Energy impairment may cause brain oxidative stress triggering a migraine as a protective response

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Individuals who experience migraines are prone to a brain energy deficit between attacks, whether through increased demand or inadequate energy production according to a new analysis which finds that an energy impairment may cause brain oxidative stress, triggering a migraine as a protective response.

This analysis sheds light on why migraines occur and helps explain how a migraine aura is kindled and propagates, and why migraines tend to improve as individuals age according to Jonathan Borkum, an adjunct associate professor of psychology at the University of Maine.

Borkum’s analysis, which was published as a review article in the journal Neurochemical Research, characterizes migraines as a homeostatic response set in motion by oxidant-sensing switches in the body that extrapolate individual neuronal metabolism to the entire brain.

When brain energy is inadequate, overproduction of oxidants, which are mild toxins, is stimulated. Borkum hypothesizes that oxidant buildup alerts the brain to the energy imbalance, and elicits the migraine attack as a corrective response.

While brain energy deficits have been observed in individuals prone to migraine, the mechanism that triggers an attack based on energy imbalance in the brain was not previously understood.

According to Borkum, the human brain balances the level of antioxidant defense with the amount of energy produced and vice versa, to create a tightly regulated cycle that maintains energy production and cellular redox potential in a narrow optimal range.

The oxidative stress created by the energy imbalance associated with migraine threatens neuronal viability in the short term and is suspected as a cause of neurodegenerative disease in the long term.

Borkum demonstrates that energy deficiency, whether resulting from increased energy demand in a hyperexcitable brain or decreased energy supply from mitochondrial impairment, creates oxidative stress as an inherent feature of cellular metabolism.

This stress induces migraines in susceptible individuals via oxidant-sensing ion channels in the pain receptors sited in the membrane that covers the brain.

The brain’s response to migraine attacks includes reducing brain energy demands, increasing mitochondrial biogenesis, suppressing apoptosis, releasing varied growth factors, stimulating neurogenesis, reducing the production of reactive oxidative species and raising the level of antioxidant defense.

These protective mechanisms, which seek to balance energy production and demand in the brain, suggest that the migraine attack is itself a corrective process initiated to protect the brain from oxidative stress and energy imbalance.

The implication is that new migraine prevention therapies that treat brain energy deficit and oxidative stress simultaneously will likely be more effective than those that target either separately.


Migraine is a common neurological disorder, characterised by moderate to severe headache and nausea. While there is not currently a cure for migraine, there are treatments and lifestyle changes that can help patients manage their migraine and enjoy a normal life. 

Studies have shown that migraine affects over 4.9 million Australians (1). It is more common in women than men, which is thought to be due to hormonal factors (2).

Migraine can begin in childhood, but often appears in a patient in their 20s or 30s. It is relatively uncommon after the age of 40, however different migraine types affect patients in different stages of life. Migraine can be a complex and varied disorder with a spectrum of severity, types and symptoms. Fortunately, there are a variety of new treatments and research increasing our understanding and helping to more effectively treat and prevent migraine.

Symptoms

Migraine attacks can have a number of different symptoms and affect patients in different ways. However, there are some symptoms that characterise migraine attacks and set them apart from other headache disorders such as tension headache or cluster headache. According to the International Headache Society, a migraine can be diagnosed when:

(a) the pain has at least two of the following characteristics;

one sided
moderate to severe intensity
throbbing
aggravated by movement (i.e. walking, going up stairs)

(b) there is at least one of the following associated symptoms:

nausea
vomiting
photophobia (sensitivity to light)
phonophobia (sensitivity to noise)

(c) the headache lasts for between 4 and 72 hours. (3)

For some people, the head pain is the most distressing part of the attack, but the associated symptoms can be equally or more debilitating. Other symptoms that may be experienced include:

  • osmophobia (sensitivity to smell)
  • aura (including visual disturbances such as bright zigzag lines, flashing lights, difficulty in focusing or blind spots lasting 20-45 minutes)
  • difficulty in concentrating, confusion
  • a feeling of being generally extremely unwell
  • problems with articulation or co-ordination
  • diarrhoea
  • stiffness of the neck and shoulders
  • tingling, pins and needles or numbness or even one-sided limb weakness
  • speech disturbance
  • motor weakness
  • vertigo.

Many of these symptoms are connected to specific migraine subtypes or complications.

The majority of people with migraine experience episodic migraine, which refers to a frequency of fewer than 14 days with migraine each month. Chronic migraine occurs in 7.6% of Australian migraine sufferers (1) and refers to patients with migraine symptoms (either aura or headache) on 15 days or more a month. It’s important to see a doctor for chronic migraine, as patients often require daily preventive medications rather than just acute treatments.

Stages of Migraine

Migraine can be divided into four distinct phases:

1. Early Warning Symptoms (prodromal)

A significant number of migraine patients experience warning symptoms for up to 24 hours before the attacks start but may not recognise these signs until they know what to look for. These symptoms include:

  • Changes in mood, varying from feeling elated, on top of the world and full of energy, flying through the day’s work and accomplishing twice as much as usual, to feeling depressed and irritable
  • Nausea, changes in appetite (intense hunger or sugar craving), lack of appetite, constipation, diarrhoea
  • Neurological changes, drowsiness, incessant yawning, difficulty finding the right words (dysphasia), dislike of light and sound, difficulty in eye focus
  • Changes in behaviour, agitated, obsessional, clumsy
  • Muscle stiffness, particularly in the neck and shoulders
  • Frequent urination.

Many of these symptoms are thought to arise in the hypothalamus and brainstem, the deep-seated part of the brain (4).

2. Aura

Aura accompanies migraine attacks for about 20% of migraine patients (5). The most common aura symptoms are visual, sensory or speech/language symptoms, referred to as typical aura. Visual symptoms affect 90% of patients who experience migraine with aura. Common disturbances include: 

  • bright zigzag lines; 
  • flashing lights; 
  • difficulty in focusing, and; 
  • blind spots (6). 

Aura affects the visual field of both eyes despite often seeming to affect only one. Aura lasts 5-60 minutes before the vision normally restores itself. Other types of aura include brainstem aura (vertigo, tinnitus, difficulty talking or decreased consciousness) and hemiplegic migraine (causing motor weakness). All of these symptoms are fully reversible and normally only last one hour, with the exception of motor weakness which can last days, or even weeks. 

3. Headache

Those experiencing migraine with aura may or may not have a gap of up to an hour between the end of the aura and the onset of the head pain. Regardless of whether one experiences aura, the headache experience is common. The headache phase can last between four hours up to three days. It is often throbbing and on one side of the head, but can affect both sides. It can be on the same or opposite side to the aura. Movement makes it worse. The most common accompanying symptoms in this phase are nausea, vomiting and sensitivity to light, sound and smell. 

4. Recovery (postdrome)

The post-attack phase is referred to as the ‘postdrome’. The way an attack ends varies greatly. Sleep is restorative for some. Being sick can make children feel much better. For others, effective medication can improve attacks, while sometimes nothing works except the headache burning itself out. Patients may feel drained for about 24 hours, while others may feel energetic or even euphoric. Other common symptoms in this recovery phase are fatigue, nausea, and a continuing sensitivity to light and sound (5).

Causes & Risk Factors

Migraine can be caused by a number of different biological mechanisms and environmental factors. The biology behind migraine is complex and not fully understood. It involves the activation of trigeminovascular pathways and central parts of the brain including the brain stem (7). The trigeminovascular system controls sensation in your face and jaw – which is why trigeminal disorders cause head pain. The brain is thought to be in an altered state of excitability, which can also lead to disruptive symptoms like nausea, light sensitivity and aura (7). 

Neurotransmitters are chemical ‘messengers’ that communicate between neurons. These play a very important role in brain function (8). When the brain is more sensitive, neurotransmitters can become overactive and trigger pain signals. 

Neurotransmitters also control things like hunger, wakefulness, anxiety and focus. This causes many of the prodromal symptoms (like food cravings, irritability or trouble sleeping), and also causes nausea, photophobia, and phonophobia during an attack. The difficulty in migraine treatment arises because there are often many different neurotransmitters active during an attack. Some patients may be more responsive to treatment that addresses their serotonin neurotransmitters, while others might find treatment more effective if it inhibits calcitonin gene-related peptides (CGRPs). 

Key neurotransmitters involved

NeurotransmitterAssociate treatmentsWhat it does
CGRPsCGRP monoclonal antibodies (Aimovig, Emgality, Ajovy)CGRPs play a vital role in the dilation of blood vessels. In migraine, this dilation affects the trigeminal nerve, causing pain. CGRPs are also thought to be key in causing light sensitivity (7).
SerotoninTriptans & Ditans
SSRIs
Ergotamines
Serotonin is known as the ‘happy hormone’, but these neurotransmitters also affect the swelling of blood vessels. Symptoms affected by serotonin include head pain, sleep interruption, shifts in mood, and difficulty with memory and thought.
DopamineNDRIs
MAOIs
Dopamine affects our cognition, pleasure, mood, and sleep. You may notice symptoms such as lack of motivation or emotional control, drowsiness, and trouble focusing. Dopamine is also strongly linked to nausea – migraine patients seem to be hypersensitive to this neurotransmitter, and it can cause yawning, vomiting and dizziness (7).
GABAButalbital
Anti-epileptic medication
GABA regulates anxiety, and contributes to motor control and vision, amongst other functions. Symptoms include anxiety, sleep disturbance, and panic attacks.
General neuron communicationNerve stimulation devices (i.e. Cefaly)These nerve stimulation devices work by delivering electrical or magnetic pulses to specific nerves (i.e. the trigeminal nerve), to reduce the frequency and severity of migraine attacks. They reduce neuron activity overall, rather than chemically targeting specific neurotransmitters.

Migraine can also be understood through its physical mechanisms, as pain is often caused by the dilation (swelling) or inflammation of blood vessels. In this case, doctors may prescribe beta blockers or nonsteroidal anti-inflammatory drugs (NSAIDs).

The cause of migraine aura, and its role in an attack, is still being researched. Only 25-30% of migraine patients experience aura, so doctors believe that its connection to the overall cause of migraine attacks is minimal (7). The most commonly accepted explanation of aura is that it occurs due to cortical spreading depression (CSD), which is a wave of atypical activity that moves across the brain, altering the function of brain cells and blood vessels (9). As this activity moves across the brain, it can shut down parts of the brain, explaining why visual aura may appear to travel across the visual cortex.

Despite understanding the neuro-chemical processes occurring during a migraine attack, it is unclear why some people experience migraine while others do not. Some risk factors exist, including: 

  • Family history. There is often a familial link with migraine, with one study showing that 90% of migraine patients have a family history of the condition (10).
  • Gender. Women are more than twice as likely to experience migraine than men, due to hormonal factors (1).
  • Depression and anxiety. Due to the association between migraines and serotonin, migraine patients often experience depression and anxiety as a comorbidity of their migraine (11).
  • Childhood abuse. Physical, emotional and sexual abuse have all been associated with migraine. Abuse is known to negatively impact cognitive and neuropsychological development, and these alterations seem to predict migraine and other pain-related conditions (12). Emotional abuse has been most significantly linked to migraine (13).

Triggers

Triggers vary significantly from person to person, to the point where almost anything could set off a migraine for someone with a certain level of sensitivity and adverse response to otherwise normal stimuli. It can be difficult to identify which triggers affect you, for a number of reasons – you might be set off by a particular combination of triggers, or there might have been a number of environmental factors to consider such as sleep or stress levels, making it hard to identify the true cause. Other times, people confuse their prodrome symptoms (in the days preceding a migraine attack) for triggers. They could experience neck pain or discomfort in the lead up to an attack, and mistake this to be a trigger – when it is actually a symptom caused by the migraine itself.

However, there are a number of common triggers to look out for, and keeping a migraine diary can help to narrow down this list.

Common triggers

  • Heightened emotions. Stress is the most common emotional trigger, but arguments and excitement can also trigger a migraine attack.
  • Sleep. Lack of sleep and oversleeping can both be triggers.
  • Diet. Missed, delayed or inadequate meals are common triggers, but certain foods are also known to cause migraine (i.e. chocolate, citrus, aged cheeses/meats, cultured products and many other processed foods)
  • Food additives. Caffeine (also found in coffee), MSG, aspartame, etc.
  • Alcohol. Wine is a very common trigger, but certain beers and spirits affect some people. It may also affect your sleep which triggers an attack a day or two later.
  • Sensory triggers. Bright/flickering lights, strong smells (e.g. gasoline, perfume), loud/jarring sounds.
  • Changes in environment. Travel, altitude, weather (especially changes in barometric pressure).
  • Screen usage. Overuse or incorrect use of computers, poor posture, going to the cinema, watching videos.
  • Hormonal changes. Specifically in women, hormonal fluctuations can cause migraine – particularly menstruation, perimenopause, or menopause.
  • Exercise. Especially vigorous exercise like running. High impact exercise may also be a trigger. 

Types of Migraine

Apart from common migraine and migraine with aura, other types of migraine include:

Migraine Aura without Headache

Some migraine patients experience aura symptoms (visual, sensory or speech/language issues) without the subsequent head pain. They may experience other symptoms of a migraine attack, such as nausea or sensitivity to light and sound, but without headache. Aura without headache has been reported in previous cases as a result of someone having migraine attacks earlier in life, then the headache stopping as they get older. However, migraine aura can also start later in life (after the age of 40), with a patient never experiencing headache. A doctor should be consulted if these symptoms develop later in life, as some symptoms overlap with brain tumours, TIAs (a “mini-stroke”) and epilepsy (14).

Menstrual Migraine

A menstrual migraine is a type of migraine that only occurs for someone around the time of menstruation. It could either occur as a part of pre-menstrual syndrome (PMS) or during their period. While the cause of menstrual migraine can’t be definitively identified, it is widely thought to be triggered by the drop in estrogen (2).

Vestibular Migraine

Vestibular migraine is a type of aura characterised by dizziness, vertigo and balance disturbance. In contrast to regular migraine aura, which precedes head pain, vestibular symptoms can persist throughout the entire attack, or even occur in headache-free periods.

Status Migrainosus

This term describes migraine that may last longer than 72 hours. Also known as status migraine. Symptoms of nausea and light sensitivity may resolve after a couple of days but the headache persists.

Abdominal Migraine

Abdominal migraine is a disorder most common in young children, resulting in periodic abdominal pain. Some children also experience nausea and vomiting. Over two thirds of children with abdominal migraine also experience headache.

Treatment of Migraine

Much can be done about migraine. Treatment is not just a matter of taking a tablet but a case of each individual developing a migraine management plan that will likely involve lifestyle modifications, medication and complementary therapies.

Medication

Some people can manage migraine with medications available from a pharmacy. For many others, these are not sufficiently effective. If this is the case, or you are unsure about the cause or nature of your headache, or if your symptoms change, it is important you consult a doctor. Studies show that 50% of people with migraine have not been diagnosed. Even if you have previously consulted a doctor and the prescribed treatment has not been successful it is worth going again. Migraine can be managed, but effective management involves an ongoing partnership between you and your doctor. Some medications are given once the headache has begun (acute treatment) and others taken daily to reduce the frequency of attacks (preventive treatment).

Acute Treatment

Acute treatments refer to medications used to treat an acute attack at the onset of symptoms. These include:

  • aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs)
  • paracetamol
  • triptans such as sumatriptan (Imigran), naratriptan (Naramig), zolmitriptan (Zomig), rizatriptan (Maxalt), eletriptan (Relpax) that are based on the serotonin molecule
  • ergotamine compounds that appear to provide relief by constricting cranial blood vessels
  • narcotic-type analgesics 
  • anti-nausea medications (domperidone, metoclopramide, prochlorperazine) 

Preventive Treatment

Prophylactic or preventive medication is taken daily, monthly or at regular intervals, regardless of whether a headache is present, to reduce the incidence of severe or frequent attacks. These are often recommended if acute treatment is needed on 3-4 days per month. A drug is trialled at a tolerable, effective dose for about 8-12 weeks to assess response. These include:

  • beta blockers such as propranolol (Inderal), timolol (Blocadren), atenolol (Tenormin) and metoprolol (Lopresor, Betaloc) that block the beta-receptors on which adrenaline works in the nervous system as well as on blood vessels
  • serotonin antagonists such as methysergide (Deseril), pizotifen (Sandomigran) and cyproheptadine (Periactin)
  • anti-CGRPs (calcitonin gene-related peptides) which are monoclonal antibodies that target the release of CGRP which are involved in the cascade of a migraine attack
  • nerve stimulators (e.g. Cefaly device, springTMS)
  • sodium valproate or valproic acid (eg Epilim), an anti-epileptic drug shown to reduce the intensity of migraine
  • topiramate, an antiepileptic drug, shown to reduce frequency of migraine 
  • calcium-channel blockers such as verapamil (Isoptin) that stop the constriction of blood vessels by preventing the use of calcium necessary for this reaction
  • antidepressants such as amitriptyline (eg. Tryptanol) have an action on headache that is independent of their antidepressant action
  • onabotulinumtoxin A (eg. Botox) is not just a beauty treatment. It has been proven to help those with chronic migraine and is listed on the PBS.
  • feverfew, a herbal remedy
  • riboflavin 200mg twice daily has been reported as useful.

All can be effective. All may have side effects. All, except feverfew and riboflavin, are prescription drugs. Many were initially introduced for some other problem and were also observed to reduce headache. 

Complementary Therapies

Complementary therapies may also be used to further reduce the frequency or severity of migraine attacks.

  • Acupuncture: Stimulating acupoints may ease pain by encouraging production of endorphins (natural painkillers).
  • Alexander technique: Can help prevent tension headaches by relieving poor posture and pressure that results from it.
  • Aromatherapy: Combines various scented oils and promotes relaxation and eases tension.
  • Biofeedback: Can be used to treat tension-type and migraine – patients learn to control blood pressure, heart rate, and spasms in the arteries supplying the brain through a sensory device.
  • Chiropractic therapy: Based on the theory that most diseases of the body are a result of a misalignment of the vertebral column with pressure on the adjacent nerves that may affect blood vessel and muscle function. Manual techniques purport to adjust the misalignment. Extreme caution should be taken with sharp movements of the neck or head in those with migraine. Many neurologists will discourage patients from chiropractic care due to this risk.
  • Homeopathy: Uses active substances found in certain medications highly diluted.
  • Hydrotherapy:  Splashing your face with cold water before lying down for an hour may ease headache. Alternating hot and cold showers dilates then constricts the blood vessels, stimulating circulation. Ice pack on head is another option.
  • Hypnotherapy: May help a patient cope with headache by altering the way the body interprets messages of pain.
  • Massage: Can reduce muscle tension throughout the body, thereby reducing headache.
  • Meditation: Stress is a major trigger for some migraine patients. A 2014 study showed that meditation had the potential to reduce the number of migraine attacks and reduce their duration (15).
  • Naturopathy: Uses only natural substances in small amounts and aims to provide a healthier balance of bodily processes.
  • Osteopathy: Manipulation of the neck or cranial, osteopathy may be used to correct misalignments of the vertebrae that practitioners believe may trigger some migraine attacks.
  • Physiotherapy: Treating muscle tension or rehabilitation from injuries in the back, shoulders or neck areas may help reduce negative stimuli that may lead to headache.
  • Relaxation techniques: Geared towards reducing pressure in the body and the level of stress chemicals that may worsen headache.
  • Shiatsu: Combination of massage and pressure can restore the “energy balance” and induce relaxation.
  • Yoga: Can relieve muscle tension in the back of the neck and correct posture.

References:

  1. Deloitte Access Economics, 2018, Migraine in Australia Whitepaper. Retrieved from: https://www2.deloitte.com/au/en/pages/economics/articles/migraine-australia-whitepaper.html
  2. S Sacco et al, 2012, Migraine in women: the role of hormones and their impact on vascular diseaseshttps://doi.org/10.1007/s10194-012-0424-y 
  3. International Headache Society, 2018, 1. Migraine. Retrieved from: https://ichd-3.org/1-migraine/
  4. R Burstein et al, 2015, Migraine: Multiple Processes, Complex Pathophysiology. https://doi.org/10.1523/JNEUROSCI.0373-15.2015 
  5. MW Weatherall, 2015, The diagnosis and treatment of chronic migrainehttps://doi.org/10.1177%2F2040622315579627 
  6. International Headache Society, 2018, 1.2 Migraine with aura. Retrieved from: https://ichd-3.org/1-migraine/1-2-migraine-with-aura/
  7. PJ Goadsby et al, 2017, Pathophysiology of Migraine: A Disorder of Sensory Processinghttps://doi.org/10.1152/physrev.00034.2015 
  8. L Panawala, 2017, Difference Between Neuropeptides and Neurotransmitters. Retrieved from: https://www.researchgate.net/publication/318305704_Difference_Between_Neuropeptides_and_Neurotransmitters
  9. A Charles & S Baca, 2013, Cortical spreading depression and migrainehttps://doi.org/10.1038/nrneurol.2013.192 
  10. Migraine Research Foundation, 2020, Migraine Facts. Retrieved from: https://migraineresearchfoundation.org/about-migraine/migraine-facts/
  11. HT Chu et al, 2018, Associations Between Depression/Anxiety and Headache Frequency in Migraineurs: A Cross‐Sectional Studyhttps://doi.org/10.1111/head.13215 
  12. G Tietjen & N Faedda, 2017, “Child Abuse and Headache in Children and Adolescents”. In V Guidetti et al (Eds.), Headache and Comorbidities in Childhood and Adolescence (pp. 45-62). Cham, Switzerland: Springer Nature
  13. G Tietjen et al, 2017, Emotional Abuse History and Migraine Among Young Adults: A Retrospective Cross‐Sectional Analysis of the Add Health Datasethttps://doi.org/10.1111/head.12994 
  14. DR Shah et al, 2018, Current Aura Without Headachehttps://doi.org/10.1007/s11916-018-0725-1 
  15. R Wells et al, 2014, Meditation for Migraines: A Pilot Randomized Controlled Trialhttps://doi.org/10.1111/head.12420 
  16. NP Barnes, 2015, Migraine headache in children. PMID: 26044059. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/26044059/ 
  17. DC Buse et al, 2020, Comorbid and co-occurring conditions in migraine and associated risk of increasing headache pain intensity and headache frequency: results of the migraine in America symptoms and treatment (MAST) studyhttps://doi.org/10.1186/s10194-020-1084-y 
  18. Q Zhang et al, 2019, The exploration of mechanisms of comorbidity between migraine and depressionhttps://doi.org/10.1111/jcmm.14390 
  19. C Lampl et al, 2016, Headache, depression and anxiety: associations in the Eurolight projecthttps://doi.org/10.1186/s10194-016-0649-2 
  20. A Vgontzas & J Pavlović, 2018, Sleep Disorders and Migraine: Review of Literature and Potential Pathophysiology Mechanismshttps://doi.org/10.1111/head.13358 
  21. R Budhiraja et al, 2011, Prevalence and Polysomnographic Correlates of Insomnia Comorbid with Medical Disordershttps://doi.org/10.5665/SLEEP.1114 
  22. S Nahas et al, 2020, Gastrointestinal Comorbidities Representing a Relative Contraindication to NSAID Use: Results From the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study. Retrieved from: https://n.neurology.org/content/94/15_Supplement/116/tab-article-info 
  23. S Sacco et al, 2015, Migraine and risk of ischaemic heart disease: a systematic review and meta‐analysis of observational studieshttps://doi.org/10.1111/ene.12701 
  24. J Liao et al, 2018, Epilepsy and migraine—Are they comorbidity?https://doi.org/10.1016/j.gendis.2018.04.007 
  25. A Aamodt et al, 2007, Is Headache Related to Asthma, Hay Fever, and Chronic Bronchitis? The Head‐HUNT Studyhttps://doi.org/10.1111/j.1526-4610.2006.00597.x
  26. Migraine World Summit, 2019, Sleep, Insomnia and Energy [Dr. Christine Lay interview]. Retrieved from https://www.migraineworldsummit.com/2019-christine-lay/

More information: Jonathan M. Borkum, Brain Energy Deficit as a Source of Oxidative Stress in Migraine: A Molecular Basis for Migraine Susceptibility, Neurochemical Research (2021). DOI: 10.1007/s11064-021-03335-9

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