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.
Background
Cytokines are important endogenous substances that are involved in immune and inflammatory responses. Neurogenic inflammation has been proposed to play a role in migraine involving altered ...cytokine levels. Therefore, we aimed to provide a systematic review on the current knowledge on cytokine levels in migraine patients during and outside attacks.
Methods
Databases of PubMed and Embase were systematically searched for studies investigating cytokine levels in migraine patients during and outside attacks.
Results
Screening yielded identification of 45 articles investigating 18 cytokines in total. We found that the interictal level of the anti-inflammatory cytokine, interleukin 10, was decreased, while the level of transforming growth factor beta 1 was increased in migraine patients compared to controls. Levels of pro-inflammatory cytokines, tumor necrosis factor α and interleukin 6, were increased outside attacks compared to controls. Ictal levels of cytokines were unchanged or varying compared to the interictal state in migraine patients. Three studies reported dynamic cytokines levels during the course of an attack.
Conclusion
The findings of the current review underline a possible involvement of cytokines in the proposed inflammatory mechanisms of migraine. However, future studies are needed to expand our knowledge of the exact role of cytokines in the migraine pathophysiology with focus on cytokines TNF-α, IL-1ß, IL-6 and IL-10 while applying refined methodology.
The origin of migraine pain is unknown, but may involve the dura mater. In unilateral migraine without aura, Khan et al. report that the middle meningeal artery is the only artery with greater ...circumference increase on the pain side versus non-pain side, suggesting a meningeal contribution to migraine headache.
Abstract
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 findings suggest that vasodilation of the middle meningeal artery may be a surrogate marker for activation of dural perivascular nociceptors, indicating a meningeal site of migraine headache.
10.1093/brain/awy300_video1
awy300media1
5983750185001
To present an updated and streamlined overview of the metabolic and biochemical aspect of the migraine pathophysiology based on findings from phosphorous (P) and hydrogen (H) magnetic resonance ...spectroscopy (MRS) studies.
Despite of the variation in the methodology and quality of the MRS migraine studies over time, some results were consistent and reproducible. P-MRS studies suggested reduced availability of neuronal energy and implied a mitochondrial dysfunction in the migraine brain. H-MRS studies reported interictal abnormalities in the excitatory and inhibitory neurotransmitters, glutamate and γ-aminobutyric acid (GABA), suggesting persistent altered excitability in migraine patients. N-Acetylaspartate levels were decreased in migraine, probably due to a mitochondrial dysfunction and abnormal energy metabolism. The reported abnormalities may increase the susceptibility of migraine patients to excitatory stimulation, such as migraine attack triggers.
Several biochemical aspects of the migraine pathophysiology remain to be elucidated using MRS, such as the migraine attack, correlation to disease severity, and medication efficacy. Nevertheless, to identify a biomarker in migraine, MRS may be a valuable noninvasive technique.
Background
Migraine prevention with erenumab and migraine induction by calcitonin gene-related peptide (CGRP) both carry notable individual variance. We wanted to explore a possible association ...between individual efficacy of anti-CGRP treatment and susceptibility to migraine induction by CGRP.
Methods
Thirteen migraine patients, previously enrolled in erenumab anti-CGRP receptor monoclonal antibody trials, received CGRP in a double-blind, placebo-controlled, randomized cross-over design to investigate their susceptibility to migraine induction. A standardized questionnaire was used to assess the efficacy of previous antibody treatment. The patients were stratified into groups of high responders and poor responders. Primary outcomes were incidence of migraine-like attacks and area under the curve of headache intensity after infusion of CGRP and placebo. All interviews and experiments were performed in laboratories at the Danish Headache Center, Copenhagen, Denmark.
Results
Ten high responders and three poor responders were included. CGRP induced migraine-like attacks in ten (77%) patients, whereof two were poor responders, compared to none after placebo (
p
= 0.002). The area under the curve for headache intensity was greater after CGRP, compared to placebo, at 0–90 min (
p
= 0.009), and 2–12 h (
p
= 0.014). The median peak headache intensity score was 5 (5–9) after CGRP, compared to 2 (0–4) after placebo (
p
= 0.004).
Conclusions
Patients with an excellent effect of erenumab are highly susceptible to CGRP provocation. If an association is evident, CGRP provocation could prove a biomarker for predicting antibody treatment efficacy.
Trial registration
Retrospectively registered at clinicaltrials.gov with identifier:
NCT03481400
.
Tension-type headache (TTH) and migraine are two common primary headaches distinguished by clinical characteristics according to the 3
rd
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
Endothelin-1 (ET-1) is a highly potent vasoconstrictor peptide released from vascular endothelium. ET-1 plays a major role in cerebrovascular disorders and likely worsens the outcome of acute ...ischaemic stroke and aneurismal subarachnoid haemorrhage through vasoconstriction and cerebral blood flow (CBF) reduction. Disorders that increase the risk of stroke, including hypertension, diabetes mellitus, and acute myocardial infarction, are associated with increased plasma levels of ET-1. The in vivo human cerebrovascular effects of systemic ET-1 infusion have not previously been investigated. In a two-way crossover, randomized, double-blind design, we used advanced 3 tesla MRI methods to investigate the effects of high-dose intravenous ET-1 on intra- and extracranial artery circumferences, global and regional CBF, and cerebral metabolic rate of oxygen (CMRO2) in 14 healthy volunteers. Following ET-1 infusion, we observed a 14% increase of mean arterial blood pressure, a 5% decrease of middle cerebral artery (MCA) circumference, but no effects on extracerebral arteries and no effects on CBF or CMRO2. Collectively, the findings indicate MCA constriction secondarily to blood pressure increase and not due to a direct vasoconstrictor effect of ET-1. We suggest that, as opposed to ET-1 in the subarachnoid space, intravascular ET-1 does not exert direct cerebrovascular effects in humans.
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.
Abstract 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 ultra-high 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 was lower at 7T (p<0.001), with no differences in SNR or 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 gamma-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 investigations of excitatory-inhibitory mechanisms in brain disorders.
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
).
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