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Migraine Pathophysiology and Treatment: Current Approaches and New Horizons

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: closed (10 September 2022) | Viewed by 22554

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Dr. Filippo Baldacci

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Guest Editor

Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
Interests: clinical neurology; Alzheimer’s disease; headache; migraine; neurodegeneration; biomarkers

Dr. Ciro De Luca

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Guest Editor

Laboratory of Neuronal Networks Morphology and Systems Biology, Department of Mental and Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Interests: neurology; neuroanatomy; clinical neurophysiology; migraine; synaptic plasticity models; glial cells
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Special Issue Information

Dear Colleagues,

Migraine is the most common neurological disorder and one of the most disabling painful conditions worldwide.
The pathophysiology of migraines has been investigated from bench to bedside with novel and recent clinical opportunities. Nevertheless, many details of the migraine's conundrum still need to be elucidated.

This Special Issue invites the submission of manuscripts that investigate or critically describe the neurophysiological details and unsolved clinical issues of migraine. Other primary headaches and neurological and psychiatric disorders could be considered if the connection with migraine neurophysiology is fully detailed. This issue will welcome the submission of studies from basic and clinical scientists with a particular interest in the development of pathophysiological biomarkers of migraine.

Population studies or behavioral and clinical assessments are appropriate if the analytic methods and assessment tools are innovative (e.g., for the validation of clinical tests, machine learning approaches, or meta-analyses) or if they reveal novel insights for diagnosis (phenotype characterization) or clinical management (predictive factors for treatment response) that have not been previously reported.

Dr. Filippo Baldacci
Dr. Ciro De Luca
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

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

neurology
migraine
biomarkers
pathophysiology
precision-medicine
neuroimaging
electrophysiology
neuropsychology
diagnosis
prognosis
comorbidities

Published Papers (10 papers)

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Editorial

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4 pages, 200 KiB

Open AccessEditorial

Dissecting Migraine: The Future of Anatomical, Functional, and Liquid Biomarkers

by Ciro De Luca and Filippo Baldacci

J. Clin. Med. 2022, 11(19), 5538; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11195538 - 21 Sep 2022

Cited by 1 | Viewed by 795

Abstract

Migraine is a common yet enigmatic disease that, despite its high prevalence and familial presentation, lacks exhaustive genetic or environmental causative factors [...] Full article

(This article belongs to the Special Issue Migraine Pathophysiology and Treatment: Current Approaches and New Horizons)

Research

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9 pages, 261 KiB

Open AccessEditor’s ChoiceArticle

Migraine Prevention through Ketogenic Diet: More than Body Mass Composition Changes

by Mariarosaria Valente, Riccardo Garbo, Francesca Filippi, Alice Antonutti, Veronica Ceccarini, Yan Tereshko, Cherubino Di Lorenzo and Gian Luigi Gigli

J. Clin. Med. 2022, 11(17), 4946; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11174946 - 23 Aug 2022

Cited by 17 | Viewed by 3476

Abstract

The ketogenic diet (KD) is gaining attention as a preventive treatment for migraine, which is sustained by many pre-clinical and clinical data. KD is also used for weight loss, and there is a relation between migraine and weight excess, but it is speculated that KD efficacy on migraine may go beyond this effect. We conducted a retrospective observational study on 23 migraine patients who received a KD and were evaluated at the baseline and then after 3 months both from a neurological and a nutritional point of view, including body mass composition analysis. We observed a reduction in monthly headache days (12.5 ± 9.5 vs. 6.7 ± 8.6; p < 0.001) and in days of acute medication intake (11.06 ± 9.37 vs. 4.93 ± 7.99; p = 0.008). We also observed a reduction in patients’ weight (73.8 ± 15.2 vs. 68.4 ± 14.6; p < 0.001) and BMI (26.9 ± 6.2 vs. 23.7 ± 8.1; p < 0.001) with a decrement of the fat mass (28.6 ± 12.5 vs. 20.6 ± 9.8; p < 0.001). Patients who responded to KD and those who did not had no differences with respect to weight or fat mass loss. These data corroborate the utilization of KD as a preventive treatment for migraine and suggest that the efficacy of such an intervention is not only due to weight or fat mass loss but probably relies on other mechanisms specific to KD. Full article

(This article belongs to the Special Issue Migraine Pathophysiology and Treatment: Current Approaches and New Horizons)

19 pages, 3671 KiB

Open AccessArticle

Questionnaire-Based Survey during COVID-19 Vaccination on the Prevalence of Elderly’s Migraine, Chronic Daily Headache, and Medication-Overuse Headache in One Japanese City—Itoigawa Hisui Study

by Masahito Katsuki, Junko Kawahara, Yasuhiko Matsumori, Chinami Yamagishi, Akihito Koh, Shin Kawamura, Kenta Kashiwagi, Tomohiro Kito, Akio Entani, Toshiko Yamamoto, Miyako Otake, Takashi Ikeda and Fuminori Yamagishi

J. Clin. Med. 2022, 11(16), 4707; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11164707 - 11 Aug 2022

Cited by 17 | Viewed by 2287

Abstract

Background: The prevalence of headache disorders, migraine, chronic daily headache (CDH), and medication-overuse headache (MOH) among the elderly in Japan has not been sufficiently investigated. We performed a questionnaire-based survey and revealed 3-month headache prevalence and headaches’ characteristics. Methods: The population aged over 64 was investigated in Itoigawa during their third coronavirus disease 2019 vaccination. Migraine, MOH was defined as The International Classification of Headache Disorders Third edition. CDH was defined as a headache occurring at least 15 days per month. K-means++ were used to perform clustering. Results: Among 2858 valid responses, headache disorders, migraine, CDH, and MOH prevalence was 11.97%, 0.91%, 1.57%, and 0.70%, respectively. Combined-analgesic and non-opioid analgesic were widely used. Only one migraineur used prophylactic medication. We performed k-means++ to group the 332 MOH patients into four clusters. Cluster 1 seemed to have tension-type headache-like headache characteristics, cluster 2 seemed to have MOH-like headache characteristics, cluster 3 seemed to have severe headaches with comorbidities such as dyslipidemia, stroke, and depression, and cluster 4 seemed to have migraine-like headache characteristics with photophobia and phonophobia. Conclusions: This is the largest prevalence survey in the Japanese elderly. Headache disorders are still the elderly’s burden. Clustering suggested that severe headaches associated with some comorbidities may be unique to the elderly. Full article

(This article belongs to the Special Issue Migraine Pathophysiology and Treatment: Current Approaches and New Horizons)

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13 pages, 595 KiB

Open AccessArticle

Potential Add-On Effects of Manual Therapy Techniques in Migraine Patients: A Randomised Controlled Trial

by Elena Muñoz-Gómez, Pilar Serra-Añó, Sara Mollà-Casanova, Núria Sempere-Rubio, Marta Aguilar-Rodríguez, Gemma V. Espí-López and Marta Inglés

J. Clin. Med. 2022, 11(16), 4686; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11164686 - 11 Aug 2022

Cited by 7 | Viewed by 2144

Abstract

Objective: To ascertain whether the combination of soft tissue and articulatory manual techniques is more effective than either one of these techniques alone for reducing migraine impact; Methods: Seventy-five participants with migraine were randomly divided into three groups (n = 25 per group): (i) soft tissue (STG), (ii) articulatory (AG), and (iii) combined treatment (STAG). Pain, frequency of occurrence, duration, disability and impact, depression and anxiety levels, and perception of change were analysed at baseline, post intervention (T2) and at four-week follow-up (T3); Results: STAG showed a significantly greater reduction in pain versus STG and AG at T2 (p < 0.001; p = 0.014) and at T3 (p < 0.001; p = 0.01). Furthermore, STAG achieved a significantly greater reduction in pain duration versus STG at T2 (p = 0.020) and T3 (p = 0.026) and a greater impression of change versus STG (p = 0.004) and AG (p = 0.037) at T3. Similar effects were observed in all groups for frequency of occurrence, migraine disability, impact, and depression and anxiety levels; Conclusions: A combined manual therapy protocol including soft tissue and articulatory techniques yields larger improvements on pain and perception of change than either technique alone, yet the three therapeutic approaches show similar benefits for reducing pain, disability and impact caused by the migraine, depression or anxiety levels. Full article

(This article belongs to the Special Issue Migraine Pathophysiology and Treatment: Current Approaches and New Horizons)

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11 pages, 1234 KiB

Open AccessArticle

Distortion Product Otoacoustic Emissions and Their Suppression as Predictors of Peripheral Auditory Damage in Migraine: A Case-Control Study

by Maria Albanese, Stefano Di Girolamo, Lorenzo Silvani, Eleonora Ciaschi, Barbara Chiaramonte, Matteo Conti, Francesco Maria Passali, Battista Di Gioia, Nicola Biagio Mercuri and Arianna Di Stadio

J. Clin. Med. 2021, 10(21), 5007; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10215007 - 27 Oct 2021

Cited by 4 | Viewed by 1840

Abstract

Although several cochleo-vestibular symptoms are commonly associated with migraine, only a limited number of studies have been done in this regard. Some reported abnormalities in audiometry, auditory brainstem response and vestibular tests, considering these manifestations mainly related to central etiology. However, increasing evidence also suggests a peripheral involvement of the inner ear in migraine. The aim of this study was to investigate the peripheral auditory pathway in migraineurs using otoacoustic emissions (OAEs), to detect alteration of cochlear functioning and possible relationship with disease severity. Sixty-two migraineurs and sixty matched controls were enrolled in the study and underwent a routine neuro-otolaryngology examination; self-administered questionnaires were used to evaluate subjective perception of hearing disability. DPOAE and their suppression were lower in migraineurs compared to controls and significantly related to the disease duration. Altered DPOAE exposed migraineurs to the risk of affecting by migraine without aura, of presenting with ocular and/or auditory symptoms during attack and of using more painkillers. Concomitant dopaminergic symptoms and/or allodynia such as the acute non-consumption of triptans were significant determinants of decreased contralateral suppression of DPOAE among migraineurs. This potential subclinical cochlear impairment in migraine detected by OAEs may represent the earliest sign of sensorineural damage in these patients, providing a promising tool for the initial diagnosis and an opportunity to monitor disease course and treatment response over time. Full article

(This article belongs to the Special Issue Migraine Pathophysiology and Treatment: Current Approaches and New Horizons)

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9 pages, 565 KiB

Open AccessArticle

CGRP Inhibitors and Oxidative Stress Biomarkers in Resistant Migraine: A Real-Life Study with Erenumab, Fremanezumab, and Galcanezumab

by Ciro De Luca, Filippo Baldacci, Sonia Mazzucchi, Irene Lombardo, Letizia Curto, Martina Ulivi, Lucia Chico, Michele Papa, Gabriele Siciliano and Sara Gori

J. Clin. Med. 2021, 10(19), 4586; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10194586 - 04 Oct 2021

Cited by 13 | Viewed by 2308

Abstract

Patients with high-frequency resistant migraine and medication-overuse headache are still the main clinical challenge in tertiary headache centers. The approval of targeted antibodies against the calcitonin gene-related peptide (CGRP) and its receptor represents a powerful instrument. In this study, we observed how biological and clinical features of resistant migraineurs responded to erenumab, fremanezumab, or galcanezumab. We found a reduction in advanced oxidation protein products (AOPP) as a biomarker of improved redox state after six months of treatment. We also found that treatment efficacy was precocious and maintained with high individual responder rates. In particular, seven out of ten patients achieved a reduction of 50% from the baseline at three months, which was maintained at six months, while about one out of our patients experienced a 75% reduction in headache frequency from the first month of treatment. The migraine disability assessment (MIDAS) and the associated fatigue, anxiety, and sleep quality also significantly improved. The allodynia symptom dropped from moderate/severe to mild/absent as a sign of central sensitization reduction. Our study confirmed the safety and efficacy of CGRP inhibition in real-life, high-challenging patients. Additional evidence is needed to understand the role of oxidative stress as a migraine biomarker. Full article

(This article belongs to the Special Issue Migraine Pathophysiology and Treatment: Current Approaches and New Horizons)

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10 pages, 523 KiB

Open AccessArticle

Changes in Cerebral Blood Flow after Erenumab Treatment in Good and Non-Responders—A Pilot Study of Migraine Patients

by Magdalena Nowaczewska, Marcin Straburzyński, Grzegorz Meder and Wojciech Kaźmierczak

J. Clin. Med. 2021, 10(11), 2523; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10112523 - 07 Jun 2021

Cited by 9 | Viewed by 2753

Abstract

Erenumab showed efficacy in migraine prevention, however we cannot identify which patients to treat by predicting efficacy response. The aim of this study was to compare changes in cerebral blood flow (CBF) reflected by transcranial Doppler (TCD) in erenumab good responders (GR) and non-responders, in order to identify a parameter that could predict the treatment response. In this study, migraineurs treated with erenumab underwent clinical and TCD evaluations before and 6 weeks after the treatment, including data on migraine type, monthly migraine days (MMD), medication overuse headache (MOH) presence, mean blood flow velocity (Vm) and pulsatility index (PI) in cerebral arteries (CA). GR were defined as reporting ≥50% reduction in MMD. Thirty women were enrolled, of mean age 40.53 years, 20 with chronic migraine, 14 with MOH, and 19 were GR. Baseline Vm values in right CA and basilar artery (BA) were significantly lower in GR as compared with non-responders. Vm values in all arteries significantly increased after the treatment as compared with corresponding baseline values, but only in GR. A significant negative correlation was observed between baseline Vm in right CA and treatment effectiveness. Baseline Vm in right CA and basilar artery is reduced in erenumab GR as compared with non-responders. This asymmetry normalizes after the treatment with significant Vm increase in CA which may reflect CBF increase in GR only. Lower baseline Vm in right CA may predict erenumab efficacy; however, these results should be replicated in a larger cohort. Full article

(This article belongs to the Special Issue Migraine Pathophysiology and Treatment: Current Approaches and New Horizons)

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16 pages, 2017 KiB

Open AccessArticle

Urinary Proteomics Reveals Promising Biomarkers in Menstrually Related and Post-Menopause Migraine

by Elisa Bellei, Stefania Bergamini, Cecilia Rustichelli, Emanuela Monari, Michele Dal Porto, Alessandro Fiorini, Aldo Tomasi and Anna Ferrari

J. Clin. Med. 2021, 10(9), 1854; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10091854 - 24 Apr 2021

Cited by 6 | Viewed by 2108

Abstract

Migraine is an invalidating neuro-vascular disorder largely spread in the world population. Currently, its pathophysiology is not yet completely understood. The purpose of this study was to investigate the urinary proteome of women suffering from menstrually related migraine (MM) and post-menopause migraine (PM) in comparison with non-headache women as controls, to search potential biomarkers of these migraine sub-types. Urine samples were analyzed by mono-dimensional gel electrophoresis (SDS-PAGE) and two-dimensional gel electrophoresis (2DE) coupled to liquid chromatography-mass spectrometry (LC-MS/MS). Twenty-one urinary proteins were found significantly dysregulated in MM and PM (p < 0.05). The STRING Analysis database revealed interaction between 15 proteins, which were mainly involved in the immune and inflammatory response. Seven of the most considerable proteins were further quantified by western blot: protein S100A8 (S10A8), up-regulated in MM, uromodulin (UROM), alpha-1-microglobulin (AMBP), gelsolin (GELS), prostaglandin-H2 D-isomerase (PTGDS), over-expressed in PM, apolipoprotein A-I (APOA1), and transthyretin (TTHY), respectively down- and up-regulated in both migraineur groups vs controls. These candidate biomarkers might be involved in the neurophysiological network of MM and PM, thus helping to better understand the pathophysiology of these migraine forms. If validated in large-scale studies, this protein cluster could become a distinctive target for clinical applications in migraine diagnosis and treatment. Full article

(This article belongs to the Special Issue Migraine Pathophysiology and Treatment: Current Approaches and New Horizons)

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14 pages, 1341 KiB

Open AccessArticle

Supersaturation of VEP in Migraine without Aura Patients Treated with Topiramate: An Anatomo-Functional Biomarker of the Disease

by Ciro De Luca, Sara Gori, Sonia Mazzucchi, Elisa Dini, Martina Cafalli, Gabriele Siciliano, Michele Papa and Filippo Baldacci

J. Clin. Med. 2021, 10(4), 769; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10040769 - 15 Feb 2021

Cited by 7 | Viewed by 1678

Abstract

Migraine is a primary headache with high prevalence among the general population, characterized by functional hypersensitivity to both exogenous and endogenous stimuli particularly affecting the nociceptive system. The hyperresponsivity of cortical neurons could be due to a disequilibrium in the excitatory/inhibitory signaling. This study aimed to investigate the anatomo-functional pathway from the retina to the primary visual cortex using visual evoked potentials (VEP). Contrast gain protocol was used in 15 patients diagnosed with migraine without aura (at baseline and after 3 months of topiramate therapy) and 13 controls. A saturation (S) index was assessed to monitor the response of VEP’s amplitude to contrast gain. Non-linear nor monotone growth of VEP (S < 0.95) was defined as supersaturation. A greater percentage of migraine patients (53%) relative to controls (7%) showed this characteristic. A strong inverse correlation was found between the S index and the number of days separating the registration of VEP from the next migraine attack. Moreover, allodynia measured through the Allodynia Symptoms Check-list (ASC-12) correlates with the S index both at baseline and after 3 months of topiramate treatment. Other clinical characteristics were not related to supersaturation. Topiramate therapy, although effective, did not influence electrophysiological parameters suggesting a non-intracortical nor retinal origin of the supersaturation (with possible involvement of relay cells from the lateral geniculate nucleus). In conclusion, the elaboration of visual stimuli and visual cortex activity is different in migraine patients compared to controls. More data are necessary to confirm the potential use of the S index as a biomarker for the migraine cycle (association with the pain-phase) and cortical sensitization (allodynia). Full article

(This article belongs to the Special Issue Migraine Pathophysiology and Treatment: Current Approaches and New Horizons)

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Review

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Open AccessReview

Targeting Peripheral N-Methyl-D-Aspartate Receptor (NMDAR): A Novel Strategy for the Treatment of Migraine

by Veberka Kalatharan and Mohammad Al-Mahdi Al-Karagholi

J. Clin. Med. 2023, 12(6), 2156; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm12062156 - 10 Mar 2023

Cited by 4 | Viewed by 1989

Abstract

Backgrounds: Several acute and preventive medications were developed for the treatment of migraine. Yet, a significant proportion of patients reports an inadequate response and a lack of tolerability, emphasizing the need for new options. Glutamate is the most important excitatory neurotransmitter in the brain, and glutamate receptors including N-Methyl-D-Aspartate Receptor (NMDAR) are expressed at several levels of the trigeminovascular system, which is the anatomical and physiological substrate of migraine pain. Objective: To review preclinical and clinical studies investigating the role of the NMDAR in migraine pathophysiology. Methods: No protocol was registered for this study. References for the present review were identified from a narrative search of the PubMed database. Search terms such as glutamate, migraine, N-Methyl-D-Aspartate Receptor, and NMDAR were used. No restrictions were made in terms of the language and date of publication. Results: In animal models, administration of monosodium glutamate (MSG) activated and sensitized trigeminovascular neurons. In healthy human participants, consumption of MSG caused headaches, craniofacial sensitivity, and nausea. In in vivo models and through immunolabeling, NMDAR subunits NR1, NR2A, and NR2B were expressed in trigeminal ganglion neurons. In humans, NMDAR antagonists such as ketamine and memantine caused a significant reduction in pain intensity and monthly headache frequency. Conclusions: Accumulative evidence indicates that NMDAR is a promising new target for the treatment of migraine. Selective NMDAR antagonists without central effects are needed to investigate their therapeutic benefit in the treatment of migraine. Full article

(This article belongs to the Special Issue Migraine Pathophysiology and Treatment: Current Approaches and New Horizons)

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