The neural mechanism responsible for migraine remains unclear. While an external trigger has been proposed to initiate a migraine, it has also been proposed that changes in brainstem function are critical for migraine headache initiation and maintenance. Although the idea of altered brainstem function has some indirect support, no study has directly measured brainstem pain modulation circuitry function in migraineurs particularly immediately before a migraine. In male and female humans, we performed fMRI in 31 controls and 31 migraineurs at various times in their migraine cycle. We measured brainstem function during noxious orofacial stimulation and assessed resting-state functional connectivity. First, we found that, in individual migraineurs, pain sensitivity increased over the interictal period but then dramatically decreased immediately before a migraine. Second, despite overall similar pain intensity ratings between groups, in the period immediately before a migraine, compared with controls and other migraine phases, migraineurs displayed greater activation in the spinal trigeminal nucleus during noxious orofacial stimulation and reduced functional connectivity of this region with the rostral ventromedial medulla. Additionally, during the interictal phase, migraineurs displayed reduced activation of the midbrain periaqueductal gray matter and enhanced periaqueductal gray connectivity with the rostral ventromedial medulla. These data support the hypothesis that brainstem sensitivity fluctuates throughout the migraine cycle. However, in contrast to the prevailing hypothesis, our data suggest that, immediately before a migraine attack, endogenous analgesic mechanisms are enhanced and incoming noxious inputs are less likely to reach higher brain centers.

The neural mechanism responsible for migraine remains unclear. While the role of an external trigger in migraine initiation remains vigorously debated, it is generally assumed that migraineurs display altered brain function between attacks. This idea stems from relatively few brain imaging studies with even fewer studies exploring changes in the 24 h period immediately prior to a migraine attack. Using functional magnetic resonance imaging, we measured infra-slow oscillatory activity, regional homogeneity, and connectivity strengths of resting activity in migraineurs directly before (n = 8), after (n = 11), and between migraine attacks (n = 26) and in healthy control subjects (n = 78). Comparisons between controls and each migraine group and between migraine groups were made for each of these measures. Directly prior to a migraine, increased infra-slow oscillatory activity occurred in brainstem and hypothalamic regions that also display altered activity during a migraine itself, that is, the spinal trigeminal nucleus, dorsal pons, and hypothalamus. Furthermore, these midbrain and hypothalamic sites displayed increased connectivity strengths and regional homogeneity directly prior to a migraine. Remarkably, these resting oscillatory and connectivity changes did not occur directly after or between migraine attacks and were significantly different to control subjects. These data provide evidence of altered brainstem and hypothalamic function in the period immediately before a migraine and raise the prospect that such changes contribute to the expression of a migraine attack.

Background The exact mechanisms responsible for migraine remain unknown, although it has been proposed that changes in brainstem anatomy and function, even between attacks, may contribute to the initiation and maintenance of headache during migraine attacks. The aim of this investigation is to use brainstem-specific analyses of anatomical and diffusion weighted images to determine if the trigeminal system displays altered structure in individuals with migraine. Methods Voxel-based morphometry of T1-weighted anatomical images (57 controls, 24 migraineurs) and diffusion tensor images (22 controls, 24 migraineurs) were used to assess brainstem anatomy in individuals with migraine compared with controls. Results We found grey matter volume decreases in migraineurs in the spinal trigeminal nucleus and dorsomedial pons. In addition, reduced grey matter volume and increased free water diffusivity occurred in areas of the descending pain modulatory system, including midbrain periaqueductal gray matter, dorsolateral pons, and medullary raphe. These changes were not correlated to migraine frequency, duration, intensity or time to next migraine. Conclusion Brainstem anatomy changes may underlie changes in activity that result in activation of the ascending trigeminal pathway and the perception of head pain during a migraine attack.

Chronic migraine is a disabling neurological disorder that imposes a considerable burden on individual and socioeconomic outcomes. Chronic migraine is defined as headaches occurring on at least 15 days per month with at least eight of these fulfilling the criteria for migraine. Chronic migraine typically evolves from episodic migraine as a result of increasing attack frequency and/or several other risk factors that have been implicated with migraine chronification. Despite this evolution, chronic migraine likely develops into its own distinct clinical entity, with unique features and pathophysiology separating it from episodic migraine. Furthermore, chronic migraine is characterized with higher disability and incidence of comorbidities in comparison to episodic migraine. While existing migraine studies primarily focus on episodic migraine, less is known about chronic migraine pathophysiology. Mounting evidence on aberrant alterations suggest that pronounced functional and structural brain changes, central sensitization and neuroinflammation may underlie chronic migraine mechanisms. Current treatment options for chronic migraine include risk factor modification, acute and prophylactic therapies, evidence-based treatments such as onabotulinumtoxinA, topiramate and newly approved calcitonin gene-related peptide or receptor targeted monoclonal antibodies. Unfortunately, treatments are still predominantly ineffective in aborting migraine attacks and decreasing intensity and frequency, and poor adherence and compliance with preventative medications remains a significant challenge. Novel emerging chronic migraine treatments such as neuromodulation offer promising therapeutic approaches that warrant further investigation. The aim of this narrative review is to provide an update of current knowledge and perspectives regarding chronic migraine background, pathophysiology, current and emerging treatment options with the intention of facilitating future research into this debilitating and largely indeterminant disorder.

Background There is evidence of altered resting hypothalamic activity patterns and connectivity prior to a migraine, however it remains unknown if these changes are driven by changes in overall hypothalamic activity levels. If they are, it would corroborate the idea that changes in hypothalamic function result in alteration in brainstem pain processing sensitivity, which either triggers a migraine headache itself or allows an external trigger to initiate a migraine headache. We hypothesise that hypothalamic activity increases immediately prior to a migraine headache and this is accompanied by altered functional connectivity to pain processing sites in the brainstem. Methods In 34 migraineurs and 26 healthy controls, we collected a series comprising 108 pseudo-continuous arterial spin labelling images and 180 gradient-echo echo planar resting-state functional magnetic resonance volumes to measure resting regional cerebral blood flow and functional connectivity respectively. Images were pre-processed and analysed using custom SPM12 and Matlab software. Results Our results reflect that immediately prior to a migraine headache, resting regional cerebral blood flow decreases in the lateral hypothalamus. In addition, resting functional connectivity strength decreased between the lateral hypothalamus and important regions of the pain processing pathway, such as the midbrain periaqueductal gray, dorsal pons, rostral ventromedial medulla and cingulate cortex, only during this critical period before a migraine headache. Conclusion These data suggest altered hypothalamic function and connectivity in the period immediately prior to a migraine headache and supports the hypothesis that the hypothalamus is involved in migraine initiation.