No abstract

Several studies suggested that migraine attack onset shows a circadian variation; however, there has not been an overview and synthesis of these findings. A PubMed search with keywords “migraine” AND “circadian” resulted in ten studies directly investigating this topic. Results of these studies mostly show that migraine attacks follow a monophasic 24-hour cyclic pattern with an early morning or late night peak while other studies reported an afternoon peak and also a biphasic 24-hour cycle of attacks. The identified studies showed methodological variation including sample size, inclusion of medication use, comorbidities, and night or shift workers which could have contributed to the contradictory results. Several theories emerged explaining the diurnal distribution of migraine attacks suggesting roles for different phenomena including a morning rise in cortisol levels, a possible hypothalamic dysfunction, a circadian variation of migraine triggers, sleep stages, and a potentially different setting of the circadian pacemaker among migraineurs. At the moment, most studies show an early morning or late night peak of migraine attack onset, but a significant amount of studies reveals contradictory results. Further studies should investigate the arising hypotheses to improve our understanding of the complex mechanism behind the circadian variation of migraine attacks that can shed light on new targets for migraine therapy.

Background The main goal of this research was to explore whether migraineurs had a higher level of perceived stress than healthy controls during the times of the coronavirus and related restrictive measures, and to examine the relationship between different subtypes of rumination and perceived stress in these groups. We measured two facets of depressive rumination, brooding and reflection, along with rumination about the current COVID-19 situation to see whether these different subtypes of rumination explained perceived stress among migraineurs and healthy controls. Methods Healthy adults (n = 64) and migraine patients (n = 73) filled out self-report questionnaires online. A multiple linear regression model was used to test whether depressive rumination (i.e. brooding and reflection) and COVID-related rumination explained perceived stress among adults with and without migraine during the times of COVID-19, after controlling for gender, age, migraine/control group status and migraine disability. Results Although we did not find any difference in the level of perceived stress among migraineurs and the control group, perceived stress was more strongly associated with brooding as well as COVID-related rumination among migraineurs than healthy controls. COVID-related rumination and brooding (but not reflection) explained the level of perceived stress after controlling for gender, age, migraine/control group status and migraine disability. Conclusions The similar degree of perceived stress among migraineurs and the control group may imply that there is great variation in the personal experience of people regarding the pandemic, that may be determined by numerous other factors. Our results demonstrate that ruminating about the pandemic and related difficulties, as well as brooding (but not reflection) appear to be associated with higher level of perceived stress during the times of the coronavirus. This association was slightly stronger among migraineurs, hinting at the increased vulnerability of this patient group in stressful situations like the COVID-19 pandemic. Our results also suggest that ruminating about the pandemic and its consequences is weakly associated with trait-level depressive rumination, thus may be more contingent on specific factors.

Altered periaqueductal gray matter (PAG) functional connectivity contributes to brain hyperexcitability in migraine. Although tryptophan modulates neurotransmission in PAG projections through its metabolic pathways, the effect of plasma tryptophan on PAG functional connectivity (PAG-FC) in migraine has not been investigated yet. In this study, using a matched case-control design PAG-FC was measured during a resting-state functional magnetic resonance imaging session in migraine without aura patients (n = 27) and healthy controls (n = 27), and its relationship with plasma tryptophan concentration (TRP) was assessed. In addition, correlations of PAG-FC with age at migraine onset, migraine frequency, trait-anxiety and depressive symptoms were tested and the effect of TRP on these correlations was explored. Our results demonstrated that migraineurs had higher TRP compared to controls. In addition, altered PAG-FC in regions responsible for fear-cascade and pain modulation correlated with TRP only in migraineurs. There was no significant correlation in controls. It suggests increased sensitivity to TRP in migraine patients compared to controls. Trait-anxiety and depressive symptoms correlated with PAG-FC in migraine patients, and these correlations were modulated by TRP in regions responsible for emotional aspects of pain processing, but TRP did not interfere with processes that contribute to migraine attack generation or attack frequency.

The existence of “sex phenotype” in migraine is a long-standing scientific question. Fluctuations of female sex hormones contribute to migraine attacks, and women also have enhanced brain activity during emotional processing and their functional brain networks seem to be more vulnerable to migraine-induced disruption compared to men. Periaqueductal grey matter (PAG) is a core region of pain processing and modulation networks with possible sex-related implications in migraine. In our study, sex differences of PAG functional resting-state connectivity were investigated in the interictal state in 32 episodic migraines without aura patients (16 women and 16 men). A significant main effect of sex was detected in PAG connectivity with postcentral, precentral, and inferior parietal gyri, and further differences were found between right PAG and visual areas (superior occipital gyrus, calcarine, and cuneus), supplementary motor area, and mid-cingulum connectivity. In all cases, PAG functional connectivity was stronger in female migraineurs compared to males. However, higher average pain intensity of migraine attacks correlated with stronger connectivity of PAG and middle temporal, superior occipital, and parietal gyri in male migraineurs compared to females. Migraine-related disability is also associated with PAG connectivity but without sex differences. Our results indicate that sex differences in PAG connectivity with brain regions involved in sensory and emotional aspects of pain might contribute to the “sex-phenotype” in migraine. The stronger functional connectivity between PAG and pain processing areas may be a sign of increased excitability of pain pathways even in resting-state in females compared to male migraineurs, which could contribute to female vulnerability for migraine. However, pain intensity experienced by male migraineurs correlated with increased connectivity between PAG and regions involved in the subjective experience of pain and pain-related unpleasantness. The demonstrated sex differences of PAG functional connectivity may support the notion that the female and male brain is differently affected by migraine.