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Objective: Chronic migraine (CM) is a significant public health problem that affects 2.2% of the global population. Onabotulinumtoxin A (OnabotA) is a safe and effective prophylactic treatment for patients with CM. The standard injection interval for OnabotA is 12 weeks. Nevertheless, some patients experience a wearing-off effect (WOE) in the weeks preceding the next scheduled cycle. The objectives of this study are to determine the prevalence of early WOE, to analyze variables that could be clinical predictors and to specify which interval is the most appropriate to define the existence of this phenomenon. Methods: This is a prospective single-center study of consecutive adult patients with CM who, after failing previous prophylactic therapies, started OnabotA treatment following the PREEMPT protocol between June and December of 2021. Results: A total of 59 patients (93.2% female, age 44 ± 12 years) were included. A total of 37 patients (64.9%) fulfilled medication overuse criteria. Of the total patients, 40.6% reported WOE and this was more frequent after the first cycle (35.6%). Depression and anxiety disorder was a statistically significant clinical predictor of WOE (OR 3.4; CI 95% 1.22–10.84; p = 0.028). A better cut-off point to consider WOE seems to be at 10 weeks. Conclusions: Early WOE is common in patients on OnabotA treatment for CM. Individualizing the standard 12-week injection, using total doses of 195 U, and managing psychiatric comorbidities with pharmacological and non-pharmacological strategies may improve treatment outcomes and reduce OnabotA WOE. [ABSTRACT FROM AUTHOR]

Background: Individuals using onabotulinumtoxinA as a preventive migraine treatment often use acute treatments for breakthrough attacks. Data on real-world effectiveness of the small-molecule calcitonin gene–related peptide (CGRP) receptor antagonist ubrogepant in combination with onabotulinumtoxinA are limited. Methods: COURAGE, a prospective, multiple attack, observational study, evaluated the real-world effectiveness of ubrogepant (50 or 100 mg) for acute treatment of migraine in people receiving onabotulinumtoxinA, an anti-CGRP monoclonal antibody (mAb), or both. This analysis focused only on onabotulinumtoxinA users. The Migraine Buddy app was used to identify eligible participants and track response to treated attacks. For each ubrogepant-treated attack, meaningful pain relief (MPR) and return to normal function (RNF) at 2 and 4 h post-dose over 30 days was assessed. MPR was defined as a level of relief that is meaningful to the participant, usually occurring before the pain is all gone. After 30 days, satisfaction was reported on a 7-point scale and overall acute treatment optimization was evaluated using the migraine Treatment Optimization Questionnaire-4 (mTOQ-4). Results: This analysis included 122 participants who received ubrogepant and onabotulinumtoxinA and reported on 599 ubrogepant-treated attacks. Following the first ubrogepant-treated attack, MPR was achieved in 53.3% of participants 2 h post-dose and in 76.2% of participants 4 h post-dose. RNF was achieved in 25.4% of participants 2 h post-dose and in 45.9% of participants 4 h post-dose. MPR and RNF results were similar across up to 10 ubrogepant-treated attacks. After 30 days, satisfaction with ubrogepant in combination with onabotulinumtoxinA was reported by 69.8% of participants and acute treatment optimization (defined as mTOQ-4 score ≥ 4) was achieved in 77.6%. Conclusions: In this prospective real-world effectiveness study, ubrogepant treatment in onabotulinumtoxinA users with self-identified migraine was associated with high rates of MPR and RNF at 2 and 4 h as well as satisfaction and acute treatment optimization. Although the lack of a contemporaneous control group limits causal inference, these findings demonstrate the feasibility of using a novel, app-based design to evaluate the real-world effectiveness and satisfaction of treatments. [ABSTRACT FROM AUTHOR]

The article presents the discussion on effect of greater occipital nerve block (GONB) in migraine. Topics include Prepulse inhibition (PPI) of the BR is a decrease in BR excitability due to the conditioning stimulus and representing sensory gating at the brainstem; and analyzing the electrophysiological findings in patients with the clinical response after GONB.

Background and Objectives: Trigger points (TrPs) are prevalent in patients with migraine headaches. Needling interventions targeting TrPs in migraine patients may reduce the intensity and frequency of headaches, yet systematic reviews reveal a lack of robust evidence. Intramuscular electrical stimulation (IMES) is a modality that delivers electrical current into muscles and TrPs, with recent studies suggesting it may amplify the therapeutic effects of dry needling peripherally and centrally. This could be advantageous for patients with migraine and symptomatic TrPs. Materials and Methods: This study will implement a multiple baseline single-case experimental design (SCED). In a clinical setting, a SCED study lends itself to conducting research with only a few patients that each serve as their own controls. In this SCED study, four participants with chronic migraine will be enrolled in a non-concurrent manner and randomized to one of four baseline measurement periods (4, 5, 6 or 7 weeks), leading to four potentially different start dates for each participant in the intervention phase. During the intervention phase, patients will receive five sessions of dry needling with IMES, one session per week for five weeks. The primary outcome measure will be headache frequency, i.e., the reduction in the number of headache days over a one-month period using electronic headache diary data from the Migraine Buddy smartphone application. Secondary outcome measures will be changes in mean migraine pain intensity using a numeric pain rating scale (NPRS), migraine disability using the Migraine Disability Assessment Test (MIDAS), the Headache Impact Test (HIT-6), and changes in selected cervical musculoskeletal impairments including pressure pain thresholds (PPTs) over TrPs, the craniocervical flexion test (CCFT), and cervical active range of motion (AROM). Primary and secondary outcome measures will be analyzed separately using both visual and statistical analyses. Results: Actively recruiting participants. This project was approved by the Mass General Brigham Institutional Review Board (protocol #2023P000931) and is registered with ClinicalTrials.gov (NCT05893914). Conclusions: This study will seek to determine the effects of a five-week intervention period of IMES to TrPs in the posterior cervical muscles of subjects with chronic migraine. [ABSTRACT FROM AUTHOR]

Medication-overuse headache (MOH) can develop from primary headaches. MOH is usually the result of overuse of symptomatic medications. It is a noteworthy personal and societal burden. The identification and treatment of patients at risk for MOH is an essential component of MOH management. Medication overuse can be modifiable and can advance from episodic to chronic migraine. Treatment for MOH is complex, and experts in the field have varied views on the most appropriate strategy for MOH treatment. The objective of this review is to give a comprehensive synopsis of the literature for the management of MOH. Treatment strategies, such as detoxification and prevention, are the debatable issues. Medication withdrawal is the foundation for management. The available literature suggested abrupt withdrawal with preventive approaches for early management. Bridging therapy could be useful to get relief from withdrawal symptoms. Multidisciplinary choices proved beneficial in supporting withdrawal and preventing relapse. Worldwide, the termination of overused medications has been observed as a standard treatment strategy; however, patient-specific approaches should be taken.

Background: Mindfulness gained considerable attention for migraine management, but RCTs are lacking. We aimed to assess the efficacy of a six-sessions mindfulness-based treatment added to treatment as usual (TaU) in patients with Chronic Migraine (CM) and Medication Overuse Headache (MOH) on headache frequency, medication intake, quality of life, disability, depression and anxiety, cutaneous allodynia, awareness of inner states, work-related difficulties, and disease cost. Methods: In this Phase-III single-blind RCT carried out in a specialty Italian headache center, 177 patients with CM and MOH were randomized 1:1 to either TaU (withdrawal from overused drugs, education on proper medication use and lifestyle issues, and tailored prophylaxis) or mindfulness-based intervention added to TaU (TaU + MIND). The mindfulness-based intervention consisted of six group session of mindfulness practice and 7–10 min daily self-practice. The primary endpoint was the achievement of ≥ 50% headache frequency reduction at 12 months compared to baseline, and was analyzed on an intention-to-treat principle using Pearson's Chi-Squared test. Secondary endpoints included medication intake, quality of life (QoL), disability, depression and anxiety, cutaneous allodynia, awareness of inner states, work-related difficulties, and disease cost. The secondary endpoints were analyzed using per-protocol linear mixed models. Results: Out of the 177 participants 89 were randomized to TaU and 88 to TaU + MIND. Patients in the TaU + MIND group outperformed those in TaU for the primary endpoint (78.4% vs. 48.3%; p < 0.0001), and showed superior improvement in headache frequency, QoL and disability, headache impact, loss of productive time, medication intake, and in total, indirect and direct healthcare costs. Conclusions: A mindfulness-based treatment composed of six-week session and 7–10 min daily self-practice added on to TaU is superior to TaU alone for the treatment of patients with CM and MOH. Trial registration: MIND-CM was registered on clinicaltrials.gov (NCT03671681) on14/09/2018. [ABSTRACT FROM AUTHOR]

Background: Whether ultrasound‐guided stellate ganglion block (SGB) is a valuable therapeutic option for the treatment of patients with chronic migraine (CM) is worth exploring. If SGB is proven to be effective for CM, the identification of potential predictors for the effectiveness of SGB warrants further investigation. This study aimed to investigate the effectiveness and safety of SGB in patients with CM and to explore the predictive factors for its treatment effectiveness. Methods: This is a retrospective observational study. We retrospectively analyzed the effects of SGB for the treatment of patients with CM under ultrasound guidance, between January 2018 and June 2022. The follow‐up time was approximately 1 month, 2 months, and 3 months after the last SGBs. The response criterion was defined as a reduction in pain intensity of > 50% measured using the most severe numerical rating scale (NRS) score compared to pretreatment baseline, without an increase in the dose or the type of analgesic or anxiolytic/antidepressant medication, otherwise unresponsive to SGB. Univariable and multivariable analyses were performed to identify the predictive factors for SGB response. Results: Ninety‐seven patients were included in this study. SGB was effective in most of the CM patients, with an effective rate of 90.7%, 82.5%, and 71.1% after 1, 2, and 3 months of the last SGBs, respectively. At 3‐month follow‐up, 95.7% responsive patients benefited from repeated SGBs. In patients receiving repeated SGB treatments, the number of SGBs in responsive patients was significantly greater than those in patients with no response at 3‐month follow‐up (3.41 ± 1.31 vs. 2.68 ± 0.67, p = 0.02). Comorbid anxiety or depression was a negative predictor of SGB effectiveness at 3‐month follow‐up (B = −0.25, 95% CI −0.45 to −0.05, p = 0.01). The overall adverse events rate associated with ultrasound‐guided SGB was 9.3%. There were no serious complications; all adverse events were transient, with hoarseness being the most common adverse event. Conclusions: Ultrasound‐guided SGB was an effective and safe treatment for CM patients. The majority of responsive patients with CM benefited from repeated SGBs. CM patients who needed repeated SGBs may obtain good and sustained analgesic effect after receiving a greater number of SGBs. Patients without comorbidities such as anxiety or depression were more likely to benefit from SGB treatments. [ABSTRACT FROM AUTHOR]

Background: The objective is to review the technique of onabotulinumtoxinA injection treatment in the glabellar and frontal regions using the PREEMPT (Phase III REsearch Evaluating Migraine Prophylaxis Therapy) paradigm, with review of the aesthetic issues related to the procedure. OnabotulinumtoxinA is an effective medication for the prevention of chronic migraine. The PREEMPT injection paradigm has been validated in randomized clinical trials and real‐world settings. This treatment includes injections in the forehead and glabella area. In addition, for aesthetic uses, glabella onabotulinumtoxinA injections are done in similar muscles specifically the procerus, corrugator supercilii, and frontalis muscles. Often patients who have been injected with onabotulinumtoxinA for chronic migraine have concerns about their appearance and will ask if they can see an aesthetic injector to improve this. This is a difficult issue as onabotulinumtoxinA should be injected with an interval of 10–12 weeks to avoid development of antibodies against onabotulinumtoxinA, so all injections (migraine and aesthetic) should ideally be done close together; however, if an aesthetic injection is done on the same day as a PREEMPT injection, the effect of the PREEMPT injection will not yet be visible as it takes time for onabotulinumtoxinA effects to be seen. Thus, there is a risk of a potential overdose in a particular area if aesthetic injections are done without input from the PREEMPT injector. Methods: This is a narrative review supported by photographic documentation showing the technique of onabotulinumtoxinA injection of the upper face, considering anatomical differences between patients, and combining the needs in neurology and aesthetic medicine fields. Results: Practitioners treating chronic migraine often modify some of the principles of the PREEMPT paradigm. Many practitioners are unsure about injections in the glabellar and frontal areas. The authors present a technique for using the PREEMPT protocol and adapting this to the individual patient's anatomy to prevent an unsightly appearance or ptosis. In addition, sites are provided where an aesthetic injector could inject to improve the patient's appearance without overlapping with the PREEMPT injection sites. Conclusion: Adherence to the PREEMPT injection protocol provides an evidence‐based approach to achieving clinical benefit for patients with chronic migraine. Aesthetic elements of the treatment of the glabella and forehead require additional attention. The authors provide practical considerations and recommendations regarding this. [ABSTRACT FROM AUTHOR]

Background: Despite high efficacy and tolerability, not all patients with chronic migraine benefit from anti-CGRP monoclonal antibodies. We aimed to identify the clinical predictors of the response to galcanezumab treatment in patients with chronic migraine from real-world data. Methods: We prospectively recruited patients with CM who underwent galcanezumab injections between December 2019 and February 2022. Treatment response was determined after three months of follow-up and was defined as ≥ 50% reduction in monthly headache days. The migraine characteristics, comorbidities, and other treatment responses were compared between the responder and non-responder groups. Results: Of 238 patients with CM, 153 (64.3%) showed treatment response. The responder group was younger, had lower frequency of baseline headache days, and had more accompanying symptoms such as nausea, vomiting, and photophobia. Better triptan response and less depression were also observed in the responder group. Multivariable regression analysis revealed that the everyday headache (OR = 0.351, 95% CI = 0.133–0.874, p = 0.017), depression (OR = 0.439, 95% CI = 0.216–0.896, p = 0.024) and absence of accompanying symptoms (OR = 0.314, 95% CI = 0.118–0.834, p = 0.020) were significantly associated with response to galcanezumab treatment. Conclusions: Our real-world data showed the efficacy of galcanezumab in patients with CM, regardless of medication overuse. Everyday headache, presence of depression, and absence of accompanying symptoms of migraine were significant predictors of a poor response. [ABSTRACT FROM AUTHOR]

Objective: this post hoc analysis aimed to evaluate the efficacy of fremanezumab in difficult-to-treat chronic migraine (CM) patients with and without psychiatric comorbidities (PCs), mainly anxiety and/or depression. Methods: We assessed data from CM patients with and without PCs who failed at least 3 preventives and eventually received at least 3 consecutive monthly doses of fremanezumab 225 mg. Outcomes included the crude response (≥50% reduction in monthly headache days (MHDs)) rates to fremanezumab from the baseline to the last clinical follow-up. The changes in MHDs; MHDs of moderate/greater severity; monthly days with intake of abortive medication; and the proportion of patients' changing status from with PCs to decreased/without PCs were also compared. Disability and quality of life (QOL) outcomes were also assessed. Results: Of 107 patients enrolled, 65 (60.7%) had baseline PCs. The percentage of patients with (n = 38/65; 58.5%) and without (n = 28/42; 66.6%) PCs that achieved a ≥50% reduction in MHDs with fremanezumab was comparable (p = 0.41), whereas MHDs were significantly reduced (difference vs. baseline) in both patients with PCs (mean −8.9 (standard error: 6.8); p < 0.001) and without PCs (−9.8 (7.5); p < 0.001). Both groups experienced significant improvements in all other efficacy, disability, and QOL outcomes at comparable rates, including in MHD reduction. A significant proportion of fremanezumab-treated patients with baseline PCs de-escalated in corresponding severities or even reverted to no PCs (28/65; 43.1%) post-fremanezumab. Conclusions: fremanezumab appears to be effective as a preventive treatment in difficult-to-treat CM patients with and without PCs while also being beneficial in reducing the severity of comorbid anxiety and/or depression. [ABSTRACT FROM AUTHOR]

The phase II study aimed to evaluate the safety and efficacy of non-invasive infrared polarized light device on patients with chronic migraine (CM). Forty patients aged between 18 and 60 years with a diagnosis of CM were included. Sociodemographic and clinical information were obtained by face-to-face interviews with the patients and they had migraine diary containing headache information before and monthly during 4 months of the treatment. Clinical data included age of migraine onset, duration of disease as years, total headache days per month, severity of headache assessed by visual analogue scale (VAS), number of painkillers used monthly, and impact of headache on patients' home, work and social life activities. Short form-36 (SF-36) was used to examine for the quality of life. Migraine therapy devices; both active and inactive, were given to the patients to use at home according to study protocol, double-blinded, randomized, sham-controlled trial. Statistical analysis was performed using the SAS University Edition 9.4 program. A total of 40 patients, 36 (90%) were female and t he mean age was 37.50 ± 9.77 years. The mean duration of migraine was 12.74 ± 9.55 years. Migraine therapy device was well tolerated without any side effects. [ABSTRACT FROM AUTHOR]

Introduction. This study aimed to evaluate the knowledge and standard of treatment of chronic migraine with botulinum toxin by Polish aesthetic medicine professionals. Rationale for the study. Onabotulinum toxin A injections are used as a preventive treatment for chronic migraine. Besides neurologists, healthcare professionals of multiple specialisms can offer this treatment. Aesthetic medicine professionals commonly use the treatment to extend the scope of their practice. This may bring about a situation wherein physicians with different levels of experience and training are providing botulinum toxin injections for chronic migraine. Material and methods. An online survey asking about patient qualification procedures, the level of adherence to the PREEMPT paradigm, product-, technique-, dosing-, and treatment intervals-related aspects of the treatment, efficacy evaluation practices and concerns about the use of botulinum toxin in chronic migraine was sent to 110 Polish physicians practicing aesthetic medicine. Results. The response rate was 73.6%. The results of the survey revealed multiple deviations from the current paradigm of treatment of chronic migraine with botulinum toxin, from improper patient qualification through treatment procedure to the evaluation of the efficacy. Only around one-third of professionals evaluated the observed effectiveness of therapy as very good. Most respondents wanted to expand their knowledge and skills in chronic migraine treatment. Conclusions. There is a considerable willingness among aesthetic medicine specialists to treat patients with chronic migraine with botulinum toxin. The current levels of knowledge and skills in this treatment are limited, and multiple physicians declared deviations from the diagnostic criteria and the therapeutic protocol. Transferring aesthetic medicine practices to neurology treatment is common and may result in a lack of effectiveness of treatment or even intensification of symptoms. An appropriate educational programme should be implemented for all physicians authorised to administer BoNT-A in Poland. [ABSTRACT FROM AUTHOR]

The article presents an original method for the automatic assessment of the quality of event-related potentials (ERPs), based on the calculation of the coefficient ε, which describes the compliance of recorded ERPs with some statistically significant parameters. This method was used to analyze the neuropsychological EEG monitoring of patients suffering from migraines. The frequency of migraine attacks was correlated with the spatial distribution of the coefficients ε, calculated for EEG channels. More than 15 migraine attacks per month was accompanied by an increase in calculated values in the occipital region. Patients with infrequent migraines exhibited maximum quality in the frontal areas. The automatic analysis of spatial maps of the coefficient ε demonstrated a statistically significant difference between the two analyzed groups with different means of migraine attack numbers per month. [ABSTRACT FROM AUTHOR]

Migraine is a leading cause of disability worldwide, yet it remains underrecognized and undertreated, especially in the pediatric and adolescent population. Chronic migraine occurs approximately in 1% of children and adolescents requiring preventive treatment. Topiramate is the only FDA-approved preventative treatment for children older than 12 years of age, but there is conflicting evidence regarding its efficacy. OnabotulinumtoxinA is a known and approved treatment for the management of chronic migraine in people older than 18 years. Several studies examine its role in the pediatric population with positive results; however, the clear-cut benefit is still unclear. OnabotulinumtoxinA seems not only to improve disability scores (PedMIDAS) but also to improve the quality, characteristics, and frequency of migraines in the said population. This systematic review aims to summarize the evidence on the efficacy, dosing, administration, long-term outcomes, and safety of onabotulinumtoxinA in pediatric and adolescent migraine. Eighteen studies met the eligibility criteria and were included in this review. The mean monthly migraine days (MMDs), decreased from of 21.2 days per month to 10.7 after treatment. The reported treatment-related adverse effects were mild and primarily injection site related and ranged from 0% to 47.0%. Thus, this review provides compelling evidence suggesting that OnabotulinumtoxinA may represent a safe and effective preventive treatment option for pediatric migraine.

Chronic migraine is a disease with a high burden on patients from both a working and quality of life point of view. The pathophysiology of this subtype of migraine is due to several factors, such as medication overuse. Nevertheless, the detrimental recurring of headache attacks with central and peripheral sensitization plays a central role and explains some additional symptoms complained about by these patients even in the interictal phase. OnabotulinumtoxinA is a therapy indicated for chronic migraine since it has proven to reduce peripheral sensitization, showing even efficacy on central symptoms. The aim of this narrative review is to present the current evidence regarding the effect of OnabotulinumtoxinA on sensitization and interictal symptoms.

Abstract Background The definitive pathogenic mechanisms underlying chronic migraine (CM) remain unclear. Mounting evidence from functional and structural magnetic resonance imaging (MRI) studies suggests that the caudate nucleus (CN) plays a role in the cognitive, sensory, and emotional integration of pain information in patients with migraine. However, evidence concerning the role played by CN in CM patients is limited. Here, we used the CN as the seed to explore patterns of functional connectivity (FC) among healthy controls (HCs), patients with episodic migraine (EM), and patients with CM. Methods We included 25 HCs, 23 EM patients, and 46 CM patients in this study. All participants underwent resting-state functional MRI scans on a GE 3.0T MRI system. We performed seed-based FC analyses among the three groups using the bilateral CNs as seeds. We also compared the subgroups of CM (with and without medication overuse headache, males and females) and performed Pearson’s correlation analyses between FC values and the clinical features of CM patients. Results FC values between the right CN and five clusters (mainly involved in emotion, cognition, and sensory-related brain regions) were higher in CM patients than in HCs. Compared to EM patients, enhanced FC values between the bilateral precuneus, left anterior cingulate gyrus, right middle cingulate cortex, right lingual gyrus, and right CN were shown in the CM patients. There were no significant differences between CM patients with and without MOH, males and females. FC values between the bilateral calcarine cortex, lingual gyrus, and right CN were positively correlated with body mass index. Moreover, right CN-related FC values in the left calcarine cortex and right lingual gyrus were inversely correlated with visual analogue scale scores for headaches. Conclusion Our results revealed abnormal right CN-based FC values in CM patients, suggesting dysfunction of brain networks associated with pain perception and multi-regulation (emotion, cognition, and sensory). Aberrant FC of the CN can provide potential neuroimaging markers for the diagnosis and treatment of CM.

Abstract Background and purpose New daily persistent headache (NDPH) and chronic migraine (CM) are two different types of headaches that might involve vascular dysregulation. There is still a lack of clarity about altered brain perfusion in NDPH and CM. This study aimed to investigate the cerebral perfusion variances of NDPH and CM using multi-delay pseudo-continuous arterial spin-labeled magnetic resonance imaging (pCASL-MRI). Methods Fifteen patients with NDPH, 18 patients with CM, and 15 age- and sex-matched healthy controls (HCs) were included. All participants underwent 3D multi-delay pCASL-MRI to obtain cerebral perfusion data, including arrival-time-corrected cerebral blood flow (CBF) and arterial cerebral blood volume (aCBV). The automated anatomical labeling atlas 3 (AAL3) was used to parcellate 170 brain regions. The CBF and aCBV values in each brain region were compared among the three groups. Correlation analyses between cerebral perfusion parameters and clinical variables were performed. Results Compared with HC participants, patients with NDPH were found to have decreased CBF and aCBV values in multiple regions in the right hemisphere, including the right posterior orbital gyrus (OFCpost.R), right middle occipital gyrus (MOG.R), and ventral anterior nucleus of right thalamus (tVA.R), while patients with CM showed increased CBF and aCBV values presenting in the ventral lateral nucleus of left thalamus (tVL.L) and right thalamus (tVL.R) compared with HCs (all p

Abstract Background To investigate specific brain regions and neural circuits that are responsible for migraine chronification. Methods We established a mouse model of chronic migraine with intermittent injections of clinically-relevant dose of nitroglycerin (0.1 mg/kg for 9 days) and validated the model with cephalic and extracephalic mechanical sensitivity, calcitonin gene-related peptide (CGRP) expression in trigeminal ganglion, and responsiveness to sumatriptan or central CGRP blockade. We explored the neurons that were sensitized along with migraine chronification and investigated their roles on migraine phenotypes with chemogenetics. Results After repetitive nitroglycerin injections, mice displayed sustained supraorbital and hind paw mechanical hyperalgesia, which lasted beyond discontinuation of nitroglycerin infusion and could be transiently reversed by sumatriptan. The CGRP expression in trigeminal ganglion was also upregulated. We found the pERK positive cells were significantly increased in the central nucleus of the amygdala (CeA), and these sensitized cells in the CeA were predominantly protein kinase C-delta (PKC-δ) positive neurons co-expressing CGRP receptors. Remarkably, blockade of the parabrachial nucleus (PBN)-CeA CGRP neurotransmission by CGRP8–37 microinjection to the CeA attenuated the sustained cephalic and extracephalic mechanical hyperalgesia. Furthermore, chemogenetic silencing of the sensitized CeA PKC-δ positive neurons reversed the mechanical hyperalgesia and CGRP expression in the trigeminal ganglion. In contrast, repetitive chemogenetic activation of the CeA PKC-δ positive neurons recapitulated chronic migraine-like phenotypes in naïve mice. Conclusions Our data suggest that CeA PKC-δ positive neurons innervated by PBN CGRP positive neurons might contribute to the chronification of migraine, which may serve as future therapeutic targets for chronic migraine. Graphical Abstract

Abstract Background Controlled and real-world evidence have demonstrated the efficacy of calcitonin gene related peptide (CGRP) monoclonal antibodies (MABs) in migraine. However, data on the over-one-year sustained effectiveness of CGRP MABs in resistant chronic migraine (CM) is sparse. Methods This is a two-year real-world prospective analysis of an ongoing single centre audit conducted in patients with resistant CM. Patients received monthly erenumab for six months before assessing its effectiveness. Responders were considered those who achieved at least 30% reduction in monthly migraine days (MMD) by month 6, compared to baseline. Secondary outcomes were also analysed, including changes of the Headache Impact Test version 6 (HIT-6). Results One hundred sixty-four patients [135 (82.3%) females; mean age 46 SD 14) years] were included in the audit and 160 patients analysed. Patients had failed a mean of 8.4 preventive treatments at baseline. At month 6, 76 patients (48%) were 30% responders to erenumab, 50 patients (31%) were 50% responders and 25 (15%) were 75% responders. The mean reduction in MMD at month 6 was 7.5 days compared to baseline (P

Abstract The Greek Society of Migraine and Headache Patients (GSMHP), maintaining a strong commitment to research and information, conducted its second web-based online survey named "Migraine in Greece—2020", following its first one conducted in 2018. The 2020 study included 2,105 migraine patients who were called to answer 151 questions. The purposes of the current research were to record the demographic and clinical characteristics of migraine patients in Greece, including the severity and effects of migraine on respondents' quality of life, as well as to survey the effects of the coronavirus pandemic on the course of migraine. Our population, internet-based study provides data that will hopefully contribute to better comprehend the clinical phenotype and course of migraine during the COVID-19 pandemic.

Abstact Background DRAGON was a phase 3, randomised, double-blind, placebo-controlled study which evaluated the efficacy and safety of erenumab in patients with chronic migraine (CM) from Asia not adequately represented in the global pivotal CM study. Methods DRAGON study was conducted across 9 Asian countries or regions including mainland China, India, the Republic of Korea, Malaysia, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. Patients (N = 557) with CM (aged 18–65 years) were randomised (1:1) to receive once-monthly subcutaneous erenumab 70 mg or matching placebo for 12 weeks. The primary endpoint was the change in monthly migraine days (MMD) from baseline to the last 4 weeks of the 12-week double-blind treatment phase (DBTP). Secondary endpoints included achievement of ≥ 50% reduction in MMD, change in monthly acute headache medication days, modified migraine disability assessment (mMIDAS), and safety. Study was powered for the primary endpoint of change from baseline in MMD. Results At baseline, the mean (SD) age was 41.7 (± 10.9) years, and 81.5% (n = 454) patients were women. The mean migraine duration was 18.0 (± 11.6) years, and the mean MMD was 19.2 (± 5.4). 97.8% (n = 545) randomised patients completed the DBTP. Overall, demographics and baseline characteristics were balanced between the erenumab and placebo groups except for a slightly higher proportion of women in the placebo group. At Week 12, the adjusted mean change from baseline in MMD was − 8.2 days for erenumab and − 6.6 days for placebo, with a statistically significant difference for erenumab versus placebo (adjusted mean difference vs placebo: − 1.57 [95%CI: − 2.83, − 0.30]; P = 0.015). A greater proportion of patients treated with erenumab achieved ≥ 50% reduction in MMD versus placebo (47.0% vs 36.7%, P = 0.014). At Week 12, greater reductions in monthly acute headache medication days (− 5.34 vs − 4.66) and mMIDAS scores (− 14.67 vs − 12.93) were observed in patients treated with erenumab versus placebo. Safety and tolerability profile of erenumab was comparable to placebo, except the incidence of constipation (8.6% for erenumab vs 3.2% for placebo). Conclusion DRAGON study demonstrated the efficacy and safety of erenumab 70 mg in patients with CM from Asia. No new safety signals were observed during the DBTP compared with the previous trials. Trial registration NCT03867201

Hikmet Saçmacı,1 Nermin Tanik,1 Levent Ertuğrul İnan2 1Department of Neurology, Yozgat Bozok University, School of Medicine, Yozgat, 66100, Turkey; 2Department of Neurology, Ministry of Health Ankara Research and Training Hospital, Ankara, 06230, TurkeyCorrespondence: Hikmet Saçmacı, Department of Neurology, Yozgat Bozok University, School of Medicine, Erdogan Akdag Campus, Ataturk Road 7. Km 66900, Yozgat, 66100, Turkey, Tel +0354 212 62 01, Fax +0354 212 11 93, Email hsacmaci@hotmail.comObjective: Recent studies have shown that sleep problems occur in migraineurs and poor sleep causes chronification, but the mechanisms by which chronic migraine affects sleep quality are still unknown. This review aims to analyze commonly reported sleep disturbances in chronic migraine (CM) and determine the effect of CM on sleep quality.Materials and Methods: We conducted a comprehensive review of all published articles on CM and sleep quality from inception to March 2022 in the literature. Clinical trials, observational studies, and case series (≥ 20 cases) were included. Two reviewers and a supervisor reviewed the titles and abstracts of all search results with predefined inclusion and exclusion criteria. PubMed search for randomized controlled trials and open studies on CM and sleep quality reported in English between 1983 and 2022 was conducted using the keywords including chronic migraine, sleep, insomnia, sleep quality, polysomnography, and Pittsburgh Sleep Quality Index.Results: A total of 535 potentially relevant articles were found. A total of 455 articles and reviews, meta-analyses published in any language other than English, with other exclusion criteria, were excluded from the review. In the remaining articles, 36 clinical studies, reviewing sleep quality and its association with migraine, were identified and reviewed. Evidence from this review shows that poor sleep and migraine chronicity are intertwined with other accompanying comorbidities and dysregulation of circadian rhythm that innovative treatments promise to bring relief to both poor sleep as well as migraine.Conclusion: Sleep disorders are common in CM and the association between migraine chronification and sleep quality is bidirectional. Comorbid conditions with accompanying frequent attacks in migraine may impair sleep quality. While the maladaptive pain process worsens sleep, poor sleep quality also negatively affects migraine pain. Sleep disturbance, which is affected by worsening migraine attacks, causes deterioration in the quality of life, loss of workforce, and economic burden.Keywords: chronic migraine, sleep, sleep quality, insomnia, sleep disorders

Abstract To identify and validate the neural signatures of resting-state oscillatory connectivity for chronic migraine (CM), we used machine learning techniques to classify patients with CM from healthy controls (HC) and patients with other pain disorders. The cross-sectional study obtained resting-state magnetoencephalographic data from 240 participants (70 HC, 100 CM, 35 episodic migraine [EM], and 35 fibromyalgia [FM]). Source-based oscillatory connectivity of relevant cortical regions was calculated to determine intrinsic connectivity at 1–40 Hz. A classification model that employed a support vector machine was developed using the magnetoencephalographic data to assess the reliability and generalizability of CM identification. In the findings, the discriminative features that differentiate CM from HC were principally observed from the functional interactions between salience, sensorimotor, and part of the default mode networks. The classification model with these features exhibited excellent performance in distinguishing patients with CM from HC (accuracy ≥ 86.8%, area under the curve (AUC) ≥ 0.9) and from those with EM (accuracy: 94.5%, AUC: 0.96). The model also achieved high performance (accuracy: 89.1%, AUC: 0.91) in classifying CM from other pain disorders (FM in this study). These resting-state magnetoencephalographic electrophysiological features yield oscillatory connectivity to identify patients with CM from those with a different type of migraine and pain disorder, with adequate reliability and generalizability.

BackgroundRefractory migraine is a poorly described complication of migraine in which migraine has chronified and become resistant to standard treatments. The true prevalence is unknown, but medication resistance is common in headache clinic patient populations. Given the lack of response to treatment, this patient population is extremely difficult to treat with limited guidance in the literature.ObjectiveTo review the diagnostic, pathophysiological, and management challenges in the refractory migraine population.DiscussionThere are no accepted, or even ICHD-3 appendix, diagnostic criteria for refractory migraine though several proposed criteria exist. Current proposed criteria often have low bars for refractoriness while also not meeting the needs of pediatrics, lower socioeconomic status, and developing nations. Pathophysiology is unknown but can be hypothesized as a persistent “on” state as a progression from chronic migraine with increasing central sensitization, but there may be heterogeneity in the underlying pathophysiology. No guidelines exist for treatment of refractory migraine; once all guideline-based treatments are tried, treatment consists of n-of-1 treatment trials paired with non-pharmacologic management.ConclusionRefractory migraine is poorly described diagnostically, its pathophysiology can only be guessed at by extension of chronic migraine, and treatment is more the art than science of medicine. Navigating care of this refractory population will require multidisciplinary care models and an emphasis on future research to answer these unknowns.

Background: According to our previous study, the loss of inhibitory interneuron function contributes to central sensitization in chronic migraine (CM). Synaptic plasticity is a vital basis for the occurrence of central sensitization. However, whether the decline in interneuron-mediated inhibition promotes central sensitization by regulating synaptic plasticity in CM remains unclear. Therefore, this study aims to explore the role of interneuron-mediated inhibition in the development of synaptic plasticity in CM. Methods: A CM model was established in rats by repeated dural infusion of inflammatory soup (IS) for 7 days, and the function of inhibitory interneurons was then evaluated. After intraventricular injection of baclofen [a gammaaminobutyric acid type B receptor (GABABR) agonist] or H89 [a protein kinase A (PKA) inhibitor), behavioral tests were performed. The changes in synaptic plasticity were investigated by determining the levels of the synapseassociated proteins postsynaptic density protein 95 (PSD95), synaptophysin (Syp) and synaptophysin-1(Syt-1)]; evaluating the synaptic ultrastructure by transmission electron microscopy (TEM); and determining the density of synaptic spines via Golgi-Cox staining. Central sensitization was evaluated by measuring calcitonin gene-related peptide (CGRP), brain-derived neurotrophic factor (BDNF), c-Fos and substance P (SP) levels. Finally, the PKA/Fyn kinase (Fyn)/tyrosine-phosphorylated NR2B (pNR2B) pathway and downstream calcium-calmodulin-dependent kinase II (CaMKII)/c-AMP-responsive element binding protein (pCREB) signaling were assessed. Results: We observed dysfunction of inhibitory interneurons, and found that activation of GABABR ameliorated CM-induced hyperalgesia, repressed the CMevoked elevation of synapse-associated protein levels and enhancement of synaptic transmission, alleviated the CM-triggered increases in the levels of central sensitization-related proteins, and inhibited CaMKII/pCREB signaling via the PKA/Fyn/pNR2B pathway. The inhibition of PKA suppressed the CM-induced activation of Fyn/pNR2B signaling. Conclusion: These data reveal that the dysfunction of inhibitory interneurons contributes to central sensitization by regulating synaptic plasticity through the GABABR/PKA/Fyn/pNR2B pathway in the periaqueductal gray (PAG) of CM rats. Blockade of GABABR-pNR2B signaling might have a positive influence on the effects of CM therapy by modulating synaptic plasticity in central sensitization. [ABSTRACT FROM AUTHOR]

Background: Galcanezumab is a monoclonal antibody acting against the calcitonin gene‐related peptide approved for the preventive treatment of migraine. The aim of this article is to explore its effectiveness and safety of galcanezumab in chronic migraine (CM) with medication overuse‐headache (MOH). Methods: Seventy‐eight patients were consecutively enrolled at the Modena headache center and followed up for 15 months. Visits were scheduled every 3 months, and the following variables were collected: the number of migraine days per month (MDM); the painkillers taken per month (PM); the number of days per month in which the patient took, at least, one painkiller; the six‐item headache impact test; and the migraine disability assessment questionnaire (MIDAS) score. Demographic features of the analyzed sample were collected at the baseline and adverse events (AEs) were collected at every visit. Results: After 12 months, galcanezumab significantly reduced the MDM, the PM, the number of days on medication, the HIT‐6 as well as the MIDAS scores (all p <.0001). The greatest amelioration was obtained in the first trimester of treatment. A higher MDM, a higher NRS score at the baseline, and a higher number of failed preventive treatments negatively predict the CM relief at the year of treatment. No serious AEs were registered and only one drop‐out was due to AE. Conclusions: Galcanezumab is effective and safe for the treatment of patients affected by CM and MOH. Patients with a higher impairment at the baseline may found less benefits with galcanezumab. [ABSTRACT FROM AUTHOR]

Objective: Assess the long‐term efficacy and safety of erenumab in patients with chronic migraine with acute medication overuse. Background: Overuse of acute medication in patients with chronic migraine has been linked to greater pain intensity and disability and may diminish the effectiveness of preventive therapies. Methods: This 52‐week open‐label extension study followed a 12‐week double‐blind placebo‐controlled study in which patients with chronic migraine were randomized 3:2:2 to placebo or once‐monthly erenumab 70 mg or 140 mg. Patients were stratified by region and medication overuse status. Patients received erenumab 70 mg or 140 mg throughout or switched from erenumab 70 to 140 mg (based on protocol amendment to augment safety data at higher dose). Efficacy was assessed in patients with and without medication overuse at parent study baseline. Results: Of 609 patients enrolled in the extension study, 252/609 (41.4%) met the criteria for medication overuse at parent study baseline. At Week 52, the mean change in monthly migraine days from parent study baseline was −9.3 (95% confidence interval: −10.4, −8.1 days) in the medication overuse subgroup versus −9.3 (−10.1, −8.5 days) in the non‐medication overuse subgroup (combined erenumab doses); proportion of patients achieving ≥50% reduction in monthly migraine days at Week 52 was 55.9% (90/161; 48.2%, 63.3%) versus 61.3% (136/222; 54.7%, 67.4%), respectively. Among baseline users of acute migraine‐specific medication, the mean change in monthly migraine‐specific medication days at Week 52 was −7.4 (−8.3, −6.4 days) in the medication overuse subgroup versus −5.4 (−6.1, −4.7 days) in the non–medication overuse subgroup. Most patients (197/298; 66.1%) in the medication overuse subgroup transitioned to non‐overuse status by Week 52. Erenumab 140 mg was associated with numerically greater efficacy than erenumab 70 mg across all endpoints. No new safety signals were identified. Conclusion: Long‐term erenumab treatment demonstrated sustained efficacy and safety in patients with chronic migraine with and without acute medication overuse. [ABSTRACT FROM AUTHOR]

Objective: To explore whether patients with chronic migraine and medication overuse headache (CM + MOH) present with decision‐making deficit. Background: Factors underlying MOH in patients with CM remain unclear. Whether the process of decision‐making plays a role in MOH is still controversial. Decision‐making varies in the degree of uncertainty: under ambiguity where the probability of outcome is unknown, and under risk where probabilities are known. Methods: Decisions under ambiguity and risk were assessed with the Iowa Gambling Task and the Cambridge Gambling Task, respectively, whereas executive function was assessed by the Wisconsin Card Sorting Test. Results: A total of 75 participants: 25 patients with CM + MOH, 25 with CM, and 25 age‐ and sex‐similar healthy controls (HCs), completed this cross‐sectional study. There was no significant difference in headache profiles except for more frequent analgesic use (mean ± SD: 23.5 ± 7.6 vs. 6.8 ± 3.4 days; p < 0.001) and higher Severity of Dependence Scores (median [25th−75th percentile]: 8 [5–11] vs. 1 [0–4]; p < 0.001) in patients with CM + MOH compared to CM. Total net score (mean ± SD) on the Iowa Gambling Task in patients with CM + MOH, CM, and HCs were − 8.1 ± 28.7, 10.9 ± 29.6, and 14.2 ± 28.8, respectively. There was a significant difference between the three groups (F(2, 72) = 4.28, p = 0.017), with patients with CM + MOH making significantly more disadvantageous decisions than patients with CM (p = 0.024) and HCs (p = 0.008), while the CM and HC groups did not differ (p = 0.690). By contrast, there was no significant difference between the groups in the Cambridge Gambling Task and the Wisconsin Card Sorting Test. Furthermore, performance on the Iowa Gambling Task was inversely correlated with analgesic consumption (r = −0.41, p = 0.003), suggesting that decision‐making under ambiguity may be related to MOH. Conclusions: Our data suggest that patients with CM + MOH had impaired decisions under ambiguous, but not risky situations. This dissociation indicates disrupted emotional feedback processing rather than executive dysfunction, which may underlie the pathogenesis of MOH. [ABSTRACT FROM AUTHOR]

Background & Objective: A need exists for prophylactic treatment options for chronic migraine. Our aim was to evaluate and compare the effect of greater occipital nerve (GON) and transnasal sphenopalatine ganglion (SPG) blockade on headache days, responder rate, attack severity, attack frequency, and medication overuse in patients with chronic migraine. Methods: This was a retrospective study. The GON blockade was performed at the proximal level under ultrasound guidance with 1.5 cc 0.5% bupivacaine, and the SPG blockade was performed transnasally with 0.5 cc 0.5% bupivacaine applied for 30 minutes with swab sticks. Patients who completed bilateral blocks applied in four weekly sessions were included in the analysis. Results: Seventy patients (GON=37, SPG=33) were included in the study. Both groups showed a significant improvement in the number of days with headache, severity of attacks, and frequency of attacks at the first- and third-month follow-up visits compared to the baseline (p<0.001). Responder rates were similar at the first- and third-month follow-up visits (r= 3.707, p=0.054; r=0.071, p=0.790, respectively). At the third-month follow-up, the prevalence of medication overuse decreased from 78% to 13% in the GON group and from 57% to 9% in the SPG group, and these differences were statistically significant (p<0.001 for both groups). No significant difference was noted in efficacy between the treatment groups (p=0.714). No significant adverse effects occurred in either group. Conclusion: Both proximal GON blockade and minimally invasive SPG blockade are effective and safe options for prophylaxis in patients with chronic migraine. [ABSTRACT FROM AUTHOR]

Objective: To report the effcacy of different anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) on headache frequency, intensity, and duration. Background: Blockade of CGRP receptors or neuropeptide with anti-CGRPmAbs have been successfully used for several years for the prevention of chronic and episodic migraine. The response is usually assessed by improvement seen in the number of days with headache per month. However, clinical praxis indicates that sole reliance on the frequency of headaches might be insuffcient to interpret the effcacy of these treatments. Methods: Retrospective review of a case with a meticulous headache diary who has tried three different anti-CGRP mAbs for chronic migraine prevention. Results: The patient has been diagnosed with chronic migraine and was first treated with erenumab, followed by fremanezumab and thereafter galcanezumab due to several reasons. In addition to significant improvement in all three parameters analyzed with anti-CGRP mAb treatment, the most important and valuable effect on the patient's quality of life was decreased duration and frequency of headaches. At present, the patient is receiving fremanezumab treatment with an excellent tolerability. Conclusion: There is a clear need for careful follow-up and detailed daily records of headaches showing the frequency, duration, and severity for the evaluation of anti-CGRP mAbs treatment. This study shows the importance of this information in order formedical professionals tomake an informed decision regarding the best course of anti-CGRP mAbs treatment in cases of side effects or lack of effcacy. [ABSTRACT FROM AUTHOR]

Some 14% of global prevalence, based on high-income country populations, suffers from migraine. Chronic migraine is very disabling, being characterized by at least 15 headache days per month of which at least 8 days present the features of migraine. Onabotulinumtoxin A, targeting the machinery for exocytosis of neurotransmitters and neuropeptides, has been approved for use in chronic migraine since 2010. This systematic review and meta-analysis appraises the safety of onabotulinumtoxin A treatment for chronic migraine and the occurrence of treatment-related adverse events (TRAEs) in randomized, clinical studies in comparison with placebo or other comparators and preventative treatments according to the most updated Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 recommendations. The search retrieved 888 total records. Nine studies are included and seven were eligible for meta-analysis. The present study demonstrates that toxin produces more TRAEs than placebo, but less than oral topiramate, supporting the safety of onabotulinumtoxin A, and highlights the heterogeneity of the studies present in the literature (I2 = 96%; p < 0.00001). This points to the need for further, adequately powered, randomized clinical trials assessing the safety of onabotulinumtoxin A in combination with the newest treatment options. [ABSTRACT FROM AUTHOR]

In this randomized, double-blind, placebo-controlled study, we evaluated the efficacy of an individualized technique of subcutaneous injection of botulinum toxin type A (BoNT-A) targeted (SjBoT) to the occipital or trigeminal skin area in non-responder patients with chronic migraine (CM). Patients who had not previously responded to at least two treatments of intramuscular injections of BoNT-A were randomly assigned (2:1) to receive two subcutaneous administrations of BoNT-A (up to 200 units) with the SjBoT injection paradigm or placebo. Following the skin area where the maximum pain began, treatment was given in the trigeminal or occipital region bilaterally. The primary endpoint changed in monthly headache days from baseline to the last 4 weeks. Among 139 randomized patients, 90 received BoNT-A and 49 received placebo, and 128 completed the double-blind phase. BoNT-A significantly reduced monthly headache days versus placebo (−13.2 versus −1.2; p < 0.0001) in the majority of patients who had cutaneous allodynia. Other secondary endpoints, including measures for disability (Migraine Disability Assessment questionnaire from baseline 21.96 to 7.59 after treatment, p = 0.028), also differed. Thus, in non-responder patients with CM, BoNT-A significantly reduced migraine days when administered according to the "follow the origin of maximum pain" approach using SjBoT injection paradigm. [ABSTRACT FROM AUTHOR]

Objective: To evaluate changes in interictal burden with galcanezumab versus placebo in patients with episodic (EM) or chronic migraine (CM). Background: The disruptive effects of migraine occur both during attacks (ictal period) and between attacks (interictal period), affecting work, school, family, and social life. Migraine clinical trials typically assess ictal burden endpoints, neglecting interictal burden. Methods: CONQUER was a 3‐month, double‐blind study that randomized adult patients with EM or CM who had experienced failure of two to four standard‐of‐care migraine preventive medication categories to receive monthly galcanezumab (n = 232) or placebo (n = 230), followed by 3 months of open‐label galcanezumab. The mean change in interictal burden, a secondary objective, was measured using the four‐item Migraine Interictal Burden Scale (MIBS‐4). The total score for MIBS‐4 can range from zero to 12, with scores ≥5 indicating severe interictal burden. Post hoc analyses evaluated shifts in MIBS‐4 severity categories and item‐level improvement. Results: The MIBS‐4 total score indicated severe interictal burden at baseline (mean [SD]: all patients, 5.5 [3.5]; EM, 5.0 [3.4]; CM, 6.2 [3.5]). Reductions in the MIBS‐4 score were significantly greater with galcanezumab versus placebo at Month 3 (mean [SE]: all patients −1.9 [0.2] vs. −0.8 [0.2], p < 0.0001; EM, −1.8 [0.3] vs. −1.1 [0.3], p = 0.033; CM, −1.8 [0.4] vs. −0.3 [0.4], p < 0.001), with further improvement at Month 6 after all patients had received galcanezumab (mean [SE]: all patients, −2.4 [0.2] vs. −2.0 [0.2]; EM, −2.3 [0.3] vs. −2.2 [0.3]; CM, −2.1 [0.4] vs. −1.5 [0.4]). The percentage of patients with severe interictal burden decreased substantially for the galcanezumab‐treated patients, from 59% (137/232) at baseline to 27% (58/217) at Month 6 (EM from 51% [70/137] to 23% [30/131]; CM from 71% [67/95] to 33% [28/86]). Conclusion: In addition to the known efficacy of galcanezumab in the ictal period, these findings suggest treatment with galcanezumab results in a significant reduction in interictal burden. [ABSTRACT FROM AUTHOR]

Objective: To prospectively assess the efficacy and safety of fremanezumab for migraine prophylaxis in patients with failure of at least three previous preventive treatments. Changes in disability as quality‐of‐life outcomes after fremanezumab treatment were also examined. Methods: Two hundred and four patients with either high‐frequency EM (HFEM) or chronic migraine (CM), who attained at least three consecutive monthly sessions with fremanezumab 225 mg and otherwise met the inclusion criteria, were included in the study. The crude response (at least 50% reduction in monthly headache days [MHD]) rates to fremanezumab were assessed. Scores in the following efficacy outcomes were then compared from baseline to the last efficacy evaluation follow‐up: (i) MHD, (ii) monthly days with moderate/severe peak headache intensity, and (iii) monthly days with intake of abortive medication. The disability was evaluated with the Migraine Disability Assessment; the quality of life (QOL) status was assessed with the Headache Impact‐6 Test, and the EQ‐5D questionnaire. Results: In the majority of HFEM cases (n = 81/97; 83.5%) and CM patients (n = 67/107; 62.6%), fremanezumab proved effective in reducing the MHDs by at least 50% and was associated with clinically meaningful improvement in all other efficacy variables. The migraine‐related disability experienced by our patients decreased and their QOL increased. We recorded just 36 cases reporting mild adverse events, including pain, rash or pruritus (n = 26), flu‐like symptoms (n = 8), and hair loss (n = 2). Conclusion: With our prospective results, we provide further real‐world data to support the favorable benefit/risk profile of fremanezumab in the prophylaxis of both HFEM and CM. [ABSTRACT FROM AUTHOR]

Objective: To define, in a real-world population of patients with high-frequency episodic (HFEM) or chronic migraine (CM), the predictive role of socio-demographic or phenotypic profiling of responders to fremanezumab. Patients and methods: Two-hundred and four adult fremanezumab-treated patients with either HFEM or CM, who failed to at least three preventive treatments, provided data at baseline on several individual socio-demographic and phenotypic variables. These variables were analyzed for their ability to independently predict the response (50–74% response rates) or super-response (≥ 75% response rates) to fremanezumab. Patients were followed from 3–18 months of fremanezumab exposure. Results: The main finding to emerge from univariate analyses was that three baseline socio-demographic/clinical variables, i.e., age group 41–70 years (p = 0.02); female gender (p = 0.03); patients with HFEM (p = 0.001), and three clinical phenotypic variables, i.e., strict unilateral pain (p = 0.05); pain in the ophthalmic trigeminal branch (p = 0.04); and the "imploding" quality of pain (p = 0.05), were significantly related to fremanezumab response. However, in multivariate analysis, only HFEM (p = 0.02), the presence of strict unilateral (p = 0.03), and pain location in the ophthalmic trigeminal branch (p = 0.036) were independently associated with good fremanezumab response. Allodynia (p = 0.04) was the only clinical predictive variable of super-responsiveness to fremanezumab. Conclusions: A precise phenotypic profiling with identification of pain characteristics consistent with peripheral and/or central sensitization might reliably predict the responsiveness to fremanezumab in migraine prophylaxis. [ABSTRACT FROM AUTHOR]

Background: To examine whether the modulating evoked cortical oscillations could be brain signatures among patients with chronic migraine, we investigated cortical modulation using an electroencephalogram with machine learning techniques. Methods: We directly record evoked electroencephalogram activity during nonpainful, painful, and repetitive painful electrical stimulation tasks. Cortical modulation for experimental pain and habituation processing was analyzed and used to differentiate patients with chronic migraine from healthy controls using a validated machine-learning model. Results: This study included 80 participants: 40 healthy controls and 40 patients with chronic migraine. Evoked somatosensory oscillations were dominant in the alpha band. Longer latency (nonpainful and repetitive painful) and augmented power (nonpainful and repetitive painful) were present among patients with chronic migraine. However, for painful tasks, alpha increases were observed among healthy controls. The oscillatory activity ratios between repetitive painful and painful tasks represented the frequency modulation and power habituation among healthy controls, respectively, but not among patients with chronic migraine. The classification models with oscillatory features exhibited high performance in differentiating patients with chronic migraine from healthy controls. Conclusion: Altered oscillatory characteristics of sensory processing and cortical modulation reflected the neuropathology of patients with chronic migraine. These characteristics can be reliably used to identify patients with chronic migraine using a machine-learning approach. [ABSTRACT FROM AUTHOR]

Background: Migraine is a disabling neurological disease adversely affecting many aspects of life. Most patients are still required to have failed several older oral preventive therapies before being reimbursed for a preventive, migraine-specific anti-calcitonin gene-related peptide treatment. In the 24-week placebo-controlled portion of DELIVER, eptinezumab was shown to reduce migraine frequency and resulted in higher migraine responder rates compared with placebo in patients with two to four previous preventive treatment failures. This subgroup analysis assessed if demographic or clinical characteristics were associated with differences in preventive benefits. Methods: Migraine frequency reductions and responder rates (i.e., the proportion of patients reaching a ≥50% and ≥75% reduction in monthly migraine days relative to baseline) were determined in the total population and predefined subgroups by sex, age, migraine frequency (chronic migraine, episodic migraine, high-frequency episodic migraine, low-frequency episodic migraine), medication overuse, medication-overuse headache, and previous preventive treatment failures (2, >2). The primary endpoint was change from baseline in monthly migraine days over weeks 1–12. Results: Eptinezumab 100 and 300 mg reduced monthly migraine days more than placebo over weeks 1–12 (−4.8 and −5.3 vs –2.1, respectively; p < 0.0001). In most subgroups, eptinezumab-treated patients demonstrated larger monthly migraine days reductions from baseline over weeks 1–12 than patients receiving placebo, with reductions maintained or increased over weeks 13–24. For ≥50% and ≥75% migraine responder rates, the odds ratios versus placebo all numerically favored eptinezumab. Conclusion: Eptinezumab had larger monthly migraine days reductions and higher responder rates than placebo across clinically relevant subgroups showing that, across different demographic populations and clinical characteristics, eptinezumab is effective in patients with migraine and prior preventive treatment failures. Trial Registration: ClinicalTrials.gov (Identifier: NCT04418765) [ABSTRACT FROM AUTHOR]

Background: Social cognition refers to all mental operations to decipher information needed in social interactions. Here we aimed to outline the socio-cognitive profile of Chronic Migraine with Medication Overuse (CM + MO), given they are recognized to be at risk of socio-cognitive difficulties. Given the multidimensionality of this construct, we considered: (1) socio-cognitive abilities, (2) socio-cognitive beliefs, (3) alexithymia and autism traits, and (4) social relationships. Methods: Seventy-one patients suffering from CM + MO, 61 from episodic migraine (EM), and 80 healthy controls (HC) were assessed with a comprehensive battery: (1) the Faux Pas test (FP), the Strange Stories task (SS), the Reading Mind in the Eyes test (RMET), (2) the Tromsø Social Intelligence Scale, (3) the Toronto Alexithymia Scale, the Autism Spectrum Quotient, (4) the Lubben Social Network Scale, the Friendship Scale. Results: CM + MO: (1) performed similar to EM but worse than HC in the FP and SS, while they were worse than EM and HC in the RMET; (2) were similar to EM and HC in social intelligence; (3) had more alexithymic/autistic traits than EM and HC; (4) reported higher levels of contact with their family members but felt little support from the people around them than HC. Conclusions: CM + MO results characterized by a profile of compromised socio-cognitive abilities that affects different dimensions. These findings may have a relevant role in multiple fields related to chronic headache: from the assessment to the management. [ABSTRACT FROM AUTHOR]

Background: Central sensitization has been widely accepted as an underlying pathophysiological mechanism of chronic migraine (CM), activation of cannabinoid type-1 receptor (CB1R) exerts antinociceptive effects by relieving central sensitization in many pain models. However, the role of CB1R in the central sensitization of CM is still unclear. Methods: A CM model was established by infusing inflammatory soup (IS) into the dura of male Wistar rats for 7 days, and hyperalgesia was assessed by the mechanical and thermal thresholds. In the periaqueductal gray (PAG), the mRNA and protein levels of CB1R and hyperpolarization-activated cyclic nucleotide-gated cation channel 2 (HCN2) were measured by qRT–PCR and western blotting. After intraventricular injection of Noladin ether (NE) (a CB1R agonist), ZD 7288 (an HCN2 blocker), and AM 251 (a CB1R antagonist), the expression of tyrosine phosphorylation of N-methyl-D-aspartate receptor subtype 2B (pNR2B), calcium-calmodulin-dependent kinase II (CaMKII), and phosphorylated cAMP-responsive element binding protein (pCREB) was detected, and central sensitization was evaluated by the expression of calcitonin gene-related peptide (CGRP), c-Fos, and substance P (SP). Synaptic-associated protein (postsynaptic density protein 95 (PSD95) and synaptophysin (Syp)) and synaptic ultrastructure were detected to explore synaptic plasticity in central sensitization. Results: We observed that the mRNA and protein levels of CB1R and HCN2 were both significantly increased in the PAG of CM rats. The application of NE or ZD 7288 ameliorated IS-induced hyperalgesia; repressed the pNR2B/CaMKII/pCREB pathway; reduced CGRP, c-Fos, SP, PSD95, and Syp expression; and inhibited synaptic transmission. Strikingly, the application of ZD 7288 relieved AM 251-evoked elevation of pNR2B, CGRP, and c-Fos expression. Conclusions: These data reveal that activation of CB1R alleviates central sensitization by regulating HCN2-pNR2B signaling in CM rats. The activation of CB1R might have a positive influence on the prevention of CM by mitigating central sensitization. [ABSTRACT FROM AUTHOR]

Background: Migraine is one of the most prevalent and disabling medical diseases in the world. The periaqueductal gray matter and the red nucleus play an important role in its pathogenesis. Our aim was to evaluate the echogenicity of the periaqueductal gray matter and the red nucleus in patients with migraine, by means of transcranial ultrasound. Methods: In this cross-sectional study, a group of patients with migraine (according to the International Classification of Headache Disorders) and a group of control subjects with comparable age-and-sex distribution were prospectively included. We evaluated the area and echogenicity of the periaqueductal gray matter and the red nucleus by means of transcranial ultrasound, both bedside and posteriorly analyzed with the medical image viewer Horos. Results: We included 115 subjects: 65 patients with migraine (39 of them with chronic migraine and 26 with episodic migraine), and 50 controls. Median disease duration in patients with chronic migraine was 29 (IQR: 19; 40) years, with a median of 18 (IQR: 14; 27) days of migraine per month. The area of the periaqueductal gray matter was larger in patients with chronic migraine compared to episodic migraine and controls (0.15[95%CI 0.12;0.22]cm2; 0.11[95%CI 0.10;0.14]cm2 and 0.12[95%CI 0.09;0.15]cm2, respectively; p = 0.043). Chronic migraine patients showed an intensity of the periaqueductal gray matter echogenicity lower than controls (90.57[95%CI 70.87;117.26] vs 109.56[95%CI 83.30;122.64]; p = 0.035). The coefficient of variation of periaqueductal gray matter echogenicity was the highest in chronic migraine patients (p = 0.009). No differences were observed regarding the area or intensity of red nucleus echogenicity among groups. Conclusion: Patients with chronic migraine showed a larger area of echogenicity of periaqueductal gray matter, a lower intensity of its echogenicity and a higher heterogenicity within this brainstem structure compared to patients with episodic migraine and controls. The echogenicity of the periaqueductal gray matter should be further investigated as a biomarker of migraine chronification. [ABSTRACT FROM AUTHOR]

Background: No available studies demonstrate validity and meaningful change thresholds of Work Productivity and Activity Impairment (WPAI) questionnaire in patients with migraine. In this post-hoc analysis, we assessed reliability, validity, responsiveness, and meaningful within-patient change from baseline to Month 3 for Work Productivity and Activity Impairment (WPAI) domain scores in patients with episodic migraine (EM) or chronic migraine (CM). Method: The Phase 3, multicenter, randomized, double-blind, placebo-controlled CONQUER study (NCT03559257, N = 462) enrolled patients with EM or CM who failed two to four categories of prior preventive medication in past ten years. The analyses were performed for WPAI domain scores (absenteeism, presenteeism, overall work productivity, and non-work-related activity impairment). Migraine Specific Quality of Life Questionnaire version 2.1 (MSQv2.1) domain scores (Role Function-Restrictive [RFR] and Role Function-Preventive [RFP]), and monthly migraine headache days were used as anchors. Responder criteria were changes from baseline to Month 3 for each of these anchors and were defined as: increase in MSQ-RFR by ≥ 25.71 points and MSQ-RFP by ≥ 20.00 points and a 50% reduction in monthly migraine headache days. Assessments were performed for overall population, and patients with EM or CM. The meaningful change threshold was determined based on Youden index, Phi coefficient and sensitivity. Results: Of 462 randomized patients, 444 who completed WPAI questionnaire were included in post-hoc analysis. Test–retest reliability over 3 months in a stable subgroup revealed moderate correlations for non-work-related Activity Impairment (ICC = 0.446) presenteeism (ICC = 0.438) and a fair correlation for overall work productivity loss (ICC = 0.360). At baseline, all correlations between WPAI domain scores and continuous anchor variables exceeded recommended threshold of ≥ 0.30, except for WPAI domain scores with number of monthly migraine headache days. Patients achieving pre-specified responsiveness thresholds for monthly migraine headache days, and MSQ-RFP, MSQ-RFR from baseline to Month 3 (responders) showed significant improvements in WPAI domain scores compared with non-responders (P < 0.001). The meaningful change thresholds of -20 (% unit) were identified for WPAI domain scores. Conclusion: In conclusion, WPAI has sufficient validity, reliability, responsiveness, and appropriate interpretation standards to assess the impact of EM or CM on presenteeism and overall work productivity loss and non-work-related activity impairment. Trial registration: NCT number of CONQUER study, NCT03559257. [ABSTRACT FROM AUTHOR]

(1) Background: Randomized controlled trials and real-life studies demonstrated the efficacy of OnabotulinumtoxinA (OBT-A) for CM prevention. However, no studies specifically addressed its effect on pain's quantitative intensity and qualitative characteristics. (2) Methods: This is an ambispective study: a post-hoc retrospective analysis of real-life prospectively collected data from two Italian headache centers on CM patients treated with OBT-A over one year (i.e., Cy1-4). The primary endpoint was the changes in pain intensity (Numeric Rating Scale, NRS; the Present Pain Intensity (PPI) scale, the 6-point Behavioral Rating Scale (BRS-6)) and quality scale (the short-form McGill Pain Questionnaire (SF-MPQ)) scores. We also assessed the relationship between changes in intensity and quality of pain and disability scale (MIDAS; HIT-6) scores, monthly headache days (MHDs), and monthly acute medication intake (MAMI) (3) Results: We retrieved 152 cases (51.5 years SD 11.3, 80.3% females). From baseline to Cy-4, MHDs, MAMI, NRS, PPI, and BRS-6 scores decreased (consistently p < 0.001). Only the throbbing (p = 0.004), splitting (p = 0.018), and sickening (p = 0.017) qualities of pain collected in the SF-MPQ were reduced. Score variations in MIDAS related to those in PPI scales (p = 0.035), in the BRS-6 (p = 0.001), and in the NRS (p = 0.003). Similarly, HIT-6 score changes related to PPI score modifications (p = 0.027), in BRS-6 (p = 0.001) and NRS (p = 0.006). Conversely, MAMI variation was not associated with qualitative or quantitative pain score modifications except BRS-6 (p = 0.018). (4) Conclusions: Our study shows that OBT-A alleviates migraine by reducing its impact on multiple aspects, such as frequency, disability, and pain intensity. The beneficial effect on pain intensity seems specific to pain characteristics related to C-fiber transmission and is associated with a reduction in migraine-related disability. [ABSTRACT FROM AUTHOR]

Migraine disorders are common in populations of children and adolescents. There are different pharmacological treatments for migraine in young patients, but none have specific indications, and doubts about their efficacy exist. The feasibility and effectiveness of behavioral approaches have already been documented in clinical experiences, and they are generally associated with fewer or no unpleasant effects. Among them, mindfulness practice offers a suitable alternative to other adolescent treatments. We present the results of a pilot study, the Be-Home Kids program, performed during the COVID-19 emergency. It was delivered by web and included education on drug use, lifestyle issues, and six sessions of mindfulness-based behavioral practice. We assessed headache frequency, medication intake, and other psychological variables and followed twenty-one adolescents with chronic or high-frequency episodic migraine without aura for 12 months. Results indicated an overall clinical improvement, particularly a 64% reduction in headache frequency over 12 months. In conclusion, our results indicate that a combined treatment which includes patients' education and six sessions of mindfulness-based practice delivered over the web, can be of great support in reducing headache frequency, medication intake, and the associated psychological burden disability in adolescent migraine patients. [ABSTRACT FROM AUTHOR]

Background: Chronic headaches and medication overuse headache are common and burdening conditions. No studies have evaluated the prevalence of chronic headache and medication overuse headache in an unselected Italian population. Methods: We performed a three-year cross-sectional and longitudinal population-based study to investigate prevalence, natural history, and prognostic factors of chronic headache. We delivered a self-administered questionnaire to 25,163 subjects. Chronic headache patients were interviewed by General Practitioners. After three years, medication overuse headache patients were invited to undergo a neurological evaluation at our Center. Results: 16,577 individuals completed the questionnaire; 6878 (41,5%) were episodic headache sufferers and 636 (3.8%) were chronic headache subjects. 239 (1.4%) patients were acute medication over-users. All medication overuse headache patients had migraine or headache with migrainous features. At the three-year follow-up of 98 patients, we observed conversion to episodic headaches in 53 (54.1%) patients. 27 (50.9%) patients remitted spontaneously. Conclusions: We present the first prevalence data on chronic headache and medication overuse headache in an unselected Italian population and a high rate of spontaneous remission. These data support the interpretation of medication overuse headache as a specific migraine-related disorder that may reflect chronic migraine's dynamic nature, the need for more specific medication overuse headache diagnostic criteria, and highlight the priority of targeted public health policies. [ABSTRACT FROM AUTHOR]