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Bench-to-Bedside Approach to Migraine: How Pathophysiology Could Influence Novel Therapeutic...
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Bench-to-Bedside Approach to Migraine: How Pathophysiology Could Influence Novel Therapeutic Approaches and Back

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: 31 May 2025 | Viewed by 1936

Special Issue Editors

Dr. Alessandro Vigano

E-Mail Website
Guest Editor
IRCCS Fondazione Don Carlo Gnocchi, 20148 Milan, Italy
Interests: migraine pathophysiology; non-pharmacological treatments in migraine
Dr. Matteo Castaldo

E-Mail Website
Guest Editor
Clinical Psychophysiology and Clinical Neuropsychology Labs, Parma University, 43121 Parma, Italy
Interests: migraine; central sensitization; quantitative sensory testing; musculoskeletal impairments; chronic pain; cognitive interventions

Special Issue Information

Dear Colleagues,

It is increasingly acknowledged that migraine represents the second biggest cause of disability in the general population worldwide, accounting for about 5% of global years lived with disability (YLDs). Although it is the first  cause for YLDs in the 15–49-year age range, with the increased life expectancy, migraine also has a great impact on the elderly population.

Over the last decades, the migraine spectrum has moved from simply pain in the head region to a constellation of symptoms, including autonomic symptoms, cognitive alterations, vestibular involvement, psychiatric and psychological comorbidities, musculoskeletal impairments and chronic overlapping pain conditions as frequent comorbidities (e.g., chronic pelvic pain, temporomandibular disorder, irritable bowel syndrome). These aspects have emerged as key elements in determining the onset and trajectory of migraine though the patient’s life. However, the mechanisms linking these conditions together remain mostly unexplored. A deeper investigation of the common root and pathophysiological overlap amongst them could provide a better comprehension of migraine and associated comorbidities, possibly increasing the chance of highlighting new therapeutic targets. On the other hand, studying the neurophysiological effects of non-pharmacological interventions could reveal pleotropic actions explaining the clinical benefit obtained when more aspects of the migraine spectrum improve.

The aim of this Special Issue is to collect scientific papers that provide insight into the mechanisms underlying the available pharmacological and non-pharmacological treatment options for migraine through neurophysiology and imaging investigations, molecular biomarkers and neuromodulation. Parallel to this, basic research that could serve as ground knowledge for new treatments developing is equally welcomed.

Dr. Alessandro Vigano
Dr. Matteo Castaldo
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • migraine
  • comorbidities
  • pathophysiology
  • pharmacological interventions
  • non-pharmacological interventions
  • chronicization
  • neurophysiological or neuroimaging for disability or clinical response

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Published Papers (3 papers)

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Research

11 pages, 844 KiB  
Article
Influence of Constipation in the Behavior of Circulating Alpha- and Beta-CGRP Levels in Chronic/High-Frequency Migraine Patients After CGRP Monoclonal Antibodies
by Gabriel Gárate, Marcos Polanco, Jorge Madera, María Muñoz-San Martín, Marta Pascual-Mato, Vicente González-Quintanilla and Julio Pascual
Biomedicines 2025, 13(5), 1254; https://doi.org/10.3390/biomedicines13051254 - 21 May 2025
Viewed by 74
Abstract
Background/Objectives: Migraines contain neurological and gastrointestinal manifestations. The first specific migraine preventive drugs, CGRP monoclonal antibodies (mAbs), though efficacious and very well-tolerated in general, induce constipation as their main adverse event. Our goal was to analyze the role of the two isoforms [...] Read more.
Background/Objectives: Migraines contain neurological and gastrointestinal manifestations. The first specific migraine preventive drugs, CGRP monoclonal antibodies (mAbs), though efficacious and very well-tolerated in general, induce constipation as their main adverse event. Our goal was to analyze the role of the two isoforms of CGRP in the development of constipation in patients treated with mABs. Methods: We prospectively measured by ELISA circulating alpha- and beta-CGRP levels in 133 high-frequency episodic/chronic migraine patients before and three months after mAbs treatment and correlated these levels with a number of clinical variables, including the development of constipation during this treatment. Results: Twelve patients (9.0%) noticed de novo constipation with mAbs. Demographics, efficacy end-points, profile of preventive treatment, and comorbidities, with the exception of anxiety/depression, were superimposable between patients with or without emergent constipation. Basal alpha-CGRP levels (49.5 [29.2–73.8] pg/mL) significantly decreased at month three of treatment (40.5 [20.4–61.0] pg/mL; p < 0.0001), both in patients with and without emergent constipation. Pre-treatment circulating beta-CGRP levels (4.0 [2.1–6.2] pg/mL) remained unchanged after three months of treatment (4.3 [2.5–6.0] pg/mL; p = 0.574) in the whole series but were selectively reduced in patients with emergent constipation (p = 0.034). Conclusions: This is the first work exploring the role of the two isoforms of CGRP in the pathophysiology of constipation with mAbs. Our results suggest that the antagonism on the alpha-CGRP isoform plays a relevant role in the antimigraine action of mABs but not in the development of constipation. By contrast, the specific reduction in beta-CGRP levels in patients with emergent constipation supports the role of beta-CGRP antagonism in the development of this adverse event. Full article
(This article belongs to the Special Issue Bench-to-Bedside Approach to Migraine: How Pathophysiology Could Influence Novel Therapeutic Approaches and Back)
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18 pages, 1326 KiB  
Article
Clinical Features, Video Head Impulse Test, and Subjective Visual Vertical of Acute and Symptom-Free Phases in Patients with Definite Vestibular Migraine
by Franko Batinović, Davor Sunara, Nikolina Pleić, Vana Košta, Jelena Gulišija, Ivan Paladin, Zrinka Hrgović, Mirko Maglica and Zoran Đogaš
Biomedicines 2025, 13(4), 825; https://doi.org/10.3390/biomedicines13040825 - 30 Mar 2025
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Abstract
Background/Objectives: The most frequent neurologic cause of recurrent vertigo is vestibular migraine (VM). However, its diagnosis relies primarily on patients’ histories, as specific diagnostic tests for VM are currently lacking. We aimed to examine and compare clinical features, vestibulo-ocular reflexes (VORs), and [...] Read more.
Background/Objectives: The most frequent neurologic cause of recurrent vertigo is vestibular migraine (VM). However, its diagnosis relies primarily on patients’ histories, as specific diagnostic tests for VM are currently lacking. We aimed to examine and compare clinical features, vestibulo-ocular reflexes (VORs), and subjective visual vertical (SVV) between the ictal (IC) and inter-ictal (II) phases in VM patients. Methods: A repeated-measures study involved 31 patients with definite VM. Vestibular function was assessed using a video head impulse test (vHIT) to evaluate VOR results, and SVV testing to determine verticality perception. Otoneurological examination, including migraine-related disability, was noted. Analyses of repeated measures for numerical traits (SVV deviations, VOR, and clinical outcomes) were conducted using a linear mixed model (LMM), with phase, age, and sex as fixed effects and individual-specific random intercepts. Differences between the IC and II phases for dichotomous variables were analyzed using the χ2 or Fisher’s exact test. Results: The LMM analysis revealed that SVV deviations were significantly higher ictally (IC-ly) (β = 0.678, p = 1.51 × 10−6) than interictally (II-ly). VOR results remained normal across phases (p > 0.05), and refixation saccades did not differ significantly based on vHIT results (p > 0.05). Nausea (100% vs. 38.71%, p = 6.591 × 10−8), photophobia (100% vs. 35.48%, p = 1.839 × 10−8), and phonophobia (90.32% vs. 6.45%, p = 9.336 × 10−12) were significantly more frequent IC-ly than II-ly. Conclusions: Our findings highlight phase-dependent alterations in spatial orientation, with increased SVV deviations IC-ly despite stable VOR. The significant differences in migraine-associated symptoms reinforce the dynamic nature of VM. These results emphasize the importance of timing in vestibular assessments and suggest that SVV testing during IC VM episodes may enhance diagnostic accuracy. Full article
(This article belongs to the Special Issue Bench-to-Bedside Approach to Migraine: How Pathophysiology Could Influence Novel Therapeutic Approaches and Back)
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9 pages, 777 KiB  
Article
Imaging the Brainstem Raphe in Medication-Overuse Headache: Pathophysiological Insights and Implications for Personalized Care
by Annika Mall, Christine Klötzer, Luise Bartsch, Johanna Ruhnau, Sebastian Strauß and Robert Fleischmann
Biomedicines 2025, 13(1), 131; https://doi.org/10.3390/biomedicines13010131 - 8 Jan 2025
Viewed by 718
Abstract
Background/Objectives: Medication-overuse headache (MOH) is a disabling condition affecting patients with chronic migraine resulting from excessive use of acute headache medication. It is characterized by both pain modulation and addiction-like mechanisms involving the brainstem raphe, a region critical to serotonergic signaling. This [...] Read more.
Background/Objectives: Medication-overuse headache (MOH) is a disabling condition affecting patients with chronic migraine resulting from excessive use of acute headache medication. It is characterized by both pain modulation and addiction-like mechanisms involving the brainstem raphe, a region critical to serotonergic signaling. This study investigates whether alterations in the brainstem raphe, assessed via transcranial sonography (TCS), are associated with MOH and independent of depressive symptoms, aiming to explore their utility as a biomarker. Methods: This prospective case-control study included 60 migraine patients (15 with MOH) and 7 healthy controls. Comprehensive clinical and psychometric assessments were performed to evaluate headache burden, medication use, and depressive symptoms. TCS was used to assess brainstem raphe echogenicity, with findings analyzed using generalized linear models adjusted for depression. Results: Non-visibility of the brainstem raphe was significantly associated with MOH, with an unadjusted odds ratio (OR) of 6.88 (95% CI: 1.32–36.01, p = 0.02). After adjusting for depressive symptoms, this association remained significant, with an adjusted OR of 1.85 (95% CI: 1.02–3.34, p = 0.041). TCS demonstrated good intraclass correlation, highlighting its reproducibility and ability to detect changes relevant to MOH pathophysiology. Conclusions: Brainstem raphe alterations are associated with MOH and may serve as a potential biomarker for its diagnosis and management. TCS offers a non-invasive, cost-effective tool for identifying MOH-specific mechanisms, which could improve clinical decision-making and support personalized care in chronic headache disorders. Further studies are needed to validate these findings and refine the clinical applications of brainstem-focused diagnostics. Full article
(This article belongs to the Special Issue Bench-to-Bedside Approach to Migraine: How Pathophysiology Could Influence Novel Therapeutic Approaches and Back)
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