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La parakinésie brachiale oscitante
Yawning: its cycle, its role
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Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
 
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
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mystery of yawning 

 

 

 

 

mise à jour du
19 janvier 2017
Brain
2016;139(Pt 7):1987-93
Migraine
The migraine generator revisited:
continuous scanning of the migraine cycle over 30 days
and three spontaneous attacks
Schulte LH, May A.
 

Chat-logomini

 
 
Abstract
Functional imaging using positron emission tomography and later functional magnetic resonance imaging revealed a particular brainstem area that is believed to be specifically activated in migraine during, but not outside of the attack, and consequently has been coined the 'migraine generator'. However, the pathophysiological concept behind this term is not undisputed and typical migraine premonitory symptoms such as fatigue and yawning, but also a typical association of attacks to circadian and menstrual cycles, all make the hypothalamus a possible regulating region of migraine attacks. Neuroimaging studies investigating native human migraine attacks however are scarce and for methodological but also clinical reasons there are currently no studies investigating the last 24 h before headache onset. Here we report a migraine patient who had magnetic resonance imaging every day for 30 days, always in the morning, to cover, using functional imaging, a whole month and three complete, untreated migraine attacks. We found that hypothalamic activity as a response to trigeminal nociceptive stimulation is altered during the 24 h prior to pain onset, i.e. increases towards the next migraine attack. More importantly, the hypothalamus shows altered functional coupling with the spinal trigeminal nuclei and the region of the migraine generator, i.e. the dorsal rostral pons during the preictal day and the pain phase of native human migraine attacks. These data suggest that although the brainstem is highly linked to the migraine biology, the real driver of attacks might be the functional changes in hypothalamo-brainstem connectivity.
 
Introduction
Among the more than 200 headache types, migraine is the second most common headache syndrome that affects between 12 and 14% of the population. Migraine is predominantly a cycling episodic disorder that manifests in attacks of headache, photophobia, phonophobia and nausea with a certain circadian rhythmicity. Extensive research over the past 20 years has broadened our understanding of the underlying mechanisms and pathogenesis. Due to technological improvements, brain imaging techniques have gained importance in the quest to understand cycling headache syndromes and speciÞc emphasis has been placed to understand neuronal activation in headache syndromes using functional MRI.
 
Several independent functional studies have established the crucial role of the brainstem in acute and chronic migraine (Weiller et al., 1995; Stankewitz et al., 2011) and the hypothalamic area in tri- gemino-autonomic headaches (May, 2005). A recent study reinforced the speciÞc brainstem Þndings in migraine by comparing brain responses during trigeminal pain processing in migraine patients with those of healthy control subjects (Stankewitz et al., 2011). The main Þnding was that the activity of the spinal trigeminal nuclei in response to nociceptive stimulation showed a cycling behaviour over the migraine interval where the trigeminal activation level increased signiÞcantly towards the next migraine attack. However, this Þnding came from a cohort study, where the time towards the next attack was determined retrospectively, i.e. per telephone contact after the experiment until the next attack occurred. These data cannot answer the question of whether the trigeminal pain system is dysfunctional in itself or if other structures modulate its activity.
 
From a clinical perspective, the hypothalamus would be the most likely 'modulator' of the trigeminal pain system as the many facets of a migraine attack, such as yawning, fatigue and craving but also circadian rhythmicity of at- tacks (Fox and Davis, 1998; Fox, 2005; Alstadhaug et al., 2007; Nascimento et al., 2014) could be best explained when considering the biological role of the limbic system. Using PET, one study reported increased cerebral blood þow bilaterally in the hypothalamus during an acute attack in migraine patients (Denuelle et al., 2007) and even more recently some hypothalamic activity was reported very early in nitroglycerin-triggered attacks (Maniyar et al., 2014). Based on resting state data Moulton et al. (2014) suggested that hypothalamic connectivity with autonomic circuits and the locus coeruleus in migraine may be altered. A problem of all the above-mentioned studies is the variance of cohort studies involving the interpretation of averaged imaging data and the fact that most studies investigate only a small space of time of the migraine cycle, i.e. the attack compared to a random day between attacks. However, just as the migraine cycle spans several days and contains up to Þve phases (prodromes, aura, headache, resolution, and recovery) (Blau, 1992), the trigeminal activ- ity in migraine patients is not constant but strongly variable (Stankewitz and May, 2007; Stankewitz et al., 2011). Thus the ultimate answer as to which areas of the brain and brainstem might in fact generate migraine attacks comes probably from individual data which may give us a more differentiated view as data differ from subject to subject depending on the time to the next migraine attack.
 
Discussion
The main Þnding of this study is that the hypothalamus, depending on the state of the migraine cycle, exhibits an altered functional coupling with the spinal trigeminal nuclei and the region of the dorsal rostral pons. More speciÞcally, the hypothalamus is signiÞcantly more active within the last 24h preceding the onset of migraine pain and shows the greatest functional coupling with the spinal trigeminal nuclei, whereas during the ictal state, the hypothalamus is functionally coupled with the dorsal rostral pons, an area that was previously coined 'the migraine generator' (Bahra et al., 2001; Denuelle et al., 2007).
 
In recent years migraine has primarily been understood and discussed as a cyclic disorder with physiological func- tioning and changing activity of certain areas of the brain and brainstem during different stages of the migraine cycle (Weiller et al., 1995; Judit et al., 2000; Stankewitz and May, 2007; Stankewitz et al., 2011; Maniyar et al., 2014). Increased hypothalamic activity in the hours preced- ing migraine pain onset has only been shown once imme- diately before NO-triggered migraine-like headache (Maniyar et al., 2014). The authors speculated that an activation in this area in the preictal phase might represent a dysfunction that could potentially modulate the top-down inhibitory effect on the trigeminocervical complex (Maniyar et al., 2014). It has to be said that activation in the hypo- thalamic region in this PET study was not seen, when all preictal scans were compared against baseline scans. Nevertheless, our data representing spontaneous untreated attacks suggest nitroglycerin-induced and spontaneous at- tacks to be very similar, including imaging data.
 
Scanning the same person 30 days in a row signiÞcantly reduces variance and allows monitoring common and headache speciÞc brain activations as a response to nociceptive stimuli throughout the migraine cycle. One way to analyse these data is to contrast different states (e.g. interictal, preictal, ictal, and postictal) with each other. Another opportunity offered by this method is to use the migraine states as a regressor and, over all 30 days, compute the activity in the brain which signiÞcantly follows this regressor. When we contrasted the ictal with the interictal state we found a strong and speciÞc activation in the rostral pons, the region which in earlier studies has been tightly linked to attack generation (Weiller et al., 1995; Bahra et al., 2001; Stankewitz et al., 2011). This region was not prominently activated when contrasting the preictal with the interictal state, where the hypothalamus was speciÞcally activated. In the postictal phase, only the visual cortex showed stronger activity as a response to pain compared to the ictal phase. That the visual cortex activates as a response to pain in interictal migraineurs is well known (Boulloche et al., 2010). Taken together with the Þndings from the preictal and ictal phase as well as the correlation contrast, this could point towards increasing multisensory integration of visual and nociceptive stimulation towards the next migraine attack with a subsequent deactivation during the pain phase of a migraine attack. This phenomenon however could also represent a baseline problem: in a situation of already increased trigeminal nociceptive input the pain-related visual cortex activity might constitutively be higher leading to lesser responses to additional painful stimulation. It appears that each region is functionally highly linked to a speciÞc phase in the migraine cycle, a suggestion that is emphasized when weighing all states over all cycles and all days.
 
From a biological level it is probably more important to understand whether such phase-speciÞc activations have any functional consequences and to explore possible relationships between these areas. It is therefore highly interesting that the hypothalamic activity is not only phase locked to the preictal phase but, in this phase, has a strong functional coupling with the trigeminal nuclei, which was not seen in the other phases. We also found that the spinal trigeminal nuclei increase activity towards the next migraine attack and were thus able to replicate Þndings from a previous study from our own group (Stankewitz et al., 2011). The functional coupling between the hypothalamus and the trigeminal nuclei is signiÞcantly weaker in the ictal phase, when the hypothalamus is strongly coupled to the dorsal rostral pons. This suggests that the activation in this area in the preictal phase does not represent a mere dysfunction but that the change in functional connectivity of the hypothalamus with the tri- geminal nuclei and the rostral pons drives the different phases, probably by activating the top-down inhibitory effect on the trigeminocervical complex in the preictal phase and activating the dorsal pons in the ictal phase, eventually leading to the attack. The current Þndings thus corroborate the theory that the hypothalamus might be the true generator of migraine attacks.
 
In conclusion, our data suggest the hypothalamus to be the primary generator of migraine attacks which, due to speciÞc interactions with speciÞc areas in the higher and lower brainstem, could alter the activity levels of the key regions of migraine pathophysiology.