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Migraine is a complex neurological disorder with neuroinflammation playing a crucial role in its pathogenesis. This review provides an overview of the neuroinflammation mechanisms in migraine, focusing on both cellular and molecular aspects. At the cellular level, we examine the role of glial cells, including astrocytes, microglia, oligodendrocytes in the central nervous system, and Schwann cells and satellite glial cells in the peripheral nervous system. On the molecular level, we explore the signaling pathways, including IL-1β, TNF-α, IL-6, and non-coding RNAs, that mediate cell interactions or independent actions. Some of the molecular signaling pathways mentioned, such as TNF-α and IL-1β, have been investigated as druggable targets. Recent advancements, such as [11C] PBR28-targeted imaging for visualizing astrocyte activation and single-cell sequencing for exploring cellular heterogeneity, represent breakthroughs in understanding the mechanisms of neuroinflammation in migraine. By considering factors for personalized treatments, estrogen and TRPM8 emerge as promising therapeutic targets regarding sexual dimorphism. These advancements may help bridge the gap between preclinical findings and clinical applications, ultimately leading to more precise and personalized options for migraine patients., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Rodent migraine models have been developed to study the underlying molecular mechanisms of migraine, but these need further development and validation to stay relevant. The glyceryl trinitrate (GTN) mouse model with tactile hypersensitivity as the primary readout, has been highly used to understand the pathophysiology of migraine. Nevertheless, this readout has questionable translatability to the experience of spontaneous pain and additional readouts are needed to improve this model. We explored the applicability of several spontaneous behaviours and burrowing activity as additional markers to detect effects of repeated GTN injections in mice. We used the Laboratory Animal Behaviour Observation Registration and Analysis System (LABORAS) test system to understand the potential effect of GTN on locomotion and other behavioral parameters in two different experiments. Burrowing was used to investigate the potential effect on GTN on a voluntary innate behavior of mice. We found no clear effect of GTN on either locomotion or burrowing in these experiments. With our experimental design, there was no significant difference between GTN and vehicle and neither locomotion nor burrowing activity will readily supplement the von Frey test. The search for additional none-evoked markers of pain in rodent migraine models will continue., (© 2024. The Author(s).)

Patent foramen ovale (PFO) may be an underlying factor in the pathogenesis of migraine, vasospastic angina, and Takotsubo cardiomyopathy. This article reviews the role that PFO may play in each of these clinical entities and discusses potential interventions. It also proposes a novel clinical syndrome wherein PFO may be the unifying link among migraine, coronary vasospasm, and Takotsubo cardiomyopathy in predisposed individuals., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose of Review: Chronic migraine is a disabling progressive disorder without effective management approaches. Animal models have been developed and used in chronic migraine research. However, there are several problems with existing models. Therefore, we aimed to summarize and analyze existing animal models to facilitate translation from basic to clinical., Recent Findings: The most commonly used models are the inflammatory soup induction model and the nitric oxide donor induction model. In addition, K ATP openers have also been used in model induction. Based on the above models, some molecular targets have been identified, such as glutamate receptors. However, each model has its shortcomings and characteristics, and there are still some common problems that need to be solved, such as spontaneous headache, evaluation criteria after model establishment, and identification methods. In this review, we summarized and highlighted the advantages and limitations of the currently commonly used animal models of chronic migraine with a special focus on drug discovery and current therapeutic strategies, and discussed the directions that can be worked on in the future., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Migraine, a common neurological disorder, impacts over a billion individuals globally. Its complex aetiology involves various signalling cascades. Hypoxia causes headaches such as high-altitude headache and acute mountain sickness which share phenotypical similarities with migraine. Epidemiological data indicate an increased prevalence of migraine with and without aura in high-altitude populations. Experimental studies have further shown that hypoxia can induce migraine attacks. This review summarizes evidence linking hypoxia to migraine, delves into potential pathophysiological mechanisms and highlights research gaps., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Purpose: This study aimed to evaluate the choroidal vascular characteristics of patients followed up with different headache diagnoses., Design: Prospective comparative study., Methods: This study included 21 patients with migraine with visual aura (MwA), 20 with migraine without aura, 29 patients experiencing episodic tension-type headache, and 30 healthy participants. The participants was performed refraction values, axial length, and intraocular pressure were examined. Choroidal thickness was determined in all participants with HD-line optical coherence tomography (OCT) in the subfoveal, nasal, and temporal quadrants 500 µm from the fovea. Using special image processing software, luminal area (LA), stromal area, total choroidal area, and choroidal vascular index (CVI) values were calculated in both macular and peripapillary regions. OCT was also used to perform peripapillary retinal nerve fiber layer (pRNFL) thickness and optic disc head measurements., Results: Spherical refraction, axial length, and intraocular pressure values did not significantly differ among the four groups with similar gender and age distributions ( P > 0.05). The LA values in both macular and peripapillary regions were found to be statistically significantly lower in the MwA group ( P = 0.007 and P = 0.005, respectively). There was no statistically significant difference among the groups in terms of the remaining choroidal area parameters or CVI values ( P > 0.05). The groups also did not show any significant difference in the pRNFL or optic disc head measurements performed in different quadrants ( P > 0.05)., Conclusion: While LA, one of the choroidal vascular parameters, was found to be lower in the MwA group in both the macular and peripapillary regions, there were no statistically significant differences between the groups in terms of the peripapillary or macular CVI values., (Copyright © 2024 Copyright: © 2024 Indian Journal of Ophthalmology.)

The foramen ovale plays a vital role in sustaining life in-utero; however, a patent foramen ovale (PFO) after birth has been associated with pathologic sequelae in the systemic circulation including stroke/transient ischemic attack (TIA), migraine, high altitude pulmonary edema, decompression illness, platypnea-orthodeoxia syndrome (POS) and worsened severity of obstructive sleep apnea. Importantly, each of these conditions is most commonly observed among specific age groups: migraine in the 20 to 40s, stroke/TIA in the 30-50s and POS in patients >50 years of age. The common and central pathophysiologic mechanism in each of these conditions is PFO-mediated shunting of blood and its contents from the right to the left atrium. PFO-associated pathologies can therefore be divided into (1) paradoxical systemic embolization and (2) right to left shunting (RLS) of blood through the PFO. Missing in the extensive literature on these clinical syndromes are mechanistic explanations for the occurrence of RLS, including timing and the volume of blood shunted, the impact of age on RLS, and the specific anatomical pathway that blood takes from the venous system to the left atrium. Visualization of the flow pattern graphically illustrates the underlying RLS and provides a greater understanding of the critical flow dynamics that determine the frequency, volume, and pathway of flow. In the present review, we describe the important role of foramen ovale in in-utero physiology, flow visualization in patients with PFO, as well as contributing factors that work in concert with PFO to result in the diverse pathophysiological sequelae., Competing Interests: Conflict of Interest Dr. Horlick serves as a consult to Abbott Vascular. Dr. Carroll serves on the Steering Committee of the RESPECT trial and is a consultant to Abbott Vascular and Holistick Medical. Dr. Krasuski reports serving as a consultant to Actelion/Janssen Pharmaceuticals, Bayer Pharmaceuticals, Gore Medical and Neptune Medical. He receives research funding from the Adult Congenital Heart Association, Actelion, Artivion, Corvia, Medtronic and Edwards Lifesciences. Dr. Shah and Dr. Kass report no conflicts., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the ocular surface (OS) parameters in the pediatric migraine patients (PMPs)., Methods: This prospective case-control study consisted of 51 PMPs (PMP group) and 55 healthy pediatric patients (HPP group). In all participants, tear function was evaluated subjectively using the Ocular Surface Disease Index (OSDI) questionnaire, objectively using Schirmer tear test (STT) and tear film disintegration time (TBUT), and with clinical and laboratory examinations (conjunctival impression cytology). The PMP group was subdivided into two groups according to their aura., Results: The mean age and gender distribution of the study groups were almost the same ( P > 0.05 for both of them). In the PMP group, both the STT value and the TBUT value were significantly lower than those determined in the HPP group ( P = 0.021 and P = 0.018, respectively). In the PMP group, the OSDI scores were higher than those in the HPP group ( P = 0.032). In the PMP group, the goblet cell density values were lower than those in the HPP group ( P = 0.01). With regard to the aura, the TBUT and STT values were nonsignificantly lower in the PMP aura-positive group than in the PMP aura-negative group ( P > 0.05 for both of them). The OSDI assessment was similar in both the groups. With regard to the goblet cell count, it was observed to be less in the PMP aura-positive group than in the PMP aura-negative group ( P = 0.01)., Conclusion: Influence of OS in children with migraine was also demonstrated using the samples taken from the conjunctiva. These changes were also demonstrated by objective tests such as STT and TBUT. Both clinical objective evaluations and pathologic changes were more prominent in the migraine with aura group., (Copyright © 2024 Copyright: © 2024 Indian Journal of Ophthalmology.)

Background and Aim: Migraine is a common disabling conditions which, globally, affects 15.2% of the population. It is the second cause of health loss in terms of years lived with disability, the first among women. Despite being so common, it is poorly recognised and too often undertreated. Specialty centres and neurologists with specific expertise on headache disorders have the knowledge to provide specific care: however, those who do not regularly treat patients with migraine will benefit from a synopsis on the most relevant and updated information about this condition. This paper presents a comprehensive view on the hallmarks of migraine, from genetics and diagnostic markers, up to treatments and societal impact, and reports the elements that identify migraine specific features., Main Results: The most relevant hallmark of migraine is that it has common and individual features together. Besides the known clinical manifestations, migraine presentation is heterogeneous with regard to frequency of attacks, presence of aura, response to therapy, associated comorbidities or other symptoms, which likely reflect migraine heterogeneous genetic and molecular basis. The amount of therapies for acute and for prophylactic treatment is really wide, and one of the difficulties is with finding the best treatment for the single patient. In addition to this, patients carry out different daily life activities, and might show lifestyle habits which are not entirely adequate to manage migraine day by day. Education will be more and more important as a strategy of brain health promotion, because this will enable reducing the amount of subjects needing specialty care, thus leaving it to those who require it in reason of refractory condition or presence of comorbidities., Conclusions: Recognizing the hallmarks of migraine and the features of single patients enables prescribing specific pharmacological and non-pharmacological treatments. Medical research on headaches today particularly suffers from the syndrome of single-disease approach, but it is important to have a cross-sectional and joint vision with other close specialties, in order to treat our patients with a comprehensive approach that a heterogeneous condition like migraine requires., (© 2024. The Author(s).)

Background: To gain a comprehensive understanding of the altered sensory processing in patients with migraine, in this study, we developed an electroencephalography (EEG) protocol for examining brainstem and cortical responses to sensory stimulation. Furthermore, machine learning techniques were employed to identify neural signatures from evoked brainstem-cortex activation and their interactions, facilitating the identification of the presence and subtype of migraine., Methods: This study analysed 1,000-epoch-averaged somatosensory evoked responses from 342 participants, comprising 113 healthy controls (HCs), 106 patients with chronic migraine (CM), and 123 patients with episodic migraine (EM). Activation amplitude and effective connectivity were obtained using weighted minimum norm estimates with spectral Granger causality analysis. This study used support vector machine algorithms to develop classification models; multimodal data (amplitude, connectivity, and scores of psychometric assessments) were applied to assess the reliability and generalisability of the identification results from the classification models., Results: The findings revealed that patients with migraine exhibited reduced amplitudes for responses in both the brainstem and cortical regions and increased effective connectivity between these regions in the gamma and high-gamma frequency bands. The classification model with characteristic features performed well in distinguishing patients with CM from HCs, achieving an accuracy of 81.8% and an area under the curve (AUC) of 0.86 during training and an accuracy of 76.2% and an AUC of 0.89 during independent testing. Similarly, the model effectively identified patients with EM, with an accuracy of 77.5% and an AUC of 0.84 during training and an accuracy of 87% and an AUC of 0.88 during independent testing. Additionally, the model successfully differentiated patients with CM from patients with EM, with an accuracy of 70.5% and an AUC of 0.73 during training and an accuracy of 72.7% and an AUC of 0.74 during independent testing., Conclusion: Altered brainstem-cortex activation and interaction are characteristic of the abnormal sensory processing in migraine. Combining evoked activity analysis with machine learning offers a reliable and generalisable tool for identifying patients with migraine and for assessing the severity of their condition. Thus, this approach is an effective and rapid diagnostic tool for clinicians., (© 2024. The Author(s).)

Migraine is a prevalent neurological disorder, particularly among individuals aged 20-50 years, with significant social and economic impacts. Despite its high prevalence, the pathogenesis of migraine remains unclear. In this review, we provide a comprehensive overview of cortical spreading depolarization/depression (CSD) and its close association with migraine aura, focusing on its role in understanding migraine pathogenesis and therapeutic interventions. We discuss historical studies that have demonstrated the role of CSD in the visual phenomenon of migraine aura, along with modern imaging techniques confirming its propagation across the occipital cortex. Animal studies are examined to indicate that CSD is not exclusive to migraines; it also occurs in other neurological conditions. At the cellular level, we review how CSD is characterized by ionic changes and excitotoxicity, leading to neuronal and glial responses. We explore how CSD activates the trigeminal nervous system and upregulates the expression of calcitonin gene-related peptides (CGRP), thereby contributing to migraine pain. Factors such as genetics, obesity, and environmental conditions that influence the CSD threshold are discussed, suggesting potential therapeutic targets. Current treatments for migraine, including prophylactic agents and CGRP-targeting drugs, are evaluated in the context of their expected effects on suppressing CSD activity. Additionally, we highlight emerging therapies such as intranasal insulin-like growth factor 1 and vagus nerve stimulation, which have shown promise in reducing CSD susceptibility and frequency. By elucidating the molecular and cellular mechanisms of CSD, this review aims to enhance the understanding of migraine pathogenesis and support the development of targeted therapeutic strategies.

Researchers have conducted extensive research on the correlation between brain resting-state functional activities (RSFA) and migraine. However, we still do not fully understand the exact nature of the causal relationship between these RSFA and migraine. We conducted a bidirectional two-sample Mendelian randomization (MR) study to investigate the causal association between migraine and RSFA. We gathered summary statistics from genome-wide association studies for 191 resting-state functional magnetic resonance imaging phenotypes. We employed various analytical methods for bidirectional two-sample MR analyses. This included inverse variance weighted, weighted median, MR Egger, and the constrained maximum likelihood approaches. We also conducted pleiotropy and heterogeneity analyses to evaluate the robustness and reliability. We found the functional connectivity between the default mode and the central executive network (OR = 1.39, p = 4.77 × 10 -4 , FDR corrected p value = 0.040) and the intensity of spontaneous brain activity in the calcarine or lingual gyrus within the visual network (OR = 0.74, p = 5.94 × 10 -4 , FDR corrected p value = 0.040) having a causal effect on the risk of migraine. Our MR analysis provided genetic support for these networks, which may play an important role in influencing migraine susceptibility., (© 2024. The Author(s).)

Background: Patients with migraine are vulnerable to insufficient sleep, but the impact of sleep restriction is largely unknown. In addition, the importance of sleep may be different in patients with migraine who mostly have attack onsets during sleep, so called sleep-related migraine, compared to patients with non-sleep-related migraine. In this study we investigate the effect of sleep restriction on endogenous pain modulation in patients with migraine and healthy controls. We also compared the effect of sleep restriction in sleep-related and in non-sleep-related migraine., Methods: Measurements were conducted in 39 patients with migraine between attacks and 31 controls, once after habitual sleep and once after two consecutive nights of partial sleep restriction. There were 29 and 10 patients with non-sleep-related and sleep-related migraine respectively. Test stimulus was 2-min tonic noxious heat to the left volar forearm. Temporal summation was calculated as the regression coefficient for rated pain in the late part of this 2-min stimulation. Conditioning stimulus was right hand-immersion in 7 °C water. Conditioned pain modulation was defined as the difference in rated pain with and without the conditioning stimulus and was calculated for temporal summation and mean rated pain for the test stimulus. The effect of sleep restriction on temporal summation and conditioned pain modulation was compared in migraine subjects and controls using two-level models with recordings nested in subjects., Results: Conditioned pain modulation for temporal summation of heat pain tended to be reduced after sleep restriction in patients with migraine compared to controls (p = 0.060) and, in an exploratory analysis, was reduced more after sleep restriction in sleep-related than in non-sleep-related migraine (p = 0.017). No other differences between groups after sleep restriction were found for temporal summation or conditioned pain modulation., Conclusion: Patients with migraine may have a subtly altered endogenous pain modulation system. Sleep restriction may have an increased pronociceptive effect on this system, suggesting a mechanism for vulnerability to insufficient sleep in migraine. This effect seems to be larger in sleep-related migraine than in non-sleep-related migraine., (© 2024. The Author(s).)

Background: Migraine-related perfusion changes are documented but inconsistent across studies due to limited sample size and insufficient phenotyping. The phasic and spatial dynamics across migraine subtypes remains poorly characterized. This study aimed to determine spatiotemporal dynamics of gray matter (GM) perfusion in migraine., Methods: We prospectively recruited episodic (EM) and chronic migraine (CM) patients, diagnosed with the International Headache Society criteria and healthy controls (HCs) between 2021 and 2023 from the headache center in a tertiary medical center, and adjacent communities. Magnetic resonance (3-tesla) arterial spin labeling (ASL) was conducted for whole brain cerebral blood flow (CBF) in all participants. The voxel-wise and whole brain gray matter (GM) CBF were compared between subgroups. Spatial pattern analysis of CBF and its correlations with headache frequency were investigated regarding different migraine phases and subtypes. Sex- and age-adjusted voxel-wise and whole brain GM comparisons were performed between HCs and different EM and CM phases. Spatial pattern analysis was conducted by CBF clusters with phasic differences and spin permutation test. Correlations between headache frequency and CBF were investigated regarding different EM and CM phases., Results: Totally 344 subjects (172 EM, 120 CM, and 52 HCs) were enrolled. Higher CBF in different anatomical locations was identified in ictal EM and CM. The combined panels of the specific locations with altered CBF in ictal EM on receiver operating characteristic curve analysis demonstrated areas under curve of 0.780 (vs. HCs) and 0.811 (vs. preictal EM). The spatial distribution of ictal-interictal CBF alteration of EM and CM were not correlated with each other (p = 0.665; r = - 0.018). Positive correlations between headache frequency and CBF were noted in ictal EM and CM regarding whole GM and specific anatomical locations., Conclusions: Patients with migraine exhibited unique spatiotemporal CBF dynamics across different phases and distinct between subtypes. The findings provide neurobiological insights into how selected anatomical structures engage in a migraine attack and adapt to plastic change of repeated attacks along with chronicity., (© 2024. The Author(s).)

Background: High-frequency episodic migraine (HFEM) has gained attention in the field of headache research and clinical practice. In this narrative review, we analyzed the available literature to assess the evidence that could help decide whether HFEM may represent a distinct clinical and/or biological entity within the migraine spectrum., Methods: The output of the literature search included 61 papers that were allocated to one of the following topics: (i) socio-demographic features and burden; (ii) clinical and therapeutic aspects; (iii) pathophysiology; and (iv) classification., Results: Multiple features differentiate subjects with HFEM from low-frequency episodic migraine and from chronic migraine: education, employment rates, quality of life, disability and psychiatric comorbidities load. Some evidence also suggests that HFEM bears a specific profile of activation of cortical and spinal pain-related pathways, possibly related to maladaptive plasticity., Conclusions: Subjects with HFEM bear a distinctive clinical and socio-demographic profile within the episodic migraine group, with a higher disease burden and an increased risk of transitioning to chronic migraine . Recognizing HFEM as a distinct entity is an opportunity for the better understanding of migraine and the spectrum of frequency with which it can manifest, as well as for stimulating further research and more adequate public health approaches., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article (past 4 years). FC: None. RDI received personal fees for participating in speaking at scientific events from Eli-Lilly, TEVA and Lundbeck. He has participated in an advisory board for Pfizer and AbbVie. MC: None. FB: None. GV received personal fees for participating in speaking at scientific events from Lundbeck. DM reports support from Abbvie for participating in advisory boards; consulting fees from LifeSciences Consultants, fees from Medscape for organizing educational programs; and personal fees from Lundbeck for lecturing at symposia. PP-R reports support for the present study from AbbVie and personal fees for consulting from AbbVie, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer and Teva. She has received personal fees for speaking from AbbVie, Dr Reddy's, Eli Lilly, Lundbeck, Medscape, Novartis and Teva, and has had grants paid to her research group from AbbVie, AGAUR, EraNet Neuron, FEDER RIS3CAT, Instituto Investigacion Carlos III, International Headache Society, Novartis and Teva. She is a member of the Scientific Advisory Board for Lilly Foundation Spain.PJG reports, over the last 36 months, grants from Celgene and Kallyope; personal fees from Aeon Biopharma, Abbvie, Amgen, eNeura, CoolTech LLC, Dr Reddys’, Eli-Lilly and Company, Epalex, Linpharma, Lundbeck, Man&Science, Novartis, Pfizer, Sanofi, Satsuma, Shiratronics and Teva Pharmaceuticals; personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners and Vector Metric; fees for educational materials from CME Outfitters; as well as publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UptoDate and Wolters Kluwer. CT reports support from Abbvie and Novartis for investigator-initiated trials; consulting fees from Abbvie, Eli Lilly, Dompé, Ipsen, Lundbeck, Pfizer, Teva and Medscape for participating in advisory boards; support from Abbvie, Eli Lilly, Dompé, Ipsen, Lundbeck, Pfizer and Teva for attending meetings; and personal fees from Abbvie, Eli Lilly, Lundbeck, Pfizer and Teva for lecturing at symposia. She is principal investigator of clinical trials sponsored by Abbvie, Biohaven, Eli Lilly, Ipsen, Lundbeck, Pfizer and Teva. She has received research grants from the European Commission, the Italian Ministry of Health and the Migraine Research Foundation.

Background: Somatosensory tinnitus (ST) is associated with activation of the auditory pathway by trigeminal or cervical afferents., Objective: This is a cross-sectional observational study that aims to verify the association of ST with TMD, bruxism, migraine and psychosocial aspects., Methods: This study was conducted at the Tinnitus Outpatient Clinic of the Clinical Hospital Complex of the Federal University of Paraná. Specific ST characteristics, were evaluated according to the last consensus for the diagnosis of ST. Two groups with 39 individuals each one were formed, the ST group (STG) and the comparison group (CG). TMD was classified according to the Diagnostic Criteria for Temporomandibular Disorders and migraine by the International Classification of Headaches. The presence of probable sleep and awake bruxism was associated with individual's reports and clinical inspections. The applied questionnaires investigated oral behaviours (OB), sleep quality (SQ), psychosocial aspects (PA), central sensitization (CS), tinnitus impact on quality of life (TIQF), and graded chronic pain scale (GCPS)., Results: The STG showed a significant association with modulation manoeuvres and trigger points; myalgias and arthralgia; disc displacement with and without reduction; subluxation; bruxism; and presence of migraine. For the same group, we found a significant association with OB, PA, CS, TIQF and GCPS. There was no significant difference between groups regarding SQ., Conclusion: There is a significant association between the presence of ST and the occurrence of TMD, probable sleep and awake bruxism, and migraine. There is also a greater impairment of OB, PA, CS and TIQF., (© 2024 John Wiley & Sons Ltd.)

Purpose: Palinopsia (persistent afterimages and/or trailing) is a common but poorly understood symptom of the neurological condition visual snow syndrome. This study aimed to collect a phenotypical description of palinopsia in visual snow syndrome and probe for abnormalities in temporal visual processing, hypothesizing that palinopsia could arise from increased visibility of normal afterimage signals or prolonged visible persistence., Methods: Thirty controls and 31 participants with visual snow syndrome (18 with migraine) took part. Participants completed a palinopsia symptom questionnaire. Contrast detection thresholds were measured before and after brief exposure to a spatial grating because deficient contrast adaptation could increase afterimage visibility. Temporal integration and segregation were assessed using missing-element and odd-element tasks, respectively, because prolonged persistence would promote integration at wide temporal offsets. To distinguish the effects of visual snow syndrome from comorbid migraine, 25 people with migraine alone participated in an additional experiment., Results: Palinopsia was common in visual snow syndrome, typically presenting as unformed images that were frequently noticed. Contrary to our hypotheses, we found neither reduced contrast adaptation (F(3.22, 190.21) = 0.71, P = 0.56) nor significantly prolonged temporal integration thresholds (F(1, 59) = 2.35, P = 0.13) in visual snow syndrome. Instead, participants with visual snow syndrome could segregate stimuli in closer succession than controls (F(1, 59) = 4.62, P = 0.04, ηp2 = 0.073) regardless of co-occurring migraine (F(2, 53) = 1.22, P = 0.30). In contrast, individuals with migraine alone exhibited impaired integration (F(2, 53) = 4.44, P = 0.017, ηp2 = 0.14)., Conclusions: Although neither deficient contrast adaptation nor prolonged visible persistence explains palinopsia, temporal resolution of spatial cues is enhanced and potentially more flexible in visual snow syndrome.

Background: The prodrome or premonitory phase is the initial phase of a migraine attack, and it is considered as a symptomatic phase in which prodromal symptoms may occur. There is evidence that attacks start 24-48 hours before the headache phase. Individuals with migraine also report several potential triggers for their attacks, which may be mistaken for premonitory symptoms and hinder migraine research., Methods: This review aims to summarize published studies that describe contributions to understanding the fine difference between prodromal/premonitory symptoms and triggers, give insights for research, and propose a way forward to study these phenomena. We finally aim to formulate a theory to unify migraine triggers and prodromal symptoms. For this purpose, a comprehensive narrative review of the published literature on clinical, neurophysiological and imaging evidence on migraine prodromal symptoms and triggers was conducted using the PubMed database., Results: Brain activity and network connectivity changes occur during the prodromal phase. These changes give rise to prodromal/premonitory symptoms in some individuals, which may be falsely interpreted as triggers at the same time as representing the early manifestation of the beginning of the attack. By contrast, certain migraine triggers, such as stress, hormone changes or sleep deprivation, acting as a catalyst in reducing the migraine threshold, might facilitate these changes and increase the chances of a migraine attack. Migraine triggers and prodromal/premonitory symptoms can be confused and have an intertwined relationship with the hypothalamus as the central hub for integrating external and internal body signals., Conclusions: Differentiating migraine triggers and prodromal symptoms is crucial for shedding light on migraine pathophysiology and improve migraine management., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: GS received personal fees from AbbVie. KHK received travel grant from AbbVie and honoraria for participation in advisory board from Medison Pharma. MF received personal fees from Novartis and Teva. AÇA, IC, FF, HK, MK, DO, DAM, AP, DS and JS declared no conflict of interest. EC has received honoraria from Novartis, Chiesi, Lundbeck, TEVA, Lilly, Medscape. PPR reports that within the prior 36 months, having received honoraria as a consultant and speaker for: AbbVie, Amgen, Biohaven, Chiesi, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer and Teva. Her research group has received research grants from Novartis, Teva, AbbVie, EraNET Neuron, RIS3CAT FEDER, AGAUR, ISCIII and International Headache Society, and has received funding for clinical trials from Alder, Amgen, Biohaven, Eli Lilly, Lundbeck, Novartis and Teva. She is the Honorary Secretary of the International Headache Society. She is a member of the Clinical Trials Guideline Committee of the International Headache Society. She serves as an associate editor for Cephalalgia, Headache, The Journal of Headache and Pain, Neurologia and Revista de Neurologia. She is the founder of www.midolordecabeza.org. PP-R does not own stocks from any pharmaceutical company.

Migraine is highly prevalent and debilitating. The persistent headaches in this condition are thought to arise from the activation and sensitization of the trigeminovascular pathway. Both clinical and animal model studies have suggested that neuroimmune interactions contribute to the pathophysiology of migraine headache. In this review, we first summarize the findings from human studies implicating the dysregulation of the immune system in migraine, including genetic analyses, measurement of circulatory factors, and neuroimaging data. We next discuss recent advances from rodent studies aimed at elucidating the neuroimmune interactions that manifest at various levels of the trigeminovascular pathway and lead to the recruitment of innate and adaptive immune cells as well as immunocompetent glial cells. These cells reciprocally modulate neuronal activity via multiple pro- and anti-inflammatory mediators, thereby regulating peripheral and central sensitization. Throughout the discussions, we highlight the potential clinical and translational implications of the findings., Competing Interests: Declaration of interests J.Z. and Y.Q.C. report a patent application for the compositions and methods for the treatment of headache disorders. The authors declare no other conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose of Review: Neuromodulation approaches have been a part of a revolution in migraine therapies with multiple devices approved or in development. These devices vary in the nerve(s) being targeted, implantable versus noninvasive form factors as well as their effectiveness for acute pain reduction or migraine prevention. This review will summarize these recent advancements and approaches that are being developed which build upon prior work and improved technology that may help enhance the effectiveness as well as the patient experience., Recent Findings: Both noninvasive and implantable devices primarily targeting cranial nerves have shown the ability to help alleviate migraine symptoms. Multiple prospective and retrospective studies have demonstrated clinically meaningful reductions in headache intensity with noninvasive approaches, while prevention of migraine demonstrates more modest effects. Implantable neuromodulation technologies focusing on occipital and supraorbital stimulation have shown promise in migraine/headache prevention in chronic migraine patients, but there is a need for improvements in technology to address key needs for surgical approaches., Summary: Electrical neuromodulation approaches in the treatment of migraine is undergoing a transformation towards improved outcomes with better technologies that may suit various patient needs on a more individualized basis., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: It is important to discriminate different headaches in clinical practice, and neurocognitive biomarkers may serve as objective tools. Several reports have suggested potential cognitive impairment for primary headaches, whereas cognitions within specific domains remain elusive, e.g., emotional processing. In this study, we aimed to characterize processing of facial expressions in migraine and tension-type headache (TTH) by analyzing expression-related visual mismatch negativity (EMMN) and explored whether their processing patterns were distinct., Methods: Altogether, 73 headache patients (20 migraine with aura (MA), 28 migraine without aura (MwoA), 25 TTH) and 27 age-matched healthy controls were recruited. After a battery of mood/neuropsychological evaluations, an expression-related oddball paradigm containing multiple models of neutral, happy and sad faces was used to investigate automatic emotional processing., Results: We observed cognitive impairment in all headache patients, especially in attention/execution subdomains, but no discrepancy existed among different headaches. Although analyses of P1/N170 did not reach significant levels, amplitude of early and late EMMN was markedly diminished in MA and MwoA compared with controls and TTH, regardless of happy or sad expression. Moreover, sad EMMN was larger (more negative) than happy EMMN only in controls, while not in all headache groups., Conclusions: Our findings implied that migraine, rather than TTH, might lead to more severe impairment of automatic emotional processing, which was manifested as no observable EMMN elicitation and disappearance of negative bias effect. The EMMN component could assist in discrimination of migraine from TTH and diagnosis of undefined headaches, and its availability needed further validations., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Cortical spreading depolarization is one possible pathogenesis of migraine, of which slow neurophysiological change is barely recorded in conventional EEG settings. Using wide-band EEG conditions, we reappraised the features of EEG in migraineurs, including subdelta-band EEG changes., Methods: This retrospective study included 144 patients with migraine. We delineated EEG of focal delta slow (FDS) (1-4 Hz) by time constant (TC) 0.3 s and focal subdelta slow (FSDS) (< 1 Hz) by TC 2 s. Relationships between clinical variables and EEG findings were evaluated., Results: Of 144 patients, 39 had aura and 105 did not. FSDS and FDS were observed in 38 and 58 patients, respectively. No EEG was recorded during the aura. In multivariate analysis with the phase of migraine, family history, age, and percentage of sleep during EEG recording, the phase of migraine was related to the occurrence of FSDS (postdrome vs interictal, prodrome, and headache respectively (OR = 49.00 [95% CI = 3.89-616.66], 46.28 [2.99-715.78], 32.79 [2.23-481.96], p = 0.0026, 0.0061, 0.011). FDS was clinically unremarkable for differential evaluation., Conclusions: Wide-band EEG abnormality in migraineurs, i.e., FSDS, can be affected by migraine phase., Significance: Wide-band EEG finding could be a biomarker related to clinical variables in migraines., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: We aim to critically review animal and human studies of the glymphatic system in migraine and propose a model for how the glymphatic system may function in migraine, based on the available evidence., Recent Findings: Early studies in animal models report migraine attacks temporarily disrupt glymphatic flow. Human imaging studies suggest chronic migraine may be associated with alterations in glymphatic system function, albeit with conflicting results. Presently, it remains unknown whether repetitive migraine attacks or frequent nights of insomnia impair glymphatic system function over time in those with migraine, and whether alterations in glymphatic function could contribute to worsening migraine disability or risk for cognitive disease. Longitudinal studies of glymphatic function in patients with migraine and insomnia, with inclusion of cognitive assessments, may be informative., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Migraine and insomnia are prevalent conditions that often co-occur, each exacerbating the other and substantially impacting the quality of life. The locus coeruleus (LC), a brainstem region responsible for norepinephrine synthesis, participates in pain modulation, sleep/wake cycles, and emotional regulation, rendering it a potential nexus in the comorbidity of migraine and insomnia. Disruptions in the LC-noradrenergic system have been hypothesized to contribute to the comorbidities of migraine and insomnia, although neuroimaging evidence in humans remains scarce. In this study, we aimed to investigate the intrinsic functional connectivity (FC) network of the LC in patients with comorbid migraine and subjective chronic insomnia and patients with migraine with no insomnia (MnI) using resting-state functional magnetic resonance imaging (rs-fMRI) and seed-based FC analyses., Methods: In this cross-sectional study, 30 patients with comorbid migraine and chronic insomnia (MI), 30 patients with MnI, and 30 healthy controls (HCs) were enrolled. Participants underwent neuropsychological testing and rs-fMRI. The LC-FC network was constructed using seed-based voxel-wise FC analysis. To identify group differences in LC-FC networks, voxel-wise covariance analysis was conducted with sex and age as covariates. Subsequently, a partial correlation analysis was conducted to probe the clinical relevance of aberrant LC-FC in patients with MI and MnI., Results: Except for the insomnia score, no other significant difference was detected in demographic characteristics and behavioral performance between the MI and MnI groups. Compared with HCs, patients with MI exhibited altered LC-FC in several brain regions, including the dorsomedial prefrontal cortex (DMPFC), anterior cerebellum, dorsolateral prefrontal cortex (DLPFC), thalamus, and parahippocampal gyrus (PHG). Lower FC between the LC and DLPFC was associated with greater insomnia severity, whereas higher FC between the LC and DMPFC was linked to longer migraine attack duration in the MI group., Conclusion: Our findings reveal the presence of aberrant LC-FC networks in patients with MI, providing neuroimaging evidence of the interplay between these conditions. The identified LC-FC alterations may serve as potential targets for therapeutic interventions and highlight the importance of considering the LC-noradrenergic system in the management of MI., (© 2024. The Author(s).)

Background: Chronic migraine is a severe and common neurological disorder, yet its precise physiological mechanisms remain unclear. The IGF1/IGF1r signaling pathway plays a crucial role in pain modulation. Studies have shown that IGF1, by binding to its receptor IGF1r, activates a series of downstream signaling cascades involved in neuronal survival, proliferation, autophagy and functional regulation. The activation of these pathways can influence nociceptive transmission. Furthermore, alterations in IGF1/IGF1r signaling are closely associated with the development of various chronic pain conditions. Therefore, understanding the specific mechanisms by which this pathway contributes to pain is of significant importance for the development of novel pain treatment strategies. In this study, we investigated the role of IGF1/IGF1r and its potential mechanisms in a mouse model of chronic migraine., Methods: Chronic migraine was induced in mice by repeated intraperitoneal injections of nitroglycerin. Mechanical and thermal hypersensitivity responses were assessed using Von Frey filaments and radiant heat, respectively. To determine the role of IGF1/IGF1r in chronic migraine (CM), we examined the effects of the IGF1 receptor antagonist ppp (Picropodophyllin) on pain behaviors and the expression of calcitonin gene-related peptide (CGRP) and c-Fos., Result: In the nitroglycerin-induced chronic migraine model in mice, neuronal secretion of IGF1 is elevated within the trigeminal nucleus caudalis (TNC). Increased phosphorylation of the IGF1 receptor occurs, predominantly co-localizing with neurons. Treatment with ppp alleviated basal mechanical hypersensitivity and acute mechanical allodynia. Furthermore, ppp ameliorated autophagic dysfunction and reduced the expression of CGRP and c-Fos., Conclusion: Our findings demonstrate that in the chronic migraine (CM) model in mice, there is a significant increase in IGF1 expression in the TNC region. This upregulation of IGF1 leads to enhanced phosphorylation of IGF1 receptors on neurons. Targeting and inhibiting this signaling pathway may offer potential preventive strategies for mitigating the progression of chronic migraine., (© 2024. The Author(s).)

Background: The pathophysiology of migraine remains poorly understood, yet a growing number of studies have shown structural connectivity disruptions across large-scale brain networks. Although both structural and functional changes have been found in the cerebellum of migraine patients, the cerebellum has barely been assessed in previous structural connectivity studies of migraine. Our objective is to investigate the structural connectivity of the entire brain, including the cerebellum, in individuals diagnosed with episodic migraine without aura during the interictal phase, compared with healthy controls., Methods: To that end, 14 migraine patients and 15 healthy controls were recruited (all female), and diffusion-weighted and T1-weighted MRI data were acquired. The structural connectome was estimated for each participant based on two different whole-brain parcellations, including cortical and subcortical regions as well as the cerebellum. The structural connectivity patterns, as well as global and local graph theory metrics, were compared between patients and controls, for each of the two parcellations, using network-based statistics and a generalized linear model (GLM), respectively. We also compared the number of connectome streamlines within specific white matter tracts using a GLM., Results: We found increased structural connectivity in migraine patients relative to healthy controls with a distinct involvement of cerebellar regions, using both parcellations. Specifically, the node degree of the posterior lobe of the cerebellum was greater in patients than in controls and patients presented a higher number of streamlines within the anterior limb of the internal capsule. Moreover, the connectomes of patients exhibited greater global efficiency and shorter characteristic path length, which correlated with the age onset of migraine., Conclusions: A distinctive pattern of heightened structural connectivity and enhanced global efficiency in migraine patients compared to controls was identified, which distinctively involves the cerebellum. These findings provide evidence for increased integration within structural brain networks in migraine and underscore the significance of the cerebellum in migraine pathophysiology., (© 2024. The Author(s).)

Magnetoencephalography/electroencephalography (M/EEG) can provide insights into migraine pathophysiology and help develop clinically valuable biomarkers. To integrate and summarize the existing evidence on changes in brain function in migraine, we performed a systematic review and meta-analysis (PROSPERO CRD42021272622) of resting-state M/EEG findings in migraine. We included 27 studies after searching MEDLINE, Web of Science Core Collection, and EMBASE. Risk of bias was assessed using a modified Newcastle-Ottawa Scale. Semi-quantitative analysis was conducted by vote counting, and meta-analyses of M/EEG differences between people with migraine and healthy participants were performed using random-effects models. In people with migraine during the interictal phase, meta-analysis revealed higher power of brain activity at theta frequencies (3-8 Hz) than in healthy participants. Furthermore, we found evidence for lower alpha and beta connectivity in people with migraine in the interictal phase. No associations between M/EEG features and disease severity were observed. Moreover, some evidence for higher delta and beta power in the premonitory compared to the interictal phase was found. Strongest risk of bias of included studies arose from a lack of controlling for comorbidities and non-automatized or non-blinded M/EEG assessments. These findings can guide future M/EEG studies on migraine pathophysiology and brain-based biomarkers, which should consider comorbidities and aim for standardized, collaborative approaches., (© 2024. The Author(s).)

Background: Migraine affects one in ten individuals worldwide and is the second leading cause of disability. Studies have shown an association between migraine and the musculoskeletal system, and myofascial trigger points (MTrPs) play an essential role. Additionally, those with myofascial pain have been proven to experience higher levels of depression and anxiety. Understanding the association between MTrPs and migraine is crucial for developing targeted treatment strategies. Additionally, recognizing the link between MTrPs and migraine-related depression and anxiety underscores the importance of a holistic approach to migraine management. By addressing both musculoskeletal and neurological factors, healthcare providers can provide more effective and personalized care for migraine patients. This study aims to determine the association between MTrPs with migraine-related disability, anxiety, depression, and migraine characteristics., Methods: This cross-sectional study included 68 migraine patients from an outpatient neurology clinic. The number of MTrPs was determined through examination by an experienced neurologist during a migraine-free period using the recommended international criteria. We evaluated anxiety and depression with the Hospital Anxiety and Depression Scale (HADS) and disability with the Migraine Disability Assessment Scale (MIDAS)., Results: We enrolled 68 patients (22 males) with a mean age of 36.23 ± 9.63 years. The mean number of MTrPs was 2.75 ± 2.934. MTrPs were positively correlated with severity (CC: 0.576, P-value < 0.001). There was no association between MTrPs and HADS-D or MIDAS, but migraine patients with abnormal HADS-A scores had more MTrPs than patients with normal HADS-A scores (0.6 ± 0.84 vs 3.56 ± 3.11, P-value:0.013)., Conclusions: The number of MTrPs is associated with higher anxiety levels and headache intensity. Further research could investigate the impact of MTrP-based therapies on anxiety among individuals suffering from migraines., (© 2024. The Author(s).)

Background and Objectives: About a quarter of migraine cases among women have menstrual migraine (MM), which is usually more severe, longer lasting, and less responsive to treatment than typical migraine. Randomized controlled trials (RCTs) have evaluated the efficacy of several medication in the acute and preventive treatment of MM; this meta-analysis compared the effectiveness of these treatments., Methods: We conducted systematic searches in the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase databases. The primary outcomes of acute treatment trials were pain relief at 2 and 24 h after treatment compared with placebo or another treatment. The three endpoints we checked for studying MM prevention were: no recurrence of headaches each month, a 50% reduction in monthly migraine days from baseline, and a decrease in the mean number of headache days per month., Results: Out of 342 studies, 26 RCTs met the criteria. Triptans, combined with or without other analgesics, were superior to placebo in providing pain relief in the acute treatment and prevention of MM. Among the treatments, sumatriptan and lasmiditan demonstrated superior pain relief at 2 h (OR: 4.62) and 24 h (OR: 4.81). Frovatriptan exhibited effectiveness in preventing headache recurrence, whereas galcanezumab and erenumab displayed significant preventive benefits in reducing headache days per month., Conclusion: Sumatriptan and lasmiditan are effective first-line treatments for acute MM. For prevention, frovatriptan may be the more effective of triptans. Compared with triptans, CGRP monoclonal antibodies, here including erenumab and galcanezumab, are more effective in reducing headache days, and therefore, in preventing MM., (© 2024. The Author(s).)

Purpose: During the non-attack period, people with migraine may show retinal dysfunction. This study builds on previous work by exploring the possibility of foveal and non-foveal visual field and electroretinographic deficits and determining the overlap in eccentricity of such localized visual deficits in people with migraine., Methods: Visual fields and multifocal electroretinography (mf-ERG) were tested in 27 people with migraine (aged 19-45 years) and 18 non-headache controls (aged 20-46 years). Data were averaged according to 5 concentric rings at < 1.5 degrees (foveal) and 5 degrees, 10 degrees, 15.5 degrees, and 22 degrees eccentricities (non-foveal). Linear mixed effects modelling was used to predict mf-ERG amplitude, mf-ERG peak time, and visual field sensitivity with fixed effects of eye, group, and eccentricity., Results: Foveal mf-ERG responses, and visual field sensitivity across all eccentricities (foveal and non-foveal) were similar between the migraine and control groups (P > 0.05). In contrast, the non-foveal mf-ERG was reduced in amplitude in people with migraine relative to controls (P < 0.001), and this group difference depended on eccentricity (P < 0.001) - most prominently, in the parafoveal region (ring 2, P = 0.001)., Conclusions: Retinal electrophysiological deficits were observed in people with migraine in the parafoveal region (between 1.5 degrees and 5 degrees eccentricity), without corresponding visual field deficits. This suggests a spatially localized area of retinal neuronal dysfunction in people with migraine that is insufficient to manifest as a visual field sensitivity loss using standard perimetric methods. Our study highlights the added confound of migraine when conducting standard clinical retinal electrophysiological tests for conditions such as glaucoma, particularly non-foveally.

The study investigated associations between chronotypes (Morning [M], Neither [N], Evening [E]), sociodemographic characteristics, body mass index (BMI), smoking habits, years with migraines, sleep quality (PSQI), anxiety (HADS-A), depression (HADS-D), migraine disability (MIDAS), headache frequency, and pain intensity (VAS) in 80 individuals with migraine. Significant age differences emerged ( p < 0.001), with M-types being the oldest. BMI also varied, with M-types presenting the highest median BMI ( p = 0.005). While migraine duration and headache frequency showed no significant variance, sleep quality did, with E-types reporting the poorest sleep ( p = 0.030). Anxiety and depression were significantly worse in E-types (HADS-A: p = 0.002; HADS-D: p = 0.010). Differences in MIDAS levels were notable ( p = 0.038); however, differences in MIDAS scores were not significant (p = 0.115). Pain intensity varied, with E-types experiencing the most severe pain (p = 0.009). Post-hoc analysis showed higher MIDAS scores in E-types compared to N-types (χ 2 = 6.56, p = 0.038, ε 2 = 0.0831). The findings highlight the need for thorough patient evaluations and tailored care, considering the complex interplay of factors affecting migraine severity, particularly among different chronotypes.

Background: It is still debatable whether the mechanisms underlying photophobia are related to altered visual cortex excitability or specific abnormalities of colour-related focal macular retino-thalamic information processing., Methods: This cross-sectional study examined Ganzfeld blue-red (B-R) and blue-yellow (B-Y) focal macular cone flash ERG (ffERG) and focal-flash visual evoked potentials (ffVEPs) simultaneously in a group of migraine patients with (n = 18) and without (n = 19) aura during the interictal phase, in comparison to a group of healthy volunteers (HVs) (n = 20). We correlate the resulting retinal and cortical electrophysiological responses with subjective discomfort from exposure to bright light verified on a numerical scale., Results: Compared to HVs, the amplitude and phase of the first and second harmonic of ffERG and ffVEPs were non-significantly different in migraine patients without aura and migraine patients with aura for both the B-R and the B-Y focal stimuli. Pearson's correlation test did not disclose correlations between clinical variables, including the photophobia scale and electrophysiological variables., Conclusions: These results do not favour interictal functional abnormalities in L-M- and S-cone opponent visual pathways in patients with migraine. They also suggest that the discomfort resulting from exposure to bright light is not related to focal macular retinal-to-visual cortex pathway., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Background: OnabotulinumtoxinA (onabotA), is assumed to achieve its therapeutic effect in migraine through blocking activation of unmyelinated meningeal nociceptors and their downstream communications with central dura-sensitive trigeminovascular neurons in the spinal trigeminal nucleus (SPV). The present study investigated the mechanism of action of onabotA by assessing its effect on activation and sensitization of dura-sensitive neurons in the SPV by cortical spreading depression (CSD). It is a follow up to our recent study on onabotA effects on activation and sensitization of peripheral trigeminovascular neurons., Methods: In anesthetized male and female rats, single-unit recordings were used to assess effects of extracranial injections of onabotA (five injections, one unit each, diluted in 5 μl of saline were made along the lambdoid (two injection sites) and sagittal (two injection sites) suture) vs. vehicle on CSD-induced activation and sensitization of high-threshold (HT) and wide-dynamic range (WDR) dura-sensitive neurons in the SPV., Results: Single cell analysis of onabotA pretreatment effects on CSD-induced activation and sensitization of central trigeminovascular neurons in the SPV revealed the ability of this neurotoxin to prevent activation and sensitization of WDR neurons (13/20 (65%) vs. 4/16 (25%) activated neurons in the control vs. treated groups, p  = 0.022, Fisher's exact). By contrast, onabotA pretreatment effects on CSD-induced activation and sensitization of HT neurons had no effect on their activation (12/18 (67%) vs. 4/7 (36%) activated neurons in the control vs. treated groups, p  = 0.14, Fisher's exact). Regarding sensitization, we found that onabotA pretreatment prevented the enhanced responses to mechanical stimulation of the skin (i.e. responses reflecting central sensitization) in both WDR and HT neurons. In control but not treated WDR neurons, responses to brush ( p =  0.004 vs. p =  0.007), pressure ( p  = 0.002 vs. p  = 0.79) and pinch ( p  = 0.007 vs. 0.79) increased significantly two hours after CSD. Similarly, in control but not treated HT neurons, responses to brush ( p =  0.002 vs. p =  0.79), pressure ( p  = 0.002 vs. p  = 0.72) and pinch ( p  = 0.0006 vs. p  = 0.28) increased significantly two hours after CSD. Unexpectedly, onabotA pretreatment prevented the enhanced responses of both WDR and HT neurons to mechanical stimulation of the dura (commonly reflecting peripheral sensitization). In control vs. treated WDR and HT neurons, responses to dural stimulation were enhanced in 70 vs. 25% ( p  = 0.017) and 78 vs. 27% ( p  = 0.017), respectively., Conclusions: The ability of onabotA to prevent activation and sensitization of WDR neurons is attributed to its preferential inhibitory effects on unmyelinated C-fibers. The inability of onabotA to prevent activation of HT neurons is attributed to its less extensive inhibitory effects on the thinly myelinated Aδ-fibers. These findings provide further pre-clinical evidence about differences and potentially complementary mechanisms of action of onabotA and calcitonin gene-related peptide-signaling neutralizing drugs., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RB is the John Hedley-Whyte Professor of Anesthesia and Neuroscience at the Beth Israel Deaconess Medical Center and Harvard Medical School. He has received research support from the NIH: R01 NS094198-01A1, R37 NS079678, R01NS095655, R01 NS104296, R21 NS106345, Allergan, Teva, Dr Ready, Eli Lilly, Trigemina and the Migraine Research Foundation. He is a reviewer for NINDS, holds stock options in AllayLamp and Percept; serves as consultant, advisory board member, or has received honoraria from: Alder, Allergan, Biohaven, Dr Reddy's Laboratory, Eli Lilly, GlaxoSmithKline, Merck, Teva and Trigemina. CME fees from Healthlogix, Medlogix, WebMD/Medscape, and Patents 9061025, 11732265.1, 10806890, US2021-0015908, WO21007165, US2021-0128724, WO210054RBr, BD, AMA and MFB are employees of Allergan, an AbbVie Company.The other authors declare that they have no conflicts of interest.

Background: The periaqueductal gray (PAG) is at the center of a powerful descending antinociceptive neuronal network, and is a key node in the descending pain regulatory system of pain. However, less is known about the altered perfusion of PAG in chronic migraine (CM)., Aim: To measure the perfusion of PAG matter, an important structure in pain modulation, in CM with magnetic resonance (MR) perfusion without contrast administration., Methods: Three-dimensional pseudocontinuous arterial spin labeling (3D-PCASL) and brain structure imaging were performed in 13 patients with CM and 15 normal subjects. The inverse deformation field generated by brain structure image segmentation was applied to the midbrain PAG template to generate individualized PAG. Then the perfusion value of the PAG area of the midbrain was extracted based on the individual PAG mask., Results: Cerebral blood flow (CBF) value of PAG in CM patients (47.98 ± 8.38 mL/100 mg min) was significantly lower than that of the control group (59.87 ± 14.24 mL/100 mg min). Receiver operating characteristic (ROC) curve analysis showed that the area under the curve was 0.77 (95% confidence interval [CI], 0.60, 0.94), and the cutoff value for the diagnosis of CM was 54.83 mL/100 mg min with a sensitivity 84.60% and a specificity 60%., Conclusion: Imaging evidence of the impaired pain conduction pathway in CM may be related with the decreased perfusion in the PAG, which could be considered as an imaging biomarker for the diagnosis and therapy evaluation., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

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., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: C.M.K., G.L., L.K.M., K.B., A.M. and E.N. declare that they have no personal, financial, or relational conflicts of interest with this work. F.P. has served as a consultant or received research funding from Voyager, SiteOne Therapeutics, Nektar, Amgen, Acadia, Blackthorn, Teva, Eli Lilly, Hoba, Allergan, Ipsen, and Proximagen and has served as a founder of Catalina Pharma, Axon Therapeutics, Scientific Advisory Board Regulonix, and Condor Pharma. D.W.D. reports the following conflicts within the past 12 months: Consulting: AEON, Amgen, Clexio, Cerecin, Ctrl M, Allergan, Alder, Biohaven, Linpharma, Lundbeck, Promius, Eli Lilly, eNeura, Novartis, Impel, Satsuma, Theranica, Vedanta, WL Gore, Nocira, XoC, Zosano, Upjohn (Division of Pfizer), Pieris, Revance, Equinox. Honoraria: CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, Academy for Continued Healthcare Learning, Majallin LLC, Medlogix Communications, MJH Lifesciences, Miller Medical Communications, Southern Headache Society (MAHEC), WebMD Health/Medscape, Wolters Kluwer, Oxford University Press, Cambridge University Press. Research Support: Department of Defense, National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, Patient Centered Outcomes Research Institute (PCORI). Stock Options/Shareholder/Patents/Board of Directors: Ctrl M (options), Aural analytics (options), ExSano (options), Palion (options), Healint (Options), Theranica (Options), Second Opinion/Mobile Health (Options), Epien (Options/Board), Nocira (options), Matterhorn (Shares/Board), Ontologics (Shares/Board), King-Devick Technologies (Options/Board), Precon Health (Options/Board). Patent 17189376.1-1466:vTitle: Botulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis.

This study investigated the sex-specific associations between pain perception and testosterone levels in healthy controls (HCs) and patients with migraine. Male and female HCs and migraine patients were recruited. A series of questionnaires were completed by the participants to evaluate their psychosocial profiles, which included data on mood, stress, and sleep quality. Heat pain thresholds and suprathreshold pain ratings at 45 °C (referred to as the pain perception score [PPS]) were assessed using the Thermode system. Salivary testosterone levels were analyzed using a commercial enzyme-linked immunosorbent assay kit. A total of 88 HCs (men/women: 41/47, age: 29.9 ± 7.7 years) and 75 migraine patients (men/women: 30/45, age: 31.1 ± 7.7 years) completed all assessments. No significant differences were observed in either the psychosocial profiles or heat pain thresholds and PPSs between the sexes in the control and migraine groups. A positive correlation between testosterone levels and PPSs was identified in the male controls (r = .341, P = .029), whereas a negative correlation was identified in the female controls (r = -.407, P = .005). No such correlations were identified in the migraine group. This study confirms that a negative association is present between PPSs and testosterone levels in female controls, which is in line with the findings that testosterone is associated with reduced pain perception. Our study is the first to demonstrate a sex-specific association between PPSs and testosterone levels in HCs. Moreover, this study also revealed that the presence of migraine appears to disrupt this association. PERSPECTIVE: This study revealed that testosterone levels demonstrate opposite associations with pain perception in healthy men and women. However, the presence of migraine appears to disrupt this sex-specific association., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To examine cerebral functional alterations associated with sensory processing in patients with migraine and constant photophobia., Background: Migraine is a common headache disorder that presents with photophobia in many patients during attacks. Furthermore, some patients with migraine experience constant photophobia, even during headache-free intervals, leading to a compromised quality of life., Methods: This prospective, case-control study included 40 patients with migraine (18 male and 22 female) who were recruited at an eye hospital and eye clinic. The patients were divided into two groups: migraine with photophobia group, consisting of 22 patients (10 male and 12 female) with constant photophobia, and migraine without photophobia group, consisting of 18 patients (eight male and 10 female) without constant photophobia. We used 18 F-fluorodeoxyglucose and positron emission tomography to compare cerebral glucose metabolism between the two patient groups and 42 healthy participants (16 men and 26 women)., Results: Compared with the healthy group, both the migraine with photophobia and migraine without photophobia groups showed cerebral glucose hypermetabolism in the bilateral thalamus (p < 0.05, family-wise error-corrected). Moreover, the contrast of migraine with photophobia minus migraine without photophobia patients showed glucose hypermetabolism in the bilateral medial thalamus (p < 0.05, family-wise error-corrected)., Conclusions: The medial thalamus may be associated with the development of continuous photophobia in patients with migraine., (© 2024 American Headache Society.)

Sleep disorders have a high comorbidity rate with vestibular diseases. The results of some small sample clinical studies have confirmed the effect of sleep deprivation on vestibular function. However, the mechanism of the effect of sleep disorder on vestibular system is still unclear. This article analyzes the possible mechanism of the effect of sleep disorders on vestibular function from the aspects of neuroanatomy and neurotransmitters, and summarizes the relationship between sleep disorder and benign paroxysmal positional vertigo, Meniere's disease, vestibular migraine and other diseases., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Introduction: Cognitive symptoms are reported commonly throughout all phases of a migraine; however, there is a paucity of objective cognitive profiling. Previous studies have been limited by practice effect, and variable populations., Methods: Participants completed 1 month of daily testing with a computerised cognitive battery involving a simple reaction (SRT), choice reaction (CRT) and a working memory test (WM). Results were correlated with their diary to identify interictal scores, and scores during each phase of a migraine, and non-migraine headache days., Results: A total of 16 patients with episodic migraine participated. During the headache phase of a migraine, responses to SRT, CRT and WM tasks were significantly slower and less accurate than interictally. During the postdrome, WM task performance was slower and less accurate. Non-migraine headache days were not associated with significant change., Conclusion: The headache and postdromal phase of a migraine day was associated with objective evidence of cognitive dysfunction in patients with episodic migraine., (© 2024. The Author(s).)

Objective: To describe the association between day-to-day peak pain severity and clinical factors in individuals with chronic migraine (CM)., Background: Little is known about how clinical factors relate to day-to-day pain severity in individuals with CM., Methods: Adults with CM were enrolled into this observational prospective cohort study that collected daily data about headache, associated symptoms, and lifestyle factors using a digital health platform (N1-Headache™) for 90 days. "Migraine days" were defined as days in which a headache occurred that had features described by the International Classification of Headache Disorders criteria. On these days, peak pain severity was recorded on a 4-point scale; on non-headache days peak pain severity was imputed as "0/none". The associations between peak pain severity and 12 clinical factors were modeled and adjusted for sex, age, daily headache, presence of menstrual bleeding, day of the week, and disability. All numerical and Likert scale variables were standardized prior to analysis., Results: Data were available for 392 participants (35,280 tracked days). The sample was predominantly female (90.6%), with a mean (standard deviation) age of 39.9 (12.8) years. In the final multivariable model with random intercept and slopes, higher than typical self-reported levels of standardized stress (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.04-1.11), standardized irritability (OR 1.05, 95% CI 1.02-1.08), standardized sadness (OR 1.05, 95% CI 1.02-1.07), fatigue (OR 1.25, 95% CI 1.15-1.36), eyestrain (OR 1.38, 95% CI 1.26-1.52), neck pain (OR 1.94, 95% CI 1.76-2.13), skin sensitivity (OR 1.61, 95% CI 1.44-1.80), and dehydration (OR 1.29, 95% CI 1.18-1.42) were associated with higher reported peak pain severity levels, while standardized sleep quality (OR 0.96, 95% CI 0.93-0.99) and standardized waking feeling refreshed (OR 0.84, 95% CI 0.81-0.88) were associated with lower reported peak pain severity levels. The inclusion of a random intercept and random slopes improved upon more parsimonious models and illustrated large differences in individuals' reporting of peak severity according to the levels of the associated clinical factors., Conclusion: Our data showed that the experience of CM, from a pain severity perspective, is complex, related to multiple clinical variables, and highly individualized. These results suggest that future work should aim to study a personalized approach to both medical and behavioral interventions for CM based on which clinical factors relate to the individual's experience of pain severity., (© 2024 The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Objective: Our aim was to survey astrocyte and microglial activation across four brain regions in a mouse model of chronic migraine., Background: Chronic migraine is a leading cause of disability, with higher rates in females. The role of central nervous system neurons and glia in migraine pathophysiology is not fully elucidated. Preclinical studies have shown abnormal glial activation in the trigeminal nucleus caudalis of male rodents. No current reports have investigated glial activation in both sexes in other important brain regions involved with the nociceptive and emotional processing of pain., Methods: The mouse nitroglycerin model of migraine was used, and nitroglycerin (10 mg/kg) or vehicle was administered every other day for 9 days. Prior to injections on days 1, 5, and 9, cephalic allodynia was determined by periorbital von Frey hair testing. Immunofluorescent staining of astrocyte marker, glial fibrillary protein (GFAP), and microglial marker, ionized calcium binding adaptor molecule 1 (Iba1), in male and female trigeminal nucleus caudalis, periaqueductal gray, somatosensory cortex, and nucleus accumbens was completed., Results: Behavioral testing demonstrated increased cephalic allodynia in nitroglycerin- versus vehicle-treated mice. An increase in the percent area covered by GFAP+ cells in the trigeminal nucleus caudalis and nucleus accumbens, but not the periaqueductal gray or somatosensory cortex, was observed in response to nitroglycerin. No significant differences were observed for Iba1 staining across brain regions. We did not detect significant sex differences in GFAP or Iba1 quantification., Conclusions: Immunohistochemical analysis suggests that, at the time point tested, immunoreactivity of GFAP+ astrocytes, but not Iba1+ microglia, changes in response to chronic migraine-associated pain. Additionally, there do not appear to be significant differences between males and females in GFAP+ or Iba1+ cells across the four brain regions analyzed., (© 2024 American Headache Society.)

Background and Objectives : Migraine is a leading cause of disability worldwide, with complex pathophysiological mechanisms involving oxidative and nitrosative stress. Recent research suggests that Indole-3-Propionic Acid (IPA) may have a neuroprotective role in reducing nitrosative stress. This study aims to elucidate the roles of IPA and nitrosative stress biomarkers in migraine patients, focusing on their potential as therapeutic targets. Materials and Methods : This cross-sectional, case-control study included 57 migraine patients and 30 healthy controls. Patients were categorized into episodic migraine (EM) and chronic migraine (CM) groups. Socio-demographic and clinical characteristics were documented through structured interviews. Validated scales such as the Visual Analog Score (VAS), Headache Impact Test 6 (HIT-6), Migraine Disability Assessment Test (MIDAS), Migraine 24 h Quality of Life Scale (24 h QoL), Mini-Mental State Examination (MMSE), and Migraine Attacks-Subjective Cognitive Impairments Scale (Mig-SCog) were administered. Venous blood samples were collected, and serum levels of IPA, Nitric Oxide (NO), Nitric Oxide Synthase (NOS), and Peroxynitrite (ONOO - ) were measured using ELISA and spectrophotometric methods. Results : Significant differences in serum IPA and NO levels were observed between migraine patients and controls. Specifically, higher serum IPA levels were found in the EM group, while higher serum NO levels were observed in the CM group. Elevated NO levels correlated with increased migraine attack frequency. Conversely, serum IPA levels showed a negative correlation with attack frequency, suggesting a protective role. Specifically, NO levels were positively correlated with the number of painful days, NSAID usage, VAS scores, HIT-6 scores, and MIDAS scores, while negatively correlated with 24 h QoL scores. Conclusions : The study highlights the significant involvement of IPA and nitrosative stress in migraine pathophysiology. Elevated IPA levels, particularly in EM patients, suggest its potential neuroprotective role. These findings underscore the importance of targeting oxidative and nitrosative stress pathways in developing effective migraine therapies.

Migraine is a ubiquitous neurological disorder that affects approximately 1 billion people worldwide. Migraine is the second leading cause of illness in people of all ages worldwide. Uncertainty in migraine diagnosis leads to unnecessary testing and increases the treatment costs. To date, the pathogenesis of migraine is not fully understood, but it is generally believed that migraine involves the trigeminal nerve and its axonal projections to intracranial blood vessels. Pain signals from the trigeminal neurovascular system are transmitted to the brain, resulting in migraines. As an important component of complementary and alternative medicine, traditional Chinese medicine (TCM) has shown significant efficacy in the treatment of migraine, and has attracted increasing attention worldwide. This review is based on the pathophysiology of migraines in modern medicine. To explore the comprehensive treatment of migraine using TCM, acupuncture, and various other TCM treatments., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

To investigate neurovascular changes; including macular vascular density (VD), thickness of the ganglion cell layer (GCL) and optic nerve head (ONH) parameters in episodic migraine patients. 80 eyes of 40 episodic migraine patients were recruited. Thirty patients having a dominant side of migraine headache were statistically analyzed (5 male and 25 female; mean age 31.67 ± 9.54 years) and compared to 25 eyes of 25 healthy volunteers (5 male and 20 female; mean age of 34.4 ± 12.11 years, p = 0.361). The posterior segment was imaged with Topcon DRI optical coherence tomography (OCT) (Triton Swept source OCT Topcon, Japan), and OCT angiography (OCTA). Comparing the dominant side of migraine patients to controls we found a significant decrease of the VD in the central zone of the superficial and deep capillary plexus (SCP, p = 0.01; DCP, p = 0.004) and an enlarged foveal avascular zone (FAZ, p = 0.054). The GCL thickness was significantly reduced in the central ring (GCL + p = 0.042, GCL +  + p = 0.029), as well as the retinal nerve fiber layer (RNFL) thickness in the temporal quadrant (p = 0.021) and border tissue of Elschnig diameter (BTE, p = 0.035). The duration of migraine showed an inverse correlation with SCP in the nasal quadrant (p = 0.016, r = - 0.445) and with all DCP regions [DCP superior (p = 0.004, r = - 0.519), DCP inferior (p = 0.004, r = - 0.519), DCP nasal (p = 0.006, r = - 0.496), DCP temporal (p = 0.005, r = - 0.508), DCP CSF (p < 0.001, r = - 0.634)]. The dominant side compared to the non-dominant side showed a significant deterioration of the VD in the inferior (p = 0.04) and temporal quadrants (p = 0.023); furthermore, a significant decrease in the GCL +  + inner ring thickness (p = 0.046). Microvascular damage and consequent structural alterations of the retina and optic nerve head occur in the eyes of episodic migraine patient in association with the lateralization of the headache., (© 2024. The Author(s).)

Background: The role of beta calcitonin gene-related peptide (beta-CGRP) in gastrointestinal tract is obscure, but experimental models suggest an effect on the homeostasis of the intestinal mucosa. We measured beta-CGRP circulating levels in a large series of subjects with a recent diagnosis of inflammatory bowel disease (IBD), in order to assess the potential role of this neuropeptide in IBD pathogenesis., Methods: Morning serum beta-CGRP levels were measured by ELISA (CUSABIO, China) in 96 patients recently diagnosed of IBD and compared with those belonging from 50 matched healthy controls (HC) and 50 chronic migraine (CM) patients., Results: Beta-CGRP levels were lower in patients with IBD (3.1 ± 1.9 pg/mL; 2.9 [2.4-3.4] pg/mL) as compared to HC (4.7 ± 2.6; 4.9 [4.0-5.8] pg/mL; p < 0.001) and to CM patients (4.6 ± 2.6; 4.7 [3.3-6.2] pg/mL; p < 0.001). Beta-CGRP levels in CM were not significantly different to those of HC (p = 0.92). Regarding IBD diagnostic subtypes, beta-CGRP levels for ulcerative colitis (3.0 ± 1.9pg/mL; 2.5 [2.1-3.4] pg/mL) and Crohn's disease (3.3 ± 2.0 pg/mL; 3.2 [2.4-3.9] pg/mL) were significantly lower to those of HC (p < 0.01 and p < 0.05, respectively) and CM (p < 0.01 and p < 0.05, respectively)., Conclusions: We have found a significant reduction in serum beta-CGRP levels in patients with a recent diagnosis of all kinds of IBD as compared to two control groups without active intestinal disease, HC and CM, which may suggest a role for this neuropeptide in the pathophysiology of IBD. Our data indicate a protective role of beta-CGRP in the homeostasis of the alimentary tract., (© 2024. The Author(s).)

Migraine, a primary headache disorder whose mechanism remains incompletely understood, appears to involve the activation of the trigeminovascular system (TS) during attacks. Research suggests that inflammatory processes mediated by the immune system may play a role in migraine pathophysiology. Neuroinflammation is often associated with migraine attacks, with cytokines serving as crucial mediators in the process. Elevated levels of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), have been observed in the blood and cerebrospinal fluid of individuals experiencing migraine attacks. These cytokines have the capacity to sensitize pain pathways in the brain, thereby increasing sensitivity to pain stimuli. This phenomenon, known as central sensitization, is believed to contribute to the intensity and persistence of migraine pain. Kynurenines, endogenous mediators of glutamatergic mechanisms, can significantly influence the pathophysiology of primary headache disorders. The kynurenine system is collectively known as the kynurenine pathway (KP), which can act on multiple receptors, such as glutamate receptors, aryl hydrocarbon receptors (AhRs), G protein-coupled receptors 35 (GPR35), and α-7 nicotinic acetylcholine (α7 nACh) receptors. These receptors are also found on various cells of the immune system, so the role of the KP in the pathomechanism of primary headaches may also be mediated through them. In this review, our goal is to show a possible link between the receptors of the KP and immune system in the context of inflammation and migraine. Migraine research in recent years has focused on neuropeptides, such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as potential pathogenic factors and possible therapeutic approaches. These peptides share many similarities in their characteristics and roles. For instance, they exhibit potent vasodilation, occur in both the peripheral and central nervous systems, and play a role in transmitting nociception and neurogenic inflammation. The investigation of potential connections between the aforementioned neuropeptides and the kynurenine pathway could play a significant role in uncovering the pathomechanism of migraine and identifying new drug candidates., (© 2024. The Author(s).)

Objective: To investigate the differences in resting-state functional connectivity (FC) between patients with vestibular migraine (VM) and migraine without aura (MwoA) in order to infer the possible neuroimaging mechanisms of VM. Methods: Thirty VM patients admitted to the Department of Neurology of the Second Affiliated Hospital of Xuzhou Medical University from December 2019 to December 2022 were selected as the experimental group (EG) (6 males and 24 females, with mean age of 38.3 years) and 26 MwoA patients as the control group (7 males and 19 females, mean age 35.5 years). General demographic and clinical data such as gender, age, year of education, course of disease and frequency of attacks were collected for all the patients, as well as data of Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Montreal Cognitive Assessment (MoCA), headache Visual Arialogue Scale (VAS), Headache Impact Test 6 (HIT-6) and Migraine Disability Assessment Questionnaire (MIDAS). VM patients were also assessed by Dizziness Handicap Inventory (DHI), dizziness VAS and Vestibular Disorders Activities of Daily Living (VADL) scales. All patients underwent resting-sate functional Magnetic Resonance Imaging (fMRI) scans. Bilateral parietal opercular cortex 2 (OP2) and primary visual cortex (V1) were used as regions of interests (ROIs). Differences in FC between ROIs and other brain regions were calculated between the two groups. In view of the brain regions with significant differences, z-values of FC were extracted for each subject in the EG, and Pearson partial correlation analysis was conducted between z-values of FC and clinical characteristics of patients, P <0.05 was considered to have significant correlation. SPSS 22.0 was used for statistical analysis. Results: There was no significant difference in gender, age, years of education, course of disease, frequency of attack and scores of MoCA, HAMA and HAMD between the two groups ( P >0.05). Headache VAS, HIT-6 and MIDAS scores in VM patients were significantly lower than those in MwoA patients ( P <0.05). Compared with MwoA patients, the FC between left OP2 and bilateral precuneus and left thalamus was significantly increased in VM patients, and the FC between right OP2 and left thalamus and right anterior cingulate gyrus were significantly increased ( P <0.05, False Discovery Rate correction). Correlation analysis showed that the FC between left OP2 and left precuneus was positively correlated with DHI score in VM patients ( P =0.007, r =0.480), and the FC between right OP2 and left thalamus was positively correlated with the disease course in VM patients ( P =0.015, r =0.439). Conclusions: The pathogenesis of VM may be related to the altered FC of vestibular, pain and visual-motor networks, abnormalities of these neural pathways may be important imaging biomarkers of VM pathogenesis.

Migraines are a type of headache that occur with other neurological symptoms, but the pathophysiology remains unclear. In this issue of the JCI, Nelson-Maney and authors used constitutive and inducible knockouts of the CGRP receptor components, elegantly demonstrating an essential function of CGRP in modulating meningeal lymphatic vessels (MLVs) in migraine. CGRP was shown to induce rearrangement of membrane-bound gap junction proteins in MLVs, resulting in a reduced CSF flux into cervical lymph nodes. The authors also provided evidence of a primary role for CGRP in modulating neuro-immune function. Finally, by showing that blocking CGRP signaling in MLVs attenuated pain behavior associated with acute migraine in rodents, the authors provided a target for pharmacological blockade of CGRP in relation to primary headache disorders.

A relationship between migraine without aura (MO) and patent foramen ovale (PFO) has been observed, but the neural basis underlying this relationship remains elusive. Utilizing independent component analysis via functional magnetic resonance imaging, we examined functional connectivity (FC) within and across networks in 146 patients with MO (75 patients with and 71 patients without PFO) and 70 healthy controls (35 patients each with and without PFO) to elucidate the individual effects of MO and PFO, as well as their interaction, on brain functional networks. The main effect of PFO manifested exclusively in the FC among the visual, auditory, default mode, dorsal attention and salience networks. Furthermore, the interaction effect between MO and PFO was discerned in brain clusters of the left frontoparietal network and lingual gyrus network, as well as the internetwork FC between the left frontoparietal network and the default mode network (DMN), the occipital pole and medial visual networks, and the dorsal attention and salience networks. Our findings suggest that the presence of a PFO shunt in patients with MO is accompanied by various FC changes within and across networks. These changes elucidate the intricate mechanisms linked to PFO-associated migraines and provide a basis for identifying novel noninvasive biomarkers., (© 2024. The Author(s).)

Migraine is a complex and highly incapacitating neurological disorder that affects around 15% of the general population with greater incidence in women, often at the most productive age of life. Migraine physiopathology is still not fully understood, but it involves multiple mediators and events in the trigeminovascular system and the central nervous system. The identification of calcitonin gene-related peptide as a key mediator in migraine physiopathology has led to the development of effective and highly selective antimigraine therapies. However, this treatment is neither accessible nor effective for all migraine sufferers. Thus, a better understanding of migraine mechanisms and the identification of potential targets are still clearly warranted. Voltage-gated calcium channels (VGCCs) are widely distributed in the trigeminovascular system, and there is accumulating evidence of their contribution to the mechanisms associated with headache pain. Several drugs used in migraine abortive or prophylactic treatment target VGCCs, which probably contributes to their analgesic effect. This review aims to summarize the current evidence of VGGC contribution to migraine physiopathology and to discuss how current pharmacological options for migraine treatment interfere with VGGC function. PERSPECTIVE: Calcitonin gene-related peptide (CGRP) represents a major migraine mediator, but few studies have investigated the relationship between CGRP and VGCCs. CGRP release is calcium channel-dependent and VGGCs are key players in familial migraine. Further studies are needed to determine whether VGCCs are suitable molecular targets for treating migraine., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)