Background: Cutaneous allodynia is a clinical marker of central sensitization in migraine and is associated with greater migraine severity and poorer outcomes. Fibromyalgia (FM) is a frequent comorbidity of migraine that may further enhance central sensitization, whereas small fibre pathology (SFP) has been identified in a substantial proportion of FM patients. Whether FM comorbidity and peripheral small-fibre abnormalities contribute to cutaneous allodynia in patients with migraine remains unclear. We investigated cutaneous allodynia and migraine characteristics in patients with migraine with and without FM and, within the FM cohort, according to skin biopsy findings. Methods: In this retrospective cross-sectional study, 212 patients with migraine were included: 106 patients with FM who had undergone skin biopsy (65 with pathological and 41 with normal biopsy findings) and 106 patients without FM with the same sex distribution and comparable age. FM and migraine were diagnosed according to current clinical criteria. Cutaneous allodynia was assessed using a standardized clinical checklist. Skin biopsy was performed at the proximal thigh and distal leg, and SFP was defined by reduced intraepidermal nerve fibre density (IENFD). The comparison between patients with and without FM was the primary analysis; comparisons according to skin biopsy findings and correlations with IENFD were secondary analyses. Migraine characteristics, allodynia, and migraine-related disability were compared across groups. Results: The proportion of chronic migraine (CM) was similar in patients with and without FM (19.8% vs. 21.7%; p=0.866). Cutaneous allodynia was more frequent in patients with FM than in those without FM (82.1% vs. 64.2%; p=0.005), and moderate-to-severe allodynia affected 50.9% vs. 16.0% of patients, respectively (p<0.001). Median allodynia scores were 6 (interquartile range [IQR] 4-8) in patients with FM and pathological biopsy findings, 6 (3-7) in those with normal biopsy findings, and 3 (2-5) in patients without FM (p<0.001; ε2=0.133), with no difference between the two FM subgroups; allodynia scores were not associated with proximal or distal IENFD. Greater allodynia was associated with greater migraine-related disability among participants with available Migraine Disability Assessment (MIDAS) data, including after adjustment for age, headache frequency, and FM status (partial ρ=0.267, p=0.002). Conclusions: FM comorbidity identifies patients with migraine with a greater burden of cutaneous allodynia, independently of migraine chronification. This sensory hypersensitivity was not clearly related to the presence or extent of structural small-fibre loss, supporting a predominant contribution of central sensitization. Structural and functional assessments of small fibres, including trigeminal territories, may further clarify the contribution of peripheral abnormalities to migraine-related allodynia in FM.
Calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are both implicated in migraine, but whether they undergo similar acute release from primary sensory terminals remains uncertain. We compared stimulus-evoked CGRP-like immunoreactivity (CGRP-LI) and PACAP-like immunoreactivity (PACAP-LI) in superfused mouse spinal cord tissue. Spinal cords from 14 male C57BL/6 mice were pooled and distributed among six superfusion chambers per stimulus. After two baseline fractions, tissues were exposed to capsaicin (10 μM) or high K+ (40 mM KCl), followed by a post-stimulation fraction. Capsaicin and high K+ produced marked CGRP responses, with mean stimulation-minus-baseline increases of 44.89 and 47.19 pg/mg, respectively, both Holm-adjusted p<0.001. In contrast, PACAP responses were −0.12 and 0.009 pg/mg, with Holm-adjusted p=0.742 and p=0.888. The geometric mean stimulation-to-baseline responses were 23.23-fold and 18.57-fold for CGRP, compared with 0.86-fold and 1.00-fold for PACAP. The corresponding CGRP-to-PACAP ratios of fold responses were 26.99 and 18.51. These findings show a marked dissociation between acute CGRP and PACAP release in this pooled ex vivo spinal cord preparation. They suggest that PACAP should not be assumed to behave as a CGRP-like co-transmitter during acute stimulation of primary sensory neuron (PSN) terminals.
Background: Local gyrification findings in pediatric migraine may vary according to how cortical folding is measured. We aimed to describe similarities and differences between conventional FreeSurfer-derived and shape-adaptive Lyu measures in patient-control comparisons and comparisons based on sex, age, migraine frequency, and associated symptoms. Methods: Comparisons addressed diagnosis, sex and age within both groups, and monthly migraine days (MMDs; <8 vs. ≥8), photophobia and/or phonophobia, and nausea and/or vomiting within patients. Both measures were assessed using Permutation Analysis of Linear Models (PALM) with threshold-free cluster enhancement (TFCE) and family-wise error (FWE) correction. Findings were compared according to statistical significance, effect direction, and anatomical distribution. Results: Both measures identified lower local gyrification in patients than in healthy controls and in female than in male patients, with different anatomical and hemispheric distributions. Among healthy controls, only the conventional measure identified lower gyrification in females than in males. Neither measure identified significant differences in age-related comparisons or comparisons based on migraine frequency or associated symptoms. Conclusions: The two gyrification measures agreed in effect direction for selected contrasts but differed in anatomical localization. These descriptive findings do not establish spatial concordance, methodological superiority, or a specific cortical signature of pediatric migraine. Harmonized comparisons and independent validation are required.
Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are accumulating signals of potential benefit in headache disorders, but the cellular locus of any anti-cephalalgic action is unknown. A direct effect on the trigeminovascular system would require GLP1R to be expressed by cells of the trigeminal ganglion (TG), and we therefore investigated whether GLP1R is expressed by TG neurons or non-neuronal cells. Methods: We reanalysed public single-cell/single-nucleus transcriptomic data from mouse and human TG, quantifying GLP1R detection per cell type with exact binomial 95% confidence intervals (CIs). GLP1R and the second incretin receptor GIPR were benchmarked against validated G protein-coupled receptor (GPCR) drug targets and nociceptor markers, and GLP1R detection was verified in pancreatic islets, where it is expressed. Results: GLP1R was detected in 0.09% of mouse and 0.05% of human trigeminal neurons, whereas validated GPCR drug targets were robustly detected in the same cells. GLP1R was undetected in the peptidergic subtype and ≤0.17% across the other mouse neuronal subtypes, was at the limit of detection in human neurons, and was at or below the limit of detection in all human non-neuronal compartments, while GPCRs and compartment markers labelled their expected populations. The same pipeline detected GLP1R in pancreatic beta cells, confirming assay sensitivity. Conclusions: Across both mouse and human TG, GLP1R transcripts were not detectably expressed by neurons or non-neuronal cells. The anti-headache signals of GLP-1 RAs are therefore unlikely to be initiated by GLP1R within TG cell bodies and more plausibly reflect extraganglionic mechanisms.
Background: Migraine is a complex neurovascular disorder that extends beyond recurrent pain attacks. Although migraine is primarily considered a disorder of neuronal dysfunction, accumulating neuroimaging and experimental evidence suggests subtle structural and molecular brain alterations. Neurofilament light chain (NfL) is a well-established biomarker of axonal injury and neurodegeneration, but its role in migraine remains unclear. The present study aimed to compare plasma NfL levels between adults with migraine and healthy controls, and to explore potential associations with clinical and demographic characteristics. Methods: This study included patients with migraine fulfilling the International Classification of Headache Disorders (ICHD-3) criteria and a group of healthy subjects as controls. Plasma NfL concentrations were quantified using the fully automated Lumipulse® immunoassay platform (Fujirebio, Gent, Belgium). Associations between plasma NfL levels and demographic and clinical characteristics were analyzed using correlation analyses and regression models adjusted for relevant confounders. Results: A total of 60 patients with migraine (42 with chronic migraine [CM], 70%) and 22 healthy controls were enrolled. Mean plasma NfL levels did not differ between migraine patients and controls (11.10±4.96 pg/mL vs. 11.20±6.00 pg/mL, respectively; p=0.935) or between episodic and CM subgroups. Moreover, no significant correlations were observed between NfL levels and age, monthly migraine days (MMD), migraine-related disability, pain intensity, aura, medication-overuse headache (MOH), or acute medication intake. Conclusions: Migraine, including its chronic form, was not associated with detectable neuroaxonal damage based on circulating NfL levels, suggesting that neuroaxonal injury is not a prominent feature of the disease. Larger longitudinal studies are warranted to further clarify the role of neuroaxonal biomarkers in migraine pathophysiology.
