Migraine Pathophysiology

Summary

Migraine is a disabling neurovascular disorder

Key diencephalic and brainstem nuclei play critical roles in the

pathophysiology of migraine

Functional imaging has revealed the dorsal pons is activated during

migraine and the hypothalamus in the premonitory phase

Migraine is among the most common neurological disorders affecting

humans, which is ranked 7th most disabling by the WHO. The underlying
pathophysiology will be discussed herein; however the readers are also
directed towards recent reviews exploring novel genetic susceptibility loci
and therapeutic targets.1,2 It is now widely accepted that migraine is a
disease of the brain with the pain component reliant on activation and
disrupted modulation of the trigeminovascular system (Figure 1).3
The anatomy of the trigeminovascular system
The trigeminovascular system originates in the dense plexus of
nociceptors which innervate the cranial vasculature and dura matter, the
central projections of which travel via the trigeminal ganglion (TG) and
synapse on second order neurons in the dorsal horn giving rise to the
trigeminal cervical complex (TCC). Activation of these sensory afferents
results in the release of a number of neuropeptides, in both humans and
animals, which have actions on the cerebrovasculature and spinal cord.
The TCC has direct ascending connections with areas of the brainstem
(locus coeruleus (LC) and periaqueductal grey (PAG)), thalamus and
hypothalamus via the trigeminothalamic and trigeminohypothalamic
tracts en route to cortical structures. In addition to the ascending
projections there is also a reflex connection from the TCC to the
parasympathetic system via the superior salivatory nucleus (SuS) and
sphenopalantine ganglion (SPG). This connection results in cranial
autonomic features, which are seen in approximately 30-40% of
migraineurs, are diagnostic for cluster headache and, currently a target of
neurostimulation and proposed action of oxygen, 4 and efferent
connections from the facial and cervical dermatomes (via cervical ganglia,
CG).
Migraine is a disorder of dysfunctional central sensory processing

A combination of seminal preclinical and brain imaging studies have

highlighted the importance of key pontine, brainstem and diencephalic
structures involved in the pain neuroaxis in migraine.
Thalamus
The trigeminothalamic tract terminates in multiple thalamic nuclei, which
are activated in migraine, SUNCT and cluster headache, and are involved
in the parallel processing of nociceptive information, en route to cortical
areas.4 Trigeminovascular activation in experimental models activates
specific nuclei which have been shown to be possible sites of action for
anti-migraine therapeutics including the triptans. Moreover, sensitisation
of thalamic neurons has been implicated in the spread of cutaneous
allodynia and where convergent inputs from light sensitive ganglion cells
exist, photophobia.5
Trigeminovascular modulation
It is now widely accepted that disruption of normal pain modulatory tone
plays a critical role in primary headaches (Figure 1 above). The
hypothalamus has a critical role in the pain neuroaxis and a multitude of
functions, which may underlie certain migraine premonitory symptoms.
The hypothalamus (and the associated A11 nuclei) has clear projections to
the
TCC
and
is
activated
during
headache
disorders 6 and
trigeminovascular stimulation. Recently the hypothalamic orexinergic 7 and
dopaminergic8 pathways have gained attention for their role in
trigeminovascular modulation and associated symptoms, with a dual
orexin receptor antagonist currently undergoing phase 2 clinical trials.

Figure 1: Headache pathophysiology (Ref. 3)

Activation of the trigeminovascular system results in neuronal activation
in numerous pontine and brainstem regions including the LC and PAG. 913
Stimulation of these nuclei can result in altered cerebral blood flow and
inhibition of trigeminal neuronal activity, while pharmacological
modulation can result in inhibition or facilitation of trigeminovascular
nociceptive processing.14 Interestingly the brainstem has been implicated
in the generation of central sensitisation, with a likely role in disease
chronification.
While we have not discussed the role of cortical spreading depression
(CSD) here, we refer the reader to an excellent recent review 15 and
imaging data below regarding the occurrence of CSD like events in
humans, thought to underlie the aura of migraine.
Pathophysiology

The mechanisms of migraine remain incompletely understood. However,

new technologies have allowed formulation of current concepts that may
explain parts of the migraine syndrome.
Vascular theory
In the 1940s and 1950s, the vascular theory was proposed to explain the
pathophysiology of migraine headache. Wolff et al believed that ischemia
induced by intracranial vasoconstriction is responsible for the aura of
migraine and that the subsequent rebound vasodilation and activation of
perivascular nociceptive nerves resulted in headache.
This theory was based on the following 3 observations:

Extracranial vessels become distended and pulsatile during a

migraine attack

Stimulation of intracranial vessels in an awake person induces

headache

Vasoconstrictors (eg, ergots) improve the headache, whereas

vasodilators (eg, nitroglycerin) provoke an attack

However, this theory did not explain the prodrome and associated
features. Nor did it explain the efficacy of some drugs used to treat
migraines that have no effect on blood vessels and the fact that most
patients do not have an aura. Moreover, with the advent of newer imaging
technologies, researchers found that intracranial blood flow patterns were
inconsistent with the vascular theory.
No consistent flow changes have been identified in patients suffering from
migraine headache without aura. Regional cerebral blood flow (rCBF)
remains normal in the majority of patients. However, bilateral decrease in
rCBF, beginning at the occipital cortex and spreading anteriorly, has been
reported. More recently, Perciaccante has shown that migraine is
characterized by a cardiac autonomic dysfunction.[11]
As a result of these anomalous findings, the vascular theory was
supplanted by the neurovascular theory.
Neurovascular theory
The neurovascular theory holds that a complex series of neural and
vascular events initiates migraine.[12] According to this theory, migraine is
primarily a neurogenic process with secondary changes in cerebral
perfusion.[13]

At baseline, a migraineur who is not having any headache has a state of

neuronal hyperexcitability in the cerebral cortex, especially in the occipital
cortex.[14] This finding has been demonstrated in studies of transcranial
magnetic stimulation and with functional magnetic resonance imaging
(MRI).
This observation explains the special susceptibility of the migrainous brain
to headaches.[15] One can draw a parallel with the patient with epilepsy
who similarly has interictal neuronal irritability.
Cortical spreading depression
In 1944, Leao proposed the theory of cortical spreading depression (CSD)
to explain the mechanism of migraine with aura. CSD is a well-defined
wave of neuronal excitation in the cortical gray matter that spreads from
its site of origin at the rate of 2-6 mm/min.
This cellular depolarization causes the primary cortical phenomenon or
aura phase; in turn, it activates trigeminal fibers, causing the headache
phase. The neurochemical basis of the CSD is the release of potassium or
the excitatory amino acid glutamate from neural tissue. This release
depolarizes the adjacent tissue, which, in turn, releases more
neurotransmitters, propagating the spreading depression.
Oligemia
Positron emission tomography (PET) scanning demonstrates that blood
flow is moderately reduced during a migrainous aura, but the spreading
oligemia does not correspond to vascular territories. The oligemia itself is
insufficient to impair function. Instead, the flow is reduced because the
spreading depression reduces metabolism.
Although CSD is the disturbance that presumably results in the clinical
manifestation of migraine aura, this spreading oligemia can be clinically
silent (ie, migraine without aura). Perhaps a certain threshold is required
to produce symptoms in patients having aura but not in those without
aura. A study of the novel agent tonabersat, which inhibits CSD, found
that the agent helped to prevent migraine attacks with aura only,
suggesting that CSD may but not be involved in attacks without aura.[16]
Trigeminovascular system
Activation of the trigeminovascular system by CSD stimulates nociceptive
neurons on dural blood vessels to release plasma proteins and paingenerating substances such as calcitonin gene-related peptide, substance
P, vasoactive intestinal peptide, and neurokinin A. The resultant state of

sterile inflammation is accompanied by further vasodilation, producing

pain.
The initial cortical hyperperfusion in CSD is partly mediated by the release
of trigeminal and parasympathetic neurotransmitters from perivascular
nerve fibers, whereas delayed meningeal blood flow increase is mediated
by a trigeminal-parasympathetic brainstem connection. According to
Moulton et al, altered descending modulation in the brainstem has been
postulated to contribute to the headache phase of migraine; this leads to
loss of inhibition or enhanced facilitation, resulting in trigeminovascular
neuron hyperexcitability.[17]
Metalloproteinases
In addition, through a variety of molecular mechanisms, CSD upregulates
genes, such as those encoding for cyclo-oxygenase 2 (COX-2), tumor
necrosis factor alpha (TNF-alpha), interleukin-1beta, galanin, and
metalloproteinases. The activation of metalloproteinases leads to leakage
of the blood-brain barrier, allowing potassium, nitric oxide, adenosine, and
other products released by CSD to reach and sensitize the dural
perivascular trigeminal afferent endings.[18]
Increased net activity of matrix metalloproteinase2 (MMP-2) has been
demonstrated in migraineurs. Patients who have migraine without aura
seem to have an increased ratio of matrix metalloproteinase9 (MMP-9) to
tissue inhibitors of metalloproteinase1 (TIMP-1), in contrast to a lower
MMP-9/TIMP-1 ratio in patients who have migraine with aura.[19] Measured
levels of MMP-9 alone are the same for migraine patients with or without
aura.[20]
Hypoxia
In an experimental study, acute hypoxia was induced by a single episode
of CSD. This was accompanied by dramatic failure of brain ion
homeostasis and prolonged impairment of neurovascular and
neurometabolic coupling.[21]
Vasoactive substances and neurotransmitters
Perivascular nerve activity also results in release of substances such as
substance P, neurokinin A, calcitonin gene-related peptide, and nitric
oxide, which interact with the blood vessel wall to produce dilation,
protein extravasation, and sterile inflammation. This stimulates the
trigeminocervical complex, as shown by induction of c-fos antigen by PET
scan. Information then is relayed to the thalamus and cortex for

registering of pain. Involvement of other centers may explain the

associated autonomic symptoms and affective aspects of this pain.
Neurogenically induced plasma extravasation may play a role in the
expression of pain in migraine, but it may not be sufficient by itself to
cause pain. The presence of other stimulators may be required.
Although some drugs that are effective for migraine inhibit neurogenic
plasma extravasation, substance P antagonists and the endothelin
antagonist bosentan inhibit neurogenic plasma extravasation but are
ineffective as antimigraine drugs. Also, the pain process requires not only
the activation of nociceptors of pain-producing intracranial structures but
also reduction in the normal functioning of endogenous pain-control
pathways that gate the pain.
Migraine center
A potential "migraine center" in the brainstem has been proposed, based
on PET-scan results showing persistently elevated rCBF in the brainstem
(ie, periaqueductal gray, midbrain reticular formation, locus ceruleus)
even after sumatriptan-produced resolution of headache and related
symptoms. These were the findings in 9 patients who had experienced
spontaneous attack of migraine without aura. The increased rCBF was not
observed outside of the attack, suggesting that this activation was not
due to pain perception or increased activity of the endogenous
antinociceptive system.
The fact that sumatriptan reversed the concomitant increased rCBF in the
cerebral cortex but not the brainstem centers suggests dysfunction in the
regulation involved in antinociception and vascular control of these
centers. Thalamic processing of pain is known to be gated by ascending
serotonergic fibers from the dorsal raphe nucleus and from aminergic
nuclei in the pontine tegmentum and locus ceruleus; the latter can alter
brain flow and blood-brain barrier permeability.
Because of the set periodicity of migraine, linkage to the suprachiasmatic
nucleus of the hypothalamus that governs circadian rhythm has been
proposed. Discovering the central trigger for migraine would help to
identify better prophylactic agents.
Brainstem activation
PET scanning in patients having an acute migraine headache
demonstrates activation of the contralateral pons, even after medications
abort the pain. Weiler et al proposed that brainstem activation may be the
initiating factor of migraine.

Once the CSD occurs on the surface of the brain, H + and K+ ions diffuse to
the pia mater and activate C-fiber meningeal nociceptors, releasing a
proinflammatory soup of neurochemicals (eg, calcitonin generelated
peptide) and causing plasma extravasation to occur. Therefore, a sterile,
neurogenic inflammation of the trigeminovascular complex is present.
Once the trigeminal system is activated, it stimulates the cranial vessels
to dilate. The final common pathway to the throbbing headache is the
dilatation of blood vessels.
Cutaneous allodynia
Burstein et al described the phenomenon of cutaneous allodynia, in which
secondary pain pathways of the trigeminothalamic system become
sensitized during a migrainous episode. [22] This observation demonstrates
that, along with the previously described neurovascular events,
sensitization of central pathways in the brain mediates the pain of
migraine.
Dopamine pathway
Some authors have proposed a dopaminergic basis for migraine. [23] In
1977, Sicuteri postulated that a state of dopaminergic hypersensitivity is
present in patients with migraine. Interest in this theory has recently been
renewed.
Some of the symptoms associated with migraine headaches, such as
nausea, vomiting, yawning, irritability, hypotension, and hyperactivity, can
be attributed to relative dopaminergic stimulation. Dopamine receptor
hypersensitivity has been shown experimentally with dopamine agonists
(eg, apomorphine). Dopamine antagonists (eg, prochlorperazine)
completely relieve almost 75% of acute migraine attacks.
Magnesium deficiency
Another theory proposes that deficiency of magnesium in the brain
triggers a chain of events, starting with platelet aggregation and
glutamate release and finally resulting in the release of 5hydroxytryptamine, which is a vasoconstrictor. In clinical studies, oral
magnesium has shown benefit for preventive treatment and intravenous
magnesium may be effective for acute treatment, particularly in certain
subsets of migraine patients.[24]
Endothelial dysfunction
Vascular smooth muscle cell dysfunction may involve impaired cyclic
guanosine monophosphate and hemodynamic response to nitric oxide.

[25]

Nitric oxide released by microglia is a potentially cytotoxic

proinflammatory mediator, initiating and maintaining brain inflammation
through activation of the trigeminal neuron system.
Nitric oxide levels continue to be increased even in the headache-free
period in migraineurs.[26] In premenopausal women with migraine,
particularly in those with migraine aura, increased endothelial activation,
which is a component of endothelial dysfunction, is evident.[27]
Serotonin and migraine
The serotonin receptor (5-hydroxytryptamine [5-HT]) is believed to be the
most important receptor in the headache pathway. Immunohistochemical
studies have detected 5-hydroxytryptamine1D (5-HT1D) receptors in
trigeminal sensory neurons, including peripheral projections to the dura
and within the trigeminal nucleus caudalis (TNC) and solitary tract, while
5-HT1B receptors are present on smooth muscle cells in meningeal
vessels; however, both can be found in both tissues to some extent and
even in coronary vessels.
All the currently available triptans (see Medication) are selective 5-HT1B/D
full agonists. These agents may decrease headache by abolishing
neuropeptide release in the periphery and blocking neurotransmission by
acting on second-order neurons in the trigeminocervical complex.
Migraine risk factors
Predisposing vascular risk factors for migraine include the following [28] :

Increased levels of C-reactive protein

Increased levels of interleukins

Increased levels of TNF-alpha and adhesion molecules (systemic

inflammation markers)

Oxidative stress and thrombosis

Increased body weight

High blood pressure

Hypercholesterolemia

Impaired insulin sensitivity

High homocysteine levels

Stroke

Coronary heart disease

Transformed migraine/medication overuse headache

In some patients, migraine progresses to chronic migraine. Acute overuse
of symptomatic medication is considered one of the most important risk
factors for migraine progression. Medication overuse headache can occur
with any analgesic, including acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and aspirin. In
addition, Bigal and Lipton identified the following associations of
medication with progression to chronic migraine[29] :

Opiates - Critical dose of exposure is around 8 days per month; the

effect is more pronounced in men

Barbiturates - Critical dose of exposure is around 5 days per month;

the effect is more pronounced in women

Triptans - Migraine progression is seen only in patients with high

frequency of migraine at baseline (10-14 days/mo)

In the study, the effect of anti-inflammatory medications varied with

headache frequency. These agents were protective in patients with fewer
than 10 days of headache at baseline but induced migraine progression in
patients with a high frequency of headaches at baseline.[29]