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Migraine is a pain disorder accompanied by various symptoms. The insula, a "cortical hub," is involved in many functions. Few studies have focused on the insula in migraine. We explored the resting-state functional connectivity between the insula and other brain areas in rats subjected to repeated meningeal nociception which was commonly used as animal model of migraine. Inflammatory soup was infused through supradural catheters in conscious rats. The rats were subdivided based on the frequency of the inflammatory soup infusions. Magnetic resonance imaging data were acquired on rats 21 days after inflammatory soup infusion and functional connectivity seeded on the insula was analyzed. In the low-frequency inflammatory soup group, magnetic resonance imaging was performed again 1 h after the glyceryl trinitrate injection following baseline scanning. The cerebellum showed increased functional connectivity with the insula in the inflammatory soup groups. The insula showed increased functional connectivity with the medulla and thalamus in the ictal period in the low-frequency inflammatory soup rats. In the high-frequency inflammatory soup group, several areas showed increased functional connectivity with the insula, including the pons, midbrain, thalamus, temporal association cortex, and retrosplenial, visual, and sensory cortices. Our findings support the hypothesis that the headache phase of migraine depends on the activation and sensitization of the trigeminovascular system, and that the chronification of migraine may be related to higher brain centers and limbic cortices. The insula may be a new target for treatment of migraine. [ABSTRACT FROM AUTHOR]

Background: Cluster headache (CH), a rare primary headache disorder, is currently thought to be a genetic susceptibility which play a role in CH susceptibility. A large numbers of genetic association studies have confirmed that the HCRTR2 (Hypocretin Receptor 2) SNP rs2653349, and the ADH4 (Alcohol Dehydrogenase 4) SNP rs1126671 and rs1800759 polymorphisms are linked to CH. In addition, the CLOCK (Circadian Locomotor Output Cycles Kaput) gene is becoming a research hotspot for CH due to encoding a transcription factor that serves as a basic driving force for circadian rhythm in humans. The purpose of this study was to evaluate the association between CH and the HCRTR2, ADH4 and CLOCK genes in a Chinese CH case-control sample. Methods: We genotyped polymorphisms of nine single nucleotide polymorphisms (SNPs) in the HCRTR2, ADH4 and CLOCK genes to perform an association study on a Chinese Han CH case-control sample (112 patients and 192 controls),using Sequenom MALDI-TOF mass spectrometry iPLEX platform. The frequencies and distributions of genotypes and haplotypes were statistically compared between the case and control groups to identify associations with CH. The effects of SNPs on CH were further investigated by multiple logistic regression. Results: The frequency of the HCRTR2 SNP rs3800539 GA genotype was significantly higher in cases than in controls (48.2% vs.37.0%). The GA genotypes was associated with a higher CH risk (OR = 1.483, 95% CI: 0.564-3.387, p = 0.038), however, after Bonferroni correction, the association lost statistical significance. Haplotype analysis of the HCRTR2 SNPs showed that among eight haplotypes, only H1-GTGGGG was linked to a reduced CH risk (44.7% vs. 53.1%, OR = 0.689, 95% CI =0.491~0.966, p = 0.030). No significant association of ADH4, CLOCK SNPs with CH was statistically detected in the present study. Conclusions: Association between HCRTR2, ADH4,CLOCK gene polymorphisms and CH was not significant in the present study, however, haplotype analysis indicated H1-GTGGGG was linked to a reduced CH risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We explored the atypical functional connectivity between the anterior cingulate cortex and other brain areas in rats subjected to repeated meningeal nociception. The rat model was established by infusing an inflammatory soup through supradural catheters in conscious rats. Rats were subdivided according to the frequency of the inflammatory soup infusions. Functional connectivity analysis seeded on the anterior cingulate cortex was performed on rats 21 days after inflammatory soup infusion. Glyceryl trinitrate was injected following baseline scanning in the low-frequency inflammatory soup group and magnetic resonance imaging data were acquired 1 h after the injection. The rats exhibited nociceptive behavior after high-frequency inflammatory soup infusion. The anterior cingulate cortex showed increased functional connectivity with the cerebellum in the inflammatory soup groups. The medulla showed increased functional connectivity with the anterior cingulate cortex in the ictal period in the low-frequency inflammatory soup rats. Several areas showed increased functional connectivity with the anterior cingulate cortex in the high-frequency inflammatory soup group, including the pontine tegmentum, midbrain, thalamus, corpus callosum, hippocampus, and retrosplenial, visual, sensory, and motor cortices. This study indicated that the medulla participates in the early stage of a migraine attack and may be associated with the initiation of migraine. Sensitization of the trigeminal nociceptive pathway might contribute to the cutaneous allodynia seen in chronic migraine. Brain areas important for memory function may be related to the chronification of migraine. Electrophysiological studies should examine those migraine-related areas and provide new targets for migraine treatment and prevention.

Objective Although nociceptive sensitisation is an important pathophysiological process in migraine and migraine chronification, its underlying mechanisms remain unclear. Toll-like receptor 4 (TLR4), a pattern-recognition molecule, has a critical role in both neuropathic pain and morphine tolerance. The present study examined whether elements of the TLR4 pathway contribute to hyperalgesia induced by dural inflammation in rats. Methods A rat model of migraine was established by infusing a dural inflammatory soup. A group pretreated with TAK-242 was used to inhibit the activation of TLR4. The protein levels of TLR4 and its downstream molecules in the trigeminal pathway were examined by Western blot and immunofluorescence. The expression of activated microglia and astrocytes was also analysed. Levels of interleukin-1 beta, tumour necrosis factor-alpha, and brain-derived neurotrophic factor were measured by enzyme-linked immunosorbent assay. Results Acute inflammatory soup infusion induced time-dependent facial mechanical hyperalgesia, which was blocked by TAK-242 pretreatment. The inflammatory soup stimulus increased the production of TLR4 downstream molecules and interleukin-1 beta. Higher levels of microglia activation and brain-derived neurotrophic factor release were observed following the administration of the inflammatory soup but were alleviated by TAK-242. Conclusions These data suggest that the TLR4 signalling pathway promotes hyperalgesia induced by acute inflammatory soup delivery by stimulating the production of proinflammatory cytokines and activating microglia.

Voxel-based morphometry is used to detect structural brain changes in patients with migraine. However, the relevance of migraine and structural changes is not clear. This study investigated structural brain abnormalities based on voxel-based morphometry using a rat model of recurrent headache. The rat model was established by infusing an inflammatory soup through supradural catheters in conscious male rats. Rats were subgrouped according to the frequency and duration of the inflammatory soup infusion. Tactile sensory testing was conducted prior to infusion of the inflammatory soup or saline. The periorbital tactile thresholds in the high-frequency inflammatory soup stimulation group declined persistently from day 5. Increased white matter volume was observed in the rats three weeks after inflammatory soup stimulation, brainstem in the in the low-frequency inflammatory soup-infusion group and cortex in the high-frequency inflammatory soup-infusion group. After six weeks' stimulation, rats showed gray matter volume changes. The brain structural abnormalities recovered after the stimulation was stopped in the low-frequency inflammatory soup-infused rats and persisted even after the high-frequency inflammatory soup stimulus stopped. The changes of voxel-based morphometry in migraineurs may be the result of recurrent headache. Cognition, memory, and learning may play an important role in the chronification of migraines. Reducing migraine attacks has the promise of preventing chronicity of migraine.

Functional connectivity (FC) has been used to investigate the pathophysiology of migraine. We aimed to identify atypical FC between the periaqueductal gray (PAG) and other brain areas in rats induced by repeated meningeal nociception. The rat model was established by infusing an inflammatory soup (IS) through supradural catheters in conscious rats. Quiescent and face-grooming behaviors were observed to assess nociceptive behavior. FC analysis seeded on the PAG was performed on rats 21 days after IS infusion. The rats exhibited nociceptive behavior correlates of human behaviors associated with migraine after IS infusion. The PAG showed increased FC with the prefrontal cortex, cingulate gyrus, and motor cortex but decreased FC with the basal ganglia, dorsal lateral thalamus, internal capsule and prelimbic cortex in the rat model. The atypical FC of the PAG with brain regions in the rat model that are involved in nociception, somatosensory processing, emotional processing, and pain modulation are consistent with the clinical data from migraineurs, indicate that resting-state FC changes in migraine patients may be a consequence of headache attacks, and further validate this rat model of chronic migraine.