: T. Wilson Parry, “Neolithic Man and the Penetration of the Living Human Skull,” The Lancet 218, no. 5651 (1931): 1388–90.

28. As Foxhall notes: Katherine Foxhall, “How a Nurse With a Hole in Her Skull Changed the Medical History of Migraines,” Time, June 18, 2019, https://time.com/5609191/how-a-nurse-with-a-hole-in-her-skull-changed-the-medical-history-of-migraines/.

29. The Greek god Hephaestus: Leonardo B. C. Brasiliense et al., “The Legacy of Hephaestus: The First Craniotomy,” Neurosurgery 67, no. 4 (2010): 881–84, https://doi.org/10.1227/NEU.0b013e3181ee022b.

30. In the story: “Hua Tuo: Chinese Physician and Surgeon,” Britannica, accessed March 28, 2022, https://www.britannica.com/biography/Hua-Tuo.

31. one belonging: “Chronic Migraine—Bala Cynwyd, PA: Optimum Neurology,” accessed March 28, 2022, https://www.optimumneurology.com/contents/conditions-we-treat/chronic-migraine.

32. in a 2011 paper: Katherine Latimer et al., “Dr. Harvey Cushing’s Attempts to Cure Migraine Based on Theories of Pathophysiology: Historical Vignette,” Journal of Neurosurgery 115, no. 5 (2011): 924–28, https://doi.org/10.3171/2011.5.JNS101855.

33. “It is believed”: Rachid Assina, Christina E. Sarris, and Antonios Mammis, “The History of Craniotomy for Headache Treatment,” Neurosurgical Focus 36, no. 4 (2014): 1–6, https://doi.org/10.3171/2014.1.FOCUS13549.

34. “He seemed to see”: Yu Jeat Chong et al., “Current Perspective on Retinal Migraine,” Vision (Basel, Switzerland) 5, no. 3 (2021): 38, https://doi.org/10.3390/vision5030038.

35. Several works: Brian May, Takako Tomoda, and Michael Wang, “The Life and Medical Practice of Hua Tuo,” Pacific Journal of Oriental Medicine 14, no. October (2000): 40–54.

36. “It occasions”: J. M. S. Pearce, “The Neurology of Aretaeus: Radix Pedis Neurologia,” European Neurology 70, no. 1–2 (2013): 106–12, https://doi.org/10.1159/000352031.

37. The torpedo fish: Gregory Tsoucalas et al., “The ‘Torpedo’ Effect in Medicine,” International Maritime Health 65 (2014): 65–67, https://doi.org/10.5603/IMH.2014.0015.

38. Consequently: Peter J. Koehler and Christopher J. Boes, “A History of Non-drug Treatment in Headache, Particularly Migraine,” Brain 133, no. 8 (2010): 2489–2500, https://doi.org/10.1093/brain/awq170.

39. Caelius Aurelianus: J. M. S. Pearce, “Historical Aspects of Migraine,” Journal of Neurology, Neurosurgery, and Psychiatry 49, no. 10 (1986): 1097–1103, https://doi.org/10.1136/jnnp.49.10.1097.

40. His work: Mervyn J. Eadie, Headache: Through the Centuries (New York: Oxford University Press, 2012).

41. At the same time: Peter J. Goadsby, “The Vascular Theory of Migraine—A Great Story Wrecked by the Facts,” Brain 132, no. 1 (2009): 6–7, https://doi.org/10.1093/brain/awn321.

42. Writing of one patient: Pearce, “Historical Aspects of Migraine,” 1099.

43. seven-book medical compendium: Magiorkinis et al., “Headaches in Antiquity and During the Early Scientific Era.”

44. Tulp wrote: P. J. Koehler, “Prevalence of Headache in Tulp’s Observationes Medicae (1641) with a Description of Cluster Headache,” Cephalalgia 13, no. 5 (1993): 318–20, https://doi.org/10.1046/j.1468-2982.1993.1305318.x.

45. A century later: Pearce, “Gerardi van Swieten: Descriptions of Episodic Cluster Headache,” Journal of Neurology, Neurosurgery and Psychiatry 78, no 11 (2007), 1248–1249.

Chapter 4: Blood vs. Brains

1. Some research today: Léa LenglarT et al., “Brain to Belly: Abdominal Variants of Migraine and Functional Abdominal Pain Disorders Associated with Migraine,” Journal of Neurogastroenterology and Motility 27, no. 4 (2021): 482–94, https://doi.org/10.5056/jnm20290.

2. The precise nature: Mahsa Arzani et al., “Gut-Brain Axis and Migraine Headache: A Comprehensive Review,” Journal of Headache and Pain 21, no. 1 (2020): 15, https://doi.org/10.1186/s10194-020-1078-9.

3. The subject of dietary triggers: Margaret Slavin et al., “What Is Needed for Evidence-Based Dietary Recommendations for Migraine: A Call to Action for Nutrition and Microbiome Research,” Headache: The Journal of Head and Face Pain 59, no. 9 (2019): 1566–81, https://doi.org/10.1111/head.13658.

4. Katherine Foxhall recounts: Katherine Foxhall, Migraine: A History (Baltimore: Johns Hopkins University Press, 2019), 84.

5. Fatty foods: Olli T. Raitakari et al., “Enhanced Peripheral Vasodilation in Humans After a Fatty Meal,” Journal of the American College of Cardiology 36, no. 2 (2000): 417–22, https://doi.org/10.1016/S0735-1097(00)00758-0.

6. black pepper: Taqvi, Shah, and Gilani, “Blood Pressure Lowering and Vasomodulator Effects of Piperine,” Journal of Cardiovascular Pharmacology 52, no. 5 (2008): 452.

7. Fothergill’s writing: Foxhall, Migraine: A History, 84.

8. This might be: Foxhall, Migraine: A History, 91.

9. In her thesis: Wilkinson and Isler, “The pioneer woman’s view of migraine: Elizabeth Garrett Anderson’s thesis ‘Sur la migraine,’” Cephalalgia 19, no. 1 (1999): 3-15.

10. From a second translation: Wilkinson and Isler, 7.

11. “As has already”: Wilkinson and Isler, 11.

12. and both published: Edward Liveing, On Megrim, Sick-Headhache, and Some Allied Disorders: A Contribution to the Pathology of Nerve-Storms (London: Churchill, 1873), Internet Archive, http://archive.org/details/BIUSante_37938; Peter Wallwork Latham, On Nervous or Sick-Headache: Its Varieties and Treatment (Cambridge : Deighton, Bell; London: Bell and Daldy, 1873), Internet Archive, http://archive.org/details/BIUSante_37568.

13. As a 2012 reanalysis: Mervyn J. Eadie, Headache: Through the Centuries (New York: Oxford University Press, 2012), 134.

14. “to serve contemporary ends”: Mark W. Weatherall, “The Migraine Theories of Liveing and Latham: A Reappraisal,” Brain 135, no. 8 (2012): 2560–68, https://doi.org/10.1093/brain/aws020.

15. the physician always: Eadie, Headache: Through the Centuries.

16. even as critics: Kevin Mullane and Michael Williams, “Alzheimer’s Therapeutics: Continued Clinical Failures Question the Validity of the Amyloid Hypothesis—but What Lies Beyond?,” Biochemical Pharmacology 85, no. 3 (2013): 289–305, https://doi.org/10.1016/j.bcp.2012.11.014.

17. raising further questions: Simon Makin, “The Amyloid Hypothesis on Trial,” Nature 559, no. 7715 (2018): S4–7, https://doi.org/10.1038/d41586-018-05719-4.

18. Whether the amyloid hypothesis: Dan Samorodnitsky, “What Now for the Amyloid Hypothesis?,” Drug Discovery News, February 7, 2023, accessed February 12, 2024, https://www.drugdiscoverynews.com/what-now-for-the-amyloid-hypothesis-15611.

19. but some critics have argued: Yasemin Saplakoglu, “What Causes Alzheimer’s? Scientists Are Rethinking the Answer,” Quanta Magazine, December 8, 2022, https://www.quantamagazine.org/what-causes-alzheimers-scientists-are-rethinking-the-answer-20221208/.

20. Matters were not helped: Charles Piller, “Blots on a Field?,” Science 377, no. 6604, July 21, 2022, accessed February 12, 2024, https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease.

21. Eadie mentions: Eadie, Headache: Through the Centuries, 138.

22. eventually became inpsired: A Karwautz et al., “Freud and Migraine: The Beginning of a Psychodynamically Oriented View of Headache a Hundred Years Ago,” Cephalalgia 16, no. 1 (1996): 22–26, https://doi.org/10.1046/j.1468-2982.1996.1601022.x.

23. “I was suffering”: Ernst L. Freud, ed., Letters of Sigmund Freud (New York, Basic Books, 1975), Internet Archive, http://archive.org/details/lettersofsigmundfreudthebyernstfreud.

24. As the funk musician: Cocaine Is a Hell of a Drug, 2013, https://www.youtube.com/watch?v=Q_4bp8bBNVw.

25. While known: Stephen D. Silberstein, Stephen B. Shrewsbury, and John Hoekman, “Dihydroergotamine (DHE)—Then and Now: A Narrative Review,” Headache: The Journal of Head and Face Pain 60, no. 1 (2020): 40–57, https://doi.org/10.1111/head.13700.

26. the isolation of ergotamine: M. R. Lee, “The History of Ergot of Rye (Claviceps purpurea) II: 1900–1940,” Journal of the Royal College of Physicians of Edinburgh 39, no. 4 (2009): 365–69, https://doi.org/10.4997/jrcpe.2009.416.

27. Novel methods: Silberstein, Shrewsbury, and Hoekman, “Dihydroergotamine (DHE)—Then and Now,” Headache 60, no. 1 (2020-1): 40-57.

28. and several countries: “Alert Communication: Consent to Distribute Cafergot Tablets (Ergotamine Tartrate 1 Mg + Caffeine 100 Mg) Will Be Prohibited Under Section 36 of the Medicines Act 1981 on 1 May 2020,” Medsafe: New Zealand Medicines and Medical Devices Safety Authority, November 20, 2019, accessed February 19, 2024, https://www.medsafe.govt.nz/safety/Alerts/Cafergot%20Prohibited.asp.

Chapter 5: Pillar to Post

1. I learned: “New York State Department of Health Determination Order No. 98–99 1a,” May 18, 1998.

2. His license: “New York State Department of Health Determination Order No. 98–99 1b,” September 10, 1998.

3. A newspaper account: Nicole Bode, “Leering, Dirty Doctor Matthew Miller Harassed Nurses, Patients, Sales Reps,” Daily News (New York, NY), February 24, 2019, Archive.today, February 25, 2024, https://archive.md/7sqF4.

4. Most people will: K. R. Kessler and R. Benecke, “Botulinum Toxin: From Poison to Remedy,” Neurotoxicology 18, no. 3 (1997): 761–70.

5. not unheard-of tool for migraine: LaPorta, “Relief From Migraine Headache With Aripiprazole Treatment,” Headache: The Journal of Head and Face Pain 47, no. 6 (2007): 922-926.

6. Some research: Jasem Y. Al-Hashel et al., “Migraine Misdiagnosis as a Sinusitis, a Delay That Can Last for Many Years,” Journal of Headache and Pain 14 (2013): 97, https://doi.org/10.1186/1129-2377-14-97.

7. A systematic review: Alina Buture et al., “Systematic Literature Review on the Delays in the Diagnosis and Misdiagnosis of Cluster Headache,” Neurological Sciences 40, no. 1 (2019): 25–39, https://doi.org/10.1007/s10072-018-3598-5.

8. An earlier study: Todd D. Rozen and Royce S. Fishman, “Cluster Headache in the United States of America: Demographics, Clinical Characteristics, Triggers, Suicidality, and Personal Burden,” Headache: The Journal of Head and Face Pain 52, no. 1 (2012): 99–113, accessed February 3, 2024, https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/j.1526-4610.2011.02028.x.

9. “Delays in diagnosis”: Buture et al., “Systematic Literature Review.”

10. observational study: Anna Ferrari et al., “Polypharmacy Among Headache Patients: A Cross-Sectional Study,” CNS Drugs 32, no. 6 (2018): 567–78, https://doi.org/10.1007/s40263-018-0522-8.

11. It had long been considered axiomatic: Tfelt-Hansen and Olesen, “Taking the Negative View of Current Migraine Treatments,” CNS Drugs 26, no. 5 (2012): 375-382.

12. A separate study: Marianna Delussi et al., “Failure of Preventive Treatments in Migraine: An Observational Retrospective Study in a Tertiary Headache Center,” BMC Neurology 20 (2020): 256, accessed February 25, 2022, https://doi.org/10.1186/s12883-020-01839-5.

13. “headache medicine specialists”: Randolph W. Evans and Kamalika Ghosh, “A Survey of Headache Medicine Specialists on Career Satisfaction and Burnout,” Headache: The Journal of Head and Face Pain 55, no. 10 (2015): 1448–57, https://doi.org/10.1111/head.12708.

14. “We became”: Evans and Ghosh, “A Survey of Headache Medicine Specialists.”

15. The average medical student: Hao Huang and Mia T Minen, “Eleven Reasons People Decide to Choose Headache Medicine: There May Be a Headache Medicine Provider Shortage but There Are Ways to Foster Interest,” Headache: The Journal of Head and Face Pain 60, no. 8 (2020): 1846–52, https://doi.org/10.1111/head.13838.

16. One 2020 study: Olivia Begasse de Dhaem et al., “Workforce Gap Analysis in the Field of Headache Medicine in the United States,” Headache: The Journal of Head and Face Pain 60, no. 2 (2020): 478–81, https://doi.org/10.1111/head.13752.

17. The UCNS was formed: “About UCNS,” United Council for Neurologic Subspecialties, accessed February 25, 2024, https://www.ucns.org/Online/Online/About_UCNS.aspx.

18. A 2019 letter: “UCNS Certification,” United Council for Neurologic Subspecialties, PDF file, accessed February 25, 2024, https://www.asnweb.org/files/2019%20Annual%20Meeting/UCNS%20Certification%20Recognition.pdf.

19. For roughly 70 percent: Richard B. Lipton et al., “Diagnosis, Consultation, Treatment, and Impact of Migraine in the US: Results of the OVERCOME (US) Study,” Headache: The Journal of Head and Face Pain 62, no. 2 (2022): 122–40, https://doi.org/10.1111/head.14259.

20. but one 2016 survey: Mia T Minen et al., “Migraine Diagnosis and Treatment: A Knowledge and Needs Assessment Among Primary Care Providers,” Cephalalgia 36, no. 4 (2016): 358–70, https://doi.org/10.1177/0333102415593086.

21. A 2023 study: Manuel E. Machado-Duque et al., “Potentially Inappropriate Use of Opioids in the Management of Migraine in Colombia,” Biomedicines 11, no. 9 (2023): 2385, https://doi.org/10.3390/biomedicines11092385.

22. but mostly: “Opioids and Migraine,” American Headache Society, accessed February 25, 2024, https://americanheadachesociety.org/research/library/opioids-and-migraine.

23. Millions of primary headache patients: Seonkyeong Yang et al., “Trends in the Management of Headache Disorders in US Emergency Departments: Analysis of 2007–2018 National Hospital Ambulatory Medical Care Survey Data,” Journal of Clinical Medicine 11, no. 5 (2022): 1401, https://doi.org/10.3390/jcm11051401.

24. A 2022 analysis: Darcy Banco et al., “Sex and Race Differences in the Evaluation and Treatment of Young Adults Presenting to the Emergency Department with Chest Pain,” Journal of the American Heart Association 11, no. 10 (2022): e024199, https://doi.org/10.1161/JAHA.121.024199.

25. It’s not a new phenomenon: Diane E. Hoffmann and Anita J. Tarzian, “The Girl Who Cried Pain: A Bias Against Women in the Treatment of Pain,” SSRN Scholarly Paper (Rochester, NY, 2001), https://doi.org/10.2139/ssrn.383803.

26. A pair of 2021 psychological experiments: Lanlan Zhang et al., “Gender Biases in Estimation of Others’ Pain,” Journal of Pain 22, no. 9 (2021): 1048–59, https://doi.org/10.1016/j.jpain.2021.03.001.

27. Remarkably: Patrick Lucey et al., “Painful Data: The UNBC-McMaster Shoulder Pain Expression Archive Database” (Face and Gesture 2011, IEEE Computer Society, 2011), 57–64, https://doi.org/10.1109/FG.2011.5771462.

28. compared to the general population: Thomas Dresler et al., “Understanding the Nature of Psychiatric Comorbidity in Migraine: A Systematic Review Focused on Interactions and Treatment Implications,” Journal of Headache and Pain 20, no. 1 (2019), https://doi.org/10.1186/s10194-019-0988-x.

29. can be inherently disabling: Richard B. Lipton et al., “The Effect of Psychiatric Comorbidities on Headache‐Related Disability in Migraine: Results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study,” Headache: The Journal of Head and Face Pain 60, no. 8 (2020): 1683–96, https://doi.org/10.1111/head.13914.

30. a retrospective analysis: X. Michelle Androulakis et al., “Suicide Attempts in US Veterans with Chronic Headache Disorders: A 10-Year Retrospective Cohort Study,” Journal of Pain Research 14 (2021): 2629–39, https://doi.org/10.2147/JPR.S322432.

31. compared to the general population: Mark A. Louter et al., “Cluster Headache and Depression,” Neurology 87, no. 18 (2016): 1899–906, https://doi.org/10.1212/WNL.0000000000003282.

Chapter 6: Painful Thrusts

1. Wolff is responsible: Rebecca Akkermans, “Harold G Wolff,” The Lancet Neurology 14, no. 10 (2015): 982–83, https://doi.org/10.1016/S1474-4422(15)00184-2.

2. Numbers vary: Lou Grangeon et al., “Genetics of Migraine: Where Are We Now?,” Journal of Headache and Pain 24, no. 1 (2023): 12, https://doi.org/10.1186/s10194-023-01547-8.

3. Interestingly, migraine: Michael Bjørn Russell et al., “Migraine Without Aura and Migraine with Aura Are Distinct Disorders. A Population-Based Twin Survey,” Headache: The Journal of Head and Face Pain 42, no. 5 (2002): 332–36, https://doi.org/10.1046/j.1526-4610.2002.02102.x.

4. “He . . . had all of us”: Helen Goodell, “Thirty Years of Headache Research in the Laboratory of the Late Dr. Harold G. Wolff,” Headache: The Journal of Head and Face Pain 6, no. 4 (1967): 158–71, https://doi.org/10.1111/j.1526-4610.1967.hed0604158.x.

5. These early influences: J. N. Blau, “Harold G Wolff: The Man and His Migraine,” Cephalalgia 24, no. 3 (2004): 215–22, https://doi.org/10.1111/j.1468-2982.2003.00642.x.

6. “His interest was:” Joanna Leslie Kempner, Not Tonight: Migraine and the Politics of Gender and Health (Chicago: University of Chicago Press, 2014), 35.

7. “The Elaboration”: Goodell, “Thirty Years of Headache Research.”

8. and other descriptions: Blau, “Harold G Wolff.”

9. Wolff described: Kempner, Not Tonight: Migraine and the Politics of Gender and Health, 40.

10. wrote a book: Kathleen O’Shea, So Much More Than a Headache, The Kent State University Press, accessed February 18, 2024, https://www.kentstateuniversitypress.com/2019/more-than-headach/.

11. Alvarez, a Wolff admirer: Kempner, Not Tonight: Migraine and the Politics of Gender and Health, 40.

12. in 1951: “Dr. Walter Alvarez, Writer, Dies,” Santa Cruz Sentinel, June 20, 1978.

13. He frequently opined: Walter C. Alvarez, “Dr. Alvarez,” column, Tucson Daily Citizen, June 14, 1965, Newspaper Archive, https://newspaperarchive.com/other-articles-clipping-jun-14-1965-4312706/.

14. In the late 1920s: Goodell, “Thirty Years of Headache Research.”

15. Repeated this setup: J. R. Graham, H.G. Wolff, “Mechanism of Migraine Headache and Action of Ergotamine Tartrate,” Archives of Neurology And Psychiatry 39, no. 4 (April 1, 1938): 737, https://doi.org/10.1001/archneurpsyc.1938.02270040093005.

16. Kempner seems: Kempner, Not Tonight: Migraine and the Politics of Gender and Health, 41.

17. “A person with migraine”: “Headaches Among Man’s Most Common Ills,” Lawrence Journal World, October 28, 1964, Newspaper Archive, https://newspaperarchive.com/other-articles-clipping-oct-28-1964-4890411/.

18. Ten years later: John Fetler, “World View,” Colorado Springs Gazette, November 4, 1973, Newspaper Archive, https://newspaperarchive.com/other-articles-clipping-nov-04-1973-4370802/.

19. Many patients report: Joanne Dudeney et al., “Are Psychological Interventions Efficacious for Adults with Migraine? A Systematic Review and Meta-analysis,” Headache: The Journal of Head and Face Pain 62, no. 4 (2022): 405–19, https://doi.org/10.1111/head.14260.

20. have argued that the same: William J. Mullally, Kathryn Hall, and Richard Goldstein, “Efficacy of Biofeedback in the Treatment of Migraine and Tension Type Headaches,” Pain Physician 12, no. 6 (2009): https://pubmed.ncbi.nlm.nih.gov/19935987/, 1005–11.

21. A recent review: Louise Sharpe et al., “Psychological Therapies for the Prevention of Migraine in Adults,” Cochrane Database of Systematic Reviews 2019, no. 7, https://doi.org/10.1002/14651858.CD012295.pub2.

22. The Italian scientist: Patricia Mack Whitaker-Azmitia, “The Discovery of Serotonin and Its Role in Neuroscience,” Neuropsychopharmacology 21, no. 1 (1999): 2–8, https://doi.org/10.1016/S0893-133X(99)00031-7.

23. Later, when researchers: Maurice M. Rapport, Arda Alden Green, and Irvine H. Page, “Serum Vasoconstrictor (Serotonin): IV. Isolation and Characterization,” Journal of Biological Chemistry 176, no. 3 (1948): 1243–51, https://doi.org/10.1016/S0021-9258(18)57137-4.

24. Wolff himself: P. J. Koehler and P. C. Tfelt-Hansen, “History of Methysergide in Migraine,” Cephalalgia 28, no. 11 (2008): 1126–35, https://doi.org/10.1111/j.1468-2982.2008.01648.x.

25. albeit in patients: A. M. Ostfeld et al., “Studies in Headache: A Summary of Evidence Implicating a Locally Active Chemical Agent in Migraine,” Transactions of the American Neurological Association, 81st Meeting (1956): 35–36, https://pubmed.ncbi.nlm.nih.gov/13432093/ (login required).

26. Other researchers: Patrick P. A. Humphrey, “The Discovery and Development of the Triptans, a Major Therapeutic Breakthrough,” Headache: The Journal of Head and Face Pain 48, no. 5 (2008): 685–87, https://doi.org/10.1111/j.1526-4610.2008.01097.x.

27. although to date: Dan Levy, Alejandro Labastida-Ramirez, and Antoinette MaassenVanDenBrink, “Current Understanding of Meningeal and Cerebral Vascular Function Underlying Migraine Headache,” Cephalalgia 39, no. 13 (2019): 1606–22, https://doi.org/10.1177/0333102418771350.

28. In 1961: F. Sicuteri, A. Testi, and B. Anselmi, “Biochemical Investigations in Headache: Increase in the Hydroxyindoleacetic Acid Excretion During Migraine Attacks,” International Archives of Allergy and Applied Immunology 19, no. 1 (1961): 55–58, https://doi.org/10.1159/000229194.

29. He immediately focused: Patrick P. A. Humphrey, “The Discovery of a New Drug Class for the Acute Treatment of Migraine,” Headache: The Journal of Head and Face Pain 47, no. s1 (2007): S10–S19, https://doi.org/10.1111/j.1526-4610.2007.00672.x.

30. I’ve also sometimes: “Steven Wright Jokes,” Prof. Michael Huemer (website), accessed February 24, 2024, https://spot.colorado.edu/~huemer/wright.htm.

31. “We knew that 5HT2”: Humphrey, “The Discovery of a New Drug Class.”

32. international study group: The Subcutaneous Sumatriptan International Study Group, “Treatment of Migraine Attacks with Sumatriptan,” New England Journal of Medicine 325, no. 5 (1991): 316–21, https://doi.org/10.1056/NEJM199108013250504.

33. U.S. regulators gave the nod: U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Approval Package for Imitrex, 13, accessed March 30, 2024, https://www.accessdata.fda.gov/drugsatfda_docs/nda/96/020080ap.pdf.

34. Debates would quickly ensue: P. P. A. Humphrey and P. J. Goadsby, “The Mode of Action of Sumatriptan Is Vascular? A Debate,” Cephalalgia 14, no. 6 (1994): 401–10; https://doi.org/10.1046/j.1468-2982.1994.1406401.x.

35. “Glaxo is gearing up”: “Glaxo Introduces Migraine Drug,” Cedar Rapids Gazette, March 21, 1993.

36. The piece: “New Miracle Drug Giving Hope to Migraine Sufferers,” Pasadena Star-News, April 8, 1993.

37. AdAge magazine: Michael Wilke, “Leading the Charge: Glaxo Wellcome’s Imitrex Was the First Migraine Drug to Use Direct-to-Consumer Advertising,” AdAge, March 16, 1998, Archive.today, March 30, 2024, https://archive.md/wEkLu.

38. Old Imitrex ads: Play Pause Video, “Imitrex Commercial (1997),” YouTube, video, June 8, 2017, https://www.youtube.com/watch?v=wc2fPZ3Io7s.

39. at least one study: Ying Xia, Christina M. L. Kelton, and Jeff J. Guo, “Twenty Years of Triptans in the United States Medicaid Programs: Utilization and Reimbursement Trends from 1993 to 2013,” Cephalalgia 36, no. 14 (2016): 1305–15, https://doi.org/10.1177/0333102416629237.

40. “We do not know whether”: Humphrey, “The Discovery of a New Drug Class,” S15.

41. “His narrowness is evident”: Blau, “Harold G Wolff.”

Chapter 7: The Malingerers

1. He plugged into a community: Clusterbusters—The Cluster Headache Advocacy Group website, accessed March 2, 2024, https://clusterbusters.org/.

2. The group’s forums: Ellen X. Yan, “LSD and Shrooms May Treat Cluster Headaches,” Harvard Crimson, October 10, 2008, https://www.thecrimson.com/article/2008/10/10/lsd-and-shrooms-may-treat-cluster/.

3. A post: statler, “Open Thread,” forum, archBOSTON, May 17, 2010, Internet Archive Wayback Machine, https://web.archive.org/web/20240303163617/https://archboston.com/community/threads/%F0%9F%94%B7-open-thread.961/page-36#post-101610.

4. A week later: Joe Fitzgerald, “A Prayer for Another’s Son,” Boston Herald, June 10, 2010, Archive.today, https://archive.md/qitMI.

5. I’d written an essay: Tom Zeller Jr., “There Has Never Been a Better Time to Have a Headache,” New York Times, July 23, 2021, sec. Opinion, https://www.nytimes.com/2021/07/23/opinion/headaches-research-cure.html.

6. A 2024 analysis: Pengfei Zhang et al., “Metaphorical Use of ‘Headache’ and ‘Migraine’ in Media: A Longitudinal Study of 1.3 Million Articles in Major Publications,” Headache: The Journal of Head and Face Pain 64, no. 2 (2024): 172–78, https://doi.org/10.1111/head.14661.

7. The open-source dataset: Cornell Newsroom Summarization Dataset, accessed March 2, 2024, https://lil.nlp.cornell.edu/newsroom/index.html.

8. His career shooting average: Scottie Pippen career stats, ESPN, accessed March 4, 2024, https://www.espn.com/nba/player/stats/_/id/663/scottie-pippen.

9. on par with his superstar teammate: Michael Jordan career stats, ESPN, accessed March 4, 2024, https://www.espn.com/nba/player/stats/_/id/1035/michael-jordan.

10. “All I remember”: Scottie Pipper and Michael Arkush, Unguarded (New York: Atria Books, 2021), 96, https://www.simonandschuster.com/books/Unguarded/Scottie-Pippen/9781982165208.

11. Tribune sportswriter: Bernie Linciome, “No Covering Up This Bulls’ Mess,” Chicago Tribune, June 4, 1990, Archive.today, https://archive.md/HtHSx.

12. “Got a headache, Scottie?!”: “Scottie Pippen Still Battling a Curse—a Migraine Headache—That Has Haunted Him,” Chicago Tribune, May 24, 1991, Archive.today, https://archive.md/ByelP.

13. “Whatever Jordan”: “How The Last Dance Changed the Way We Think About Michael Jordan,” ESPN, May 18, 2020, https://www.espn.com/nba/story/_/id/29180240.

14. Joanna Kempner uses a single word: Joanna Leslie Kempner, Not Tonight: Migraine and the Politics of Gender and Health (Chicago: University of Chicago Press, 2014), 92–93.

15. And it’s worth noting: Anupom Roy, “The End of Stigma? Changes in the Social Experience of Long-Term Illness, by Gill Green,” book review, Anthropology & Medicine 17, no. 3 (2010): 343–45, https://www.tandfonline.com/doi/full/10.1080/13648470.2010.526701.

16. Alliance for Headache Disorders Advocacy: AHDA: Alliance for Headache Disorders Advocacy website, accessed April 8, 2024, https://allianceforheadacheadvocacy.org/.

17. (CHAMP): CHAMP: Coalition for Headache and Migraine Patients website, accessed April 8, 2024, https://headachemigraine.org/.

18. Migraine World Summit: Migraine World Summit website, accessed April 8, 2024, https://migraineworldsummit.com/.

19. Miles for Migraine: Miles For Migraine website, accessed April 8, 2024, https://www.milesformigraine.org/.

20. quite so pat: Joanna Kempner, “Brains Under Siege: Assessing the Harmful Effects of Migraine-Related Stigma,” Neurology 102, no. 3 (February 13, 2024): e209192, https://doi.org/10.1212/WNL.0000000000209192.

21. One study: Rachel Kahn Best and Alina Arseniev-Koehler, “The Stigma of Diseases: Unequal Burden, Uneven Decline,” American Sociological Review 88, no. 5 (2023): 938–69, https://doi.org/10.1177/00031224231197436.

22. Writing in the journal Headache: Robert E. Shapiro, “What Will It Take to Move the Needle for Headache Disorders? An Advocacy Perspective,” Headache: The Journal of Head and Face Pain 60, no. 9 (2020): 2059–77, https://doi.org/10.1111/head.13913.

23. “It is, thus far, an invisible disease”: Jonathan Chang and Meghna Chakrabarti, “The Science of Headache Disorders,” On Point, WBUR, transcript, May 6, 2022, https://www.wbur.org/onpoint/2022/05/06/the-science-of-headache-disorders.

24. “Even the heaviest”: Provocations: Spiritual Writings of Søren Kierkegaard (New York: Plough Publishing House) 160.

25. The neurologist: Oliver Sacks, Migraine (New York: PenguinRandomHouse), 7.

Chapter 8: Awakenings (and Cats)

1. They were making: “The battle for better brain health,” BBC StoryWorks, accessed March 17, 2024, http://www.bbc.com/storyworks/facing-forward/the-battle-for-better-brain-health.

2. was first described: Michael G. Rosenfeld et al., “Production of a Novel Neuropeptide Encoded by the Calcitonin Gene via Tissue-Specific RNA Processing,” Nature 304, no. 5922 (1983): 129–35, https://doi.org/10.1038/304129a0.

3. The paper: George C. Cotzias, Melvin H. Van Woert, and Lewis M. Schiffer, “Aromatic Amino Acids and Modification of Parkinsonism,” New England Journal of Medicine 276, no. 7 (1967): 374–79, accessed March 25, 2024, https://www.nejm.org/doi/full/10.1056/NEJM196702162760703.

4. His work: Vikram K. Yeragani et al., “Arvid Carlsson, and the Story of Dopamine,” Indian Journal of Psychiatry 52, no. 1 (2010): 87–88, https://doi.org/10.4103/0019-5545.58907.

5. “The most important”: “L-Dopa for Treating Parkinson’s Disease,” Lasker Foundation, accessed March 16, 2024, https://laskerfoundation.org/winners/l-dopa-for-treating-parkinsons-disease/.

6. four years later: Michael A. Moskowitz et al., “Neurotransmitters and the Fifth Cranial Nerve: Is There a Relation to the Headache Phase of Migraine?,” The Lancet 314, no. 8148 (1979): 883–85, https://doi.org/10.1016/S0140-6736(79)92692-8.

7. In 1983: Lee-Yuan Liu-Chen, Marc R. Mayberg, and Michael A. Moskowitz, “Immunohistochemical Evidence for a Substance P–Containing Trigeminovascular Pathway to Pial Arteries in Cats,” Brain Research 268, no. 1 (1983): 162–66, https://doi.org/10.1016/0006-8993(83)90402-X.

8. helped to identify: L. -I. Larsson et al., “Immunohistochemical Localization of a Vasodilatory Polypeptide (VIP) in Cerebrovascular Nerves,” Brain Research 113, no. 2 (1976): 400–404, https://doi.org/10.1016/0006-8993(76)90951-3.

9. Biographies frequently mention: Udani Samarasekera, “Lars Edvinsson: Bench-to-Bedside Discovery,” The Lancet Neurology 21, no. 1 (2022): 27, https://doi.org/10.1016/S1474-4422(21)00323-9.

10. In an almost casual aside: Lars Edvinsson, “Functional Role of Perivascular Peptides in the Control of Cerebral Circulation,” Trends in Neurosciences 8, (1985): 126-131.

11. Olesen, who had already: Jes Olesen et al., “Spreading Cerebral Oligemia in Classical- and Normal Cerebral Blood Flow in Common Migraine,” Headache: The Journal of Head and Face Pain 22, no. 6 (1982): 242–48, https://doi.org/10.1111/j.1526-4610.1982.hed2206242.x.

12. The activists were sentenced: Steven Morris, David Ward, and Riazat Butt, “Jail for Animal Rights Extremists Who Stole Body of Elderly Woman from Her Grave,” The Guardian, May 11, 2006, sec. UK news, https://www.theguardian.com/uk/2006/may/12/animalwelfare.topstories3.

13. They absconded: Jim Edwards, “Activists Post Photos of Novartis CEO’s Family Grave; Threaten to Flush Mom’s Ashes Down Toilet,” CBS News, August 24, 2009, https://www.cbsnews.com/news/activists-post-photos-of-novartis-ceos-family-grave-threaten-to-flush-moms-ashes-down-toilet/.

14. Goadsby and Edvinsson: Inger Jansen-Olesen et al., “Vasoactive Intestinal Peptide (VIP) Like Peptides in the Cerebral Circulation of the Cat,” Journal of the Autonomic Nervous System 49, Supplement (1994): 97–103, https://doi.org/10.1016/0165-1838(94)90095-7.

15. A similar release: P. J. Goadsby, L. Edvinsson, and R. Ekman, “Vasoactive Peptide Release in the Extracerebral Circulation of Humans During Migraine Headache,” Annals of Neurology 28, no. 2 (1990): 183–87, https://doi.org/10.1002/ana.410280213.

16. the pair would go on: Peter J. Goadsby and Lars Edvinsson, “Human In Vivo Evidence for Trigeminovascular Activation in Cluster Headache. Neuropeptide Changes and Effects of Acute Attacks Therapies,” Brain 117, no. 3 (1994): 427–34, https://doi.org/10.1093/brain/117.3.427.

17. Researchers in the UK: Linda M. McLatchie et al., “RAMPs Regulate the Transport and Ligand Specificity of the Calcitonin-Receptor-Like Receptor,” Nature 393, no. 6683 (1998): 333–39, https://doi.org/10.1038/30666.

18. Olesen and other researchers: L. H. Lassen et al., “CGRP May Play a Causative Role in Migraine,” Cephalalgia 22, no. 1 (2002): 54–61, https://doi.org/10.1046/j.1468-2982.2002.00310.x.

19. The pair had demonstrated: Goadsby, Edvinsson, and Ekman, “Vasoactive Peptide Release in the Extracerebral Circulation of Humans During Migraine Headache.”

20. “For a decade”: Lars Edvinsson and Peter J. Goadsby, “Discovery of CGRP in Relation to Migraine,” Cephalalgia 39, no. 3 (2019): 331–32, https://doi.org/10.1177/0333102418779544.

21. Multiple animal studies: Ray Hill, “NK1 (Substance P) Receptor Antagonists—Why Are They Not Analgesic in Humans?,” Trends in Pharmacological Sciences 21, no. 7 (2000): 244–46, https://doi.org/10.1016/s0165-6147(00)01502-9.

22. But as failures: H.-C. Diener, “Rpr100893, A Substance-P Antagonist, Is Not Effective in the Treatment of Migraine Attacks,” Cephalalgia 23, no. 3 (2003): 183–85, https://doi.org/10.1046/j.1468-2982.2003.00496.x.

23. “These are highly effective”: Arne May and Peter J. Goadsby, “Substance P Receptor Antagonists in the Therapy of Migraine,” Expert Opinion on Investigational Drugs 10, no. 4 (2001): 673–78, https://doi.org/10.1517/13543784.10.4.673.

24. The CGRP inhibitor: Jamie Ducharme, “A Treatment for Migraines,” Best Inventions 2018, Time, accessed March 23, 2024, https://time.com/collection/best-inventions-2018/5455662/aimovig/.

25. including a lifetime achievement award: “Go Behind the Scenes with Groundbreaking Neuroscientist Cen Xu,” Amgen, October 26, 2020, accessed March 25, 2024, https://www.amgen.com/stories/2020/10/go-behind-the-scenes-with-groundbreaking-neuroscientist-cen-xu.

26. Boheringer Ingelheim: Henri Doods et al., “Pharmacological Profile of BIBN4096BS, the First Selective Small Molecule CGRP Antagonist,” British Journal of Pharmacology 129, no. 3 (2000): 420–23, https://doi.org/10.1038/sj.bjp.0703110.

27. The results of the trial: Jes Olesen et al., “Calcitonin Gene-Related Peptide Receptor Antagonist BIBN 4096 BS for the Acute Treatment of Migraine,” New England Journal of Medicine 350, no. 11 (2004): 1104–10, https://doi.org/10.1056/NEJMoa030505.

28. At Bristol Myers Squibb: Carmen Drahl, “BMS-927711Bristol-Myers Squibb,” Chemical & Engineering News, April 16, 2012, accessed March 24, 2024, https://cen.acs.org/articles/90/i16/BMS-927711Bristol-Myers-Squibb.html.

29. “I am pleased to tell you”: “Merck 2006 Annual Business Briefing—Final,” Fair Disclosure Wire, December 12, 2006.

30. Two years later: “Merck Abandons Development of Migraine Drug,” HCP Live, July 29, 2011, https://www.hcplive.com/view/merck-abandons-development-of-migraine-drug.

31. A postmortem: P. Christopher H. Gottschalk, “Telcagepant—Almost Gone, but Not to Be Forgotten (Invited Editorial Related to Ho et al., 2015),” Cephalalgia 36, no. 2 (2016): 103–5, https://doi.org/10.1177/0333102415584311.

32. Amgen was already busy: Carl D. Davis and Cen Xu, “The Tortuous Road to an Ideal CGRP Function Blocker for the Treatment of Migraine,” Current Topics in Medicinal Chemistry 8, no. 16 (2008): 1468–79, https://doi.org/10.2174/156802608786264218.

33. Looking back: Alan M. Rapoport, “Gepant Safety & Lack of Liver Toxicity: Highlights from AAN 2019,” MDedge, June 18, 2019, accessed March 24, 2024, https://www.mdedge.com/migraine-icymi/article/203105/headache-migraine/gepant-safety-lack-liver-toxicity-highlights-aan.

34. called the ditans: Dimos D. Mitsikostas et al., “The 5-HT1F Receptor as the Target of Ditans in Migraine—from Bench to Bedside,” Nature Reviews Neurology 19, no. 8 (2023): 489–505, https://doi.org/10.1038/s41582-023-00842-x.

35. after it acquired: Vishnu Priyan, “Pfizer Acquires Biopharma Firm Biohaven for $11.6bn,” Pharmaceutical Technology (blog), October 4, 2022, https://www.pharmaceutical-technology.com/news/pfizer-acquires-biohaven-pharmaceutical/.

36. which was acquired: Richard A. Gonzalez, “Three Factors That Drove the Transformational Integration of AbbVie, Allergan,” AbbVie, Pharmaceutical Research & Development, November 30, 2022, accessed March 24, 2024, https://www.abbvie.com/who-we-are/our-stories/three-factors-that-drove-transformational-integration-abbvie-allergan.html.

37. claims to have spent: Eric Sagonowsky, “Novartis, Amgen Settle Their Dueling Lawsuits over Migraine Drug Aimovig,” Fierce Pharma,” February 1, 2022, https://www.fiercepharma.com/pharma/novartis-amgen-settle-their-dueling-lawsuits-over-migraine-drug-aimovig.

38. the market: “CGRP Inhibitors Market Booms at 12% CAGR, Soaring from US$300 Million to US$663 Million by 2030, Persistence Market Research,” Yahoo! Finance, January 17, 2024, https://finance.yahoo.com/news/cgrp-inhibitors-market-booms-12-161500064.html.

39. They settled: Sagonowsky, “Novartis, Amgen Settle Their Dueling Lawsuits.”

40. but a Massachusetts federal judge: Kevin Dunleavy, “In Emgality patent case against Teva, Lilly wins reversal of $177M verdict,” Fierce Pharma, September 27, 2023, https://www.fiercepharma.com/pharma/lilly-gets-reversal-against-teva-judge-overturns-176m-verdict.

41. with some studies touting: Katharina Kaltseis et al., “Monoclonal Antibodies against CGRP (R): Non-Responders and Switchers: Real World Data from an Austrian Case Series,” BMC Neurology 23, no. 1 (April 28, 2023): 174, https://doi.org/10.1186/s12883-023-03203-9.

42. others are closer: Caio Vinicius de Meira Grava Simioni, “Why Are CGRP Monoclonal Antibodies Not Yet the First Line Treatment in Migraine Prevention?,” Arquivos de Neuro-Psiquiatria 80, no. 5 Suppl. 1 (2022): 214–17, https://doi.org/10.1590/0004-282X-ANP-2022-S125.

43. even miraculous—results: Bianca Raffaelli et al., “Clinical Evaluation of Super-Responders vs. Non-Responders to CGRP(-Receptor) Monoclonal Antibodies: A Real-World Experience,” Journal of Headache and Pain 24, no. 1 (2023): 16, https://doi.org/10.1186/s10194-023-01552-x.

44. And yet there is emerging evidence: Thanin Asawavichienjinda, Seelwan Sathitratanacheewin, and Ronpichai Chokesuwattanaskul, “‘Wearing-off’ Efficacy of CGRP Monoclonal Antibodies for Migraine Prevention: A Meta-analysis of Randomized Controlled Trials,” Cephalalgia 43, no. 4 (2023), accessed March 25, 2024, https://journals.sagepub.com/doi/full/10.1177/03331024231161261.

45. some physicians have urged caution: Lawrence Robbins, “At Stake: The Possible Long-Term Side Effects of Prescribing CGRP Antagonists,” MedCentral, February 24, 2020, https://www.medcentral.com/neurology/migraine/stake-possible-long-term-side-effects-cgrp-antagonists.

46. One potential complication: Richard H. Woods, “Alopecia Signals Associated with Calcitonin Gene-Related Peptide Inhibitors in the Treatment or Prophylaxis of Migraine: A Pharmacovigilance Study,” Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 42, no. 10 (2022): 758–67, https://doi.org/10.1002/phar.2725.

47. are seeing increased numbers: U.S. Food and Drug Administration, “FDA Adverse Events Reporting System (FAERS) Public Dashboard,” accessed March 25, 2024, https://fis.fda.gov/sense/app/95239e26-e0be-42d9-a960-9a5f7f1c25ee/sheet/45beeb74-30ab-46be-8267-5756582633b4/state/analysis.

48. Scientists are tracking: Miguel Ruiz et al., “Alopecia as an Emerging Adverse Event to CGRP Monoclonal Antibodies: Cases Series, Evaluation of FAERS, and Literature Review,” Cephalalgia 43, no. 2 (February 2023): 3331024221143538, https://doi.org/10.1177/03331024221143538.

49. “The CGRP-targeting therapies”: Andrew C. Charles et al., “Calcitonin Gene-Related Peptide-Targeting Therapies Are a First-Line Option for the Prevention of Migraine: An American Headache Society Position Statement Update,” Headache: The Journal of Head and Face Pain 64, no. 4 (2024): 333–41, accessed March 25, 2024, https://doi.org/10.1111/head.14692.

50. even as other neuropeptides: Masaru Tanaka et al., “From CGRP to PACAP, VIP, and Beyond: Unraveling the Next Chapters in Migraine Treatment,” Cells 12, no. 22 (2023): 2649, https://doi.org/10.3390/cells12222649.

51. “I do believe”: Advances in Migraine Science, “Debate: Migraine and Cluster Headache Are Two Distinct Disorders | Drs. Petersen & Peng | ICAMS 2022,” YouTube, video, March 22, 2022, https://www.youtube.com/watch?v=uUimmnDVTTE.

52. “Opening of the channel”: Amalie Clement et al., “The ATP Sensitive Potassium Channel (KATP) Is a Novel Target for Migraine Drug Development,” Frontiers in Molecular Neuroscience 16 (2023), https://www.frontiersin.org/articles/10.3389/fnmol.2023.1182515.

53. That study: Mohammad Al-Mahdi Al-Karagholi et al., “Effect of KATP Channel Blocker Glibenclamide on Levcromakalim-Induced Headache,” Cephalalgia 40, no. 10 (2020): 1045–54, https://doi.org/10.1177/0333102420949863.

54. The paper was eventually published: Thien Phu Do et al., “Second Messenger Signalling Bypasses CGRP Receptor Blockade to Provoke Migraine Attacks in Humans,” Brain 146, no. 12 (2023): 5224–34, https://doi.org/10.1093/brain/awad261.

55. and a follow-up analysis: Bianca Raffaelli et al., “Activation of ATP-Sensitive Potassium Channels Triggers Migraine Attacks Independent of Calcitonin Gene-Related Peptide Receptors: A Randomized Placebo-Controlled Trial,” Cephalalgia 44, no. 1 (): 03331024231222916, https://doi.org/10.1177/03331024231222916.

Chapter 9: Feast, Famine, and the NIH

1. Helping to End Addiction Long-term: U.S. Department of Health and Human Services, National Institutes of Health, “The Helping to End Addiction Long-term Initiative,” accessed July 20, 2023, https://heal.nih.gov/.

2. in its fiscal 2009 report: GovInfo, “Senate Report 110–410—Departments of Labor, Health and Human Services, and Education, and Related Agencies Appropriation Bill, 2009,” accessed April 6, 2024, https://www.govinfo.gov/content/pkg/CRPT-110srpt410/html/CRPT-110srpt410.htm.

3. The 2019 House appropriations committee report: GovInfo, “House Report 115–862—Departments of Labor, Health and Human Services, and Education, and Related Agencies Appropriations Bill, 2019,” accessed April 6, 2024, https://www.govinfo.gov/content/pkg/CRPT-115hrpt862/html/CRPT-115hrpt862.htm.

4. As a 2023 report: Drew C. Aherne, “Appropriations Report Language: Overview of Development and Components,” Congressional Research Service, March 22, 2023, accessed January 27, 2025, https://crsreports.congress.gov/product/pdf/R/R44124/13.

5. a radio appearance: Jonathan Chang and Meghna Chakrabarti, “The Science of Headache Disorders,” On Point, WBUR, transcript, May 6, 2022, https://www.wbur.org/onpoint/2022/05/06/the-science-of-headache-disorders.

6. A 2023 study: Nikolaj Siersbæk et al., “Real-World Evidence on the Economic Implications of CGRP-mAbs as Preventive Treatment of Migraine,” BMC Neurology 23, no. 1 (2023): 254, https://doi.org/10.1186/s12883-023-03302-7.

7. Assuming the incidence: Fred Cohen et al., “Prevalence and Burden of Migraine in the United States: A Systematic Review,” Headache: The Journal of Head and Face Pain 64, no. 5 (2024): 516–32, https://doi.org/10.1111/head.14709.

8. pointed me to a 2004 entry: “I’m Outa Sorts Tonight,” Say What? (blog), September 4, 2004, accessed April 1, 2024, https://onekgguy.blogspot.com/2004/09/im-outa-sorts-tonight.html.

9. One early analysis: X. Henry Hu et al., “Burden of Migraine in the United States: Disability and Economic Costs,” Archives of Internal Medicine 159, no. 8 (1999): 813–18, https://doi.org/10.1001/archinte.159.8.813.

10. A more updated accounting: Machaon Bonafede et al., “Direct and Indirect Healthcare Resource Utilization and Costs Among Migraine Patients in the United States,” Headache: The Journal of Head and Face Pain 58, no. 5 (2018): 700–714, https://doi.org/10.1111/head.13275.

11. By comparison: U.S. Centers for Disease Control and Prevention, “Health and Economic Costs of Chronic Diseases,” accessed March 23, 2023, https://www.cdc.gov/chronic-disease/data-research/facts-stats/.

12. A 2020 study out of Australia: Susan Tu Student et al., “The Health and Productivity Burden of Migraines in Australia,” Headache: The Journal of Head and Face Pain 60, no. 10 (2020): 2291–303, https://doi.org/10.1111/head.13969.

13. In China, a 2019 analysis: Takao Takeshima et al., “Prevalence, Burden, and Clinical Management of Migraine in China, Japan, and South Korea: A Comprehensive Review of the Literature,” Journal of Headache and Pain 20, no. 1 (2019): 111, https://doi.org/10.1186/s10194-019-1062-4.

14. but a 2018 analysis: Casey K. Choong et al., “Health Care Utilization and Direct Costs Among Patients Diagnosed with Cluster Headache in U.S. Health Care Claims Data,” Journal of Managed Care & Specialty Pharmacy 24, no. 9 (2018): 921–28, https://doi.org/10.18553/jmcp.2018.24.9.921.

15. A 2022 analysis: Anja Sofie Petersen et al., “The Economic and Personal Burden of Cluster Headache: A Controlled Cross-Sectional Study,” Journal of Headache and Pain 23, no. 1 (2022): 58, https://doi.org/10.1186/s10194-022-01427-7.

16. interagency meeting: U.S. Department of Health and Human Services, National Institutes of Health, Interagency Pain Research Coordinating Committee Meeting—September 2014, video, September 24, 2014, https://videocast.nih.gov/watch=14528.

17. the NIH had announced: “Announcing a Simplified Review Framework for NIH Research Project Grant Applications—NIH Extramural Nexus,” October 19, 2023, accessed February 9, 2025, https://nexus.od.nih.gov/all/2023/10/19/announcing-a-simplified-review-framework-for-nih-research-project-grant-applications/.

18. the agency’s premiere criterion: “Who Can Get Disability,” Social Security Administration, accessed April 3, 2024, https://www.ssa.gov/disability/eligibility.

19. issued a mixed decision: “Shapiro v. United States Social Security Administration,” The FOIA Project (blog), accessed April 2, 2024, https://foiaproject.org/case_detail/?title=on&style=foia&case_id=33137.

20. filed an amicus brief: Robert E Shapiro, “In the United States Court of Appeals for the Second Circuit,” Reporters Committee for the Freedom of the Press, filed December 15, 2022, accessed January 27, 2025, https://www.rcfp.org/briefs-comments/shapiro-v-ssa/.

21. interpretation ruling: “SSR 19-4p: Titles II and XVI: Evaluating Cases Involving Primary Headache Disorders,” Social Security Administration, accessed April 3, 2024, https://www.ssa.gov/OP_Home/rulings/di/01/SSR2019-04-di-01.html.

22. In fiscal year 2022: U.S. Department of Health and Human Services, National Institutes of Health, “NIH Research Grants—Digital Media Kit,” https://www.nih.gov/news-events/nih-research-grants-digital-press-kit.

23. NIH largesse: Lindsay R. Pool et al., “Size and Characteristics of the Biomedical Research Workforce Associated with U.S. National Institutes of Health Extramural Grants,” FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology 30, no. 3 (2016): 1023–36, https://doi.org/10.1096/fj.14-264358.

24. has long argued: U.S. Department of Health and Human Services, National Institutes of Health, NIH Center for Scientific Review, “About CSR,” accessed April 5, 2024, https://public.csr.nih.gov/AboutCSR.

25. A 2019 Congressional Research Service report: Judith A Johnson and Kavya Sekar, “The National Institutes of Health (NIH): Background and Congressional Issues,” Congressional Research Service, April 19, 2019, accessed January 27, 2025, https://crsreports.congress.gov/product/pdf/R/R41705/27.

26. according to a 2023 CRS analysis: “National Institutes of Health (NIH) Funding: FY1996-FY2023,” accessed January 27, 2025, https://crsreports.congress.gov/product/pdf/R/R43341/45.

27. the 2009 Senate appropriations committee report: “Senate Report 110–410—Departments of Labor, Health and Human Services, and Education, and Related Agencies Appropriation Bill, 2009.”

28. The 2019 House report: “House Report 115–862—Departments of Labor, Health and Human Services, and Education, and Related Agencies Appropriations Bill, 2019,” accessed January 27, 2025, https://www.govinfo.gov/content/pkg/CRPT-115hrpt862/html/CRPT-115hrpt862.htm.

29. available online: U.S. Department of Health and Human Services, National Institutes of Health, RePORT, “Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC),” accessed January 27, 2025, https://report.nih.gov/funding/categorical-spending#/.

30. Headache on the Hill event: “Headache on the Hill,” Alliance for Headache Disorders Advocacy, accessed April 7, 2024, https://allianceforheadacheadvocacy.org/headache-on-the-hill/.

31. possibly spurred: Rob Stein, “NIH Plans to Lift Ban On Research Funds for Part-Human, Part-Animal Embryos,” NPR, August 4, 2016, Gene Editing Raises Hopes, Fears special series, https://www.npr.org/sections/health-shots/2016/08/04/488387729/nih-plans-to-lift-ban-on-research-funds-for-part-human-part-animal-embryos.

32. “NIH believes”: U.S. Department of Health and Human Services, National Institutes of Health, “Report on NIH Funding vs. Global Burden of Disease,” 2017, https://report.nih.gov/report-nih-funding-vs-global-burden-disease.

33. a reformation: Rob Stein, “With Trump Coming into Power, the NIH Is in the Crosshairs,” NPR, November 12, 2024, sec. Health, https://www.npr.org/2024/11/12/nx-s1-5183014/trump-election-2024-nih-rfk.

34. which earned the ire: Pamela Paul, “When Public Health Loses the Public,” New York Times, January 18, 2024, sec. Opinion, https://www.nytimes.com/2024/01/18/opinion/public-health-trust.html.

35. Proposals for modernizing: U.S. Senate Committee on Health, Education, Labor & Pensions, “Ranking Member Cassidy Releases New Proposals to Modernize NIH,” press release, May 9, 2024, https://www.help.senate.gov/ranking/newsroom/press/ranking-member-cassidy-releases-new-proposals-to-modernize-nih.

36. “We will reform”: Jay Bhattacharya (@DrJBhattacharya): “I Am Honored and Humbled by President @realDonaldTrump’s nomination of me to be the next @NIH director. We will reform American scientific institutions so that they are worthy of trust again and will deploy the fruits of excellent science to make America healthy again!,” X (formerly Twitter), November 27, 2024, https://x.com/DrJBhattacharya/status/1861586856590320071.

37. But several studies have shown: “How Much Does the United States Spend on Prescription Drugs Compared to Other Countries?,” Peterson Foundation (blog), accessed January 30, 2025, https://www.pgpf.org/article/how-much-does-the-united-states-spend-on-prescription-drugs-compared-to-other-countries/.

38. and when measuring daily dosage amounts: “The Global Use of Medicines 2022,” accessed January 30, 2025, https://www.iqvia.com/insights/the-iqvia-institute/reports-and-publications/reports/the-global-use-of-medicines-2022.

39. and many others will be harmed: “The Dark Side of the Pharmaceutical Industry,” AJMC, April 14, 2016, accessed February 12, 2025, https://www.ajmc.com/view/the-dark-side-of-the-pharmaceutical-industry.

40. sometimes markedly so: Jason D. Buxbaum et al., “Contributions Of Public Health, Pharmaceuticals, And Other Medical Care To US Life Expectancy Changes, 1990-2015,” accessed February 12, 2025, https://Doi.Org/10.1377/Hlthaff.2020.00284, September 8, 2020, https://doi.org/10.1377/hlthaff.2020.00284.

41. Kennedy, who infamously recommended: “As Measles Spreads, Kennedy Embraces Remedies Like Cod Liver Oil,” New York Times, March 4, 2025, https://www.nytimes.com/2025/03/04/health/texas-measles-outbreak-kennedy.html.

42. the NIH announced: “NIH Announces It’s Slashing Funding for Indirect Research Costs,” NBC News, February 8, 2025, https://www.nbcnews.com/politics/politics-news/nih-announces-slashing-funding-indirect-research-costs-rcna191337.

43. but many critics suggested: Bianca Quilantan, “Higher Education Leaders Decry NIH Cuts in Research Funding,” POLITICO, February 10, 2025, accessed February 12, 2025, https://www.politico.com/newsletters/weekly-education/2025/02/10/higher-education-leaders-decry-nih-cuts-in-research-funding-00203284.

44. Lawsuits aimed at blocking the cuts: Ellie Wolfe Cohn Meredith, “Johns Hopkins Sues Federal Government over NIH Funds,” The Baltimore Banner, February 11, 2025, accessed February 12, 2025, https://www.thebaltimorebanner.com/education/higher-education/johns-hopkins-nih-federal-funds-lawsuit-FUEQYYTVNFEZJMSVCASDET3NJY/.

45. continues to press the case: Robert E. Shapiro et al., “Migraine-Related Stigma and Its Relationship to Disability, Interictal Burden, and Quality of Life,” Neurology 102, no. 3 (2024): e208074, https://doi.org/10.1212/WNL.0000000000208074.

46. Most familiar drugs: U.S. Food and Drug Administration, Center for Drug Evaluation and Research, “Frequently Asked Questions on Patents and Exclusivity,” accessed November 11, 2024, https://www.fda.gov/drugs/development-approval-process-drugs/frequently-asked-questions-patents-and-exclusivity.

47. sometimes by making minor tweaks: Gregory H. Jones et al., “Strategies That Delay or Prevent the Timely Availability of Affordable Generic Drugs in the United States,” Blood 127, no. 11 (2016): 1398–402, https://doi.org/10.1182/blood-2015-11-680058.

48. a practice known: Federal Trade Commission, “Pay for Delay,” accessed November 11, 2024, https://www.ftc.gov/news-events/topics/competition-enforcement/pay-delay.

49. This is an FDA-granted status: U.S. Food and Drug Administration, Center for Drug Evaluation and Research, “Small Business Assistance: Frequently Asked Questions for New Drug Product Exclusivity,” November 11, 2024, https://www.fda.gov/drugs/cder-small-business-industry-assistance-sbia/small-business-assistance-frequently-asked-questions-new-drug-product-exclusivity.

Chapter 10: The Blind Men and the Elephant

1. For decades: Bronson S. Ray and Harold G. Wolff, “Experimental Studies on Headache: Pain-Sensitive Structures of the Head and Their Significance in Headache,” Archives of Surgery 41, no. 4 (1940): 813–56, https://doi.org/10.1001/archsurg.1940.01210040002001.

2. The French researchers: Denys Fontaine et al., “Dural and Pial Pain-Sensitive Structures in Humans: New Inputs from Awake Craniotomies,” Brain 141, no. 4 (2018): 1040–48, https://doi.org/10.1093/brain/awy005.

3. The proximate reason: “Referred Pain,” Cleveland Clinic, accessed March 9, 2024, https://my.clevelandclinic.org/health/symptoms/25238-referred-pain.

4. he sent me a paper: Neil H. Raskin, Yoshio Hosobuchi, and Sharon Lamb, “Headache May Arise from Perturbation of Brain,” Headache: The Journal of Head and Face Pain 27, no. 8 (1987): 416–20, https://doi.org/10.1111/j.1526-4610.1987.hed2708416.x.

5. educational video: NIHNINDS, Truth or Myth: The Brain Does Not Feel Pain, YouTube, video, March 17, 2022, https://www.youtube.com/watch?v=R-yFKSbH_dg.

6. One 2013 study: Mollie M. Johnston, Sheldon E. Jordan, and Andrew C. Charles, “Pain Referral Patterns of the C1 to C3 Nerves: Implications for Headache Disorders,” Annals of Neurology 74, no. 1 (2013): 145–48, https://doi.org/10.1002/ana.23869.

7. Recent research: Sanne Andersen et al., “Pressure Pain Thresholds Assessed over Temporalis, Masseter, and Frontalis Muscles in Healthy Individuals, Patients with Tension-Type Headache, and Those with Migraine—a Systematic Review,” Pain 156, no. 8 (2015): 1409–23, https://doi.org/10.1097/j.pain.0000000000000219.

8. And a July 2023 paper: Rodrigo Noseda and Luis Villanueva, “Central Generators of Migraine and Autonomic Cephalalgias as Targets for Personalized Pain Management: Translational Links,” European Journal of Pain 27, no. 9 (2023): 1126–38, https://doi.org/10.1002/ejp.2158.

9. An old Buddhist parable: Eugene Watson Burlingame, Buddhist Parables (New Haven, CT: Yale University Press, 1922), 75–76, http://archive.org/details/buddhistparables00burl.

10. The nineteenth-century American poet: John Godfrey Saxe, “The Blind Men and the Elephant,” 1873, CommonLit, accessed March 10, 2024, https://www.commonlit.org/en/texts/the-blind-men-and-the-elephant (login required).

11. The proposition was simple: Advances in Migraine Science, Debate: Migraine Attacks Are of Peripheral Origin | Drs. Thien P. Do & Anders Hougaard | ICAMS 2022, YouTube, video, March 30, 2022, https://www.youtube.com/watch?v=NC0nlcKohz0.

12. One study in particular: Laura H. Schulte, Jan Mehnert, and Arne May, “Longitudinal Neuroimaging over 30 Days: Temporal Characteristics of Migraine,” Annals of Neurology 87, no. 4 (2020): 646–51, https://doi.org/10.1002/ana.25697.

13. In a paper copublished: Thien Phu Do et al., “Migraine Attacks Are of Peripheral Origin: The Debate Goes On,” Journal of Headache and Pain 24, no. 1 (2023): 3, https://doi.org/10.1186/s10194-022-01538-1.

14. In a 2012 perspective paper: Andrew Charles, “Migraine Is Not Primarily a Vascular Disorder,” Cephalalgia 32, no. 5 (2012): 431–32.

15. Olesen’s study: Jes Olesen et al., “Timing and Topography of Cerebral Blood Flow, Aura, and Headache During Migraine Attacks,” Annals of Neurology 28, no. 6 (1990): 791–98, https://doi.org/10.1002/ana.410280610.

16. Other studies: G. G. Schoonman et al., “Migraine Headache Is Not Associated with Cerebral or Meningeal Vasodilatation—a 3T Magnetic Resonance Angiography Study,” Brain 131, no. 8 (2008): 2192–200, https://doi.org/10.1093/brain/awn094.

17. Olesen and Ashina themselves: A. Rahmann et al., “Vasoactive Intestinal Peptide Causes Marked Cephalic Vasodilation, but Does Not Induce Migraine,” Cephalalgia 28, no. 3 (2008): 226–36, https://doi.org/10.1111/j.1468-2982.2007.01497.x.

18. a 2013 commentary: Andrew Charles, “Vasodilation out of the Picture as a Cause of Migraine Headache,” The Lancet Neurology 12, no. 5 (2013): 419–20, https://doi.org/10.1016/S1474-4422(13)70051-6.

19. work done by the Denmark group: Faisal Mohammad Amin et al., “Magnetic Resonance Angiography of Intracranial and Extracranial Arteries in Patients with Spontaneous Migraine Without Aura: A Cross-Sectional Study,” The Lancet Neurology 12, no. 5 (2013): 454–61, https://doi.org/10.1016/S1474-4422(13)70067-X.

20. A 2016 paper: Jacobs and Dussor, “Neurovascular Contributions to Migraine: Moving beyond Vasodilation.”

21. And yet, in 2002: Manjit S. Matharu and Peter J. Goadsby, “Persistence of Attacks of Cluster Headache After Trigeminal Nerve Root Section,” accessed March 11, 2024, https://oce-ovid-com.libproxy.mit.edu/article/00002423-200205000-00006 (login required).

22. She likened them: Mohammad Al-Mahdi Al-Karagholi et al., “Debate: Are Cluster Headache and Migraine Distinct Headache Disorders?,” Journal of Headache and Pain 23, no. 1 (2022): 151, https://doi.org/10.1186/s10194-022-01504-x.

23. A paper: Angela M. Applebee and Robert E. Shapiro, “Cluster-Migraine: Does It Exist?,” Current Pain and Headache Reports 11, no. 2 (2007): 154–57, https://doi.org/10.1007/s11916-007-0014-x.

24. who has joined: Jes Olesen et al., “Origin of Pain in Migraine: Evidence for Peripheral Sensitisation,” The Lancet. Neurology 8, no. 7 (2009): 679–90, https://doi.org/10.1016/S1474-4422(09)70090-0.

25. there are strange tributaries: Nancy Averett, “Do Animals Really Anticipate Earthquakes? Sensors Hint They Do,” Scientific American, July 31, 2020, Archive.today, https://archive.md/iJHIU.

26. And canine companions: “Migraine Service Dogs,” American Migraine Foundation, August 26, 2022, accessed March 19, 2024, https://americanmigrainefoundation.org/resource-library/migraine-service-dogs/.

27. ultimate prize: Bill McGuire, “How to Stop an Earthquake,” BBC Science Focus, April 26, 2018, accessed March 17, 2024, https://www.sciencefocus.com/planet-earth/how-to-stop-an-earthquake.

Epilogue: Our Many Forking Paths

1. seeking to patent: Andrew Charles, Guido Faas, and Dmitri Yousef Yengej, “Microchip Based Recording of Neurovascular Activity and Behavior,” United States Patent application US20240041386A1, filed October 18, 2023, issued February 8, 2024, Google Patents, https://patents.google.com/patent/US20240041386A1/en.

2. reported in early 2024: Lanfranco Pellesi, Messoud Ashina, and Paolo Martelletti, “Targeting the PACAP-38 Pathway Is an Emerging Therapeutic Strategy for Migraine Prevention,” Expert Opinion on Emerging Drugs 29, no. 1 (2024): 57–64, https://doi.org/10.1080/14728214.2024.2317778.

3. implanted devices: “Occipital nerve stimulation: Effective migraine treatment?” Mayo Clinic, accessed April 9, 2024, https://www.mayoclinic.org/diseases-conditions/migraine-headache/expert-answers/occipital-nerve-stimulation/faq-20057788.

4. claims to stimulate: “Relivion MG—Drug-Free Migraine Relief Never Felt So Good,” Relivion, accessed April 9, 2024, https://www.relivion.com/.

5. “proprietary gentle electrical energy”: “How gammaCore Works,” gammaCore, accessed April 9, 2024, https://www.gammacore.com/about/how-gammacore-works/.

6. spearheading some interesting studies: Chorong Han et al., “Regulation of Headache Response and Transcriptomic Network by the Trigeminal Ganglion Clock,” Headache: The Journal of Head and Face Pain 64, no. 2 (2024): 195–210, https://doi.org/10.1111/head.14670.

7. actively recruiting: Mark J. Burish, “High Dose Vitamin D Plus Multivitamin in the Prevention of Cluster Headache,” clinical trial registration, ClinicalTrials.gov, November 27, 2023, https://clinicaltrials.gov/study/NCT04570475.

8. a notion arising: “D3 Vitamin Therapy and Loading Details,” Clusterbusters, April 25, 2023, https://clusterbusters.org/resource/d3-vitamin-therapy-and-loading-details/.

9. A 2019 randomized: David Yarnitsky et al., “Remote Electrical Neuromodulation (REN) Relieves Acute Migraine: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial,” Headache: The Journal of Head and Face Pain 59, no. 8 (2019): 1240–52, https://doi.org/10.1111/head.13551.

10. follow-up analysis: Jessica Ailani et al., “Real-World Analysis of Remote Electrical Neuromodulation (REN) for the Acute Treatment of Migraine,” Frontiers in Pain Research 2 (2021), https://doi.org/10.3389/fpain.2021.753736.

11. are continuing to probe: Risako A. Shirane et al., “Headache Horizons: The Study and Use of Psychedelics in Cluster Headache,” Practical Neurology, August 2023, accessed April 8, 2024, https://practicalneurology.com/articles/2023-aug/headache-horizons-the-study-and-use-of-psychedelics-in-cluster-headache.

12. continuing apace: Heidi G Sutherland, Bronwyn Jenkins, and Lyn R. Griffiths, “Genetics of Migraine: Complexity, Implications, and Potential Clinical Applications,” The Lancet Neurology 23, no. 4 (2024): 429–46, https://doi.org/10.1016/S1474-4422(24)00026-7.

13. as are histamine receptor modulators: Kritika Chaudhari and Basharut A. Syed, “The Pipeline and Market for Migraine Drugs,” Nature Reviews Drug Discovery 23, no. 4 (November 17, 2023): 246–47, https://doi.org/10.1038/d41573-023-00182-x.

14. It’s gaining in popularity: “Daith Piercings as Migraine Treatment,” American Migraine Foundation (blog), accessed April 9, 2024, https://americanmigrainefoundation.org/resource-library/daith-piercings-101/.

15. A 1941 short story: Jorge Luis Borges, “The Garden of Forking Paths,” 1941, Internet Archive, accessed April 10, 2024, http://archive.org/details/TheGardenOfForkingPathsJorgeLuisBorges1941.

16. though insurance coverage remains uneven: “Advocacy in Action: AHS Proposes Changes to Coverage for Home-Use Oxygen for Cluster Headache Attacks,” American Headache Society, July 21, 2021, accessed November 23, 2024, https://americanheadachesociety.org/news/advocacy-in-action-ahs-proposes-changes-to-coverage-for-home-use-oxygen-for-cluster-headache-attacks-2.

17. there is plenty of evidence: Timothy J. Steiner and Lars Jacob Stovner, “Global Epidemiology of Migraine and Its Implications for Public Health and Health Policy,” Nature Reviews Neurology 19, no. 2 (2023): 109–17, https://doi.org/10.1038/s41582-022-00763-1.

18. less likely to receive: Paul Rizzoli, “Health Disparities and Headache Treatment,” Harvard Health, February 15, 2022, https://www.health.harvard.edu/blog/health-disparities-and-headache-treatment-202202152685.

19. remains siloed: Dominique Mortel et al., “Barriers to Headache Care in Low- and Middle-Income Countries,” eNeurologicalSci 29 (2022): 100427, https://doi.org/10.1016/j.ensci.2022.100427.

20. a recent study: Olivia Begasse de Dhaem et al., “Workforce Gap Analysis in the Field of Headache Medicine in the United States,” Headache: The Journal of Head and Face Pain 60, no. 2 (2020): 478–81, https://doi.org/10.1111/head.13752.

21. To date: “UCNS Diplomate Directory,” United Council for Neurologic Subspecialties, accessed November 24, 2024, https://www.ucns.org/Online/Online/Diplomate_Directory.aspx.

22. He also pointed: Paul Steinhauser, “Biden Calls Trump Comments on US Troop Injuries in Iraq Missile Attack ‘Disgusting,’” Fox News Channel, January 24, 2020, https://www.foxnews.com/politics/biden-trump-troop-injuries-iran-missile-attack-iraq-disgusting.

23. Through efforts like Migraine Again: Migraine Again website, accessed November 23, 2024, https://www.migraineagain.com/.

24. and the annual Migraine World Summit: Migraine World Summit website, accessed November 23, 2024, https://migraineworldsummit.com/.

Index

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AbbVie, 188

advocacy

Alliance for Headache Disorders Advocacy (AHDA), 153–154, 195, 216

Clusterbusters, 11, 142–144, 154, 187

need for, 269–270

Please See Me journal, 26

for research funding, 156–157, 165, 195–199, 204–211, 214–216, 218, 222–225

Aero Medical Laboratory, 22

Aetius Amidenus, 80

Aetna, 63

Aimovig (Amgen and Novartis), 28–29, 104, 105, 181–188, 192, 195

Ajovy, 187–188, 266, 267

alcohol, 43, 168

Alliance for Headache Disorders Advocacy (AHDA), 153–154, 195, 216. See also Shapiro, Robert

allodynia, 235

Alvarez, Walter C., 124–126, 130

Alzheimer’s, 92–93, 213–214

American Academy of Neurology, 63, 112

American Board of Medical Specialties, 111

American Board of Psychiatry and Neurology, 111

American Headache Society (AHS), 23, 60–61, 63, 153–154, 189, 225

Amgen, 104, 181–187. See also Aimovig

amyloid cascade hypothesis (Alzheimer’s), 92–93

The Anatomy Lesson of Dr. Nicolaes Tulp (Rembrandt), 80

Anderson, Elizabeth Garrett, 85–86

animal experiments, for headache research, 127–128, 172, 175–179, 257–260

anticonvulsants, 102

antipsychotic drugs, 102–103

Aretaeus of Cappadocia, 76

aripiprazole, 102–103

artificial intelligence (AI), 4, 257–260

Ashina, Messoud, 31–32, 36–37, 167–169, 190–192, 242, 245

Athens University, 72

Auden, W. H., 146

aura

defined, 14

hereditability of migraine and, 119–120

prevalence of, in migraineurs, 239

triggers of, 168

vascular theories about, 89

autonomic nervous system, 42, 122–123

Avicenna (Ibn Sina), 78

Bari Aldo Moro University, 107, 113

“Beauty Is a Headache” (Lal), 123–126

Best, Rachel Kahn, 154–156

beta blockers, 102

Bhattacharya, Jay, 222

Bing, Paul Robert, 115

biofeedback therapy, 130–131

Blau, Joseph Norman, 137

blood-brain barrier, 137, 186, 187, 238, 242, 244, 253

blood circulation. See vascular system

The Body in Pain (Scarry), 4

Boehringer Ingelheim, 182, 252

Borges, Jorges Luis, 264–265

botulinum toxin (Botox), 61–62, 102, 263

Brain, French study on meninges, 230–231, 237

brain anatomy. See also neurotransmitters; trigeminal nerve

blood-brain barrier, 137, 186, 187, 238, 242, 244, 253

brain stem, 90

brain stem, primordial, 70

Broca’s area, 72, 90

cranial vasculature, Wolff on, 123, 127–132, 137, 174

dura mater, 179, 181, 230, 231, 233, 241, 246

gyrencephalic (human) vs. lissencephalic (rat), 178

hypothalamus, 14, 42–43, 52, 122–123, 253

meninges and, 27, 77, 78, 132–133, 137, 175, 230–231, 237

nociception and, 160–161, 172, 230–235, 237, 240, 241, 246, 249 (See also pathophysiology of headaches, contemporary beliefs)

occipital cortex, 68

parenchyma, 232–233

Brain Prize, 29, 32, 35, 167–171, 181, 243

A Brain Wider Than the Sky (Levy), 163

Brindley, James, 21

Bristol Myers Squibb, 183

Broca, Paul, 86, 90

Broca’s area, 72, 90

Bruegel, Pieter, 146

Brunton, Thomas Lauder, 73–74

burden-of-disease question. See research funding

Burish, Mark, 163

Burstein, Rami, 207–208, 219

Caelius Aurelianus, 77–78

caffeine, 95

calcitonin gene-related peptide (CGRP) inhibition, 167–193

for cluster headaches, 62–63

commercial research and introduction of, 28–30, 36, 104–105, 113, 181–187, 252

early study of, Brain Prize for, 167–171, 181

early understanding as target molecule in headache pain, 172–181

injections, 167, 187–188, 195, 266, 268

IV delivery of, 187, 266

KATP channels vs. CGRP as headache triggers, 190–193

monoclonal antibody (mAb) drugs, 186–190

pathophysiology of headaches and, 242, 246

Cao Cao (Chinese patient, fictionalized), 74, 76

Carlsson, Arvid, 172–173

carotid shunt theory of migraine, 134–135

Carroll, Lewis, 60

causes of headache. See pathophysiology of headaches

cauterization of the scalp, 77

central nervous system. See brain anatomy

centrifuge (gristmill) invention, 21–22

cephalalgia, 6, 76. See also headache pain

Cerebri Anatome (Anatomy of the Brain, Willis), 72

CGRP blockers. See calcitonin gene-related peptide (CGRP) inhibition

Charles, Andrew

career of, 23

on CGRP inhibitors, 190, 192

on Kuhn model, 91, 138

on pathophysiology of headaches, 232–233, 237, 245–246, 251, 254

on research funding, 227, 267–268

on stigma of headache disorders, 78–79

chemical messengers. See neurotransmitters

children, migraine in, 13

cilostazol, 192

circadian rhythm and headaches, 14–15, 51–52

classification system of headaches, 177

Cleveland Clinic, 131

Clusterbusters, 11, 142–144, 154, 187

cluster headaches

CGRP for, 62–63

chronic, 32

concealment by sufferers, 147–148, 199–203

dismissive attitude of medical field, 26

as distinct from migraine, 247–249

early history of, 80–81

economic loss on population basis, 204

episodic cluster headache, defined, 32

Erwin and, 141–146, 162–165

names for, 115

pain from, 1–4

pathophysiology of, 247

physical attribute theories about, 26, 123

research funding on, 163–165

stress and, 51

symptoms of, 8, 14, 26–27, 40–42

timing of, 51–52

triptans for, 136

unilateral aspects of, 81

“clusterheads,” 62

Coalition for Headache and Migraine Patients (CHAMP), 153–154

cocaine, 94

Cochrane group, 131

cognitive neuroscience field, founding of, 72

Columbia VA Healthcare System, 115

common data elements (CDEs), 220

comorbidities, with headache, 28, 109, 115, 157

Congress (U.S.), on headache research funding, 195–199, 212–216, 219, 222, 225

Connors, Marilyn J., 26

Copenhagen Acute Migraine Clinic, 35

cortical spreading depression (CSD), 239, 244, 248

corticosteroids. See prednisone

Cotzias, George, 172–173

Covid-19 research, 18–19

Critical Care Pain Observation Tool, 4

cross-tolerance, 64

crotophon, 78

daith piercing, 263

DALYs (disability adjusted life-years), 15–17, 217–219, 225

Danish Headache Center

Brain Prize for CGRP research, 167–171, 181

on central vs. peripheral origin debate, 237–247, 250–254

founding of, 250

“headache” connotation and, 149

headache provocation study, 11–13, 23, 31–32, 34–37, 158, 159, 191–193

KATP channels research, 36–37, 190–193

on neurology field specialization, 110

Darwin, Charles, 19, 70–71

Darwin, Erasmus, 19–22, 24, 29, 70, 84

Dean, Madeleine, 215–216

deep brain stimulator devices, 144

depression, 115, 132, 157

Deseril (methysergide), 29

Diamond, Seymour, 60, 61

Diamond Headache Clinic, 59–62, 65, 142

Diamond Research and Education Foundation, 61

Dickinson, Emily, 2

diet, 83–85, 103–104

dihydroergotamine (DHE), 94–95, 113

“Disability Evaluation Under Social Security” (“blue book,” SSA), 208–211

ditans, 187

Do, Thien P., 191–193, 240

Doods, Henri, 252

Dumas, Paula, 269–270

dura mater, 179, 181, 230, 231, 233, 241, 246

Dussor, Gregory, 219

Eadie, Mervyn J., 67, 89

Ebers, Georg and Ebers Papyrus, 65–69, 71

Edvinsson, Lars, 170–171, 176–180, 252

Eli Lilly, 62, 187, 188–189

Emgality, 167, 187–188, 195, 266, 268

Eng, Loren, 225

English, O. Spurgeon, 126

enteramine, 131

epileptic seizure, 90–91

episodic cluster headache, defined, 32

erenumab, 28, 186. See also Aimovig (Amgen and Novartis)

ergotamine and ergot-based preparations, 94–95, 128–129, 132–134

Erspamer, Vittorio, 131

Erwin, Jimmy, 142–144, 163

Erwin, Pam, 142–145, 163

Erwin, Will, 141–146, 162–165

Etcheberrigaray, Rene, 206–208

facial sweating, 42

Federal Aviation Administration (FAA), 201–203

fish, electrogenic species of, 67–68, 77

Fitzpatrick, Brian, 215–216

5-hydroxytryptamine (5-HT, serotonin), 131–135

Food and Drug Administration (FDA)

Aimovig approved by, 28–29, 104, 181–189

approval process of, 226

CGRP inhibitor, approval, 29

on neuromodulation, 261

on psilocybin, 62

Fothergill, John, 84–85

Foxhall, Katherine, 67, 73–74, 84–85

Frank, Arthur, 2

Freedom of Information Act (FOIA), 209–211

Freud, Sigmund, 78, 94, 122

Friedman, Arnold P., 130

gabapentin, 102

Galen, 76–77

“The Garden of Forking Paths” (Borges), 264–265

gastrointestinal theories

diet and, 83–85, 103–104

serotonin and, 131–132

genetics, hereditability of headache, 69–71, 119–120, 158

genetic studies, 263

gepants, 187, 189

Gilmore, Kevin, 199–203, 265–269

Gilmore, Tammy, 201

Glaxo, 133, 135, 179

GlaxoSmithKline, 44, 46

Glaxo Wellcome, 136

Global Burden of Diseases, Injuries, and Risk Factors Study, 16–17, 217

Goadsby, Peter

on CGRP inhibition, 30, 32–33

on pathophysiology of headaches, 41, 177–180, 237, 241–244, 247, 251–253

on public funding for research, 198, 207, 222

recognition of, 170–171

on stigma of headache disorders, 110–111, 127, 150–151

Goldberg Migraine Program (UCLA), 23, 24

Goodell, Helen, 121, 128

Gottschalk, Christopher, 110, 113, 183–184, 221, 263

Gowers, William, 90–91, 137

Graham, John, 128, 249

grants for funding. See research funding

Green, Elmer, 130–131

Grier, David, 147

gristmill (centrifuge) invention, 21–22

Gross, Charles G., 71–72, 74

gyrencephalic brain, 178

Haggett, Emma, 264–265, 266–267

Haig, Alexander, 73

Halpern, John, 143

Harvard University, 142–143

Harvey, William, 72–73

Headache: Through the Centuries (Eadie), 89

Headache Center of Excellence (Yale School of Medicine), 25

The Headache Godfather (Diamond), 61

Headache Institute, St. Luke’s Roosevelt Hospital Center, 101

Headache on the Hill event, 215–216

headache pain, 1–9, 39–58. See also cluster headaches; history of headache; migraine; pathophysiology of headaches, contemporary beliefs; remedies and treatments

communicating, 1–3, 12, 161–162

concealing pain, 39–40, 47–48, 147–148, 156–157, 199–203

DALYs (disability adjusted life-years), 15–17, 217–219, 225

as disabling, 53–57, 115

as malingering and psychogenic, 41

measuring, 3–4

perseverance by sufferers of, 6–7

prevalence and consequences of, 13–18

preventive medications and, 48–50

primary headache types and symptoms, 40–43

remedies and treatments for, 43–47

research on headaches and, 7–9

stress and role in, 50–54

Headache Through the Centuries (Eadie), 67

heart attack, 138

Helping to End Addiction Longterm (HEAL initiative, NIH), 196, 215

hemicrania, 20, 22, 78

Hephaestus (Greek god), 74

heterocrania, 77

Hippocrates, 75

histamine, 22, 32, 62–63, 65, 127–128, 142

history of headache, 59–81. See also pathophysiology of headaches, early beliefs

drug therapy effectiveness and, 62–65

early cluster headache evidence, 80–81

early written records of, 33, 65–69, 75–79

genetic persistence of headache and, 69–71

Neolithic and Paleolithic evidence of, 71–75

nineteenth- and twentieth-century remedies, 59–62

seventeenth-century remedies, 72, 79–80

A Hole in the Head (Gross), 71–72, 74

Horton, Bayard T., 115

Hougaard, Anders, 238–240, 244

Hua Tuo (Chinese physician, fictionalized), 74, 76

humors, 21, 76, 78, 85

Humphrey, Patrick, 133–135, 137, 139

hypothalamus, 14, 42–43, 52, 122–123, 253

Ibn Sina (Avicenna), 78

imaging studies, 4, 22–27, 42–43, 52, 239–240

Imitrex, 135, 136

inhalers, 45–46, 94–95

injectable treatment, features of, 28, 37, 43–44, 46–47, 94–95, 185

insurance coverage, 63, 99, 136–137, 208–211

International Association for the Study of Pain, 196

International Classification of Headache Disorders (ICHD-3), 40

International Conference on Advances in Migraine Sciences, 238

International Headache Congress, 225

International Headache Society, 40, 177

Jefferson Headache Center, 147

Jensen, Rigmor Højland, 36, 250, 254–255

Jordan, Michael, 152–153

Kaiser, Jocelyn, 213–214

KATP channels, 36–37, 190–193

Kempner, Joanna, 120–121, 124, 130, 153, 159

Kennedy, Robert F., Jr., 222–223

Kierkegaard, Søren, 158–159

Kim, Peter, 183

Koehler, P. J., 81

Koroshetz, Walter, 195–198

Kothmann, Konrad, 65

Kuhn, Thomas, 91–93, 138

Labarraque, Henri, 85

lacrimation, 42

Lal, Gobind Behari, 123–126

Lance, James, 177, 178

Landis, Story, 197, 206–208, 224–228

Landscape with the Fall of Icarus (Bruegel), 146

Latham, Peter Wallwork, 88–90

Leão, Aristides, 239

let-down headache, 51, 131

levcromakalim, 30–31, 32–37, 191–193

levodopa (L-Dopa), 172–173

Levy, Andrew, 162

Lipton, Richard B., 35

lissencephalic brain, 178

Liveing, Edward, 88–90

liver toxicity, 183–184, 185, 187

The London Practice of Physick (Willis), 72–73

Lowe, Zach, 152–153

LSD, 94, 143

Lundbeck Foundation, 167–171

Lundbeck (pharmaceutical company), 167, 187

malingering, defined, 153. See also stigma of pain

Mann, Karen, 26–27

Manual of Diseases of the Nervous System (Gowers), 90–91

marijuana, 43, 266

Matharu, Manjit, 247

May, Arne, 180–181

McCleary, Joel, 54

McKinley, David, 215–216

medicalization of disease, 154, 156

medical profession. See neurology field; patient-doctor relationship; pharmaceutical industry

megrim, 20

men, cluster headaches in, 8, 13–14

meninges, 27, 77, 78, 132–133, 137, 175, 230–231, 237. See also pathophysiology of headaches, contemporary beliefs

Merck, 183, 184

methysergide, 29, 132–133

migraine. See also aura

aura and, 14, 89, 119–120, 168, 239

cortical spreading depression (CSD), 239, 244, 248

diagnosing difficulty, 100–105 (See also patient-doctor relationship)

as distinct from cluster headaches, 247–249

early history of (See history of headache)

incidence across racial groups, 267

other headache disorders vs., 8

pain from, 2, 5, 53–54

pathophysiology of (See pathophysiology of headaches, contemporary beliefs)

prevalence among population, 210

stress and, 50–51

symptoms, premonitory, 239–240

symptoms of, overview, 14, 41

terminology for, 77–78

unilateral aspects of, 68, 174

Wolff on “migraine personality,” 119–127, 129–130

Migraine: A History (Foxhall), 67

Migraine Again (advocacy organization), 269

Migraine (Sacks), 159

Migraine World Summit, 269

miosis, 42

MK-0974 (telcagepant), 183–184

Møller, Jesper Sloth, 170, 171

monoclonal antibody (mAb) drugs, 186–190

Moskowitz, Michael, 170–176, 231–232, 252

National Alzheimer’s Project Act (2011), 214

National Headache Foundation, 61, 112, 182

National Hospital Ambulatory Medical Care Survey, 114

National Institutes of Health (NIH), 165

on animal experimentation, 176

headache science allocation of, 196, 217, 227

Helping to End Addiction Longterm (HEAL initiative), 196, 215

National Institute for Neurological Disorder and Stroke (NINDS) role, 195–197, 206–208, 212, 215, 219–220, 224–228, 233

Report on NIH Funding vs. Global Burden of Disease, 217

Research Portfolio Online Reporting Tool (RePORT), 211–222

Trump administration and funding of, 206, 222–223, 267

National Migraine Foundation, 153–154

Nature, UCLA article in, 172

NaV1.8 sodium channel studies, 260

Neolithic history of headache, 71–75

neonatal encephalopathy, 16–17

neurology field

neurology, terminology for, 72

professional associations, 60–61, 63

stigma of headache specialists, 108–112, 127, 267

neuromodulation devices, 260–263

neuropathic pain, 234

neuroscience field, founding of, 72. See also pharmaceutical industry; research funding for headache disorders; research on headache disorders

neurotransmitters. See also calcitonin gene-related peptide (CGRP) inhibition

dopamine, 172

histamine, 22, 32, 62–63, 127–138, 142

known elements of headache mechanics elevation about, 24, 25

neurokinin 1 (Substance P), 175–177, 180

serotonin, 131–135

nicotine, 52

nitroglycerin, 31–32, 36–37

nociplastic pain, 234–236

“normal science” model, 91–93, 138

Not Tonight (Kempner), 121

Novartis, 104, 105, 179, 181–188, 192, 195. See also Aimovig

Nurtec, 187, 188

Observationes Medicae (Tulp), 80–81

occipital cortex, 68

Olesen, Jes, 35, 169–171, 177, 179–180, 182, 242, 245, 252

“On Being Ill” (Woolf), 4

On Megrim, Sick-Headache and Some Allied Disorders (Liveing), 88

On Nervous or Sick-Headache (Latham), 88

opioids, 112, 143

Optimum Neurology, 75

Oribasius, 80

Oringel, Amy, 100–105, 266

O’Shea, Kathy, 124–125

Oshinsky, Michael, 195–197, 218–221

Osler, William, 74

overdosing, 54–57

oxygen, 45, 143, 203, 263, 266

“Pain Has An Element of Blank” (Dickinson), 2

Paleolithic history of headache, 71–75

parenchyma, 232–233

Parkinson’s disease, 109, 163–164, 172–174, 228

Parry, Thomas Wilson, 74

patents, pharmaceutical, 182, 188, 225–227. See also pharmaceutical industry; individual names of drugs

pathophysiology of headaches, contemporary beliefs, 229–255

“The Blind Men and the Elephant” parable and, 236–237

brain as insensate debated, 229–233

central vs. peripheral origin debate, 237–247, 250–254

historical beliefs about, 79–80 (See also history of headache)

meninges as source of pain, French study on, 230–231, 237

migraine and cluster headaches as distinct disorders, 247–249

nociception and, 160–161, 172, 230–235, 237, 240, 241, 246, 249

nociplastic pain concept and, 233–236

pain perception, overview, 160–161, 172

peripheral origin of pain, defined, 237

referred pain, 231

research on headache disorders on, 14–15

threshold of, 254–255

triggers of attacks, 168

UCLA article in Nature on, 172 (See also Goadsby, Peter)

vascular system and, 20–25, 45

pathophysiology of headaches, early beliefs, 83–95

ergot-based preparations and, 94–95

gastrointestinal upset theories about, 83–85

neuronal theories of, 85–87, 89–91, 93–94, 137–138

“normal science” model and, 91–93, 138

vascular-related theories, 85, 87–89

patient-doctor relationship, 97–117

diagnosis, refusal of, 157

diagnosis and management difficulty, 97–106, 112–113, 115–117

diagnosis of migraine incidence across racial groups, 267

headache specialists as disproportionate to population, 35, 222

interaction difficulties, 113–115

polypharmacy for headache patients, 106–108

primary care physicians, headache treatment by, 112

stigma of headache medicine profession, 108–112, 127, 267

unethical/illegal behavior by medical profession, 99–100, 116–117

women patients and dismissive attitude of medical profession, 26–27, 78–79, 113–115, 124–125

Paulus Aeginita, 80

Pellesi, Lanfranco, 11–13, 23, 34–37, 159

Peng, Kuan-Po, 248–249

peripheral origin of pain, 237. See also pathophysiology of headaches, contemporary beliefs

Petersen, Anja Sofie, 110, 190, 247–251, 254

Pfizer, 188

pharmaceutical industry. See also calcitonin gene-related peptide (CGRP) inhibition; individual names of pharmaceutical companies

advertising by, 187–188

American drug consumption rates, 222–223

ditans, 187

drug research, 18–19, 27–34

gepants, 187, 189

investment in research by, 225–228

legal battles between drug companies, 188–189

over-the-counter, 13

patents by, 182, 188, 225–227 (See also individual names of drugs)

preventive medications, 48–50

small-molecule drugs, features of, 182–187

physical attribute theories, about headache sufferers, 26, 123, 125–130

Pippen, Scottie, 152–153

Pittsburgh Sun-Telegraph, 123–126

pituitary adenylate cyclase-activating polypeptide (PACAP) trials, 260

Please See Me journal, 26

potassium channels, KATP, 36–37, 190–193

Powers, Scott, 219

prednisone, 43, 48–49

prevention of headaches. See also calcitonin gene-related peptide (CGRP) inhibition

abortive treatment vs., 28, 48–50

difficulty of, 18

as goal, 28

research on, 113 (See also research funding for headache disorders)

Price, Rebecca, 233

primary care physicians, headache treatment by, 112

primary headaches. See also cluster headaches; migraine

classification system of, 177

defined, 8

tension-type headaches, 40–41

primordial brain stem, 70

psilocybin (psychedelic mushrooms), 1, 5–6, 25, 62, 142–143, 266

ptosis, 42

Ray, Bronson, 230, 237

referred pain, 231

remedies and treatments. See also calcitonin gene-related peptide (CGRP) inhibition; histamine; pathophysiology of headaches; psilocybin (psychedelic mushrooms); sumatriptan

antidepressants and serotonin, 132

biofeedback therapy, 130–131

botulinum toxin (Botox), 61–62, 102, 263

cocaine and, 94

cross-tolerance, 64

deep brain stimulator devices, 144

diagnosing and treatment difficulty, 102–106

drug therapy effectiveness, 62–65

ergotatmine and ergot-based preparations, 94–95

hoarding of, 46–47, 98–99, 136–137

individuals’ response to, 106

inhalable oxygen, 45, 60, 143

inhalers, 45–46, 94–95

injectables, 28, 37, 43–44, 46–47, 94–95, 185

insurance coverage for, 63, 99, 136–137, 208–211

LSD and, 94, 143

marijuana and, 43, 266

nonpharmaceutical, overview, 103–104

opioids and, 112, 143

overdosing from, 53–57

polypharmacy and, 106–108

preventive vs. abortive, 46, 48–50

psilocybin (psychedelic mushrooms), 1, 5–6, 25, 62, 142–143, 266

triptans, 5, 23, 27–28, 43–44, 46

research funding for headache disorders, 195–228

advocacy for, 156–157, 165, 195–199, 204–211, 214–216, 218, 222–225

burden-of-disease question about, 16–17, 196, 205–206, 216–218, 224–225, 228

on cluster headaches, 163–165

Congress (U.S.) on, 195–199, 212–216, 219, 222, 225

headache and economic cost calculation, 199, 203–211

headache patients’ suffering and need for, 199–203

NIH’s Research Portfolio Online Reporting Tool (RePORT) and, 211–222

payline scores, defined, 207

pharmaceutical industry investment in, 225–228

Trump administration and effect on, 206, 222–223, 267–268

research on headache disorders, 11–37, 119–139. See also research funding for headache disorders; individual names of researchers

as “beautiful,” 13

common data elements (CDEs), 220

Covid-19 research vs., 18–19

cranial vasculature, 123, 127–132, 137, 174

drug research, 18–19, 27–34

early work in, 19–22

headache prevalence and consequences in relation to, 13–18

headache provocation study (Danish Headache Center), 11–13, 23, 31–32, 34–37

imaging studies, 4, 22–27, 42–43, 52, 239–240

lack of, 7–9, 13, 35

“migraine personality,” 119–127, 129–130

new areas of, 257–263

rhinovirus research vs., 18

serotonin and, 131–135

sex distribution of researchers, 250

triptans, development of, 135–139

Research Portfolio Online Reporting Tool (RePORT, NIH), 211–222

Rolan, Paul, 17, 97

Rosenfeld, Michael, 172

Sacks, Oliver, 159

safety

of CGRP inhibition, 30

liver toxicity from drugs, 183–184, 185, 187

of methysergide (Deseril, Sansert), 29

of triptans, 138

Sandoz, 94, 95, 132

Sansert (methysergide), 29

Sarkar, Monica, 109

Saxe, John Godfrey, 236–237

Scarry, Elaine, 4

Schindler, Emmanuelle, 25

Schulte, Laura, 240

serotonin, 131–135

sex differences and headaches

men and cluster headache prevalence, 8, 13–14, 248

Not Tonight (Kempner), 121

sex distribution of researchers, 250

Wolff on “migraine personality,” 121–127, 129–130

women patients, as majority of migraine patients, 8, 13, 33–34, 41, 248

women patients, physical attribute theories, 125–130

women patients and dismissive attitude of medical field, 26–27, 78–79, 113–115, 124–125

Shameless (Showtime), 151–152, 211

Shapiro, Robert

career background of, 204–206

FOIA filing and lawsuit, 209–211

on migraine and cluster headaches in tandem, 249

research funding advocacy by, 156–157, 165, 195–199, 204–211, 214–216, 218, 222–225

Showtime, 151–152, 211

silent migraine (migraine aura without headache), 14

Simon, Susan, 135–136

sleep, cluster headaches during, 51–52

SMA Foundation, 225

SmithKline Beecham, 182

Snoer, Agneta, 110, 250–251, 254–255

Social Security Disability Insurance (SSDI, Social Security Administration), 208–211

spinal muscular atrophy (SMA), 224–225

Starling, Amaal, 110, 157, 189, 216–217

St. Augustine, 2

Stern, Ludwig, 67

stigma of headache medicine profession, 108–112, 127, 267

stigma of pain, 141–165. See also advocacy; research funding for headache disorders; individual names of advocacy organizations

blame of victims, emergence of, 85

communicating pain and, 161–162

concealment of pain and, 147–148, 156–157

edge cases, compassion for, 64–65

Erwin and, 141–146, 162–165

headache and migraine terms as trivialized, 150–154

judgment/disgust perceived by others, 154–156

malingering, defined, 153

medical establishment on, 5–6, 25–27, 41

pain as misunderstood, 5–6, 41

pain as unattributed and, 148–150, 218

research funding and, 163–165 (See also research funding for headache disorders)

Social Security Disability Insurance on headache disorders, 208–211

subjectiveness of pain and, 146–147

suffering from pain and, 158–160

St. Luke’s Roosevelt Hospital Center, 101

Stoll, Arthur, 94

stress, 50–54, 130–131

stroke, 16–17, 138

The Structure of Scientific Revolutions (Kuhn), 91

Substance P (neurokinin 1), 175–177, 180

“suicide headache,” 2

sumatriptan

development of, 135–138

early marketing of, 179

efficacy of, 5, 23, 43–44, 46, 103

insurance coverage for, 99

pathophysiology of headaches and, 240

safety of, 95

sympathetic nervous system, 88–89

symptoms. See also aura

of cluster headaches, 14, 26–27, 40–43

let-down headache, 51, 131

of migraine, 14, 41, 239–240

triggers of, 43, 168, 190–193

telcagepant (MK-0974), 183–184

tension-type headaches, 40–41

Teva Pharmaceuticals, 187, 188

timing of headaches, 14–15, 51–52

Tissot, Samuel, 83–84

topiramate, 43, 48, 102

trepanation, 71–75, 77

trigeminal nerve

electromagnetic impulse to, 68, 144

pain sensation and, 230

sensory input, 161, 175–177, 230–233, 254, 261

stress and, 50

trigeminal autonomic cephalalgias, 41 (See also cluster headaches)

trigeminovascular system, 176–179, 247, 248

Wolff on, 122

triptans, 5, 23, 27–28, 43–44, 46, 103, 135–139. See also sumatriptan

Trump, Donald, 206, 222–223, 267–268

Truth or Myth (NIH video), 233

Tulp, Nicolaes, 80–81

Uarda (Ebers), 65–67

UCLA Goldberg Migraine Program, 23, 24, 172, 247, 257. See also Charles, Andrew; Goadsby, Peter

unethical/illegal behavior by doctors, 99–100, 116–117

Unguarded (Pippen), 152–153

United Council for Neurologic Subspecialties (UCNS), 111

University of Copenhagen, 237–247

University of Florence, 132

University of Michigan, 154–156

University of Southern California, 23–24

University of Texas at Dallas, 246

University of Washington, 16

Van Halmaal, Isaak, 81

Van Swieten, Gerhard, 81

Van Woert, Melvin, 173

vascular system. See also pathophysiology of headaches

drugs targeting, 27

as headache cause suspect, 20–25, 45

histamine and, 62

known elements of headache mechanics elevation about, 24, 25

vascular theory of migraine, 88–89, 138

vasoconstriction and serotonin, 132–134

vasoconstriction and triptans, 137, 138

vasodilators in Danish Headache Center study, 31–32, 36–37

verapamil and, 49–50

Wolff on cranial vasculature, 123, 127–132, 137, 174

Vasella, Daniel, 179

verapamil, 43, 48–50, 56–58

Veterans Health Administration, 115

visual analog scale, 3

Vyepti, 187, 266

Walding, Emily, 53–54, 266

Watt, James, 21

Weinberg, Rachel, 147–148, 266

Weiss, Edward, 126

Welch, Peter, 215–216

Will Erwin Headache Research Foundation, 163

Willis, Thomas, 72, 79–80

Wold, Bob, 11, 62–63, 142–144, 187

Wolff, Harold

on cranial vasculature, 123, 127–132, 137, 174, 230, 237

on “migraine personality,” 119–127, 129–130

women patients. See sex differences and headaches

Woolf, Clifford J., 234–236

Woolf, Virginia, 4

World Bank, 15

World Health Organization (WHO), 13, 15, 17, 171

Xu, Cen, 181–187, 252, 253

Yale School of Medicine, Headache Center of Excellence, 25, 113

YLLs (years of life lost), 15

Zeus (Greek god), 74

Zoonomia (Darwin), 19–21

About the Author

TOM ZELLER JR. is cofounder and editor in chief of Undark, a nonprofit digital magazine exploring the intersection of science and society. Previously, he was a reporter and columnist at the New York Times, an editor at large for National Geographic magazine, and a Knight Science Journalism fellow at the Massachusetts Institute of Technology (MIT). He lives in Lolo, Montana. The Headache is his first book.

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Mariner Books traces its beginnings to 1832 when William Ticknor cofounded the Old Corner Bookstore in Boston, from which he would run the legendary firm Ticknor and Fields, publisher of Ralph Waldo Emerson, Harriet Beecher Stowe, Nathaniel Hawthorne, and Henry David Thoreau. Following Ticknor’s death, Henry Oscar Houghton acquired Ticknor and Fields and, in 1880, formed Houghton Mifflin, which later merged with venerable Harcourt Publishing to form Houghton Mifflin Harcourt. HarperCollins purchased HMH’s trade publishing business in 2021 and reestablished their storied lists and editorial team under the name Mariner Books.

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This book contains advice and information relating to health care. It should be used to supplement rather than replace the advice of your doctor or another trained health professional. If you know or suspect you have a health problem, it is recommended that you seek your physician’s advice before embarking on any medical program or treatment. All efforts have been made to assure the accuracy of the information contained in this book as of the date of publication. This publisher and the author disclaim liability for any medical outcomes that may occur as a result of applying the methods suggested in this book.

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