Research Review By Dr. Josh Plener©


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Date Posted:

July 2020

Study Title:

Mechanisms of migraine as a chronic evolutive condition


Andreou A & Edvinsson L

Author's Affiliations:

Headache Research, Wolfson CARD, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom (UK); The Headache Centre, Guy’s and St. Thomas’, NHS Foundation Trust, London, UK.

Publication Information:

The Journal of Headache and Pain 2019; 20(1): 117.

Background Information:

Migraines affect approximately 15% of the general population (1) and present typically with intense head pain and various associated, unpleasant symptoms. According to the World Health Organization, migraines are the most prevalent, disabling and long-term neurological condition when factoring in years lost due to disability (2).

For most patients, migraine is not a static disorder – rather, it evolves and changes over time. Advancements in research have resulted in a deeper understanding of the mechanisms behind migraines. However, our understanding of this condition, particularly its ‘evolutive’ nature requires further research. This paper aimed to outline the existing evidence and theories pertaining to this concept.


Migraine as a life span disorder

Migraines can affect individuals at any age, showing an age-dependent shift in symptomatology and presentation. Children experience migraines in shorter duration, with greater paroxysmal symptoms (i.e. vomiting, abdominal pain, vertigo etc.). Their headaches are also not always unilateral and accompanying symptoms may include mild intolerance to light but rarely to noise (3). The gender distribution for childhood migraine varies depending on the cited research.

In adults, migraines are more prevalent in women compared to men: 12-17% vs 4-6% (6, 7). This is thought to be a result of the hormone estrogen, as migraine frequency decreases in post-menopausal women (8-10). Vomiting and cranial autonomic features in adults are less frequent compared to pediatric patients (4, 5).

In more elderly patients with migraine, autonomic symptoms tend to decrease. A possible reason for this is a change in connectivity between the hypothalamus and different autonomic control centres (11), as paroxysmal symptoms are associated with increased parasympathetic activities.

Genetic and epigenetic components of migraine

Genetic factors may contribute to an individual’s migraine susceptibility, while environmental factors can contribute to the development of a migraine attack (12, 13).

There are multiple genetic variants that can influence someone’s susceptibility to migraines. The majority of molecular pathways involved in migraine pathophysiology are related to vascular function, while a smaller number are related to metal ion homeostasis pathways and ion channel activity (13). Therefore, migraine susceptibility appears to be more dependent on vascular dysfunction, with neuronal dysfunction playing a secondary role. Future work may provide further insight into genetic mechanisms that result in episodic migraines transforming into a chronic form in some individuals, but not in others.

Epigenetics refers to the modification of gene expression without altering the actual underlying DNA sequence. Examples of epigenetic factors include things like early life events, environmental factors, stress, inflammation and brain plasticity, all of which are individual factors. The role of epigenetics in migraine evolution is not well understood, however it is possible that epigenetic changes in DNA expression could influence migraine susceptibility. A small number of studies appear to support its role in the migraine process, but at this time further studies with larger samples are required to validate these findings.

Brain changes in migraine patients

Differences in white and gray matter have been reported in migraine patients compared to controls. Research has demonstrated an increased prevalence of deep white matter lesions, especially in women with auras as part of their migraine syndrome (14-16). In children, these white matter lesions appear to not be prevalent. Other cortical structural changes that are present in migraine patients include thickening in the somatosensory cortex (or increased age-related thinning in episodic migraine!), decreased grey matter in the cingulate cortex and reduced volume of the medial prefrontal cortex (17-21). Gray matter changes seem to correlate with headache frequency and have also been noted in the region of the thalamus, as well as reduced striatal volume in migraine patients with and without aura. Brainstem and hypothalamus alterations have also been noted.

The cause of all of these structural brain changes remains unknown and their importance in the biology of migraines is uncertain. Their presence however, is suggestive that migraine can induce progressive anatomical changes that may contribute to the ‘evolutive’ nature of this condition for most patients. Detecting such changes in brain structure is obviously beyond our capability as chiropractors, but this information should speak to the complexity of how migraines both originate and evolve over time.

The evolution of a migraine attack

Different phases of a migraine (each discussed in more detail in the next sections):
  1. Premonitory phase (prior to headache onset): characterized by symptoms such as excessive yawning, thirst, food craving, cognitive difficulties and mood changes (22).
  2. Transient neurological symptoms (Aura): These are typically visual alterations that occur just before the actual headache. Additional symptoms can include speech difficulties, confusion and numbness. (23).
  3. Intense headache attack: This is usually ipsilateral, exacerbated by movement and associated with hypersensitivity to sensory stimuli (i.e. light and smells) and nausea (24).
  4. Postdrome phase: This encompasses symptoms of fatigue, neck stiffness, and concentration and comprehension difficulties (25).
Between episodes, individuals are susceptible to another attack due to genetic predisposition and various triggers. Migraine triggers are abundant and vary individually, but the most common are thought to be stress and lack of sleep (26).

Premonitory phase and triggering mechanism of migraine

There is growing evidence linking migraine attack triggers and the hypothalamus. One function of the hypothalamus is to control circadian rhythms, which migraines appear to possess (27). To illustrate, migraine attacks occur at set times (i.e. daily, monthly or seasonal). The hypothalamus also regulates homeostasis (27). Perhaps not coincidentally, premonitory symptoms of a migraine are associated with homeostatic functions, such as arousal, sleep and feeding, and disturbances in homeostatic function can trigger migraine attacks (26). For example, sleep disturbances can trigger attacks in over 50% of migraine patients. Brain imaging studies add additional evidence linking the hypothalamus to this phase. These studies reveal an increase in blood flow to the hypothalamus during the very early stages of migraine attacks (28, 29).

Dopaminergic mechanisms (such as yawning) also appear to play a role in the premonitory phase.

Migraine aura

Aura symptoms typically occur in 15-20% of migraine patients (30). Auras usually develop gradually over 15-20 minutes and last less then 60 minutes (24). Cortical spreading depression (CSD) is a wave of neuronal depolarization linked to depressed neuronal activity and blood flow changes (31). This is believed to be the cause of the aura (32), however the mechanism of how CSD is triggered is not understood.

Headache phase

The headache phase involves activation of the ascending trigeminothalamic pathway. Pain during a migraine attack is the result of intracranial structures (such as dura and intracranial vasculature) which are innervated by the trigeminal nerve (33). Trigeminal fibres transmit sensory information from intracranial structures and synapse on second-order neurons within the trigeminocervical complex, which give rise to the main ascending trigeminothalamic pathway relaying information to third order neurons mainly in the contralateral thalamus. Finally, this information is processed in the higher cortical areas. The trigeminocervical complex includes the trigeminal nucleus caudalis, C1 and C2 spinal levels. This has always been postulated as a possible reason why neck treatments (like SMT) can provide migraine relief.

The thalamus appears to be a key player in migraine pain due to its involvement in multisensory integration, which may influence neuronal excitability in migraine attacks. Neuroimaging studies have demonstrated altered connectivity between the thalamus and pain modulating cortical areas which correlate to migraine symptoms (34, 35). In addition, thalamocortical activation appears to be involved in associated migraine symptoms such as hypersensitivity to visual and auditory stimuli (36, 37).

Trigeminal system and its role in sustaining head pain in migraine:

Evidence has suggested that the peripheral trigeminal system plays a key role in pain felt during a migraine - highlighted by the following lines of research:
  • Referred pain patterns of migraine headaches are located in similar locations to referred pain when stimulating meningeal and cerebral arteries during awake brain surgery (33, 38-40). These arteries are innervated by trigeminal fibres.
  • Calcitonin-gene-related-peptide (CGRP) levels are increased during a migraine attack, and CGRP origin is from the trigeminal nerve (41-43).
  • Chemicals that do not cross the blood brain barrier, such as CGRP and histamine, can trigger a migraine attack (44, 45). Provocation of non-migraine suffers with these chemicals do not result in a migraine attack, suggesting a sensitized trigeminal nerve in migraine sufferers.
  • Migraine treatments that do not cross the blood brain barrier, such as peripherally injected botulin toxin, demonstrates the important role of the peripheral trigeminal fibres and trigeminal ganglion (46).
Vascular changes in migraine:

Historically, vascular changes were thought to be the main driver of migraine attacks. The thought was that distention of the large cranial arteries would result in the headache (33). However, this has come into question as spontaneous dilatation alone cannot result in migraine pain (for example, spontaneous dilatation during a general blood pressure decrease does not result in a migraine attack). Further research is needed in order to properly understand the role blood vessels have on factors contributing to the pathophysiology of migraines. It is possible that blood vessels are involved in the pathophysiology of migraine, but not vasodilation in particular. For example, blood vessels and the nervous system have bidirectional communication without the need for vascular tone changes (47). Various cell types are present in blood vessels that release and respond to numerous mediators (i.e. cytokines, ATP, NO) and many of these can sensitize trigeminal neurons.

Postdrome phase

Approximately 80% of patients report at least one non-headache symptom following their migraine (25). This phase of the migraine is not well understood and is currently the least researched. Recent studies have demonstrated a reduced brain blood flow except for a persistent increase in blood flow to the occipital cortex (29).

The Evolutive Nature of Migraine Chronicity

The transition from an episodic to a chronic migraine diagnosis is based on the cut-off of > 15 migraine days per month (24). Chronic migraine sufferers have a significantly higher incidence of family history of migraine, menstrual aggravation of migraines, identifiable trigger factors, associated symptoms, and early morning awakening with headache (49). Some risk factors that can double the risk of migraines becoming chronic include: increased migraine attack frequency and overuse of acute migraine medication (50-52), ineffective acute treatment leading to medication overuse (53), depression (54) and lifestyle factors such as stress, high caffeine intake and obesity (50, 55).

The role of inflammation and central sensitization in chronic migraines:

The question remains if inflammation contributes to activating the trigeminal system resulting in chronic migraine headaches (56). NSAIDs are common treatment options for acute headaches, while greater occipital nerve steroid injections are used as a preventive method in chronic migraine patients, thus suggesting an inflammatory role in migraine pathology (57-60). In addition, animal studies support an inflammatory role. CGRP increases during a migraine attack (41), which can lead to continuous activation of C-fibres and A-delta-fibres. These can release inflammatory cytokines not only in the dura but in neuronal cell bodies located in the trigeminal ganglion. Inflammatory cytokines have been suggested to be involved in the initiation and progression of a migraine attack (61).

Central sensitization is a state of hyperalgesia or allodynia (62). Due to the development of peripheral sensitization that can occur in the trigeminal system during an attack, this could lead to the development of central sensitization. Approximately 80% of migraine suffers develop cutaneous allodynia during an attack, mostly localized to the area of ipsilateral head pain (63, 64). Upper body allodynia seen in migraine patients may be a result of the spread of neuronal sensitization from hyperexcitable second order neurons in the trigeminocervical complex to third order thalamic neurons (62, 63). Peripheral treatments, such as botulinum toxin, aimed at blocking trigeminal fibres can block chronic migraines in 60-70% of patients…certainly an interesting finding that requires further investigation!

Clinical Application & Conclusions:

These authors propose that migraine is an evolving pathophysiological condition, the clinical phenotype of which can change throughout someone’s lifetime (i.e. the migraines can progress from episodic to chronic or even abolish/resolve completely). In addition, signs and symptoms may evolve or change as an individual ages. Clinically, it is important to gain a detailed history of migraine patients, especially chronic migraine sufferers, in order to track symptom progression. Despite existing research that has enhanced our understanding of migraines in many areas, such as the role of genetics and epigenetics on migraine susceptibility, more research is needed on this fascinating condition.

Study Methods:

This narrative review article presented a discussion about the mechanism behind migraines, and therefore no statistical analysis was conducted nor was a specific description of their methodology provided.

Study Strengths / Weaknesses:

  • This article provides a comprehensive overview of migraine mechanisms and presents up-to-date research.
  • The article informs readers where more research is required and where limitations currently exist.
  • Further discussion on treatment options could help provide a complete picture for clinicians.
  • There was no discussion about the quality of the literature used for this review.

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