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Background Gut microbiota disturbance is increasingly suggested to be involved in the pathogenesis of migraine but this connection remains unsubstantiated. This study aimed to investigate whether the gut microbiome influences migraine-related hyperalgesia. Methods Nitroglycerin-induced hyperalgesia was evaluated in mice with different gut microbiota statuses as follows: Specific pathogen-free mice; germ-free mice; specific pathogen-free mice treated with antibiotics to deplete the gut microbiome (ABX mice); and germ-free mice transplanted with the gut microbial profile from specific pathogen-free mice (GFC mice). Moreover, nitroglycerin-induced hyperalgesia was compared between recipient mice transplanted with gut microbiota from a patient with migraine and those that received gut microbiota from a sex- and age-matched healthy control. Results In specific pathogen-free mice, a decreased mechanical threshold in the hind paw, increased grooming time, increased c-Fos expression level and decreased calcitonin gene-related peptide expression level as well as increased tumor necrosis factor-α concentration in the trigeminal nucleus caudalis were observed after nitroglycerin administration compared with saline treatment. However, increased basal sensitivity and higher basal concentrations of TNF-α in the trigeminal nucleus caudalis were observed in germ-free and ABX mice, while no significant difference in hyperalgesia was observed between the nitroglycerin group and saline group in germ-free and ABX mice. Moreover, significant hyperalgesia was induced by nitroglycerin administration in GFC mice. The mice transplanted with the gut microbial profile from a patient with migraine had more severe nitroglycerin-induced hyperalgesia than the mice receiving microbiota from a matched healthy control. Conclusion Our findings highlight the involvement of the gut microbiome in normal mechanical pain sensation and pathogenesis of migraine.

Background A previous study by our team reported the prevalence of primary headache disorders and factors associated with headache among nurses in three hospitals in North China. The aim of this cross-sectional survey was to learn more about how medical nurses in South China were affected by headache. Additionally, we determined the prevalence of headache and measured the impact of headache among doctors in mainland China for the first time. Methods Stratified random cluster sampling was used to select 280 physicians and 365 nurses from various departments in four hospitals in Sanya, which is one of southernmost cities in China. Information was collected on demographic data, occupational factors and headache characteristics by using a structured questionnaire. Results Among 645 medical staff, 548 (85%) responded (doctors = 240, nurses = 308). Among the medical staff, the 1-year prevalence of primary headache disorders was 50%, with 25.9% experiencing migraine and 24.1% experiencing tension-type headache (TTH). The prevalence of migraine in female doctors was higher than that in female nurses, although this difference was not significant (32.4% vs. 29.8%, P = 0.628). Multivariate analysis showed that being female and working in other specialties (Emergency Department & Radiology Department) remained independent risk factors for migraine in doctors (OR 2.314 and 3.223). In nurses, being married was a risk factor for migraine (OR 3.728), and job titles remained an independent risk factor for migraine and TTH (OR 2.294 and 4.695). Working more than 6 night-shifts per month was associated with an increased prevalence of migraine and TTH in doctors; the same was true in nurses for migraine, but not for TTH. Conclusion The prevalence of primary headache disorders in both nurses and doctors is higher than that in the general population in South China. Our study shows that occupation, geography and sex may play an important role. Further, female doctors are more susceptible than female nurses to migraine. The risk factors relevant to headache that were found in this study should provide an important reference for promoting occupational health in medical staff, especially female doctors in China.

Background Mutations in ATP1A2, the gene encoding the α2 subunit of Na+/K+-ATPase, are the main cause of familial hemiplegic migraine type 2 (FHM2). The clinical presentation of FHM2 with mutations in the same gene varies from pure FHM to severe forms with epilepsy and intellectual disability, but the correlation of these symptoms with different ATP1A2 mutations is still unclear. Methods Ten ATP1A2 missense mutations were selected according to different phenotypes of FHM patients. They caused pure FHM (FHM: R65W, R202Q, R593W, G762S), FHM with epilepsy (FHME: R548C, E825K, R938P), or FHM with epilepsy and intellectual disability (FHMEI: T378N, G615R, D718N). After ouabain resistance and fluorescence modification, plasmids carrying those mutations were transiently transfected into HEK293T and HeLa cells. The biochemical functions were studied including cell survival assays, membrane protein extraction, western blotting, and Na+/K+-ATPase activity tests. The electrophysiological functions of G762S, R938P, and G615R mutations were investigated in HEK293T cells using whole-cell patch-clamp. Homology modeling was performed to determine the locational distribution of ATP1A2 mutations. Results Compared with wild-type pumps, all mutations showed a similar level of protein expression and decreased cell viability in the presence of 1 µM ouabain, and there was no significant difference among the mutant groups. The changes in Na+/K+-ATPase activity were correlated with the severity of FHM phenotypes. In the presence of 100 µM ouabain, the Na+/K+-ATPase activity was FHM > FHME > FHMEI. The ouabain-sensitive Na+/K+-ATPase activity of each mutant was significantly lower than that of the wild-type protein, and there was no significant difference among all mutant groups. Whole-cell voltage-clamp recordings in HEK293T cells showed that the ouabain-sensitive pump currents of G615R were significantly reduced, while those of G762S and R938P were comparable to those of the wild-type strain. Conclusions ATP1A2 mutations cause phenotypes ranging from pure FHM to FHM with epilepsy and intellectual disability due to varying degrees of deficits in biochemical and electrophysiological properties of Na+/K+-ATPase. Mutations associated with intellectual disability presented with severe impairment of Na+/K+-ATPase. Whether epilepsy is accompanied, or the type of epilepsy did not seem to affect the degree of impairment of pump function.

Background As a disorder of brain dysfunction, migraine has been associated with cognitive decline. However, no consistent results with respect to the attention function in migraineurs have been found, and the relationship between attentional inhibition and migraine is also unclear. In this study, the attentional inhibition function was evaluated using event-related potentials (ERPs) while migraine patients and healthy controls were performing the color–word Stroop task. Methods In this study, 75 migraine patients and 41 age-, gender-, and education-matched healthy controls were enrolled. The Stroop task was performed, and both behavioral and ERP data were analyzed. Results As to the behavioral data, the migraine group had a longer reaction time compared to the control group, but no difference in Stroop effect was observed. With respect to ERP components, the amplitudes of both early and late medial frontal negativity (MFN) were decreased in the migraine group. Additionally, obvious differences in the early MFN and sustained potential (SP) amplitudes were found between patients with and without allodynia. Conclusions At the behavioral level, migraine patients exhibited decreased executive ability but no obvious decline in inhibition. By contrast, a decline in attentional inhibition during the migraine interictal phase was confirmed by the analysis of ERP components, mainly those associated with changes in the conflict-monitoring stage, independent of confounding factors such as age, education, medication and mood disorders. Migraine patients with allodynia exhibited some significant differences in early MFN and SP compared to those without, supporting the hypothesis that migraine chronification aggravates the decline in attentional inhibition.

Additional file 1: Supplementary Figure 1. Representative images of transfection efficiency of wild-type and mutant constructs with 100μm scales. Supplementary Figure 2. Survival assays in HeLa cells. The survival rate of each mutant was significantly reduced compared to the wild-type (R65W: P = 0.032, other mutants: P < 0.0001, two-way ANOVA). Supplementary Figure 3. Survival assays in HEK293T cells. The survival rate of each mutant was significantly reduced compared to the wild-type (R65W: P = 0.016, other mutants: P < 0.0001, two-way ANOVA). Supplementary Figure 4. Survival assays in HeLa cells in the absence of ouabain. The survival rates of cells in each mutant group were similar to those in the WT group (P > 0.05, two-way ANOVA). Supplementary Table 1. Clinical characteristics of previously published patients with studied ATP1A2 mutations.

Background Migraine is characterized by a hypersensitivity to environmental stimulation which climaxes during headache attacks but persists during attack-free period. Despite ongoing debates about the nature of the mechanisms giving rise to this abnormality, the presence of deficient inhibitory cortical processes has been proposed to be one possible mechanism underlying its pathogenesis. Empirical evidence supporting this claim is mainly based on previous accounts showing functional cortical disexcitability in the sensory domain. Considering that a general inhibitory control process can play an important role across early to later stage of information processing, this may indicate the important role other dimensions of inhibitory control can play in migraine disability. The present study examined the pathophysiological features of inhibitory control that takes place during suppression of prepotent responses in migraineurs. Methods Twenty-two patients with migraine without aura (mean age = 30.86 ± 5.69 years; 19 females) during the interictal period and 25 healthy controls (mean age = 30.24 ± 3.52 years; 18 females) were recruited. We used a stop signal task in combination with event-related potentials (ERPs) to examine participants’ neural activity supporting response inhibition. Results Behaviorally, migraineurs exhibited prolonged stop signal reaction times relative to healthy controls. At the neural level, the amplitude of the stop-N2 over fronto-central, central and centro-parietal scalp regions, a component of the ERPs related to conflict monitoring during early, non-motoric stages of inhibition, was significantly increased in migraineurs. Meanwhile, the amplitude of the stop-P3 over central and centro-parietal scalp regions, a component of the ERPs reflecting late-stage inhibition of the motor system and cognitive evaluation of motor inhibition, was also significantly increased in migraineurs. Ultimately, our time-frequency analysis further revealed increased delta activity in migraineurs. Conclusions Consistent with the theory that alterations in cognitive cortical processes are a key signature of migraine, our findings revealed an abnormal state of suppressing prepotent responses in migraineurs, which can be attributed to cortical disexcitability of the pre-frontal executive network and centro-parietal sensorimotor network. These novel findings extend to show the existence of dysfunctional inhibition control that occurs during suppression of prepotent responses in migraneurs.