Review

Functional MRI of migraine

Todd J Schwedt, Chia-Chun Chiang, Catherine D Chong, David W Dodick

Migraine is a disabling neurological condition manifesting with attacks of headache, hypersensitivities to visual, Lancet Neurol 2015; 14: 8191
auditory, olfactory and somatosensory stimuli, nausea, and vomiting. Exposure to sensory stimuli, such as odours, Mayo Clinic, 5777 East Mayo
visual stimuli, and sounds, commonly triggers migraine attacks, and hypersensitivities to sensory stimuli are Boulevard, Phoenix, USA
(T J Schwedt MD, C-C Chiang MD,
prominent during migraine attacks, but can persist with less magnitude between attacks. Functional MRI (fMRI) has
C D Chong PhD,
been used to investigate the mechanisms that lead to migraine sensory hypersensitivities by measuring brain responses Prof D W Dodick MD)
to visual, olfactory, and painful cutaneous stimulation, and functional connectivity analyses have investigated the Correspondence to:
functional organisation of specic brain regions and networks responsible for sensory processing. These studies have Dr Todd J Schwedt, Mayo Clinic,
consistently shown atypical brain responses to sensory stimuli, absence of the normal habituating response between 5777 East Mayo Boulevard,
Phoenix, AZ 85054, USA
attacks, and atypical functional connectivity of sensory processing regions. Identication of the mechanisms that lead
Schwedt.todd@mayo.edu
to migraine sensory hypersensitivities and that trigger migraine attacks in response to sensory stimuli might help to
better understand neural dysfunction in migraine and provide new targets for migraine prevention, and could provide
fMRI biomarkers that indicate early responses to preventive therapy.

Introduction therapies in migraine. Normalisation of these atypical

Migraine is a disabling and common neurological
disorder with a 1-year prevalence of 12% in the general
population.1 A migraine attack comprises moderate-to-
severe intensity headache, with a combination of nausea,
vomiting, and hypersensitivities to visual, auditory,
olfactory, and somatosensory stimuli.2,3 Visual, olfactory,
and auditory stimuli are also common triggers of
migraine attacks.46 About a third of patients with
migraine have aura associated with at least some of their
migraine attacks.7 Although many dierent neurological
symptoms can occur during a migraine aura, visual
symptoms are the most common.8 Between migraine
attacks, migraineurs often have persistent but less
prominent migraine symptoms, including hyper-
sensitivity to visual, auditory, olfactory, and somato-
sensory stimuli.3
Because migraine is mainly a disorder of brain
function, brain functional MRI (fMRI) studies are useful
to study the underlying mechanisms of migraine.
Although the aura and headache associated with
migraine have been attributed to abnormal
vasoconstriction and vasodilation of intracranial arteries,
the symptoms are now known to be mostly due to brain
dysfunction.9 Minor and transient changes in the calibre
of extracranial and intracranial arteries might occur
during a migraine attack, but such changes are not
always a component of migraine.10 fMRI is also useful to
study sensory hypersensitivities in migraine. The sensory
hypersensitivities that trigger and are present both
during and between migraine attacks are specic to
migraine and are not noted to the same extent in other
headache or pain disorders. A description of the
mechanisms underlying these features of migraine
should lead to an improved understanding of
pathophysiology and possibly to mechanistic distinction
of migraine from other headache and pain disorders.
Furthermore, fMRI localisation of atypical stimulus-
induced activations and atypical functional connectivity
in migraineurs might identify targets for preventive
imaging ndings might serve as biomarkers of an early
response to preventive therapies in migraine. In the past
few years there has been a substantial increase in the
number of published migraine fMRI studies, which have
helped to identify the location and clinical signicance of
migraine-associated brain dysfunction.
Many studies examined stimulus-induced brain
activation; most have used noxious thermal stimulation
of the skin, trigemino-nociceptive activation by
intranasal ammonia, olfactory stimuli, or visual stimuli.
Other studies have used analyses of functional
connectivity to investigate the organisation of specic
brain regions and functional networks implicated in
migraine pathophysiology. Most fMRI studies of
migraine have focused on the migraineur between
migraine attacks, in the so-called interictal phase,
whereas only a few have been done during the migraine
attack (ie, in the so-called ictal phase). fMRI studies of
migraine have enhanced our understanding of
hypersensitivities in migraine, including identication
of brain regions and networks that contribute to atypical
processing of sensory stimuli. This kind of processing is
a key feature of migraine that leads to increased
sensitivity to painful and non-painful touch, and visual
and olfactory stimuli, and enables typically non-noxious
environmental stimuli, such as ashing lights and
odours, to trigger migraine attacks. In this Review we
summarise the ndings of fMRI studies that investigated
migraine hypersensitivities, describe how these have
helped to clarify understanding of the anatomy and
biology of migraine, discuss the limitations of these
studies, and propose avenues for future research using
fMRI to study migraine.
Painful stimuli
Atypical processing of somatosensory stimuli is
suggested by physiological studies showing that, during
a migraine attack, most migraineurs are hypersensitive
to stimulation of the skin that would not normally be

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 Review

considered noxious, and that a proportion of these
migraineurs maintain a state of hypersensitivity to
somatosensory stimuli between migraine attacks.11,12
Hypersensitivity occurs in body regions innervated by
the trigeminal nerve and in extracranial regions,
implicating central sensitisation.13,14 Somatosensory
hypersensitivity results in the development of cutaneous
allodynia in around two-thirds of migraineurs during a
migraine attack.1517 A migraineur with cutaneous
allodynia nds normally non-noxious stimuli of the skin
to be painful, and thus experiences pain or discomfort in
response to stimuli such as a light touch of the face or
scalp, wearing hair in a tight ponytail, wearing heavy
earrings or eyeglasses, or a shirt collar buttoned tightly.
Brain activation patterns in response to painful stimuli
have been investigated in several migraine fMRI studies
(table 1).
Pain-inducing heat applied to the skin of the head, face,
or upper extremity has been used in fMRI studies of
migraine. Typically, heat is applied with an MRI-compatible
contact thermode with the temperature individualised to
each patient to elicit pain of moderate or severe intensity.

Cohort (n) Region studied Timing Stimulus Main ndings

Schwedt et al (2014)18 Episodic migraine (24) Whole brain Interictal Heat Stronger activation in lentiform nuclei, fusiform gyrus, subthalamic
Control (27) nucleus, hippocampus, middle cingulate cortex, somatosensory
cortex, dorsolateral prefrontal cortex; and weaker activation in
precentral gyrus and superior temporal gyrus in episodic migraineurs
than in healthy controls
Stankewitz et al (2013)19 Episodic migraine interictal (20) Whole brain Interictal and Ammonia Activation patterns in anterior insular cortex, middle cingulate cortex,
Episodic migraine ictal (10) ictal and thalamus suggest sensitisation to pain stimuli in interictal
Control (20) episodic migraineurs and habituation to pain stimuli in controls
Maleki et al (2012)20 High-frequency episodic migraine* (10) Hippocampus Interictal Heat Stronger hippocampal deactivation in low-frequency episodic
Low-frequency episodic migraine (10) migraineurs than in high-frequency episodic migraineurs
Maleki et al (2012)21 Episodic migraine: Whole brain Interictal Heat Stronger activation in insular cortex, primary somatosensory cortex,
Men (11) and putamen in men with episodic migraine than in women with
Women (11) episodic migraine
Stronger activation in caudate, superior temporal, superior frontal,
precuneus, posterior cingulate, sensory nucleus, and spinal trigeminal
nucleus of brainstem in women with episodic migraine than in men
with episodic migraine
Maleki et al (2012)22 High-frequency episodic migraine*(10) Results reported as ROI: Interictal Heat Stronger activation of primary somatosensory cortex and temporal
Low-frequency episodic migraine (10) somatosensory cortex, pole; and weaker activation of anterior insular cortex and cingulate
cingulate cortex, anterior gyrus in high-frequency episodic migraine than in low-frequency
insula, and temporal pole episodic migraine
Russo et al (2012)23 Episodic migraine (16) Whole brain Interictal Heat Stronger activation in anterior cingulate cortex; and weaker
Control (16) activation in secondary somatosensory cortex and pons in episodic
migraineurs than in healthy controls
Maleki et al (2011)24 High-frequency episodic migraine*(10) Whole brain Interictal Heat Weaker activation in caudate, putamen, and pallidum in high-
Low-frequency episodic migraine (10) frequency episodic migraineurs than in low-frequency episodic
migraineurs
Moulton et al (2011)25 Episodic migraine ictal (8) Whole brain (interictal vs Interictal and Heat Weaker activation in dorsolateral pons (probably the nucleus
Episodic migraine interictal (8) controls) ictal cuneiformis) in episodic migraineurs with ictal allodynia than in
Control (8) ROI (ictal vs interictal): controls
temporal pole and Stronger activation in temporal pole and parahippocampal gyrus in
parahippocampal gyrus ictal episodic migraineurs than in interictal episodic migraineurs
Stankewitz et al (2011)26 Episodic migraine interictal (20) Whole brain (ictal vs Interictal and Ammonia Weaker activation of spinal trigeminal nuclei in interictal or ictal
Episodic migraine pre-ictal (10) interictal) ictal migraineurs than in controls
Episodic migraine ictal (13) Spinal trigeminal nuclei Stronger activation in spinal trigeminal nuclei in pre-ictal than in
Control (20) (pre-ictal vs ictal vs interictal migraineurs
interictal vs control) The stronger the activity in the trigeminal nuclei, the closer the
migraineur was in days to their next migraine attack
Aderjan et al (2010)27 Episodic migraine (15) Whole brain Interictal Ammonia Decreased activation in prefrontal cortex, anterior cingulate cortex,
Control (15) red nucleus, and ventral medulla from day 1 to day 8 in episodic
migraineurs
Increased activation in these regions from day 1 to day 8 in controls
Burstein et al (2010)28 Allodynic episodic migraine ictal (8) Thalamus Interictal and Heat and Stronger activation of several thalamic regions in ictal phase than in
Allodynic episodic migraine interictal (8) ictal brush interictal phase
Moulton et al (2008)29 Episodic migraine ictal allodynia (12) Brainstem Interictal Heat Weaker activation in dorsolateral pons (probably the nucleus
Controls (12) cuneiformis) in episodic migraineurs with ictal allodynia than in
controls

ROI=region of interest. *High-frequency episodic migraine is dened as 814 headache days per month. Low-frequency episodic migraine is dened as 12 headache days per month.

Table 1: fMRI studies of migraine using pain stimuli

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In 2010, Stankewitz and colleagues30 published a new
method of eliciting trigeminal nerve pain in fMRI studies
by using intranasal ammonia. According to the
investigators, the ammonia, stimulates the nasal mucosa,
leading to irritation of the rst and second branches of the
trigeminal nerve, resulting in short-lasting, stinging or
stabbing pain sensations.30 Similar to the brain activation
in response to noxious heat, pain elicited by intranasal
ammonia results in activation in several pain processing
regions, including the insular cortex, thalamus, middle
cingulate cortex, amygdala, precentral gyrus, calcarine
sulcus, cerebellum, middle temporal gyrus, rostral
medulla, lower pons, caudate nucleus, supramarginal
gyrus, anterior cingulate cortex, postcentral gyrus, and
pallidum.30
Studies of thermal pain-induced activation and
intranasal ammonia-induced activation in specic
brain regions in the interictal period showed that
migraineurs have regional brain activation that diers
in intensity from controls.18,19,23,2527,29 Increased thermal
pain-induced activation was localised to regions within
the temporal pole, parahippocampal gyrus, anterior
cingulate cortex, lentiform nuclei, fusiform gyrus,
subthalamic nucleus, hippocampus, middle cingulate
cortex, somatosensory cortex, and dorsolateral
prefrontal cortex (gure 1).18,23,25 Reduced thermal pain-
induced activation in migraineurs was localised in
migraineurs to areas in the secondary somatosensory
cortex, precentral gyrus, superior temporal gyrus, and
brainstem.18,23,29 Although few patients with migraine
have been studied during a migraine attack, some
studies have shown increased thermal pain-induced
activation of the temporal pole, parahippocampal gyrus
and many thalamic areas compared with interictal
activation patterns in the same patients.25,28 Thus,
Postcentral gyrus
Precentral gyrus
Dorsolateral
prefrontal cortex
Temporal pole
Superior temporal gyrus
Figure 1: Pain-induced brain activations that dier in migraineurs versus controls
Brain regions with interictal pain-induced activity in migraineurs diering from that in controls are depicted on the surface of the brain and midline. Red areas show
more activation in migraineurs than in controls. Blue areas show less activation in migraineurs than in controls. Shaded areas do not represent the exact location,
size, or extent of dierential activity in brain regions.
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Review
migraineurs have atypical pain-induced activation of
brain regions that participate in various aspects of pain
processing, including sensory-discriminative, aective,
cognitive, and modulatory processing of pain.
fMRI data suggest that an imbalance in the facilitation
and the inhibition of pain signalling might contribute
to hypersensitivity in migraine. Migraineurs in the
interictal period who reported symptoms of allodynia
during migraine attacks, but no allodynia in the
interictal period, had less thermal pain-induced
activation in the dorsolateral pons, a region containing
the nucleus cuneiformis, than did controls.29 Because
the nucleus cuneiformis is predominantly an inhibitory
region in the descending pathways, hypoactivation of
this region suggests decreased inhibition of the pain
response in migraineurs, which could lead to allodynia
during a migraine attack. Results from a study27 in
which trigemino-nociception in migraineurs was
stimulated with ammonia delivered daily for
8 consecutive days support the notion that migraineurs
have inadequate inhibition of pain signalling pathways.
Recurrent stimulation decreased activation of the
prefrontal cortex, rostral anterior cingulate cortex, red
nucleus, and ventral medulla in patients with migraine,
whereas controls had increased activation in these
regions with stimulation.27 The decreased activation in
these brain regions, which are involved in endogenous
pain control, might represent inadequate pain
inhibition in migraineurs and suggests that the
recurrent pain of migraine leads to progressively less
pain inhibition over time.
Furthermore, physiological studies have shown an
absence of normal habituation (decrement in response
to repetitive stimuli) in the brains of migraineurs in the
interictal period in response to various stimuli. The
Middle cingulate cortex
Anterior cingulate cortex
Secondary
somatosensory
cortex
Lentiform nuclei
Hippocampus
Fusiform gyrus
Parahippocampal Pons
gyrus
Ventral medulla
Subthalamic
nucleus
Greater activation in migraine
Less activation in migraine
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decrease in habituation probably relates to dysfunctional
inhibition or increased facilitation of sensory
information and perhaps further contributes to atypical
pain processing in migraine.31 A lack of habituation in
interictal migraineurs was shown in an fMRI study19 that
exposed migraineurs and healthy controls to recurrent
painful stimulation with intranasal ammonia. Controls
habituated to the ammonia during the course of the
study, whereas the interictal migraineurs showed
increased activation in the anterior insula, middle
cingulate, and thalamus. These fMRI results lend
support to the notion that recurrent attacks of pain or
prolonged pain associated with migraine could increase
sensitivity to pain interictally because of decreased
habituation and the development of sensitisation.
investigated in an fMRI study (table 2).38 No dierences in
brain activation were noted when interictal migraineurs
were compared with healthy controls. However, during
spontaneous and untreated migraine attacks, migraineurs
had greater activation in the amygdala, insular cortex,
temporal pole, superior temporal gyrus, rostral pons, and
cerebellum than they did in the interictal state (gure 2).
Consistent with the frequent reports of osmophobia
during an attack, the study showed hyper-responsiveness
to olfactory stimuli in specic brain regions.38
Furthermore, because a region in the rostral pons might
be one of the earliest brain regions activated in a migraine
attack (ie, a so-called migraine generator), odour-induced
activation of the rostral pons in migraineurs might be a
mechanism by which odours trigger migraine attacks.

Olfactory stimuli Visual stimuli

Migraineurs are hypersensitive to odours during and
between migraine attacks. 2543% of migraineurs report
olfactory hypersensitivity during an attack, whereas
about a third of migraineurs report olfactory hyper-
sensitivity between migraine attacks (table 2).4143
Furthermore, half of migraineurs report that odours,
such as cigarette smoke, perfumes, and certain food
smells, can trigger migraines.41,44
The processing of olfactory stimuli (rose odour) by
migraineurs during and between migraine attacks was
Migraineurs are sensitive to visual stimuli, such as lights
and patterns, during and between migraine attacks. Light
of less intensity is needed to cause visual discomfort
interictally in migraineurs compared with controls, and
light of even less intensity causes visual discomfort
during an attack compared with the interictal state.45,46
Around 45% of migraineurs report symptoms of light
hypersensitivity in the interictal state, and about 90%
report that they have these symptoms during a migraine
attack.6,45,47,48 Additionally, 40% of migraineurs report that

Cohort (n) Region studied Timing Stimulus Main ndings

32 Episodic migraine with aura (18) Whole brain Interictal Visual (pattern) Stronger activation in V5, V3, precuneus, and middle frontal, superior occipital,
Griebe et al (2014)
Control (18) and intraparietal sulcus in migraineurs than in controls
Datta et al (2013)33 Episodic migraine with aura (25) Whole brain Interictal Visual (pattern) Stronger activation of primary visual cortex and lateral geniculate in
Episodic migraine without aura (25) Primary visual migraineurs with aura than in both other groups
Control (25) cortex, lateral
geniculate
Hougaard et al Episodic migraine with aura (20) Whole brain Interictal Visual (pattern) Stronger activation in inferior parietal lobe, superior parietal lobe or intraparietal
(2013)34 Control (20) (symptomatic vs sulcus, and inferior frontal lobe in symptomatic than in asymptomatic
asymptomatic hemisphere; similar results in symptomatic hemisphere compared with controls
hemisphere) No dierence in activation of asymptomatic hemisphere versus equivalent
hemisphere in controls
Antal et al (2011)35 Episodic migraine (24 [12 with aura]) Motion- Interictal Visual (pattern and Stronger activation in left superior-anterior portion of middle temporal
Control (12) responsive middle motion) complex in migraineurs with aura and migraineurs without aura than in
temporal area controls
Weaker activation in inferior-posterior portion of middle temporal complex in
migraineurs with aura and migraineurs without aura than in controls
Huang et al (2011)36 Episodic migraine (11 [7 with aura]) Visual cortex Interictal Visual (pattern) Stronger activation in visual cortex in migraineurs than in controls; combined
Control (11) analysis of individuals with and without aura
Martin et al (2011)37 Episodic migraine (19 [7 with aura]) Occipital cortex Interictal Visual (light) Higher number of voxels corresponding to activation (but no increase in signal
Control (19) intensity in migraineurs); combined analysis of individuals with and without
aura
Stankewitz et al Episodic migraine interictal (20) Whole brain Interictal Odour Brain activation in interictal migraineurs and controls did not dier
(2011)38 Episodic migraine ictal (13) and ictal Stronger activation of amygdala, insular cortex, temporal pole, superior
Control (20) temporal gyrus, rostral pons, and cerebellum in ictal than interictal migraineurs
Vincent et al (2003)39 Episodic migraine with aura (5) ROI not reported Interictal Visual (pattern) Activation of contralateral extrastriate visual cortex shown in more migraineurs
Control (5) than healthy controls
Cao et al (2002)40 Migraineurs with visually triggered Brainstem, Interictal Visual (pattern) Activation of red nucleus and substantia nigra precedes occipital cortex
attacks (12) occipital cortex and ictal activation and migraine symptoms in ictal migraineurs

ROI=region of interest. V3=visual area 3. V5=visual area 5.

Table 2: fMRI studies of migraine using visual or olfactory stimuli

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Superior temporal gyrus
(odour)
Insular cortex
(floor of the
Sylvian fissure)
(odour)
Temporal pole
(painful heat, odour)
Figure 2: Stimulus-induced brain activations that dier in ictal versus interictal migraineurs
Brain regions with pain, visual, and odour-induced activation that dier in migraineurs during a migraine versus between migraines are depicted on the surface of the
brain and midline. Red areas show more activation during a migraine attack than in the interictal period. No areas have less activity during a migraine attack than in the
interictal period. Shaded areas do not represent the exact location, size, or extent of dierential activity in brain regions.
visual stimuli can trigger their migraines.7 In view of
these associations, several studies have used fMRI to
investigate migraineurs responses to visual stimuli.
Some of these studies specically investigated patients
with migraine who had aura, because visual cortex
hyperexcitability might predispose the brain to visual
hypersensitivity and visual aura (table 2, gure 3).49
fMRI studies of visual stimuli-induced brain activation
noted that migraineurs were hyper-responsive to such
stimuli. Results from several studies32,36,37,39 show that
migraineurs viewing visually stimulating patterns (eg,
black and white stripes) have high activation in the
primary and extrastriate visual cortices. Results from
one study37 that used light as the stimulus showed
migraineurs had a larger photoresponsive area (ie, a
greater number of voxels corresponding to areas of
brain activation) than did controls, but there was no
dierence with respect to intensity of the blood oxygen-
level dependent (BOLD) signal. A study33 comparing
visual pattern-induced brain activity in migraineurs
with aura, migraineurs without aura, and controls,
showed that migraineurs with aura had greater
activation in the primary visual cortex and lateral
geniculate than did the migraineurs without aura or
controls. There were no signicant dierences in brain
activation between the migraineurs without aura, and
controls. These results lend support to the notion that
visual cortex hyperexcitability is associated with
migraine with aura. Finally, researchers in one study35
investigated activation of the motion-responsive middle
temporal complex in response to a moving visual
stimulus and noted that migraineurs had greater
activation of the left superior-anterior portion of this
region than did non-migraineurs. These data show that
hyper-responsiveness to visual stimuli in migraine
extends beyond the visual cortex.
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Review
Parahippocampal gyrus
(painful heat) Posterior thalamus
(painful heat)
Amygdala
(odour)
Occipital cortex
(visual) Midbrain: red nucleus
and substantial nigra
Cerebellum Pons (odour) (visual)
(odour)
Greater activation during
migraine attacks
To add to the understanding of how visual stimuli
might trigger a migraine attack, brainstem activation in
association with visually triggered migraine attacks was
studied in 12 migraineurs. Four patients developed
migraine with visual aura and eight developed
headaches without aura in response to viewing a
ickering checkerboard.40 Activation in the red nucleus
and substantia nigra was identied in 75% of these
migraineurs. Red nucleus and substantia nigra
activation preceded the onset of the symptoms of
visually triggered migraine and increased signal
intensity in the occipital cortex. Similar to the studies of
the neural processing of odour, these results indicate
that brainstem structures have a role early in or during
initiation of a migraine attack and suggest a potential
pathway in which exposure to external stimuli could
trigger a migraine attack.38
A potential clinical use of fMRI is in the measurement
of the early eects of treatment. An fMRI study36 of visual
stimulation showed that migraineurs who were shown a
striped visual pattern had higher ratings of discomfort
and activation in the visual cortex than did non-
migraineurs.36 However, when these migraineurs wore
precision ophthalmic tints (ie, eyeglasses with tinted
lenses that best reduce visual discomfort for each patient)
their visual discomfort decreased and activation in the
visual cortex normalised. This study shows that visual
hypersensitivity in migraineurs can be reduced, and
eectiveness can be measured both with subjective
patient reports of reduced visual discomfort and
objectively by normalisation of measures of visual cortex
hyper-reactivity.
Lending support to the notion that normal habituation
to recurrent stimuli is absent in migraineurs in the
interictal period, haemodynamic refractory eects (ie,
less BOLD activity in response to a second stimulus that
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is delivered in close temporal proximity to the rst
stimulus) on fMRI were absent in migraineurs in a study
in which they were exposed to paired visual stimuli.50
Whereas controls had reduced activation in response to
the second stimulation within each pair, haemodynamic
refractory eects were not seen in migraineurs. Thus,
the absence of interictal habituation in people with
migraine goes beyond the processing of pain to include
other senses, such as vision.
Functional connectivity in migraine
Analysis of functional connectivity with fMRI investigates
the functional organisation of the brain based on
temporal correlations in BOLD signal uctuations in
dierent brain regions.51 Most functional connectivity
analyses are done when the brain is at rest, when the
person being studied is not performing a task and is not
being stimulated. In the resting state there is continuous
low-frequency uctuation in the BOLD signal throughout
the brain. Brain regions with temporal correlations in
BOLD signal are deemed to be functionally connected or
functionally communicating.52 The presence of functional
connections and the strength of such functional
connections can be atypical in the presence of
neurological diseases including migraine.
Studies of functional connectivity in migraine have
consistently shown migraineurs to have aberrant
functional organisation in the brain, mostly in regions
that participate in the processing of pain.20,22,24,5367 Many
studies have shown positive correlations between the
frequency of migraine attacks or number of years with
migraine and the extent of atypical functional
connectivity.54,56,57,58,60,6266 A direct relation between
migraine and atypical functional connectivity is
suggested by these correlations; however, longitudinal
studies are needed to establish whether atypical
Superior parietal lobule
Middle frontal gyrus
Inferior frontal gyrus
Figure 3: Visual stimuli-induced brain activations that dier in migraineurs versus controls
Brain regions with interictal visual stimuli-induced activation in migraineurs that dier from those in healthy controls are depicted on the surface of the brain and
midline. Red areas show more activation in migraineurs than in controls. No areas have less activity in migraineurs than in controls. Shaded areas do not represent
the exact location, size, or extent of dierential activity in brain regions.
86
functional connectivity might predispose individuals to
migraine or is the result of recurrent migraines.
Functional connectivity studies comparing migraineurs
with healthy controls show atypical connectivity between
many regions involved in the processing of pain.2122,5366
Brain regions shown to have atypical functional
connectivity in migraineurs include those involved in
sensory-discriminative processing of pain (eg,
somatosensory cortex, posterior insula), aective-
emotional processing (eg, anterior insula, anterior
cingulate cortex, and amygdala), cognitive processing (eg,
hippocampus, parahippocampal gyrus, and orbitofrontal
cortex), and pain modulation (eg, periaqueductal grey,
nucleus cuneiformis).53,54,56,57,60,61,6567 Migraineurs have
atypical functional connectivity of several resting-state
networks including the salience network, default mode
network, central-executive network, somatomotor
network, and frontoparietal attention network
(table 3).53,54,56,57,58,6067 Two small studies57,59 investigated
functional connectivity of regions in the pain-modulating
descending pathways of the brainstem in patients with
migraine who report symptoms of cutaneous allodynia
during their attacks. These studies showed atypical
functional connectivity of the periaqueductal grey and
nucleus cuneiformis to other pain processing regions in
migraineurs with allodynia. Atypical functional
connectivity in these brainstem regions suggests that
altered functional organisation of areas involved in pain
inhibition is associated with the development of central
sensitisation and cutaneous allodynia in migraine, but
these results will need to be replicated in larger studies.
Limitations of fMRI studies of migraine
Several limitations of the published fMRI studies make
drawing of conclusions about stimulus-induced brain
activity and functional connectivity in migraine dicult.
Intraparietal
sulcus
Inferior
parietal lobule Precuneus
Lateral
geniculate
nucleus
Visual cortex
Greater activation in migraine
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First, fMRI studies of migraine generally include small the results. Furthermore, there are few replication studies
numbers of patients, which limits the statistical power of conrming the fMRI results. Additional studies are needed
the study, often resulting in less than optimum methods to to increase condence in the results of fMRI studies and to
determine signicance and limiting the generalisability of establish the generalisability of these ndings.

Cohorts (n) Analysis Main ndings

Schwedt Migraine with severe allodynia (8) ROI: periaqueductal grey and nucleus Stronger functional connectivity of periaqueductal grey and nucleus cuneiformis to other
(2014)59 Migraine with no allodynia (8) cuneiformis sensory discriminative regions in brainstem, thalamus, insular cortex, and cerebellum and with
high-order pain processing regions in frontal and temporal lobes in migraineurs with severe
allodynia than in migraineurs with no allodynia
Hadjikhani Migraine (22) ROI: amygdala Stronger functional connectivity of amygdala to visceroceptive insular cortex in migraineurs
(2013)53 Control (20) than in all other cohorts; stronger functional connectivity of amygdala with insular cortex,
Carpal tunnel syndrome (11) secondary somatosensory cortex, thalamus, Heschls gyrus, and temporal pole in migraineurs
Trigeminal neuralgia (9) than in controls
Jin (2013)54 Episodic migraine (21) ROI: anterior cingulate cortex Stronger functional connectivity of anterior cingulate cortex to middle temporal, orbitofrontal
Control (21) cortex, and dorsolateral prefrontal cortex in migraineurs than in contols
Maleki (2013)20 High-frequency episodic migraine* (10) ROI: hippocampus Weaker functional connectivity of hippocampus to supramarginal gyrus, temporal pole,
Low-frequency episodic migraine (10) fronto-orbital, nucleus accumbens, anterior insular cortex, middle frontal, and paracingulate
gyrus in high-frequency episodic migraineurs than in low-frequency epidsodic migraine
Schwedt Chronic migraine (20) ROI: anterior cingulate cortex, Atypical functional connectivity of ROI to pain-facilitating and pain-inhibiting regions in
(2013)60 Control (20) anterior insula, and amygdala sensory-discriminative, cognitive, and integrative domains (anterior insular cortex, amygdala,
pulvinar, mediodorsal thalamus, middle temporal, and periaqueductal grey) in migraineurs
Tessitore Episodic migraine (20) Intrinsic connectivity networks in Weaker functional connectivity of superior frontal gyrus and temporal pole to other regions of
(2013)61 Control (20) default mode network the default mode network in migraineurs than in controls
Xue (2013)62 Episodic migraine (18) Amplitude of low-frequency Decreased amplitude of low-frequency uctuation in prefrontal cortex, and rostral anterior
Control (18) uctuation and functional cingulate cortex and increased amplitude of low-frequency uctuation in thalamus in
connectivity in ROI (anterior cingulate migraineurs
cortex, thalamus, prefrontal cortex, Stronger functional connectivity of rostral anterior cingulate cortex to frontal lobe and parietal
and insular cortex) lobe; thalamus with caudate, temporal lobe, and putamen; prefrontal cortex with precuneus,
parietal lobe, and temporal lobe; and insular cortex with temporal pole, frontal lobe, and parietal
lobe in migraineurs than in controls
Yuan (2013)66 Episodic migraine (40) ROI: basal ganglia Stronger functional connectivity of caudate nucleus to parahippocampal gyrus, amygdala,
Control (40) insular cortex, and putamen; and nucleus accumbens with parahippocampal, anterior cingulate
cortex, orbitofrontal cortex, and posterior cingulate cortex in migraineurs than in controls
Zhao (2013)67 Episodic migraine (40) Regional homogeneity (whole brain) Abnormal regional homogeneity in thalamus, inferior frontal, middle occipital, insular cortex,
Control (20) caudate, middle frontal gyrus, middle temporal gyrus, inferior occipital gyrus, anterior
cingulate cortex, medial frontal lobe, superior temporal lobe, amygdala, lentiform nucleus,
uncus, superior frontal lobe, temporal pole, cerebellum, pons, medulla, midbrain,
hippocampus, lingual gyrus, cuneus, inferior parietal gyrus, postcentral gyrus, precuneus,
fusiform gyrus, and posterior cingulate cortex in migraineurs
Liu (2012)56 Episodic migraine (43) 90 ROI Brain hubs related to pain processing have abnormal nodal centrality (precentral gyrus, inferior
Control (43) frontal gyrus, parahippocampal gyrus, anterior cingulate cortex, thalamus, temporal pole, and
inferior parietal gyrus) in migraineurs
Maleki (2012)21 Episodic migraine: ROI: insular cortex and precuneus Stronger negative functional connectivity of insular cortex to primary somatosensory cortex,
Men (11) posterior cingulate cortex, precuneus, temporal pole; and stronger functional connectivity of
Women (11) precuneus with amygdala and primary somatosensory cortex in women with episodic migraine
than in men with episodic migraine
Maleki (2012)22 High-frequency episodic migraine* (10) ROI: postcentral gyrus, anterior insula, Stronger functional connectivity of postcentral gyrus to anterior cingulate cortex, posterior
Low-frequency episodic migraine (10) temporal pole, and anterior cingulate insular cortex, pulvinar, parahippocampus, hypothalamus, putamen, frontal pole, and
cortex weaker functional connectivity to substantia nigra; stronger anterior cingulate cortex
functional connectivity with frontal pole, temporal pole, inferior temporal gyrus, pulvinar,
and parahippocampal gyrus; stronger anterior insula functional connectivity with anterior
cingulate cortex, putamen, parahippocampal gyrus, hippocampus; stronger temporal pole
functional connectivity with postcentral gyrus, middle and superior temporal gyrus, and
frontal pole in high-frequency episodic migraine than in low-frequency episodic migraine
Russo (2012)58 Episodic migraine (14) Frontoparietal network Weaker functional connectivity in right frontoparietal network, specically in middle frontal
Control (14) gyrus and dorsal anterior cingulate cortex, in migraineurs than in controls
Xue (2012)63 Episodic migraine (23) Independent components analysis of Intrinsic connectivity diered in the three intrinsic connectivity networks in migraineurs
Control (23) default mode network, central compared with healthy controls: greater intranetwork functional connectivity of middle frontal
executive network, and salience gyrus in the right lateralised central executive network and greater intranetwork functional
network connectivity of inferior frontal gyrus in the left lateralised central executive network; and
decreased intranetwork functional connectivity of supplementary motor area in the salience
network; and greater intrinsic default mode network and right central executive network
connectivity to right anterior insula
(Table 3 continues on next page)

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 Review
Cohorts (n) Analysis
(Continued from previous page)
Yu (2012)64 Episodic migraine (26) Regional homogeneity (whole brain)
Control (26)
Yuan (2012)66 Episodic migraine (21) Voxel-mirrored homotopic
Control (21) connectivity and ROI (anterior
cingulate cortex)
Liu (2011)55 Episodic migraine: Graph theory analysis (whole brain;
Men (18) 90 ROI)
Women (20)
Controls (38)
Mainero (2011)57 Episodic migraine (17) ROI: periaqueductal grey
Controls (17)
Episodic migraine with allodynia (5)
Episodic migraine with no allodynia (5)
Maleki (2011)24 High-frequency episodic migraine* (10) ROI: basal ganglia, periaqueductal
Low-frequency episodic migraine (10) grey, pulvinar nuclei, and
hypothalamus
All studies were done when patients with migraine were interictal (ie, between migraine attacks). *High-frequency episodic migraine is dened as 814 headache days per month. Low-frequency episodic
migraine is dened as 12 headache days per month. ROI=region of interest.
Table 3: Functional connectivity MRI studies of migraine
Substantial variation in methods of data collection and
analysis in fMRI studies makes it dicult to develop a
cohesive model of the specic brain regions and networks
that are atypical in migraine. For example, variation in
the methods used does not enable a proper meta-analysis
of studies showing brain regions that have atypical
activation in response to painful stimuli in people with
migraine. The use of analyses based on the region of
interest, rather than whole-brain analyses, is a substantial
limitation of these studies. Additional fMRI studies
using whole-brain analyses are needed to understand
atypical stimulus-induced activity and atypical functional
connectivity in migraine. Furthermore, the laterality of
migraine symptoms should be taken into account in
fMRI studies. A study34 comparing the symptomatic
brain hemisphere (ie, brain hemisphere contralateral to
the hemield in which visual aura symptoms occur) and
the asymptomatic brain hemisphere in migraineurs, and
the same brain areas in controls, showed that the
symptomatic hemisphere was hyper-reactive to visual
stimuli compared with the asymptomatic hemisphere in
migraineurs and compared with controls. However,
brain activation in response to stimuli did not dier
between the asymptomatic hemisphere in migraineurs
and the same brain hemisphere in controls. Thus, fMRI
studies of migraine activation might need to focus on the
usual side of migraine symptoms. Additionally, fMRI
studies of migraine vary in the methods used to create a
stimulus, the resolution used in MRI, and the thresholds
set for statistical signicance.
88
Main ndings
Decreased regional homogeneity in anterior cingulate cortex, prefrontal cortex, orbitofrontal
cortex, and supplementary motor area in episodic migraineurs
Weaker interhemispheric functional connectivity in the anterior cingulate cortex in episodic
migraineurs than in healthy controls; with bilateral anterior cingulate cortex as ROI, migraineurs
had stronger functional connectivity between left anterior cingulate cortex and bilateral
orbitofrontal cortex and right dorsolateral prefrontal cortex, and stronger functional connectivity
between right anterior cingulate cortex and bilateral orbitofrontal cortex than did controls
Abnormal topological organisation, including small-world properties, resilience, nodal centrality,
and inter-regional connections in migraineurs compared with controls
Stronger functional connectivity of periaqueductal grey to ventrolateral prefrontal cortex,
supramarginal gyrus, anterior insula, precentral gyrys, postcentral gyrus, and thalamus in
episodic migraineurs than in healthy controls
Weaker functional connectivity of periaqueductal grey to prefrontal, anterior cingulate cortex,
and anterior insula in migraineurs with allodynia than in migraineurs without allodynia
Weaker functional connectivity of caudate nucleus to middle frontal, insular cortex, temporal
pole, and parahippocampus; weaker nucleus accumbens functional connectivity to posterior
cingulate cortex, superior parietal, and hippocampus; stronger putamen functional
connectivity with hippocampus, caudate, middle frontal gyrus, anterior insula; and stronger
globus pallidus functional connectivity to middle temporal lobe, supramarginal gyrus,
thalamus, hippocampus, insular cortex, and temporal pole in high-frequency episodic
migraineurs than in low-frequency episodic migraineurs
Further heterogeneity might also be introduced by the
dierent analytical techniques used in functional
connectivity analyses of migraine: 1) region-of-interest
(functional connectivity among chosen regions or between
chosen regions and the rest of the brain); 2) independent
components analysis (masked computational separation
of the whole brain into functional networks or into its
functional subcomponents); 3) voxel-mirrored homotopic
connectivity (measurement of functional connectivity
between voxels in one hemisphere of the brain and
symmetric counterparts on the other hemisphere as a
measure of interhemispheric functional connectivity);
and 4) regional homogeneity (measurement of
synchronization of uctuations in BOLD in local voxels).
Similarly, the use of medications and the potential eects
of comorbidities in migraine (eg, anxiety, depression, and
myofascial pain) have not been adequately taken into
account in many studies.
Dierences in the timing of data collection are another
limitation in migraine fMRI studies. Migraineurs can be
studied during a migraine attack or between migraine
attacks. However, the exact intervals between fMRI, the
preceding migraine, and the next migraine probably
aect the results. Investigators used trigemino-
nociceptive stimulation by intranasal ammonia to study
patients with migraine at several timepoints during and
between migraine attacks.26 The recorded strength of
spinal trigeminal nuclei activation in response to this
stimulus was dependent on the timing of fMRI: interictal
migraineurs had weaker activation in the spinal
www.thelancet.com/neurology Vol 14 January 2015

trigeminal nuclei than did healthy controls, but activation
in the spinal trigeminal nuclei strengthened as the
migraineurs neared their next migraine attack. Similarly,
if one presumes that brain activation changes as a patient
progresses through a migraine attack, the exact timing of
fMRI in relation to migraine attacks probably has a
substantial eect on the imaging results.
Most studies do not explicitly account for sex-specic
dierences in migraineurs. However, such dierences
have been shown in migraine fMRI studies.21,55 One
study21 showed that women have greater pain-induced
activation compared with men in the caudate nucleus,
superior temporal lobe, superior frontal lobe, precuneus,
posterior cingulate, sensory nucleus, and spinal
trigeminal nuclei of the brainstem, whereas men had
greater activation than women in the insular cortex,
primary somatosensory cortex, and putamen. Studies
investigating the dierences in functional connectivity
between male and female migraineurs showed that
functional connectivity diered according to sex.21,55 Sex-
related dierences in the topological organisation of
resting-state networks and in the functional connectivity
of the insular cortex and of the precuneus have been
identied. fMRI studies should, therefore, carefully
match participants according to sex or investigate male
and female migraineurs independently.
Longitudinal studies are needed to establish whether
the dierences in brain activation or functional
connectivity detected by fMRI in patients with migraine
predispose a person to migraine or result from recurrent
migraine attacks. Prospective longitudinal studies to
assess associations in migraine patterns (eg, increasing or
decreasing headache frequency) with changes in brain
activation and changes in functional connectivity, shown
by fMRI, might help to elucidate the direction of the
relation and help to identify early biomarkers to predict
improvements in, or worsening, migraine patterns. Such
studies should take into account the eects on brain
activation of drugs to treat migraine, ageing, and the
development of comorbidities. The large sample sizes
needed for this type of analysis almost certainly necessitate
multicentre collaborative eorts.
The inability to establish whether the results of fMRI
studies are specic to migraine or represent other types
of pain is a shortcoming in the medical literature on
migraine. One functional connectivity study53 compared
migraineurs not only with healthy controls, but also
with patients with carpal tunnel syndrome and patients
with trigeminal neuralgia. The migraineurs had stronger
functional connectivity between the amygdala and
visceroceptive insula compared with people in the other
groups. Future studies comparing migraineurs with
patients with other headache types and other pain types
are needed to establish the specicity of fMRI results in
migraine studies. These studies should focus on brain
regions and networks that might contribute to the
unique features of migraine, such as the co-occurrence
www.thelancet.com/neurology Vol 14 January 2015
Review
and interaction of headache with visual, olfactory, and
auditory symptoms. Studies show the presence and
intensity of stimuli in one sensory modality (eg, visual)
mediate the presence and intensity of symptoms in
other sensory domains (eg, intensity of headache pain in
migraine), suggesting that multisensory integration
might play a part in migraine pathophysiology.3 Thus,
fMRI studies of brain regions with roles in multisensory
integration might be useful to dierentiate migraine
from other headache types and other pain disorders.
Notably, the temporal pole is involved in multisensory
integration and has atypical activation in response to
stimuli and atypical functional connectivity in several
migraine fMRI studies.20,22,24,25,38,53,56,61,63,67
Conclusions and future research
fMRI studies consistently show that migraine is
associated with atypical brain activation, in response to
painful, olfactory, and visual stimuli, and atypical
functional connectivity. Atypical brain activity and
functional connectivity involve several areas of the brain,
a nding consistent with migraine being a complex
neurological disorder with atypical processing of several
types of sensory stimuli (somatosensory, visual, and
olfactory). fMRI studies of migraine show a combination
of enhanced sensory facilitation and reduced inhibition
in response to sensory stimuli, and reduced or absent
habituation to stimuli interictally. Correlations between
the extent of brain abnormalities on fMRI and headache
frequency or number of years with migraine suggest
that migraine has a cumulative eect on brain function
or that the extent of underlying abnormalities on fMRI
positively correlates with the risk of more severe
migraine. Several avenues exist for future fMRI research
on migraine to improve the quality and clinical
signicance of these data. fMRI studies with large
numbers, more stringent statistical analyses, and
replicate studies would increase condence in the
validity of study results. Large, multicentre, longitudinal
studies are needed to investigate associations between
changes in the frequency and number of years with
migraine and corresponding changes on fMRI. Such
studies would advance understanding of the mechanisms
of migraine transformation (moving from less frequent
headaches to more frequent headaches) and migraine
reversion (moving from more frequent to less frequent
headaches) and might help to identify baseline
biomarkers predictive of transformation and reversion.
Similarly, studies of this kind should investigate the
eects of migraine therapies on fMRI measures and
could help to identify baseline biomarkers that predict
treatment response. Neuroimaging studies that
dierentiate migraine from other headache types and
other types of pain are also needed. Whether the ndings
from fMRI studies of migraine are specic to migraine
or are shared with other headache types and other types
of chronic pain is unknown. Investigation of the
89
 Review
Search strategy and selection criteria
We searched PubMed for English language articles on
patients with migraine published between 1966 and
March 25, 2014. The following search terms were used:
migraine and MRI, migraine and fMRI, migraine and 12
blood oxygen-level dependent, migraine and functional
connectivity. The reference lists of included articles and the
authors own les were searched for additional articles.
Articles that used fMRI to investigate migraine
hypersensitivities were considered for inclusion in this
Review. Publications were selected for inclusion on the basis
of their relevance to the topic, originality, and the extent to
which the study results were deemed to contribute to the
migraine neuroimaging specialty.
specicity of fMRI ndings in migraine is a crucial step
before fMRI can be used in the diagnosis and
management of patients with migraine. Although
migraine is a symptom-based diagnosis, and neuro-
imaging would typically not be needed to assign a
diagnosis, a diagnostic test would be very useful in some
situations for which the diagnosis is otherwise uncertain.
Analyses of functional connectivity in the resting state
might be particularly useful with respect to diagnosis
because collection of these imaging data does not
require patients to participate in tasks or to be
stimulated and the imaging does not require signicant
acquisition time.
Contributors
TJS and C-CC searched the medical literature, wrote, edited, and
approved the Review. CDC and DWD wrote, edited, and approved the
Review.
Declaration of interests
We declare no competing interests.
Acknowledgments
Our work is partly funded by a grant from US National Institutes of
Health (K23NS070891) to TJS.
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