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Tension-type headache (TTH) and migraine are two common primary headaches distinguished by clinical characteristics according to the 3rd edition of the International Classification of Headache Disorders. Migraine is identified by specific features such as being more prevalent in females, being aggravated by physical activity, certain genetic factors, having photophobia, phonophobia, nausea, vomiting, or aura, and responding to specific drugs. Nonetheless, TTH and migraine share some common characteristics, such as onset occurring in the 20 s, and being triggered by psychological factors like stress, moderate pain severity, and mild nausea in chronic TTH. Both conditions involve the trigeminovascular system in their pathophysiology. However, distinguishing between TTH and migraine in clinical practice, research, and epidemiological studies can be challenging, as there is a lack of specific diagnostic tests and biomarkers. Moreover, both conditions may coexist, further complicating the diagnostic process. This review aims to explore the similarities and differences in the pathophysiology, epidemiology, burden and disability, comorbidities, and responses to pharmacological and non-pharmacological treatments of TTH and migraine. The review also discusses future research directions to address the diagnostic challenges and improve the understanding and management of these conditions. Graphical Abstract: [Figure not available: see fulltext.]

Background: Neck pain is a frequent complaint among patients with migraine and seems to be correlated with the headache frequency. Neck pain is more common in patients with chronic migraine compared to episodic migraine. However, prevalence of neck pain in patients with migraine varies among studies. Objective: To estimate the prevalence of neck pain in patients with migraine and non-headache controls in observational studies. Methods: A systematic literature search on PubMed and Embase was conducted to identify studies reporting prevalence of neck pain in migraine patients. This review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data was extracted by two independent investigators and results were pooled using random-effects meta-analysis. The protocol was registered with PROSPERO (CRD42021264898). Results: The search identified 2490 citations of which 30 contained relevant original population based and clinic-based data. Among these, 24 studies provided data eligible for the analysis. The meta-analysis for clinic-based studies demonstrated that the pooled relative frequency of neck pain was 77.0% (95% CI: 69.0–86.4) in the migraine group and 23.2% (95% CI:18.6–28.5) in the non-headache control group. Neck pain was more frequent in patients with chronic migraine (87.0%, 95% CI: 77.0–93.0) compared to episodic migraine (77.0%, 95% CI: 69.0–84.0). Neck pain was 12 times more prevalent in migraine patients compared to non-headache controls and two times more prevalent in patients with chronic migraine compared to episodic migraine. The calculated heterogeneity (I2 values) ranged from 61.3% to 72.0%. Conclusion: Neck pain is a frequent complaint among patients with migraine. The heterogeneity among the studies emphasize important aspects to consider in future research of neck pain in migraine to improve our understanding of the driving mechanisms of neck pain in a major group of migraine patien

Migraine is a neurovascular disorder that affects over 1 billion people worldwide. Its widespread prevalence, and associated disability, have a range of negative and substantial effects not only on those immediately affected but also on their families, colleagues, employers, and society. To reduce this global burden, concerted efforts are needed to implement and improve migraine care that is supported by informed health-care policies. In this Series paper, we summarise the data on migraine epidemiology, including estimates of its very considerable burden on the global economy. First, we present the challenges that continue to obstruct provision of adequate care worldwide. Second, we outline the advantages of integrated and coordinated systems of care, in which primary and specialist care complement and support each other; the use of comprehensive referral and linkage protocols should enable continuity of care between these systems levels. Finally, we describe challenges in low and middle-income countries, including countries with poor public health education, inadequate access to medication, and insufficient formal education and training of health-care professionals resulting in misdiagnosis, mismanagement, and wastage of resources.

In the pons, glutamatergic mechanisms are involved in regulating inhibitory descending pain modulation, serotoninergic neurotransmission as well as modulating the sensory transmission of the trigeminovascular system. Migraine involves altered pontine activation and structural changes, while biochemical, genetic and clinical evidence suggests that altered interictal pontine glutamate levels may be an important pathophysiological feature of migraine abetting to attack initiation. Migraine without aura patients were scanned outside attacks using a proton magnetic resonance spectroscopy protocol optimized for the pons at 3 Tesla. The measurements were performed on two separate days to increase accuracy and compared to similar repeated measurements in healthy controls. We found that interictal glutamate (i.e. Glx) levels in the pons of migraine patients (n = 33) were not different from healthy controls (n = 16) (p = 0.098), while total creatine levels were markedly increased in patients (9%, p = 0.009). There was no correlation of glutamate or total creatine levels to migraine frequency, days since the last attack, usual pain intensity of attacks or disease duration. In conclusion, migraine is not associated with altered interictal pontine glutamate levels. However, the novel finding of increased total creatine levels suggests that disequilibrium in the pontine energy metabolism could be an important feature of migraine pathophysiology.

Background: The paroxysmal nature of migraine is a hallmark of the disease. Some patients report increased attack frequency at certain seasons or towards the end of the week, while others experience diurnal variations of migraine attack onset. This systematic review investigates the chronobiology of migraine and its relation to the periodicity of attacks in existing literature to further understand the oscillating nature of migraine. Main body: PubMed and Embase were systematically searched and screened for eligible articles with outcome measures relating to a circadian, weekly or seasonal distribution of migraine attacks. We found that the majority of studies reported morning hours (6 am–12 pm) as the peak time of onset for migraine attacks. More studies reported Saturday as weekly peak day of attack. There was no clear seasonal variation of migraine due to methodological differences (primarily related to location), however four out of five studies conducted in Norway reported the same yearly peak time indicating a possible seasonal periodicity phenomenon of migraine. Conclusions: The findings of the current review suggest a possible role of chronobiologic rhythms to the periodicity of migraine attacks. Future studies are, however, still needed to provide more knowledge of the oscillating nature of migraine.

The middle meningeal artery is a proposed surrogate marker for activation of trigeminal nociceptors during migraine. Previous studies focused on the extracranial part of the artery; hence, vasoreactivity in the intradural arteries during migraine is unknown. Thirty-four patients with migraine without aura were given sildenafil on one day and calcitonin gene-related peptide on another in double-blind crossover fashion. Patients were scanned with 3.0 T MR angiography before drug administration and again 6 hours later during induced attacks of migraine. We measured circumference of the intradural segment of the middle meningeal artery before and during induced migraine attacks. The middle cerebral and superficial temporal arteries were also examined. Fourteen patients had attacks during the second scan after both study drugs and 11 had a migraine after either one or the other, resulting in a total of 39 attacks included in the final analysis. Mean circumference of the intradural middle meningeal artery at baseline was 3.18 mm with an increase of 0.11 mm during attacks (P = 0.005), corresponding to a relative dilation of 3.6% [95% CI: 1.4%-5.7%]. Middle cerebral artery dilated by 9.4% [95% CI: 7.1%-11.7%] and superficial temporal artery by 2.3% [95% CI: 0.2%-4.4%]. Our study shows that the intradural middle meningeal artery and the middle cerebral artery are dilated during migraine induced by calcitonin gene-related peptide as well as sildenafil. We propose that intradural vasculature is affected by migraine-driven activation of trigeminal afferents during migraine attacks.

Migraine is a complex disorder, involving peripheral and central brain structures, where mechanisms and site of attack initiation are an unresolved puzzle. While abnormal pontine neuronal activation during migraine attacks has been reported, exact implication of this finding is unknown. Evidence suggests an important role of glutamate in migraine, implying a possible association of pontine hyperactivity to increased glutamate levels. Migraine without aura patients were scanned during attacks after calcitonin gene-related peptide and sildenafil in a double-blind, randomized, double-dummy, cross-over design, on two separate study days, by proton magnetic resonance spectroscopy and pseudo-continuous arterial spin labeling at 3T. Headache characteristics were recorded until 24 h after drug administrations. Twenty-six patients were scanned during migraine, yielding a total of 41 attacks. Cerebral blood flow increased in dorsolateral pons, ipsilateral to pain side during attacks, compared to outside attacks (13.6%, p = 0.009). Glutamate levels in the same area remained unchanged during attacks (p = 0.873), while total creatine levels increased (3.5%, p = 0.041). In conclusion, dorsolateral pontine activation during migraine was not associated with higher glutamate levels. However, the concurrently increased total creatine levels may suggest an altered energy metabolism, which should be investigated in future studies to elucidate the role of pons in acute migraine.

Glutamate detection in pons and thalamus using proton magnetic resonance spectroscopy (1H-MRS) after an intervention is of interest for studying various brain disorders. However, 1H-MRS in these brain regions is challenging and time-consuming, especially in longitudinal study designs. 1H-MRS of more cortical structures at the ultrahigh magnetic field strength of 7T yields an improved spectral output, including separation of the glutamate signal from the glutamine signal, in a shorter and more feasible scan time, as compared to conventional clinical field strengths. For this purpose, we compared the feasibility of 1H-MRS at 3T and 7T in pons and thalamus by applying a longitudinal study design of repeated measures on same day and three separate days at both field strength in five healthy participants. Total 1H-MRS acquisition time was reduced by a factor 3.75 for pons and by a factor 3 for thalamus at 7T as compared to 3T. We found higher spectral signal-to-noise ratio (SNR) (p < 0.001), lower linewidth (p = 0.001) and lower Cramér–Rao lower bounds (CRLB) (p < 0.001) for the combined glutamate and glutamine signal (Glx) in thalamus at 7T as compared to 3T. In pons, CRLB of Glx and SNR were lower at 7T (p = 0.002 and p = 0.006), with no differences in linewidth compared to 3T. Mean within-subject variability of Glx concentration estimates was lower at 7T compared to 3T for both pons and thalamus. At 7T, it was possible to assess glutamate and γ-aminobutyric acid (GABA) simultaneously in pons and thalamus. In conclusion, 1H-MRS at 7T resulted in improved spectral quality while allowing shorter scan times than at 3T as well as estimation of the pure glutamate signal in pons and thalamus. This opens up the opportunity for multimodal study designs and multiregional subcortical 1H-MRS research. Glutamate and GABA measurement at 7T in pons and thalamus is advantageous for future investigat

Objective: To investigate whether intravenously infused provokes migraine aura and migraine headache in migraine patients with aura. Background: Migraine with aura has been associated with endothelial dysfunction and increased stroke risk. The initiating mechanism of migraine aura symptoms is not known. Experimental provocation of migraine headache using vasoactive peptides has provided tremendous advances in the understanding of migraine pathophysiology but substances that can induce migraine aura have not been identified. Endothelin-1 (ET-1), an endogenous, potent vasoconstrictor peptide released from the vascular endothelium, has been proposed to trigger migraine aura. This hypothesis is based on reports of increased plasma ET-1 levels early during the migraine attacks and the observation that ET-1 applied to the cortical surface potently induces the cortical spreading depolarization, the underlying electrophysiological phenomenon of migraine aura, in animals. Further, endothelial damage due to, for example, carotid puncture and vascular pathology is known to trigger aura episodes. Methods: We investigated whether intravascular ET-1 would provoke migraine aura in patients. Using a two-way crossover, randomized, placebo-controlled, double-blind design, we infused high-dose (8 ng/kg/minutes for 20 minutes) intravenous ET-1 in patients with migraine with typical aura. The primary end-point was the difference in incidence of migraine aura between ET-1 and placebo. Experiments were carried out at a public tertiary headache center (Danish Headache Center, Rigshospitalet Glostrup, Denmark). Results: Fourteen patients received intravenous ET-1. No patients reported migraine aura symptoms or migraine headache during or up to 24 hours following the ET-1 infusion. Four patients reported mild to moderate headache only on the ET-1 day, 3 patients reported moderate headache on the placebo day, and 1 patient reported mild headache on both days. No serious adverse events occu

Background: Sildenafil and calcitonin gene-related peptide are vasoactive substances that induce migraine attacks in patients. The intradural arteries are thought to be involved, but these have never been examined in vivo. Sildenafil is the only migraine-inducing compound for which cephalic, extracranial artery dilation is not reported. Here, we investigate the effects of sildenafil and calcitonin gene-related peptide on the extracranial and intradural parts of the middle meningeal artery. Methods: In a double-blind, randomized, three-way crossover, placebo-controlled head-to-head comparison study, MR-angiography was recorded in healthy volunteers at baseline and twice after study drug (sildenafil/ calcitonin gene-related peptide/saline) administration. Circumferences of extracranial and intradural middle meningeal artery segments were measured using semi-automated analysis software. The area under the curve for circumference change was compared using paired t-tests between study days. Results: Twelve healthy volunteers completed the study. The area under the curve Baseline-120min was significantly larger on both the sildenafil and the calcitonin gene-related peptide day in the intradural middle meningeal artery (calcitonin gene-related peptide, p = 0.013; sildenafil, p = 0.027) and the extracranial middle meningeal artery (calcitonin gene-related peptide, p = 0.0003; sildenafil, p = 0.021), compared to placebo. Peak intradural middle meningeal artery dilation was 9.9% (95% CI [2.9–16.9]) after sildenafil (T 30min ) and 12.5% (95% CI [8.1–16.8]) after calcitonin gene-related peptide (T 30min ). Peak dilation of the extracranial middle meningeal artery after calcitonin gene-related peptide (T 30min ) was 15.7% (95% CI [11.2–20.1]) and 18.9% (95% CI [12.8–24.9]) after sildenafil (T 120min ). Conclusion: An important novel finding is that both sildenafil and calcitonin gene-related peptide dilate intradural art

The origin of migraine pain is unknown but possibly implicates the dura mater, which is pain sensitive in proximity to the meningeal arteries. Therefore, subtle changes in vessel calibre on the head pain side could reflect activation of dural perivascular nociceptors that leads to migraine headache. To test this hypothesis, we measured circumference changes of cranial arteries in patients with cilostazol-induced unilateral migraine without aura using 3 T high resolution magnetic resonance angiography. The middle meningeal artery was of key interest, as it is the main supply of the dura mater. We also measured the superficial temporal and external carotid arteries as additional extracranial segments, and the middle cerebral, the cerebral and cavernous parts of the internal carotid (ICAcerebral and ICAcavernous), and the basilar arteries as intracranial arterial segments. Magnetic resonance angiography scans were performed at baseline, migraine onset, after sumatriptan, and ≥27 h after migraine onset. Thirty patients underwent magnetic resonance angiography scans, of which 26 patients developed unilateral attacks of migraine without aura and were included in the final analysis. Eleven patients treated their migraine with sumatriptan while the remaining 15 patients did not treat their attacks with analgesics or triptans. At migraine onset, only the middle meningeal artery exhibited greater circumference increase on the pain side (0.24 ± 0.37 mm) compared to the non-pain side (0.06 ± 0.38 mm) (P = 0.002). None of the remaining arteries revealed any pain-side specific changes in circumference (P > 0.05), but exhibited bilateral dilation. Sumatriptan constricted all extracerebral arteries (P < 0.05). In the late phase of migraine, we found sustained bilateral dilation of the middle meningeal artery. In conclusion, onset of migraine is associated with increase in middle meningeal artery circumference specific to the head pain side. Our findin

Background: Sildenafil and calcitonin gene-related peptide both dilate the intradural segments of the middle meningeal artery measured with 3.0 tesla (T) MR angiography. Here we hypothesized that an increase in field strength to 7.0 T and concomitant enhanced voxel resolution would lower variance in measurements of dilation in the intradural middle meningeal artery. Methods: Five subjects completed two sessions at respectively 3.0 T and 7.0 T. Each session comprised MR angiography scans once before and twice after administration of sildenafil, calcitonin gene-related peptide or placebo in a three-way, crossover, double-blind, placebo-controlled design. Results: Standard deviations of arterial circumference revealed no difference between 3.0 T and 7.0 T measurements (p = 0.379). We found a decrease in standard deviation from our original angiography analysis software (QMra) to a newer (LAVA) software package (p < 0.001). Furthermore, we found that the dilation after sildenafil and calcitonin gene-related peptide were comparable between 3.0 T and 7.0 T. Conclusions: Our findings suggest no gain from the increase in voxel resolution but cemented dilatory findings from earlier. The implemented software update improved variance in circumference measurements in the intradural middle meningeal artery, which should be exploited in future studies. Trial registration: The study is part of a parent study, which is registered at ClinicalTrials.gov (NCT03143465).

Objective: Migraine displays clinical heterogeneity of attack features and attack triggers. The question is whether this heterogeneity is explained by distinct intracellular signaling pathways leading to attacks with distinct clinical features. One well-known migraine-inducing pathway is mediated by cyclic adenosine monophosphate and another by cyclic guanosine monophosphate. Calcitonin gene-related peptide triggers migraine via the cyclic adenosine monophosphate pathway and sildenafil via the cyclic guanosine monophosphate pathway. To date, no studies have examined whether migraine induction mediated via the cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways yields similar attacks within the same patients. Methods: Patients were subjected to migraine induction on two separate days using calcitonin gene-related peptide (1.5 µg/min for 20 minutes) and sildenafil (100 mg) in a double-blind, randomized, double-dummy, cross-over design. Data on headache intensity, characteristics and accompanying symptoms were collected until 24 hours after drug administration. Results: Thirty-four patients were enrolled and 27 completed both study days. Seventeen patients developed migraine after both study drugs (63%; 95% CI: 42–81). Eight patients developed migraine on one day only (seven after sildenafil and one after calcitonin gene-related peptide). Two patients did not develop migraine on either day. Headache laterality, nausea, photophobia and phonophobia were similar between drugs in 77%, 65%, 100%, and 94%, respectively, of the 17 patients who developed attacks on both days. Conclusion: A majority of patients developed migraine after both calcitonin gene-related peptide and sildenafil. This supports the hypothesis that the cyclic adenosine monophosphate and cyclic guanosine monophosphate intracellular signaling pathways in migraine induction converge in a common cellular determinator, which ultimately triggers the same attacks. Trial registration: Cl

Background: Initiating mechanisms of migraine headache remain poorly understood and a biomarker of migraine does not exist. Inflammation pertaining to the wall of cerebral arteries and brain parenchyma has been suggested to play a role in migraine pathophysiology. Objective: We conducted the first experimental human study to investigate macrophage-mediated inflammation as a possible biomarker of migraine. Methods: Using ultrasmall superparamagnetic iron oxide (USPIO)-enhanced 3T magnetic resonance imaging (MRI), we investigated the presence of macrophages in cerebral artery walls and in brain parenchyma of patients with migraine without aura. We used the phosphodiesterase-3-inhibitor cilostazol as an experimental migraine trigger, and investigated both patients who received sumatriptan treatment, and patients who did not. To validate our use of USPIO-enhanced MRI, we included a preclinical mouse model with subcutaneous capsaicin injection in the trigeminal V1 area. The study is registered at ClinicalTrials.gov with the identifier NCT02549898. Results: A total of 28 female patients with migraine without aura underwent a baseline MRI scan, ingested cilostazol, developed a migraine-like attack, and underwent an USPIO-enhanced MRI scan > 24 hours after intravenous administration of USPIO. Twelve patients treated their attack with 6 mg s.c. sumatriptan, while the remaining 16 patients received no migraine-specific rescue medication. The preclinical model confirmed that USPIO-enhanced MRI detects macrophage-mediated inflammation. In patients, however, migraine attacks were not associated with increased USPIO signal on the pain side of the head compared to the non-pain side. Conclusion: Our findings suggest that migraine without aura is not associated with macrophage-mediated inflammation specific to the head pain side.

Objective: To review and discuss the literature on the role of thalamic structure and function in migraine. Discussion: The thalamus holds an important position in our understanding of allodynia, central sensitization and photophobia in migraine. Structural and functional findings suggest abnormal functional connectivity between the thalamus and various cortical regions pointing towards an altered pain processing in migraine. Pharmacological nociceptive modulation suggests that the thalamus is a potential drug target. Conclusion: A critical role for the thalamus in migraine-related allodynia and photophobia is well established. Additionally, the thalamus is most likely involved in the dysfunctional pain modulation and processing in migraine, but further research is needed to clarify the exact clinical implications of these findings.

Background: Sildenafil and calcitonin gene-related peptide both dilate the intradural segments of the middle meningeal artery measured with 3.0 tesla (T) MR angiography. Here we hypothesized that an increase in field strength to 7.0T and concomitant enhanced voxel resolution would lower variance in measurements of dilation in the intradural middle meningeal artery. Methods: Five subjects completed two sessions at respectively 3.0T and 7.0T. Each session comprised MR angiography scans once before and twice after administration of sildenafil, calcitonin gene-related peptide or placebo in a three-way, crossover, double-blind, placebo-controlled design. Results: Standard deviations of arterial circumference revealed no difference between 3.0T and 7.0T measurements (p=0.379). We found a decrease in standard deviation from our original angiography analysis software (QMra) to a newer (LAVA) software package (p= 0.379). We found a decrease in standard deviation from our original angiography analysissoftware (QMra) to a newer (LAVA) software package (p < 0.001). Furthermore, we found that the dilation aftersildenafil and calcitonin gene-related peptide were comparable between 3.0 T and 7.0 T. Conclusions: Our findings suggest no gain from the increase in voxel resolution but cemented dilatory findingsfrom earlier. The implemented software update improved variance in circumference measurements in the intraduralmiddle meningeal artery, which should be exploited in future studies.