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BACKGROUND: We wished to explore possible sexual dimorphism in mechanisms sensitizing or activating meningeal nociceptors that can promote the headache phase of migraine. METHODS: Male and female C57BL6J mice received either supradural orexin B and an inflammatory mediator cocktail (IM) with migraine-like pain behaviors and photophobia recorded. Expression of orexin 2 receptor (OX2R) in trigeminal ganglion (TG) and phosphorylated extracellular signal-regulated kinases (ERK) levels in trigeminal nucleus caudalis (TNC) were evaluated. Orexin B-induced excitability of TG cells was assessed with patch-clamp electrophysiology. Intranasal delivery of CRISPR/Cas9 plasmids was used to edit the expression of OX2R in the TG. RESULTS: Supradural orexin B induced migraine-like pain behaviors, photophobia and increased TNC ERK phosphorylation exclusively in males. Blockade of orexin signaling with supradural suvorexant, a dual orexin receptor antagonist, prevented, but did not reverse, migraine-like pain in males induced by supradural IM cocktail. OX2R expression was higher in male TG and orexin B increased TG neuron excitability in males. Intranasal OX2R CRISPR/Cas9 reduced TG receptor expression and orexin B-induced TNC ERK phosphorylation and prevented migraine-like pain induced by supradural orexin B in males. CONCLUSIONS: Our studies reveal a male-specific mechanism of TG nociceptor sensitization and migraine-like pain behavior mediated by orexin B/OX2R signaling. Sexually dimorphic mechanisms of trigeminal nociceptor sensitization and activation offer opportunities to improve patient outcomes by considering patient sex and may influence clinical trial design and interpretation.

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Importance: Patients with chronic migraine and medication overuse headaches (CM-MOH) represent a particularly burdened subpopulation. This trial provides first, to our knowledge, American Academy of Neurology class I evidence for a preventive therapy in CM-MOH. Objective: To assess erenumab efficacy and safety in patients with nonopioid CM-MOH. Design, Settings, and Participants: This randomized, double-blind, parallel-group, placebo-controlled trial took place at 67 centers in North America, Europe, and Australia from October 7, 2019, to November 2, 2022. This report reflects the primary analysis conducted in January 2023, using a database snapshot from December 1, 2022, which contains the complete dataset of the double-blind treatment period (DBTP). Participants included adults with CM-MOH who had 1 or more preventive treatment failure(s). There were 992 participants screened and 620 participants enrolled (584 in nonopioid cohort and 36 in opioid cohort). Interventions: Erenumab, 70 mg, 140 mg, or placebo, once monthly for 24 weeks. Main Outcomes and Measures: The primary end point was MOH remission at month 6. Secondary end points included change from baseline in mean monthly acute headache medication days (AHMD) at month 6 and sustained MOH remission throughout the DBTP. Safety end points were adverse events and changes in vital signs. Results: The primary analysis population included 584 participants in the nonopioid-treated cohort with a mean age of 44 years and 482 participants were female (82.5%). Baseline demographics and disease characteristics were balanced across groups. At month 6, 134 participants in the erenumab, 140 mg group (69.1%) (odds ratio [OR], 2.01; 95% CI, 1.33-3.05; P < .001 vs placebo) and 117 in the erenumab, 70 mg group (60.3%) (OR, 1.37; 95% CI, 0.92-2.05; P = .13 vs placebo) achieved MOH remission vs 102 participants in the placebo group (52.6%). AHMD use was also reduced in the erenumab groups vs placebo. Least squares mean (standard error) change from baseline in average monthly AHMD was -9.4 (0.4) days in the erenumab, 140 mg group (difference from placebo, -2.7; 95% CI, -3.9 to -1.6; P < .001) and -7.8 (0.4) days in the erenumab, 70 mg group (difference from placebo, -1.2; 95% CI, -2.4 to -0.1; P = .03), vs -6.6 (0.4) days in the placebo group. MOH remission throughout the DBTP was sustained in 119 participants (61.3%,) 96 participants (49.5%), and 73 participants (37.6%) in the erenumab, 140 mg, 70 mg, and placebo groups, respectively. Adverse events were consistent with the known safety profile of erenumab. Treatment-emergent adverse events incidence in the combined erenumab group was 66.8% (259 participants; constipation 15.2% (59 participants) and COVID-19 13.9% (54 participants) were most common. Conclusions and Relevance: In this study, monthly, 140 mg, erenumab injections safely and effectively achieved MOH remission in patients with nonopioid CM-MOH within 6 months. Trial Registration: ClinicalTrials.gov Identifier: NCT03971071.

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BACKGROUND AND OBJECTIVES: Ubrogepant is a calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine. The PRODROME trial previously demonstrated that ubrogepant treatment during prodrome prevents the onset of moderate or severe headache. In this analysis of the PRODROME trial, the benefits of ubrogepant treatment during the prodrome on patient-reported outcomes (PROs) are evaluated. METHODS: PRODROME was a multicenter, randomized, double-blind, placebo-controlled, crossover trial that enrolled adults who experienced 2-8 migraine attacks per month with moderate-severe headache pain. Eligible participants treated 2 qualifying prodrome events, defined as a migraine attack with prodromal symptoms when the participant was confident a headache would follow within 1-6 hours. Participants were randomized to treatment sequence A (placebo then ubrogepant 100 mg) or sequence B (ubrogepant 100 mg then placebo). This analysis evaluated the ability to function normally over 24 hours (secondary end point) and at specific time points after dose (additional end point). Other PRO end points included activity limitation over 24 hours and satisfaction with study medication at 8 and 24 hours. RESULTS: Of 518 randomized participants, 477 comprised the modified intent-to-treat population. After treatment of qualifying prodrome events, a significantly greater ability to function normally over 24 hours was observed for participants after treatment with ubrogepant 100 mg compared with placebo (odds ratio [OR] 1.66, 95% CI 1.40-1.96; p < 0.0001). As early as 2 hours after dose, a greater proportion of ubrogepant-treated participants reported "no disability, able to function normally" compared with placebo (OR 1.76, 95% CI 1.32-2.35; nominal p = 0.0001). Ubrogepant administered during the prodrome was also associated with a greater reduction in activity limitations over 24 hours after dose (OR 2.07, 95% CI 1.61-2.67; nominal p < 0.0001). At 8 and 24 hours after dose, rates of being "satisfied" or "extremely satisfied" were greater for ubrogepant than for placebo (8 hours: OR 2.37, 95% CI 1.78-3.15; nominal p < 0.0001; 24 hours: OR 2.32, 95% CI 1.78-3.02; nominal p < 0.0001). DISCUSSION: Ubrogepant 100 mg administered during the prodrome was associated with significantly greater ability to function normally, greater reduction in activity limitations over 24 hours, and greater satisfaction with study medication, compared with placebo. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT04492020. Submitted: July 27, 2020; first patient enrolled: August 21, 2020. clinicaltrials.gov/ct2/show/NCT04492020. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that taking ubrogepant 100 mg during a migraine prodrome allows more patients to function normally over the next 24 hours.

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OBJECTIVE: To identify and disseminate research priorities for the headache field that should be areas of research focus during the next 10 years. BACKGROUND: Establishing research priorities helps focus and synergize the work of headache investigators, allowing them to reach the most important research goals more efficiently and completely. METHODS: The Headache Research Priorities organizing and executive committees and working group chairs led a multistakeholder and international group of experts to develop headache research priorities. The research priorities were developed and reviewed by clinicians, scientists, people with headache, representatives from headache organizations, health-care industry representatives, and the public. Priorities were revised and finalized after receiving feedback from members of the research priorities working groups and after a public comment period. RESULTS: Twenty-five research priorities across eight categories were identified: human models, animal models, pathophysiology, diagnosis and management, treatment, inequities and disparities, research workforce development, and quality of life. The priorities address research models and methods, development and optimization of outcome measures and endpoints, pain and non-pain symptoms of primary and secondary headaches, investigations into mechanisms underlying headache attacks and chronification of headache disorders, treatment optimization, research workforce recruitment, development, expansion, and support, and inequities and disparities in the headache field. The priorities are focused enough that they help to guide headache research and broad enough that they are widely applicable to multiple headache types and various research methods. CONCLUSIONS: These research priorities serve as guidance for headache investigators when planning their research studies and as benchmarks by which the headache field can measure its progress over time. These priorities will need updating as research goals are met and new priorities arise.

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Tools used for the identification, evaluation, and monitoring of concussion have not been sufficiently studied in youth or real-world settings. Normative and reliability data on sideline concussion assessment measures in the youth athlete population is needed. Pre-season normative data for 515 athletes (93.5% male) aged 5 to 16 on the Standardized Assessment of Concussion (SAC/SAC-Child), modified Balance Errors Scoring System (mBESS), Timed Tandem Gait (TTG), and the King-Devick Test (KDT) are provided. A total of 212 non-injured athletes repeated the measures post-season to assess test-retest reliability. Mean performance on the SAC-C, mBESS, TTG, and KDT tended to improve with age. KDT was the only measure that demonstrated good to excellent stability across age ranges (ICC = 0.758 to 0.941). Concentration was the only SAC/SAC-C subtest to demonstrate moderate test-retest stability (ICC = 0.503 to 0.706). TTG demonstrated moderate to good (ICC = 0.666 to 0.811) reliability. mBESS demonstrated poor to moderate reliability (ICC = -0.309 to 0.651). Commonly used measures of concussion vary regarding test-retest reliability in youth. The data support the use of at least annual sport concussion baseline assessments in the pediatric population to account for the evolution in performance as the child ages. Understanding the variation in the stability and the evolution of baseline performance will enable improved identification of possible injury.

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The small molecule calcitonin gene-related peptide receptor antagonists (gepants) are the only drug class with medicines indicated for both the acute and preventive treatment of migraine. Given this dual capacity to both treat and prevent, along with their favorable tolerability profiles and lack of an association with medication-overuse headache, headache specialists have begun to use gepants in ways that transcend the traditional categories of acute and preventive treatment. One approach, called situational prevention, directs patients to treat during the interictal phase, before symptoms develop, in situations of increased risk for migraine attacks. Herein, we present three patients to illustrate scenarios of gepant use for situational prevention. In each case, a gepant was started in anticipation of a period of increased headache probability (vulnerability) and continued for a duration of 1 day to 5 consecutive days. Although this approach may expose patients to medication when headache may not have developed, the tolerability and safety profile and preventive effect of gepants may represent a feasible approach for some patients. Situational prevention is an emerging strategy for managing migraine before symptoms develop in individuals who can identify periods when the probability of headache is high. This paper is intended to increase awareness of this strategy and stimulate future randomized, placebo-controlled trials to rigorously assess this strategy.

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OBJECTIVE: To characterize the long-term (56-week) benefits of continuous onabotulinumtoxinA treatment response in individuals with chronic migraine (CM) who achieved reduction to <15 headache days/month with treatment. BACKGROUND: There are limited data exploring reductions in monthly headache days to levels consistent with episodic migraine among those experiencing CM. Understanding the impact of sustained preventive treatment response in CM can provide important information about the impact of successful therapy. METHODS: The two Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy trials of onabotulinumtoxinA in adults included a 24-week, randomized, double-blind, placebo-controlled phase and a 32-week open-label phase. Data were pooled to determine proportions of individuals with <15 headache days/month while on treatment during several time periods in the double-blind phase (Weeks 21-24; any 12 consecutive weeks; Weeks 13-24) and the entire study (Weeks 53-56; any 12 consecutive weeks; any 4-week period). We assessed the long-term impact on mean monthly headache days and changes from baseline on the six-item Headache Impact Test (HIT-6) and Migraine-Specific Quality of Life questionnaire version 2.1 (MSQv2.1). RESULTS: We analyzed 1384 participants with chronic migraine (double-blind: onabotulinumtoxinA, n = 688; placebo, n = 696; open-label: n = 688 [onabotulinumtoxinA]). The discontinuation rates prior to the completion of the full 56-week treatment period for onabotulinumtoxinA and placebo were 25.4% (n = 175) and 29.3% (n = 204), respectively. During Weeks 13-24 of the double-blind phase, significantly more onabotulinumtoxinA-treated (386/688 [56.1%]) than placebo-treated (342/696 [49.1%]) individuals had <15 headache days/month (p = 0.010), with fewer monthly headache days for onabotulinumtoxinA versus placebo responders. The proportions of participants achieving <15 monthly headache days with onabotulinumtoxinA were 60.9% (419/688) at Weeks 25-56, 81.1% (558/688) at Weeks 53-56, and 79.4% (546/688) during any consecutive 12-week period. Mean changes from baseline on the HIT-6 and MSQv2.1 questionnaire surpassed within-group minimal important difference thresholds in all periods. At Week 24, onabotulinumtoxinA-treated participants who achieved <15 monthly headache days during Weeks 21-24 had a greater mean HIT-6 score reduction (-6.5 vs. -1.4) and greater mean MSQv2.1 Role-Function Restrictive score improvements (21.3 vs. 6.4) than those who did not achieve <15 monthly headache days during the same period. CONCLUSIONS: Participants who achieved <15 monthly headache days with onabotulinumtoxinA treatment achieved meaningful benefits in headache-related disability and migraine-specific quality of life compared with those who remained at or above the 15-monthly headache days threshold. Sustained benefits observed over 56 weeks support long-term onabotulinumtoxinA use for the prevention of CM.

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BACKGROUND: Large conductance  calcium-activated potassium (BKCa) channels have been implicated in the neurobiological underpinnings of migraine. Considering the clinical similarities between migraine and persistent post-traumatic headache (PPTH), we aimed to examine whether MaxiPost (a BKCa channel opener) could induce migraine-like headache in persons with PPTH. METHODS: This is a randomized double-blind, placebo-controlled, two-way crossover study from September 2023 to December 2023. Eligible participants were adults with PPTH after mild traumatic brain injury who reported having no personal history of migraine. The randomized participants received a single dose of either MaxiPost (0.05 mg/min) or placebo (isotonic saline) that was infused intravenously over 20 minutes. The two experiment sessions were scheduled at least one week apart to avoid potential carryover effects. The primary endpoint was the induction of migraine-like headache after MaxiPost as compared to placebo within 12 hours of drug administration. The secondary endpoint was the area under the curve (AUC) values for headache intensity scores between MaxiPost and placebo over the same 12-hour observation period. RESULTS: Twenty-one adult participants (comprising 14 females and 7 males) with PPTH were enrolled and completed both experiment sessions. The proportion of participants who developed migraine-like headache was 11 (52%) of 21 participants after MaxiPost infusion, in contrast to four (19%) participants following placebo (P = .02). Furthermore, the median headache intensity scores, represented by AUC values, were higher following MaxiPost than after placebo (P < .001). CONCLUSIONS: Our results indicate that BKCa channel opening can elicit migraine-like headache in persons with PPTH. Thus, pharmacologic blockade of BKCa channels might present a novel avenue for drug discovery. Additional investigations are nonetheless needed to confirm these insights and explore the therapeutic prospects of BKCa channel blockers in managing PPTH. GOV IDENTIFIER: NCT05378074.

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BACKGROUND: Chronic migraine exerts substantial negative impacts on daily functioning. Efforts to manage impaired functioning may result in medication overuse, which contributes to the worsening profile and chronification of migraine. The Migraine Functional Impact Questionnaire (MFIQ) is a recently developed measure assessing the impact of migraine on physical, social, and emotional function. OBJECTIVE: The objective of this analysis was to assess changes in MFIQ scores following initiation or modification of migraine preventive medication and determine if changes in function are associated with changes in other aspects of migraine burden, such as headache frequency, headache intensity, and symptoms of anxiety and depression. METHODS: This is a secondary analysis of data from the Medication Overuse Treatment Strategy (MOTS) trial, a prospective pragmatic clinical trial that investigated two treatment strategies for those with chronic migraine and medication overuse. Data from both treatment arms were pooled and analyzed using a pre-post design. Prior to and 12 weeks following initiation or modification of migraine preventive medication, participants completed a series of questionnaires that captured migraine characteristics, medication use, migraine-related physical impairment (MFIQ), anxiety (Generalized Anxiety Disorder-7), and depression (Patient Health Questionnaire 9 [PHQ-9]) symptoms. Changes from baseline in all measures were assessed using the paired t-test. Relationships between changes in MFIQ scores and other measures were assessed using linear regression. Multivariable modeling was performed to determine which additional variables contributed to the change in MFIQ beyond that already explained by an individual variable. Model terms were selected by using elastic net regularization. Only those participants who completed the baseline and 12-week MFIQ were included in this analysis. RESULTS: Of the 537 patients, 88.2% were female, and the average age was 45 years (standard deviation 13). The mean frequency of days with moderate-to-severe headache improved 39.2% from 13.5 per 30 days at baseline to 8.1 per 30 days at week 12. The mean MFIQ Usual Activities Global score improved by 15.0 points (on a 100-point scale). All five domains (Usual Activities Global, Usual Activities, Social Function, Emotional Function, Physical Function) of the MFIQ improved by a mean of at least 13.0 points. Changes in PHQ-9 score, followed by changes in headache frequency, had the strongest associations with change in all domains of the MFIQ. CONCLUSIONS: The negative impact of chronic migraine with medication overuse on physical, social, and emotional functioning substantially lessened following initiation or modification of migraine preventive medication. Improved functioning, as measured by the MFIQ, was most strongly associated with reductions in depression scores and headache frequency, highlighting the importance of recognizing and monitoring changes in depressive symptoms, in addition to headache frequency and functional impairment, when evaluating response to preventive medications.

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BACKGROUND: Atogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine in adults. These analyses evaluated the proportions of clinical trial participants who experienced sustained responses to atogepant over 12 or 52 weeks of treatment. METHODS: These were post hoc analyses of ADVANCE, a 12-week, double-blind, randomized trial of atogepant 10, 30, and 60 mg once daily vs. placebo for the preventive treatment of episodic migraine, and a separate open-label long-term safety (LTS) trial of atogepant 60 mg once daily over 52 weeks. The 60 mg dose of atogepant was used to detect safety issues. An initial response was defined as ≥50%, ≥75%, or 100% reduction from baseline in MMDs in month 1 for ADVANCE or quarter 1 for the LTS trial. The proportions of participants who continued to experience a response above each response-defining threshold through each subsequent month (for ADVANCE) or each quarter (for LTS) were calculated. RESULTS: In ADVANCE, sustained response rates during months 2 and 3 varied with dose and were as follows: 70.8-81.1% following an initial ≥50% response, 47.3-61.9% following an initial ≥75% response, and 34.8-41.7% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during month 1, more than 79% continued to experience at least a 50% response during both months 2 and 3. During the LTS trial, sustained response rates through quarters 2, 3, and 4 were 84.7% following an initial ≥50% response, 72.6% following an initial ≥75% response, and 37.8% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during quarter 1, more than 90% continued to experience at least a 50% response through quarters 2, 3, and 4. CONCLUSION: Over 70% of participants who experienced an initial response with atogepant treatment had a sustained response with continued treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03777059 (submitted: December 13, 2018); NCT03700320 (submitted: September 25, 2018).

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Sexual dimorphism has been revealed for many neurological disorders including chronic pain. Prelicinal studies and post-mortem analyses from male and female human donors reveal sexual dimorphism of nociceptors at transcript, protein and functional levels suggesting different mechanisms that may promote pain in men and women. Migraine is a common female-prevalent neurological disorder that is characterized by painful and debilitating headache. Prolactin is a neurohormone that circulates at higher levels in females and that has been implicated clinically in migraine. Prolactin sensitizes sensory neurons from female mice, non-human primates and humans revealing a female-selective pain mechanism that is conserved evolutionarily and likely translationally relevant. Prolactin produces female-selective migraine-like pain behaviors in rodents and enhances the release of calcitonin gene-related peptide (CGRP), a neurotransmitter that is causal in promoting migraine in many patients. CGRP, like prolactin, produces female-selective migraine-like pain behaviors. Consistent with these observations, publicly available clinical data indicate that small molecule CGRP-receptor antagonists are preferentially effective in treatment of acute migraine therapy in women. Collectively, these observations support the conclusion of qualitative sex differences promoting migraine pain providing the opportunity to tailor therapies based on patient sex for improved outcomes. Additionally, patient sex should be considered in design of clinical trials for migraine as well as for pain and reassessment of past trials may be warranted.

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OBJECTIVE: While a substantial body of research describes the disabling impacts of migraine attacks, less research has described the impacts of migraine on physical functioning between migraine attacks. The objective of this study is to describe physical impairment during and between migraine attacks as a dimension of burden experienced by people living with chronic migraine. METHODS: The physical impairment domain of the Migraine Physical Function Impact Diary was recorded in headache diaries from the Medication Overuse Treatment Strategy trial. Days with moderate to severe headache were used to approximate migraine attacks. Factor analysis and regression analysis were used to describe associations between migraine and physical impairment. RESULTS: 77,662 headache diary entries from 720 participants were analyzed, including 25,414 days with moderate to severe headache, 19,149 days with mild headache, and 33,099 days with no headache. Mean physical impairment score was 41.5 (SD = 26.1) on days with moderate to severe headache, 12.8 (SD = 15.0) on days with mild headache, and 5.2 (SD = 13.1) on days with no headache. Physical impairment on days with mild headache and days with no headache was significantly associated with days since last moderate to severe headache, physical impairment with last moderate to severe headache, mild headache (compared to no headache), depression, hypersensitivities and cranial autonomic symptoms. CONCLUSIONS: Physical impairment occurs on migraine and non-migraine days. Study participants with frequent headaches, symptoms of depression, hypersensitivities and cranial autonomic symptoms experience physical impairment at a higher rate on days with no headache and days with mild headache.Clinical Trial Registration: ClinicalTrials.gov (NCT02764320).

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OBJECTIVE: To evaluate unmet needs among individuals with episodic migraine (EM) in the United States (US). BACKGROUND: Data are limited on the impact of headache frequency (HF) and preventive treatment failure (TF) on the burden of migraine in the US. METHODS: A retrospective, cross-sectional analysis of 2019 National Health and Wellness Survey (NHWS) data was conducted from an opt-in online survey that identified respondents (aged ≥18 years) in the US with self-reported physician-diagnosed migraine. Participants were stratified by HF (low: 0-3 days/month; moderate-to-high: 4-14 days/month) and prior preventive TF (preventive naive; 0-1 TF; ≥2 TFs). Comparisons were conducted between preventive TF groups using multivariable regression models controlling for patient demographic and health characteristics. RESULTS: Among individuals with moderate-to-high frequency EM, the NHWS identified 397 with ≥2 TFs, 334 with 0-1 TF, and 356 as preventive naive. The 36-item Short-Form Health Survey (version 2) Physical Component Summary scores were significantly lower among those with ≥2 TFs, at a mean (standard error [SE]) of 41.4 [0.8] versus the preventive-naive 46.8 [0.9] and 0-1 TF 44.5 [0.9] groups; p < 0.001 for both). Migraine Disability Assessment Scale scores were significantly higher in the ≥2 TFs, at a mean (SE) of 37.7 (3.9) versus preventive-naive 26.8 (2.9) (p < 0.001) and 0-1 TF 30.1 (3.3) (p = 0.011) groups. The percentages of time that respondents experienced absenteeism (mean [SE] 21.6% [5.5%] vs. 13.4% [3.6%]; p = 0.022), presenteeism (mean [SE] 55.0% [8.3%] vs. 40.8% [6.5%]; p = 0.015), overall work impairment (mean [SE] 59.4% [5.6%] vs. 45.0% [4.4%]; p < 0.001), and activity impairment (mean [SE] 56.8% [1.0%] vs. 44.4% [0.9%]; p < 0.001) were significantly higher in the ≥2 TFs versus preventive-naive group. Emergency department visits (preventive-naive, p = 0.006; 0-1 TF, p = 0.008) and hospitalizations (p < 0.001 both) in the past 6 months were significantly higher in the ≥2 TFs group. Direct and indirect costs were significantly higher in the ≥2 TFs (mean [SE] $24,026 [3460]; $22,074 [20]) versus 0-1 TF ($10,897 [1636]; $17,965 [17]) and preventive-naive ($11,497 [1715]; $17,167 [17]) groups (p < 0.001 for all). Results were similar in the low-frequency EM group. CONCLUSIONS: In this NHWS analysis, individuals with more prior preventive TFs experienced significantly higher humanistic and economic burden regardless of HF.

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BACKGROUND: Women show increased prevalence and severity of migraine compared to men. Whether small molecule calcitonin gene-related peptide receptor (CGRP-R) antagonists (i.e., gepants) and monoclonal antibodies targeting either the CGRP-R or the CGRP peptide might show sexually dimorphic outcomes for acute and preventive therapy has not been established. METHODS: We conducted a subpopulation analysis of available published data from FDA reviews to evaluate potential sex differences in the response rates of ubrogepant, rimegepant and zavegepant for acute migraine therapy. Available data from FDA reviews of erenumab, fremanezumab, galcanezumab and eptinezumab, approved CGRP-R and CGRP monoclonal antibodies and of atogepant were examined for prevention outcomes based on patient sex. Preventive outcomes were analyzed separately for patients with episodic migraine and chronic migraine. RESULTS: In women, the three approved gepants produced statistically significant drug effects regardless of dose tested on the FDA mandated co-primary endpoints, the proportion of patients achieving two-hour pain-freedom and the proportion of patients free of their most bothersome symptom at two hours post-dose. In women, the average placebo-subtracted two-hour pain-freedom proportion was 9.5% (CI: 7.4 to 11.6) and the average numbers needed to treat was 11. The free from most bothersome symptom at two hours outcomes were also significant in women. The gepant drugs did not reach statistically significant effects on the two-hour pain-freedom endpoint in the men, with an average drug effect of 2.8% (CI: -2.5 to 8.2) and an average number needed to treat of 36. For freedom from most bothersome symptom at two hours post-dose endpoint, differences were not significant in male patients. The treatment effect in each of the gepant studies was always numerically greater in women than in men. In evaluation of prevention outcomes with the antibodies or atogepant using the change from the specified primary endpoint (e.g., monthly migraine days), the observed treatment effect for episodic migraine patients almost always favored drug over placebo in both women and men. For chronic migraine patients the treatment effects of antibodies were similar in men and women and always favored the drug treated group.Conclusion/Interpretation: Small molecule CGRP-R antagonists are effective in acute migraine therapy in women but available data do not demonstrate effectiveness in men. CGRP-targeting therapies are effective for migraine prevention in both male and female episodic migraine patients but possible sex differences remain uncertain. In male and female chronic migraine patients, CGRP/CGRP-R antibodies were similarly effective. The data highlight possible differential effects of CGRP targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women.

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Background and Objectives: Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players. Methods: The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested. Results: Approximately 36.7% of NFL players had diagnosed SA compared with 30% of the former college football players and 16.7% of the controls. Former NFL players and college football players also had higher ESS scores compared with the controls. Years of football play was not associated with any of the sleep metrics. Among the former NFL players, diagnosed SA was associated with worse Executive Function and Psychomotor Speed factor scores, greater BDI-II scores, and higher flortaucipir PET standard uptake value ratios, independent of age, race, body mass index, and APOE ε4 gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup. Discussion: Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health.

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BACKGROUND: Persistent headache attributed to traumatic injury to the head is divided into two subtypes, one attributed to moderate or severe traumatic injury and another attributed to mild traumatic injury (i.e., concussion). The latter is much more prevalent, in part because more than 90% of cases with traumatic brain injury are classified as mild. The pathophysiology of persistent post-traumatic headache is poorly understood and the underlying mechanisms are likely multifactorial. There is currently no approved treatment specifically for persistent post-traumatic headache, and management strategies rely on medications used for migraine or tension-type headache. Therefore, high-quality trials are urgently needed to support clinical decision-making and optimize management strategies. International guidelines can facilitate appropriate trial design and ensure the acquisition of high-quality data evaluating the efficacy, tolerability, and safety of available and novel pharmacological therapies for the preventive treatment of persistent post-traumatic headache. METHODS: The development of this guideline was based on a literature review of available studies in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, along with a review of previously published guidelines for controlled trials of preventive treatment for episodic and chronic migraine. The identified literature was critically appraised, and due to the scarcity of scientific evidence, recommendations were primarily based on the consensus of experts in the field. OBJECTIVE: To provide guidelines for designing state-of-the-art controlled clinical trials aimed at evaluating the effectiveness of preventive treatments for persistent post-traumatic headache attributed to mild traumatic brain injury.

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Migraine and sleep disorders are common co-morbidities. Patients frequently link their sleep to migraine attacks suggesting a potential causal relationship between these conditions. However, whether migraine pain promotes or disrupts sleep or whether sleep disruption can increase the risk of migraine remains unknown. We assessed the potential impact of periorbital allodynia, a measure consistent with migraine-like pain, from multiple preclinical models on sleep quantity and quality. Additionally, we evaluated the possible consequences of sleep deprivation in promoting susceptibility to migraine-like pain. Following the implantation of electroencephalogram/electromyography electrodes to record sleep, mice were treated with either single or repeated systemic injections of nitroglycerin at the onset of their active phase (i.e. nocturnal awake period). Neither single nor repeated nitroglycerin affected the total sleep time, non-rapid eye movement sleep, rapid eye movement sleep, sleep depth or other measures of sleep architecture. To account for the possible disruptive effects of the surgical implantation of electroencephalogram/electromyography electrodes, we used immobility recordings as a non-invasive method for assessing sleep-wake behaviour. Neither single nor repeated nitroglycerin administration during either the mouse sleep (i.e. daylight) or active (i.e. night) periods influenced immobility-defined sleep time. Administration of an inflammatory mediator mixture onto the dura mater at either sleep or active phases also did not affect immobility-defined sleep time. Additionally, inhalational umbellulone-induced migraine-like pain in restraint-stressed primed mice did not alter immobility-defined sleep time. The possible influence of sleep disruption on susceptibility to migraine-like pain was evaluated by depriving female mice of sleep over 6 h with novel objects, a method that does not increase circulating stress hormones. Migraine-like pain was not observed following acute sleep deprivation. However, in sleep-deprived mice, subthreshold doses of systemic nitroglycerin or dural calcitonin gene-related peptide induced periorbital cutaneous allodynia consistent with migraine-like pain. Our data reveal that while migraine-like pain does not significantly disrupt sleep, sleep disruption increases vulnerability to migraine-like pain suggesting that a therapeutic strategy focused on improving sleep may diminish migraine attacks.

RESUMEN

Neurological conditions are the leading cause of death and disability combined. This public health crisis has become a global priority with the introduction of WHO's Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders 2022-2031 (IGAP). 18 months after this plan was adopted, global neurology stakeholders, including representatives of the OneNeurology Partnership (a consortium uniting global neurology organisations), take stock and advocate for urgent acceleration of IGAP implementation. Drawing on lessons from relevant global health contexts, this Health Policy identifies two priority IGAP targets to expedite national delivery of the entire 10-year plan: namely, to update national policies and plans, and to create awareness campaigns and advocacy programmes for neurological conditions and brain health. To ensure rapid attainment of the identified priority targets, six strategic drivers are proposed: universal community awareness, integrated neurology approaches, intersectoral governance, regionally coordinated IGAP domestication, lived experience-informed policy making, and neurological mainstreaming (advocating to embed brain health into broader policy agendas). Contextualised with globally emerging IGAP-directed efforts and key considerations for intersectoral policy design, this novel framework provides actionable recommendations for policy makers and IGAP implementation partners. Timely, synergistic pursuit of the six drivers might aid WHO member states in cultivating public awareness and policy structures required for successful intersectoral roll-out of IGAP by 2031, paving the way towards brain health for all.

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