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Abstract Background Migraine is a complex neurological disorder with significant heterogeneity in its clinical presentation and molecular mechanisms. Calcitonin gene-related peptide (CGRP) has emerged as a key player in migraine pathophysiology, but challenges remain in its utilization as a biomarker. This study aimed to investigate salivary CGRP levels during migraine attacks across the frequency spectrum and explore associations with clinical variables. Methods A prospective longitudinal pilot study was conducted, recruiting migraine patients from an outpatient headache clinic. Salivary CGRP levels were measured at interictal, onset, post-2 h of onset and end-of-attack. Using generalized linear mixed models, we explored the effect of CGRP changes over the attack in presence of depressive symptoms (DS), acute attack treatment, and after three-months of erenumab treatment. Finally, patients were classified and compared according to their CGRP phenotype. Results A total of 44 migraine patients were included (90.9% women), with 80 migraine attacks analyzed. Salivary CGRP levels increased at the onset of migraine attacks. We observed statistically significant interactions between DS and both the linear (Est. [SE]: 19.4 [5.8], p = 0.001) and quadratic terms of time (-19.1 [6.0], p = 0.002). Additionally, a significant three-way interaction within the use of acute treated attack (linear-term: -18.5 [6.2], p = 0.005; quadratic-term: 19.2 [6.8], p = 0.005) was also found. Molecular phenotyping revealed that 72.7% (32/44) of patients presented only CGRP-dependent attacks, while 27.3% (12/44) presented non-CGRP-dependent migraine attacks. Patients with only CGRP-dependent attacks were associated with younger age, shorter disease evolution time, a higher proportion of aura, and fewer monthly headache days (p

The situation derived from the Coronavirus disease (COVID-19) and lockdowns ordered to control the pandemic led to unprecedented problems in different areas of people’s well-being. This study aimed to explore the acute effects of the first lockdown on self-perceived sleep quality, as well as the risk/protective factors that modulated this impact. The sample was composed by 1,275 respondents ranging in age from 18 to 55 years. Participants wererecruited during the COVID-19 first lockdown in Spain. They wereevaluated regarding theirself reported sleep problems before and during lockdown, as well as other areas related to the impact of lockdown (e.g., on diet, physical activity, or use of digital media), psychological states (positive and negative affect), and traits (impulsivity). Most participants (66.7%) reported a decrease in their self-perceived sleep quality during the pandemic. Correlational analyses showed that maintaining good levels of physical activity and diet quality during the pandemic were positively associated with sleep quality; furthermore, greater levels of positive affect, living in bigger homes during lockdown, and age were positively associated with sleep quality as well. On the contrary, negative affect, female sex, and the impact of the pandemic on various domains (mental health, relationship quality, personal finances, and the use of digital media) were negatively related to self-perceived sleep quality. In brief, this study supports the impact of the COVID-19 pandemic on self-perceived sleep quality and provides a preliminary foundation for identifying protective and risk factors contributing to sleep quality during lockdowns and other situations of distress.

El consumo de pornografía es una práctica muy extendida. En la mayoría de casos, no conlleva consecuencia negativa alguna; no obstante, algunas personas desarrollan un patrón de consumo excesivo y problemático. Uno de los factores que aumenta el riesgo de desarrollar un uso problemático de pornografía (UPP) es el estado de ánimo disfórico (concretamente, el estado de ánimo depresivo). Asimismo, la rumiación (forma disfuncional de regulación emocional) perpetúa el malestar emocional, lo cual podría exacerbar el vínculo entre depresión y UPP. El objetivo de este estudio fue examinar si la rumiación mediaba o moderaba la relación entre depresión, frecuencia de uso de pornografía (FUP) y UPP. Con este propósito, 220 participantes entre 18-74 años completaron una batería de cuestionarios online donde se evaluaban las principales variables del estudio. La depresión tuvo un efecto directo, positivo y significativo en el UPP ( =0.96***), pero no en la FUP ( =-0.02). De igual modo, la rumiación tuvo un efecto directo, positivo y significativo en el UPP ( =0.12*), pero no en la FUP ( =0.008). En cuanto a los análisis de mediación, la rumiación no mediaba entre la depresión y el UPP ( =0.01), pero sí entre la depresión y la FUP ( =0.03*). Asimismo, la rumiación no moderó la relación entre depresión y FUP ( =0.001) ni entre depresión y UPP ( =-0.003). Estos resultados sugieren que el estado emocional modula fuertemente el consumo de pornografía (aumentando el riesgo de desarrollar un UPP), pero que la rumiación no media este vínculo ni modera su relación. El único caso en el que la rumiación desempeña un papel a la hora de explicar el nexo entre depresión y pornografía es en el caso de la FUP. Así, es posible que personas con depresión y tendencia a rumiar usen la pornografía con mayor frecuencia, pero no por ello de forma más problemática.

Abstract Background Migraine is one of the main causes of disability worldwide. Anti-CGRP monoclonal antibodies (MAbs) have proven to be safe and efficacious as preventive migraine treatments. However, their use is restricted in many countries due to their apparently high cost. Cost-benefit studies are needed. Objective To study the cost-benefit of anti-CGRP MAbs in working-age patients with migraine. Methods This is a prospective cohort study of consecutive migraine patients treated with anti-CGRP MAbs (erenumab, fremanezumab and galcanezumab) following National reimbursement policy in a specialized headache clinic. Migraine characteristics and the work impact scale (WPAI) were compared between baseline (M0) and after 3 (M3) and 6 months (M6) of treatment. Using WPAI and the municipal average hourly wage, we calculated indirect costs (absenteeism and presenteeism) at each time point. Direct costs (emergency visits, acute medication use) were also analysed. A cost-benefit study was performed considering the different costs and savings of treating with MAbs. Based on these data an annual projection was conducted. Results From 256 treated working-age patients, 148 were employed (89.2% women; mean age 48.0 ± 8.5 years), of which 41.2% (61/148) were responders (> 50% reduction in monthly headache days (MHD)). Statistically significant reductions between M0 and M3/M6 were found in absenteeism (p

BackgroundReal-world studies have shown the sustained therapeutic effect and favourable safety profile of OnabotulinumtoxinA (BoNTA) in the long term and up to 4 years of treatment in chronic migraine (CM). This study aims to assess the safety profile and efficacy of BoNTA in CM after 5 years of treatment in a real-life setting.MethodsWe performed a retrospective chart review of patients with CM in relation to BoNTA treatment for more than 5 years in 19 Spanish headache clinics. We excluded patients who discontinued treatment due to lack of efficacy or poor tolerability.Results489 patients were included [mean age 49, 82.8% women]. The mean age of onset of migraine was 21.8 years; patients had CM with a mean of 6.4 years (20.8% fulfilled the aura criteria). At baseline, patients reported a mean of 24.7 monthly headache days (MHDs) and 15.7 monthly migraine days (MMDs). In relation to effectiveness, the responder rate was 59.1% and the mean reduction in MMDs was 9.4 days (15.7 to 6.3 days; p

Abstract Tris(trifluoromethyl)copper(III), Cu(CF3)3, was prepared for the first time and fully characterized in the form of weakly coordinated highly reactive solvent neutral adducts (DMF)2Cu(CF3)3 and (MeCN)Cu(CF3)3. Free Cu(CF3)3 is an elusive molecule of distorted T‐shaped geometry with Lewis acid properties, which is stabilized by solvation. Substitution of solvent molecules with monoanionic ligands in mild conditions afforded the first Cu(III)(CF3)3 carboxylates [Cu(CF3)3(OAc)]− and [Cu(CF3)3(OBz)]− and Cu(III) nitrito complex [Cu(CF3)3(ONO)]−. An improved synthesis of valuable Grushin's trifluoromethylation reagents via the intermediacy of (MeCN)Cu(CF3)3 was developed. (DMF)2Cu(CF3)3 demonstrated promising properties in photoinduced radical C‐H trifluoromethylation. Oxidation state theoretical studies showed the Cu(CF3)3 compounds to be borderline between classical Cu(III) and inverted ligand field Cu(I) assignment.

The health and socio-economic challenges arising from the COVID-19 pandemic have led to greater reliance on the internet to meet basic needs and responsibilities. Greater engagement in online activities may have negative mental and physical health consequences for some vulnerable individuals, particularly under mandatory self-isolation or ‘lockdown’ conditions. The present study investigated whether changes in levels of involvement in online activities during the COVID-19 pandemic (i.e., watching TV series, online sexual activities, video games, social networks, gambling, online shopping, and instant messaging) were associated with problematic internet use, as well as whether certain psychological risk factors (positive/negative affect and impulsivity) were significant predictors of these changes. A total of 1,275 participants (66.1% female, aged between 18-55 years) completed an online survey while in lockdown in Spain (April 15th-23rd, 2020). The survey assessed current engagement in seven different online activities and their engagement prior to the COVID-19 pandemic, as well as psychological risk factors (affect and impulsivity). Most participants (between 60.8%-98.6% depending on the activity) reported no changes in participation in online activities, but there was a significant increase in weekly internet use (between 25 and 336 min). However, increased internet use was not accompanied by a corresponding increase in problematic use, except for problematic TV series watching and video gaming. Psychological risk factors considered in the study (affect, impulsivity traits) were largely minor or non-significant predictors. Thus, increased internet use during the lockdown in Spain was not related to a proportional growth in problematic usage, suggesting that these behavioral changes may constitute adaptive coping strategies in the context of the pandemic.

Abstract Background Migraine is a cyclic, neurosensory disorder characterized by recurrent headaches and altered sensory processing. The latter is manifested in hypersensitivity to visual stimuli, measured with questionnaires and sensory thresholds, as well as in abnormal cortical excitability and a lack of habituation, assessed with visual evoked potentials elicited by pattern-reversal stimulation. Here, the goal was to determine whether factors such as age and/or disease severity may exert a modulatory influence on sensory sensitivity, cortical excitability, and habituation. Methods Two similar experiments were carried out, the first comparing 24 young, episodic migraine patients and 28 healthy age- and gender-matched controls and the second 36 middle-aged, episodic migraine patients and 30 healthy age- and gender-matched controls. A neurologist confirmed the diagnoses. Migraine phases were obtained using eDiaries. Sensory sensitivity was assessed with the Sensory Perception Quotient and group comparisons were carried out. We obtained pattern-reversal visual evoked potentials and calculated the N1-P1 Peak-to-Peak amplitude. Two linear mixed-effects models were fitted to these data. The first model had Block (first block, last block) and Group (patients, controls) as fixed factors, whereas the second model had Trial (all trials) and Group as fixed factors. Participant was included as a random factor in both. N1-P1 first block amplitude was used to assess cortical excitability and habituation was defined as a decrease of N1-P1 amplitude across Blocks/Trials. Both experiments were performed interictally. Results The final samples consisted of 18 patients with episodic migraine and 27 headache-free controls (first experiment) and 19 patients and 29 controls (second experiment). In both experiments, patients reported increased visual hypersensitivity on the Sensory Perception Quotient as compared to controls. Regarding N1-P1 peak-to-peak data, there was no main effect of Group, indicating no differences in cortical excitability between groups. Finally, significant main effects of both Block and Trial were found indicating habituation in both groups, regardless of age and headache frequency. Conclusions The results of this study yielded evidence for significant hypersensitivity in patients but no significant differences in either habituation or cortical excitability, as compared to headache-free controls. Although the alterations in patients may be less pronounced than originally anticipated they demonstrate the need for the definition and standardization of optimal methodological parameters.

Chronic migraine (CM) significantly affects underage individuals. The study objectives are (1) to analyze the effectiveness and safety of onabotulinumtoxinA (BTX-A) in adolescents with CM; (2) to review the literature on BTX-A use in the pediatric population. This prospective observational study included patients under 18 years old with CM treated with BTX-A (PREEMPT protocol) as compassionate use. Demographic, efficacy (monthly headache days—MHD; monthly migraine days—MMD; acute medication days/month—AMDM) and side effect data were collected. A ≥ 50% reduction in MHD was considered as a response. Effectiveness and safety were analyzed at 6 and 12 months. A systematic review of the use of BTX-A in children/adolescents was conducted in July 2023. In total, 20 patients were included (median age 15 years [14.75–17], 70% (14/20) females). The median basal frequencies were 28.8 [20–28] MHD, 18 [10–28] MMD and 10 [7.5–21.2] AMDM. Compared with baseline, at 6 months (n = 20), 11 patients (55%) were responders, with a median reduction in MHD of −20 days/month (p = 0.001). At 12 months (n = 14), eight patients (57.1%) were responders, with a median reduction in MHD of −17.5 days/month (p = 0.002). No adverse effects were reported. The literature search showed similar results. Our data supports the concept that BTX-A is effective, well tolerated, and safe in adolescents with CM resistant to oral preventatives.

Abstract Background Anti-CGRP monoclonal antibodies have shown notable effectiveness and tolerability in migraine patients; however, data on their use in elderly patients is still lacking, as clinical trials have implicit age restrictions and real-world evidence is scarce. In this study, we aimed to describe the safety and effectiveness of erenumab, galcanezumab and fremanezumab in migraine patients over 65 years old in real-life. Methods In this observational real-life study, a retrospective analysis of prospectively collected data from 18 different headache units in Spain was performed. Migraine patients who started treatment with any anti-CGRP monoclonal antibody after the age of 65 years were included. Primary endpoints were reduction in monthly migraine days after 6 months of treatment and the presence of adverse effects. Secondary endpoints were reductions in headache and medication intake frequencies by months 3 and 6, response rates, changes in patient-reported outcomes and reasons for discontinuation. As a subanalysis, reduction in monthly migraine days and proportion of adverse effects were also compared among the three monoclonal antibodies. Results A total of 162 patients were included, median age 68 years (range 65–87), 74.1% women. 42% had dyslipidaemia, 40.3% hypertension, 8% diabetes, and 6.2% previous cardiovascular ischaemic disease. The reduction in monthly migraine days at month 6 was 10.1 ± 7.3 days. A total of 25.3% of patients presented adverse effects, all of them mild, with only two cases of blood pressure increase. Headache and medication intake frequencies were significantly reduced, and patient-reported outcomes were improved. The proportions of responders were 68%, 57%, 33% and 9% for reductions in monthly migraine days ≥ 30%, ≥ 50%, ≥ 75% and 100%, respectively. A total of 72.8% of patients continued with the treatment after 6 months. The reduction in migraine days was similar for the different anti-CGRP treatments, but fewer adverse effects were detected with fremanezumab (7.7%). Conclusions Anti-CGRP mAbs are safe and effective treatments in migraine patients over 65 years old in real-life clinical practice. Graphical Abstract

Abstract Background Several studies have described potential microRNA (miRNA) biomarkers associated with migraine, but studies are scarcely reproducible primarily due to the heterogeneous variability of participants. Increasing evidence shows that disease-related intrinsic factors together with lifestyle (environmental factors), influence epigenetic mechanisms and in turn, diseases. Hence, the main objective of this exploratory study was to find differentially expressed miRNAs (DE miRNA) in peripheral blood mononuclear cells (PBMC) of patients with migraine compared to healthy controls in a well-controlled homogeneous cohort of non-menopausal women. Methods Patients diagnosed with migraine according to the International Classification of Headache Disorders (ICHD-3) and healthy controls without familial history of headache disorders were recruited. All participants completed a very thorough questionnaire and structured-interview in order to control for environmental factors. RNA was extracted from PBMC and a microarray system (GeneChip miRNA 4.1 Array chip, Affymetrix) was used to determine the miRNA profiles between study groups. Principal components analysis and hierarchical clustering analysis were performed to study samples distribution and random forest (RF) algorithms were computed for the classification task. To evaluate the stability of the results and the prediction error rate, a bootstrap (.632 + rule) was run through all the procedure. Finally, a functional enrichment analysis of selected targets was computed through protein–protein interaction networks. Results After RF classification, three DE miRNA distinguished study groups in a very homogeneous female cohort, controlled by factors such as demographics (age and BMI), life-habits (physical activity, caffeine and alcohol consumptions), comorbidities and clinical features associated to the disease: miR-342-3p, miR-532-3p and miR-758-5p. Sixty-eight target genes were predicted which were linked mainly to enriched ion channels and signaling pathways, neurotransmitter and hormone homeostasis, infectious diseases and circadian entrainment. Conclusions A 3-miRNA (miR-342-3p, miR-532-3p and miR-758-5p) novel signature has been found differentially expressed between controls and patients with migraine. Enrichment analysis showed that these pathways are closely associated with known migraine pathophysiology, which could lead to the first reliable epigenetic biomarker set. Further studies should be performed to validate these findings in a larger and more heterogeneous sample.

Background and Purpose Methods Results Conclusions Patients presenting at the emergency room (ER) with headache often encounter a hostile atmosphere and experience delays in diagnosis and treatment. The aim of this study was to design a protocol for the ER with the goal of optimizing the care of patients with urgent headache to facilitate diagnosis and expedite treatment.A narrative literature review was conducted via a MEDLINE search in October 2021. The “Code Headache” protocol was then developed considering the available characteristics and resources of the ER at a tertiary care center within the Spanish National Public Health system.The Code Headache protocol comprises three assessments: two scales and one checklist. The assessments identify known red flags and stratify patients based on suspected primary/secondary headaches and the need for pain treatment. Initial assessments, performed by the triage nurse, aim to first exclude potentially high morbidity and mortality etiologies (HEAD1 scale) and then expedite appropriate pain management (HEAD2 scale) based on scoring criteria. HEAD1 evaluates vital signs and symptoms of secondary serious headache disorders that can most benefit from earlier identification and treatment, while HEAD2 assesses symptoms indicative of status migrainosus, pain intensity, and vital signs. Subsequently, ER physicians employ a third assessment that reviews red flags for secondary headaches (grouped under the acronym ‘PEACE’) to guide the selection of complementary tests and aid diagnosis.The Code Headache protocol is a much needed tool to facilitate quick clinical assessment and improve patient care in the ER. Further validation through comparison with standard clinical practice is warranted. [ABSTRACT FROM AUTHOR]

Migraine-related stigma is a pervasive issue impacting nearly half of chronic migraine patients, with significant consequences for their quality of life, disability and mental health. Despite its profound effects, migraine stigma remains under-recognised in both clinical practice and research. This narrative review explores the three primary types of stigmas affecting migraine patients: public, structural and internalised. Public stigma involves negative societal attitudes and stereotypes that trivialise the condition. Structural stigma is reflected in policies that restrict access to necessary care and resources. Internalised stigma occurs when patients absorb these negative views, leading to self-blame and diminished self-worth. Addressing these different types of stigmas is crucial for improving the understanding, diagnosis and treatment of migraine. Educational efforts, advocacy and policy reform are essential strategies in this context. A deep understanding of stigma is vital for developing effective interventions that enhance clinical management and patient quality of life. Ultimately, reducing stigma can lead to better health outcomes and a more comprehensive approach to migraine care. [ABSTRACT FROM AUTHOR]

Abstract Background Patient-Reported Outcomes (PROs) have been developed to numerically quantify disability, impact and quality of life. They have been widely used in migraine clinical trials. However, we still do not know which PRO more accurately reflects preventive treatment response from a patient’s perspective or which one may help us with treatment decisions in clinical practice. They have been used to enforce the efficacy results in clinical trials and real-world evidence so far. The aim of this study was to analyze which PROM is (1) better correlated with all primary efficacy endpoints and (2) which one is better associated with treatment continuation with CGRP-mAbs at week-12, which is usually the moment when this decision is made. Methods Patients with migraine who had received 3 administrations of CGRP-mAbs were evaluated in this prospective cohort study. Primary efficacy outcomes considered: a change in migraine days (MMD), headache days (MHD), pain intensity (INT), acute medication days (AMD) and 50% responder rate. The Spearman coefficient (rs) was the measure used for quantify the strength of the correlation between PROMs and treatment efficacy outcomes changes. A stepwise logistic regression identified which PROM was independently associated with treatment continuation at week-12. Results 263 patients completed 12 weeks of treatment. The efficacy outcomes and PROMs scores were statistically significantly reduced at week-12 for all patients. The role function-restrictive (RFR) domain of the Migraine-Specific Quality of Life (MSQ) questionnaire was statistically significantly correlated with all primary efficacy outcomes. Relative changes in MSQ total score (OR[95%]: 0.840[0.619-0.973]; p=0.037) and Patient Global Impression of Change (PGIC) scale (OR[95%]: 15.569[6.254-31.533]; p