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Background: Central sensitization is an important pathophysiological mechanism of chronic migraine (CM), and microglia activation in trigeminocervical complex (TCC) contributes to the development of central sensitization. Emerging evidence implicates that blocking sphingosine-1-phosphate receptor 1 (S1PR1) can relieve the development of chronic pain and inhibit the activation of microglia. However, it is unclear whether S1PR1 is involved in the central sensitization of CM. Therefore, the purpose of this study is to explore the role of S1PR1 and its downstream signal transducers and activators of transcription 3 (STAT3) signaling pathway in the CM, mainly in inflammation. Methods: Chronic intermittent intraperitoneal injection of nitroglycerin (NTG) established a mouse model of CM. First, we observed the changes and subcellular localization of S1PR1 in the trigeminocervical complex (TCC). Then, W146, a S1PR1 antagonist; SEW2871, a S1PR1 agonist; AG490, a STAT3 inhibitor were applied by intraperitoneal injection to investigate the related molecular mechanism. The changes in the number of microglia and the expression of calcitonin gene-related peptide (CGRP) and c-fos in the TCC site were explored by immunofluorescence. In addition, we studied the effect of S1PR1 inhibitors on STAT3 in lipopolysaccharide-treated BV-2 microglia. Results: Our results showed that the expression of S1PR1 was increased after NTG injection and S1PR1 was colocalized with in neurons and glial cells in the TCC. The S1PR1 antagonist W146 alleviated NTG-induced hyperalgesia and suppressed the upregulation of CGRP, c-fos and pSTAT3 in the TCC. Importantly, blocking S1PR1 reduced activation of microglia. In addition, we found that inhibiting STAT3 signal also attenuated NTG-induced basal mechanical and thermal hyperalgesia. Conclusions: Our results indicate that inhibiting S1PR1 signal could alleviate central sensitization and inhibit microglia activity caused by chronic NTG administration via STAT3 signal pathway, which provide a new clue for the clinical treatment of CM. [ABSTRACT FROM AUTHOR]

It is well‐known that topiramate as a kind of antiepileptic drug has been proved effective for migraine prevention in North America and Europe. However, topiramate is still viewed as an off‐label medication for migraine treatment in China, partly because of the limited evidence in Chinese patients. We summarize the effects of topiramate on the frequency, severity, quality‐of‐life, and adverse event among migraine patients, including children and adolescent in this review, so as to provide reference for Chinese doctors. [ABSTRACT FROM AUTHOR]

Background: Central sensitization is an important pathophysiological mechanism of chronic migraine (CM). According to our previous studies, microglial activation and subsequent inflammation in the trigeminal nucleus caudalis (TNC) contribute to the central sensitization. The P2X7 receptor (P2X7R) is a purinergic receptor expressed in microglia and participates in central sensitization in chronic pain, but its role in CM is unclear. Numerous studies have shown that P2X7R regulates the level of autophagy and that autophagy affects the microglial activation and inflammation. Recently, autophagy has been shown to be involved in neuropathic pain, but there is no information about autophagy in CM. Therefore, the current study investigated the role of P2X7R in CM and its underlying mechanism, focusing on autophagy regulation.Methods: The CM model was established by repeated intraperitoneal injection of nitroglycerin (NTG) in mice. A Von Frey filament and radiant heat were used to assess the mechanical and thermal hypersensitivity. Western blotting and immunofluorescence assays were performed to detect the expression of P2X7R, autophagy-related proteins, and the cellular localization of P2X7R. To determine the role of P2X7R and autophagy in CM, we detected the effects of the autophagy inducer, rapamycin (RAPA) and P2X7R antagonist, Brilliant Blue G (BBG), on pain behavior and the expression of calcitonin gene-related peptide (CGRP) and c-fos. In addition, the effect of RAPA and BBG on microglial activation and subsequent inflammation were investigated.Results: The expression of P2X7R was increased and was mainly colocalized with microglia in the TNC following recurrent NTG administration. The autophagic flux was blocked in CM, which was characterized by upregulated LC3-II, and accumulated autophagy substrate protein, p62. RAPA significantly improved the basal rather than acute hyperalgesia. BBG alleviated both basal and acute hyperalgesia. BBG activated the level of autophagic flux. RAPA and BBG inhibited the activation of microglia, limited the inflammatory response, and reduced the expression of CGRP and c-fos.Conclusions: Our results demonstrate the dysfunction of the autophagic process in CM. Activated autophagy may have a preventive effect on migraine chronification. P2X7R contributes to central sensitization through mediating autophagy regulation and might become a potential target for CM. [ABSTRACT FROM AUTHOR]

Previous studies have shown that vestibular migraine (VM) is a cerebral disease with recurrent vertigo. Vestibular rehabilitation (VR) is an effective type of physical therapy for minimizing vestibular symptoms, as it improves vestibular compensation in patients with VM. Currently, the cerebral regions that are associated with the pathogenesis of VM are largely unknown. To further understand the underlying mechanisms of VM, we performed resting-state functional magnetic resonance imaging (fMRI) before and after 1 month of VR in 14 patients with VM. The Dizziness Handicap Inventory (DHI), the 36-Item Short-Form Health Survey (SF-36), the Hamilton Depression Scale (HAMD) and the Hamilton Anxiety Scale (HAMA) scores were included as clinical outcomes. The amplitude of low-frequency fluctuation (ALFF) was assessed to characterize spontaneous brain activity. The correlations between the clinical characteristics and ALFF values were assessed. After 1 month of VR training, the DHI scores in patients with VM were significantly lower than those at baseline (p = 0.03), as were the HAMA scores (p = 0.02). We also found that the ALFF values in the left posterior cerebellum of VM patients increased significantly after 1 month of VR training. Moreover, the ALFF values in the left cerebellum were inversely correlated with the patients' DHI scores. Overall, this study showed that VR exercise for 1 month has a positive effect on vestibular symptoms in patients with VM. Asymmetric cerebellar hyperactivity might be a functional compensation for vestibular dysfunction in patients with VM. [ABSTRACT FROM AUTHOR]

Background: Vestibular migraine has recently been recognized as a novel subtype of migraine. However, the mechanism that relate vestibular symptoms to migraine had not been well elucidated. Thus, the present study investigated vestibular dysfunction in a rat model of chronic migraine (CM), and to dissect potential mechanisms between migraine and vertigo. Methods: Rats subjected to recurrent intermittent administration of nitroglycerin (NTG) were used as the CM model. Migraine- and vestibular-related behaviors were analyzed. Immunofluorescent analyses and quantitative real-time polymerase chain reaction were employed to detect expressions of c-fos and calcitonin gene-related peptide (CGRP) in the trigeminal nucleus caudalis (TNC) and vestibular nucleus (VN). Morphological changes of vestibular afferent terminals was determined under transmission electron microscopy. FluoroGold (FG) and CTB-555 were selected as retrograde tracers and injected into the VN and TNC, respectively. Lentiviral vectors comprising CGRP short hairpin RNA (LV-CGRP) was injected into the trigeminal ganglion. Results: CM led to persistent thermal hyperalgesia, spontaneous facial pain, and prominent vestibular dysfunction, accompanied by the upregulation of c-fos labeling neurons and CGRP immunoreactivity in the TNC (c-fos: vehicle vs. CM = 2.9 ± 0.6 vs. 45.5 ± 3.4; CGRP OD: vehicle vs. CM = 0.1 ± 0.0 vs. 0.2 ± 0.0) and VN (c-fos: vehicle vs. CM = 2.3 ± 0.8 vs. 54.0 ± 2.1; CGRP mRNA: vehicle vs. CM = 1.0 ± 0.1 vs. 2.4 ± 0.1). Furthermore, FG-positive neurons was accumulated in the superficial layer of the TNC, and the number of c-fos+/FG+ neurons were significantly increased in rats with CM compared to the vehicle group (vehicle vs. CM = 25.3 ± 2.2 vs. 83.9 ± 3.0). Meanwhile, CTB-555+ neurons dispersed throughout the VN. The structure of vestibular afferent terminals was less pronounced after CM compared with the peripheral vestibular dysfunction model. In vivo knockdown of CGRP in the trigeminal ganglion significantly reduced the number of c-fos labeling neurons (LV-CGRP vs. LV-NC = 9.9 ± 3.0 vs. 60.0 ± 4.5) and CGRP mRNA (LV-CGRP vs. LV-NC = 1.0 ± 0.1 vs. 2.1 ± 0.2) in the VN, further attenuating vestibular dysfunction after CM. Conclusions: These data demonstrates the possibility of sensitization of vestibular nucleus neurons to impair vestibular function after CM, and anti-CGRP treatment to restore vestibular dysfunction in patients with CM. [ABSTRACT FROM AUTHOR]

Objective: This study aims to investigate the factors affecting the efficacy of first oral prophylaxis in patients with chronic migraine (CM) and to assess patient compliance with their medication regimens. Method: To identify the therapeutic effect of prevention medication in 740 patients with newly diagnosed CM that did not receive any preventive treatments after 4 weeks in an open-label prospective study with retrospective baseline from January 2016 to January 2018, the factors that may affect the outcomes of preventive treatment were analyzed based on the demographic characteristics, migraine characteristics, family history of headache, and history of medication overuse. Moreover, the patients were followed up to evaluate their compliance with and the side effects of the medication at 4 weeks and at 12 weeks. Results: After 4 weeks of prophylaxis, 94.3% (n = 698) of the patients persisted with taking the medicine. The treatment was effective for 61.7% of CM patients (n = 431) and ineffective for 38.3% (n = 267). The results showed that the effectiveness of the preventive treatment was related to the number of headaches per month, and the effect was better for patients with headaches for 15–20 days/month than for those with headaches for 26–30 days/month (OR = 2.78, 95% CI: 1.26–5.75, P = 0.006). After 12 weeks of treatment, only 34.5% (n = 255) of the patients persisted with taking the medicine. The most common reason for non-compliance in CM patients is appointment difficulty in a headache clinic (31.8%). Conclusion: The effect of CM prophylaxis was related to the frequency of headache. Only 34.5% of the patients continued to take medicine after 12 weeks of treatment, suggesting that patient compliance needs to be enhanced in the prophylaxis of CM. For the Chinese headache society, the best way to increase patient compliance should be treatment at dedicated headache centers and timely visits to headache specialists. [ABSTRACT FROM AUTHOR]

Objective: This study is aimed to access the efficacy and safety of combination therapy of flunarizine plus transcutaneous supraorbital neurostimulation (tSNS) compared with either flunarizine or tSNS alone for migraine prophylaxis. Methods: Patients with episodic migraine were enrolled and randomized into 3 groups. Flunarizine 5 mg per day, or tSNS for 20 minutes daily or combination of both were prescribed consecutively for 3 months. The primary outcome measures were changes in migraine days and 50% responder rate of monthly migraine days. Secondary outcome measures were the changes in migraine intensity and intake of rescue medication. Finally, satisfaction to treatment and adverse effect were evaluated as well. Results: A total of 154 were randomized and included in the analysis. After 3 months, the monthly migraine days were decreased in 3 groups and more significant in the combination group. The 50% responder rate was significantly higher (78.43%) in the combination therapy than monotherapy of flunarizine (46.15%) or tSNS (39.22%) alone. Greater reduction of migraine intensity and intake of rescue medication was observed in combination group. There was no difference of adverse events between flunarizine group and combination group (P = .89). Conclusion: Adding tSNS to flunarizine can improve the therapeutic efficacy of migraine prophylaxis without increasing the adverse effects. In addition, tSNS is effective and safe for migraine treatment and can be a valid option for migraineurs who are reluctant to take oral medications or for patients who experience a low‐migraine frequency and/or intensity that prophylactic therapy is not indicated but desire to acquire medical intervention. [ABSTRACT FROM AUTHOR]

Background: Dizziness and vertigo are frequent complaints of outpatients in the neurological department. Our objective was to explore the epidemiological category and clinical features of patients with dizziness or vertigo in the neurological outpatient department of a tertiary hospital. Methods: We consecutively recruited all patients with dizziness and/or vertigo visiting the neurological outpatient clinic of the First Affiliated Hospital of Chongqing Medical University from January 2016 to June 2017. All patients were interviewed by 4 neurologists and they completed self-administered questionnaires. General physical and standardized neuro-otology bedside examinations were performed in all participants. Instrumental examinations and other related examinations were prescribed as needed. Results: A total of 392 patients, 272 female and 120 male, were enrolled and the ratio of males to females was 1: 2.27. The mean age was 52.39 ± 13.87 years (range 11–90). Elderly patients (≥60 years) accounted for about one-third of the patients. Peripheral vestibular disorders accounted for 54.6% of patients, central vestibular disorders (including vestibular migraine [VM]) accounted for 22.4% of patients, psychogenic vertigo in 64 (16.3%), other reasons in 9 (2.3%) and unknown in 17 (4.3%). Benign paroxysmal positional vertigo (BPPV; 30.8%), psychiatric dizziness (20.5%), and VM (14.4%) were the 3 major vestibular diseases in patients under 60 years of age; however, BPPV (27.9%), central vertigo (21.7%), and Meniere’s disease (11.7%) were more common in patients over 60 years of age. Conclusions: This study provided a classification and clinical features of vestibular disorders in a neurological outpatient department of a tertiary hospital in China. The spectrum of vertigo or dizziness is different between different age groups and clinicians should pay attention to this difference in clinical reasoning. [ABSTRACT FROM AUTHOR]

Background: Chronic headache (CrH) occurs commonly in the population, and chronic migraine (CM) accounts for much of the CrH. Diagnostic criteria for CM remain controversial, and this could lead to undertreatment of CM. The purpose of this study was to analyze the clinical profiles of CM and to field test the International Classification of Headache Disorders-3β criteria (ICHD-3β) and Expert Opinion criteria (EO) for CM application. Methods: We retrospectively reviewed the medical records of CrH patients in our headache clinic during the period. Eligible patients were selected from CrH population based on Silberstein and Lipton criteria (S-L) for CM, and meanwhile fulfilled with migraine days at least 8 days/month. Then we evaluated the characteristics of clinic profiles and outcomes between patients diagnosed CM using ICHD-3β and EO criteria. Field tested the CM criteria Of ICHD-3β and EO. Results: In a total of 710 CrH patients , 261 (36.8 %) were recruited with CM based on both S-L criteria and fulfilled at least 8 migraine days/month. Be understandable, all the 261 patients met the EO criteria, and only 185 (70.9 %) met ICHD-3β for CM. For the 76 patients who met EO but not ICHD-3β, 70 had atypical migraine attacks (probable migraine, PM), and another 6 had typical migraine attacks but less than a total history of 5 attacks. Although 173 (66.3 %) were concurrent with medication overuse, just one patient overused triptans and none used ergot agents. Clinical features were not significantly different between the ICHD-3β and EO criteria groups ( P > 0.05), and neither were outcomes of prophylaxis ( P = 0.966). Total migraine prophylaxis effectiveness was 73 %. Conclusion: Migraine-specific analgesics are rarely used in China, permitting patients with PM to avail themselves of 'migraine days' is a reasonable accommodation for this difficult condition. In our hands, use of the new EO criteria for diagnosis of CM increases the sensitivity and maintains the specificity of decision making, and therefore should be adopted in CM management practice. [ABSTRACT FROM AUTHOR]

Objectives: This study explored the clinical characteristics of vestibular migraine in Chinese subjects and performed a field test of the criteria of the International Classification of Headache Disorders 3rd edition beta version.Methods: Consecutive patients with vestibular migraine were surveyed and registered in a headache clinic during the study period. The diagnosis of vestibular migraine was made according to International Classification of Headache Disorders 3rd edition beta version. Assessments included standardized neuro-otology bedside examination, pure-tone audiogram, bithermal caloric testing, neurological imaging, cervical X-ray or magnetic resonance imaging, Doppler ultrasound of cerebral arteries and laboratory tests.Results: A total of 67 patients (62 female/five male, 47.8 ± 10.3 years old) were enrolled in this study. The mean ages of migraine and vertigo onset were 32.2 ± 11.5 and 37.9 ± 10.1 years, respectively. The most common migraine subtype was migraine without aura (79%), followed by migraine with aura (12%) and chronic migraine (9%). The duration of vertigo attacks varied from seconds to days and 25% of patients had attacks that lasted less than 5 minutes. Among the patients with short-lasting attacks, 75% of these patients had ≥5 attacks per day within 72 hours. Auditory symptoms were reported in 36% of the patients. Migraine prophylactic treatments were effective in 77% of the patients.Conclusions: Our study showed that the clinical features of vestibular migraine in China were similar to those of Western studies. The definition of vertigo episodes and migraine subtypes of vestibular migraine in International Classification of Headache Disorders 3rd edition beta version might be modified further. More than five vertigo attacks per day within 72 hours might be helpful as far as identifying vestibular migraine patients with short-lasting attacks. [ABSTRACT FROM AUTHOR]

Background: Microglial activation contributes to the development of chronic migraine (CM). The P2Y12 receptor (P2Y12R), a metabolic purinoceptor that is expressed on microglia in the central nervous system (CNS), has been indicated to play a critical role in the pathogenesis of chronic pain. However, whether it contributes to the mechanism of CM remains unknown. Thus, the present study investigated the precise details of microglial P2Y12R involvement in CM.Methods: Mice subjected to recurrent nitroglycerin (NTG) treatment were used as the CM model. Hyperalgesia were assessed by mechanical withdrawal threshold to electronic von Frey and thermal withdrawal latency to radiant heat. Western blot and immunohistochemical analyses were employed to detect the expression of P2Y12R, Iba-1, RhoA, and ROCK2 in the trigeminal nucleus caudalis (TNC). To confirm the role of P2Y12R and RhoA/ROCK in CM, we systemically administered P2Y12R antagonists (MRS2395 and clopidogrel) and a ROCK2 inhibitor (fasudil) and investigated their effects on microglial activation, c-fos, and calcitonin gene-related peptide (CGRP) expression in the TNC. To further confirm the effect of P2Y12R on microglial activation, we preincubated lipopolysaccharide (LPS)-treated BV-2 microglia with MRS2395 and clopidogrel. ELISA was used to evaluate the levels of inflammatory cytokines.Results: The protein levels of P2Y12R, GTP-RhoA, ROCK2, CGRP, c-fos, and inducible nitric oxide synthase (iNOS) in the TNC were increased after recurrent NTG injection. A double labeling study showed that P2Y12R was restricted to microglia in the TNC. MRS2395 and clopidogrel attenuated the development of tactile allodynia and suppressed the expression of CGRP, c-fos, and GTP-RhoA/ROCK2 in the TNC. Furthermore, fasudil also prevented hyperalgesia and suppressed the expression of CGRP in the TNC. In addition, inhibiting P2Y12R and ROCK2 activities suppressed NTG-induced microglial morphological changes (process retraction) and iNOS production in the TNC. In vitro, a double labeling study showed that P2Y12R was colocalized with BV-2 cells, and the levels of iNOS, IL-1β, and TNF-α in LPS-stimulated BV-2 microglia were reduced by P2Y12R inhibitors.Conclusions: These data demonstrate that microglial P2Y12R in the TNC plays a critical role in the pathogenesis of CM by regulating microglial activation in the TNC via RhoA/ROCK pathway. [ABSTRACT FROM AUTHOR]

Background: Central sensitization is an important mechanism of chronic migraine (CM) and is related to the inflammatory response of microglia. The NOD-like receptor protein 3 (NLRP3) inflammasome may regulate the inflammatory process of microglia in several neurological diseases, but its role in CM is largely unknown. Therefore, the aim of this study was to identify the precise role of microglial NLRP3 in CM.Methods: An experimental CM mouse model was established by repeated intraperitoneal (i.p) injection with nitroglycerin (NTG). We evaluated the expression levels of NLRP3 and its downstream interleukin (IL)-1β protein in the trigeminal nucleus caudalis (TNC; which is a central area relevant to migraine pain) at different time points. To further examine the effects of the NLRP3 inflammasome pathway on central sensitization of CM, we examined MCC950, an NLRP3 inflammasome-specific inhibitor, and IL-1ra, an IL-1β antagonist, whether altered NTG-induced mechanical hyperalgesia of the periorbital area and hind paw. The effect of MCC950 and IL-1ra on c-Fos, phosphorylated extracellular signal-regulated kinase (p-ERK) and calcitonin gene-related peptide (CGRP) expression in the TNC were also analyzed. The cell localization of NLRP3 and IL-1β in the TNC was evaluated by immunofluorescence staining.Results: Repeated NTG administration induced acute and chronic mechanical hyperalgesia and increased expression of NLRP3 and IL-1β. Blockade of NLRP3 or IL-1β reduced NTG-induced hyperalgesia, and this effect was accompanied by a significant inhibition of the NTG-induced increase in p-ERK, c-Fos and CGRP levels in the TNC. Immunofluorescence staining revealed that NLRP3 and IL-1β were mainly expressed in microglia in the TNC, and the IL-1β receptor, IL-1R, was mainly expressed in neurons in the TNC.Conclusions: These results indicate that NLRP3 activation in the TNC participates in the microglial-neuronal signal by mediating the inflammatory response. This process contributes to the central sensitization observed in CM. [ABSTRACT FROM AUTHOR]

Migraines are a considerable social problem and economic burden worldwide. Current acute treatments are based on inhibiting meningeal neurogenic inflammation which has poor results in some patients, whereas the site of action of prophylactic medicines are unknown; therefore, exploring new treatment mechanisms and methods is increasingly needed. Recent evidence suggests that microglia and microglia-mediated neuroinflammation are important in migraine pathogenesis. In the cortical spreading depression (CSD) migraine model, microglia were activated after multiple CSD stimulations, suggesting that microglial activation may be associated with recurrent attacks of migraine with aura. In the nitroglycerin-induced chronic migraine model, the microglial response to extracellular stimuli leads to the activation of surface purine receptors P2X4、P2X7、P2Y12, which mediate signal transduction through intracellular signalling cascades, such as the BDNF/TrkB, NLRP3/IL-1β and RhoA/ROCK signalling pathways, and release inflammatory mediators and cytokines that enhance pain by increasing the excitability of nearby neurons. Inhibition of the expression or function of these microglial receptors and pathways inhibits the abnormal excitability of TNC (trigeminal nucleus caudalis) neurons and intracranial as well as extracranial hyperalgesia in migraine animal models. These findings suggest that microglia may be central in migraine recurrent attacks and a potential target for the treatment of chronic headaches. • Repeated stimulation from cortical spreading depression leads to the cortical microglia activation, which is related to migraine auras. • Microglia activation in the caudal trigeminal spinal nucleus is involved in the central sensitization process associated with migraine, which is an important cause of chronic migraine. • Microglia are the core cells involved in recurrent and chronic migraine and may be a potential target for the treatment of chronic headaches. [ABSTRACT FROM AUTHOR]