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
Pietra, A. della; Krivoshein, G.; Ivanov, K.; Giniatullina, R.; Jyrkkanen, H.K.; Leinonen, V.; ... ; Giniatullin, R. 2023
Background Engaging the endocannabinoid system through inhibition of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), degrading endocannabinoids (endoCBs) 2... Show moreBackground Engaging the endocannabinoid system through inhibition of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), degrading endocannabinoids (endoCBs) 2-arachidonoylglycerol (2-AG) and anandamide (AEA), was proposed as a promising approach to ameliorate migraine pain. However, the activity of MAGL and FAAH and action of endoCB on spiking activity of meningeal afferents, from which migraine pain originates, has not been explored thus far. Therefore, we here explored the analgesic effects of endoCB enhancement in rat and human meningeal tissues.Methods Both MAGL and FAAH activity and local 2-AG and AEA levels were measured by activity-based protein profiling (ABPP) and LC-MS/MS, respectively, in rat meninges obtained from hemiskulls of P38-P40 Wistar rats and human meninges from elderly patients undergoing non-migraine related neurosurgery. The action on endoCBs upon administration of novel dual MAGL/FAAH inhibitor AKU-005 on meningeal afferents excitability was tested by investigating paired KCl-induced spiking and validation with local (co-)application of either AEA or 2-AG. Finally, the specific TRPV1 agonist capsaicin and blocker capsazepine were tested.Results The basal level of 2-AG exceeded that of AEA in rat and human meninges. KCl-induced depolarization doubled the level of AEA. AKU-005 slightly increased spontaneous spiking activity whereas the dual MAGL/FAAH inhibitor significantly decreased excitation of nerve fibres induced by KCl. Similar inhibitory effects on meningeal afferents were observed with local applications of 2-AG or AEA. The action of AKU-005 was reversed by CB1 antagonist AM-251, implying CB1 receptor involvement in the anti-nociceptive effect. The inhibitory action of AEA was also reversed by AM-251, but not with the TRPV1 antagonist capsazepine. Data cluster analysis revealed that both AKU-005 and AEA largely increased long-term depression-like meningeal spiking activity upon paired KCl-induced spiking.Conclusions In the meninges, high anti-nociceptive 2-AG levels can tonically counteract meningeal signalling, whereas AEA can be engaged on demand by local depolarization. AEA-mediated anti-nociceptive effects through CB1 receptors have therapeutic potential. Together with previously detected MAGL activity in trigeminal ganglia, dual MAGL/FAAH inhibitor AKU-005 appears promising as migraine treatment. Show less
Hemiplegic migraine (HM) is a rare subtype of migraine with aura. Given that causal missense mutations in the voltage-gated calcium channel α1A subunit gene CACNA1A have been identified in a... Show moreHemiplegic migraine (HM) is a rare subtype of migraine with aura. Given that causal missense mutations in the voltage-gated calcium channel α1A subunit gene CACNA1A have been identified in a subset of HM patients, we investigated whether HM patients without a mutation have an increased burden of such variants in the “CACNA1x gene family”. Whole exome sequencing data of an Australian cohort of unrelated HM patients (n = 184), along with public data from gnomAD, as controls, was used to assess the burden of missense variants in CACNA1x genes. We performed both a variant and a subject burden test. We found a significant burden for the number of variants in CACNA1E (p = 1.3 × 10−4), CACNA1H (p < 2.2 × 10−16) and CACNA1I (p < 2.2 × 10−16). There was also a significant burden of subjects with missense variants in CACNA1E (p = 6.2 × 10−3), CACNA1H (p < 2.2 × 10−16) and CACNA1I (p < 2.2 × 10−16). Both the number of variants and number of subjects were replicated for CACNA1H (p = 3.5 × 10−8; p = 0.012) and CACNA1I (p = 0.019, p = 0.044), respectively, in a Dutch clinical HM cohort (n = 32), albeit that CACNA1I did not remain significant after multiple testing correction. Our data suggest that HM, in the absence of a single causal mutation, is a complex trait, in which an increased burden of missense variants in CACNA1H and CACNA1I may contribute to the risk of disease. 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
The aim of this thesis was to identify functional biomarkers for migraine attack prediction based on neurophysiological readout parameters. The main focus of this work was on the development of... Show moreThe aim of this thesis was to identify functional biomarkers for migraine attack prediction based on neurophysiological readout parameters. The main focus of this work was on the development of methodologies to measure brain excitability over the migraine cycle, with special emphasis on identifying changes in excitability of the visual system and the occipital cortex. Applying such measures over the course of a migraine cycle could help elucidate factors that initiate the migraine attack, and might lead to better (or better timing of) preventive measures. The research described in this thesis is divided into two parts. The first part reports on the development and application of several methodologies to measure excitability of the visual system including the cortex in migraine patients and a migraine mouse model. The second part consists of two studies employing transcranial magnetic stimulation (TMS) in combination with concurrent electroencephalography (EEG) recordings to provide direct measures of cortical excitability in migraine and epilepsy. Show less
Clinic-based headache registries collect data for a wide variety of purposes including delineating disease characteristics, longitudinal natural disease courses, headache management approaches,... Show moreClinic-based headache registries collect data for a wide variety of purposes including delineating disease characteristics, longitudinal natural disease courses, headache management approaches, quality of care, treatment safety and effectiveness, factors that predict treatment response, health care resource utilization, clinician adherence to guidelines, and cost-effectiveness. Registry data are valuable for numerous stakeholders, including individuals with headache disorders and their caregivers, healthcare providers, scientists, healthcare systems, regulatory authorities, pharmaceutical companies, employers, and policymakers. This International Headache Society document may serve as guidance for developing clinic-based headache registries. Use of registry data requires a formal research protocol that includes: 1) research aims; 2) methods for data collection, harmonization, analysis, privacy, and protection; 3) methods for human subject protection; and 4) publication and dissemination plans. Depending upon their objectives, headache registries should include validated headache-specific questionnaires, patient reported outcome measures, data elements that are used consistently across studies (i.e., "common data elements"), and medical record data. Amongst other data types, registries may be linked to healthcare and pharmacy claims data, biospecimens, and neuroimaging data. Headache diagnoses should be made according to the International Classification of Headache Disorders diagnostic criteria. The data from well-designed headache registries can provide wide-ranging and novel insights into the characteristics, burden, and treatment of headache disorders and ultimately lead to improvements in the management of patients with headache. Show less
The research in this thesis is divided into two parts. Part I consists of biochemical studies in migraine, a paroxysmal brain disorder where visual disturbances may form a part of the migraine... Show moreThe research in this thesis is divided into two parts. Part I consists of biochemical studies in migraine, a paroxysmal brain disorder where visual disturbances may form a part of the migraine attack. The main objective was quantification of amine neurotransmitters and other amine molecules in cerebrospinal fluid and plasma of migraine patients, and compare these concentrations with those from healthy controls. Part II describes the clinical relation between migraine and visual snow, a brain disorder with continuous visual disturbances and that is possibly associated with migraine. Since not much is known about this relationship this thesis presents observational studies on the incidence of comorbid migraine in visual snow. Show less
This thesis provides an insight in the clinical aspects and therapy with neurostimulation in cluster headache patients. An unique cohort of Dutch cluster headache patients (LUCA - Leiden University... Show moreThis thesis provides an insight in the clinical aspects and therapy with neurostimulation in cluster headache patients. An unique cohort of Dutch cluster headache patients (LUCA - Leiden University Cluster headache neuro-Analysis programme) has been used to analyse different clinical aspects like drug-use, chronobiology and aura symptoms in cluster headache patients. Regarding neuromodulation: a case-report about occipital nerve stimulation and pregnancy is described here and a meta-analysis of non-invasive vagal nerve stimulation as acute treatment in both episodic and chronic cluster headache. Show less
The premonitory phase and early phase of both spontaneous and nitroglycerin-triggered migraine attacks were explored in this thesis, in association with clinical modulators and trigger factors.... Show moreThe premonitory phase and early phase of both spontaneous and nitroglycerin-triggered migraine attacks were explored in this thesis, in association with clinical modulators and trigger factors. Clinical research strategies, experimental designs, neuroimaging techniques and biochemical methods have revealed clinical risk factors, biochemical modulators and pharmacological triggers. Furthermore, newly discovered hypothalamus-specific alterations in metabolism and perfusion in the early phases of the migraine attack were described. Taken together, these results suggest that each migraine attack starts well before the initiation of the headache phase. The hypothalamus is postulated to have a pivotal role in the early phases of the migraine attack, and possibly affects attack susceptibility interictally as well. 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
Purpose The aim of the study was to determine (a) to which extent job demands and job resources predict work ability in employees with chronic headaches, and (b) whether work ability in these... Show morePurpose The aim of the study was to determine (a) to which extent job demands and job resources predict work ability in employees with chronic headaches, and (b) whether work ability in these employees is more hampered by high demands and more enhanced by resources than in employees without chronic disease. Methods All employees with chronic headaches (n = 593) and without chronic disease (n = 13,742) were selected from The Netherlands Working Conditions Survey conducted in 2013. This survey assessed amongst others job characteristics and various indicators of work ability, i.e. sick leave, employability, work engagement, and emotional exhaustion. Hierarchical regression analyses were conducted for employees with chronic headaches and compared to employees without chronic disease, controlling for age, gender and educational level. Results In employees with chronic headaches higher quantitative and emotional demands contributed to higher emotional exhaustion, and higher emotional demands to higher sick leave. Higher cognitive demands were however associated with higher work engagement. Higher autonomy was related to higher employability and lower emotional exhaustion. Higher supervisor and colleague support was associated with higher employability, higher engagement and lower emotional exhaustion. Higher supervisor support was associated with lower sick leave. Supervisor support emerged as a stronger predictor for emotional exhaustion in the employees with chronic headaches than in the employees without chronic disease. Conclusions Job demands and job resources are important for work ability in employees with chronic headaches. Furthermore, results suggest that these employees benefit more strongly from supervisor support than employees without chronic disease. Show less
Feuerecker, M.; Oosterhout, W.P.J. van; Feuerecker, B.; Matzel, S.; Schelling, G.; Rehm, M.; ... ; Chouker, A. 2016
What kinds of personal goals, aspirations and plans do Dutch youths consider important in their lives? And how does experience of setbacks when pursuing these goals and means of coping with these... Show moreWhat kinds of personal goals, aspirations and plans do Dutch youths consider important in their lives? And how does experience of setbacks when pursuing these goals and means of coping with these frustrations influence their psychological well-being and experience of headache? These are some of the main questions addressed in this research project by means of a series of questionnaire and diary studies among high-school students. Goals were most commonly reported in the area of interpersonal relationships, followed by health and body, their future, school, leisure and personal development. Importance of adolescent aspirations and thoughts and emotions related to these goals were shaped to a large extent by personal and contextual characteristics such as gender, age and ethnicity. Goal importance did not differ according to experience of headache, however, youths with weekly headache reported higher levels of frustration in personal goal pursuits compared to their headache-free peers. Frustration in pursuit of especially self and health goals was related to higher depressive symptoms and lower quality of life in a cross-sectional questionnaire study. Furthermore, frustration predicted next-day lower well-being and greater headache complaints in a prospective diary study. Moreover, dwelling on the negative aspects of the situation (catastrophizing), repetitive thoughts about the frustration (rumination) and the belief that one is unable to cope well with the setback predicted next-day poorer psychological well-being. This was one of the first studies to assess the contribution of self and emotion regulation factors to well-being and headache in adolescence and offers insights into possible targets for intervention with youths 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
This thesis describes the results of a large questionnaire-based study on the epidemiology of chronic frequent headache (CFH) in the Dutch adult population. It also includes information on triptan ... Show moreThis thesis describes the results of a large questionnaire-based study on the epidemiology of chronic frequent headache (CFH) in the Dutch adult population. It also includes information on triptan (over)use from the Drug Information Project (GIP database) and the results of a withdrawal trial in General Practice. Lastly, clinical features of children with CFH seen at a tertiary referral centre are presented. The conclusions are as follows: The prevalence of CFH is 4%. CFH is associated with analgesic overuse, psychiatric comorbidity, sleeping problems, smoking, a history of head trauma and low educational level. Female sex is a risk factor for headache, not for chronic headache in particular, and there is no association between oral contraceptive use and CFH. Psychological factors play a role. CFH is associated with catastrophizing, low internal pain control, and high external pain control. Especially catastrophizing seems to be important for the impact of headache on daily life. Personality factors do not pose an additional risk factor for chronification. CFH patients have more overall somatic and psychiatric comorbidity than patients with infrequent headaches. Both high headache frequency and comorbidity contribute to their low quality of life. Medication overuse headache in the general population mainly concerns analgesic overuse. Many use analgesics inappropriately and lack prophylactic medication. Ten percent of triptan users are overusers and account for half of the total costs of triptan therapy. CFH and analgesic overuse also occurs in children and leads to frequent school absenteeism and sleeping problems. An active approach by GP's to identify patients with CFH and analgesic overuse and explain the need for withdrawal is not effective. A letter with discontinuation advice may be effective. Show less
The objective of the investigations described in this thesis was the development of novel PK-PD modelling for the characterisation and prediction of the effects of anti-migraine drugs in clinical... Show moreThe objective of the investigations described in this thesis was the development of novel PK-PD modelling for the characterisation and prediction of the effects of anti-migraine drugs in clinical investigations. The Markov approach has first been applied to migraine data by Hassani and Ebutt. They used a two-state approach that distinguished between headache and no headache. This approach is appropriate for describing the pain free response, but not the pain relief response, as this endpoint would require that an additional state be included. Moreover, this model does not consider a relationship between drug concentration and transition rate. Rather, dose was used as a predictor of pain resolution. Markov models and other state-space models have always enjoyed much appeal in the analysis of disease progression. However, they have seen little application in PK-PD modelling. The current series of studies attempts to evaluate the usefulness of Markov models in determining the PK-PD relationships of 5-HT1B/1D receptor agonists. Show less