Migraine headaches are among the most common and debilitating conditions in today’s world, claiming the number 3 and 6 spots, respectively, globally . The current treatments have various degrees of efficacy with many patient-years being spent trying to find a combination of interventions that work for each unique presentation. While there are new medications that have been added to the preventative toolkit, many migraineurs are still left with residual headache days and chronic uncertainty. With symptom-based solutions, one can only get so far. With each new neuropeptide or inflammatory marker found to be implicated in migraine pathology a new therapy is kickstarted, but what about the why? It’s 2020 and we still don’t have a unifying theory on migraine pathology, probably due to its multifaceted presentation. My hope with this blog is that people who are suffering can work toward finding out their idiosyncratic why.
Pain in the Brain
Although most all of the machinery to interpret and issue the conscious representation of pain is localized in the brain, the brain tissue has no actual capacity to register a pain signal. The pain that is experienced during a migraine is a result of a couple of different processes.
First, the inflammatory mediators released prior to the onset of the migraine cause the blood vessels in the brain and its coverings to expand. The change in diameter and the mechanical properties of the vessel affects a part of the brainstem called the trigeminal cervical complex (TCC), which forwards the signal to other areas of the brain that generate pain perception . The inflammatory mediators also directly activate the TCC and other brain centers that modulate pain sensitivity and intensity.
Second, the frequent stimulation of neuronal pathways by noxious and painful signals create neuroplasticity. This means that, over time, the brain gets very skilled in performing these tasks, which in many cases will lead to what is called central sensitization - basically, normal stimuli like sunlight, odor, touch, sound, will be perceived as irritants. With enough irritation, the brain has the potential to instigate a migraine, or at least the premonitory symptoms that lead to one. These events are the crescendo of the migraine process, far beyond the cellular and subcellular level that we will be exploring. Nonetheless, it is important to know the endgame.
Familial Migraines and What They Tell Us
We’ll start with the rare ones. While it’s unlikely that anyone with familial hemiplegic migraines (FHM) doesn’t know they have it, it is important all migraineurs understand the why behind FHM because it provides insight into a probable piece of the global puzzle. FHM is a genetically inherited condition that is rooted in ion (calcium, sodium, potassium), energy, and neurotransmitter transport dysfunction. Essentially, these genetic abnormalities lead to brain cells being hypersensitive, resulting in neuronal excitation with normally non-excitable stimuli or events. Such liberal firing patterns can result in what is coined the cortical spreading depression (CSD). The CSD typically begins in one region (like the visual or somatosensory cortex) of the brain, and the individual will likely experience aural symptoms1 depending on where it starts. It is important to note that a CSD is neither necessary nor sufficient for a migraine, but its presence strongly predicts it. So, in some sense, one piece of migraine pathology lies in neuronal excitability dynamics. This is of course why anti-seizure medications (valproic acid, topiramate, gabapentin, etc.) are used so frequently to prevent and attenuate migraine attacks. However, by attempting to stabilize the group of neurons that are trigger happy, the rest of the brain is collateral – hence the many neurologically dulling side effects of these therapies. The triptans also seem to work by reducing the CSD, in addition to other roles. The question remains then, how can we support the body and brain to improve the resting state (see fig. 1 below) of the rowdy neurons and allow the rest of them to go about business as usual? Well, in individuals without FHM (and perhaps them, too) the answer may lay in little organelles called mitochondria.
The resting membrane potential of a neuron (red line, -70mV). Converging inputs from excitatory neurons leads to the gradual depolarization of the neuron, which is usually around -55mV (blue line). From there, the action potential is generated and cannot be reversed. The margin of hyper-excitability is the reduction in polarization of the neuron, bringing it closer to the threshold to fire and thereby needing less stimulation to evoke an action potential.
Mitochondria are responsible for many vital functions – cellular respiration, fatty acid oxidation, cell signaling, maintenance of ion homeostasis, and others . As key players in calcium sequestration and energy production, mitochondria regulate the membrane potential both directly and indirectly. A critical clinical correlate here to support the mitochondrial involvement in migraines is a rare condition called mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Individuals with this genetic disorder also have a greatly increased prevalence of migraines, supporting the somewhat obvious notion that migraines may be instigated by poor mitochondrial function. Additionally, a number of clinical trials with various mitochondrial-supporting agents have been successful in reducing migraine severity, number of attacks, and headache days.
Since mitochondria are primarily metabolic machines that transform food into fuel usable by cells, dietary composition is a core contributor to baseline mitochondrial function (when overt mutations are not present). Several recent studies reveal the utility and efficacy of low-carbohydrate and ketogenic diets in reducing migraine pathology, which came about initially from studying the diets for seizures . The burning of fatty acids rather than carbohydrates is a more energetically favorable process that results in more energy production with less oxidative stress. The brain’s ability to use ketones efficiently for fuel is the reason a low-carbohydrate, high fat diet is so transformative for seizure disorders and migraines. With data that show that seizures and migraines both respond very favorably to ketogenic diets and anti-epileptic drugs, it is reasonable to conclude that mitochondrial dysfunction, along with altered neuronal excitability, is common to both.
Mitochondria are maternally inherited, so the potential mitochondrial function of each person is determined by the health the egg they came from, which of course depends on the overall health of their mother. Chronic illness and stress significantly impact egg quality and, consequently, the mitochondrial endowment of offspring . This can be good news for young women who suffer from migraines that would like to have kids, as many lifestyle changes can promote healthier ovaries and follicles. On the other hand, if you know your parents had chronic health conditions that may have contributed to your current health state, then taking measures to enhance mitochondria, anti-oxidant systems, sleep, exercise, and nutrition can make a significant impact in quality of life.
Another reason that mitochondria are so important in migraine is their involvement in generating oxidative stress. Oxidative stress is a broad term, and in the context of a normal individual it should be perceived as a crucial and beneficial process of life. However, under pathological circumstances, excess oxidative stress, mediated by oxidative species like superoxide, hydrogen peroxide, and hydroxyl radicals can lead to abnormal cell death and chronic inflammation. 90% of normal reactive molecules are generated by the mitochondria, and typically stout anti-oxidant systems get rid of most of them. But, what if the mitochondria aren’t as resilient as they should be? As energy demands in the brain increase, whether it’s to prepare for an exam, perform daily work duties, etc., mitochondria are called upon to generate the supply – and oxidative species are a byproduct. When not efficiently cleared, excess oxidative stress signals a gradually increasing call for inflammation, mediated by a class of molecules like prostaglandins and leukotrienes. Here is where non-steroidal anti-inflammatory drugs (NSAID - naproxen, ibuprofen, diclofenac, ketorolac) come in for the treatment of migraine headaches. But again, we see the focus on stopping secondary and tertiary processes from generating the migraine experience, which is wonderful, but it is still missing the primary point. As noted in the first section, inflammatory mediators lead to vasodilation, pain generation, and further sensitization of those pathways. To reiterate, one of the reasons a low carbohydrate/high fat diet is effective in conditions of mitochondrial dysfunction is that metabolism of fatty acids and ketones produces less oxidative species than metabolism of carbohydrates. Ensuring that the diet is rich in vegetables, low-fructose fruit, and unsaturated fats (like olive and avocado oil) will promote oxidative resiliency.
Many migraineurs only experience symptoms around their menstrual cycle and ovulation, or have exacerbations around them. As if women didn’t have enough to deal with already! So, what’s the deal with these migraines? Well, they may be due to core changes during the menstrual cycle. The first is the decline in estradiol that is noted shortly after ovulation, although it is not as stark as the decline noted at the onset of menses. Indeed, while only some report post-ovulation headaches, peri-menstrual (after onset of menses) migraines are much more common, affecting 70% of female migraineurs . The throbbing, pulsatile nature of these terrible phenomena often begs a vascular explanation, and treatments to reduce the dilation of blood vessels in the brain are quite effective. However, taken at its core, the problem is estrogen flux around the time of the period. The resulting responses that yield a migraine are only symptoms; treating them does not address the core problem. Literature suggests that continuous, low-dose estrogen supplementation is greatly curative . Still, it is important to note that menstruation is only a trigger for migraine – meaning the underlying process we outlined in the above sections still applies. So how might sex hormones, estrogen in particular, instigate the rise in neuronal excitability?
Estrogen signaling is a complex and governs so much more than female reproductive ability. Even in men, who classically ignore the necessity of estrogen, it is absolutely critical for gender identity, gonadal development, bone strength, and libido. On a deeper level, estrogen stimulates gene transcription, cellular growth, synthesis of mitochondria, mitochondrial complexes, and the anti-oxidant systems. All of these are important for the integrity of neuronal energy and excitability. The argument that estrogen should not be used in migraine with aura is based on the increased2 risk for venous thromboembolism (blood clot) and subsequent stroke. However, the argument is up for debate. Supporting hormone balance in the natural fluctuations of the menstrual cycle may be what some migraineurs need to reinforce their mitochondrial and neuronal function.
Many people who have migraines have musculoskeletal triggers. Imbalanced muscle tone in muscles that stabilize the head send chronic signals of instability. Much of the upper cervical musculature receives nerve supply from cranial nerves and collaterals of the trigeminocervical complex, which is the gateway for central sensitization. There is also the musculature in the jaw, which is actually directly supplied by the trigeminal system. So, it’s pretty easy to see why jaw clenching, teeth grinding, and the stress surrounding that may serve as triggers. In this scenario the obvious target for treatment is the muscles themselves, for which muscle relaxing agents, such as carisoprodol and tizanidine, paralytic agents like Botox, or nerve blocks are used. These solutions will always have their risks, but they can surely help reduce the use of opioid use and emergency room visits. On the other hand, we have to ask the question of why the muscles are tight in the first place, as dulling their ability to signal what they are trying to convey to the brain may not be the best long-term solution. Is it your posture? Is it the integrity of your connective tissue? Is it the way your brain is regulating muscular tone? The neurology of posture is quite complex, but let’s suffice to say many things can disrupt the normal postural alignment. Perhaps part of your why is neuromuscular in origin.
I hope that everyone that reads this, but especially those who suffer from migraines, comes away with a better understanding of what a migraine is and the many different components that contribute to it. All too often there is a sense of hopelessness among migraineurs on the journey to find something that works for them, simply so they can go about their normal lives. Too many practitioners fail to listen, and then fail to educate and to explain what is currently known about why these people suffer. Well, here are some potentially new avenues to explore – support the brain cells and their energy dynamics by supporting mitochondria, utilize an anti-inflammatory food plan, consider hormonal therapies, try out a ketogenic diet (or at least a low-carbohydrate one), and perhaps think about postural training or rehabilitation. All of these avenues can be explored in many, many different ways, and if you need some direction or guidance, then we at Precision Regenerative and Functional Medicine are here to help.
1An aura is a wave of innocuous, or non-painful, sensory experience. Examples include increased/decreased hunger, visual floaters, scotomas, visual halos, yawning more than usual, flashing lights, speech difficulty, weakness, and many other odd symptoms.
2Users of oral contraceptives had a relative threefold increased risk of venous thromboembolism (VTE) compared with nonusers, but the absolute difference was 0.8 events per 10,000 people per year among women not taking estrogen and 3.0 per 10,000 people per year among women taking estrogen. A difference of 2 events per year in a group of 10,000 people. While the difference is statistically significant it is not clinically significant, especially considering the risks associated with menopause and increasing age without estrogen. It is important to note that these data were not from a group of women suffering from migraine with aura, meaning that the combination of increased clotting risk from the migraine pathology could make the estrogen replacement riskier than currently appreciated. Another important point is route of administration, as transdermal estrogen is not associated with increased risk of VTE.
[1 ] Bonafede, M., Sapra, S., Shah, N., Tepper, S., Cappell, K., & Desai, P. (2018). Direct and Indirect Healthcare Resource Utilization and Costs Among Migraine Patients in the United States. Headache: The Journal Of Head And Face Pain, 58(5), 700-714. doi: 10.1111/head.13275
 Calhoun, A. (2018). Understanding Menstrual Migraine. Headache: The Journal Of Head And Face Pain, 58(4), 626-630. doi: 10.1111/head.13291
 Goadsby, P., Holland, P., Martins-Oliveira, M., Hoffmann, J., Schankin, C., & Akerman, S. (2017). Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiological Reviews, 97(2), 553-622. doi: 10.1152/physrev.00034.2015
 Gross, E., Klement, R., Schoenen, J., D’Agostino, D., & Fischer, D. (2019). Potential Protective Mechanisms of Ketone Bodies in Migraine Prevention. Nutrients, 11(4), 811. doi: 10.3390/nu11040811
 Prasad, S., Tiwari, M., Pandey, A., Shrivastav, T., & Chaube, S. (2016). Impact of stress on oocyte quality and reproductive outcome. Journal Of Biomedical Science, 23(1). doi: 10.1186/s12929-016-0253-4
 Spinelli, J., & Haigis, M. (2018). The multifaceted contributions of mitochondria to cellular metabolism. Nature Cell Biology, 20(7), 745-754. doi: 10.1038/s41556-018-0124-1
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