Functional neuroimaging of migraine

Functional neuroimaging of migraine

revue neurologique 169 (2013) 380–389 Available online at Migraine Functional neuroimaging of migraine Imagerie fonctionnell...

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revue neurologique 169 (2013) 380–389

Available online at


Functional neuroimaging of migraine Imagerie fonctionnelle et migraine M. Denuelle *, N. Fabre Service de neurologie et d’explorations fonctionnelles neurologiques, hoˆpital de Rangueil, CHU Toulouse Rangueil, 1, avenue Jean-Poulhe`s, TSA 50032, 31059 Toulouse cedex 9, France

info article


Article history:

This review summarizes the history of migraine imaging and key findings of studies on

Received 18 September 2012

functional neuroimaging in migraine and describes how these data have changed our view

Received in revised form

of the disorder. Functional neuroimaging during migraine attacks and also interictally has

27 January 2013

initiated the description of ‘‘the migraine brain’’. These studies have led to the demons-

Accepted 4 February 2013

tration of cortical spreading depression in migraine with aura, the crucial role for the

Published on line 18 April 2013

brainstem during migraine attacks, and cortical hypersensitivity in migraineurs modulated by the trigeminal pathway, explaining sensory sensitization such as photophobia and

Keywords :

osmophobia. # 2013 Elsevier Masson SAS. All rights reserved.

Migraine PET Functional MRI Mots cle´s : Migraine TEP IRM fonctionnelle

r e´ s u m e´ Cette revue de la litte´rature reprend l’histoire des donne´es d’imagerie fonctionnelle dans la migraine et les principaux re´sultats qui ont permis de faire e´voluer notre connaissance de la maladie. Les e´tudes d’imagerie fonctionnelle re´alise´es pendant les crises mais e´galement a` distance des crises de migraine ont permis de de´velopper le concept de « cerveau migraineux ». En effet, elles ont montre´ que la maladie migraineuse e´tait une maladie centrale avec la pre´sence d’une de´pression corticale envahissante durant l’aura migraineuse, le roˆle crucial des noyaux du tronc ce´re´bral durant la crise de migraine ainsi qu’une hyperexcitabilite´ corticale module´e par le trijumeau responsable de l’hypersensibilite´ sensorielle comme la photophobie et l’osmophobie. # 2013 Elsevier Masson SAS. Tous droits re´serve´s.



Improvements in pathophysiology of most diseases are made through a combination of fundamental, epidemiological and imaging discoveries. Concerning migraine, functional imaging

has played a major role. Nowadays positrons emission tomography (PET) and functional MRI are the main tools of neuroimaging, allowing the capture of neurovascular events during a migraine attack. Imaging spontaneous migraine attacks is particularly difficult because the attack onset is unpredictable and

* Corresponding author. E-mail address: [email protected] (M. Denuelle). 0035-3787/$ – see front matter # 2013 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.neurol.2013.02.002

revue neurologique 169 (2013) 380–389

scheduling neuroimaging exams is impossible. Thanks to purposeful research and also sometimes to serendipity, functional neuroimaging has permitted the demonstration of hemodynamic events and specific neuronal activities during migraine with and without aura, allowing considerable improvements in understanding this disease (Table 1).


History of migraine imaging


Vascular theory of migraine

Throughout most of the 20th century, one theory has prevailed, sustained by Wolff et al., studies (Wolff et al., 1963). The aura was thought to be caused by a vasoconstriction and a resulting relative decrease of cerebral blood flow in visual and/or sensory cortices. The headache was thought to be caused by a rebound vasodilatation which resulted in mechanical activation of nociceptive neurons within the walls of the engorged vessels. This dogma in which migraine is caused by changes in the diameter of cerebral vessels is known as the ‘‘vascular theory of migraine’’.

2.2. ‘‘The vasospastic model of the migraine attack is too simplistic’’. Olesen This theory has been shattered by the works of the Danish school led by Olesen in the eighties. Olesen et al. studied cerebral blood flow using intracarotid Xenon with a new imaging system resulting in a better spatial resolution and allowing serial rCBF measurements throughout a migraine attack. In this study six cases of migraine with aura provoked by the carotid puncture were followed from the normal state into the prodromal phase and in three cases further into the headache phase (Olesen et al., 1981). One patient with common migraine was similarly followed during his only classic attack. This study showed that the attacks were initiated by a focal hyperemia. During the aura, in all patients occurred a posterior oligemia, which gradually spread anteriorly without respecting arterial boundaries. Furthermore, in four patients a severe headache was present concomitantly with an oligemia and not hyperemia as expected in the vascular theory. Consequently, the authors concluded this paper by these terms: ‘‘the vasospastic model of the migraine attack is too simplistic’’. Indeed, in this study three main results disagreed with the vascular theory:  the reduction in regional cerebral blood flow (rCBF) observed during the aura was insufficient to cause ischemia;  the anterior spread of the oligemia did not respect arterial boundaries;  the migraine headache appeared during a phase of oligemia. Thus a cortical phenomenon, the cortical spreading depression described by Leao, being the first event responsible of this spreading oligemia was likely the explanation of the migraine aura.


However, this paper has been vigorously discussed. According to Olesen et al. studies, it could be concluded that there were two types of migraine: the migraine with aura characterized by a spreading oligemia and the migraine without aura characterized by the absence of significant modification of rCBF during the attack. However, patients with migraine can suffer from alternatively attacks with and without aura and it seems quite unlikely that this would be the result of two different diseases. The pro and con battle lasted 20 years and stopped with Hadjikhani’s paper (Hadjikhani et al., 2001) showing irrefutably a cortical spreading depression (CSD) during migraine aura.

2.3. Is the migraine aura due to a cortical spreading depression? In the forties, Leao described in animals a wave of cortical neuronal depression spreading through the cortex at a definite speed (3 mm/min) following a localised chemical or electrical cortical stimulation (Leao, 1944). This phenomenon was called ‘‘cortical spreading depression’’ (CSD). In parallel to this neuronal activity depression, Leao noted profound modifications of vascular diameters. This work remained forgotten for near two decades. At the same moment, Lashley in 1941, unaware of Leao’s works described his own ophthalmic aura (Lashley, 1941). This observation is remarkable because Lashley was both a specialist in visual cortex physiology and a migraineur with visual aura and was able to report on a map of the visual cortex the progression of his own scotoma. Lashley summarized his observation in these terms: ‘‘Maps of scotomas of ophthalmic migraine . . . suggest that a wave of intense excitation is propagated at a rate of about 3 mm per minute across the visual cortex. This wave is followed by complete inhibition of activity, with recovery progressing at the same rate’’. In 1959, Milner stated in a short note, totally unnoticed at this time, that ‘‘attention should be drawn to the striking similarity between the time courses of scintillating scotomas and Leao’s spreading depression’’ (Milner, 1958). Apart from this short note by Milner on a possible correspondence between the scotomas of migraine and CSD of Leao, no attention was attracted to the observations of Lashley and Leao until Olesen and Lauritzen’s studies in 1980s.


Migraine and cortical spreading depression

3.1. Migraine aura is due to a cortical spreading depression Twenty years after Olesen et al., a cortical spreading depression during migraine aura was confirmed by Hadjikhani and colleagues using functional MRI (Hadjikhani et al., 2001). During an exercise-induced visual aura in one patient with migraine, a focal increase in BOLD signal (possibly reflecting a vasodilation) was observed within the visual cortex followed by a decrease of the BOLD signal (possibly reflecting a vasoconstriction after the initial vasodilation). The main result of this study was that this decreased BOLD signal progressed slowly over the occipital cortex, with a perfect


revue neurologique 169 (2013) 380–389

Table 1 – Summary of PET and fMRI studies in migraine. n

Timing of recordings

Main findings

Woods et al., 1994 H2O15 PET study

1 MO

During spontaneous attack

Bilateral spreading cerebral hypoperfusion

Weiller et al., 1995 H2O15 PET study

9 MO

During spontaneous attack, after pain relief by sumatriptan and interictally

During attack, activation in brainstem, cingulate, auditory and visual association cortices After pain relief, persistence of isolated brainstem activation

Andersson et al., 1997 H2O15 PET study


During red wine- provoked attack, after pain relief by sumatriptan and interictally

Significant reduction in rCBF and rCMRO2 in visual cortex but no change in rOER during the headache

Bednarczyk et al., 1998 H2O15 PET study

9 MO

During spontaneous attack and interictally

Reduced CBF and CBV during the headache

Cao et al., 1999 fMRI study

6 MWA 2 MO

During visually triggered migraine attack

Onset of headache or visual change preceded by suppression of initial occipital activation provoked by visual stimulation

Bahra et al., 2001 H2O15 PET study

1 MO

During glyceryl trinitrate induced attack

Activation in the dorsal rostral brainstem

Hadjikhani et al., 2001 fMRI study


During visual aura

BOLD signal changes with characteristics of cortical spreading depression and congruent with the retinotopy of the visual percept

Cao et al., 2002 fMRI study

23 MWA 3MO compared with 10 controls

During visually triggered migraine attack

Activation in the red nucleus and substantia nigra (before occipital activation or onset of visually triggered symptoms in 75% of patients)

Matharu et al., 2004 H2O15 PET study

8 chronic migraine

Suboccipital stimulator switched ON and partially activated

Activation in the dorsal pons, anterior cingulate cortex and cuneus correlated to stimulation-induced paresthesia scores

Afridi et al., 2005b H2O15 PET study

24 MO

Before, during and after glyceryl trinitrate-induced attack

Activation of dorsal pontine ipsilateral to headache side

Afridi et al., 2005a H2O15 PET study

3 MO, 2 MWA

During spontaneous attack and interictally

Activation in left dorsal pons, anterior and posterior cingulate, cerebellum, thalamus, insula, prefrontal cortex and temporal lobes Decreased rCBF in right dorsal pons

Afridi et al., 2005a H2O15 PET study


During glyceryl trinitrate-induced attack

Activation in the primary visual cortex during the aura

Fumal et al., 2006 FDG-PET study

16 chronic migraine with analgesic overuse compared with control population (68)

Before and 3 weeks after medication withdrawal

Reversible metabolic changes in pain processing structures but persistent orbitofrontal hypofunction

Denuelle et al., 2007, 2008 H2O15 PET study

7 MO

During spontaneous attack, after pain relief by sumatriptan and interictally

Activation in brainstem and hypothalamus persisting after headache relief. Significant bilateral posterior hypoperfusion persisting after headache relief

Demarquay et al., 2008 H2O15 PET study

10 MO, 1 MWA compared with 12 controls

Interictally with and without olfactory stimulation

With olfactory stimulation, higher activation in migraineurs than in controls in piriform and temporal cortex, and lower activation in frontal, temporo-parietal, posterior cingular cortex, dorsal pons

Moulton et al., 2008 fMRI study

12 MO compared with 12 controls

Interictally during thermal pain stimulation

Hypofunction of nucleus cuneiformis (component of brainstem pain modulatory circuit)


revue neurologique 169 (2013) 380–389

Table 1 (Continued ) n

Timing of recordings

Main findings

Boulloche et al., 2010 H2O15 PET study

4 MWA, 3 MO compared with 7 controls

Interictally, with and without luminous stimulation, and with and without painful stimulation

With luminous stimulation, activation of visual cortex bilaterally in migraineurs but not in controls Concomitant pain stimulation allowed visual cortex activation in control subjects and potentiated its activation in migraineurs

Burstein et al., 2010 fMRI study

8 migraine with allodynia

Interictally and during spontaneous migraine attack with mechanical and thermal stimulation

Larger activation of posterior thalamus during migraine with allodynia than interictally in response of brush and heat stimulation

Denuelle et al., 2011 H2O15 PET study

8 MO

During spontaneous attack with and without luminous stimulation

Activation in visual cortex during migraine attacks and after headache relief but not during the attack-free interval

Stankewitz et al., 2011 fMRI study

6 MWA, 14 MO compared with 20 controls

Interictally and during spontaneous migraine attacks with trigeminal nociceptive stimulation

Activity of spinal trigeminal nuclei in response to nociceptive stimulation showed a cycling behavior over the migraine interval

Stankewitz and May. 2011 fMRI study

6 MWA, 14 MO compared with 20 controls

Interictally and during spontaneous attacks with olfactory stimulation

Activation of limbic structures and in the rostral pons in response to olfactory stimulation specifically during migraine attack

Ferraro et al., 2012 fMRI study

9 medication-overuse headache compared with 9 controls

During painful mechanical stimulation immediately and 6 months after beginning medication withdrawal

Reduced pain-related activity in the primary somatosensory cortex, inferior parietal lobule and supramarginal gyrus immediately after beginning withdrawal

MO: migraine without aura; MWA: migraine with aura; CBF: cerebral blood flow (rCBF if regional); CBV: cerebral blood volume; CMRO2: oxygen metabolism; OER: oxygen extraction.

congruence with the retinotopy of the visual aura, confirming the primary neural nature of the phenomenon; thus a phenomenon exactly resembling a CSD and the confirmation of what Lashley had predicted more than half a century before. Therefore, after the demonstration by neuroimaging of the role of CSD in migraine with aura, experimental studies were designed to demonstrate a link between CSD and activation of the trigeminovascular system, model in animals of the migraine headache. It has been shown in animals that a CSD could induce a blood flow increase in the middle meningeal artery dependent upon trigeminal and parasympathetic activation (Bolay et al., 2002). Consistent with this fact, it has been demonstrated that a focal stimulation of the rat visual cortex inducing a CSD was followed by an activation of meningeal nociceptors in the trigeminal ganglion and in the spinal trigeminal nucleus (Zhang et al., 2011). These data imply that CSD may activate neurons of the trigemino-cervical complex and as a consequence CSD may be the trigger for migraine attack by activating the trigeminovascular system. However the link between CSD and headache in patients is still a matter of debate (Charles, 2010; Ebersberger et al., 2001).

3.2. Does a cortical spreading depression exist in migraine without aura? The absence of hemodynamic changes during migraine without aura was admitted after Olesen et al. works for near

two decades. However H2O15 PET studies demonstrating the existence of a posterior cortical hypoperfusion in migraine without aura challenged this opinion. The first paper in 1994 by Woods and colleagues has been largely commented amongst the migraine specialists’ community (Woods et al., 1994). This time, serendipity played a major role: a patient with migraine without aura, enrolled in a PET study for another purpose, developed at that moment a spontaneous attack allowing the capture of rCBF from the very beginning of the attack through its full development. A bilateral decrease in CBF, starting in the visual association areas and spreading anteriorly, suggesting a phenomenon compatible with a CSD was shown. Importantly, the patient did not experience any visual symptom during the PET study. This study raised the question of a cortical spreading depression mainly affecting the visual cortex in migraine without aura and of its meaning in the absence of visual symptoms. In the wake of Woods et al. paper, other PET studies have specially been designed to investigate either spontaneous or provoked attacks in migraine without aura. A PET study in nine patients scanned within 13 hours of the onset of a spontaneous migraine without aura attack, showed a global hypoperfusion (Bednarczyk et al., 1998). This hypoperfusion persisted for at least 6 hours. Another PET study including 10 attacks of migraine with and without aura, attacks provoked by red wine observed a 23% decrease in blood flow and a 22.5% decrease in metabolism in the primary visual


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cortex (Andersson et al., 1997). No significant differences in regional CBF were detected during either the aura or the headache phase. More recently, seven patients with migraine without aura were studied within 4 hours after spontaneous attack onset and after headache relief by sumatriptan (Denuelle et al., 2008). Compared with the attack-free interval, a posterior cortical hypoperfusion was found during the headache phase and persisted after headache relief by sumatriptan. However in other studies, hypoperfusion was not found during migraine without aura attacks (Afridi et al., 2005a; Weiller et al., 1995). This discrepancy between PET studies results may be explained by methodological differences and by the time between PET acquisition and migraine attack onset (Denuelle et al., 2009). In summary, PET studies revealed, in migraine without aura, a posterior hypoperfusion, exactly as, 20 years earlier, in migraine with aura, using xenon 133 CBF studies. As a CSD was undoubtedly shown in migraine with aura, the question of a silent CSD (without visual symptoms) was asked. How, if a CSD developing in the visual cortex is the common primary event in migraine with and without aura, in one case it can give a scintillating scotoma and in another case nothing? How can a cortical area with such a high neuronal density remain silent when being the place of a CSD? And even more, how CSD could be predominantly asymptomatic since the majority of migraine attacks are not preceded by aura? If the relationship between the aura symptoms and CSD seems indisputable, the temporal link between posterior hypoperfusion and CSD remains unclear. According to Olesen et al. study (Olesen et al., 1990), oligemia starts before the aura onset and extends into the headache phase outlasting the aura symptoms. This discrepancy between hemodynamics and symptoms of aura and headache was also found in studies of visual triggered attacks using BOLD-fMRI (Cao et al., 1999). In perfusion weighted imaging during spontaneous migraine with aura, the rCBF decrease persisted up to 2.5 hours into the headache phase (Sanchez del Rio et al., 1999). In Bednarczyk et al. PET study (Bednarczyk et al., 1998), a global hypoperfusion was found within a mean time of 13.3 hours from the onset of headache. In Denuelle et al. PET study, the posterior hypoperfusion persisted 6 h after the attack onset (Denuelle et al., 2008). It is difficult to explain how a CSD characterized by a sustained suppression of neuronal activity concerning such an extended cortical area, with such duration would not induce more significant neurological deficits. The absence of aura symptoms is difficult to reconcile with the extreme perturbations induced by CSD in cellular function in large cortical areas. Astrocytic calcium waves could be an alternative mechanism to explain the spreading hypoperfusion in migraine with and without aura. Recent studies indicate that astrocytes may be actively involved in the initiation and propagation of CSD, as well as the accompanying vascular response (Charles and Brennan, 2009). Indeed astrocytes play a key role in the neurovascular unit in coupling neuronal activity and vascular tone. Intercellular calcium waves occur in conjunction with CSD in multiple in vitro and in vivo models but CSD and astrocyte calcium waves can also occur

independently or faster and further than concomitant CSD. More recently, it has been found that vasodilation of cortical surface arterioles could travel ahead of the CSD wave front with characteristics that are consistent with an intrinsic vascular mechanism of propagation, and that vasodilation could be propagated into areas beyond the spread of electrophysiological changes of CSD wave (Brennan et al., 2007). Therefore astrocyte calcium waves and intrinsic vascular tone modifications spreading beyond a spatially limited CSD event or even more in the absence of CSD could explain hypoperfusion in migraine without aura attack in the absence of significant neurological symptoms that might be expected with CSD.


Activation during migraine attacks


Brainstem activation during migraine attack

Weiller et al., for the first time, demonstrated with PET brainstem activations during spontaneous attacks of migraine without aura. Following this princeps study, other studies have shown activation in brainstem structures during migraine attacks either spontaneous or triggered, in migraine with or without aura but also in chronic migraine (Afridi et al., 2005a, 2005b; Bahra et al., 2001; Cao et al., 2002; Denuelle et al., 2007; Matharu et al., 2004). These activations roughly correspond to the dorsal raphe nucleus, periaqueductal grey, locus coeruleus (Denuelle et al., 2007; Weiller et al., 1995), red nucleus, substantia nigra (Cao et al., 2002) and the dorsolateral pons (Afridi et al., 2005b; Denuelle et al., 2007; Matharu et al., 2004). The dorsal midbrain activation corresponds to the brain region which causes migraine-like headache when stimulated in patients with electrodes implanted for pain control (Raskin et al., 1987; Veloso et al., 1998). Moreover lesions from multiple sclerosis (Haas et al., 1993) or vascular malformation (Goadsby, 2002; Katsarava et al., 2003) in these same regions also produce migraine. In addition PET study of 5HT1A receptor availability (using [18F]MPPF PET tracer, a selective 5-HT1A antagonist) during the first stage of odourtriggered migraine attacks showed an increased [18F]MPPF binding potential in an area referred to as the pontine raphe when comparing headache-free migraineurs and controls (Demarquay et al., 2011). Even if this result remains of complex interpretation, it emphasizes the role of brainstem nuclei in the migraine development. Indeed these brainstem nuclei are involved in the control of cerebral vasculature, playing a complex role in the control of intra and extra cerebral vasculature. The pioneer experimental works in animals conducted by Lance et al. in the eighties have shown that stimulation of brainstem nuclei provoked vascular changes that can be transposed to migraine (Lance et al., 1983). Electrical stimulation of the locus coeruleus in monkeys at physiological frequencies reduces blood flow in the ipsilateral internal carotid artery by some 20% (Goadsby et al., 1982). Moreover, studies in cats have shown that the diminution in rCBF produced by such a stimulation is maximal in the occipital cortex (Goadsby and Duckworth, 1989), the area of the brain affected by hypoperfusion during migraine attack.

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Neuroimaging studies in migraineurs support the hypothesis of a primary brainstem dysfunction responsible of posterior hypoperfusion. In the study by Cao and colleagues of visual triggered attacks using BOLD-fMRI, brainstem activation preceded neuronal suppression in the occipital cortex and the onset of visually triggered symptoms (Cao et al., 2002, 1999). In Denuelle et al. study, both brainstem activations and posterior hypoperfusion persisted after sumatriptan injection and headache relief (Denuelle et al., 2008). This fact suggests a link between brainstem nuclei activation and hypoperfusion and not with migraine symptoms since both persisted after headache relief. Moreover, brainstem nuclei are at the core of the pain processing pathway. These areas have bidirectional connections with the trigeminovascular system, responsible of the headache pain, as well as connections with diencephalic structures that are involved in pain processing, such as hypothalamus and thalamus. The descending modulation of trigeminovascular nociceptive transmission through midbrain nuclei is complex and brainstem may contribute to both inhibitory and facilitory modulation of migraine pain (Akerman et al., 2011). Importantly, the brainstem areas that were activated during migraine headache also remained active after successful treatment (Afridi et al., 2005b; Bahra et al., 2001; Denuelle et al., 2007; Weiller et al., 1995), which suggests that the activity of brainstem nuclei is not simply a response to pain but an underlying brain activation that is perhaps at the core of the disorder. An fMRI study has examined interictal changes in the brainstem in response to experimental pain stimuli (Moulton et al., 2008). Nucleus cuneiformis, a component of brainstem pain modulatory circuits, appears to be hypofunctional in migraineurs interictally compared to controls. This result suggests a dysfunction of brainstem descending pain modulation even between attacks in migraineurs. A more intriguing finding reported recently was the observation that characteristics of trigeminal transmission in the trigeminal nucleus caudalis may predict migraine attacks. Studies imaging migraineurs interictally during trigeminal-evoked pain showed that there was a lower activation bilaterally in the lower pons corresponding to the spinal trigeminal nuclei compared to controls, whereas imaging migraineurs pre-ictally (scanned between 12 and 48 h before their migraine attack started) showed an increase in the level of trigeminal activation (Stankewitz et al., 2011). This activation level seems to be rapidly downregulated just before or at the beginning of acute headache. Even if these data cannot answer the question of whether the trigeminal pain system is dysfunctional in itself or whether other structures modulate its activity, the authors suggest that the activation level of the spinal trigeminal nuclei may be influenced by brainstem nuclei as PAG or raphe nuclei or by the hypothalamus.


Hypothalamic activation during migraine attack

As early as 1989, Lance hypothesized that internal biological rhythms and/or external triggers such as stressful events and excessive afferent stimulation may initiate migraine attack via


activation of the hypothalamus and its down-stream connections with brainstem nuclei. Hypothalamic activation has been reported in one study within 4 hours after onset of spontaneous migraine attacks (Denuelle et al., 2007). Although several other studies have not been able to identify hypothalamic activation (Afridi et al., 2005a; Bahra et al., 2001), this may be related to the timing of the measurements during the attacks or to the spontaneous or provoked nature of the attacks. Many of the premonitory symptoms that are seen up to 48 hours before the onset of headache in migraine are regulated by the hypothalamus, including sleep disturbances (Goder et al., 2001), changes in wakefulness and alertness (Dalkvist et al., 1984), changes in mood, craving for food, thirst, and fluid retention (Blau, 1980; Giffin et al., 2003). Other arguments for the hypothalamic initiation of migraine attacks are:  the circadian rhythmicity of the onset of migraine attacks, with a peak incidence in the early morning (Solomon et al., 1992);  the fact that sleep disturbances (insomnia or prolonged sleep) are migraine precipitants (Sahota and Dexter, 1990);  the correlation of hormonal fluctuations with migraine frequency in females (MacGregor, 2000). Moreover hypothalamic projections to the trigeminocervical complex may regulate trigeminovascular nociceptive traffic through orexin and somatostatin signaling (Holland and Goadsby, 2007). Furthermore, the finding of hypothalamic activation in migraine closed the debate of the specificity of hypothalamic activation in trigemino-autonomic cephalalgias.


Thalamic activation during migraine attack

The thalamus is known to be a major centre for the processing of nociceptive inputs, and imaging studies in humans have confirmed that there is neuronal activation in the controlateral thalamus during migraine (Afridi et al., 2005b; Bahra et al., 2001). The thalamus is now considered to be pivotal in the manifestation of extracephalic allodynia (perception of pain in response to normally innocuous stimuli). A recent study with functional MRI compared the effects of experimentally induced extracephalic allodynia on thalamic trigeminovascular neurons both in a rodent model of migraine and in migraineurs having extracephalic allodynia (Burstein et al., 2010). In rats, over 50% of thalamic neurons were hyperresponsive to noxious and innocuous inputs from controlateral extracranial and extra cephalic areas. In migraine patients, there were increased responses in a similar thalamic area (pulvinar) that are induced by a brush or innocuous heat to the hand during migraine attack than before or after the attack. In migraine patients, innocuous stimuli on the hand provoked a thalamic activation in the same area (pulvinar) during and outside a migraine attack. Even more intriguing is the observation that this same thalamic area may be involved in other manifestations of ictal hypersensitivity to sensory stimuli including photophobia (Noseda et al., 2010).


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5. Imaging data of associated migraine symptoms as photophobia and osmophobia Migraine is a complex brain disorder involving not only headache but also altered perception of light (photophobia), sound (phonophobia) and odour (osmophobia) during and outside migraine attacks. Photophobia and phonophobia are included as diagnostic criteria for migraine by the International Headache Society classification. During migraine attacks, osmo-, photo- and phonophobia augment the patients discomfort, increasing the headache intensity and also, in many patients, nausea and vomiting. This sensory sensitivity in migraineurs seems to be constitutional for it persists at a lower level between attacks (Main et al., 1997; Mulleners et al., 2001; Vanagaite et al., 1997; Woodhouse and Drummond, 1993; Demarquay et al., 2006). Whereas the non-pain symptoms of migraine argue for a disturbance of sensory processing from the central nervous system, neuroimaging study exploring photophobia, phonophobia or osmophobia are rare and quite new. Osmophobia and photophobia in migraineurs have been recently studied with neuroimaging in the hypothesis of a sensory dysmodulation in migraineurs during and also at a lower degree between attacks.



In the hypothesis of different functional olfactory neural networks in migraine, a PET study has investigated migraineurs with interictal olfactory hypersensitivity versus controls (Demarquay et al., 2008). Eleven migraineurs with olfactory hypersensitivity and twelve controls were studied with PET during olfactory stimulation and odourless air. Significant differences were found in cerebral activation patterns as well as in baseline rCBF between migraineurs and controls in both olfactory and non-olfactory brain regions. Higher rCBF were observed in migraineurs compared to controls in the piriform cortex (which is part of the primary olfactory cortex) during both olfactory and non-olfactory conditions. The authors suggest that hyperactivity of the piriform cortex could result in facilitated triggering of the trigeminovascular system in response to odours during the interictal or pre-ictal period. During olfactory stimulation, the neural network activated in migraineurs is different than in controls. This is consistent with the hypothesis of a hyperactive olfactory system in migraineurs with olfactory hypersensitivity. Another study failed to demonstrate brain activation differences during olfactory stimulation (rose odour) between migraineurs interictally and controls (Stankewitz and May, 2011). But in opposition to Demarquay et al. study in which migraineurs were selected because of their olfactory hypersensitivity, in this study the patients were included ignoring any specific criteria regarding sensitivity to odours or trigger factors. However, during spontaneous migraine attack, olfactory stimulation induced significantly higher BOLD signal intensities in limbic structures (amygdale and insular cortices) and in the rostral pons compared to the interictal phase. These findings point to an increased sensitivity in migraineurs to odour stimuli during the migraine attack compared to the

interictal state. Moreover, the increased activity in pons during migraine attack is of course driven by olfactory stimulation but also indirectly by the ictal state. As pons is known to be implicated in migraine pain, it points to the relationship between olfactory and trigemino-nociceptive pathway. These interactions could explain clinically the odour-triggered migraine and increase of headache by olfactory stimulation resulting from activation by odour of the trigeminovascular system via the brainstem nuclei.



Two PET studies have investigated photophobia in migraine. The first H2O15 PET study explored the interaction between visual cortex and trigeminal nociception (Boulloche et al., 2010). Seven migraineurs between attacks and seven matched controls were studied with three luminous intensities (continuous luminous stimulation covering the whole visual field facilitating habituation) and with or without pain in the trigeminal territory. When no concomitant pain stimulation was applied, luminous stimulations activated bilaterally the visual cortex in migraineurs (cuneus, lingual gyrus, posterior cingulate cortex), but not in controls (as expected by the characteristics of luminous stimulation). Concomitant pain stimulation allowed visual cortex activation in controls and potentiated its activation in migraineurs. Whatever the conditions the activations volume was larger in migraineurs than in controls. According to these results, migraineurs’ visual cortex is hyperresponsive (or hyperexcitable) to light compared to controls and there is an interaction between trigeminal pain and light in migraineurs and also in controls. Interaction between visual and trigeminal pathway seems to play a key role in photophobia pathophysiology. Clinically, migraine headache increases photophobia and light exposure can worsen acute migraine headache. Clinical studies have shown that pain stimulation in the V1 territory decreased tolerance to light (Drummond, 1997; Kowacs et al., 2001) while light stimulation lowered the trigeminal nociceptive threshold (Drummond and Woodhouse, 1993). Interestingly, a recent study in rats provides an anatomical substrate for this interaction between visual cortex activation and trigeminal activation. Neurons have been identified in the lateral posterior thalamus which could be excited by dural stimulation (dependant on trigeminal pathway) and whose activity was increased by exposing animals to bright light (Noseda et al., 2010). Intrinsically photosensitive retinal ganglion cells innervate these thalamic neurons, and axons from these thalamic neurons project to somatosensory and visual cortices. So this study demonstrates that light modulates the activity of a subset of trigeminovascular thalamic neurons that receive input from the retina and project to multiple cortical areas. Using diffusion weighted imaging and probabilistic tractography in humans, a non-image forming visual pathway from the optic chiasm to the pulvinar, and from the pulvinar to several associative cortical brain regions has been defined (Maleki et al., 2012). The authors suggest that this direct pathway from optic nerve to posterior thalamus could be an anatomical substrate for exacerbation of migraine headache by light in the human.

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In a second H2O15 PET study, painful photophobia, defined as headache enhancement induced by continuous luminous stimulation was explored during spontaneous migraine attacks (Denuelle et al., 2011). Eight migraineurs were studied during migraine attacks, after headache relief by sumatriptan and during attack-free interval. Luminous stimulation with low intensity activated the visual cortex during migraine attacks and after headache relief but not during the attack-free interval. The visual cortex activation was statistically higher during migraine headache than after pain relief. Thus migraine attacks seem to increase visual cortex excitability or responsiveness when compared to attack-free intervals. Moreover, independently of pain, the visual cortex remained hyperresponsive (or hyperexcitable) to light after headache relief by sumatriptan compared with attack-free interval. The visual cortex activation during migraine headache could be explained by interaction between visual and trigeminal nerve pathways, as described above. But the persistence of visual cortex activation after headache relief is independent of trigeminal activation. This hyperresponsiveness or hyperexcitability could be under brainstem nuclei modulation as brainstem activation persists after headache relief (Weiller et al., 1995) and can directly modulate neuronal excitability of sensory cortex via the thalamus (Devilbiss et al., 2006; Filippov et al., 2004, 2008). According to PET studies results, a hypothesis could be proposed to explain the pathophysiology of photophobia in migraine. Between attacks the visual cortex of migraineurs is hyperresponsive to light compared with controls and this visual cortex hyperexcitability can explain why migraineurs report an uncomfortable sense of glare between attacks. During the ictal period (including premonitory phase, migraine headache, and after pain relief), the visual cortex excitability could possibly be enhanced by brainstem activation, explaining photophobia in migraineurs during the preand postictal phases (Giffin et al., 2003). And then activation of the trigeminovascular system potentiates the visual cortex excitability via posterior thalamus and could explain why headache and sensitivity to light increase in a vicious circle during migraine attack.


Chronic migraine

Sometimes migraine may transform from an episodic to a chronic form (i.e. 15 or more days with headache per month). Even if overuse of acute medication is the most frequent factor associated with transformation of episodic into chronic daily headache (Mathew et al., 1982), the precised mechanisms underlying the development of chronic migraine are not understood. Few studies have evaluated functional changes associated with disease progression or transformation. 18F-fluorodeoxyglucose PET was used to study patients while they experienced an analgesic-overuse headache and 3 weeks after withdrawal of the overused medication (Fumal et al., 2006). Despite similar pain levels at the time of testing at both time points, several brain areas involved in pain processing, such as bilateral insula, bilateral thalamus, orbitofrontal cortex, ventral striatum and anterior cingulated cortex, and inferior parietal lobule were


significantly less active metabolically than in healthy subjects. After analgesic withdrawal, all these areas metabolically normalized, with the exception of the orbitofrontal cortex, which remained hypometabolic suggesting a role for this structure in a predisposition to analgesic overuse. Indeed orbitofrontal cortex dysfunction has also been shown in substance dependence (Tanabe et al., 2009). The selective impairment of sensory pain processing due to chronic migraine condition and the association of medicationoveruse headache with reversible metabolic changes in pain processing structures is also demonstrated in a recent fMRI study (Ferraro et al., 2012). In this study, patients with medication-overuse headache were compared with healthy controls, and reduced pain-related activity was reported in primary somatosensory cortex, inferior parietal lobule and supramarginal gyrus during medication withdrawal. These changes normalized 6 months after withdrawal suggesting that overuse-related abnormalities in pain processing are fully reversible, which is well in line with the clinical experience that a large proportion of patients improve after withdrawal of acute headache medications.



Functional neuroimaging during migraine attacks and also interictally has initiated the description of ‘‘the migraine brain’’. These studies have permitted the demonstration of a cortical spreading depression in migraine with aura, the evidence of a posterior hypoperfusion in migraine without aura, the crucial role for the brainstem during migraine attack, and a cortical hypersensitivity in migraineurs modulated by trigeminal pathway explaining sensory sensitization as photophobia and osmophobia. All these studies stimulate basic research to elucidate these data. Nowadays it is premature to propose a unique model linking all these events. It is tempting to suggest that activation of brainstem nuclei is the first event of a migraine attack, eliciting a posterior cortical hypoperfusion and a CSD in some individuals whose cortex is susceptible to oligemia for specific reasons like genetic factors. But we must be aware of theories the fate of which is often to be wrong. We must rely on improvements in neuroimaging aand on the necessity of studying, if possible, migraine attack from its premonitory phase to its total ending.

Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.


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