Epigenetic DNA methylation changes associated with headache chronification: A retrospective case-control study.

Background The biological mechanisms of headache chronification are poorly understood. We aimed to identify changes in DNA methylation associated with the transformation from episodic to chronic headache. Methods Participants were recruited from the population-based Norwegian HUNT Study. Thirty-six female headache patients who transformed from episodic to chronic headache between baseline and follow-up 11 years later were matched against 35 controls with episodic headache. DNA methylation was quantified at 485,000 CpG sites, and changes in methylation level at these sites were compared between cases and controls by linear regression analysis. Data were analyzed in two stages (Stages 1 and 2) and in a combined meta-analysis. Results None of the top 20 CpG sites identified in Stage 1 replicated in Stage 2 after multiple testing correction. In the combined meta-analysis the strongest associated CpG sites were related to SH2D5 and NPTX2, two brain-expressed genes involved in the regulation of synaptic plasticity. Functional enrichment analysis pointed to processes including calcium ion binding and estrogen receptor pathways. Conclusion In this first genome-wide study of DNA methylation in headache chronification several potentially implicated loci and processes were identified. The study exemplifies the use of prospectively collected population cohorts to search for epigenetic mechanisms of disease.

[Headache News]. / Neues bei Kopfschmerzen.

A review of the latest and most relevant information on different disorders of head and facial pain is presented. News from epidemiologic studies regarding the relationship between migraine and patent foramen ovale, the cardiovascular risk in migraine, and migraine behavior during menopause, and the development of white matter lesions or migraine genetics are presented. Regarding pathophysiology there are very recent insights regarding the role of the hypothalamus during prodromal phase and the interplay of brain-stem and hypothalamus during the attack. In the last year studies and metaanalysis generated new knowledge for the use of triptans in general as in menstrual related migraine and hemiplegic variants. Furthermore, new hope rises for the CGRP (calcitonin-gene related peptide)-antagonists, as the data for ubrogepant do not suggest hepatotoxicity but efficacy. In prophylactic migraine treatment the news are manly on how the new therapeutic approach with monoclonal antibodies against CGRP or its receptor is moving on. Additional newly generated data for already known prophylactic agents as for new approaches are compactly discussed. Although main developments in headache focus on migraine new data on trigemino-autonomic headache trigeminal neuralgia and new daily persistant headache became available.

Oxytocin receptor: Expression in the trigeminal nociceptive system and potential role in the treatment of headache disorders.

AIMS: Our studies investigated the location of oxytocin receptors in the peripheral trigeminal sensory system and determined their role in trigeminal pain. METHODS: Oxytocin receptor expression and co-localization with calcitonin gene-related peptide was investigated in rat trigeminal ganglion using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the effects of facial electrocutaneous stimulation and adjuvant-induced inflammation of the temporomandibular joint on oxytocin receptor expression in the trigeminal ganglion. Finally, the effects of oxytocin on capsaicin-induced calcitonin gene-related peptide release from dural nociceptors were investigated using isolated rat dura mater. RESULTS: Oxytocin receptor immunoreactivity was present in rat trigeminal neurons. The vast majority of oxytocin receptor immunoreactive neurons co-expressed calcitonin gene-related peptide. Both electrocutaneous stimulation and adjuvant-induced inflammation led to a rapid upregulation of oxytocin receptor protein expression in trigeminal ganglion neurons. Oxytocin significantly and dose-dependently decreased capsaicin-induced calcitonin gene-related peptide release from dural nociceptors. CONCLUSION: Oxytocin receptor expression in calcitonin gene-related peptide containing trigeminal ganglion neurons, and the blockade of calcitonin gene-related peptide release from trigeminal dural afferents suggests that activation of these receptors may provide therapeutic benefit in patients with migraine and other primary headache disorders.

Neural Plasticity in Common Forms of Chronic Headaches.

Headaches are universal experiences and among the most common disorders. While headache may be physiological in the acute setting, it can become a pathological and persistent condition. The mechanisms underlying the transition from episodic to chronic pain have been the subject of intense study. Using physiological and imaging methods, researchers have identified a number of different forms of neural plasticity associated with migraine and other headaches, including peripheral and central sensitization, and alterations in the endogenous mechanisms of pain modulation. While these changes have been proposed to contribute to headache and pain chronification, some findings are likely the results of repetitive noxious stimulation, such as atrophy of brain areas involved in pain perception and modulation. In this review, we provide a narrative overview of recent advances on the neuroimaging, electrophysiological and genetic aspects of neural plasticity associated with the most common forms of chronic headaches, including migraine, cluster headache, tension-type headache, and medication overuse headache.

Episodic Syndromes That May Be Associated With Migraine: A.K.A. "the Childhood Periodic Syndromes".

Previously called "childhood periodic syndromes that are commonly precursors of migraine" in International Headache Classification of Headache Disorders (ICHD)-II, these disorders were renamed "episodic syndromes that may be associated with migraine" in ICHD-III beta. The specific disorders reviewed in this article include: benign paroxysmal torticollis, benign paroxysmal vertigo, abdominal migraine, and cyclical vomiting syndrome, as well as infantile colic, which was recently added under the appendix section in ICHD-III beta.

CADASIL with a novel NOTCH3 mutation (Cys478Tyr).

Recently, an increasing number of NOTCH3 mutations have been described to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Here, we report 2 CADASIL patients from a Japanese family, who were found to possess a novel NOTCH3 mutation. The proband only had chronic headache, and her mother had previously suffered a minor stroke. Although the patients' clinical symptoms were mild, their distinctive magnetic resonance imaging (MRI) features suggested CADASIL. Genetic analysis revealed that both patients had a novel heterozygous NOTCH3 mutation (p.Cys478Tyr) leading to stereotypical cysteine loss. The present finding suggests that genetic testing for NOTCH3 mutations in patients with distinctive MRI features, even if the symptoms are as mild as chronic headache, should help to broaden the mutational and clinical spectrum of CADASIL.

Genetic mechanisms in the intergenerational transmission of health.

This paper uses a sample of adoptees to study the genetic mechanisms underlying intergenerational associations in chronic health conditions. I begin by estimating baseline intergenerational models with a sample of approximately 125,000 parent-child pairs, and find that children with a parent who has a specific chronic health condition are at least 100% more likely to have the same condition themselves. To assess the role of genetic mechanisms in generating these strong correlations, I estimate models using a sample of approximately 2400 adoptees, and find that genetic transmission accounts for only 20-30% of the baseline associations. As falsification tests, I repeat this exercise using health measures with externally established levels of genetic determination (height and chicken pox), and the results suggest that comparisons of biological and adopted children are a valid method of isolating genetic effects in this sample. Finally, to corroborate these adoptee-based estimates, I examine health correlations among monozygotic twins, which provide an upper bound estimate of genetic influences, and find a similarly modest role for genetic transmission. I conclude that intergenerational health transmission is an important hindrance to overall socioeconomic mobility, but that the majority of transmission occurs through environmental factors or gene-environment interactions, leaving scope for interventions to effectively mitigate health persistence.

Headache among CADASIL patients with R544C mutation: prevalence, characteristics, and associations.

BACKGROUND AND AIM: There are variations of migraine prevalence in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) among different regions of the world. Previous studies on Asian CADASIL patients have not provided detailed descriptions of the characteristics of their headaches. The aims of this study were to determine prevalence and characteristics of headaches and to investigate associations between headache and other clinical symptoms or brain magnetic resonance imaging (MRI) findings among homogenous group of patients having the same R544C mutation. METHODS: In this cross-sectional study, we enrolled 53 CADASIL patients with the R544C mutation between May 2010 and April 2011. We obtained the history of headache using a structured questionnaire and detailed interview. Other clinical features and brain MRI findings were also assessed for potential associations. RESULTS: Overall headache prevalence was 45.3% (24 patients). Among them, 21 patients (87.5%) were classified as having tension-type headache, followed by migraine (two patients) and unclassifiable headaches (one patient). Except for alcohol consumption, no significant associations were observed between the headaches and other clinical features or brain MRI findings. CONCLUSION: Migraine was found in only 3.8% of CADASIL patients with the R544C mutation. Such a low prevalence of migraine may hinder clinical detection of CADASIL among ethnically Asian patients.

15th International Headache Congress: basic science highlights.

The 15th Congress of the International Headache Society was held in Berlin from June 23rd to 26th of 2011. Interesting new data from several areas of the basic sciences of headache were presented. This is a review of some of the most exciting platform and poster presentations of the meeting. Research addressing 3 general areas of interest is presented in this review: pathophysiology, pharmacology, and genetics.

Recent advances in headache research.

The understanding of the pathophysiology of primary headache disorders, especially migraine, has substantially improved over the last two decades. As a result, migraine is now mainly considered to be a disorder of the brain, rather than the vasculature or the meninges. In addition, the insights of the complex pathophysiological mechanisms and the brain structures involved in the disease facilitate the development of new therapeutic approaches. At the recent Annual Meeting of the American Headache Society in Washington (DC, USA) the latest scientific advances, as well as their clinical implications, were highlighted.

Genomic expression patterns in medication overuse headaches.

BACKGROUND: Chronic daily headache (CDH) and chronic migraine (CM) are one of the most frequent problems encountered in neurology, are often difficult to treat, and frequently complicated by medication-overuse headache (MOH). Proper recognition of MOH may alter treatment outcome and prevent long term disability. OBJECTIVE: This study identifies the unique genomic expression pattern MOH that respond to cessation of the overused medication. METHODS: Baseline occurrence of MOH and typical pattern of response to medication cessation were measured from a large database. Whole blood samples from patients with CM with or without MOH were obtained and their genomic profile was assessed. Affymetrix human U133 plus2 arrays were used to examine the genomic expression patterns prior to treatment and 6-12 weeks later. Headache characterisation and response to treatment based on headache frequency and disability were compared. RESULTS: Of 1311 patients reporting daily or continuous headaches, 513 (39.1%) reported overusing analgesic medication. At follow-up, 44.5% had a 50% or greater reduction in headache frequency, while 41.6% had no change. Blood genomic expression patterns were obtained on 33 patients with 19 (57.6%) overusing analgesic medication with a unique genomic expression pattern in MOH that responded to cessation of analgesics. Gene ontology of these samples indicated a significant number were involved with brain and immunological tissues, including multiple signalling pathways and apoptosis. CONCLUSIONS: Blood genomic patterns can accurately identify MOH patients that respond to medication cessation. These results suggest that MOH involves a unique molecular biology pathway that can be identified with a specific biomarker.

Comorbidity between headache and epilepsy in a pediatric headache center.

The purpose of this study was to analyse the comorbidity between headache and epilepsy in a large series of children with headache (1,795). Fifty-six cases (3.1%) suffered from idiopathic headache and idiopathic or cryptogenic epilepsy or unprovoked seizures. There was a strong association between migraine and epilepsy: in migraineurs (46/56) the risk of epilepsy was 3.2 times higher when compared with tension-type headache, without significant difference between migraine with and without aura (P = 0.89); children with epilepsy had a 4.5-fold increased risk of developing migraine than tension-type headache. In cases with comorbidity, focal epilepsies prevailed (43/56, 76.8%). Migraineurs affected by focal epilepsies (36/56) had a three times higher risk of having a cryptogenic epilepsy (27/36, 75%) than an idiopathic epilepsy (9/36, 25%) (P = 0.003). In migraine with aura, epilepsy preceded migraine in 71% of cases. Photosensitivity (7/56, 12.5%) and positive family history for epilepsy (22/56, 39%) were frequent in cases with comorbidity.

Refractory migraine and chronic migraine: pathophysiological mechanisms.

Migraine is a complex disorder of the brain whose mechanisms are only now being unravelled. It is common, disabling, and economically costly. Brain imaging has suggested a role for the brainstem. While the disorder is almost certainly inherited, the degree to which this contributes to a treatment refractory state is not clear. Indeed, no specific structural or pharmacological explanation can be seen from the data as they have been generated. It is clear that patients with more frequent headache are very likely to go on to even more frequent headache, but again these data are complex. A challenge going forward is to establish the biology of these very challenging patients who undoubtedly have substantial disability.

Recent advances in the pharmacogenomics of pain and headache.

Liability to spontaneous and experimental pain is genetically determined and there is considerable variability in the antinociceptive effects of drugs commonly used in treating pain conditions and migraine attacks. The causes for variability involve still unknown genetic aspects. Recently, a third gene, SCN1A, was discovered as a cause of familial hemiplegic migraine (FHM). Recent advances in the genetics of pain and pain disorders include the discovery of the role of the sodium ion channel SCN9A in neuropathic pain as well as in inability to experience pain, and of GTP cyclohydrolase (GCH1) in setting the sensitivity to pain in normal individuals and modulating liability to chronic pain. Catechol-O-methyltransferase (COMT) and the cytochrome P450 variant allele CYP3A5 modulate the genetic response to opioid medications in humans. Variability in drug pharmacokinetics and adverse drug reactions of pain medications are also very much related to genetic variation, especially in CYP genes. Pharmacogenomic studies of headache and pain are still in their infancy, but these recent advances in the genetics of migraine and pain arguably hold the promise of individualised treatments and prevention of adverse drug reactions.

Chronic daily headache: risk factors and pathogenetic considerations.

Chronic daily headache (CDH) is a major clinical concern, although it is still plagued by difficulties with classification and definitions. CDH usually evolves from an episodic headache, mainly migraine. Drug overuse and other somatic or psychological traits are considered risk factors for CDH. The neurobiology underlying this clinical evolution is incompletely understood. There is evidence of a progressive dysfunction of central pain systems in some individuals probably genetically predisposed.

Neurobiology in primary headaches.

Primary headaches such as migraine and cluster headache are neurovascular disorders. Migraine is a painful, incapacitating disease that affects a large portion of the adult population with a substantial economic burden on society. The disorder is characterised by recurrent unilateral headaches, usually accompanied by nausea, vomiting, photophobia and/or phonophobia. A number of hypothesis have emerged to explain the specific causes of migraine. Current theories suggest that the initiation of a migraine attack involves a primary central nervous system (CNS) event. It has been suggested that a mutation in a calcium gene channel renders the individual more sensitive to environmental factors, resulting in a wave of cortical spreading depression when the attack is initiated. Genetically, migraine is a complex familial disorder in which the severity and the susceptibility of individuals are most likely governed by several genes that vary between families. Genom wide scans have been performed in migraine with susceptibility regions on several chromosomes some are associated with altered calcium channel function. With positron emission tomography (PET), a migraine active region has been pointed out in the brainstem. In cluster headache, PET studies have implicated a specific active locus in the posterior hypothalamus. Both migraine and cluster headache involve activation of the trigeminovascular system. In support, there is a clear association between the head pain and the release of the neuropeptide calcitonin gene-related peptide (CGRP) from the trigeminovascular system. In cluster headache there is, in addition, release of the parasympathetic neuropeptide vasoactive intestinal peptide (VIP) that is coupled to facial vasomotor symptoms. Triptan administration, activating the 5-HT(1B/1D) receptors, causes the headache to subside and the levels of neuropeptides to normalise, in part through presynaptic inhibition of the cranial sensory nerves. These data suggest a central role for sensory and parasympathetic mechanisms in the pathophysiology of primary headaches. The positive clinical trial with a CGRP receptor antagonist offers a new promising way of treatment.

[An update on the familial headache syndromes].

Migraine is a common form of the chronic headache syndromes. Although the pathogenesis of migraine still remains enigmatic, there have been remarkable progress in headache research. Point mutations of P/Q-type Ca2+ channel alpha 1 subunit (CACNA1A) gene have been identified in familial hemiplegic migraine (FHM), which linked to chromosome 19 (FHM-1, OMIM 141500). Na-K ATPase alpha2 gene has been identified as the causative gene for FHM linked to 1q21-23 (FHM-2, OMIM 602481). Common forms of migraine (i.e. migraine with and without aura) seems to be caused from multifactorial genetic factors and environmental factors. An association study of allelic variation at Codon 23 (Cys or Ser) of 5HT2C-R gene in Japanese samples revealed that the Ser allele frequency in migraine with aura was significantly higher than that in the non-headache controls. However, negative association of this polymorphism have been reported in Caucasian migrainures. The C677T allelic variation of 5,10-methylenetetrahydrofolate reductase (MTHFR) are focused on in association with the coronary heart diseases and the cerebrovascular diseases. The T allelic frequency in migraine sufferers was significantly higher than that in controls. The C677T mutation of MTHFR is one of the genetic risk factors for migraine. These observations are confirmed in Turkish, Australian and Spanish samples. Positive associations of angiotensin converting enzyme (ACE) gene, endotheline receptor-A (ET-A) gene, and insulin receptor gene have been reported. Using the genomewide screen technology, significant linkage between the migraine with aura and a marker on 4q24 has been reported in Finnish families. The genome wide screen analysis will be one of the powerful strategies on exploring migraine gene. Genetic study of migraine headache is a promised and fruitful field and will provide deep understanding to migraine headache. Discovery of new responsible or susceptible genes to migraine will also open an avenue to develop new therapeutic strategy of migraine.

Genetic and environmental influences on recurrent headaches in eight to nine-year-old twins.

The major objective of the present study was to estimate genetic and environmental influences on recurrent headaches in prepubescent twins. A nationwide cohort of 8 to 9-year-old Swedish twins (n = 1,480) was screened for nonsymptomatic and recurrent headaches through a questionnaire mailed to their parents (75% response frequency). Among positives, 79% of headaches were classified as migraine or tension-type headache in close accordance with the International Headache Society criteria. The prevalences of migraine and nonmigrainous headaches were 2.4% and 11.3%, respectively, and without significant differences between the sexes or zygosity types. Inheritance on liability to recurrent headaches was estimated to 70% (a2 = 0.70, 95% CI = 0.54-0.82) for boys and girls but the genetic effect was found to be uncorrelated between the sexes. We conclude that genetic and individual specific effects are important for recurrent headaches of migrainous and nonmigrainous types in prepubescent children, and that different genetic etiologies might exist for boys and girls.