Abstract: BACKGROUND: There is conflicting evidence for the association between migraine and increased mortality risk. The aim of this study was to investigate the relationship between migraine and non-migrainous headache, and all-cause mortality and cardiovascular mortality. METHODS: In this prospective population-based cohort study from Norway, we used baseline data from the second Nord-Trondelag Health Survey (HUNT2), performed between 1995 and 1997 in the County of Nord-Trondelag. These data were linked with a comprehensive mortality database with follow-up through the year 2011. A total of 51,853 (56% of invited) people were categorized based on their answers to the headache questions in HUNT2 (headache free, migraine or non-migrainous headache). Hazard ratios (HRs) of mortality during a mean of 14.1 years of follow-up were estimated using Cox regression. RESULTS: During the follow-up period 9408 died, 4321 of these from cardiovascular causes. There was no difference in all-cause mortality between individuals with migraine and non-migrainous headache compared to those without headache or between headache status and mortality by cardiovascular disease. There was, however, among men with migraine without aura a reduced risk of death by cardiovascular diseases (HR 0.72, 95% confidence interval 0.56-0.93). This relationship was not evident in women. CONCLUSION: In this large, prospective cohort study there was no evidence for a higher all-cause mortality or cardiovascular mortality among individuals with migraine.

Abstract: BACKGROUND: There is little knowledge about how factors early in life affect the development of migraine and tension-type headache. We aimed to examine whether growth restriction in utero is associated with development of migraine and frequent tension-type headache in adults. METHODS: The population-based Nord-Trondelag Health Study (HUNT 3) contained a validated headache questionnaire, which differentiated between migraine and tension-type headache. These data were linked to information on weight and gestational age at birth from the Norwegian Medical Birth Registry. In total 4557 females and 2789 males, aged 19-41 years, were included in this registry-based study. Participants were categorized as appropriate for gestational age (AGA, 10th-90th percentile), small for gestational age (SGA, 3rd-10th percentile) or very small for gestational age (VSGA, < 3rd percentile). Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for migraine and tension-type headache, with exposure being growth restriction at birth. RESULTS: The effect of growth restriction on migraine was modified by sex, with a significant association in males (p<0.001), but not in females (p = 0.20). In particular, males born VSGA were at increased risk of developing migraine (OR 2.73, 95% CI 1.63-4.58, p<0.001), with an intermediate risk among those born SGA (OR 1.50, 95% CI 0.96-2.35, p = 0.08) compared to those born AGA. There was no significant association between growth restriction and frequent TTH (p = 0.051). CONCLUSION: Growth restriction was associated with increased risk of migraine in adulthood among males, but not among females. This suggests that migraine might, in part, be influenced by early life events, and that males seem to be particularly vulnerable.

Abstract: BACKGROUND AND PURPOSE: During the past decade, several population-based studies have found an inverse association between blood pressure (BP) and headache. However, most of them have a cross-sectional design or lack a validated definition of a headache-free population at baseline. Therefore, additional population-based studies using a clearly defined headache-free population and a prospective design are warranted. METHODS: Data from two large epidemiological studies, the Nord-Trondelag Health Survey 1995-1997 (HUNT 2) and 2006-2008 (HUNT 3), were used to evaluate the association between BP (systolic, diastolic and pulse pressure) at baseline and headache (migraine and tension type headache) at follow-up. RESULTS: An inverse relationship was found between all three BP measures at baseline in HUNT 2 and any headache in HUNT 3, more evident for systolic BP [odds ratio (OR) 0.90 per 10 mmHg increase in systolic BP, 95% confidence interval (CI) 0.87-0.93, P

Abstract: Medication-overuse headache (MOH) is relatively common, but its incidence has not been calculated and there are no prospective population-based studies that have evaluated risk factors for developing MOH. The aim of this study was to estimate incidences of and identify risk factors for developing chronic daily headache (CDH) and MOH. This longitudinal population-based cohort study used data from the Nord-Trondelag Health Surveys performed in 1995-1997 and 2006-2008. Among the 51,383 participants at baseline, 41,766 were eligible approximately 11 years later. There were 26,197 participants (responder rate 63%), among whom 25,596 did not report CDH at baseline in 1995-1997. Of these, 201 (0.8%) had MOH and 246 (1.0%) had CDH without medication overuse (CDHwoO) 11 years later. The incidence of MOH was 0.72 per 1000 person-years (95% confidence interval 0.62-0.81). In the multivariate analyses, a 5-fold risk for developing MOH was found among individuals who at baseline reported regular use of tranquilizers [odds ratio 5.2 (3.0-9.0)] or who had a combination of chronic musculoskeletal complaints, gastrointestinal complaints, and Hospital Anxiety and Depression Scale score >/= 11 [odds ratio 4.7 (2.4-9.0)]. Smoking and physical inactivity more than doubled the risk of MOH. In contrast, these factors did not increase the risk of CDHwoO. In this large population-based 11-year follow-up study, several risk factors for MOH did not increase the risk for CDHwoO, suggesting these are pathogenetically distinct. If the noted associations are causal, more focus on comorbid condition, physical activity, and use of tobacco and tranquilizers may limit the development of MOH.

Abstract: BACKGROUND: Headache has not been established as a risk factor for dementia. The aim of this study was to determine whether any headache was associated with subsequent development of vascular dementia (VaD), Alzheimer's disease (AD) or other types of dementia. METHODS: This prospective population-based cohort study used baseline data from the Nord-Trondelag Health Study (HUNT 2) performed during 1995-1997 and, from the same Norwegian county, a register of cases diagnosed with dementia during 1997-2010. Participants aged >/=20 years who responded to headache questions in HUNT 2 were categorized (headache free; with any headache; with migraine; with nonmigrainous headache). Hazard ratios (HRs) for later inclusion in the dementia register were estimated using Cox regression analysis. RESULTS: Of 51,383 participants providing headache data in HUNT 2, 378 appeared in the dementia register during the follow-up period. Compared to those who were headache free, participants with any headache had increased risk of VaD ( N = 63) (multivariate-adjusted HR = 2.3, 95% CI 1.4-3.8, P = 0.002) and of mixed dementia (VaD and AD ( N = 52)) (adjusted HR = 2.0, 95% CI 1.1-3.5, P = 0.018). There was no association between any headache and later development of AD ( N = 180). CONCLUSION: In this prospective population-based cohort study, any headache was a risk factor for development of VaD.

Abstract: Background The association between headache and paranasal sinus disease is still unclear. Because of symptom overlap, the two conditions are not easily studied on the basis of symptoms alone. The aim of the present study was to investigate whether paranasal sinus opacification on magnetic resonance imaging (MRI) was associated with migraine, tension-type headache (TTH) or unclassified headache. Methods This was a cross-sectional study of 844 randomly selected participants (442 women, age range 50-65 years, mean age 57.7 years). Based on 14 headache questions, participants were allocated to four mutually exclusive groups: migraine, TTH, unclassified headache or headache free. On MRI, opacifications as mucosal thickening, polyps/retention cysts and fluid in the five paired sinuses were measured and recorded if >/=1 mm. For each participant, opacification thickness was summed for each sinus and, in addition, a total sum of all sinuses was calculated. Opacification in each sinus was compared between headache-free participants and the headache groups using non-parametric tests, and the total sum was compared by logistical regression. Results No significant association was found between paranasal sinus opacification and headache in general, nor when headache was differentiated into migraine, TTH and unclassified headache. This was also true in separate analyses of mucosal thickening and fluid and of opacification from each paranasal sinus. Conclusion Migraine, TTH and unclassified headache were found not to be associated with an increased degree of paranasal sinus opacification at MRI.

Abstract: BACKGROUND: In four previous clinic-based MRI studies headache sufferers (in particular migraineurs) had more perivascular spaces (PVS) than individuals who were headache-free. METHODS: The present study was part of a large longitudinal, epidemiological study (Nord-Trondelag Health Survey (HUNT)). The 1006 participants, age 50-65 years at inclusion, had participated in all previous HUNT surveys (1-3), and been randomly selected to a population-based imaging study of the head (HUNT-MRI, 2007-2009). The number of visible PVS in the basal ganglia (BG) and hemispheric white matter (HWM) was compared in headache sufferers (migraine with and without aura, non-migrainous headache) and people who were headache-free. RESULTS: The results showed in general small differences between headache sufferers and headache-free participants. In the cross-sectional analysis migraineurs without aura had fewer PVS than headache-free individuals in BG (OR = 0.84, 95% CI = 0.76--0.94, p value = 0.003) and in BG and HWM together (OR = 0.97, 95% CI = 0.95-1.00, p value = 0.046). No difference between long-term headache sufferers and long-term headache-free individuals with regard to number of PVS was found. DISCUSSION: In contrast to previous studies, the present large, blinded, population-based study showed no increase in number of dilated PVS among headache sufferers. Fewer PVS among those with migraine without aura may be a spurious finding.

Abstract: Objective Earlier epidemiological studies have shown that headaches are frequent among adolescents, especially girls. In particular, recurrent primary headache disorders such as migraine and tension-type headaches are common complaints in this age group. Headaches are increasingly being recognized as a significant health problem in adolescents and can lead to significant disabilities by affecting their lives, their school performance and their social lives. The aim of this study was to compare the prevalence of primary headaches among adolescents aged 16-20 years in Norway in two periods. Very few replicate studies have re-evaluated the prevalence of primary headaches in this age range and it is uncertain whether the prevalence is increasing. Methods Two cross-sectional, population-based studies were conducted in Norway from 1995 to 1997 (Young-HUNT 1) and from 1999 to 2001 (Young-HUNT 2). In Young-HUNT 1, 2594 adolescents in 2nd and 3rd grade in upper secondary school (aged 16-20 years) completed a comprehensive questionnaire including one question regarding headache during the last 12 months. In addition, 1730 of the students were interviewed about their headache complaints. In Young-HUNT 2, 2373 adolescents aged 16-20 years completed the same questionnaire and 1655 were interviewed in the same way as the earlier survey. The interviews were performed by trained nurses, and respondents were asked if they had experienced recurrent headache during the last year. If so, the headache was classified as migraine (MI), tensiontype headache (TTH) or non-classifiable headache (NCH). Headache frequency during the past year was recorded according to the following categories: Less than 1 day per month (less than monthly), 1-3 days per month (monthly), 1-5 days per week (weekly), or more than 5 days per week (daily). Results The participation rate was 88% in Young-HUNT 1 and 81% in Young-HUNT 2. The overall prevalence of having had headaches during the last 12 months did not change significantly (79.4% versus 77.5%; OR: 0.89, 95%CI: 0.79-1.02, p = 0.09), whereas the prevalence of recurrent headaches increased from 30.3% in Young-HUNT 1 to 35.4% in Young-HUNT 2 (OR: 1.26, 95%CI: 1.09-1.46, p = 0.002). The prevalence of tension-type headache changed significantly from 19.0% to 21.9% (OR: 1.20, 95%CI: 1.02-1.42, p = 0.03). Also the prevalence of migraine tended to increase (7.5% versus 8.7%, OR: 1.18, 95%CI: 0.92-1.52, p = 0.18). The overall frequency of recurrent headache changed towards more monthly and less weekly headache. Conclusions This is the first large-scale population-based study among adolescents in Norway assessing changes in the prevalence of primary headaches over a four-year period of time. The overall prevalence of recurrent headaches increased significantly from Young-HUNT 1 to Young-HUNT 2. An increase was seen in all types of recurrent headaches and was significant for tension-type headache. Implications Earlier follow-up studies have examined changes in prevalence of recurrent headaches in young age, but the results are diverging. Our findings support the impression that the prevalence of recurrent headache among adolescents is increasing, and underlines the need for prospective designed studies with emphasis on prognosis and etiological factors.

Abstract: BACKGROUND AND PURPOSE: Headache has been associated with various lifestyle and psychosocial factors, one of which is smoking. The aim of the present study was to investigate whether the association between smoking intensity and headache is likely to be causal. METHOD: A total of 58 316 participants from the Nord-Trondelag Health (HUNT) study with information on headache status were genotyped for the rs1051730 C>T single-nucleotide polymorphism (SNP). The SNP was used as an instrument for smoking intensity in a Mendelian randomization analysis. The association between rs1051730 T alleles and headache was estimated by odds ratios with 95% confidence intervals. Additionally, the association between the SNP and migraine or non-migrainous headache versus no headache was investigated. All analyses were adjusted for age and sex. RESULTS: There was no strong evidence that the rs1051730 T allele was associated with headache in ever smokers (odds ratio 0.99, 95% confidence interval 0.95-1.02). Similarly, there was no association between the rs1051730 T allele and migraine or non-migrainous headache versus no headache. CONCLUSION: The findings from this study do not support that there is a strong causal relationship between smoking intensity and any type of headache. Larger Mendelian randomization studies are required to examine whether higher smoking quantity can lead to a moderate increase in the risk of headache subtypes.

Abstract: BACKGROUND: Headache is the most frequent symptom following head injury, but long-term follow-up of headache after head injury entails methodological challenges. In a population-based cohort study, we explored whether subjects hospitalized due to a head injury more often developed a new headache or experienced exacerbation of previously reported headache compared to the surrounding population. METHODS: This population-based historical cohort study included headache data from two large epidemiological surveys performed with an 11-year interval. This was linked with data from hospital records on exposure to head injury occurring between the health surveys. Participants in the surveys who had not been hospitalized because of a head injury comprised the control group. The head injuries were classified according to the Head Injury Severity Scale (HISS). Multinomial logistic regression was performed to investigate the association between head injury and new headache or exacerbation of pre-existing headache in a population with known pre-injury headache status, controlling for potential confounders. RESULTS: The exposed group consisted of 294 individuals and the control group of 25,662 individuals. In multivariate analyses, adjusting for age, sex, anxiety, depression, education level, smoking and alcohol use, mild head injury increased the risk of new onset headache suffering (OR 1.74, 95% CI 1.05-2.87), stable headache suffering (OR 1.70, 95% CI 1.15-2.50) and exacerbation of previously reported headache (OR 1.93, 95% CI 1.24-3.02). The reference category was participants without headache in both surveys. CONCLUSION: Individuals hospitalized due to a head injury were more likely to have new onset and worsening of pre-existing headache and persistent headache, compared to the surrounding general population. The results support the entity of the ICHD-3 beta diagnosis “persistent headache attributed to traumatic injury to the head”.

Abstract: 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.