Abnormal Thalamo-Cortical Interactions in Overlapping Communities of Migraine: An Edge Functional Connectivity Study.

OBJECTIVE: Migraine has been demonstrated to exhibit abnormal functional connectivity of large-scale brain networks, which is closely associated with its pathophysiology and has not yet been explored by edge functional connectivity. We used an edge-centric approach combined with motif analysis to evaluate higher-order communication patterns of brain networks in migraine. METHODS: We investigated edge-centric metrics in 108 interictal migraine patients and 71 healthy controls. We parcellated the brain into networks using independent component analysis. We applied edge graph construction, k-means clustering, community overlap detection, graph-theory-based evaluations, and clinical correlation analysis. We conducted motif analysis to explore the interactions among regions, and a classification model to test the specificity of edge-centric results. RESULTS: The normalized entropy of lateral thalamus was significantly increased in migraine, which was positively correlated with the baseline headache duration, and negatively correlated with headache duration reduction following preventive medications at 3-month follow-up. Network-wise entropy of the sensorimotor network was significantly elevated in migraine. The community similarity between lateral thalamus and postcentral gyrus was enhanced in migraine. Migraine patients showed overrepresented L-shape and diverse motifs, and underrepresented forked motifs with lateral thalamus serving as the reference node. Furthermore, migraine patients presented with overrepresented L-shape triads, where the postcentral gyrus shared different edges with the lateral thalamus. The classification model showed that entropy of the lateral thalamus had the highest discriminative power, with an area under the curve of 0.86. INTERPRETATION: Our findings indicated an abnormal higher-order thalamo-cortical communication pattern in migraine patients. The thalamo-cortical-somatosensory disturbance of concerted working may potentially lead to aberrant information flow and deficit pain processing of migraine. ANN NEUROL 2023;94:1168-1181.

Profile of Chinese Cluster Headache Register Individual Study (CHRIS): Clinical characteristics, diagnosis and treatment status data of 816 patients in China.

BACKGROUND: The clinical profile of cluster headache may differ among different regions of the world, warranting interest in the data obtained from the initial Chinese Cluster Headache Register Individual Study (CHRIS) for better understanding. METHODS: We conducted a multicenter, prospective, longitudinal cohort study on cluster headache across all 31 provinces of China, aiming to gather clinical characteristics, treatment approaches, imaging, electrophysiological and biological samples. RESULTS: In total 816 patients were enrolled with a male-to-female ratio of 4.33:1. The mean age at consultation was 34.98 ± 9.91 years, and 24.89 ± 9.77 years at onset. Only 2.33% were diagnosed with chronic cluster headache, and 6.99% had a family history of the condition. The most common bout was one to two times per year (45.96%), lasting two weeks to one month (44.00%), and occurring frequently in spring (76.23%) and winter (73.04%). Of these, 68.50% experienced one to two attacks per day, with the majority lasting one to two hours (45.59%). The most common time for attacks was between 9 am and 12 pm (75.86%), followed by 1 am and 3 am (43.48%). Lacrimation (78.80%) was the most predominant autonomic symptom reported. Furthermore, 39.22% of patients experienced a delay of 10 years or more in receiving a correct diagnosis. Only 35.67% and 24.26% of patients received common acute and preventive treatments, respectively. CONCLUSION: Due to differences in ethnicity, genetics and lifestyle conditions, CHRIS has provided valuable baseline data from China. By establishing a dynamic cohort with comprehensive multidimensional data, it aims to advance the management system for cluster headache in China.

Adult-onset combined oxidative phosphorylation deficiency type 14 manifests as epileptic status: a new phenotype and literature review.

BACKGROUND: Combined oxidative phosphorylation deficiency (COXPD) is a severe disorder with early onset and autosomal recessive inheritance, and has been divided into 51 types (COXPD1-COXPD51). COXPD14 is caused by a mutation in the FARS2 gene, which encodes mitochondrial phenylalanyl-tRNA synthetase (mt-PheRS), an enzyme that transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, an increasing number of FARS2 variations have been subsequently identified, which present three main phenotypic manifestations: early onset epileptic encephalopathy, hereditary spastic paraplegia, and juvenile-onset epilepsy. To our knowledge, no adult cases have been reported in the literature. METHODS: We report in detail a case of genetically confirmed COXPD14 and review the relevant literature. RESULTS: Approximately 58 subjects with disease-causing variants of FARS2 have been reported, including 31 cases of early onset epileptic encephalopathy, 16 cases of hereditary spastic paraplegia, 3 cases of juvenile-onset epilepsy, and 8 cases of unknown phenotype. We report a case of autosomal recessive COXPD14 in an adult with status epilepticus as the only manifestation with a good prognosis, which is different from that in neonatal or infant patients reported in the literature. c.467C > T (p.T156M) has been previously reported, while c.119_120del (p.E40Vfs*87) is novel, and, both mutations are pathogenic. CONCLUSIONS: This case of autosomal recessive COXPD14 in an adult only presented as status epilepticus, which is different from the patients reported previously. Our study expands the mutation spectrum of FARS2, and we tended to define the phenotypes based on the clinical manifestation rather than the age of onset.

Effect of erenumab on the reversion from chronic migraine to episodic migraine in an Asian population: A post hoc analysis of the DRAGON study.

BACKGROUND: Erenumab is a fully human monoclonal antibody that selectively targets the calcitonin gene-related peptide receptor. It has been proven to be safe and efficacious in patients with episodic migraine (EM) and chronic migraine (CM) as demonstrated in phase 2 and 3 clinical trials including patients from Europe, Japan, and the United States. Reversion from CM to EM, as indicated by a reduction in the frequency of headache days, is an important indicator for efficacy outcome, though it has not been analyzed widely in patients with CM to date. OBJECTIVE: Primary results of the DRAGON study demonstrated the efficacy and safety of erenumab in patients with CM from China and other Asian countries. This post hoc analysis evaluated the rate of reversion from CM to EM in the overall population and in subgroups of patients defined by baseline demographic and clinical characteristics (age, body mass index, gender, prior preventive treatment failure, medication overuse status, and disease duration). METHODS: Reversion from CM to EM was defined as a reduction in headache frequency to < 45 headache days over the 12 weeks of the double-blind treatment period. In addition, migraine-related disability and disease impact on functional impairment were assessed within each treatment group in reverters and non-reverters using the Headache Impact Test-6 (HIT-6), Migraine Physical Function Impact Diary (MPFID), and modified Migraine Disability Assessment (mMIDAS). RESULTS: Overall, 557 patients with CM were randomized to monthly erenumab 70 mg (n = 279) or placebo (n = 278), of whom 52.3% (146 of 279) treated with erenumab reverted from CM to EM compared to 41.0% (114 of 278) in the placebo group (odds ratio [OR] 1.59, 95% confidence interval: 1.1-2.2; p = 0.007). Treatment with erenumab resulted in a greater mean change (standard error) from baseline in the HIT-6 total score for reverters versus non-reverters compared to placebo (erenumab: -9.5 [0.6] vs. -5.1 [0.5]; placebo: -8.9 [0.7] vs. -4.9 [0.5]). A similar pattern was observed for mMIDAS score in erenumab treatment groups versus placebo (erenumab: -22.1 [1.2] vs. -6.3 [1.8]; placebo: -19.9 [1.3] vs. -7.9 [1.6]). Substantial improvements were reported in MPFID-Physical Impairment (PI) and Everyday Activities (EA) scores in reverters versus non-reverters in erenumab treatment groups (MPFID-PI: -5.9 [0.3] vs. -1.9 [0.6]; MPFID-EA: -7.9 [0.4] vs. -3.4 [0.6]) and in placebo (MPFID-PI: -5.4 [0.4] vs. -1.0 [0.5]; MPFID-EA: -7.1 [0.5] vs. -3.2 [0.5]). CONCLUSIONS: This analysis demonstrated that a greater proportion of patients treated with erenumab reverted from CM to EM compared to patients treated with placebo. The reversion from CM to EM was reflected by the greater improvements in patient-reported outcomes in the erenumab group.

Delayed epistaxis after endoscopic transnasal pituitary tumor resection: clinical characteristics, risk factors, treatment and prevention.

BACKGROUND: Delayed epistaxis after endoscopic transnasal pituitary tumor resection (ETPTR) is a critical complication, tending to cause aspiration or hemorrhagic shock. This study assessed clinical characteristics, risk factors, and provide treatment and prevention advice of this complication. METHODS: This was a retrospective monocentric analysis of 862 patients who underwent ETPTR. Statistical analyses of clinical data revealed the incidence, sources and onset time of delayed epistaxis. Univariate analysis and binary logistic regression were used to identify risk factors. RESULTS: The incidence of delayed epistaxis was 2.78% (24/862), with an average onset time of 20.71 ± 7.39 days. The bleeding sources were: posterior nasal septal artery branch of sphenopalatine artery (12/24), multiple inflammatory mucosae (8/24), sphenopalatine artery trunk (3/24) and sphenoid sinus bone (1/24). Univariate analysis and binary logistic regression analysis confirmed that hypertension, nasal septum deviation, chronic rhinosinusitis and growth hormone pituitary tumor subtype were independent risk factors for delayed epistaxis. Sex, age, history of diabetes, tumor size, tumor invasion and operation time were not associated with delayed epistaxis. All patients with delayed epistaxis were successfully managed through endoscopic transnasal hemostasis without recurrence. CONCLUSIONS: Delayed epistaxis after ETPTR tends to have specific onset periods and risk factors. Prevention of these characteristics may reduce the occurrence of delayed epistaxis. Endoscopic transnasal hemostasis is recommended as the preferred treatment for delayed epistaxis.

Migraine-like headache in subjects with isolated Lambl's excrescences: a case series and literature review.

AIM: Lambl's excrescences are mobile, thin, fibrinous connective tissue strands typically found on left-sided cardiac values. Migraine is positively associated with structural cardiac anomalies. However, it remains unclear whether Lambl's excrescences are associated with migraine. METHODS: Retrospective review of 182 inpatients with Lambl's excrescences confirmed by transesophageal echocardiogram in Chinese PLA General Hospital since January 2010. Among them, those with isolated Lambl's excrescences presented with migraine-like headache were included. We collected information on the demographics and clinical profiles of all participants, and performed follow-up visits. RESULTS: A total of 8 patients presented with migraine-like headache among 15 patients with isolated Lambl's excrescences. They included 2 men and 6 women, with an average age of 44.63 ± 12.24 years. Among these patients, 3 had visual aura, and 6 manifested infarct-like lesions on magnetic resonance imaging, of which 2 developed lesions after first visit. During follow-up, 4 patients suffering from intervention for Lambl's excrescences dramatically reduced headache recurrence compared to the other 4 patients only receiving migraine preventive medications. CONCLUSIONS: This study supports the hypothesis that microemboli from isolated Lambl's excrescences could cause migraine-like headache. And intervention for Lambl's excrescences may be crucial for preventing headache recurrence.

This study supports the hypothesis that microemboli from isolated Lambl's excrescences could cause migraine-like headache.The small sample size study fails to make management recommendations.

Alleviation of migraine related pain and anxiety by inhibiting calcium-stimulating AC1-dependent CGRP in the insula of adult rats.

BACKGROUND: Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood. METHODS: The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats. RESULTS: The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application. CONCLUSIONS: Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.

The crucial role of locus coeruleus noradrenergic neurons in the interaction between acute sleep disturbance and headache.

BACKGROUND: Both epidemiological and clinical studies have indicated that headache and sleep disturbances share a complex relationship. Although headache and sleep share common neurophysiological and anatomical foundations, the mechanism underlying their interaction remains poorly understood. The structures of the diencephalon and brainstem, particularly the locus coeruleus (LC), are the primary sites where the sleep and headache pathways intersect. To better understand the intricate nature of the relationship between headache and sleep, our study focused on investigating the role and function of noradrenergic neurons in the LC during acute headache and acute sleep disturbance. METHOD: To explore the relationship between acute headache and acute sleep disturbance, we primarily employed nitroglycerin (NTG)-induced migraine-like headache and acute sleep deprivation (ASD) models. Initially, we conducted experiments to confirm that ASD enhances headache and that acute headache can lead to acute sleep disturbance. Subsequently, we examined the separate roles of the LC in sleep and headache. We observed the effects of drug-induced activation and inhibition and chemogenetic manipulation of LC noradrenergic neurons on ASD-induced headache facilitation and acute headache-related sleep disturbance. This approach enabled us to demonstrate the bidirectional function of LC noradrenergic neurons. RESULTS: Our findings indicate that ASD facilitated the development of NTG-induced migraine-like headache, while acute headache affected sleep quality. Furthermore, activating the LC reduced the headache threshold and increased sleep latency, whereas inhibiting the LC had the opposite effect. Additional investigations demonstrated that activating LC noradrenergic neurons further intensified pain facilitation from ASD, while inhibiting these neurons reduced this pain facilitation. Moreover, activating LC noradrenergic neurons exacerbated the impact of acute headache on sleep quality, while inhibiting them alleviated this influence. CONCLUSION: The LC serves as a significant anatomical and functional region in the interaction between acute sleep disturbance and acute headache. The involvement of LC noradrenergic neurons is pivotal in facilitating headache triggered by ASD and influencing the effects of headache on sleep quality.

Rimegepant orally disintegrating tablet 75 mg for acute treatment of migraine in adults from China: a subgroup analysis of a double-blind, randomized, placebo-controlled, phase 3 clinical trial.

BACKGROUND: Rimegepant orally disintegrating tablet (ODT), an oral small-molecule calcitonin gene-related peptide receptor antagonist, is indicated for acute and preventive treatment of migraine in the United States and other countries. Previously, a large clinical trial assessed the efficacy and safety of rimegepant ODT 75 mg for the acute treatment of migraine in adults living in China or South Korea. A post hoc subgroup analysis of this trial was performed to evaluate the efficacy and safety of rimegepant for acute treatment of migraine in adults living in China. METHODS: Eligible participants were ≥ 18 years of age and had a ≥ 1-year history of migraine, with 2 to 8 attacks of moderate or severe pain intensity per month and < 15 headache days per month during the 3 months before screening. Participants self-administered rimegepant ODT 75 mg or matching placebo to treat a single migraine attack of moderate or severe pain intensity. The co-primary endpoints were pain freedom and freedom from the most bothersome symptom (MBS) at 2 h post-dose. Key secondary endpoints included pain relief at 2 h post-dose, ability to function normally at 2 h post-dose, use of rescue medication within 24 h post-dose, and sustained pain freedom from 2 to 24 h and 2 to 48 h post-dose. All p values were nominal. Safety was assessed via treatment-emergent adverse events (TEAEs), electrocardiograms, vital signs, and routine laboratory tests. RESULTS: Overall, 1075 participants (rimegepant, n = 538; placebo, n = 537) were included in the subgroup analysis. Rimegepant was more effective than placebo for the co-primary endpoints of pain freedom (18.2% vs. 10.6%, p = 0.0004) and freedom from the MBS (48.0% vs. 31.8%, p <  0.0001), as well as all key secondary endpoints. The incidence of TEAEs was comparable between the rimegepant (15.2%) and placebo (16.4%) groups. No signal of drug-induced liver injury was observed, and no study drug-related serious TEAEs were reported in the rimegepant group. CONCLUSIONS: A single dose of rimegepant 75 mg rimegepant was effective for the acute treatment of migraine in adults living in China, with safety and tolerability similar to placebo. TRIAL REGISTRATION: Clinicaltrials.gov NCT04574362 Date registered: 2020-10-05.

Unveiling the therapeutic potential of Dl-3-n-butylphthalide in NTG-induced migraine mouse: activating the Nrf2 pathway to alleviate oxidative stress and neuroinflammation.

BACKGROUND: Migraine stands as a prevalent primary headache disorder, with prior research highlighting the significant involvement of oxidative stress and inflammatory pathways in its pathogenesis and chronicity. Existing evidence indicates the capacity of Dl-3-n-butylphthalide (NBP) to mitigate oxidative stress and inflammation, thereby conferring neuroprotective benefits in many central nervous system diseases. However, the specific therapeutic implications of NBP in the context of migraine remain to be elucidated. METHODS: We established a C57BL/6 mouse model of chronic migraine (CM) using recurrent intraperitoneal injections of nitroglycerin (NTG, 10 mg/kg), and prophylactic treatment was simulated by administering NBP (30 mg/kg, 60 mg/kg, 120 mg/kg) by gavage prior to each NTG injection. Mechanical threshold was assessed using von Frey fibers, and photophobia and anxious behaviours were assessed using a light/dark box and elevated plus maze. Expression of c-Fos, calcitonin gene-related peptide (CGRP), Nucleus factor erythroid 2-related factor 2 (Nrf2) and related pathway proteins in the spinal trigeminal nucleus caudalis (SP5C) were detected by Western blotting (WB) or immunofluorescence (IF). The expression of IL-1ß, IL-6, TNF-α, Superoxide dismutase (SOD) and malondialdehyde (MDA) in SP5C and CGRP in plasma were detected by ELISA. A reactive oxygen species (ROS) probe was used to detect the expression of ROS in the SP5C. RESULTS: At the end of the modelling period, chronic migraine mice showed significantly reduced mechanical nociceptive thresholds, as well as photophobic and anxious behaviours. Pretreatment with NBP attenuated nociceptive sensitization, photophobia, and anxiety in the model mice, reduced expression levels of c-Fos and CGRP in the SP5C and activated Nrf2 and its downstream proteins HO-1 and NQO-1. By measuring the associated cytokines, we also found that NBP reduced levels of oxidative stress and inflammation. Most importantly, the therapeutic effect of NBP was significantly reduced after the administration of ML385 to inhibit Nrf2. CONCLUSIONS: Our data suggest that NBP may alleviate migraine by activating the Nrf2 pathway to reduce oxidative stress and inflammation in migraine mouse models, confirming that it may be a potential drug for the treatment of migraine.

AMPK activation attenuates central sensitization in a recurrent nitroglycerin-induced chronic migraine mouse model by promoting microglial M2-type polarization.

BACKGROUND: Energy metabolism disorders and neurogenic inflammation play important roles in the central sensitization to chronic migraine (CM). AMP-activated protein kinase (AMPK) is an intracellular energy sensor, and its activation regulates inflammation and reduces neuropathic pain. However, studies on the involvement of AMPK in the regulation of CM are currently lacking. Therefore, this study aimed to explore the mechanism underlying the involvement of AMPK in the central sensitization to CM. METHODS: Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC). Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured. The expression of calcitonin gene-related peptide (CGRP) and cytokines, M1/M2 microglia, and NF-κB pathway activation were detected after the intervention. RESULTS: Repeated NTG injections resulted in a gradual decrease in AMPK protein expression, and the negative regulation of AMPK by increased ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression may counteract AMPK activation by increasing ADP/ATP. AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1ß, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10. Moreover, AMPK in TNC was mainly located in microglia. AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway. CONCLUSIONS: AMPK was involved in the central sensitization of CM, and the activation of AMPK reduced neuroinflammation in NTG-induced CM mice. AMPK may provide new insights into interventions for energy metabolism disorders and neurogenic inflammation in migraine.

The World Health Organization Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders and the headache revolution: from headache burden to a global action plan for headache disorders.

The World Health Organization (WHO) Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders was developed by WHO to address the worldwide challenges and gaps in provision of care and services for people with epilepsy and other neurological disorders and to ensure a comprehensive, coordinated response across sectors to the burden of neurologic diseases and to promote brain health across life-course. Headache disorders constitute the second most burdensome of all neurological diseases after stroke, but the first if young and midlife adults are taken into account. Despite the availability of a range of treatments, disability associated with headache disorders, and with migraine, remains very high. In addition, there are inequalities between high-income and low and middle income countries in access to medical care. In line with several brain health initiatives following the WHOiGAP resolution, herein we tailor the main pillars of the action plan to headache disorders: (1) raising policy prioritization and strengthen governance; (2) providing effective, timely and responsive diagnosis, treatment and care; (3) implementing strategies for promotion and prevention; (4) fostering research and innovation and strengthen information systems. Specific targets for future policy actions are proposed. The Global Action Plan triggered a revolution in neurology, not only by increasing public awareness of brain disorders and brain health but also by boosting the number of neurologists in training, raising research funding and making neurology a public health priority for policy makers. Reducing the burden of headache disorders will not only improve the quality of life and wellbeing of people with headache but also reduce the burden of neurological disorders increasing global brain health and, thus, global population health.

Acute sleep deprivation aggravates nitroglycerin-evoked hyperalgesia in mice.

Sleep deprivation can trigger migraine, and migraineurs often choose to sleep to relieve headaches during acute migraine. This study aimed to explore the effect of acute sleep deprivation on hyperalgesia induced by nitroglycerin in mice. In part one, after either 6-h sleep deprivation or 6-h normal sleep, mice were intraperitoneally injected with nitroglycerin or saline. The mechanical pain threshold and withdrawal latency of the hindpaw were measured every 30 min for 6 h. Next, the same sleep deprivation and injection procedure was performed with new mice, and mice were sacrificed 4.5 h after injection. The trigeminal nucleus caudalis and upper cervical spinal segments were taken for immunofluorescence Fos staining. In part two, after injection of saline or nitroglycerin, the mice were either deprived of sleep for 6 h or allowed to sleep without interference. The mechanical and thermal pain threshold were measured after 6 h. In part three, we compared the sleep time of mice after intraperitoneal injection of saline or nitroglycerin without interference. Sleep deprivation for 6 h did not cause any changes in the baseline pain thresholds in mice. However, pretreatment with 6-h sleep deprivation significantly prolonged the duration of hyperalgesia induced by nitroglycerin. Additionally, the expression of Fos at 4.5 h was significantly higher in the 6-h sleep deprivation and nitroglycerin group than in the other three groups. When intraperitoneal injection was given first, the mechanical pain threshold of the hind paw was significantly lower in the group that received nitroglycerin with 6-h sleep deprivation than in the other groups. Compared to the saline injection, one-time nitroglycerin injection would result in a significant increase in sleep latency and decrease in sleep duration for the normal mice. Acute sleep deprivation significantly aggravated the hyperalgesia induced by nitroglycerin in mice, which highlights the importance of sleep disorders for migraine.

Temporal alterations of pituitary adenylate cyclase activating polypeptide and its receptors in a rat model induced by recurrent chemical stimulations: Relevant to chronic migraine.

Background: Migraine is a common type of primary headache with disabling brain dysfunction. It has been found that pituitary adenylate cyclase activating polypeptide (PACAP) is involved in the pathogenesis of migraine, however, the role of PACAP and its receptors in chronic migraine remains unclear. Therefore, the present study aimed to explore the changes of PACAP and its receptors in different duration after recurrent dural inflammation soup stimulations and to investigate the co-expression between PACAP and calcitonin gene-related peptide (CGRP). Methods: Adult male rats were implanted with cannula surrounding superior sagittal sinus, which was followed by dural infusion of inflammatory soup (IS) or normal saline (NS). The rats were randomly divided into 4 groups (n = 8 for each group): IS stimulation for seven days (IS-7 group), IS stimulation for 14 days (IS-14 group), IS stimulation for 21 days (IS-21 group), and NS control for 21 days (CON group). The facial mechanical withdrawal threshold was daily measured during the whole experiment. The behavioral changes (ipsilateral and bilateral face grooming behavior) in a plastic cage of rats were observed and recorded. The expression of PACAP, its receptors (PAC1, VPAC1, VPAC2), and CGRP in the trigeminal ganglia (TG) and the trigeminal nucleus caudalis (TNC) was examined by immunohistochemistry. Immunofluorescence was used to explore the co-expression of PACAP, PAC1 receptor, and CGRP after repeated IS administration in the TG. Results: The ipsilateral facial grooming time of IS-21 group displayed an apparent increase than CON group after repeated stimulation on day 2, while significant differences were observed on day 14. No differences were found between the IS-21 and CON group in bilateral facial grooming. Dural IS stimulation induced a significantly decrease in facial mechanical withdrawal thresholds. PACAP positive cells in the regions of TNC were gradually decreased with the IS days increasing. PACAP and PAC1 receptor expression in the TG had a trend of increasing first and then decreasing. There was no significant difference in expression of VPAC1 and VPAC2 in the TG and the TNC. Immunofluorescence showed that PACAP was mainly expressed in TG neurons. PACAP and PAC1 receptor co-expression decreased gradually after repetitive IS stimulation. While the co-expression between PACAP and CGRP reached the peak in IS-7 group after repetitive IS stimulation, and then decreased. Conclusions: This study demonstrated that repetitive chemical stimulations induced a gradual decrease of PACAP in the TNC, while the PACAP and PAC1 receptor expression in TG showed dynamical changes of increasing first and then decreasing after repeated IS administration. These results suggested exhaustion of PACAP could be involved in the duration of chronic migraine and implied PACAP may contribute to the pathology of migraine through the PAC1 receptor, which was associated with CGRP.

The role of purity and frequency in the classification of perimenstrual headache.

BACKGROUND: Among all menstruation-associated headaches, only menstrual migraine has classification criteria in the International Classification of Headache Disorders 3rd edition (ICHD-3). Other menstruation-associated headaches are not generally described. The ICHD-3 classifies menstrual migraine according to headache type, timing(on days -2 to +3 of menstruation), frequency (whether headache occurs in at least two out of three menstrual cycles), and purity(whether headache occurs at other times of the menstrual cycle), and provides a reference for research on menstruation-associated headache. However, the role of frequency and purity in the classification of menstruation- associated headache is not clear Moreover, the potential risk factors for high-frequency and pure headaches have not been explored. METHODS: The study was a secondary analysis of an epidemiological survey on menstrual migraine among nurses. Among nurses who had a headache on days -2 to +3 of menstruation, headache frequency, purity, and type were described. High-frequency vs. low-frequency and pure vs. impure headache were compared according to headache features, demographics, occupation-related factors, menstruation-related factors, and lifestyle factors. RESULTS: Of all respondents, 254(18.3%) nurses who had headaches on days -2 to +3 of menstruation were included in the study. In the 254 nurses with perimenstrual headache, the proportions of migraine, tension type headache (TTH), high-frequency headache, and pure headache were 24.4%, 26.4%, 39.0%, and 42.1%, respectively. High-frequency and impure perimenstrual headache was more severe and similar to migraine. High-frequency headache was associated with more perimenstrual extremity swelling and generalized pain. Other variables were not significantly different between the groups. CONCLUSIONS: Headache except for menstrual migraine accounts for a certain proportion of menstruation-associated headache and should not be ignored in research. Headache frequency and purity are related to headache type and should be equally considered in the classification of menstruation- associated headache. Perimenstrual extremity swelling and generalized pain are potential indicators of high-frequency perimenstrual headache. TRIAL REGISTRATION: ChiCTR2200056429.

Efficacy and safety of eptinezumab in patients with chronic migraine and medication-overuse headache: a randomized, double-blind, placebo-controlled study.

BACKGROUND: For some people with migraine, despite taking greater amounts of acute headache medication (AHM), they develop an increase in monthly headache days. This cycle of increasing headache days, and in turn AHM use, can lead to a secondary headache disorder called medication-overuse headache (MOH). Preventive medications can prevent migraine from occurring and reduce reliance on AHMs, thereby preventing the cycle of MOH. This study was performed to evaluate the efficacy and safety of eptinezumab to prevent migraine/headache in a mainly Asian patient population with a dual diagnosis of chronic migraine and MOH. METHODS: SUNLIGHT was a phase 3, multicenter, double-blind, parallel-group, placebo-controlled trial. Patients aged 18-75 years with ≥ 8 migraine days/month and a diagnosis of MOH were randomly allocated (1:1) to one of two treatment groups: eptinezumab 100 mg or placebo. Monthly migraine days (MMDs) were captured using a daily electronic diary; the change from baseline in the number of MMDs over Weeks 1-12 was the primary efficacy endpoint. RESULTS: Patients were randomized to eptinezumab 100 mg (n = 93) or placebo (n = 100). Over Weeks 1-12, eptinezumab reduced mean MMDs more than placebo (difference between treatments was -1.2; p = 0.1484). Differences between treatment groups with p-values below 0.05 favoring eptinezumab were observed in 3 out of the 6 key secondary endpoints. CONCLUSION: All endpoints numerically favored eptinezumab treatment when compared to placebo; however, this study did not meet its primary endpoint and is therefore negative. No new safety signals were identified in this study, like previous reports that confirmed the safety and tolerability of eptinezumab treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04772742 (26/02/2021).

Dietary zinc intake and migraine in adults: a cross-sectional analysis of the National Health and Nutrition Examination Survey 1999-2004.

OBJECTIVE: The study examined the relationship between dietary zinc intake and migraine. BACKGROUND: Neuroinflammatory and oxidative stress are involved in the pathogenesis of migraine. Little is known about the effects of zinc, an anti-inflammatory and antioxidant trace element, on migraine. METHODS: The US National Health and Nutrition Examination Survey data from 1999 to 2004 were analyzed for this cross-sectional study. Participants who had severe headache or migraine were classified as having migraine. Dietary zinc intake was evaluated using the 24 h dietary recall system. RESULTS: A total of 11,088 participants were included, of whom, 20.2% (2236/11,088) reported having migraine disease. Compared to the lowest dietary zinc intake quintile (Q1, ≤5.9 mg/day), the adjusted odds ratios for migraine in Q2 (6.0-8.4 mg/day), Q3 (8.5-11.2 mg/day), Q4 (11.3-15.7 mg/day), and Q5 (≥15.8 mg/day) were 0.73 (95% confidence interval [CI]: 0.61-0.88, p = 0.004), 0.71 (95% CI: 0.56-0.91, p = 0.013), 0.71 (95% CI: 0.57-0.90, p = 0.008), and 0.70 (95% CI: 0.52-0.94, p = 0.029), respectively. Sensitivity analysis of zinc supplementation survey participants also showed an association between dietary zinc intake and migraine. Compared to the lowest total zinc intake quintile (Q1: 0.5-9.6 mg/day), the adjusted odds ratios for migraine in Q3 (19.3-24.3 mg/day) and Q4 (24.4-32.5 mg/day) were 0.62 (95% CI: 0.46-0.83, p = 0.019) and 0.67 (95% CI: 0.49-0.91, p = 0.045), respectively. CONCLUSIONS: Our findings indicate an inverse association between dietary zinc intake and migraine in adult Americans.

Association between migraine and cardiovascular disease mortality: A prospective population-based cohort study.

OBJECTIVE: The study assessed the association between migraine and cardiovascular disease (CVD) mortality in the US population. BACKGROUND: Previous studies have drawn different conclusions about the association between migraine and CVD mortality based on different populations; therefore, it is important to explore the relationship between migraine and CVD mortality in the US population. METHODS: This prospective cohort study included 10,644 participants from the National Health and Nutrition Examination Survey (NHANES) 1999-2004. Participants who reported having severe headache or migraine were classified as having migraine. Mortality data were obtained by linkage of the cohort database to the National Death Index as of December 31, 2019. Based on the International Classification of Diseases, Tenth Revision, CVD mortality includes the following disease codes: I00-I09 (acute rheumatic fever and chronic rheumatic heart diseases), I11 (hypertensive heart disease), I13 (hypertensive heart and renal disease), I20-I25 (ischemic heart diseases), I26-I28 (pulmonary embolism and other acute pulmonary heart diseases), I29 (various cardiovascular diseases caused by different reasons), I30-I51 (other forms of heart disease), and I60-I69 (cerebrovascular diseases). Data were analyzed from October to November 2022. RESULTS: Among 10,644 adults included in the study (mean age, 46.4 [0.3] years, 5430 men [47.4%]), 2106 (20.4%) had migraine. During a median follow-up period of 201 months, there were 3078 all-cause deaths and 997 CVD deaths. Compared to individuals without migraine, those with migraine had an adjusted hazard ratio (HR) of 1.30 (95% confidence interval [CI], 1.04-1.62; p = 0.019) for CVD mortality and 1.23 (95% CI, 1.13-1.35; p < 0.001) for all-cause mortality. In subgroup analyses, migraine was associated with CVD mortality in participants who were women (HR, 1.43; 95% CI, 1.06-1.93), aged < 45 years (HR, 1.69; 95% CI, 1.04-2.76), non-Hispanic White (HR, 1.42; 95% CI, 1.09-1.86), those with a body mass index < 30 kg/m2 (HR, 1.36; 95% CI, 1.03-1.78), former or current smokers (HR, 1.36; 95% CI, 1.00-1.85), former or current alcohol drinkers (HR, 1.33; 95% CI, 1.03-1.72), and those without metabolic syndrome (HR, 1.31; 95% CI, 1.01-1.71). The association between migraine and CVD mortality was robust in sensitivity analyses, after excluding participants who died within 2 years of follow-up (HR, 1.31; 95% CI, 1.05-1.65) or those with a history of cancer at baseline (HR, 1.28; 95% CI, 1.01-1.62). CONCLUSIONS: Migraine was associated with a higher CVD mortality rate in the US population.

The prevalence and clinical features of fibromyalgia in Chinese hospital patients with primary headache: The survey of fibromyalgia comorbid with headache.

OBJECTIVE: The aims were to explore the prevalence and clinical features of fibromyalgia in Chinese hospital patients with primary headache. BACKGROUND: Studies done in non-Chinese populations suggest that around one-third of patients with primary headache have fibromyalgia, but data from mainland China are limited. Investigations into the prevalence and clinical features of fibromyalgia in Chinese patients with primary headache would improve our understanding of these two complex disease areas and help guide future clinical practice. METHODS: This cross-sectional study included adults with primary headache treated at 23 Chinese hospitals from September 2020 to May 2021. Fibromyalgia was diagnosed using the modified 2010 American College of Rheumatology criteria. Mood and insomnia were evaluated employing the Hospital Anxiety and Depression Scale and the Insomnia Severity Index. RESULTS: A total of 2782 participants were analyzed. The fibromyalgia prevalence was 6.0% (166/2782; 95% confidence interval: 5.1%, 6.8%). Compared to primary headache patients without combined fibromyalgia, patients with primary headache combined with fibromyalgia were more likely to be older (47.8 vs. 41.7 years), women (83.7% [139/166] vs. 72.8% [1904/2616]), less educated (65.1% [108/166] vs. 45.2% [1183/2616]), and with longer-duration headache (10.0 vs. 8.0 years). Such patients were more likely to exhibit comorbid depression (34.3% [57/166] vs. 9.9% [260/2616]), anxiety (16.3% [27/166] vs. 2.7% [70/2612]), and insomnia (58.4% [97/166] vs. 17.1% [447/2616]). Fibromyalgia was more prevalent in those with chronic (rather than episodic) migraine (11.1% [46/414] vs. 4.4% [72/1653], p < 0.001) and chronic (rather than episodic) tension-type headache (11.5% [27/235] vs. 4.6% [19/409], p = 0.001). Most fibromyalgia pain was in the shoulders, neck, and upper back. CONCLUSIONS: The prevalence of fibromyalgia in mainland Chinese patients with primary headache was 6.0%. Fibromyalgia was more common in those with chronic rather than episodic headache. The most common sites of fibromyalgia pain were the neck, shoulders, and back.

Network localization of transient global amnesia beyond the hippocampus.

BACKGROUND: Transient global amnesia is common in the older adult, but the cause and mechanism remain unclear. Focal brain lesions allow for causal links between the lesion location and resulting symptoms, and we based on the reported TGA-causing lesions and used lesion network mapping to explore the causal neuroanatomical substrate of TGA. METHODS: Fifty-one cases of transient global amnesias with DWI lesions from the literature were identified, and clinical data were extracted and analyzed. Next, we mapped each lesion volume onto a reference brain and computed the network of regions functionally connected to each lesion location using a large normative connectome dataset. RESULTS: Lesions primarily occurred in the hippocampus, and in addition to the hippocampus, there are also other locations of TGA-causing lesions such as the cingulate gyrus, anterior thalamic nucleus (ATN), putamen, caudate nucleus, corpus callosum, fornix. More than 90% of TGA-causing lesions inside the hippocampus were functionally connected with the default mode network (DMN). CONCLUSION: Structural abnormality in the hippocampus was the most consistently reported in TGA, and besides the hippocampus, lesions occurring at several other brain locations also could cause TGA. The DMN may also be involved in the pathophysiology of TGA. According to the clinical and neuroimaging characteristics, TGA may be a syndrome with multiple causes and cannot be treated simply as a subtype of TIA.