BackgroundChronic migraine, a highly disabling migraine subtype, affects nearly 2% of the general population. Understanding migraine chronification is vital for developing better treatment and... Show moreBackgroundChronic migraine, a highly disabling migraine subtype, affects nearly 2% of the general population. Understanding migraine chronification is vital for developing better treatment and prevention strategies. An important factor in the chronification of migraine is the overuse of acute headache medication. However, the mechanisms behind the transformation of episodic migraine to chronic migraine and vice versa have not yet been elucidated. We performed a longitudinal epigenome-wide association study to identify DNA methylation (DNAm) changes associated with treatment response in patients with chronic migraine and medication overuse as part of the Chronification and Reversibility of Migraine clinical trial. Blood was taken from patients with chronic migraine (n = 98) at baseline and after a 12-week medication withdrawal period. Treatment responders, patients with ≥ 50% reduction in monthly headache days (MHD), were compared with non-responders to identify DNAm changes associated with treatment response. Similarly, patients with ≥ 50% versus < 50% reduction in monthly migraine days (MMD) were compared.ResultsAt the epigenome-wide significant level (p < 9.42 × 10–8), a longitudinal reduction in DNAm at an intronic CpG site (cg14377273) within the HDAC4 gene was associated with MHD response following the withdrawal of acute medication. HDAC4 is highly expressed in the brain, plays a major role in synaptic plasticity, and modulates the expression and release of several neuroinflammation markers which have been implicated in migraine pathophysiology. Investigating whether baseline DNAm associated with treatment response, we identified lower baseline DNAm at a CpG site (cg15205829) within MARK3 that was significantly associated with MMD response at 12 weeks.ConclusionsOur findings of a longitudinal reduction in HDAC4 DNAm status associated with treatment response and baseline MARK3 DNAm status as an early biomarker for treatment response, provide support for a role of pathways related to chromatin structure and synaptic plasticity in headache chronification and introduce HDAC4 and MARK3 as novel therapeutic targets. Show less
Acute withdrawal of headache medication in chronic migraine patients with medication overuse may lead to a dramatic reduction in headache frequency and severity. However, the brain networks... Show moreAcute withdrawal of headache medication in chronic migraine patients with medication overuse may lead to a dramatic reduction in headache frequency and severity. However, the brain networks underlying chronic migraine and a favorable response to acute withdrawal are still poorly understood. The goal of the present study was to characterize the pattern of intrinsic magnetic resonance imaging (MRI) functional connectivity (FC) specific to chronic migraine and to identify changes in FC that characterize subjects with CM reverting to less frequent headaches. Subjects with chronic migraine (N = 99) underwent a resting-state functional MRI scan before and after three months of medication withdrawal therapy. In addition, we included four control groups who were scanned once: healthy participants (N = 27), patients with episodic migraine (N = 25), patients with chronic back pain (N = 22), and patients with clinical depression (N = 17). Using dual regression analysis, we compared whole-brain voxel-level functional connectivity with ten well-known resting-state networks between chronic migraine and control groups, and between responders to treatment (≥50 % reduction in monthly headache days) and non-responders (<50 % reduction), before and after treatment. Subjects with chronic migraine showed differences in FC with a number of RS-networks, most of which involved the visual cortex, compared with healthy controls. A comparison with patients with episodic migraine, chronic pain and depression showed differences in the same direction, suggesting that altered patterns of functional connectivity in chronic migraine patients could to some extent be explained by shared symptomatology with other pain, depression, or migraine conditions. A comparison between responders and non-responders indicated that effective withdrawal reduced FC with the visual cortex for responders. Interestingly, responders already differed in functional connectivity of the visual cortex at baseline compared with non-responders. Altogether, we show that chronic migraine and successful medication withdrawal therapy are linked to changes in the functional connectivity of the visual cortex. These neuroimaging findings provide new insights into the pathways underlying migraine chronification and its reversibility. Show less
Al-Hassany, L.; Linstra, K.M.; Meun, C.; Berg, J. van den; Boersma, E.; Danser, A.H.J.; ... ; CREW Consortium 2023
BackgroundThe causal association between the gut microbiome and the development of migraine and its subtypes remains unclear.MethodsThe single nucleotide polymorphisms concerning gut microbiome... Show moreBackgroundThe causal association between the gut microbiome and the development of migraine and its subtypes remains unclear.MethodsThe single nucleotide polymorphisms concerning gut microbiome were retrieved from the gene-wide association study (GWAS) of the MiBioGen consortium. The summary statistics datasets of migraine, migraine with aura (MA), and migraine without aura (MO) were obtained from the GWAS meta-analysis of the International Headache Genetics Consortium (IHGC) and FinnGen consortium. Inverse variance weighting (IVW) was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness.ResultsIn IHGC datasets, ten, five, and nine bacterial taxa were found to have a causal association with migraine, MA, and MO, respectively, (IVW, all P < 0.05). Genus.Coprococcus3 and genus.Anaerotruncus were validated in FinnGen datasets. Nine, twelve, and seven bacterial entities were identified for migraine, MA, and MO, respectively. The causal association still exists in family.Bifidobacteriaceae and order.Bifidobacteriales for migraine and MO after FDR correction. The heterogeneity and pleiotropy analyses confirmed the robustness of IVW results.ConclusionOur study demonstrates that gut microbiomes may exert causal effects on migraine, MA, and MO. We provide novel evidence for the dysfunction of the gut-brain axis on migraine. Future study is required to verify the relationship between gut microbiome and the risk of migraine and its subtypes and illustrate the underlying mechanism between them. Show less
Amani, H.; Khaboushan, A.S.; Terwindt, G.M.; Tafakhori, A. 2023
Migraine is a complicated neurological disorder affecting 6% of men and 18% of women worldwide. Various mechanisms, including neuroinflammation, oxidative stress, altered mitochondrial function,... Show moreMigraine is a complicated neurological disorder affecting 6% of men and 18% of women worldwide. Various mechanisms, including neuroinflammation, oxidative stress, altered mitochondrial function, neurotransmitter disturbances, cortical hyperexcitability, genetic factors, and endocrine system problems, are responsible for migraine. However, these mechanisms have not completely delineated the pathophysiology behind migraine, and they should be further studied. The brain microenvironment comprises neurons, glial cells, and vascular structures with complex interactions. Disruption of the brain microenvironment is the main culprit behind various neurological disorders. Neuron-glia crosstalk contributes to hyperalgesia in migraine. In the brain, microenvironment and related peripheral regulatory circuits, microglia, astrocytes, and satellite cells are necessary for proper function. These are the most important cells that could induce migraine headaches by disturbing the balance of the neurotransmitters in the nervous system. Neuroinflammation and oxidative stress are the prominent reactions glial cells drive during migraine. Understanding the role of cellular and molecular components of the brain microenvironment on the major neurotransmitters engaged in migraine pathophysiology facilitates the development of new therapeutic approaches with higher effectiveness for migraine headaches. Investigating the role of the brain microenvironment and neuroinflammation in migraine may help decipher its pathophysiology and provide an opportunity to develop novel therapeutic approaches for its management. This review aims to discuss the neuron-glia interactions in the brain microenvironment during migraine and their potential role as a therapeutic target for the treatment of migraine. Show less
Hoydonckx, Y.; Singh, M.; Gilron, I.; Khan, J.; Narouze, S.; Dahan, A.; ... ; Bhatia, A. 2023
BackgroundChronic daily headaches (CDH) are common and associated with significant morbidity, poor quality of life, and substantial burden on the healthcare system. CDH tends to be refractory to... Show moreBackgroundChronic daily headaches (CDH) are common and associated with significant morbidity, poor quality of life, and substantial burden on the healthcare system. CDH tends to be refractory to conventional medical management and/or patients cannot afford expensive treatments. It is stipulated that CDH share a mechanism of central sensitization in the trigeminocervical complex, mediated by activation of the N-methyl-d-aspartate (NMDA) receptors. Ketamine, a non-competitive NMDA antagonist, has been used in the treatment of chronic pain, but its role in CDH has not been completely established. This trial aims to evaluate the effect of high-dose IV ketamine infusions (compared to placebo) on the number of headache days at 28 days post-infusion.MethodsA multicenter, placebo-controlled, randomized controlled trial will be conducted with two parallel groups and blinding of participants and outcome assessors. The study will include 56 adults with a CDH diagnosis as per ICHD-3 criteria. Participants will be randomized (1:1) to either ketamine (1 mg. kg−1 bolus followed by infusion of 1 mg. kg−1. h−1 for 6 h) or placebo (0.9% saline in the same volume and infusion rate as the trial medication) bolus and infusion for 6 h. The impact on the number of monthly headache days, headache intensity, physical activity, mood, sleep, quality of life, analgesic consumption, and adverse effects will be recorded at baseline, immediately post-infusion, and from 1 to 28 days, 29 to 56 days, and 57 to 84 days after the infusionDiscussionDespite advancements in treatment, many patients continue to suffer from CDH. This trial investigates whether high-dose IV ketamine infusions can effectively and safely improve the CDH burden as compared to a placebo infusion. This treatment could become a safe, affordable, and widely available option for patients living with refractory headache. Show less
BackgroundMigraine is a disabling neurological disorder with the pathophysiology yet to be understood. The microstructural alteration in brain white matter (WM) has been suggested to be related to... Show moreBackgroundMigraine is a disabling neurological disorder with the pathophysiology yet to be understood. The microstructural alteration in brain white matter (WM) has been suggested to be related to migraine in recent studies, but these evidence are observational essentially and cannot infer a causal relationship. The present study aims to reveal the causal relationship between migraine and microstructural WM using genetic data and Mendelian randomization (MR).MethodsWe collected the Genome-wide association study (GWAS) summary statistics of migraine (48,975 cases / 550,381 controls) and 360 WM imaging-derived phenotypes (IDPs) (31,356 samples) that were used to measure microstructural WM. Based on instrumental variables (IVs) selected from the GWAS summary statistics, we conducted bidirectional two-sample MR analyses to infer bidirectional causal associations between migraine and microstructural WM. In forward MR analysis, we inferred the causal effect of microstructural WM on migraine by reporting the odds ratio (OR) that quantified the risk change of migraine for per 1 standard deviation (SD) increase of IDPs. In reverse MR analysis, we inferred the causal effect of migraine on microstructural WM by reporting the beta value that represented SDs of changes in IDPs were caused by migraine.ResultsThree WM IDPs showed significant causal associations (p < 3.29 x 10(- 4), Bonferroni correction) with migraine and were proved to be reliable via sensitivity analysis. The mode of anisotropy (MO) of left inferior fronto-occipital fasciculus (OR = 1.76, p = 6.46 x 10(- 5)) and orientation dispersion index (OD) of right posterior thalamic radiation (OR = 0.78, p = 1.86 x 10(- 4)) exerted significant causal effects on migraine. Migraine exerted a significant causal effect on the OD of left superior cerebellar peduncle (beta = - 0.09, p = 2.78 x 10(- 4)).ConclusionsOur findings provided genetic evidence for the causal relationships between migraine and microstructural WM, bringing new insights into brain structure for the development and experience of migraine. Show less
Sacco, S.; Amin, F.M.; Ashina, M.; Bendtsen, L.; Deligianni, C.I.; Gil-Gouveia, R.; ... ; Lampl, C. 2022
Background A previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to prevent migraine. Since... Show moreBackground A previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to prevent migraine. Since then, randomized controlled trials (RCTs) and real-world evidence have expanded the evidence and knowledge for those treatments. Therefore, the EHF panel decided to provide an updated guideline on the use of those treatments. Methods The guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed a systematic review and an analysis of the literature, assessed the quality of the available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided. Results We found moderate to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in individuals with episodic and chronic migraine. For several important clinical questions, we found not enough evidence to provide evidence-based recommendations and guidance relied on experts' opinion. Nevertheless, we provided updated suggestions regarding the long-term management of those treatments and their place with respect to the other migraine preventatives. Conclusion Monoclonal antibodies targeting the CGRP pathway are recommended for migraine prevention as they are effective and safe also in the long-term. Show less
Background Migraine is a highly prevalent disorder with significant economical and personal burden. Despite the development of effective therapeutics, the causes which precipitate migraine attacks... Show moreBackground Migraine is a highly prevalent disorder with significant economical and personal burden. Despite the development of effective therapeutics, the causes which precipitate migraine attacks remain elusive. Clinical studies have highlighted altered metabolic flux and mitochondrial function in patients. In vivo animal experiments can allude to the metabolic mechanisms which may underlie migraine susceptibility. Understanding the translational relevance of these studies are important to identifying triggers, biomarkers and therapeutic targets in migraine. Main body Functional imaging studies have suggested that migraineurs feature metabolic syndrome, exhibiting hallmark features including upregulated oxidative phosphorylation yet depleted available free energy. Glucose hypometabolism is also evident in migraine patients and can lead to altered neuronal hyperexcitability such as the incidence of cortical spreading depression (CSD). The association between obesity and increased risk, frequency and worse prognosis of migraine also highlights lipid dysregulation in migraine pathology. Calcitonin gene related peptide (CGRP) has demonstrated an important role in sensitisation and nociception in headache, however its role in metabolic regulation in connection with migraine has not been thoroughly explored. Whether impaired metabolic function leads to increased release of peptides such as CGRP or excessive nociception leads to altered flux is yet unknown. Conclusion Migraine susceptibility may be underpinned by impaired metabolism resulting in depleted energy stores and altered neuronal function. This review discusses both clinical and in vivo studies which provide evidence of altered metabolic flux which contribute toward pathophysiology. It also reviews the translational relevance of animal studies in identifying targets of biomarker or therapeutic development. Show less
Background Migraine is a common brain disorder that predominantly affects women. Migraine pain seems mediated by the activation of mechanosensitive channels in meningeal afferents. Given the role... Show moreBackground Migraine is a common brain disorder that predominantly affects women. Migraine pain seems mediated by the activation of mechanosensitive channels in meningeal afferents. Given the role of transient receptor potential melastatin 3 (TRPM3) channels in mechanical activation, as well as hormonal regulation, these channels may play a role in the sex difference in migraine. Therefore, we investigated whether nociceptive firing induced by TRPM3 channel agonists in meningeal afferents was different between male and female mice. In addition, we assessed the relative contribution of mechanosensitive TRPM3 channels and that of mechanosensitive Piezo1 channels and transient receptor potential vanilloid 1 (TRPV1) channels to nociceptive firing relevant to migraine in both sexes. Methods Ten- to 13-week-old male and female wildtype (WT) C57BL/6 J mice were used. Nociceptive spikes were recorded directly from nerve terminals in the meninges in the hemiskull preparations. Results Selective agonists of TRPM3 channels profoundly activated peripheral trigeminal nerve fibres in mouse meninges. A sex difference was observed for nociceptive firing induced by either PregS or CIM0216, both agonists of TRPM3 channels, with the induced firing being particularly prominent for female mice. Application of Yoda1, an agonist of Piezo1 channels, or capsaicin activating TRPV1 channels, although also leading to increased nociceptive firing of meningeal fibres, did not reveal a sex difference. Cluster analyses of spike activities indicated a massive and long-lasting activation of TRPM3 channels with preferential induction of large-amplitude spikes in female mice. Additional spectral analysis revealed a dominant contribution of spiking activity in the alpha- and beta-ranges following TRPM3 agonists in female mice. Conclusions Together, we revealed a specific mechanosensitive profile of nociceptive firing in females and suggest TRPM3 channels as a potential novel candidate for the generation of migraine pain, with particular relevance to females. Show less
Aim Serum levels of Calcitonin Gene-Related Peptide (CGRP)-like immunoreactivity (CGRP-LI) in migraine patients before and after starting treatment with erenumab were measured to evaluate the... Show moreAim Serum levels of Calcitonin Gene-Related Peptide (CGRP)-like immunoreactivity (CGRP-LI) in migraine patients before and after starting treatment with erenumab were measured to evaluate the association with clinical treatment response. Methods Blood samples were collected from the cubital fossa before (T0) and 2-4 weeks after (T1) starting treatment with erenumab. Clinical response was monitored using a daily headache e-diary. Serum levels of CGRP-LI, assessed using radioimmunoassay, were compared between T0 and T1, correcting for migraine reduction. In addition, for both T0 and T1, linear regression models were constructed using migraine reduction as outcome and serum CGRP-LI as independent variable, corrected for age, gender and monthly migraine days (MMD) at baseline. Results Serum CGRP-LI did not differ between T0 and T1 (p = 0.30). However, there was an interaction between time and reduction in MMD (p = 0.01). Absolute reduction in MMD in the third month after treatment with erenumab was associated with serum CGRP-LI at T1, 2-4 weeks after starting treatment with erenumab (p = 0.003), but not with serum CGRP-LI at T0 (p = 0.24). Conclusion Lower serum CGRP-LI 2-4 weeks after starting treatment with erenumab was associated with a higher reduction in migraine days after three months of treatment. Although the underlying mechanisms remain to be determined, this suggests that changes in CGRP levels, shortly after starting erenumab, are important for its clinical effect. Show less
Background Migraine-attributed burden, impact, disability and migraine-impacted quality of life are important concepts in clinical management, clinical and epidemiological research, and health... Show moreBackground Migraine-attributed burden, impact, disability and migraine-impacted quality of life are important concepts in clinical management, clinical and epidemiological research, and health policy, requiring clear and agreed definitions. We aimed to formulate concise and precise definitions of these concepts by expert consensus. Methods We searched the terms migraine-attributed burden, impact, disability and migraine-impacted quality of life in Embase and Medline from 1974 and 1946 respectively. We followed a Delphi process to reach consensus on definitions. Results We found widespread conflation of concepts and inconsistent terminology within publications. Following three Delphi rounds, we defined migraine-attributed burden as "the summation of all negative consequences of the disease or its diagnosis"; migraine-attributed impact as "the effect of the disease, or its diagnosis, on a specified aspect of life, health or wellbeing"; migraine-attributed disability as "physical, cognitive and mental incapacities imposed by the disease"; and migraine-impacted quality of life as "the subjective assessment by a person with the disease of their general wellbeing, position and prospects in life". We complemented each definition with a detailed description. Conclusion These definitions and descriptions should foster consistency and encourage more appropriate use of currently available quantifying instruments and aid the future development of others. Show less
Background: The relationship between migraine and depression has been thoroughly investigated, indicating a bidirectional comorbidity. The exact temporal relationship between acute depressive... Show moreBackground: The relationship between migraine and depression has been thoroughly investigated, indicating a bidirectional comorbidity. The exact temporal relationship between acute depressive symptoms (mood changes) and the various phases of the migraine attack has not yet been examined. Methods: We performed a prospective diary study in n = 487 participants with migraine. Participants filled out a daily diary on migraine and acute depressive symptoms during a 1-month period. We randomly selected one migraine attack per participant, consisting of six days around an attack, including the interictal, premonitory, ictal, and postdromal phases. Acute depressive symptoms covered five major items from the DSM-5 classification. Primary analysis was performed using a mixed model with post-hoc testing. We also tested whether lifetime depression influenced the presence of acute depressive symptoms. Results: During a migraine headache day, patients scored higher on acute depressive symptoms than on all other days of the migraine attack (p < 0.001). There were no early warning signs for an upcoming headache attack through acute depressive symptomatology. Migraine patients with lifetime depression scored overall higher during the migraine attack than those without lifetime depression (p < 0.001). Limitations: Migraine attacks were based on self-reported migraine and one migraine attack per patient was randomly selected.Conclusion: We now clearly demonstrate that during the migraine headache phase, but not in the prodromal phase, patients report increased depressive symptomatology. No evidence was found for mood changes as an early warning sign for an upcoming migraine attack. Show less
Kursun, O.; Yemisci, M.; Maagdenberg, A.M.J.M. van den; Karatas, H. 2021
Background Neuroinflammation has an important role in the pathophysiology of migraine, which is a complex neuro-glio-vascular disorder. The main aim of this review is to highlight findings of... Show moreBackground Neuroinflammation has an important role in the pathophysiology of migraine, which is a complex neuro-glio-vascular disorder. The main aim of this review is to highlight findings of cortical spreading depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma from the inflammasome perspective. In addition, we discuss the limited data of the contribution of inflammasomes to other aspects of migraine pathophysiology, foremost the activation of the trigeminovascular system and thereby the generation of migraine pain. Main body Inflammasomes are signaling multiprotein complexes and key components of the innate immune system. Their activation causes the production of inflammatory cytokines that can stimulate trigeminal neurons and are thus relevant to the generation of migraine pain. The contribution of inflammasome activation to pain signaling has attracted considerable attention in recent years. Nucleotide-binding domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) is the best characterized inflammasome and there is emerging evidence of its role in a variety of inflammatory pain conditions, including migraine. In this review, we discuss, from an inflammasome point of view, cortical spreading depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma, the connection with genetic factors that make the brain vulnerable to CSD, and the relation of the inflammasome with diseases that are co-morbid with migraine, including stroke, epilepsy, and the possible links with COVID-19 infection. Conclusion Neuroinflammatory pathways, specifically those involving inflammasome proteins, seem promising candidates as treatment targets, and perhaps even biomarkers, in migraine. Show less
MaassenVanDenBrink, A.; Terwindt, G.M.; Cohen, J.M.; Barash, S.; Campos, V.R.; Galic, M.; ... ; Karppa, M. 2021
Background Migraine prevalence is age and sex dependent, predominating in women in early and middle adulthood; however, migraine also represents a substantial burden for men and adults of all ages.... Show moreBackground Migraine prevalence is age and sex dependent, predominating in women in early and middle adulthood; however, migraine also represents a substantial burden for men and adults of all ages. Thus, understanding this burden and the efficacy of migraine preventive medications in both sexes and across age groups is critical. The randomized, placebo-controlled, double-blind, phase 3b FOCUS study demonstrated the safety and efficacy of fremanezumab, a fully humanized monoclonal antibody (IgG2 Delta a) that selectively targets calcitonin gene-related peptide as a migraine preventive treatment for individuals with migraine and prior inadequate response to 2 to 4 migraine preventive medication classes. Here, we assessed the efficacy of fremanezumab in participants from FOCUS subgrouped by age (18-45 years and > 45 years) and sex.Methods In the FOCUS study, eligible participants were randomized (1:1:1) to 12 weeks of double-blind treatment with quarterly fremanezumab, monthly fremanezumab, or matched monthly placebo. In this post hoc analysis, we evaluated changes from baseline in monthly migraine days (primary endpoint of FOCUS) and other secondary and exploratory efficacy outcomes in prespecified age (18-45 and > 45 years) and sex subgroups.Results The modified intention-to-treat population (received >= 1 dose of study drug and had >= 10 days of postbaseline efficacy assessments for the primary endpoint) totaled 837 participants (18-45 years, n = 373; > 45 years, n = 464; male, n = 138; female, n = 699). Consistent reductions in monthly average number of migraine days during 12 weeks were observed, regardless of age (18-45 years: quarterly fremanezumab, - 4.1 days; monthly fremanezumab, - 4.7 days; placebo, - 0.9 days; P < 0.001; > 45 years: quarterly fremanezumab, - 3.6 days; monthly fremanezumab, - 3.7 days; placebo, - 0.3 days; P < 0.001) and sex (male: quarterly fremanezumab, - 4.1 days; monthly fremanezumab, - 4.6 days; placebo, - 0.3 days; P < 0.001; female: quarterly fremanezumab, - 3.6 days; monthly fremanezumab, - 3.9 days; placebo, - 0.6 days; P < 0.001). Fremanezumab also reduced monthly headache days of at least moderate severity, monthly days of acute medication use, and improved Migraine Disability Assessment scores across subgroups.Conclusions These results demonstrate the efficacy of fremanezumab in patients with difficult-to-treat migraine for reducing migraine and headache days, acute medication use, and disability, regardless of age or sex. Show less
Harder, A.V.E.; Vijfhuizen, L.S.; Henneman, P.; Dijk, K.W. van; Duijn, C.M. van; Terwindt, G.M.; Maagdenberg, A.M.J.M. van den 2021
Background Migraine is a common brain disorder but reliable diagnostic biomarkers in blood are still lacking. Our aim was to identify, using proton nuclear magnetic resonance (H-1-NMR) spectroscopy... Show moreBackground Migraine is a common brain disorder but reliable diagnostic biomarkers in blood are still lacking. Our aim was to identify, using proton nuclear magnetic resonance (H-1-NMR) spectroscopy, metabolites in serum that are associated with lifetime and active migraine by comparing metabolic profiles of patients and controls. Methods Fasting serum samples from 313 migraine patients and 1512 controls from the Erasmus Rucphen Family (ERF) study were available for H-1-NMR spectroscopy. Data was analysed using elastic net regression analysis. Results A total of 100 signals representing 49 different metabolites were detected in 289 cases (of which 150 active migraine patients) and 1360 controls. We were able to identify profiles consisting of 6 metabolites predictive for lifetime migraine status and 22 metabolites predictive for active migraine status. We estimated with subsequent regression models that after correction for age, sex, BMI and smoking, the association with the metabolite profile in active migraine remained. Several of the metabolites in this profile are involved in lipid, glucose and amino acid metabolism. Conclusion This study indicates that metabolic profiles, based on serum concentrations of several metabolites, including lipids, amino acids and metabolites of glucose metabolism, can distinguish active migraine patients from controls. Show less
BackgroundAlthough the European Medicines Agency and the US Food and Drug Administration have cleared several devices that use neuromodulation to provide clinical benefits in the acute or... Show moreBackgroundAlthough the European Medicines Agency and the US Food and Drug Administration have cleared several devices that use neuromodulation to provide clinical benefits in the acute or preventive treatment of migraine, the Clinical Trials Committee of the International Headache Society has not developed guidelines specifically for clinical trials of neuromodulation devices. In recognition of the distinct needs and challenges associated with their assessment in controlled trials, the Committee provides these recommendations for optimizing the design and conduct of controlled trials of neuromodulation devices for the acute and/or preventive treatment of migraine.MethodsAn international group of headache scientists and clinicians with expertise in neuromodulation evaluated clinical trials involving neuromodulation devices that have been published since 2000. The Clinical Trials Committee incorporated findings from this expert analysis into a new guideline for clinical trials of neuromodulation devices for the treatment of migraine.ResultsKey terms were defined and recommendations provided relative to the assessment of neuromodulation devices for acute treatment in adults, preventive treatment in adults, and acute and preventive treatment in children and adolescents. Ethical and administrative responsibilities were outlined, and a bibliography of previous research involving neuromodulation devices was created.ConclusionsAdoption of these recommendations will improve the quality of evidence regarding this important area in migraine treatment. Show less
Christensen, C.E.; Younis, S.; Lindberg, U.; Koning, P. de; Tolnai, D.; Paulson, O.B.; ... ; Ashina, M. 2021
The middle meningeal artery is a proposed surrogate marker for activation of trigeminal nociceptors during migraine. Previous studies focused on the extracranial part of the artery; hence,... Show moreThe middle meningeal artery is a proposed surrogate marker for activation of trigeminal nociceptors during migraine. Previous studies focused on the extracranial part of the artery; hence, vasoreactivity in the intradural arteries during migraine is unknown. Thirty-four patients with migraine without aura were given sildenafil on one day and calcitonin gene-related peptide on another in double-blind crossover fashion. Patients were scanned with 3.0 T MR angiography before drug administration and again 6 hours later during induced attacks of migraine. We measured circumference of the intradural segment of the middle meningeal artery before and during induced migraine attacks. The middle cerebral and superficial temporal arteries were also examined. Fourteen patients had attacks during the second scan after both study drugs and 11 had a migraine after either one or the other, resulting in a total of 39 attacks included in the final analysis. Mean circumference of the intradural middle meningeal artery at baseline was 3.18 mm with an increase of 0.11 mm during attacks (P = 0.005), corresponding to a relative dilation of 3.6% [95% CI: 1.4%-5.7%]. Middle cerebral artery dilated by 9.4% [95% CI: 7.1%-11.7%] and superficial temporal artery by 2.3% [95% CI: 0.2%-4.4%]. Our study shows that the intradural middle meningeal artery and the middle cerebral artery are dilated during migraine induced by calcitonin gene-related peptide as well as sildenafil. We propose that intradural vasculature is affected by migraine-driven activation of trigeminal afferents during migraine attacks. Show less
Enhanced activity of the glutamatergic system has been linked to migraine pathophysiology. The present study aimed to assess the involvement of the glutamatergic system in the onset of attacks. We... Show moreEnhanced activity of the glutamatergic system has been linked to migraine pathophysiology. The present study aimed to assess the involvement of the glutamatergic system in the onset of attacks. We provoked attacks by infusion of glyceryl trinitrate (GTN; 0.5 mu g/kg/min over 20 min) in 24 female episodic migraineurs without aura and 13 female age-matched healthy controls. Over the course of a single day participants were scanned three times at fixed time slots (baseline before GTN infusion, 90 min and 270 min after start of GTN infusion). Single volume proton magnetic resonance spectra (H-1-MRS) were acquired at 7 Tesla from a volume of interest (VOI, 2x2x3 cm) in the visual cortex. We assessed the concentrations of glutamate, its major precursor glutamine, and its product gamma-aminobutyric acid (GABA) over the course of a provoked attack. The preictal state was defined as the period after GTN infusion until the migraine-like headache started, independent of possible experienced premonitory symptoms, and the ictal state was defined as the period with provoked migraine-like headache. Data were analyzed using a linear mixed-effect model for repeated measures. Glutamate and glutamine levels did not change from interictal to the preictal and ictal state. GABA levels increased from interictal towards the preictal state for migraine patients compared with healthy controls. We conclude that high resolution 7T MRS is able to show changes in the glutamatergic system towards a triggered migraine attack, by revealing an increased GABA concentration associated with the onset of a migraine attack. Show less
Spontaneous and pharmacologically provoked migraine attacks are frequently preceded by nonheadache symptoms called premonitory symptoms. Here, we systematically evaluated premonitory symptoms in... Show moreSpontaneous and pharmacologically provoked migraine attacks are frequently preceded by nonheadache symptoms called premonitory symptoms. Here, we systematically evaluated premonitory symptoms in migraine patients and healthy controls after glyceryl trinitrate (GTN) infusion. In women with migraine without aura (n = 34) and age-matched female controls (n = 24), we conducted systematically a semistructured interview assessing 21 possible premonitory symptoms every 15 minutes in the 5 hours after GTN infusion (0.5 mu g/kg/min over 20 minutes). Migraine-like headaches occurred in 28/34 (82.4%) migraineurs (GTN responders). After GTN, 26/28 (92.9%) responders, 6/6 (100%) nonresponders, and 13/24 (54.2%) controls reported at least one possible premonitory symptom. Concentration difficulties (P= 0.011), yawning (P= 0.009), nausea (P= 0.028), and photophobia (P= 0.001) were more frequently reported by those migraineurs who developed a migraine-like attack vs healthy controls. Importantly, concentration difficulties were exclusively reported by those who developed a migraine-like attack. Thus, our findings support the view that GTN is able to provoke the naturally occurring premonitory symptoms and show that yawning, nausea, photophobia, and concentration difficulties are most specific for an impending GTN-induced migraine-like headache. We suggest that these symptoms may also be helpful as early warning signals in clinical practice with concentration difficulties exclusively reported by those who develop a migraine-like attack. Show less
