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Available online at www.sciencedirect.com

www.elsevier.com/locate/trap

Pathophysiology of migraine and tension-type headache


Sait Ashinaa,, Lars Bendtsenb, Messoud Ashinab
a

Department of Pain Medicine and Palliative Care, and Department of Neurology, Albert Einstein College of Medicine, Beth Israel Medical
Center, New York, New York
b
Danish Headache Center and Department of Neurology, University of Copenhagen, Glostrup Hospital, Glostrup, Copenhagen, Denmark

article info

a bs t r a c t
Migraine and tension-type headache are common in general population. Recent progress

Keywords:

in basic and clinical research has increased our understanding of pathophysiology of these

Migraine

headaches. New treatment modalities and drugs for the treatment of these headaches are

Tension-type headache

emerging. Migraine is a neurovascular headache with complex pathophysiology, which

Pathophysiology

has not been fully clarified. Genes for both migraines, with and without aura, are being
identified. Current research indicates importance of cortical spreading depression and
abnormal brain stem activity in the pathophysiology of migraine with aura. The migraine
headache most likely originates in the sensory fibers innervating intracranial and
extracranial blood vessels. Peripheral and central sensitization of trigeminovascular
nociceptive pathways may develop during migraine attacks. Central sensitization of
second- and third-order trigeminovascular nociceptive neurons may lead to transformation of episodic migraine to chronic migraine. Pericranial myofascial pain sensitivity is
increased in patients with tension-type headache and may be of importance in the
pathophysiology of this headache. Sensitization of second-order neurons at the level of
the spinal dorsal horn or trigeminal nucleus, sensitization of supraspinal neurons, and
decreased descending inhibition from supraspinal structures play a major role in the
pathophysiology of chronic tension-type headache.
& 2013 Elsevier Inc. All rights reserved.

Introduction
Both migraine and tension-type headache (TTH) are common
primary headache disorders in the population.1,2 Both conditions have an enormous socioeconomic impact on individual and the society.1,2 The pathophysiology of migraine and
TTH is not fully clarified. However, the progress in basic and
clinical research has increased our understanding of the
mechanisms of migraine.3 This has led to the development
of new treatments for migraine.
In contrast to migraine, no significant improvement in
treatment options has been seen in TTH within the last
decades. This could be due to the TTH pathophysiology,
which is less complete than that of migraine. Unfortunately,

TTH has long been the least studied type of headache due to
lack of scientific interest and acceptance among clinicians
and researchers. Fortunately, we have gained a significant
amount of knowledge on pathophysiology of TTH within the
last two decades, and we are now beginning to understand
some of the mechanisms of this condition.4,5

Pathophysiology of migraine
Migraine is regarded as a neurovascular disorder and is
considered as a chronic headache disorder with episodic
manifestations or attacks.6 Migraine can be classified as
migraine with and without aura. Aura refers to transient

n
Corresponding author at: Headache Program, Department of Pain Medicine and Palliative Care, Department of Neurology, Beth Israel
Medical Center, 10 Union Square East, Suite 2 Q-R, New York, NY 10003.
E-mail address: sashina@chpnet.org (S. Ashina).

1084-208X/$ - see front matter & 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1053/j.trap.2012.11.002

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focal neurologic symptoms, including visual disturbances,


unilateral paresthesias, and language disturbance (dysphasia), and is experienced by up to 30% of migraine sufferers in
the population.7 Moreover, migraine is a complex headache
condition occurring in a sequence of phases: premonitory
phase, possible aura, headache, and postdrome followed by
the resolution of headache. The pathophysiological mechanisms involved in each phase are probably mediated by
different neuroanatomical structures.
Genetic studies demonstrate that migraine is a genetically
complex primary headache disorder due to multiple mutations
and variations. Approximately 50% of migraineurs have a firstdegree relative who are also suffering from migraine.8,9 A large
population study in Denmark demonstrated that first-degree
relatives of persons with migraine without aura had a 1.9-fold
higher risk of migraine without aura while first-degree relatives
of persons with migraine with aura had 4-fold higher risk of
migraine with aura.10 It has been suggested that both genetic
and environmental factors are determinants for migraine without aura, whereas migraine with aura is mainly determined by
genetic factors.10 Sporadic and familial hemiplegic migraines
(SHM and FHM) are rare paroxysmal migraine conditions which
are characterized by motor aura and headache.11,12 For FHM, 3
defects have been identified in genes coding for ion transporters
or ion channels.12 Based on these findings, FHM has been
divided into 3 types.12 In FHM type I, the affected gene is
CACNA1A (on chromosome 19p13), coding for the a1A subunit
of the Cav2.1 P/Q calcium channel. In FHM type II, the ATP1A2
gene (on chromosome 1q23) is affected, coding an a2-subunit of
the astrocytic Na/K-ATPase. For FHM type III, the SCN1A gene
(on chromosome 2q24) is affected, coding for voltage-gated
sodium channel.
The initial events and factors leading to the development
of migraine attack, as well as their neuroanatomical localization, are far from clarified and are subject to debate. It has been
suggested that migraine headache originates in the nociceptive
sensory fibers conveying pain signals from intracranial and
extracranial blood vessels.13 The strongest support for this
hypothesis comes from the experiments showing that the
stimulation of intra- and extracranial arteries evokes focal head
pain.14,15 Recent study using high resolution MRI angiography
showed dilatation of intracranial and extracranial arteries on
the headache side during experimentally calcitonin generelated peptide (CGRP) induced migraine attacks.16 Another
group of scientists suggest that the initiation center for
migraine without aura is in the brain stem nuclei17,18 and
hypothesize that pain could be generated without pathologic
sensory afferent input.19 The dorsal midbrain and dorsal pons
structures were found to have increased concentrations of
nonheme iron.20 PET study has demonstrated activation of
the dorsal midbrain, including the periaqueductal gray (PAG),
and in the dorsal pons, near the locus coeruleus, in studies
with migraine without aura.21 However, it has recently been
argued that activation of pons is not specific for migraine.22
For migraine with aura, cortical spreading depression (CSD)
has long been considered as a pathophysiologic mechanism.23 Initially described in rabbits by Leao, CSD is a propagating wave of depolarization of cortical neurons at a rate of
approximately 3-5 mm/min across the cerebral cortex, followed by suppression of neuronal activity lasting for

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15

minutes.23 Olesen et al.24 were the first to show that regional


cerebral blood flow was reduced in the posterior parietal and
occipital lobes during visual aura symptoms. In humans,
functional imaging studies, including blood oxygen leveldependent (BOLD) fMRI, consistently show a slowly propagating wave of hyperactivity followed by suppressed activity,
beginning near the occipital pole and extending anteriorly at
a rate of approximately 2-3 mm/min.25 In animals, CSD
caused long-lasting blood flow enhancement within the
middle meningeal artery upon trigeminal and parasympathetic activation, and plasma protein leakage within the dura
mater.26 Thus, CSD waves can activate trigeminal nociceptive
nerve fibers in the affected hemisphere, leading to the
development of lateralized headache.26 In addition, in animals, CSD frequency was suppressed by 40%-80% by treating
with commonly used migraine prophylactic medications
such as topiramate, valproate, propranolol, amitriptyline,
and methysergide.27
Pain in migraine may originate from intra- and extracranial
perivascular nociceptors innervated by trigeminal afferent
fibers.13 When activated, trigeminal nociceptive fibers in
animals release proinflammatory and pronociceptive vasoactive neuropeptides such as substance P, neurokinin A, and
CGRP from their peripheral ending.28,29 Elevated plasma
CGRP is reported in external jugular vein during acute
migraine in humans,28,30 but findings were not confirmed in
a study comparing plasma CGRP in ictal vs interictal state.31
These findings have led to the development of highly specific
CGRP receptor antagonists with positive results in the treatment of acute migraine.32
Sensitization of trigeminovascular nociceptive second- and
third-order neurons or central sensitization has been demonstrated in migraineurs33 and animal models of migraine.
Clinic-based studies suggest that up to two-thirds of
migraine sufferers develop cutaneous allodynia, a marker of
central sensitization, during their attacks.33,34 In a population
study, prevalence of allodynia was higher in transformed
migraine (68.3%) than in episodic migraine (63.2%).35 Central
sensitization plays an important role in the pathophysiology
of chronic migraine and may be a most important mechanism of migraine chronification. Presence of cutaneous allodynia may be a risk factor for transformation of episodic
to chronic migraine, possibly through the mechanisms of
neuronal damage in the region of the periaqueductal gray
matter.36,37
Triptans, disease-specific headache abortive medications
used in treatment of migraine, are serotonin 5-HT1B/1D/1F
receptor agonists.38 Based on the anatomical localization of
these receptors, triptans may act through cranial vasoconstriction (5-HT1B receptors), peripheral neuronal inhibition
(5-HT1D receptors), and inhibition of transmission between
first- and second-order neurons of the trigeminal spinal
nucleus (5-HT1B/1D/1F receptors).38 However, the last
mechanism has been challenged by the impermeability of
blood-brain barrier to triptans.13 In animals, CDS has been
shown to disrupt blood-brain barrier by a matrix
metalloproteinase-9-dependent mechanism.39 However, it is
not clear how these findings apply to humans. Interestingly,
in a clinic-based study, when cutaneous allodynia developed
within a migraine attack, it was also associated with triptan

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refractoriness.40 Therefore, it has been suggested by one


study that the crucial site of action of triptans is on peripheral trigeminal afferents.40
In summary, migraine is a neurovascular primary headache disorder with complex pathophysiology, which has not
been fully clarified. Genome-wide association studies have
identified gene variants for common type of migraine or
migraine without aura.41 The current scientific evidence
indicates abnormal cortical activity or cortical spreading
depression and abnormal brain stem activity probably play
a major role in the pathophysiology of migraine with aura.
The migraine headache most likely originates in the sensory
fibers that convey pain signals from intracranial and extracranial blood vessels. Peripheral sensitization of first-order
neurons and central sensitization of second- and third-order
trigeminovascular nociceptive neurons may develop during
migraine attacks. Triptans, the mainstay migraine abortive
medications, work as agonists on 5-HT receptors both in
periphery and CNS via these mechanisms: constriction of
cranial vessels, inhibition of peripheral nociceptors, and
inhibition of pain transmission in CNS. Central sensitization
of second- and third-order trigeminovascular nociceptive
neurons may lead to transformation of episodic migraine to
chronic migraine.

Pathophysiology of tension-type headache


Despite the progress in basic and clinical research in recent
years, the origin of pain in TTH is unknown. Both peripheral
(nociception from pericranial myofascial tissue) and central
(increased excitability of CNS) factors may play a major role
in pathophysiology of TTH.4,42 A number of studies have
shown that the pericranial myofascial tissues are more
tender in patients with TTH than in controls, and that the
tenderness to manual palpation is associated with both the
intensity and the frequency of TTH.43,44 The origin of pain in
TTH has long been attributed to excessive muscle contraction, ischemia, and inflammation of head and neck muscles.
However, surface electromyography could not demonstrate
significantly increased activity in TTH.45 Ashina et al.46
demonstrated decreased blood flow in response to static
exercise in a tender muscle in patients with chronic TTH by
using microdialysis technique. The ischemia in tender points
was ruled out by no increase in interstitial lactate.46 Moreover, evidence of inflammatory changes in tender points
could not be demonstrated in patients with chronic TTH.47
Pain detection and tolerance thresholds to mechanical ,
thermal, and electrical stimuli were shown to be decreased in
chronic TTH sufferers.4,48-50 It has also been demonstrated
that patients with chronic TTH had a qualitatively altered
pain perception and generalized hyperalgesia.51,52 Based on
these pain perception studies, it has been suggested that
chronic pain in patients with chronic TTH may be due to
central sensitization, that is, sensitization of neurons at the
level of the spinal dorsal horn or trigeminal nucleus, or both,
induced by continuous nociceptive input from pericranial
muscles and myofascial tissues.4 Furthermore, the nitric
oxide synthase (NOS) inhibitor, NG-monomethyl-L-arginine
hydrochloride, reduced headache and pericranial myofascial

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tissue tenderness and hardness in patients with chronic


TTH.53,54 In addition, the nitric oxide (NO) donor glyceryl
trinitrate was shown to be a trigger of TTH in these
patients.55 Thus, these pharmacologic studies support the
role of central sensitization in pathophysiology of chronic
TTH because sensitization of nociceptive pathways may be
caused by or associated with activation of NOS.5 Inhibition of
NOS may become a treatment for chronic TTH in the future.5
Final evidence for the causal relationship between frequent
headache and central sensitization has come from longitudinal studies. In a recent 12-year follow-up study, it was
reported that patients who developed episodic TTH had
increased pericranial myofascial tissue tenderness, but with
normal general pain sensitivity at follow-up, whereas subjects that developed chronic TTH had normal pain sensitivity
at baseline, developed increased central pain sensitivity at
follow-up.56 This study suggests that increased pain sensitivity is a consequence of frequent TTH and not a risk
factor.56
Deficient antinociceptive activity from supraspinal structures in CNS, that is, decreased descending inhibition, may
contribute to the increased pain sensitivity in patients with
chronic TTH.57,58 A recent high-density brain electroencephalogram mapping study found impaired inhibition of
nociceptive input in patients with chronic TTH.57 Impaired
or decreased descending inhibition could play a primary role
or could be related to central sensitization in TTH. Further
longitudinal studies are needed to clarify the role of
decreased descending inhibition in TTH.
The role of environmental and psychological factors in
pathophysiology of TTH has also been investigated. Despite
stress and mental tension being the frequently reported
trigger factors for TTH, they may be nonspecific factors for
TTH pathophysiology.59 It was recently reported that stress
induces more headache in patients with chronic TTH than
in controls, possibly by hyperalgesic effects on sensitized
pain pathways.60 However, stress did not aggravate
increased or abnormal temporal summation of pain or
impaired diffuse noxious inhibitory control in patients with
TTH.61
Genetic epidemiologic studies have demonstrated an
increased familiar risk in TTH.62,63 In one study,63 compared
with the general population, first-degree relatives had a 3.1fold increased risk of chronic THH, while spouses had no
increased risk of chronic TTH. Therefore, the increased
familial risk of TTH may be caused by both genetic and
environmental factors.
In summary, pericranial myofascial pain sensitivity is
increased in patients with TTH and peripheral mechanisms
may play a role in the pathophysiology of primarily episodic
TTH. However, a strong evidence for peripheral muscle
pathology as a cause of TTH is still lacking. The increased
myofascial pain sensitivity in TTH could be due to sensitization of second-order neurons at the level of the spinal dorsal
horn or trigeminal nucleus, sensitization of supraspinal
neurons, and decreased descending inhibition from
supraspinal structures. Based on genetic epidemiologic
studies, the majority of the population can potentially
develop TTH if exposed to sufficiently strong environmental
factors.

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Conclusions and perspectives


Current research has increased our understanding of the
pathophysiology of most common primary headache disorders, migraine and TTH. Migraine is a neurovascular headache with significant genetic component. Future studies in
migraine should focus on unifying currently known, as
described in this article, pathophysiological mechanisms.
Better understanding of migraine pathophysiology would
create opportunities to continue to improve treatment. We
are also beginning to understand some of the complex
pathophysiological mechanisms leading to TTH. This will
hopefully lead to the development of more effective and
disease-specific treatment options for TTH.

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