The migraine cycle

When people think of migraine, they usually first think of headache or head pain. But migraine is much more than a headache. Migraines come with many other symptoms, not just head pain. Migraines can be split up into different phases, which occur in a predictable cycle. We will describe the brain and nervous system changes that happen at each stage of this cycle:

• (1)
  

  The inter-ictal period is the period between migraines.

  
  
• (2)
  

  The premonitory period is a period of increased symptoms that can start hours to days before a headache starts.

  
  
• (3)
  

  Migraine aura (occurring in one out of four people with migraine ) is a warning that a headache is coming. The most common symptom is a change in vision that starts right before the headache and lasts less than an hour. Other senses can be affected.

  
  
• (4)
  

  Headache is the period of head pain that can come along with other symptoms like nausea, and light and sound sensitivity.

  
  
• (5)
  

  The postdromal period is the aftermath of the headache. It occurs after the head pain goes away, but the person does not feel like they are back to normal.

In between attacks (interictal). Even when a child is not having migraine headache, they can be extra sensitive to their environment. Lights seem brighter and sounds seem louder and can be uncomfortable. Brain activity in areas that control our senses (e.g., sight, sound, touch) is different and can be increased in people with migraine. Pain and discomfort can be more easily triggered.

The day before (premonitory) . Children may behave differently from usual before they get a headache. Several hours to days prior to the headache, they may be more sensitive to light and sound, more tired, more irritable, complain of neck pain, and have difficulty concentrating. Frequent yawning and increased urination can also be signs that a migraine headache is coming. These changes have been linked to changes in brain activity.

Migraine aura . One in four people with migraine will experience a warning right before the start of the migraine headache. Migraine aura can take many forms, the most common being changes in vision. Children may experience flashing lights, sparkles, or partial visual loss. Strange smells, tingling or numbness on one side of the body, or one-sided weakness are other types of aura. Auras are caused by a wave of increased activity of brain cells in one part of the brain followed by a period when the brain cells are quiet, most often in the back of the brain that is responsible for vision.

The headache phase . Headache pain can be broken down into two parts. During the first part, i.e., at the start of the throbbing head pain, chemicals are released at the nerve endings of the face and scalp causing nerve irritation. The overactive nerves relay information to the brain that leads to the second part. During the second part, the brain itself becomes more sensitive. Pain pathways within the brain are more active. During this second part, the scalp can become sensitive to the touch. Medications used to stop headache work best before the scalp becomes sensitive, which is why it is important to take medications to treat a migraine headache early.

Aftermath of the headache (postdrome) . After the headache goes away, most children will feel tired and have difficulty concentrating. They may even crave certain foods or be very thirsty. These changes can last up to a day, but currently it is unclear what changes in the brain cause this recovery period.

Chronic migraine

Chronic migraine occurs when headache attacks happen very often (at least 15 days a month with 8 of those days being migraine headache). Pain can even be constant with times when the headache becomes more severe. Increased sensitivity of the brain seems to be present all the time in chronic migraine. It appears that the more time a person’s brain is in the midst of a migraine, the more likely they are to have a migraine. Having a good rescue therapy to stop a migraine in its tracks, may be important to keep migraines from becoming more frequent.

The effect of puberty and sex hormones

Before puberty, boys and girls get migraine at a similar rate, but after puberty girls get migraine at a higher rate than boys. This may be because of the different effects that sex hormones have on migraine. After puberty, girls can be more likely to have a headache right before or right after their monthly periods. Estrogen and progesterone might both promote migraine headaches, while testosterone may be protective. Migraine related to menstruation is not due to abnormal hormonal levels, but because of the brain’s sensitivity to normal hormonal changes. You can read more about this in a chapter related to hormones and headaches.

Migraine cycle

Inter-ictal phase. Between migraines, there is heightened sensitivity to stimuli, including photophobia and phonophobia. There is also evidence of increased responses in multiple cortical areas during this phase. Both sensory hyper-sensitivity and greater susceptibility to a migraine may be a consequence of a combination of factors including abnormal interactions between the thalamus (the main sensory relay station of the brain) and the cortex, altered connectivity of cortical structures as well as brainstem dysfunction, and a mismatch between metabolic supply and demand.

Premonitory phase. Almost 70% of children with migraine report premonitory symptoms hours to days before the onset of a migraine headache. Premonitory symptoms include fatigue, poor concentration, emotional liability, nausea, yawning, neck discomfort or stiffness, and increased sensory hyper-sensitivity—especially photophobia. The nature of these symptoms indicates that migraine is fundamentally a disorder of the central nervous system, which is supported by neurophysiologic changes during the premonitory phase of a migraine. These symptoms suggest that the beginning of a migraine may start hours to days before the headache and the migraine aura.

Aura. Migraine aura is present in one quarter of individuals. Visual auras are the most common but other aura types include sensory, motor, language, and rarely brainstem symtpoms. The pathogenesis of migraine aura has been attributed to cortical spreading depression (CSD), which consists of a wave of intense cortical neuronal activity followed by a more prolonged period of neuronal activity suppression. CSD may lead to activation of trigeminal nociceptors resulting in head pain. However, migraine often occurs in the absence of aura, premonitory symptoms precede the aura, and migraine aura can occur without headache, arguing that CSD is more likely part of the broader neurologic dysfunction that occurs in migraine.

Headache phase . The headache is typically throbbing and moderate or severe in intensity. This pain is associated with peripheral sensitization of trigeminovascular system caused by release of proinflammatory neuropeptides such as calcitonin gene-related peptide (CGRP) and others, that results in neurogenic inflammation and vasodilation. Peripheral stimulation of the trigeminal afferents leads to central sensitization of the brainstem. Central sensitization results in cutaneous allodynia and sustained headache. Once the central sensitization step is reached, triptans are no longer nearly as effective at treating the attack because they act on peripheral sensitization mechanisms. This is why it is important to advise patients to take the triptan as soon as the headache starts.

Postdrome . Over 80% of children and adolescents report a recovery period lasting up to a day following the headache phase. Most common postdromic symptoms included thirst, tiredness, visual disturbances, food cravings, paresthesias, and ocular pain.

Chronic migraine

Chronic migraine is defined as 15 or more headache days per month for 3 months with at least 8 of those days being migraine headaches. Chronic migraine is characterized by enduring central sensitization and alteration of pain processing pathways. Decreased pain thresholds in individuals with chronic compared to episodic migraine support this assertion. Importantly, repeated stimulation of circuitry involved in migraines seems to make the system more vulnerable to persistent central sensitization. High burden of episodic migraine including high headache frequency and ineffective abortive therapy in episodic migraine have been associated with progression to chronic migraine, though the causation has not been established. Still, it is likely helpful to have effective treatments for episodic migraine, given the possibility that it may help prevent the transition to chronic migraine.

Sex differences

The prevalence of migraine is similar between boys and girls until puberty, when the prevalence increases for females to a higher degree than for males. Sex differences are important for prognosis as boys are also more likely to have remission of their migraine headaches. Epidemiologic sex difference has led to research in the influence of sex hormones in migraine. There is evidence that estrogen, and estrogen withdrawal in particular, leads to increased susceptibility to a migraine. There is also preliminary evidence that testosterone confers a protective influence through anti-inflammatory, and anti-nociceptive properties.

Migraine cycle

Inter-ictal phase. Neurologic dysfunction is evident in between migraines. Sensory hypersensitivity and reduced pain thresholds are evident inter-ictally. Hyper-responsivity and lack of habituation of the sensory cortices has been shown by multiple neurophysiologic and neuroimaging modalities, which may offer a neural correlate to these symptoms. Hyper-responsivity may result from altered thalamocortical connectivity. Abnormal low frequency oscillations localized to the medial dorsal nucleus of the thalamus and increased coherence between low-frequency oscillations of the thalamus and high-frequency oscillations of the visual cortex have been noted inter-ictally. Increased resonance between the thalamus and cortex has been linked to thalamic cells displaying low-threshold calcium spike bursts. These findings are representative of altered network connectivity generally playing a role inter-ictally in migraine. Altered network connectivity has been described in multiple cortical and subcortical brain regions during the inter-ictal period including cerebral cortex, brainstem, amygdala, and thalamus . While the consequences of this altered connectivity have not been fully elucidated, it suggests that migraine involves dysfunction in multiple areas. This is consistent with the broad range of symptoms reported in migraine including sensory hypersensitivity, autonomic symptoms, and cognitive dysfunction.

An imbalance between metabolic supply and demand may also contribute. Magnetic resonance spectroscopy (MRS) demonstrates decreased N -Acetylaspartate levels indicating abnormal energy metabolism and potential mitochondrial dysfunction. Further, MRS shows abnormalities in glutamate and y-aminobutyric acid (GABA) indicating altered excitability. Increased metabolic demand coupled with impaired metabolic function may help create conditions to precipitate a migraine.

Premonitory phase. Premonitory symptoms, occurring hours to days before the headache phase, are reported in almost 70% of children with migraine. The most common symptoms include fatigue, poor concentration, emotional liability, nausea, yawning, stiff neck and neck discomfort, and increased sensory hyper-sensitivity—especially photophobia. The nature of these symptoms indicate that migraine is fundamentally a disorder of the central nervous system. This assertion is supported by the finding that the brain shows increased responses in association with premonitory symptoms measured using neuroimaging and neurophysiologic techniques. Increased hypothalamic activity has been observed and may underlie many of these symptoms including polyuria, change in appetite, and mood changes. Increased activity of the brainstem has been observed in the premonitory phase and is associated with nausea. Premonitory photophobia has been associated with increased activity measured in the occipital cortex. Cervical nerve afferents converge with trigeminal nerve afferents in the brainstem and cervical spinal cord, which may explain the occurrence of premonitory neck pain. These findings suggest that the beginning of a migraine may start well before the headache phase and even the migraine aura.

Aura. Migraine aura is present in one quarter of individuals. Visual auras are the most common but other aura types include sensory, motor, language, and brainstem symptoms and can vary within individuals. The pathogenesis of migraine aura has been attributed to cortical spreading depression (CSD). CSD is a common pathologic cortical phenomenon that is also seen following a brain insult including stroke and traumatic brain injury. CSD consists of a wave of intense cortical neuronal activity followed by a more prolonged period of neuronal activity suppression. The initial depolarization of CSD can be triggered by glutamate, and most effectively by activation of the N -methyl- d -aspartate (NMDA) glutamate receptor subtype. The depolarization is associated with dramatic ion shifts. Potassium and hydrogen ions move out of the cells, and sodium, calcium, and chloride ions move into the cell along with water leading to a decrease in the volume of the extracellular space. This wave moves across the cortex at a velocity of 2–4 mm/min. It does not respect vascular territories and is not accompanied by tissue ischemia. It occurs in a linear pattern that is spatially confined to a sulcus or gyrus.

CSD, the proposed pathophysiologic correlate of migraine aura, may lead to activation of trigeminal nociceptors that trigger head pain. It has been proposed that CSD serves as the instigator for activation of the trigeminovascular system based on animal studies. However, this point remains a topic of debate. Arguments against this hypothesis are that migraine often occurs in the absence of aura, premonitory symptoms precede migraine aura, and migraine aura can occur without the associated headache. An alternative proposal is that CSD is one component of the much broader neurologic dysfunction that occurs during migraine.

Headache phase . Over the past 40 years, the importance of the trigeminovascular system in migraine pain initiation and continuation has been further elucidated. Head pain starts with peripheral sensitization of trigeminal nerve. Collateral axons from the trigeminal ganglia and dural afferents release proinflammatory neuropeptides such as calcitonin gene-related peptide (CGRP), pituitary adenylate-cyclase activating peptide (PACAP), substance P, and neurokinin A leading to neurogenic inflammation and vasodilation. While vasodilation results from release of proinflammatory neuropeptides, it is not necessary nor sufficient to trigger a migraine. This is demonstrated by the findings that vasoactive intestinal peptide causes vasodilation, but does not induce migraine, while sildenafil and nitric oxide -induced migraines are not associated with vasodilation.

Peripheral stimulation of the trigeminal afferents leads to central sensitization as evidenced by neuronal hyper-excitability of the trigeminal nucleus caudalis (TNC) in the brain stem. Neuropeptides that are potentially involved include CGRP, glutamate via action on NMDA receptors, and calcium activity. When central sensitization occurs, it leads to cutaneous allodynia and sustained attack.

Postdrome . Over 80% of children and adolescents experience a postdromal period that lasts approximately a day following resolution of the headache. Most common postdromal symptoms included thirst, tiredness, visual disturbances, food craving paresthesias, and ocular pain. Little is known about the underlying pathophysiology of the migraine postdrome, but is an important area of future study as it could help to understand the process that leads to resolution of a migraine.

Therapies developed for migraine

The different stages of pain development during a migraine are crucial to understand, from a treatment perspective. This section reviews therapies specifically developed to treat migraine.

Triptans. Triptans are serotonin 5-HT 1B and 5-HT 1D receptor agonists that act on peripheral terminals of meningeal afferents. Therefore, they target peripheral sensitization. Consequently, they are less effective when the migraine progresses to central sensitization. In adults, triptans are 93% effective at stopping a migraine when taken prior to the onset of cutaneous allodynia. This efficacy drops to 15% after the onset of cutaneous allodynia, which is a surrogate marker for central sensitization. Triptans have the potential to inhibit the TNC centrally, but they are likely too large to cross the blood brain barrier. Interestingly, in a rat model, triptans were able to block both peripheral and central sensitization when taken early, but failed to do so once there is evidence of central sensitization. This finding underscores the importance of why taking abortive medications at the start of headache pain is critical; the headache must be stopped before the central sensitization stage is reached.

CGRP antibodies and CGRP antagonists . CGRP acts at multiple levels of the trigeminovascular system. It is important for pain transmission peripherally at the trigeminal ganglion, and also centrally at the TNC. Advances in our understanding on the important role CGRP mechanisms play in migraine pathophysiology has led to the development of two classes of therapeutics that target this system: CGRP antibodies and CGRP antagonists. CGRP antibodies were the first preventive therapy developed specifically for migraine. CGRP antibodies likely act primarily by blocking peripheral CGRP pathways because they are large molecules that cannot cross the blood brain barrier. Relatively low concentrations of CGRP antibodies have been measured centrally in rats, though a central mechanism cannot be excluded. CGRP antagonists have shown efficacy in acute migraine management. There is some evidence that CGRP antagonists may act centrally, though this remains a topic of debate because the antagonists have limited blood-brain barrier permeability.

Chronic migraine

Chronic migraine is defined as 15 or more headache days per month for 3 months with at least 8 of those days being migraine headaches. Pathophysiologic changes in chronic migraine include hyper-excitability, altered metabolism, and persistent central sensitization. Maladaptive changes in neuro-excitability and metabolism of sensory and pain processing pathways are seen in chronic migraine. Supportive of persistent central sensitization, pain thresholds are decreased and cutaneous allodynia is more common and severe in individuals with chronic migraine compared with episodic migraine. Further, rats subjected to repeated high intensity stimulation of trigeminal nociceptors develop persistent hyper-excitability in the TNC consistent with central sensitization. This finding indicates that repeated stimulation of the TNC (for instance by multiple migraines) can give rise to a state of persistent central sensitization. This is consistent with the observation that high headache frequency and ineffective abortive therapy in episodic migraine are both risk factors for conversion to chronic migraine.

Sex differences

Sex differences, due at least in part to the different effects of male and female sex hormones, play an important role in migraine. The prevalence of migraine is similar in boys and girls until puberty, after that the prevalence increases for both sexes, but with greater rise for females. For many women, the risk of having a migraine is higher between 2 days prior and 3 days after the onset of menstruation. This is attributed to estrogen withdrawal. There is more direct evidence that both estrogen and progesterone act on migraine pathophysiology as it increases susceptibility to CSD in mouse models. Testosterone, on the other hand, decreases susceptibility to CSD in mouse models and may confer a protective effect in migraine. Furthermore, testosterone has been shown to have anti-inflammatory, and anti-nociceptive properties in other disease states. Additionally, sex hormone differences can lead to differences in brain activity including alterations in pain and sensory processing. It is clear that sex hormones play an important role in migraine, but further research in their role in the pathophysiology of migraine is needed.