Andrea M. Harriott

The purpose of this study is to elucidate the role of vasopressin 1 receptors (V1Rs) in migraine with aura. Cortical spreading depolarization (SD) is a slow depolarizing wave that underlies migraine with aura, activates trigeminal nociceptors, and causes periorbital mechanical allodynia. Spreading depolarization increases fos expression in the hypothalamic paraventricular nucleus (PVN). The PVN contains oxytocin and vasopressin neurons, which bind vasopressin receptors. We examined the effect of selective vasopressin 1A receptor antagonist relcovaptan and vasopressin 1B receptor antagonist nelivaptan on SD-induced migraine-relevant behavior. Single optogenetic SD (opto-SD) was induced in male and female Thy1-ChR2-YFP adult mice that received either (10 mg/kg, i.p.) relcovaptan, nelivaptan, or vehicle immediately after SD. One hour later, periorbital mechanical thresholds were tested with von Frey monofilaments. Spontaneous pain was tested with face grimace and photosensitivity with grimace to increasing light exposure. Open field was used to test anxiety-like behavior and locomotion at 4 hours. Opto-SD decreased periorbital thresholds, which recovered by 4 hours. Opto-SD also increased grimace and resulted in an upward shift in the grimace-light intensity curve. Opto-SD produced modest reductions in distance traveled related to increased immobility episodes. These impairments were accompanied by an SD-mediated increase in activation of PVN neurons, of which subpopulations stained positive for vasopressin or oxytocin. Relcovaptan prevented recovery from opto-SD–induced periorbital allodynia. Similarly, nelivaptan also prevented recovery from opto-SD–induced periorbital allodynia. However, there was no effect of either drug on opto-SD–induced grimace, photosensitivity, or locomotion. These data are consistent with an analgesic effect of endogenous vasopressinergic receptor activation in a mouse model of migraine.

Migraine with aura is characterized by recurrent attacks of visual and, occasionally, sensory, language and/or motor disturbances, typically followed by headache. Migraine with aura can be associated with allodynia and vascular and psychiatric comorbidities. The electrophysiological cause of the aura is cortical spreading depolarization, a wave of depolarization that propagates slowly across the cortical surface, producing reversible metabolic and electrochemical perturbations. In this Review, we focus on the relationship of spreading depolarization with migraine aura and migraine headache. Abundant evidence causally links spreading depolarization to the headache phase of migraine with aura, as it can activate trigeminal nociceptors, produce dural and cortical inflammation, and induce trigeminal pain behaviour in rodents. In experimental models, migraine prophylaxis reduces susceptibility to spreading depolarization, and abortive treatments abrogate trigeminal pain behaviour that is induced by spreading depolarization. Although questions remain about the role of spreading depolarization in migraine with aura and models of spreading depolarization need to be refined, the cumulative evidence suggests that spreading depolarization is a putative target for therapeutic intervention in migraine. Elucidating the mechanisms by which spreading depolarization can induce trigeminal pain could facilitate drug discovery, and models of spreading depolarization could be effective screening platforms for migraine therapies.

Objective: The objective was to determine if migraine is independently associated with a greater odds of spontaneous coronary artery dissection (SCAD) in a case–control study. Background: There is growing evidence that migraine is associated with SCAD, a non‐atherosclerotic, non‐traumatic cause of myocardial infarction. However, few studies have examined the independent association between migraine and SCAD. Methods: A total of 1295 SCAD cases and 1291 (1:1) age, sex, and race/ethnicity matched controls presenting to the Boston, Massachusetts area, using the International Classification of Diseases ninth revision and 10th revision codes from our Research Patient Data Registry, were identified between the years 1990 and 2022. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated. For mediation, total effects, natural direct, and indirect effects were estimated using causal inference. Receiver operating characteristic (ROC) curves and area under the curve (AUC) was used to determine predictive power. Statistical significance was defined as p < 0.05. Results: Adjusting for age, sex, and race/ethnicity, the data demonstrated an almost two‐fold increased odds of SCAD in patients with migraine (aOR 1.96, 95% CI 1.48–2.6; p < 0.001). There was no effect of aura phenotype on this association. Fibromuscular dysplasia (FMD) was found only in patients with SCAD ( n = 133). After accounting for vascular risk factors, there was no longer an independent association between migraine and SCAD (aOR 0.90, 95% CI 0.63–1.29; p = 0.568). Using a model that adjusted for only demographic variables produced a ROC curve with the lowest predictive power (AUC 0.55) for SCAD, while the vascular risk factor‐adjusted model had a higher predictive power (AUC 0.83). Hypertension appeared to mediate some of the effect of migraine on SCAD (proportion of effect mediated 0.70). FMD was highly associated with an increased risk of SCAD. There remained no independent association between SCAD and migraine when FMD was included in the model. Conclusions: The migraine–SCAD association can be partially attributed to the connection between migraine and vascular comorbidities including hypertension and FMD.

Three phase 3 trials demonstrated the efficacy and safety of atogepant in episodic migraine (EM) and chronic migraine (CM) across 12-week treatment periods. This analysis evaluates improvements in efficacy and functional outcomes in the first 4 weeks of treatment with the oral calcitonin gene-related peptide receptor antagonist, atogepant, for the preventive treatment of migraine. ADVANCE, ELEVATE, and PROGRESS were phase 3, multicenter, randomized, double-blind, placebo-controlled 12-week trials. ADVANCE and ELEVATE included participants aged 18-80 years with >1 year history of EM and 4-14 monthly migraine days (MMDs). ELEVATE required previous treatment failures to 2-4 classes of oral preventives. PROGRESS included participants aged 18-80 years with >1 year history of CM, ≥15 monthly headache days, and ≥8 MMDs. This analysis reports the atogepant 60 mg once daily (QD) and placebo treatment arms. Outcomes included efficacy endpoints (reporting a migraine day on day 1, change from baseline in weekly migraine days [WMDs] at weeks 1-4, and in MMDs in the first 4 weeks) and functional endpoints evaluated by the Activity Impairment in Migraine-Diary (AIM-D) at weeks 1-4 and the European Quality-of-Life 5-Dimension 5-Level (EQ-5D-5L) at weeks 1-2 and 4. The modified intent-to-treat population included the ADVANCE (atogepant, n = 222; placebo, n = 214), ELEVATE (atogepant, n = 151; placebo, n = 154), and PROGRESS (atogepant, n = 256; placebo, n = 246) studies. Atogepant-treated participants had greater reductions in the proportion of participants with a migraine day on day 1. The odds ratio compared with placebo was 0.39 (95% CI 0.23-0.67; p = 0.0006) in ADVANCE, 0.53 (95% CI 0.29-0.94, p = 0.031) in ELEVATE, and 0.63 (95% CI 0.43-0.93, p = 0.021) in PROGRESS. Atogepant treatment reduced WMDs at weeks 1-4 and MMDs in the first 4 weeks, and improved AIM-D and EQ-5D-5L at all assessed timepoints for weeks 1-4 compared with placebo. Atogepant 60 mg QD demonstrated superiority to placebo in efficacy and functional measures in the first 4 weeks of treatment across 3 preventive studies, 2 in EM and 1 in CM. ClinicalTrials.gov NCT03777059; NCT04740827; NCT03855137. Submitted: 12/13/2018; 02/02/2021; 02/25/2019. First patient enrolled: 12/14/2018; 03/05/2021; 03/11/2019 clinicaltrials.gov/ct2/show/NCT03777059. clinicaltrials.gov/ct2/show/NCT04740827 clinicaltrials.gov/ct2/show/NCT03855137. This study provides Class II evidence that atogepant 60 mg QD reduces migraine frequency and improves functional outcomes within 4 weeks of initiation in patients with EM and patients with CM.

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. 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. 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). 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. ClinicalTrials.gov NCT04492020. Submitted: July 27, 2020; first patient enrolled: August 21, 2020. clinicaltrials.gov/ct2/show/NCT04492020. 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.

Background and Objectives Evaluation of transient ischemic attack/nondisabling ischemic strokes (TIA/NDS) in the emergency department (ED) contributes to capacity issues and increasing health care expenditures, especially high-cost duplicative imaging. Methods As an institutional quality improvement project, we developed a novel pathway to evaluate patients with TIA/NDS in the ED using a core set of laboratory tests and CT-based neuroimaging. Patients identified as ‘low risk’ through a safety checklist were discharged and scheduled for prompt outpatient tests and stroke clinic follow-up. In this prespecified analysis designed to assess feasibility and safety, we abstracted data from patients consecutively enrolled in the first 6 months. Results We compared data from 106 patients with TIA/NDS enrolled in the new pathway from April through September 2020 (age 67.9 years, 45% female), against 55 unmatched historical controls with TIA encountered from April 2016 through March 2017 (age 68.3 years, 47% female). Both groups had similar median NIHSS scores (pathway and control 0) and ABCD² scores (pathway and control 3). Pathway-enrolled patients had a 44% decrease in mean ED length of stay (pathway 13.7 hours, control 24.4 hours, p < 0.001) and decreased utilization of ED MRI-based imaging (pathway 63%, control 91%, p < 0.001) and duplicative ED CT plus MRI-based brain and/or vascular imaging (pathway 35%, control 53%, p = 0.04). Among pathway-enrolled patients, 89% were evaluated in our stroke clinic within a median of 5 business days; only 5.5% were lost to follow-up. Both groups had similar 90-day rates of ED revisits (pathway 21%, control 18%, p = 0.84) and recurrent TIA/ischemic stroke (pathway 1%, control 2%, p = 1.0). Recurrent ischemic events among pathway-enrolled patients were attributed to errors in following the safety checklist before discharge. Discussion Our TIA/NDS pathway, implemented during the initial outbreak of COVID-19, seems feasible and safe, with significant positive impact on ED throughput and ED-based high-cost duplicative imaging. The safety checklist and option of virtual telehealth follow-up are novel features. Broader adoption of such pathways has important implications for value-based health care.

Background: Migraine is more prevalent in females, raising the possibility that sex and gonadal hormones modulate migraine. We recently demonstrated that minimally invasive optogenetic spreading depolarization (opto-SD) elicits robust periorbital allodynia. The objective of this study was to test the hypothesis that opto-SD induced migraine-like pain behavior is worse in females and varies during the estrus cycle.Methods: Single or repeated opto-SDs were induced in male and female adult Thy1-ChR2-YFP transgenic mice. Von Frey monofilaments were used to test periorbital mechanical allodynia. Mouse grimace was also examined under increasing light intensity to quantify spontaneous discomfort and light-aversive behavior. Vaginal smears were obtained for estrus cycle staging at the end of behavioral testing.Results: A multi-variable regression analysis was performed using a male and female cohort to test the effect of independent variables on periorbital allodynia. Opto-SD predicted lower periorbital thresholds as compared with sham stimulation (p < 0.0001). Additionally, female sex predicted lower periorbital thresholds compared with males (p = 0.011). There were significant interactions between opto-SD and time (interactionp = 0.030) as animals tended to recover from opto-SD allodynia over time, and between sex and time (p = 0.020) as females tended to take longer to recover. Proestrus, estrus (PE) and metestrus, diestrus (MD) stages were combined to represent high versus low circulating estradiol relative to progesterone, respectively. Multi-variable regression revealed an effect of estrus cycle (p = 0.015) on periorbital thresholds. In the sham group, PE had lower thresholds than MD. However, there was no interaction between opto-SD and the estrus cycle (p = 0.364). Grimace scores were also examined at incremental light intensities. There was an effect of opto-SD (p < 0.0001), light intensity (p = 0.001) and estrus cycle (p = 0.024) on grimace without interaction among them (three-way ANOVA).Conclusions: Female sex and estrus stages with high circulating estradiol relative to progesterone lower trigeminal pain thresholds and augment photosensitivity. In females, opto-SD increased pain behavior and photosensitivity irrespective of the estrus stage.Graphical

We investigated the efficacy of inhibiting persistent Na ⁺ currents (I _NaP ) in acute rodent models of migraine with aura. Cortical spreading depression (SD) is a slow wave of neuronal and glial depolarization that underlies the migraine aura. Minimally invasive optogenetic SD (opto-SD) causes periorbital mechanical allodynia in mice, suggesting SD activates trigeminal nociceptors. Persistent Na ⁺ currents contribute to neuronal intrinsic excitability and have been implicated in peripheral and cortical excitation. We examined a preferential inhibitor of I _NaP, GS-458967, on SD-induced periorbital allodynia, SD susceptibility, and formalin-induced peripheral pain. Periorbital mechanical allodynia was tested in male and female Thy1-ChR2-YFP mice after a single opto-SD event using manual von Frey monofilaments. GS-458967 (1 mg/kg, s.c.) or vehicle was dosed immediately after opto-SD induction, and allodynia was tested 1 hour later. The electrical SD threshold and KCl-induced SD frequency were examined in the cortex in male Sprague–Dawley rats after 1 hour pretreatment with GS-458967 (3 mg/kg, s.c.) or vehicle. Effects of GS-458967 (0.5-5 mg/kg, p.o.) on spontaneous formalin hind paw behavior and locomotion were also examined in male CD-1 mice. GS-458967 suppressed opto-SD–induced periorbital allodynia and decreased susceptibility to SD. GS-458967 also diminished early and late phase formalin-induced paw-licking behavior with early phase paw licking responding to lower doses. GS-458967 up to 3 mg/kg had no impact on locomotor activity. These data provide evidence that I _NaP inhibition can reduce opto-SD–induced trigeminal pain behavior and support I _NaP inhibition as an antinociceptive strategy for both abortive and preventive treatment of migraine.