Prostaglandin-E2 levels over the course of glyceryl trinitrate provoked migraine attacks.

Administration of glyceryl trinitrate (GTN), a donor of nitric oxide, can induce migraine-like attacks in subjects with migraine. Provocation with GTN typically follows a biphasic pattern; it induces immediate headache in subjects with migraine, as well as in healthy controls, whereafter only subjects with migraine may develop a migraine-like headache several hours later. Interestingly, intravenous infusion with prostaglandin-E2 (PGE2) can also provoke a migraine-like headache, but seems to have a more rapid onset compared to GTN. The aim of the study was to shed light on the mechanistic aspect PGE2 has in migraine attack development. Therefore, PGE2 plasma levels were measured towards the (pre)ictal state of an attack, which we provoked with GTN. Blood samples from women with migraine (n = 37) and age-matched female controls (n = 25) were obtained before and âˆ¼ 140 min and âˆ¼ 320 min after GTN infusion. PGE2 levels were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. Data was analyzed using a generalized linear mixed-effect model. Immediate headache after GTN infusion occurred in 85 % of migraine participants and in 75 % of controls. A delayed onset migraine-like attack was observed in 82 % of migraine subjects and in none of the controls. PGE2 levels were not different between the interictal and preictal state (P = 0.527) nor between interictal and ictal state (defined as having migraine-like headache) (P = 0.141). Hence, no evidence was found that a rise in PGE2 is an essential step in the initiation of GTN-induced migraine-like attacks.

Cerebrospinal Fluid and Plasma Amine Profiles in Interictal Migraine.

OBJECTIVE: Impaired amine metabolism has been associated with the etiology of migraine, that is, why patients continue to get migraine attacks. However, evidence from cerebrospinal fluid (CSF) is lacking. Here, we evaluated individual amine levels, global amine profiles, and amine pathways in CSF and plasma of interictal migraine patients and healthy controls. METHODS: CSF and plasma were sampled between 8:30 am and 1:00 pm, randomly and interchangeably over the time span to avoid any diurnal and seasonal influences, from healthy volunteers and interictal migraine patients, matched for age, sex, and sampling time. The study was approved by the local medical ethics committee. Individual amines (n = 31), global amine profiles, and specific amine pathways were analyzed using a validated ultraperformance liquid chromatography mass spectrometry platform. RESULTS: We analyzed n = 99 participants with migraine with aura, n = 98 with migraine without aura, and n = 96 healthy volunteers. Univariate analysis with Bonferroni correction indicated that CSF L-arginine was reduced in migraine with aura (10.4%, p < 0.001) and without aura (5.0%, p = 0.03). False discovery rate-corrected CSF L-phenylalanine was also lower in migraine with aura (6.9%, p = 0.011) and without aura (8.1%, p = 0.001), p = 0.088 after Bonferroni correction. Multivariate analysis revealed that CSF global amine profiles were similar for both types of migraine (p = 0.64), but distinct from controls (p = 0.009). Global profile analyses were similar in plasma. The strongest associated pathways with migraine were related to L-arginine metabolism. INTERPRETATION: L-Arginine was decreased in the CSF (but not in plasma) of interictal patients with migraine with or without aura, and associated pathways were altered. This suggests that dysfunction of nitric oxide signaling is involved in susceptibility to getting migraine attacks. ANN NEUROL 2023;93:715-728.

Cortical glutamate and gamma-aminobutyric acid over the course of a provoked migraine attack, a 7 Tesla magnetic resonance spectroscopy study.

Enhanced activity of the glutamatergic system has been linked to migraine pathophysiology. The present study aimed to assess the involvement of the glutamatergic system in the onset of attacks. We provoked attacks by infusion of glyceryl trinitrate (GTN; 0.5 µg/kg/min over 20 min) in 24 female episodic migraineurs without aura and 13 female age-matched healthy controls. Over the course of a single day participants were scanned three times at fixed time slots (baseline before GTN infusion, 90 min and 270 min after start of GTN infusion). Single-volume proton magnetic resonance spectra (1H-MRS) were acquired at 7 Tesla from a volume of interest (VOI, 2x2x3 cm) in the visual cortex. We assessed the concentrations of glutamate, its major precursor glutamine, and its product gamma-aminobutyric acid (GABA) over the course of a provoked attack. The preictal state was defined as the period after GTN infusion until the migraine-like headache started, independent of possible experienced premonitory symptoms, and the ictal state was defined as the period with provoked migraine-like headache. Data were analyzed using a linear mixed-effect model for repeated measures. Glutamate and glutamine levels did not change from interictal to the preictal and ictal state. GABA levels increased from interictal towards the preictal state for migraine patients compared with healthy controls. We conclude that high resolution 7T MRS is able to show changes in the glutamatergic system towards a triggered migraine attack, by revealing an increased GABA concentration associated with the onset of a migraine attack.

Migraine prevalence in visual snow with prior illicit drug use (hallucinogen persisting perception disorder) versus without.

BACKGROUND AND PURPOSE: This study was undertaken to investigate migraine prevalence in persons with hallucinogen persisting perception disorder (HPPD) presenting as visual snow syndrome (VSS). METHODS: Persons with visual snow as a persisting symptom after illicit drug use (HPPD) were recruited via a Dutch consulting clinic for recreational drug use. A structured interview on (visual) perceptual symptomatology, details of drugs use, and medical and headache history was taken. As a control group, persons with visual snow who had never used illicit drugs prior to onset were included. The primary outcome was lifetime prevalence of migraine. Symptom severity was evaluated by the Visual Snow Handicap Inventory (VHI), a 25-item questionnaire. RESULTS: None of the 24 HPPD participants had migraine, whereas 20 of 37 (54.1%) controls had migraine (p < 0.001). VHI scores did not differ significantly between the two groups; in both groups, the median score was 38 of 100. In most HPPD cases (17/24, 70.9%), visual snow had started after intake of ecstasy; other psychedelic drugs reported included cannabis, psilocybin mushrooms, amphetamine, 4-fluoroamphetamine, 3-methylmethcathinone, 4-Bromo-2,5-dimethoxypenethylamine, and nitrous oxide. CONCLUSIONS: Whereas none of the HPPD participants had migraine, more than half of the visual snow controls without prior use of illicit drugs had migraine. This suggests that at least partly different pathophysiological factors play a role in these disorders. Users of ecstasy and other hallucinogens should be warned of the risk of visual snow. Further studies are needed to enhance understanding of the underlying neurobiology of HPPD and VSS to enable better management of these conditions.

The effect of needle size on cerebrospinal fluid collection time and post-dural puncture headache: A retrospective cohort study.

OBJECTIVE: The main objective of this study was to compare cerebrospinal fluid (CSF) collection time and patient's discomfort between 20G (a)traumatic and 22G atraumatic needles. BACKGROUND: Risk of post-dural puncture headache (PDPH) is decreased using atraumatic needles. Smaller needles may give lower risk but possibly at the cost of increased CSF collection time (due to lower flow), leading to additional patient's discomfort. METHODS: We performed a retrospective study of lumbar puncture data from a research program on CSF metabolomics and compared traumatic 20G (n = 210) with atraumatic 20G (n = 39) and 22G (n = 105) needles. In this cohort, incidence of PDPH was prospectively registered with other procedure details. Primary outcome was CSF collection time (time to fill the tube). Secondary outcomes were pain and stress scores during procedure, and incidence of PDPH. RESULTS: The time to collect 10 mL of CSF was longer for 22G needles (6.1 minutes; 95% CI 5.8-6.5) than for 20G traumatic (2.2 minutes; 95% CI 2.1-2.2) and 20G atraumatic needles (2.9 minutes; 95% CI 2.8-3.1). There were no differences in pain and stress scores. PDPH was lower for 22G atraumatic needles: odds ratio 0.41 (95% CI 0.25-0.66) versus 20G traumatic needles and 0.53 (95% CI 0.40-0.69) versus 20G atraumatic needles. Absolute PDPH rates were 69/210 (32.9%) for 20G traumatic, 13/39 (33.3%) for 20G atraumatic, and 19/105 (18.1%) for 22G atraumatic needles. CONCLUSIONS: CSF collection time is slightly longer for smaller 22G needles, but this does not lead to more discomfort for the patient.

Premonitory symptoms in glyceryl trinitrate triggered migraine attacks: a case-control study.

ABSTRACT: Spontaneous and pharmacologically provoked migraine attacks are frequently preceded by nonheadache symptoms called premonitory symptoms. Here, we systematically evaluated premonitory symptoms in migraine patients and healthy controls after glyceryl trinitrate (GTN) infusion. In women with migraine without aura (n = 34) and age-matched female controls (n = 24), we conducted systematically a semistructured interview assessing 21 possible premonitory symptoms every 15 minutes in the 5 hours after GTN infusion (0.5 µg/kg/min over 20 minutes). Migraine-like headaches occurred in 28/34 (82.4%) migraineurs (GTN responders). After GTN, 26/28 (92.9%) responders, 6/6 (100%) nonresponders, and 13/24 (54.2%) controls reported at least one possible premonitory symptom. Concentration difficulties (P = 0.011), yawning (P = 0.009), nausea (P = 0.028), and photophobia (P = 0.001) were more frequently reported by those migraineurs who developed a migraine-like attack vs healthy controls. Importantly, concentration difficulties were exclusively reported by those who developed a migraine-like attack. Thus, our findings support the view that GTN is able to provoke the naturally occurring premonitory symptoms and show that yawning, nausea, photophobia, and concentration difficulties are most specific for an impending GTN-induced migraine-like headache. We suggest that these symptoms may also be helpful as early warning signals in clinical practice with concentration difficulties exclusively reported by those who develop a migraine-like attack.

Integration of epidemiologic, pharmacologic, genetic and gut microbiome data in a drug-metabolite atlas.

Progress in high-throughput metabolic profiling provides unprecedented opportunities to obtain insights into the effects of drugs on human metabolism. The Biobanking BioMolecular Research Infrastructure of the Netherlands has constructed an atlas of drug-metabolite associations for 87 commonly prescribed drugs and 150 clinically relevant plasma-based metabolites assessed by proton nuclear magnetic resonance. The atlas includes a meta-analysis of ten cohorts (18,873 persons) and uncovers 1,071 drug-metabolite associations after evaluation of confounders including co-treatment. We show that the effect estimates of statins on metabolites from the cross-sectional study are comparable to those from intervention and genetic observational studies. Further data integration links proton pump inhibitors to circulating metabolites, liver function, hepatic steatosis and the gut microbiome. Our atlas provides a tool for targeted experimental pharmaceutical research and clinical trials to improve drug efficacy, safety and repurposing. We provide a web-based resource for visualization of the atlas (http://bbmri.researchlumc.nl/atlas/).

Metabolomics Profile in Depression: A Pooled Analysis of 230 Metabolic Markers in 5283 Cases With Depression and 10,145 Controls.

BACKGROUND: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons. METHODS: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses. RESULTS: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q < .05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms. CONCLUSIONS: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity.

Treatment effects and comorbid diseases in 58 patients with visual snow.

OBJECTIVE: To evaluate pharmacologic treatment options for visual snow and to report prevalence of comorbid diseases. METHODS: Medical charts of patients with a diagnosis of visual snow at the neurology outpatient clinic were reviewed on prescribed medication, and comorbid migraine, tinnitus, and psychiatric conditions including depression and anxiety. RESULTS: From 2007 to 2018, 58 patients were diagnosed with visual snow. Comorbid migraine was present in 51.7% of patients, lifetime depression in 41.4%, and lifetime anxiety in 44.8%. Lamotrigine was prescribed most frequently (26/58) and resulted in partial remission of symptoms in 5/26 (19.2%). No patients reported complete remission. Adverse events occurred in 13/26 (50.0%) patients. None of the other prescribed drugs (valproate [n = 7], topiramate [n = 4], acetazolamide [n = 2], flunarizine [n = 1]) led to improvement except for topiramate in one patient, who discontinued, however, because of adverse events. CONCLUSIONS: Of medication prescribed (lamotrigine, valproate, acetazolamide, flunarizine), only lamotrigine afforded some improvement in a small minority of patients. Migraine, depression, anxiety, and tinnitus were common comorbid diseases. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for some patients with visual snow, lamotrigine resulted in partial remission of symptoms.

Large-scale plasma metabolome analysis reveals alterations in HDL metabolism in migraine.

OBJECTIVE: To identify a plasma metabolomic biomarker signature for migraine. METHODS: Plasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a 1H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses. RESULTS: Decreases in the level of apolipoprotein A1 (ß -0.10; 95% confidence interval [CI] -0.16, -0.05; adjusted p = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (ß -0.10; 95% CI -0.15, -0.05; adjusted p = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (ß -0.24; 95% CI -0.36, -0.12; adjusted p = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status. CONCLUSIONS: Metabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs.

Primary headaches.

Headache disorders, characterized by recurrent headache, are among the most common disorders of the nervous system. Primary headache disorders are by definition not the result of any other underlying disease or process. In this chapter the current status of cerebrospinal fluid (CSF) research and applications for clinical practice for the three main primary headaches - migraine, cluster headache, and tension-type headache - will be described. Primary headaches are clinically diagnosed disorders, with typically normal routine CSF measurements. Research in these headaches has been focused on identifying pathophysiologic pathways with a wide array of measured molecules. CSF research in the headache field is still in the discovery phase, with most studies performed in migraine and with unreplicated findings for most of the identified molecules. From a clinical standpoint it would be of great value if CSF biomarkers could be used as disorder-specific biomarkers for difficult primary headache cases, or to predict treatment responsiveness or risk for headache chronification. These applications are currently not yet feasible. For future research into CSF biomarkers for primary headache disorders, two different strategies should be employed: hypothesis-driven and nonhypothesis-driven biochemical research, to show new avenues for treatment strategies and develop prediction models for clinical use.

Cortical glutamate in migraine.

Cortical hyperexcitability due to enhanced glutamatergic activity has been implicated in migraine pathophysiology but direct evidence is lacking. Here we assessed glutamate levels and intracellular mobility of glutamate in the visual cortex of migraineurs in-between attacks. We included 50 migraineurs (23 with aura and 27 without aura) and 24 age- and gender-matched non-headache controls. We used proton magnetic resonance spectroscopy (1H-MRS) and diffusion weighted spectroscopy at 7 T with a single volume of interest (2 × 2 × 3 cm) located in the primary and secondary visual cortex. For 1H-MRS we used a semi-LASER sequence with water referencing for absolute quantification. For diffusion weighted spectroscopy we used an adapted PRESS sequence with gradients applied in three directions and two different gradient amplitudes. Between-group differences were evaluated using analysis of covariance with the grey matter fraction in the volume of interest as covariate and post hoc comparisons with Bonferroni correction. Glutamate concentrations differed between groups (P = 0.047) and were higher in migraineurs without aura (mean ± standard deviation: 7.02 ± 0.50 mM) compared to controls (mean ± standard deviation: 6.40 ± 0.78 mM, P = 0.042). The apparent diffusion coefficient of glutamate was similar among groups (P = 0.129) suggesting similar inter- and intracellular mobility of glutamate in all three study groups. No differences were observed for concentrations and diffusion constants of other metabolites. The present study suggests that interictal glutamate levels are increased in the visual cortex of migraineurs without aura, supporting the hypothesis of cortical hyperexcitability in migraine.

Quantitative profiling of endocannabinoids and related N-acylethanolamines in human CSF using nano LC-MS/MS.

Endocannabinoids, a class of lipid messengers, have emerged as crucial regulators of synaptic communication in the CNS. Dysregulation of these compounds has been implicated in many brain disorders. Although some studies have identified and quantified a limited number of target compounds, a method that provides comprehensive quantitative information on endocannabinoids and related N-acylethanolamines (NAEs) in cerebrospinal fluid (CSF) is currently lacking, as measurements are challenging due to low concentrations under normal physiological conditions. Here we developed and validated a high-throughput nano LC-ESI-MS/MS platform for the simultaneous quantification of endocannabinoids (anandamide and 2-arachidonoylglycerol), ten related NAEs, and eight additional putatively annotated NAEs in human CSF. Requiring only 200 µl of CSF, our method has limits of detection from 0.28 to 61.2 pM with precisions of relative SD <15% for most compounds. We applied our method to CSF from 45 healthy humans and demonstrated potential age and gender effects on concentrations of endocannabinoids and NAEs. Notably, our results show that docosahexaenoylethanolamide concentrations increase with age in males. Our method may offer new opportunities to gain insight into regulatory functions of endocannabinoids in the context of (ab)normal brain function.