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.

The neural mechanisms responsible for the initiation and expression of migraines remain unknown. Although there is growing evidence of changes in brainstem anatomy and function between attacks, very little is known about brainstem function and structure in the period immediately prior to a migraine. The aim of this investigation is to use brainstem-specific analyses of diffusion weighted images to determine whether the brainstem pain processing regions display altered structure in individuals with migraine across the migraine cycle, and in particular immediately prior to a migraine. Diffusion tensor images (29 controls, 36 migraineurs) were used to assess brainstem anatomy in migraineurs compared with controls. We found that during the interictal phase, migraineurs displayed greater mean diffusivity (MD) in the region of the spinal trigeminal nucleus (SpV), dorsomedial pons (dmPons)/dorsolateral pons (dlPons), and midbrain periaqueductal gray matter (PAG)/cuneiform nucleus (CNF). Remarkably, the MD returned to controls levels during the 24-h period immediately prior to a migraine, only to increase again within the three following days. Additionally, fractional anisotropy (FA) was significantly elevated in the region of the medial lemniscus/ventral trigeminal thalamic tract in migraineurs compared with controls over the entire migraine cycle. These data show that regional brainstem anatomy changes over the migraine cycle, with specific anatomical changes occurring in the 24-h period prior to onset. These changes may contribute to the activation of the ascending trigeminal pathway by either an increase in basal traffic or by sensitizing the trigeminal nuclei to external triggers, with activation ultimately resulting in perception of head pain during a migraine attack.

Background: There is histological evidence of microstructural changes in the zygomaticotemporal branch of the trigeminal nerve in migraineurs. This raises the possibility that altered trigeminal nerve properties contribute to migraine pathophysiology. Whilst it is not possible to explore the anatomy of small trigeminal nerve branches it is possible to explore the anatomy of the trigeminal root entry zone using magnetic resonance imaging in humans. The aim of this investigation is to assess the microstructure of the trigeminal nerve in vivo to determine if nerve alterations occur in individuals with episodic migraine. Methods: In 39 migraineurs and 39 matched controls, T1-weighted anatomical images were used to calculate the volume (mm 3) and maximal cross-sectional area of the trigeminal nerve root entry zone; diffusion tensor images were used to calculate fractional anisotropy, mean diffusion, axial diffusion and radial diffusion. Results: There were significant differences between the left and right nerve of controls and migraineurs with respect to volume and not cross-sectional area. Migraineurs displayed reduced axial diffusion in the right nerve compared to the left nerve, and reduced fractional anisotropy in the left nerve compared to left controls. Furthermore, although there were no differences in mean diffusion or radial diffusion, regional analysis of the nerve revealed significantly greater radial diffusion in the middle and rostral portion of the left trigeminal nerve in migraineurs compared with controls. Conclusions: Migraine pathophysiology is associated with microstructural abnormalities within the trigeminal nerve that are consistent with histological evidence of altered myelin and/or organization. These peripheral nerve changes may provide further insight into migraine pathophysiology and enable a greater understanding for targeted treatments of pain alleviation.

Background Migraine is a neurological disorder characterized by intense, debilitating headaches, often coupled with nausea, vomiting and sensitivity to light and sound. Whilst changes in sensory processes during a migraine attack have been well-described, there is growing evidence that even between migraine attacks, sensory abilities are disrupted in migraine. Brain imaging studies have investigated altered coupling between areas of the descending pain modulatory pathway but coupling between somatosensory processing regions between migraine attacks has not been properly studied. The aim of this study was to determine if ongoing functional connectivity between visual, auditory, olfactory, gustatory and somatosensory cortices are altered during the interictal phase of migraine. Methods To explore the neural mechanisms underpinning interictal changes in sensory processing, we used functional magnetic resonance imaging to compare resting brain activity patterns and connectivity in migraineurs between migraine attacks (n = 32) and in healthy controls (n = 71). Significant differences between groups were determined using two-sample random effects procedures (p < 0.05, corrected for multiple comparisons, minimum cluster size 10 contiguous voxels, age and gender included as nuisance variables). Results In the migraine group, increases in infra-slow oscillatory activity were detected in the right primary visual cortex (V1), secondary visual cortex (V2) and third visual complex (V3), and left V3. In addition, resting connectivity analysis revealed that migraineurs displayed significantly enhanced connectivity between V1 and V2 with other sensory cortices including the auditory, gustatory, motor and somatosensory cortices. Conclusions These data provide evidence for a dysfunctional sensory network in pain-free migraine patients which may be underlying altered sensory processing between migraine attacks.