Journal of Headache and Pain最新文献

Background: Menstrual migraine (MM) is a distinct and burdensome subtype of migraine; however, comprehensive data on its clinical and social impact among Japanese females remain limited. Therefore, we aimed to clarify the clinical characteristics and social burden of MM in Japan.

Methods: A cross-sectional, population-based web survey was conducted among Japanese females (≥ 18 years) with regular menstruation who were diagnosed with migraine. Participants were classified into MM and non-MM groups. Clinical parameters assessed between MM and non-MM included pain intensity, pain duration, and headache frequency during the perimenstrual period (-2 days to + 2 days of menstruation onset). Social burden was evaluated using the Migraine Disability Assessment (MIDAS), Migraine Interictal Burden Scale (MIBS-4), Migraine-Specific Quality of Life Questionnaire (MSQ), and Work Productivity and Activity Impairment for Migraine (WPAI-M). These were compared between MM and non-MM, adjusting for potential confounders through inverse probability of treatment weighting using propensity scores.

Results: Of 266,392 screened patients, 4,592 were included in MM and 5,174 in non-MM. The mean age was 36.8 ± 8.0 years in MM and 35.5 ± 8.3 years in non-MM. MM patients experienced higher pain intensity and longer pain duration than non-MM during both perimenstrual and non-perimenstrual periods (perimenstrual periods: -2 days to + 1 day of menstruation onset: all p < 0.001 for both, +2 days of menstruation onset: intensity, p = 0.003, duration, p = 0.046; non-perimenstrual period: intensity, p < 0.001, duration, p = 0.005). MM exhibited higher MIDAS and MIBS-4 scores (both p < 0.001) and lower MSQ scores (restriction, interference, emotion: all p < 0.001), indicating greater disability and reduced quality of life. Among WPAI-M scores, presenteeism, overall work and activity impairment, were also higher in MM vs non-MM (all p < 0.001). MM demonstrated increased usage (MM: 54.0% [1,088/2,015]; non-MM: 24.0% [169/705]) and broader type of medications (MM: 13.2% [265/2,015]; non-MM: 7.1% [50/705]) during the perimenstrual period, particularly non-steroidal anti-inflammatory drugs (MM: 51.4% [801/1,557]; non-MM: 45.4% [636/1,402]).

Conclusions: This study highlights the significant burden of MM, demonstrating increased pain intensity, longer pain duration and higher headache frequency during perimenstrual period, accompanied by a concurrent increase in social burden compared to non-MM. These findings underscore the impact of clinical severity and social burden of MM in Japanese females.

Background: Restlessness or agitation is one of the core symptoms of cluster headache (CH). However, the neurological substrate underlying this phenomenon has not been thoroughly analyzed. Whether they are attributed to the core aggression circuit or other CH-related structures remains unclear. The aim of this study is to use functional neuroimaging to elucidate the underlying mechanism of restlessness or agitation in CH.

Methods: We prospectively recruited consecutive patients with CH from the Headache Clinic of Taipei Veterans General Hospital between Jan 2022 and July 2025. Patients who consistently reported either the presence or absence of restlessness during CH attacks were enrolled and categorized into two groups: restlessness and non-restlessness. All enrolled patients underwent a functional magnetic resonance imaging (fMRI) scan. In the restlessness group, patients were required to exhibit restlessness during the fMRI scan, whereas those in the non-restlessness group showed no restlessness at the time of scanning. In this study, 32 regions of interest (ROIs) relevant to CH pathophysiology and the core aggression circuit were selected. To identify restlessness-related networks, ROI-to-ROI functional connectivity was compared between the restlessness and non-restlessness groups. To investigate downstream network for restlessness, ROI-to-voxel analyses were conducted using a general linear model, with ROIs showing significant differences in the initial ROI-to-ROI analysis as seeds. Multiple comparisons were corrected using both the false discovery rate (FDR) and family-wise error (FWE) methods.

Results: A total of 24 patients with CH were recruited and categorized into two groups: restlessness (N = 14) and non-restlessness (N = 10). The ROI-to-ROI functional connectivity analysis of CH patients with restlessness revealed a significant connection between the non-pain side locus coeruleus (LC) and the pain-side substantia nigra pars compacta (SNpc), which survived FDR correction (p-FDR = 0.016). Seed-based general linear model analysis further revealed decreased connectivity between the pain-side SNpc and pain-side superior frontal gyrus, which survived FWE correction (p = 0.037). However, there were no significant cortical connectivity from the LC survived the FDR correction.

Conclusion: Our fMRI findings suggest that the neurological substrates of restlessness in CH involve the LC and SNpc rather than the core aggression network. Weakened connectivity from the SNpc to the superior frontal cortex may represent the downstream pathway contributing to restlessness in CH.

Background: Small extracellular vesicles (EVs) are nano-sized membranous particles transporting bioactive cargo, including proteins. In the central nervous system (CNS), neuron-derived EVs (nEVs) are thought to play roles in synaptic plasticity, metabolic regulation, and neuroinflammation. While their relevance in neurodegenerative and neuroinflammatory disorders is increasingly recognized, their role in migraine pathophysiology remains underexplored.

Objective: This study aimed to investigate the proteomic signature of nEVs isolated from the cortex of mice subjected to cortical spreading depolarization (CSD), a neurobiological event underlying migraine aura. We sought to identify molecular pathways activated in neurons during CSD and evaluate the potential of nEVs as biomarkers for aura-related brain activity.

Methods: CSD was induced either by pinprick in wild type mice or optogenetically in Thy-ChR2-YFP mice. Following brain perfusion and cortical tissue dissociation, total cortical EVs were isolated by ultracentrifugation whereas nEVs were isolated via immunoaffinity capture targeting neuronal L1 cell adhesion molecule (L1CAM) following nickel-based precipitation of total EVs. nEV proteome was analyzed using label-free quantitative mass spectrometry. Identified proteins were subjected to functional enrichment analysis to uncover relevant biological processes.

Results: Unbiased proteomic profiling revealed CSD-associated changes in pathways involved in transcriptional/translational regulation, cytoskeletal dynamics, stress response and metabolism. These exploratory and descriptive findings suggest that neuronal responses to CSD involve adaptive structural and metabolic alterations and are not limited to inflammatory signaling.

Conclusion: Our results highlight the potential of nEVs as dynamic reporters of cortical neuronal activity in a migraine model. Significant changes in nEV proteome suggest that the neuronal response to CSD extends beyond inflammatory signaling and encompasses adaptive mechanisms aimed at maintaining cellular homeostasis and synaptic integrity. Given their accessibility through peripheral fluids and potential capacity to reflect dynamic changes in neurons, nEVs emerge as promising candidates for investigating pathophysiology and biomarker identification in migraine.

Background: Migraine is the second leading cause of neurological disability and has a strong genetic component. Previous linkage studies have identified a candidate migraine susceptibility locus on chromosome Xq24-28, which harbors several GABA_A receptor subunit genes. Despite its inhibitory role in the central nervous system, the contribution of the GABAergic system to migraine pathophysiology remains insufficiently understood. This study elucidates the role of GABAergic neurons in chronic migraine using established rodent models. We induced basal hypersensitivity as a preclinical model of chronic migraine by administering repeated intraperitoneal injections of nitroglycerin, a well-established migraine trigger, every other day over a nine-day period. Mechanical hypersensitivity, a hallmark of migraine-associated allodynia, was assessed using von Frey filaments, before and after NTG treatment. NTG-treated animals exhibited a progressive increase in mechanical sensitivity compared to controls, consistent with the development of a chronic migraine-like state.

Results: Notably, a selective reduction in GABAergic neurons was observed in male, but not female, NTG-treated mice, specifically within key brain regions associated with pain processing and psychiatric circuits, from the locus coeruleus in the brainstem through the basal forebrain (notably the amygdala) to the neocortex and hippocampus. This loss of GABAergic neurons was accompanied by elevated expression of ΔFosB, a marker of sustained neuronal activation, and increased apoptotic signaling indicated by active caspase-3 staining. Furthermore, male chronic migraine mice showed upregulation of stress-related neuropeptides, including PACAP and its receptor PAC1, as well as downstream effectors BDNF and TRK1B. Gene expression analysis revealed downregulation of GABA signaling components in the choroid plexus of the fourth ventricle, including aberrant overexpression of the chloride cotransporter NKCC1.

Conclusion: These findings reveal a male-specific vulnerability of GABAergic neurons in chronic migraine and suggest a sex-dependent divergence in the underlying pathophysiological mechanisms. This highlights the critical need for sex-specific approaches to migraine research and therapeutic development.