Corrigendum: Editorial: Metals and cognitive decline: pathophysiology, treatment, and prevention.

[This corrects the article DOI: 10.3389/fneur.2023.1150966.].

Fall Risk, Sleep Behavior, and Sleep-Related Movement Disorders in Young Urbanites Exposed to Air Pollution.

BACKGROUND: Quadruple aberrant hyperphosphorylated tau, amyloid-ß, α-synuclein, and TDP-43 pathology had been documented in 202/203 forensic autopsies in Metropolitan Mexico City ≤40-year-olds with high exposures to ultrafine particulate matter and engineered nanoparticles. Cognition deficits, gait, equilibrium abnormalities, and MRI frontal, temporal, caudate, and cerebellar atrophy are documented in young adults. OBJECTIVE: This study aimed to identify an association between falls, probable Rapid Eye Movement Sleep Behavior Disorder (pRBD), restless leg syndrome (RLS), and insomnia in 2,466 Mexican, college-educated volunteers (32.5±12.4 years). METHODS: The anonymous, online study applied the pRBD and RLS Single-Questions and self-reported night-time sleep duration, excessive daytime sleepiness, insomnia, and falls. RESULTS: Fall risk was strongly associated with pRBD and RLS. Subjects who fell at least once in the last year have an OR = 1.8137 [1.5352, 2.1426] of answering yes to pRBD and/or RLS questions, documented in 29% and 24% of volunteers, respectively. Subjects fell mostly outdoors (12:01 pm to 6:00 pm), 43% complained of early wake up hours, and 35% complained of sleep onset insomnia (EOI). EOI individuals have an OR of 2.5971 [2.1408, 3.1506] of answering yes to the RLS question. CONCLUSION: There is a robust association between falls, pRBD, and RLS, strongly suggesting misfolded proteinopathies involving critical brainstem arousal and motor hubs might play a crucial role. Nanoparticles are likely a significant risk for falls, sleep disorders, insomnia, and neurodegenerative lethal diseases, thus characterizing air particulate pollutants' chemical composition, emission sources, and cumulative exposure concentrations are strongly recommended.

The Beneficial Clinical Effects of Teriflunomide in Experimental Autoimmune Myasthenia Gravis and the Investigation of the Possible Immunological Mechanisms.

Myasthenia gravis (MG) is an autoantibody-mediated autoimmune disease characterized by skeletal muscle weakness exacerbated with exercise. There is a need for novel drugs effective in refractory MG. We aimed to test the potential of teriflunomide, an immunomodulatory drug currently used in rheumatoid arthritis and multiple sclerosis treatment, in a murine experimental autoimmune myasthenia gravis (EAMG) model. EAMG was induced by immunizations with recombinant acetylcholine receptor (AChR). Teriflunomide treatment (10 mg/kg/day, intraperitoneal) was initiated to one group of mice (n = 21) following the third immunization and continued for 5 weeks. The disease control group (n = 19) did not receive medication. Naïve mice (n = 10) received only mock immunization. In addition to the clinical scorings, the numbers of B cells and T cells, and cytokine profiles of T cells were examined by flow cytometry. Anti-AChR-specific antibodies in the peripheral blood serum were quantified by ELISA. Teriflunomide significantly reduced clinical disease scores and the absolute numbers of CD4+ T cells and some of their cytokine-producing subgroups (IFN-γ, IL 2, IL22, IL-17A, GM-CSF) in the spleen and the lymph nodes. The thymic CD4+ T cells were also significantly reduced. Teriflunomide mostly spared CD8+ T cells' numbers and cytokine production, while reducing CD138+CD19+lambda+ plasma B cells' absolute numbers and CD138 mean fluorescent intensities, probably decreasing the number of IgG secreting more mature plasma cells. It also led to some selective changes in the measurements of anti-AChR-specific antibodies in the serum. Our results showed that teriflunomide may be beneficial in the treatment of MG in humans.

Evaluation of Utilizing the Distinct Genes as Predictive Biomarkers in Late-Onset Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by a devastating decline in cognitive activities among all types of dementia, and it severely affects the quality of life. Late-onset AD (LOAD) occurs after the age of 65 years and develops sporadically. Although aging comes first along the main risk factors underlying LOAD, disease-causing susceptibility genes have been associated with disease pathogenesis. In our study, we included the genes PARP1 , POLB , HTRA2 , SLC1A2 , HS1BP3 , and DRD3 to be investigated in LOAD patients based on their expression levels. Within this framework, we aimed to determine the possible functions of these genes in the pathophysiology of the disease. We investigated whether the utilization of these genes as biomarkers in the early diagnosis of LOAD may help the treatment scheme to be applied in the clinic. We involved 50 individuals in the study and collected peripheral blood samples from the patients and control groups for molecular genetic analysis. Subsequently, RNA was extracted from the peripheral blood samples, and expression analyzes were performed using qualitative reverse transcription polymerase chain reaction. The results obtained were evaluated by using proper statistical methods. Our results demonstrated that there was no difference between patient and control groups in terms of HTRA2 , DRD3 , HS1BP3 , and POLB genes. The expression levels of the SLC1A2 and PARP1 genes were significantly lower in the patient group compared with the control group. In conclusion, we presume that the PARP1 and SLC1A2 genes can be utilized as molecular biomarkers for LOAD.

Stratification of the Gut Microbiota Composition Landscape across the Alzheimer's Disease Continuum in a Turkish Cohort.

Alzheimer's disease (AD) is a heterogeneous disorder that spans a continuum with multiple phases, including preclinical, mild cognitive impairment, and dementia. Unlike for most other chronic diseases, human studies reporting on AD gut microbiota in the literature are very limited. With the scarcity of approved drugs for AD therapies, the rational and precise modulation of gut microbiota composition using diet and other tools is a promising approach to the management of AD. Such an approach could be personalized if an AD continuum can first be deconstructed into multiple strata based on specific microbiota features by using single or multiomics techniques. However, stratification of AD gut microbiota has not been systematically investigated before, leaving an important research gap for gut microbiota-based therapeutic approaches. Here, we analyze 16S rRNA amplicon sequencing of stool samples from 27 patients with mild cognitive impairment, 47 patients with AD, and 51 nondemented control subjects by using tools compatible with the compositional nature of microbiota. To stratify the AD gut microbiota community, we applied four machine learning techniques, including partitioning around the medoid clustering and fitting a probabilistic Dirichlet mixture model, the latent Dirichlet allocation model, and we performed topological data analysis for population-scale microbiome stratification based on the Mapper algorithm. These four distinct techniques all converge on Prevotella and Bacteroides stratification of the gut microbiota across the AD continuum, while some methods provided fine-scale resolution in stratifying the community landscape. Finally, we demonstrate that the signature taxa and neuropsychometric parameters together robustly classify the groups. Our results provide a framework for precision nutrition approaches aiming to modulate the AD gut microbiota. IMPORTANCE The prevalence of AD worldwide is estimated to reach 131 million by 2050. Most disease-modifying treatments and drug trials have failed, due partly to the heterogeneous and complex nature of the disease. Recent studies demonstrated that gut dybiosis can influence normal brain function through the so-called "gut-brain axis." Modulation of the gut microbiota, therefore, has drawn strong interest in the clinic in the management of the disease. However, there is unmet need for microbiota-informed stratification of AD clinical cohorts for intervention studies aiming to modulate the gut microbiota. Our study fills in this gap and draws attention to the need for microbiota stratification as the first step for microbiota-based therapy. We demonstrate that while Prevotella and Bacteroides clusters are the consensus partitions, the newly developed probabilistic methods can provide fine-scale resolution in partitioning the AD gut microbiome landscape.

Arsenic and selenium measurements in nail and hair show important relationships to Alzheimer's disease in the elderly.

BACKGROUND AND RESEARCH QUESTION: The relationships of Arsenic (As) and selenium (Se) to Alzheimer's Disease (AD) are not clearly known. This case-control observational study aims to investigate the possible relationship of these elements to the diagnosis and pathophysiology of the disease. METHODS: This case-control observational study was performed using 40 AD patients in different clinical stages and 40 healthy control subjects, living in a similar environment with low As exposure. The levels of As and Se in nail and hair were measured with Inductively Coupled Plasma Mass Spectrometry. The results were analysed with regards to clinical condition, age, disease duration, sex, education, living environment, and the relationship of the two elements using Mann Whitney U test and Spearman Rho or Pearson correlation tests as appropriate. RESULTS: The levels of As and Se were not related to age, disease duration, sex, education, or living environment in the study groups (p > 0.05). The levels of As and Se in hair and nail samples of all patients and patient subgroups were higher than those in the healthy subjects (p < 0.001). A positive correlation was found between the levels of As and Se in both hair and nail samples only in the patient group (p < 0.01). CONCLUSION: According to the results, As and Se levels probably increase due to some metabolic or genetic factors affecting both of them together. There may be an increase in the unregulated pool (selenomethionine) and a decrease in the regulated pool of Se (selenosycteine) in AD. Our findings need verification and the subject seems to deserve more elaborate evaluations including genetic analyses and analysis of different chemical forms of these elements.

New treatment modalities in Alzheimer's disease.

Alzheimer's disease (AD) is still a major public health challenge without an effective treatment to prevent or stop it. Routinely used acetylcholinesterase inhibitors and memantine seem to slow disease progression only to a limited extend. Therefore, many investigations on new drugs and other treatment modalities are ongoing in close association with increasing knowledge of the pathophysiology of the disease. Here, we review the studies about the new treatment modalities in AD with a classification based on their main targets, specifically pathologic structures of the disease, amyloid and tau, neural network dysfunction with special interest to the regulation of gamma oscillations, and attempts for the restoration of neural tissue via regenerative medicine. Additionally, we describe the evolving modalities related to gut microbiota, modulation, microglial function, and glucose metabolism.

Evaluation of intracerebral ventricles volume of patients with Parkinson's disease using the atlas-based method: A methodological study.

Knowing the volumetric changes in brain can allow for the estimation of the disease progression of various neurodegenerative disorders. Many studies have been shown that the volumetric changes in the some brain structures especially including the dopaminergic neurons, in patients with Parkinson's disease (PD). The objective of this study was to compare intracerebral ventricles volume in patients with PD and healthy subjects to compare an automated atlas-based method (MRIStudio software) and a manual method (ImageJ). T1-weighted brain Magnetic Resonance Imaging (MRI) data of 21 patients with PD and 20 healthy individuals were used to calculate the intracerebral ventricle volumes. Measurement results obtained by ImageJ were considered as the gold standard. We found a significant increase in the left occipital part of the lateral ventricle volume in the patients with PD compared to the control subjects (p < 0.05). Also, no significant difference was found between the two methods of measurement (p > 0.05), meaning that a substantial agreement was found between the results obtained with the atlas-based analysis and manual method. The present study showed that MRIStudio can be performed easily and accurately on routine MRI scans for which the total intracerebral ventricles volume is to be estimated in PD. We suggest that, the attained volume values of intracerebral ventricles may provide a precious data for volumetric dependences of the anatomical structures in several clinical conditions.

Schwann cell-derived periostin promotes autoimmune peripheral polyneuropathy via macrophage recruitment.

Chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain-Barre syndrome (GBS) are inflammatory neuropathies that affect humans and are characterized by peripheral nerve myelin destruction and macrophage-containing immune infiltrates. In contrast to the traditional view that the peripheral nerve is simply the target of autoimmunity, we report here that peripheral nerve Schwann cells exacerbate the autoimmune process through extracellular matrix (ECM) protein induction. In a spontaneous autoimmune peripheral polyneuropathy (SAPP) mouse model of inflammatory neuropathy and CIDP nerve biopsies, the ECM protein periostin (POSTN) was upregulated in affected sciatic nerves and was primarily expressed by Schwann cells. Postn deficiency delayed the onset and reduced the extent of neuropathy, as well as decreased the number of macrophages infiltrating the sciatic nerve. In an in vitro assay, POSTN promoted macrophage chemotaxis in an integrin-AM (ITGAM) and ITGAV-dependent manner. The PNS-infiltrating macrophages in SAPP-affected nerves were pathogenic, since depletion of macrophages protected against the development of neuropathy. Our findings show that Schwann cells promote macrophage infiltration by upregulating Postn and suggest that POSTN is a novel target for the treatment of macrophage-associated inflammatory neuropathies.

Nasu Hakola Disease: A Rare Cause of Dementia and Cystic Bone Lesions, Report of a New Turkish Family.

The differential diagnosis of young-onset progressive dementia is an issue that requires effort. Recording the family history and careful clinical evaluation are useful tools in the diagnosis. In case of genetic bases, definitive diagnosis requires molecular analysis. We report consanguineous two patients presenting with young-onset progressive dementia characterized by behavioral changes and with bone cysts. Concomitant bone pathology and inheritance pattern directed us to investigate TREM2 gene, for differential diagnosis, which resulted with the identification of a causative mutation that confirmed the diagnosis of Nasu Hakola disease. The mutation (c.113A>G) is the same for a Turkish family with Nasu Hakola disease reported before. But the presence of bone cysts and absence of epilepsy in our patients are the different findings. Molecular analysis should be considered in patients with young age onset behavioral and cognitive deficits, with white matter lesions in brain magnetic resonance imaging, if especially associated with cystic bone lesions.

A database for screening and registering late onset Pompe disease in Turkey.

The aim of this study was to search for the frequency of late onset Pompe disease (LOPD) among patients who had a myopathy with unknown diagnosis registered in the pre-diagnostic part of a novel registry for LOPD within a collaborative study of neurologists working throughout Turkey. Included in the study were 350 patients older than 18 years who have a myopathic syndrome without a proven diagnosis by serum creatine kinase (CK) levels, electrodiagnostic studies, and/or muscle pathology, and/or genetic tests for myopathies other than LOPD. Acid alpha glucosidase (GAA) in dried blood spot was measured in each patient at two different university laboratories. LOPD was confirmed by mutation analysis in patients with decreased GAA levels from either both or one of the laboratories. Pre-diagnostic data, recorded by 45 investigators from 32 centers on 350 patients revealed low GAA levels in a total of 21 patients; from both laboratories in 6 and from either one of the laboratories in 15. Among them, genetic testing proved LOPD in 3 of 6 patients and 1 of 15 patients with decreased GAA levels from both or one of the laboratories respectively. Registry was transferred to Turkish Neurological Association after completion of the study for possible future use and development. Our collaborative study enabled collection of a considerable amount of data on the registry in a short time. GAA levels by dried blood spot even from two different laboratories in the same patient may not prove LOPD. LOPD seemed to be rarer in Turkey than in Europe.

Trace metal concentrations in hair and nails from Alzheimer's disease patients: Relations with clinical severity.

BACKGROUND AND OBJECTIVES: Metals, especially transition metals, seem to be important in the pathogenesis of Alzheimer disease. This study aims to determine the relationship of trace metal elements to the pathogenesis and/or course of Alzheimer Disease in terms of clinical severity. METHODS: The hair and nail trace metal levels of 62 Alzheimer Disease patients at different clinical stages (21 mild, 20 moderate, 21 severe) and 60 healthy control subjects were measured by using inductively coupled plasma-mass spectrometry. The statistical comparisons were performed with regards to the study groups, clinical stages, disease duration and age. RESULTS: The patient and control groups were significantly different from each other in regards to Mn, Fe, Cu, Cd, Hg (p<0.001), Zn (p<0.01) in nail concentrations and, Na, Al, Pb, Co (p<0.001), Fe, Mn (p=0.001), Hg, Cu, Cd, K in hair concentrations (p<0.01). No difference was detected in the levels of Mg and Ca. Nail Na level showed differences among different clinical stages of the disease (p<0.01). In comparing the mild degree Alzheimer patients to the control group; significant differences were detected in nail Mn, Fe, Cu, Co (p<0.001), Hg, Zn (p<0.01) and, hair Pb, Al (p<0.001), Na, K levels (p<0.01). CONCLUSIONS: Our results have shown that transition and posttransition metals are especially important metals for the disease process. The relation of nail Na level with clinical stages of AD is an interesting new finding, making someone to think that alkali metals may be important in the progression of the disease.

Total intracranial and lateral ventricle volumes measurement in Alzheimer's disease: A methodological study.

Measuring of brain and its compartments' sizes from magnetic resonance (MR) images is an effective way to assess disease progression in neurodegenerative disorders, particularly Alzheimer's disease (AD). The objective of this study was to compare total intracranial volume (TIV) and lateral ventricle volume (LVV) in patients with Alzheimer's disease with those in elderly control subjects, and to compare an automated method (automatic lateral ventricle delineation [ALVIN]) and a manual method (ImageJ). MRI of the brain was performed on 20 patients with Alzheimer's disease and 18 control subjects. The TIV was calculated by a manual method and the LVV was calculated by using two methods: an automated and manual method. We found a significant increase in LVVs in Alzheimer's disease patients compared to control subjects, but no difference in TIV between the two groups. A perfect agreement, with 0.989 (0.973-0.996) intraclass correlation coefficient (ICC) and 0.978 (0.946-0.991) concordance correlation coefficient (CCC), was observed between the manual and automatic lateral ventricle measurements in Alzheimer patients. The results revealed that LVV measure has predictive performance in AD. We demonstrated that ALVIN and ImageJ are both effective in determining lateral ventricular volume, providing an objective tool for quantitative assessment of AD.

Transverse myelitis and acute motor sensory axonal neuropathy due to Legionella pneumophila: a case report.

Guillain-Barré syndrome is a rapidly progressive symmetrical muscle weakness associated with acute inflammatory disease. Transverse myelitis (TM) is the inflammation of the spinal cord characterized by rapidly evolving muscle weakness in the lower extremities, defects in sensory level and sphincter dysfunction. Guillain-Barré syndrome, and TM association occurs very rarely in childhood. A 7-year-old girl presented with complaints of neck pain, spout-style vomiting, cough, shortness of breath, and acute paraparesis with sensory and sphincter disturbance. The patient was intubated because of increased respiratory distress. A positive direct fluorescein antigen test in bronchoalveolar lavage confirmed Legionella pneumophila infection. Imaging and neurophysiologic studies were diagnostic for TM with acute motor and sensory axonal neuropathy. She was treated with a combination of high-dose methylprednisolone and intravenous immunoglobulins, and we observed incomplete recovery. The presented case is the first child with concomitant TM and acute motor and sensory axonal neuropathy related to L. pneumophila infection.

Association of amyotrophic lateral sclerosis and Behcet's disease: is there a relationship? A multi-national case series.

Neurological involvement may be seen in 5-30% of the patients with Behcet's disease (BD). Occasionally, parenchymal neurological involvement in BD can present as a spinal cord syndrome. However, motor neuron disease-like presentation is extremely uncommon. Here we are reporting five patients (all male; median age, 38) fulfilling both International Study Group criteria for BD and El Escorial criteria for amyotrophic lateral sclerosis (ALS). These patients were identified by a questionnaire sent to the members of the Neuro-Behcet Study Group of the International Study Group for BD. Three out of five patients had only motor presentations. In two patients, sensory and urinary manifestations were present as well. Spinal cord MRIs were normal in all, and brain MRIs were normal in four patients; one patient had nonspecific white matter changes. Two patients passed away 1-3 years after diagnosis of ALS, and two patients were lost to follow-up 3 and 11 years after admission; one patient is still alive 3 years after onset. The patients that are presented here might represent a rare form of neurological involvement in BD as well as sole coincidence. Larger prospective series are needed to further answer this issue.

Is headache in Behçet's disease related to silent neurologic involvement?

OBJECTIVES: Headache is an interesting issue in Behçet's disease (BD). This study aimed to investigate if headache or a special type of headache was correlated with silent neurologic involvement in BD patients without any neurologic sign. METHODS: The study was performed on 120 BD patients (30 without headache, 30 with non-structural headache of BD and 30 with migraine headache, 30 with tension type headache) and 30 healthy control subjects. Some neurophysiologic tests of brain stem; temporalis muscle exteroceptive suppression periods (ESP) and brain stem auditory evoked potentials (BAEP) were performed in the patients, when they were not in an attack period of the disease, and control subjects to investigate the presence of silent neurologic involvement and the relation between headache and silent neurologic involvement. RESULTS: Some electrophysiological abnormalities, as right BAEP 1-5 interpeak latency prolongation (p=0.01) and left ESP2 duration shortening (p<0.005), were seen in BD patients compared to healthy control subjects. Furthermore, the patients with non-structural headache of BD were found to have shorter ESP1 and 2 durations (p<0.001) and longer ESP1 latencies (p<0.05), with respect to the other patient subgroups with different types of headache and healthy control group, showing brain stem pathology. Additionally, they had longer right BAEP 3-5 interpeak latency as compared to the patient subgroup without headache (p=0.001). CONCLUSIONS: There is a silent neurologic involvement in BD and this involvement may be in relation with a particular type of vascular headache, named as non-structural headache of BD. So, in clinical evaluation of BD patients, this type of headache may be considered as a warning message for neurological involvement.

Factors that affect interictal cardiovascular autonomic dysfunction in temporal lobe epilepsy: role of hippocampal sclerosis.

The aim of this study was to evaluate possible factors affecting interictal cardiovascular autonomic function in temporal lobe epilepsy with complex partial seizures, paying special attention to hippocampal sclerosis. The study was carried out with 88 patients with epilepsy (22 with left hippocampal sclerosis, 22 with right hippocampal sclerosis, and 44 without hippocampal sclerosis) and 44 healthy subjects. All subjects underwent three tests of cardiac autonomic function: heart rate variation during resting activity, heart rate variation in response to deep breathing and blood pressure response to rising quickly from the supine position. Hippocampal sclerosis and disease duration were found to have significantly important effects on parasympathetic autonomic function, whereas seizure control and type of antiepileptic drug had significant effects on sympathetic autonomic function. This study shows that in addition to factors related to the chronic nature of epilepsy and antiepileptic drug use, hippocampal sclerosis may cause autonomic dysfunction during the interictal period in persons with temporal lobe epilepsy.

Is Toxoplasma gondii a causal agent in migraine?

BACKGROUND: Many different tissues may be parasitized by Toxoplasma gondii, particularly, lung, heart, lymphoid organs, and the central nervous tissues. Tissue cysts of this parasite in the brain may spontaneously rupture, releasing parasites that cause antibody titers to rise. In immunocompetent subjects with acquired toxoplasmosis, the most frequent symptoms were lymphadenopathy and headache. In the neurogenic inflammation theory of the pathogenesis of migraine, the cause of initial release of ions and inflammatory agents has not been established. In this study, we aimed to investigate if T. gondii infection is a possible cause of neurogenic inflammation of migraines. METHODS: The anti-T. gondii antibody status of 104 patients with migraine were studied and compared with those of control groups, 50 healthy subjects and 50 subjects with headache due to rhinosinusitis, by using a micro-enzyme-linked immunosorbent assay technique. RESULTS: Forty-six (44.2%) patients with migraine, 13 (26.0%) healthy control subjects, and 12 (24%) control subjects with rhinosinusitis were positive for anti-T. gondii IgG antibody. The rate of positivity in the migraine patient group was statistically different from those of the control groups (P < 0.05). CONCLUSIONS: The results show the presence of chronic Toxoplasma infection in patients with migraine. Toxoplasma infection may contribute to neurogenic inflammation as the pathogenesis of migraine, as many studies in the literature have reported that Toxoplasma infection causes biochemical and immunologic changes.

The effects of magnesium prophylaxis in migraine without aura.

There are inconsistent findings about the efficacy of magnesium in the prophylaxis of migraine attacks and there is no study of magnesium prophylaxis focused on migraine subtypes without aura. In this double blind, randomized, placebo controlled study; we tried to evaluate the prophylactic effects of oral magnesium in migraine patients without aura. The prophylactic effects of 600 mg/day oral magnesium citrate supplementation were assessed by means of clinical evaluation, visual evoked potential and statistical parametric mapping of brain single photon emission computerized tomography before and after a 3 month treatment period. The results of 30 patients with migraine without aura (20-55 years old with 2-5 migraine attacks per month) on magnesium treatment were compared with those of 10 patients with similar properties on placebo treatment. Migraine attack frequency, severity and P1 amplitude in visual evoked potential examination decreased after magnesium treatment with respect to pretreatment values (p < 0.001). In a comparison of the effects of magnesium treatment with those of placebo, post/pretreatment ratios of migraine attack frequency, severity and P1 amplitude in Mg treatment group were found to be significantly lower than those in placebo treatment group (attack frequency p = 0.005, attack severity p < 0.001, P1 amplitude p < 0.05). Cortical blood flow in inferolateral frontal (p < 0.001), inferolateral temporal (p = 0.001) and insular regions (p < 0.01) increased significantly after magnesium treatment with respect to the pretreatment; while such significant changes of cortical blood flow were not observed with placebo treatment. These results have made us think that magnesium is a beneficial agent in prophylaxis of migraine without aura and might work with both vascular and neurogenic mechanisms.