When I last took a look at what was happening in the treatment of migraines, I took careful pains to elucidate the differences between migraines and a plain old bad headache – the fact that migraines affect only one side of the head, and a detailed disquisition on the symptoms that many migraineurs (that’s the term for people who are prone to migraines) experience in advance of the onset of the headache. It turned out that what I was experiencing was an overdose of scruples. Judging from your comments, of which there were a good many, the denizens of Planet Gumshoe are not confusing migraines with other garden-variety headaches. Nobody responded with an “Aha! So that’s what’s been making my life miserable!”
I will once again, but more briefly, summarize the characteristics of migraines with and without aura and also go over such matters as risk factors and triggers. The main focus of this piece will, however, be managing migraines – which, of course, is what you really want to know.
There is one problem area that I will need to deal with. Let me state it briefly: the actual pathophysiology of migraines is poorly understood. If the goal of studying migraines is to arrive at treatment modalities that are consistently effective, this is far from a tiny problem. Effective treatments for many ailments have certainly been discovered by trial and error. For example, a tincture made from willow bark will ease pain and lower a fever, but who knows how many tinctures were tried before that particular one was identified. (As I’ve recounted several times before, that’s how aspirin came to be – salis, the Latin name for the willow, was the source of acetyl salicylic acid, aka aspirin).
But more often the treatment arises out of an understanding of the disease itself – what’s going on in our bodies that is making us have that undesirable response. We understand infections; the treatment is to kill or disable those pathogens that are causing the infection. We understand the malfunctions that lead to heart disease, and we have reasonably effective means of countering these malfunctions. We understand cancers, and even though we cannot always reliably stop those rapidly multiplying cancer cells, we do have the means of waging wars against them, and these wars sometimes result in outright victory, or at least a truce.
So it is with a great many human diseases and ailments. The treatment takes direct aim at the cause. Unfortunately, this is not so with migraines. The essential root cause of migraines is still somewhat mysterious. I will quote two sentences from two papers about the pathophysiology of migraine. The first is the very last line from a paper entitled “Migraine: Multiple Processes, Complex Pathophysiology.” (Burstein R et al. J Neuroscience 2015;3 5:6619-6629)
“Given the enormous burden to society, there is an urgent imperative to focus on better understanding the neurobiology of the disease to enable the discovery of novel treatment approaches.”
What the authors of that paper are saying is that, despite a great deal of meticulous research into the possible causes of this disorder, they are quite far from having it nailed down.
The second sentence is the very first line from a paper by Peter J. Goadsby, who recently chaired the meeting of the American Headache Society. The paper’s title is “Pathophysiology of Migraine.” (Goadsby PJ. Ann Indian Acad Neurol 2012;15(Suppl1):S1-S22)
“Migraine is likely to be a brain disorder involving altered regulation and control of afferents, with a particular focus on the cranium.”
I call your attention to the word “likely.” Goadsby, despite his eminence, is reluctant to assert any explanation with certainty. (“Afferent” in that sentence refers to signals travelling to any of various brain centers rather than away from those centers.) Goadsby is saying that the cause of migraine is more likely to be a brain disorder than a disorder of the vascular system, which was the explanation that had held sway for quite a number of years. That previous explanation was that the migraine headache was caused by the dilation of blood vessels around the periphery of the brain. The idea was that these dilated blood vessels would press on the sensory nerve endings, which would naturally result in a headache. This theory, the “vascular hypothesis” is supported by the greater prevalence of migraines in women; estrogen makes blood vessels more flexible, which makes them more likely to dilate and press on nerve endings.
But the vascular hypothesis fails to account for the observation that migraines are almost always on one side of the head only; why would the vasodilation phenomenon be unilateral? Also, brain imaging studies have shown that during the headache phase of the migraine, blood flow is not increased, which would be the case if the cause of the headache were vasodilation.
An alternative theory, which has more recently gained currency, is the sterile inflammatory response hypothesis. (A sterile inflammatory response, as the name suggests, is an inflammatory response to a non-infectious trigger.) This suggests that the migraine symptoms result from the release of plasma, which can press on the trigeminal nerve fibers, resulting in pain.
Several substances have been identified as possibly or likely to be involved in the pathway that leads to the characteristic headache pain. These include calcitonin gene-related peptide (CGRP) and another peptide labeled substance P, which conveys pain information. Research into forms of treatment that block these neurotransmitters has demonstrated some effectiveness in preventing migraines. .
The most successful theory, from a purely pragmatic perspective, is that migraine is a syndrome characterized by low levels of serotonin in the plasma. Serotonin (5-hydroxytryptamine, or 5-HT) has a number of physiologic effects, including the ability to suppress pain and to contribute to normal sleep. The evidence is as follows: first, during the headache phase of a migraine episode, the main metabolite of 5-HT is found in increased amounts in the urine (meaning that it is being broken down more quickly); second, during the onset of the migraine attack, 5-HT levels fall by as much as 40%; third, agents that deplete amines including 5-HT can trigger a migraine attack; and, fourth, intravenous 5-HT can abort migraine attacks. However, we need to note, intravenous 5-HT has a number of adverse effects, such as rapid vasoconstriction and increases in blood pressure, which make it unacceptable for clinical use.
Serotonin acts through a number of receptors, classified as 5-HT1 through 5-HT7. The 5-HT1 subclass includes those most likely to be involved in pathophysiology of migraine, especially 5-HT1B and 5-HT1D. Most of the current generation of migraine medications – i.e., the triptans, which we’ll say a bit more about later – are activators of those serotonin receptors. They are both potent constrictors of blood vessels in the brain, and, perhaps more important, inhibitors of the sterile inflammatory response.
Another chain of reactions that is linked to migraines involves glutamate release. A mutation which is common in about half of persons who are migraine sufferers involves the calcium channel gene. The calcium channel transports calcium ions from the plasma into cells throughout the body. This particular mutation results in increased release of glutamate. Perhaps not coincidentally, a similar mutation also resulting in higher circulating levels of glutamate, is linked with epilepsy and seizures. This may have some bearing on the widely reported heightened sensitivity to monosodium glutamate (MSG) reported by some individuals who experience migraines.
What all this comes down to, however, is that the root cause or causes of migraines have not been precisely identified. It’s clear that something is impacting the nociceptors (the nerves that detect any possible damage and transmit a warning signal in the form of pain) in the brains of migraineurs, whether it’s the dilation of the blood vessels in their immediate proximity, or an inflammatory reaction in the brain tissue triggered by an ionic reaction, or a deficiency in circulating serotonin, or an excess of glutamate, or a number of other reactions. These possible pathologies continue to be investigated, and more effective treatment modalities for migraine will – we hope! – emerge.
How common is migraine and what are the risk factors?
Migraine is a lot more common than most people would guess. Globally, the estimate is that 14.7% of the population experience migraines – that’s about a billion of us here on Planet Earth . In the US, 18% of women, 6% of men, and 10% of children have migraines from time to time – a total of 39 million.
As you see, migraines affect women at three times the rate than they affect men. The reason for this may be hormonal; women have greater levels of estrogen in their circulation than do men, and estrogen affects a number of physiologic characteristics; in particular, estrogen facilitates the dilation of arteries. Female migraineurs commonly report a significant drop in the frequency of their headaches after menopause, when estrogen levels diminish. Among children, boys tend to experience more migraines than girls, but the prevalence strongly tilts towards girls as they reach puberty. The peak ages for migraine are in the 30s, after which migraine frequency tend to decline.
A key risk factor for migraines is family history, which certainly points to genetic factors rather than external causes. However, migraineurs report a considerable number of triggers that they strongly believe bring on their own migraine episodes. Here is a list, courtesy of the National Headache Foundation, part of NIH.
Foods & beverages
- Ripened cheeses (such as cheddar, Emmenthaler, Stilton, Brie, and Camembert)
- Marinated, pickled, or fermented food
- Foods that contain nitrites or nitrates (bacon, hot dogs) or MSG (soy sauce, meat tenderizers, seasoned salt)
- Sour cream
- Nuts, peanut butter
- Sourdough bread
- Broad beans, lima beans, fava beans, snow peas
- Figs, raisins, papayas, avocados, red plums
- Citrus fruits
- Excessive amounts (more than 2 cups total) of caffeinated beverages such as tea, coffee, or cola
- Alcohol (including red wine and beer)
For many women, the menstrual cycle is a major trigger. Attacks usually occur a few days before or during their period or, for some women, at ovulation. A drop in estrogen is believed to be the culprit. As women near menopause, fluctuating estrogen levels may also trigger an increase in migraines.
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Strong perfume is an immediate trigger for some, making common spaces (offices, churches) a challenge, and the beauty counters in big department stores a particular hell. For others, it can be flickering lights—even a movie screen in a darkened theater or sunshine flashing through trees on a road as they’re driving.
The most common migraine trigger is stress. Migraine sufferers are thought to be highly responsive emotionally. Anxiety, worry, shock, and sadness can all release certain brain chemicals that lead to a migraine headache. (Ironically, the sense of release after a stressful period can also lead to migraines, which could be the cause of weekend headaches.)
The list is far, far from complete; in fact, I would question whether a complete list is possible, since migraine triggers vary enormously among individual migraineurs. For every migraineur who is apparently exquisitely sensitive to chocolate, there will be another one who can feast on chocolate with impunity; for every migraineur to whom a glass of red wine is forbidden, there will be another who can drink red wine with no ill effects, but is laid low by a cup of coffee.
As we look over the list of potential food triggers, it’s worth thinking about what’s in some of those foods that makes them risky for some migraineurs. To the list of ripened cheeses (which could go on and on and on, of course), we should add preserved and smoked meats, which also contain purines. Chocolate and coffee (and tea also) contain related methylxanthines; caffeine is a methylxanthine, but not all methylxanthines are the same; thus the migraineur who shuns chocolate may be able to drink coffee and vice versa.
And to the environmental factors, we should add the prevalence of exceedingly bright piercing lights that we see everywhere these days – bicycles with pinpoint flashing headlamps that burn little holes in the retina, flashing lights on every kind of vehicle, whether responding to an emergency or racing to the corner deli for a cup of java, the flashing lights on the deli itself, flickering LEDs and compact fluorescents. These may pose threats not only to migraineurs, but to persons who are susceptible to seizure disorders.
… but might migraineurs be a bid muddled about these triggers?
Data were presented at the 2018 meeting of the American Headache Society that cast doubt on the relationship between these triggers and migraine episodes. A study enrolled 774 migraineurs who tracked their migraine headaches and also their food consumption. Of these, just over half (53.7%) suspected that chocolate was a trigger for migraines. Most (27%) characterized chocolate as a mild trigger, 14.6% thought it was a moderate trigger, and 12% thought it was a strong trigger. But when these participants entered their actual migraine experience, using a web-enabled smartphone app, chocolate was found to be associated with an increased risk for migraine in only 10 people, which amounted to 1.7% of the 606 study subjects with enough data for analysis. For the huge majority, 95.7%, no association at all was noted. Similar results were found for nitrates and MSG.
Speaking from my habitually skeptical position, I hesitate to characterize those data as “evidence” one way or the other. A woman I know well who formerly had fairly frequent migraines pointed out that she had identified both chocolate and red wine as strong triggers and consequently avoided both. If she had been recording her migraine episodes after having eliminated both of those, there would have been zero association with either trigger. That does not mean that chocolate and red wine would not have been triggers. With due respect to the investigators who presented that data to the American Headache Society, in the opinion of Doc Gumshoe, it’s not worth much.
Participants at the AHS meeting were divided on the issue of avoiding triggers, with some experts saying that migraineurs should shun all triggers like the plague, and others opining that, on the contrary, they should go ahead and consume those triggers and “learn to cope.” The above-mentioned Peter Goadsby had his own take on the matter. I will quote what he said:
“What we’re learning by studying the premonitory phase that occurs in the days or hours before the attack, when the patient will feel tired or get a bit moody or crave sweet or savory things, is that the brain has actually started to have the attack. Chocolate is an excellent example. When the brain drives you to take some chocolate and a day and a half later you get migraine, the association is absolutely correct, but the causality is different — the mechanism has already started.
What we’re learning from the diary work is that while you can recommend general regularity, an individual needs to ask themselves whether what they’re calling a trigger is actually the beginning of their attack. That releases them from the punishment of worrying about the trigger and gives them information about what is about to happen. Obviously, if you feel you’re in the premonitory phase that is not a night to go out, to stay up late, to find your favorite alcohol. It’s a night to be careful, to look after yourself, to prepare for the next day. This understanding is going to empower patients to get better control.”
I’m not sure that Dr Goadsby is asserting that those changes in the brain in the premonitory (or as it is sometimes termed “prodromal”) phase are specifically what drive people to eat chocolate or drink red wine. Migraineurs as well as non-migraineurs can be smitten by chocolate or red wine or Camembert cravings at any time for any reason or no reason, and these do indeed originate in brain activity. The difference is that the migraineurs, looking for some kind of source for their misery, may blame whatever it was that they consumed before the headache descended on them. It’s a natural assumption, and it might or might not be correct.
Despite the positions cited above, I am not at all prepared to dismiss the idea that triggers do have something to do with migraine symptoms. I definitely agree with Goadsby that migraine is “likely” to originate in a brain disorder, but that certainly does not eliminate the possibility that there are external stimuli at work. I would definitely not concur with the view that migraineurs should go ahead and consume the triggers and “learn to cope.” For some migraineurs, coping consists of taking to their beds in a darkened room and waiting for the episode to pass. Avoiding the trigger in the first place is probably a better tactic.
What about those premonitory / prodromal symptoms?
Many migraineurs can feel the migraine coming on. Sometimes, but not always, migraineurs can head off the migraine by taking action. Sometimes simple activities can prevent the onset of the full-fledged migraine – vigorous exercise, a hot or cold shower, sex (yes, sex!), a bite of food. And sometimes taking a prescription anti-migraine medication before the migraine hits can stave off the worst of it.
A headache is not considered to be a migraine unless it is accompanied by other clinical symptoms, the most usual of which is nausea, sometimes with vomiting. Migraineurs are also extremely sensitive to light and sound, frequently taking refuge in dark, quiet rooms. In some cases, odors which are not usually thought to be unpleasant are intolerable to the migraineur. And they may experience blurry vision, stuffy nostrils, diarrhea, stomach cramps, pallor, flushing, or localized swelling of the face, hot or cold sensations, sweating, stiff neck, tenderness of the scalp, and a range of mental symptoms including anxiety, depression, irritability, and impairment of concentration.
Visual auras, experienced by a minority of migraineurs, were depicted by the 12th century mystic and musician Hildegard von Bingen, who experienced them as visions while sick in bed in a darkened room. She drew pictures of her visions that are recognized by migraineurs as nearly identical to the auras they experience – arcs of scintillating lights in a zigzag or herringbone pattern passing across the visual field and growing in size. To some migraineurs, these visual auras serve as a warning that the headache is about to attack, and a strong hint to take whatever medication they have found useful.
So, what medications have migraineurs found to be helpful?
For a start, many of the over-the-counter analgesics that are specifically marketed as anti-migraine drugs are only marginally effective. In a recent survey of migraineurs, only 17% reported that they got “a lot” of relief from these drugs. The efficacy of prescription analgesics sometimes prescribed for migraines was no better. A problem with the use of analgesics for migraine relief is that one of the effects of the migraine is gastric stasis. That means that the pain killer doesn’t get absorbed, and indeed may aggravate the nausea that migraineurs usually experience. So, while the usual remedy for non-migraine headaches is an analgesic, this may simply not work for migraines. The use of drugs usually used to treat depression or anxiety has been suggested as a potential way to provide relief of the migraine headache. However, these seem to work even less well than analgesics – only about 4% of migraineurs got “a lot” of relief from these psychoactive drugs.
Prophylactic drugs have been tried in some migraineurs, especially those whose episodes are more frequent, severe, or of greater duration. Classes of drugs include calcium channel blockers and beta blockers, which are essentially blood pressure medications, based on the idea that lowering blood pressure would relieve pressure on nerve endings in the brain. Although use of these drugs is based on the perhaps discredited vascular theory, which we discussed earlier, some physicians continue to prescribe these antihypertensive drugs for migraine sufferers, and some migraineurs report that they get some relief from these drugs.
Some older antidepressants, such as the tricyclic amitryptaline, as well as the anti-seizure drug topiramate are used chronically by some migraineurs. A new formulation of topiramate, Qudexy XR (Upsher-Smith Laboratories) was recently approved by the FDA for prevention of migraine in adults and adolescents over the age of 12. The newly approved drug is an extended-release formulation which, it is hoped, will also improve adherence to migraine prophylaxis, which currently is reported to be as low as 41% after two months, and declines further over time.
A definite drawback with these drugs is that they cannot be taken in response to a specific migraine episode. Instead, in order for them to be at all helpful, they need to be taken every day. However, the risk of adverse effects increases with chronic use of any drug, and one would have to weigh these risks extremely carefully before taking a drug every day to prevent migraines that only occur sporadically.
The first drugs specifically developed to treat migraines drugs are the triptans, which are agonists (activators) of certain serotonin receptors, designated 5-HT1B/1D. The first of these was sumatriptan (Imitrex, from Glaxo SmithKline), initially marketed as a subcutaneous injection and later as an oral medication. At least six other triptans have followed sumatriptan, and sumatriptan is now available as an oral medication, a nasal spray and also in combination with naproxen.
Most triptans usually provide reasonably prompt headache relief – i.e., within less than 2 hours. However, there are significant drawbacks to triptan use. One is that many migraineurs experience recurrence of headaches after initial relief. In some studies, 40% to 70% of migraineurs reported rebound headaches, and repeated dosing with triptans is usually not recommended. Thus, rather than taking the triptan, some migraineurs prefer to seek relief without any specific drug treatment, using their own strategies – bed-rest in a darkened room, ice-packs, warm compresses, scalp massage, sleep.
Another significant drawback is that, since a principal mechanism of action of the triptans is vasoconstriction, there is some associated cardiac risk, and migraineurs who have heart disease risk factors are not recommended to take triptans.
The differences between the seven triptans are fairly minor. Here’s a quick summary of the chief differences:
- Imitrex (sumatriptan, GSK) in a subcutaneous formulation has the fastest onset of action, about 10 minutes.
- Zomig (zolmitriptan, Impax) is available in a nasal formulation, whose onset of action is just a bit slower than that of Imitrex.
- Amerge (naratriptan, GSK) onset of action may be as long as 3 hours – the longest of any triptan.
- Axert (almotriptan, Janssen), Relpax (eletriptan, Pfizer), Frova (frovatriptan, Endo), Maxalt (rizatriptan, Merck), as well as the tablet formulations of Imitrex and Zomig, have onsets of action ranging from 30 minutes to perhaps 2 hours.
- Frova has the longest duration of action, up to 6 hours. Most of the triptans have a fairly short duration of action, in the neighborhood of 2 hours.
- Relpax may be the most effective triptan, perhaps followed by Imitrex.
- Axert and Maxalt are approved for pediatric use – Axert in children age 12 or older, and Maxalt in children age 6 or older. The nasal formulation of Zomig is also approved for children age 6 or older.
- Patients taking the short-acting triptans often take a repeat dose to get them through their migraine episode, even though this is generally not recommended.
- The adverse effects that clinicians will be on the alert for in their patients taking triptans are cardiovascular. The subcutaneous Imitrex formulation is associated with the greatest cardiac risk, while Axert appears to have the lowest cardiac risk.
- Amerge (naratriptan) has the lowest incidence of side effects, followed by Axert (almotriptan).
Migraineurs by no means need to stick with one triptan. If he or she (she, usually) feels the headache coming on quickly, the best option might be the subcutaneous Imitrex or perhaps the nasal Imitrex or Zomig. Those same options might be optimal for the person who has to cope with nausea and might not be able to manage the oral triptan formulations. On the other hand, if the migraineur is in the grip of an extended bout of prodromal symptoms and anticipates a long-lasting headache, the optimal choice might be Frova.
The differences between those seven triptans suggests that in the event that a migraineur does not get a satisfactory response to any individual triptan, the patient and clinician should keep trying the alternatives. The overall response to subcutaneous Imitrex, supposedly the most effective triptan, is about 70%. But there is evidence that in the 30% of patients who do not respond to Imitrex, up to 80% will respond to another triptan. So, adding that number (80% of 30% is 24% by my perhaps antiquated arithmetic) and we get a total response rate approaching 94%. I say, not bad, if those numbers are really on the up-and-up.
… but wouldn’t it be better to avoid the migraine in the first place?
Of course it would. However, that’s easier said than done. The first FDA-approved prophylactic treatment option for migraines was Botox, which as we all know is botulinum toxin, used cosmetically to reduce, or perhaps totally obliterate, those little facial wrinkles that identify us as grown-ups. Botox does this by blocking the receptors that trigger the contraction of facial muscles. It basically works the same way in inhibiting migraines, by preventing the contraction of tissue around pain receptors in the brain. To do this takes about 30 subcutaneous Botox injections every month at sites in the skin around the head.
Botox is approved for individuals with documented chronic migraine episodes, meaning at least 15 migraines per month. The success rate for Botox prophylaxis is moderate, reducing the incidence of migraine episodes in these chronic migraineurs by about 50%. This may not sound like much, but to a person who has been getting slammed by a killer migraine every other day, cutting that down by half is a big deal. And, of course, the chronic migraineur can combine the prophylactic treatment with drugs that reduce the severity of any single episode.
A major prophylactic breakthrough occurred just a couple of months ago, when the FDA approved Amgen’s Aimovig (erenumab), which they are co-marketing with Novartis. Aimovig’s mechanism is the inhibition of a molecule involved in triggering migraine attacks, calcitonin gene-related peptide (CGRP). Aimovig may be a valuable drug not only for persons with chronic migraine episodes, but for those with episodic migraines – a much larger patient population that has migraine episodes much less frequently than the chronic migraineurs. Aimovig was compared with placebo in three clinical trials in this population, and the results were that treatment with Aimovig resulted in between 1 and 2½ fewer monthly migraine days. Aimovig is given by means of self-injections every month, which is a considerable advantage over the 30 monthly subcutaneous injections required for every Botox treatment. The most common side effects reported by patients in the Aimovig trials were injection site reactions and mild constipation. As with Botox treatment, patients using Aimovig to reduce the frequency of their migraines can also use drugs such as triptans to reduce the severity of a single migraine episode.
About a month ago, data from a Phase 3 study in another drug for migraine prophylaxis was presented at the meeting of the American Headache Society. The drug is galcanezumab, recently given the brand name Emgality by its developer, Eli Lilly. Emgality, like Aimovig, is a CGRP inhibitor. In clinical trials it has been demonstrated to reduce migraine incidence in patients who do not respond to prophylaxis with Botox. Moreover, it is also effective in cluster headaches, which are different from migraines, and for which there has been no approved prophylactic treatment. Cluster headaches are very painful, short in duration, affect a small area of the head, and tend to occur daily during a relatively short period of time, usually one or two weeks.
Results from the EVOLVE-1 clinical trial showed that prophylactic treatment with Emgality resulted in almost 5 fewer migraine days per month relative to baseline in patients with episodic migraines, while treatment with placebo reduced migraine incidence by 2.8 days per month. Like Aimovig, Emgality is given by a self-administered subcutaneous injection once a month.
The fact that effective prophylaxis is provided by agents that inhibit the action of CGRP provides a certain amount of validation for the vascular hypothesis, namely that the pain in migraines comes from the pressure of dilated blood vessels on nerve endings, because what CGRP does appears to be to dilate those very blood vessels. But perhaps it works in some other way that has yet to be figured out. We’ll see!
From my perspective, sitting on the sidelines, the overall picture looks like this: the investigators who are diligently searching for the root cause of migraines have made some progress, but still have a way to go. The pragmatists, who are looking for treatment options that deliver benefit to the billion or so migraineurs on our planet, are considerably ahead of them. My guess is that there is no single root cause of migraines, and that as more research is carried out, a picture will emerge showing the interaction of several different factors in the brain. That will be highly satisfactory. But even more satisfactory will be the development of new, more effective treatment modalities to stop the migraine episodes in their tracks.
Despite the new developments, the words that I put at the end of my previous piece about migraines still seem appropriate:
… let me repeat the Four Golden Rules for How to Live With Migraine, according to Dr Alan Rapoport, President of the International Headache Society:
I Avoid the migraine (if possible)
II Nip the migraine in the bud when you feel it coming on
III Learn to weather the migraine
IV Live a normal life
* * * * * * *
Next up will be a wider-ranging piece in which I will attempt to catch up on what’s been going on out there. Thanks always for comments! Best to all, Michael Jorrin (aka Doc Gumshoe)
[ed. note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) who joins us to share an update on the world of health and medicine a couple times a month. He does not generally write about investments directly, but has agreed to our trading restrictions. He chooses his own topics, and his past articles can be found on his author page here.]