Real-world data on the effectiveness of rimegepant for the acute treatment of migraine is limited, particularly regarding consistency of response over multiple attacks. CONFIDENCE was a prospective observational survey study with screening and baseline questionnaires; a 28-day observational period where participants completed daily assessments on migraine occurrence, treatment, and outcomes; and an end of study questionnaire. Adults in the United States with 3–14 headache days in the last 30 days, a rimegepant prescription for the acute treatment of migraine, and plans to use rimegepant in the next 30 days were recruited in phases via the Migraine Buddy® app; firstly, those with/without preventive therapies, and then, those taking specific preventive therapies. A primary outcome of CONFIDENCE was consistency of rimegepant response across multiple attacks at the population and participant levels regardless of preventive migraine therapy. Positive treatment outcomes were defined as (1) meaningful pain relief (MPR) within 2 hours, (2) meaningful improvement in function (MIF) within 2 hours, and (3) attacks where participants reported being ‘satisfied’ or ‘extremely satisfied’ with rimegepant (treatment satisfaction). 416 participants recorded data for 2169 rimegepant-treated migraine attacks (median: 7/participant). Participants’ mean age was 40 years, 91

Autonomic dysfunction symptoms have previously been described amongst those with persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (mTBI). This novel study investigated symptoms of autonomic dysfunction amongst those with acute (< 3 months) PTH (APTH) due to mTBI and the association of these symptoms with the likelihood for PTH improvement. It was hypothesized that participants with APTH would exhibit significantly higher symptoms of autonomic dysfunction compared to healthy controls (HC), and that, individuals with APTH whose headaches improve with time would have less severe symptoms of autonomic dysfunction at baseline compared to those who did not have PTH improvement. Adults aged 18 to 70 years with APTH attributed to mTBI according to International Classification of Headache Disorders (ICHD-3) diagnostic criteria, with PTH onset between 7 and 56 days prior to enrollment, were enrolled. Participants maintained a daily headache diary and attended a baseline research visit, and 4-week and 16-week follow-up research visits. Presence and impact of autonomic symptoms were measured at each research visit using the Survey of Autonomic Symptoms (SAS). PTH improvement vs. non-improvement was determined using headache diary data. Compared to HC (n = 36), individuals with APTH (n = 56) reported significantly greater symptoms of autonomic dysfunction (SAS symptom scores) and negative impact from such symptoms (total impact scores). At the baseline research visit, mean [SD] SAS symptom score among those with APTH was 2.9 [2.0] vs. 0.9 [0.8] (p < 0.001) in HC. At baseline, the impact of autonomic symptoms measured using the SAS total impact score was 8.3 [6.2] among those with APTH vs. 2.1 [1.9] (p < 0.001) among HC. The most common and severe symptoms in the APTH group were lightheadedness, dry mouth or eyes, nausea, and cold feet. Participants who went on to have PTH improvement had numerically lower baseline autonomic symptom scores (p = 0.068) and significantly lower total impact scores (p = 0.024) than those who did not have PTH improvement. Participants with APTH due to mTBI have significantly more symptoms of autonomic dysfunction than HC. Higher baseline severity of autonomic symptoms corresponds to a lower likelihood of PTH improvement over time.

Abnormality detection is a crucial yet challenging task in medical image analysis. Distinguishing abnormalities from normal data by learning to reconstruct normal-only data alleviates the reliance on labeled datasets. However, many studies, even if unsupervised, rely on a labeled validation set to select the best model for inference from multiple training iterations. For many diseases labeled data are unavailable and substantially time consuming to obtain. To address this, AUCp - a novel metric that supports abnormality detection for unsupervised and self-supervised methods is proposed. Instead of evaluating the realism of reconstructed images to select the best of model for inference, it focuses on actual detection performance and without requiring an annotated test set. Assuming the pseudo ground truth of all unannotated samples in the test set as abnormal/positive and using traditional AUC calculation, AUCp scores are derived. Given a large and representative training set of normal samples, we show mathematical and empirical evidence that model selection using AUCp scores improves disease detection in terms of unsupervised and self-supervised methods over conventional metrics. Using two unsupervised methods for neurologic disease detection and self-supervised methods on diverse datasets, our results demonstrate that the AUCp score effectively identifies the optimal model for inference, significantly enhancing abnormality and disease detection. The corresponding implementations are available in https://github.com/mahfuzmohammad/AUCp.

This practice guideline provides updated evidence-based recommendations regarding the use of pharmacologic migraine prevention in adults. A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies published through June 6, 2024, and is available in a companion publication. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. Recommendations are provided on how to decide when it is appropriate to start a pharmacologic migraine preventive medication and how to decide which migraine preventive medication to start. Recommendations address decision making on appropriate choices of migraine preventive medications in specific situations and populations, including patients with fibromyalgia, obesity, or hypertension; considerations for older adults; treatment during pregnancy and lactation; sex-related factors in choosing medications; and treatment for patients with medication overuse. Recommendations on assessment of treatment efficacy, adverse effects, and discontinuing migraine preventive medications are provided.

Summarizing the latest medical literature to guide clinical decision-making is essential for evidence-based medicine and high-quality patient care. Yet clinicians face increasing challenges due to limited time with patients and a rapidly growing volume of published articles. Although retrieval-augmented large language models (LLMs) have shown promise in clinical summarization, human evaluations of their effectiveness in synthesizing broader scientific literature and direct comparisons to expert-written syntheses remain scarce. We constructed a RAG-based agentic AI framework using three state-of-the-art LLMs: Sonnet, GPT-4o, and Llama 3.1. A headache specialist created 13 questions, three for prompt optimization and ten for evaluation. Ten headache specialists across the United States and Canada each wrote a summary for one question, yielding four summaries per question (expert, Sonnet, GPT-4o, and Llama). The experts, blinded to authorship, critically evaluated the summaries, excluding the topic for which they wrote a summary, based on correctness, completeness, conciseness, and clinical utility, scoring each from 1 to 10 using standardized rubrics. They also ranked the summaries by preference and indicated whether they believed each summary was written by an expert or an LLM. Our study, comparing LLM- and expert-written literature summaries evaluated by headache specialists, showed that expert-written summaries were preferred, although experts sometimes found it challenging to distinguish between human- and AI-generated summaries. We also identified key expert-valued features beyond standard evaluation metrics that can guide future refinement of both human and AI literature summarization pipelines.

BACKGROUND AND OBJECTIVES:This systematic review (SR) provides updated evidence-based conclusions regarding the use of pharmacologic migraine prevention in adults to inform a new joint American Academy of Neurology (AAN) and American Headache Society practice guideline. METHODS:A multidisciplinary panel conducted an SR following the 2017 AAN Clinical Practice Guideline Process Manual. Randomized controlled trials evaluating pharmacologic preventive treatments for adults with episodic or chronic migraine were included. Searches encompassed MEDLINE, Embase, and ClinicalTrials.gov from database inception through June 6, 2024. Studies were screened in duplicate, with dual independent risk-of-bias assessment. Outcomes included change in monthly headache days, ≥50% responder rate, and validated patient-reported quality of life (QOL) measures. Raw mean differences, standardized mean differences, and risk ratios were calculated. A modified Grading of Recommendations Assessment, Development, and Evaluation process was used to classify certainty of evidence. RESULTS:A total of 217 studies met inclusion criteria. For episodic migraine, high-confidence evidence showed that galcanezumab and erenumab are more effective than placebo in reducing headache frequency. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, fremanezumab, propranolol, topiramate, and valproate. Several additional oral agents including amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan had low-confidence evidence suggesting possible benefit. For chronic migraine, high-confidence evidence supported reductions in headache frequency with fremanezumab, galcanezumab, and onabotulinumtoxinA. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, erenumab, topiramate and valproate. Across both episodic and chronic migraine populations, erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant, topiramate and onabotulinumtoxinA demonstrated improvements in patient-reported QOL outcomes on validated instruments. Evidence comparing active treatments was limited and generally of low or very low confidence, restricting conclusions about comparative effectiveness. DISCUSSION:This SR provides a comprehensive synthesis of evidence on pharmacologic migraine prevention in adults. High- and moderate-confidence findings confirm the efficacy of several established and newer preventive therapies and demonstrate improvements in patient-reported outcomes across multiple validated measures. These conclusions informed the development of evidence-based recommendations, presented in a companion publication, to guide clinicians in selecting preventive medications for adults with episodic and chronic migraine.

BackgroundPhotophobia is experienced by most individuals with migraine, and it is frequently the most bothersome symptom other than headache. Light is not perceived uniformly; spectral composition and intensity influence discomfort and can exacerbate symptoms. While monochromatic green light shows therapeutic potential, it appears visually unnatural and is impractical for daily use. This study aimed to determine whether spectrally tailored white light, more visually acceptable in everyday environments, reduces light sensitivity among those with migraine.MethodsTwenty adults (18-44 years) with episodic migraine completed two research sessions: one during an acute migraine attack and one between migraine attacks. Participants were exposed to four spectrally distinct white light conditions (red-, green-, cyan-, and blue-enriched) in a randomized order delivered at ten intensity levels (50-590 lux). After each exposure, visual discomfort was rated on a 0-10 scale. Pupil size was measured using a pupillometer. Repeated-measures ANOVAs examined the effects of light spectrum, intensity, and migraine state on visual discomfort and pupil response.ResultsMigraine attack status significantly increased visual discomfort (F(1,19) = 25.84, p < .001, η2 = .576). White light spectrum (F(3,57) = 12.47, p < .001, η2 = .396) and light intensity (F(9171) = 124.30, p < .001, η2 = .867) were associated with intensity of visual discomfort. Post-hoc analyses indicated that visual discomfort increased with increasing light intensity, especially at higher light intensities. Among all tested spectra, green-enriched white light resulted in the least visual discomfort; blue-, red-, and cyan-enriched white light produced significantly higher discomfort (all p < .001). Pupil size varied by spectrum (F(3,57) = 14.13, p < .001, η2 = .426), with green-enriched white light producing the largest pupil size.ConclusionSpectral composition, light intensity, and migraine state jointly influence both subjective and physiological responses to light. Across lighting spectra, lower light intensity was consistently associated with reduced visual discomfort, indicating greater visual comfort at lower intensities. These results identify green-enriched white light at lower intensities as a visually acceptable, migraine-conscious lighting option with potential for real-world application.

OBJECTIVES/BACKGROUND:This narrative review summarizes evidence implicating a role for the hypothalamus in the prodrome phase of a migraine attack. Prodrome is the earliest phase of the migraine attack. Understanding the migraine prodrome could lead to a better description of how migraine attacks are initiated and identification of targets for acute and preventive migraine treatment. The hypothalamus has been implicated in migraine prodrome via (1) localization of common prodrome symptoms to the hypothalamus; (2) identification of neurotransmitters, peptides, and hormones important in migraine pathophysiology for which the hypothalamus influences their production or release; and (3) brain neuroimaging studies identifying changes in hypothalamic activity and functional connectivity during the prodrome and preheadache phases of the migraine attack. METHODS:For this narrative review, PubMed was searched for relevant English language articles using the terms "hypothalamus, prodrome," "hypothalamus, premonitory," "hypothalamus, migraine," "migraine, prodrome," and "migraine, premonitory." The PubMed search was performed on October 29, 2025. Full articles were chosen for review based on their relevance to the three areas defined just above: symptom localization, neuropeptide/neurotransmitter release, and brain imaging. RESULTS:Those with migraine commonly, and often consistently, experience prodrome symptoms, including hypersensitivities to visual and auditory stimuli, neck pain, fatigue, sleep-wake disturbances, changes in appetite, mood changes, and alterations in thermoregulation perception. Many of these symptoms can be localized to functions of hypothalamic subregions and nuclei. Several neuropeptides, neurotransmitters, and hormones that contribute to prodrome and other migraine attack symptoms, including calcitonin gene-related peptide, dopamine, orexins, and pituitary adenylate cyclase-activating polypeptide, are either produced by the hypothalamus or their release is mediated by the hypothalamus. Functional neuroimaging studies of spontaneous and triggered migraine attacks have identified increased hypothalamic activity and altered hypothalamic functional connectivity before migraine headache onset, including during the prodrome. CONCLUSION:There is compelling evidence that the hypothalamus plays a role in the migraine prodrome and likely in migraine attack initiation. This is supported by many migraine prodrome symptoms localizing to hypothalamic function and functional neuroimaging studies demonstrating increased activity and altered connectivity of the hypothalamus during the prodrome phase. Further evidence and research are required to understand the hypothalamus' contribution relative to other brain regions.

Photophobia is a common and disabling symptom among those with migraine. Studies show that short-wavelength and long-wavelength light can worsen migraine pain, while narrow-band green light may provide relief. However, monochromatic lighting is not visually pleasant and practical for daily environments. This study examined whether spectral modifications of white light influence visual discomfort and migraine headache intensity during migraine attacks. In a randomized crossover design, 21 adults with migraine were studied during an untreated migraine attack. Participants were exposed to four spectral white light conditions (blue-, cyan-, green-, and red-enriched) at 400 lx for 10 minutes each, in randomized order, with 5 minutes of dark adaptation between conditions. Headache intensity was assessed pre- and post-exposure, visual discomfort was rated once per minute, and pupil size was measured at the end of each exposure. Data were analyzed using repeated-measures analysis of variance (ANOVA) with Bonferroni-adjusted pairwise comparisons. There was a significant main effect of lighting condition on visual discomfort, with blue-enriched white light causing significantly greater discomfort (mean 7.58 on a 0–10 numeric rating scale, SE 0.26) compared to all other lighting conditions (p < 0.001), and green-enriched light causing the least discomfort (mean 4.78, SE 0.25), significantly less than blue- and cyan-enriched light (p < 0.001). Headache intensity increased with blue-enriched white light (mean + 1.67 on a 0–10 numeric rating scale p < 0.001) and cyan-enriched light (+ 0.95; p < 0.001). In contrast, green-enriched and red-enriched light did not increase headache intensity (green, − 0.38; p = 0.134; red, + 0.24; p = 0.521). Pupil size varied by spectrum (F(3,60) = 8.09, p < 0.001, η2 = 0.288), with greater constriction under blue and cyan light and less under green, consistent with subjective discomfort. The spectral composition of white light influences light sensitivity and headache intensity during migraine attacks. Findings suggest that green-enriched white light may offer a practical, non-pharmacological strategy for managing migraine symptoms in everyday environments.

ABSTRACT:Mild traumatic brain injury (mTBI) commonly induces transient acute (APTH) or persistent (PPTH) post-traumatic headache (PTH) that often resembles migraine. As orexin B sensitizes male but not female murine, nonhuman primate, and human dorsal root ganglion neurons and supradural orexin B/orexin receptor 2 (OX2R) signaling elicits migraine-like pain in naïve male, but not female, mice we explored possible sexually dimorphic contributions of orexin B/OX2R to PTH. In mice of both sexes, mTBI-induced transient cephalic allodynia, a surrogate measure of APTH. After APTH resolution, allodynia was reinstated by exposure to normally innocuous stress or by inhalational delivery of a subthreshold concentration of umbellulone, a TRPA1 agonist, suggesting the expression of PPTH. In contrast to these nonselective stimuli, subthreshold supradural orexin B induced PPTH only in male mTBI mice. Intranasal delivery of a CRISPR/Cas9 plasmid to edit trigeminal OX2R expression prevented APTH and development of PPTH selectively in male mTBI mice. Daily oral suvorexant, a dual orexin receptor antagonist (DORA), beginning immediately after mTBI, prevented APTH as well as PPTH. Critically, starting suvorexant treatment after resolution of APTH also prevented stress- or umbellulone-induced PPTH. EEG/EMG-defined sleep architecture or immobility-defined sleep was not disrupted in this mTBI model suggesting that suvorexant benefits are unlikely related to sleep modulation. Our findings reveal a male-specific mechanism of PTH maintained by orexin B/OX2R signaling and suggest that approved DORAs may be beneficial in treating APTH and preventing transition to PPTH in men. Importantly, DORAs may also be effective in men with established PPTH.

Temporal information in structured electronic health records (EHRs) is often lost in sparse one-hot or count-based representations, while sequence models can be costly and data-hungry. We propose PaReGTA, an LLM-based encoding framework that (i) converts longitudinal EHR events into visit-level templated text with explicit temporal cues, (ii) learns domain-adapted visit embeddings via lightweight contrastive fine-tuning of a sentence-embedding model, and (iii) aggregates visit embeddings into a fixed-dimensional patient representation using hybrid temporal pooling that captures both recency and globally informative visits. Because PaReGTA does not require training from scratch but instead utilizes a pre-trained LLM, it can perform well even in data-limited cohorts. Furthermore, PaReGTA is model-agnostic and can benefit from future EHR-specialized sentence-embedding models. For interpretability, we introduce PaReGTA-RSS (Representation Shift Score), which quantifies clinically defined factor importance by recomputing representations after targeted factor removal and projecting representation shifts through a machine learning model. On 39,088 migraine patients from the All of Us Research Program, PaReGTA outperforms sparse baselines for migraine type classification while deep sequential models were unstable in our cohort.

To enhance the prediction of traumatic brain injury (mTBI) outcomes, we propose a deep learning approach that integrates brain computed tomography (CT) scans with corresponding synthetic T1-weighted magnetic resonance imaging (T1-MRI). Our method significantly outperforms the prediction using CT scans alone. TRACK-TBI Pilot dataset, which includes imaging and clinical outcome data from patients with TBI, is studied. The hypothesis is brain CT and T1-MRI complement each other and together will improve TBI prognosis compared to using either CT or T1-MRI alone. Since CT and T1-MRI may not be available for the same individual, we employed a specialized version of a generative adversarial network (GAN), known as fixed-point GAN (FP-GAN). FP-GAN was trained using unpaired CT and T1-MRI scans to generate synthetic T1-MRIs from real CT scans. This process produced pseudo-paired CT-MRI data, which was then used to train a deep learning classifier for outcome prediction. The classifier consists of dual parallel 3D ResNet-18 models, each independently processing T1-MRI and CT scans. We used Glasgow Outcome Scale-Extended (GOSE) scores at 3 months post-TBI as the measure of patient outcomes. To avoid data leakage, the subjects used in FP-GAN and ResNet-18 model have no overlap. We further divided the paired data, allocating 69 samples for 5-fold cross-validation and 17 samples for testing. Prognostic performance was evaluated using the area under the receiver operating characteristic curve (AUC), F1-score (the harmonic mean of precision and recall), sensitivity (true positive rate) and specificity (true negative rate). For binary classification, we defined good recovery as GOSE ≥ 7 (positive) and poor recovery (negative) as 3 ≤ GOSE ≤ 6. Accordingly, our training set consists of 24 subjects with poor recovery and 45 subjects with good recovery, while the testing set includes 5 subjects with poor recovery and 12 subjects with good recovery. A DeLong test on AUC confirms that the improvement from incorporating synthetic T1-MRI (AUC = 0.76 ± 0.10) is statistically significant (P < 0.05) compared to using CT alone (AUC = 0.68 ± 0.13). The significant improvement from using the combination of real CT and synthetic T1-MRI in sensitivity (SEN = 0.95 ± 0.07) and overall performance metrics, such as F1-score (F1 = 0.84 ± 0.03), suggests that the proposed approach provides a robust and effective prognostic approach compared to using CT alone (SEN = 0.83 ± 0.18 and F1 = 0.76 ± 0.07). This pilot research demonstrates the potential of a deep learning-based harmonization model to bridge the gap between CT and T1-MRI in TBI assessment. By integrating synthetic T1-MRI with CT, prediction performance is substantially enhanced.

AimPost-traumatic headache (PTH) attributed to mild traumatic brain injury (mTBI) frequently co-occurs with other physical, cognitive, and emotional symptoms. This study assessed associations between PTH improvement and these symptoms in individuals with acute headaches (APTH) and compared symptoms between those who had recently developed persistent PTH (PPTH) to those who had long-standing PPTH.MethodsThis study included 105 individuals with APTH (mean age = 43.4, SD = 15.8; 70 females, 35 males) and 46 individuals with PPTH (mean age = 38.2, SD = 10.9; 16 females, 30 males) with an average duration of 11.3 years from two prospective longitudinal studies. For those who had APTH, PTH improvement was assessed at three months post-enrollment using an electronic headache diary. Participants completed questionnaires evaluating physical (including headache symptoms, photosensitivity, hyperacusis, insomnia, autonomic symptoms, and disability), emotional (including depression, anxiety, pain catastrophizing, and post-traumatic stress disorder screening), and cognitive symptoms (including memory and attention). The APTH cohort completed questionnaires at baseline, follow-up #1 (three to four months from baseline), and follow-up #2 (six to seven months from baseline). Mixed Effects Models were used to analyze the temporal trend of symptoms among the APTH improved and non-improved groups.ResultsAmong the 105 individuals with APTH, 60 experienced PTH improvement and 45 did not. At baseline, compared to those who had PTH improvement, those who did not have PTH improvement had higher SCAT total scores and physical subscores, greater levels of hyperacusis, pain catastrophizing, anxiety and depression. At follow-up #1 (three to four months), these individuals continued to show more pronounced physical and emotional symptoms and worse cognitive function and insomnia. Most of these group differences persisted at follow-up #2 (six to seven months). Most symptoms showed progressive improvement over three months for individuals who had PTH improvement but not for those without PTH improvement. Furthermore, individuals with long-standing PPTH showed more severe insomnia, pain catastrophizing, and PTSD compared to those who had recently developed PPTH.ConclusionIndividuals with APTH who did not experience PTH improvement at three months had more severe physical, cognitive, and emotional symptoms at baseline compared to those who had PTH improvement. While most symptoms normalized in individuals with PTH improvement, symptoms overall persisted at three and at six months for those with PTH persistence. Individuals who had long-standing PPTH had more severe insomnia and more negative cognitive/emotional responses to pain compared to those who had recently developed PPTH.

Background and ObjectiveLimited data are available describing the frequency, severity, and consistency of prodromal symptoms followed by headache. This analysis of the PRODROME trial screening period characterized prodromal symptoms in people with migraine, including the most common symptoms and their severity, and the frequency and consistency with which prodromal symptoms were followed by headache.MethodsPRODROME was a multicenter, randomized, double-blind, placebo-controlled, crossover trial conducted in the United States that enrolled adults with 2-8 migraine attacks per month who stated they could identify prodromal symptoms that were reliably followed by a headache. The trial included a 60-day screening period designed to test the predictive validity of "qualifying prodrome events" before the onset of headache. Participants used an eDiary to report qualifying prodrome events, defined as prodromal symptoms whereby the participant was confident a headache would follow within 1-6 hours. This analysis evaluated common prodromal symptoms and their severity, time from prodrome onset to headache onset, and the percentage of participants who identified prodromal symptoms that were followed by a headache >= 75% of the time over the 60-day screening period.ResultsA total of 920 participants entered eDiary data, with a mean of 5.2 qualifying prodrome events during the 60-day screening period. A total of 4,802 qualifying prodrome events were recorded. The most common prodromal symptoms identified were sensitivity to light (57.2%; 2,748/4,802), fatigue (50.1%; 2,408/4,802), neck pain (41.9%; 2,013/4,802), sensitivity to sound (33.9%; 1,630/4,802), either difficulty thinking or concentrating (30.0%; 1,442/4,802), and dizziness (27.8%; 1,333/4,802). Of all qualifying prodrome events reported, 81.5% (3,913/4,802) were followed by headache of any intensity within 1-6 hours. For each participant, a mean of 84.4% of their qualifying prodrome events were followed by a headache within 1-6 hours, with 76.9% of participants identifying qualifying prodrome events that were followed by headache within 1-6 hours >= 75% of the time.DiscussionParticipants were able to identify migraine attacks in which prodromal symptoms were reliably followed by a headache within 1-6 hours. These findings suggest the potential for initiating treatment during the prodrome to prevent headache.Trial Registration InformationClinicalTrials.gov NCT04492020. Submitted: July 27, 2020; First patient enrolled: August 21, 2020. clinicaltrials.gov/study/NCT04492020.

Background Traumatic brain injury (TBI) commonly elicits acute (APTH) and/or persistent (PPTH) post-traumatic headache. Calcitonin gene related peptide (CGRP) has been implicated as a contributor to PTH pathophysiology. We explored the possibility of sexual dimorphism in the effects of CGRP receptor (CGRP-R) blockade in a preclinical model of PTH induced by a mild TBI (mTBI) in male or female mice. Methods Mice were lightly anesthetized and placed on a tissue paper stage prior to receiving a sham procedure or mTBI resulting from a closed-head weight drop injury. Behavioral responses to periorbital and hindpaw tactile (von Frey filaments) or thermal (hot plate) stimuli over the first 14 days post-mTBI were evaluated as measures of APTH. The PPTH phase was studied following the resolution of mTBI-induced APTH at days 14 and 28. PPTH was precipitated by exposure to bright lights (i.e., bright light stress, BLS). Olcegepant was delivered subcutaneously either repeatedly beginning 2 h after mTBI to produce a sustained block of CGRP-R signaling across the APTH phase, or as a single administration on days 14 or 28 post-mTBI to evaluate possible effects during the PPTH phase. Results mTBI, but not sham-procedure, produced periorbital and hindpaw tactile allodynia, as well as thermal hypersensitivity in mice of both sexes. APTH-related hypersensitivity was transient and resolved by day 14 post-injury. No sex differences were observed in the magnitude or duration of APTH-related pain behaviors. Sustained CGRP-R blockade was, however, significantly more effective in female than male mice in inhibiting pain behaviors in the APTH phase and in preventing the emergence of BLS-induced PPTH. CGRP-R blockade following the resolution of mTBI-induced APTH pain behaviors, on either day 14 or 28, minimally altered BLS-induced PPTH in either sex. Conclusions Sustained CGRP-R blockade starting soon after mTBI significantly inhibited APTH and prevented the expression of PPTH with greater analgesic effects in females compared to males. Delayed CGRP-R blockade beginning after resolution of APTH phase was minimally effective in preventing expression of PPTH in either sex. These data are consistent with previous observations that CGRP induces pain behaviors preferentially in females. Early and continuous CGRP blockade following mTBI may represent a viable treatment option for PTH treatment and the prevention of PTH persistence, especially in females.

OBJECTIVES:The aim of this work was to develop an American Headache Society position statement addressing diagnostic screening for migraine among girls and women. BACKGROUND:Despite its high prevalence and substantial negative impacts, migraine is underdiagnosed and undertreated. Diagnostic screening for migraine enables more patients to receive timely, appropriate, and effective management. METHODS:Development of this position statement followed the rules established by the American Headache Society Guidelines Committee. The published literature was reviewed to determine if migraine meets criteria for when disease screening is justified, to guide recommendations for screening tools, and to determine subpopulation(s) for which migraine screening is indicated. After author consensus was reached, the position statement was reviewed and approved by the American Headache Society Board of Directors. RESULTS:Migraine fulfills established criteria for conditions in which screening is appropriate since it is highly prevalent, results in significant morbidity, and exerts substantial economic and social costs. Migraine incidence and prevalence are exceptionally high among girls and women during adolescence and through menopause. Furthermore, there are valid and reliable diagnostic screening methods (e.g., ID Migraine) and effective treatments that reduce migraine symptoms and disease impact. CONCLUSION:Yearly diagnostic screening for migraine should be included as part of women's preventive healthcare services, particularly from adolescence to menopause.

A growing body of research suggests that impacts to the head, including sub-concussive impacts, carry risks for long-term detrimental effects on cognition and brain health. Despite the potential for negative health consequences associated with sub-concussive impacts, there is currently no reliable and objective method used in clinical practice to assess whether a particular sub-concussive impact affected the brain. In this preliminary study, we developed a machine-learning classifier to detect changes in brain electrophysiological activity following sub-concussive impacts that occur during soccer ball heading. We recorded EEG from soccer players before and after they repeatedly headed a soccer ball, and trained classifiers to distinguish between an individual's EEG patterns before and after these sub-concussive impacts. The classifiers were able to identify post-impact EEG recordings with significantly higher accuracy than would be expected by chance, both 1 h and 24 h after the impacts occurred. After controlling for electrophysiological changes attributed to exercise, changes to brain activity attributable to soccer heading were detectable at 24 h post-heading, but not at 1-h post-heading. The observed time-course of EEG changes mirrors a similar pattern seen in traumatic brain injury, in which an inflammatory cascade is manifest 24 to 48-h post-injury; we suggest that EEG changes following sub-concussive impacts may stem from inflammation or some other physiological process that unfolds on a similar timescale. These results are an important step toward developing an EEG-based tool that can assess whether electrophysiological consequences are present following sub-concussive head impacts.