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
This thesis explores biochemical and genetical changes associated with migraine and cluster headache. This research aims to increase knowledge of the pathophysiology and signaling pathways involved... Show moreThis thesis explores biochemical and genetical changes associated with migraine and cluster headache. This research aims to increase knowledge of the pathophysiology and signaling pathways involved in migraine and cluster headache, thereby identifying new targets for treatment. Uncovering the biological mechanisms on how patients differ from those without disease leads to a better understanding of the pathophysiology of primary headache disorders. The biological systems in our body are related to each other, and are based on the genomic blueprint and lead via epigenetics, transcription and translation to proteins and biomolecules. The first part of the dissertation focuses on the examination of biomolecules in body fluids (blood and cerebrospinal fluid) in migraineurs. Several studies showed that biomolecule concentrations differed between people with and without migraine for lipids, amino acids and metabolites of glucose metabolism. These results indicate a general disruption of the metabolic profile in migraineurs. For other substances, no differences were found. The second part of the thesis looked at the genetic blueprint of various headache disorders. There a genetic difference between people with migraine and people without migraine was found. In addition, a genetic difference between people with and without cluster headache was found. 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
Dit proefschrift beschrijft de effectiviteit en veiligheid van monoclonale antilichamen gericht tegen CGRP (fremanezumab) en de CGRP receptor (erenumab) als preventieve behandeling van... Show moreDit proefschrift beschrijft de effectiviteit en veiligheid van monoclonale antilichamen gericht tegen CGRP (fremanezumab) en de CGRP receptor (erenumab) als preventieve behandeling van migrainepatiënten in een ‘real world’ setting. Daarnaast bespreekt het factoren die voorspellend zijn voor de mate van de klinische response op deze medicatie. Show less
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
This thesis describes several studies on migraine and cluster headache which associate these primary headache syndromes with macrostructural and microstructural changes. Some of these brain changes... Show moreThis thesis describes several studies on migraine and cluster headache which associate these primary headache syndromes with macrostructural and microstructural changes. Some of these brain changes may be congenital, some may represent reversible or irreversible neuroplastic changes as a response of the brain to adapt to external stimuli and others should be considered as brain damage associated with these primary headache syndromes. Cluster headache patients have larger anterior hypothalamic volumes and wider skulls, observations that oppose previous neuroimaging findings and pathophysiological theories. Migraine is associated with microstructural changes in particularly visual processing areas in both cortical and subcortical grey matter and in white matter tracts connecting these structures. These changes might in part be irreversible or mSome migraineurs are also at increased risk of visually detectable changes on MRI, such as infratentorial microbleeds, and in male migraineurs, infratentorial hypertensities. Some migraineurs are also at increased risk of visually detectable changes on MRI, such as infratentorial microbleeds and, in male migraineurs, infratentorial hyperintensities. The underlying etiology of these types of cerebrovascular damage remains elusive and is probably the consequence of a multifactorial process. Show less
This thesis is about the relation between pain and language and focuses on migraine, a specific type of headache that comes in attacks. The first conclusion is that migraine is a signifier without... Show moreThis thesis is about the relation between pain and language and focuses on migraine, a specific type of headache that comes in attacks. The first conclusion is that migraine is a signifier without signified. A diagnosis of migraine only depends on the words of the patients by applying internationally agreed on criteria which form a discourse and artificially exclude ‘non-migraine headaches’. Further research-questions are whether so-defined migraine can destroy language and what is the role of time in its existence. The answers to these questions will be applied to selected novels that include protagonists with migraine. The aim of these analyses is not how migraine is being described, but how it is performed in and through these texts. The overall goal of this thesis is to come to a better understanding of the relation between migraine and language and vice versa, on the one hand by seeing the patient as text and on the other by seeing the text as patient. Show less
Tolner, E.A.; Chen, S.P.; Eikermann-Haerter, K. 2019
Objective To review and discuss the literature on the role of cortical structure and function in migraine. Discussion Structural and functional findings suggest that changes in cortical morphology... Show moreObjective To review and discuss the literature on the role of cortical structure and function in migraine. Discussion Structural and functional findings suggest that changes in cortical morphology and function contribute to migraine susceptibility by modulating dynamic interactions across cortical and subcortical networks. The involvement of the cortex in migraine is well established for the aura phase with the underlying phenomenon of cortical spreading depolarization, while increasing evidence suggests an important role for the cortex in perception of head pain and associated sensations. As part of trigeminovascular pain and sensory processing networks, cortical dysfunction is likely to also affect initiation of attacks. Conclusion Morphological and functional changes identified across cortical regions are likely to contribute to initiation, cyclic recurrence and chronification of migraine. Future studies are needed to address underlying mechanisms, including interactions between cortical and subcortical regions and effects of internal (e.g. genetics, gender) and external (e.g. sensory inputs, stress) modifying factors, as well as possible clinical and therapeutic implications. Show less
The research in this thesis was aimed at identifying and understanding mechanisms underlying modulating factors for and consequences of cortical spreading depression (CSD), the pathophysiological... Show moreThe research in this thesis was aimed at identifying and understanding mechanisms underlying modulating factors for and consequences of cortical spreading depression (CSD), the pathophysiological substrate for migraine aura that occurs in one-third of migraine patients. In this thesis, experimental studies on CSD were performed in wild-type (WT) and transgenic migraine mice, which express CaV2.1 Ca2+ channels with a mutated _1 subunit that contains the R192Q missense mutation. The R192Q mutation was previously identified in patients with familial hemiplegic migraine type 1 (FHM1) and causes gain-of-function effects in terms of neuronal Ca2+ influx, neurotransmission, and susceptibility to experimentally induced CSD. Using various experimental strategies, in this thesis, the FHM1 R192Q mouse model was used to study pathophysiological mechanisms of the initiation and modulation of CSD as well as of neurobiological and molecular changes that accompany CSD events. Show less
Migraine and cluster headache are disabling brain disorders. Current treatment is ineffective in many patients. The research performed in this thesis aimed at elucidating some of the molecular... Show moreMigraine and cluster headache are disabling brain disorders. Current treatment is ineffective in many patients. The research performed in this thesis aimed at elucidating some of the molecular genetic mechanisms in these two headache disorders by means of clinical and genetic studies in complex and/or monogenic forms of these diseases and related disorders. Knowledge from studies like these could be used to the benefit of patients by improving clinical diagnoses and/or by providing useful drug targets for future drug development strategies. Show less
This thesis is about migraine. Three elements are discussed. First element is preventive treatment, second element is attack treatment and the third part focuses on medication overuse headache. The... Show moreThis thesis is about migraine. Three elements are discussed. First element is preventive treatment, second element is attack treatment and the third part focuses on medication overuse headache. The preventive treatment of migraine is a valuable intervention in primary care. If preventive treatment is applied, usually only one attempt with one type of medication is performed. A number of considerations hinder GPs to address preventive treatment of migraine. Also several patient-related aspects cause that the GP differ from national guidelines. The decision to start preventive treatment is based on a complex of considerations from the patient. For example, experienced suffering from migraine and interaction with family, colleagues and general practitioner. Interest in preventive therapy increases with increased concerns about migraine symptoms. In attack treatment of migraine, most patients had a clear preference for one of both treatments. Preference correlated only moderately with the commonly used "two-hour pain-free score." Multi-attack, crossover, 'patient preference' studies are well able to detect clinically relevant differences between existing treatments. Overuse of triptans, resulting in chronic headaches is common and causes unnecessary costs. The common thread through this thesis is what patients want in migraine and which interventions they prefer: patients' preference in migraine. Show less
In this dissertation clinical genetic investigations on migraine, related syndromes and comorbid conditions are described. The first migraine syndrome studied is Familial Hemiplegic Migraine (FHM),... Show moreIn this dissertation clinical genetic investigations on migraine, related syndromes and comorbid conditions are described. The first migraine syndrome studied is Familial Hemiplegic Migraine (FHM), a monogenic migraine variant. The clinical spectrum of FHM1-3 and the relation with closely related diseases such as Alternating hemiplegia of Chilhood, Early Seizures and Cerebral Edema after Trivial Head Trauma, epilepsy and episodic ataxia were investigated. The second monogenic migraine syndrome studied is Retinal Vasculopathy with Cerebral Leukodystrophy (later renamed CHARIOT), where common migraine is part of the clinical spectrum. The identification of TREX1 as the causal gene for RVCL is described. Investigation of the clinical spectrum showed retinal, cerebral and internal organ involvement, without an apparent genotype-phenotype correlation. Endothelial dysfunction of large arteries was shown in RVCL patients and is proposed as a possible disease mechanism. Lastly, migraine patients were identified in a Dutch genetic isolate and the relation with depression and atherosclerosis was assessed. For depression it was shown that shared genetic factors, at least partly, underlie the comorbidity with migraine, in particular migraine with aura. These studies improve our insight in genetic factors and pathofysiological mechanisms involved in migraine, which may ultimately contribute to better treatment options for migraine patients Show less
Room for improvement is present in the treatment of migraine in primary care. However, inviting all patients who receive prescriptions for __2 triptans each month to have an evaluation consultation... Show moreRoom for improvement is present in the treatment of migraine in primary care. However, inviting all patients who receive prescriptions for __2 triptans each month to have an evaluation consultation with their general practitioner (GP), produces insufficient effect on headache outcomes and costs. However, it remains important to stay alert on patients who are candidate for preventive treatment. When discussing the possibility of preventive treatment, GPs should keep in mind possible barriers in patients. Also, GPs have to ask themselves if they do not deny patients a possibly effective treatment because of their own negative ideas towards preventive medication. Also, we learned that when designing pragmatic studies in primary care, there are methodological issues that make it harder to prove the effectiveness of an intervention. First, the outcomes of pragmatic studies in primary care can negatively affected by changes in the behaviour of GPs and patients in the control group. Second, the quality of life outcome measures that are often used in this type of research are harder to validate and to interpret than the more robust outcome measures that are used in clinical trials Show less
CADASIL is a hereditary cerebral small vessel disease, caused by a mutation in the NOTCH3 gene, leading to migraine with aura, cerebrovascular accidents and cognitive decline at young to middle... Show moreCADASIL is a hereditary cerebral small vessel disease, caused by a mutation in the NOTCH3 gene, leading to migraine with aura, cerebrovascular accidents and cognitive decline at young to middle adult age. MRI scans of the brain may show lacunar infarcts, white matter lesions and microbleeds. In this thesis MRI scans of the brains are used to investigate the disease course in CADASIL. It is shown that lacunar infarcts, white matter lesions and microbleeds are progressive in CADASIL patients. Vascular risk factors are not associated with rate of progression of these MRI abnormalities. However, the rate of disease progression can be predicted by measuring the amount of MRI abnormalities at baseline. Lacunar infarcts, microbleeds and increased white ventricular volume are strongly associated with cognitive decline in CADASIL. Progression of white matter hyperintensities can be predicted by measurements of cerebrovascular reactivity. Using high-field MRI we demonstrated that luminal diameters of lenticulostriate arteries are normal in CADASIL, and that lacunar infarcts in CADASIL are not the result of luminal narrowing of these vessels. High-field MRI also showed that CADASIL patients have an increased diffuse iron deposition in the putamen and caudate nucleus of the brain. Show less
The research in this thesis was aimed at identifying and characterizing novel migraine gene mutations and pathways. Several FHM and non-FHM genes were investigated in patients with monogenic... Show moreThe research in this thesis was aimed at identifying and characterizing novel migraine gene mutations and pathways. Several FHM and non-FHM genes were investigated in patients with monogenic familial hemiplegic migraine or other monogenic disorders in which migraine can be prevalent. Functional consequences of these mutations and the clinical phenotypes associated with them were investigated. Common migraine with a complex genetic background was studied using a genome-wide association analysis in an isolated population and with a meta-analysis study. Furthermore, FHM1 mice were used to study expression profiles in brain tissues that are relevant for the induction of cortical spreading depression ___ underlying the migraine aura - (i.e., the occipital cortex) and cerebellar ataxia (i.e., the cerebellum). These studies will further our insight in the molecular pathophysiology of migraine. Show less
Migraine is a severe headache syndrome, affecting approximately 33% of females and 13% of males. Patients suffer from recurring headache episodes in combination with nausea, vomiting, phono and... Show moreMigraine is a severe headache syndrome, affecting approximately 33% of females and 13% of males. Patients suffer from recurring headache episodes in combination with nausea, vomiting, phono and photophobia. It is a paroxysmal disorder for which several several trigger factors have been identified by patients. This thesis has focused on the relation between i) psychosocial stress, ii) nitroglycerin and iii) hypoxia and the occurrence of a migraine attack, as well as the mechanism of action. The first conclusion is that, in contrast to previous studies, we could not detect a correlation between psychosocial stress and migraine. The second conclusion is that normobaric hypoxia might be a trigger factor for migraine possibly through the development of mild cerebral edema. The third conclusion is that migraine can be triggered by nitroglycerin through a vascular effect without any indication of vasodilation in cerebral or meningeal arteries during the delayed provoked attack. Show less
Migraine has a strong genetic component, but the identification of these factors has proven difficult mainly because of the complex interaction of multiple loci and environmental factors.... Show moreMigraine has a strong genetic component, but the identification of these factors has proven difficult mainly because of the complex interaction of multiple loci and environmental factors. Unraveling its molecular basis and deciphering pathways leading to migraine attacks will help identifying novel treatment targets. For this thesis different genetic approaches were applied. Families with hemiplegic migraine (FHM), a rare monogenic subtype of migraine, were studied. Three genes were identified, all involved in modulation of ion influxes across neuronal and glial cell membranes. We identified many mutations in these genes and performed assays in cellular models to understand their functional consequences. In addition, we investigated the role of these genes in sporadic hemiplegic migraine (SHM). Importantly, we expanded the clinical spectrum associated with FHM genes, and established the link between migraine and epilepsy. We also performed genetic studies in common migraine families using two different approaches; the first was an outbred linkage approach with MO families, the second a family-based association approach with severe MA patients from a genetic isolate. Our results supported that, most likely, the intrinsic genetic heterogeneity in migraine families seriously hampers the identification of migraine loci and ultimately migraine genes. Show less
