It is controversial to what extent afterimages, as distinct visual phenomena, are altered in patients with migraine and whether they have a specific role in migraine pathophysiology.

The aim of this cross-sectional study was to investigate the duration of afterimages in patients with migraine, migraine with aura (MwA), and migraine without aura (MwoA), compared to healthy controls (HCs).

Adults with migraine, MwA, and MwoA, diagnosed according to The International Classification of Headache Disorders, third edition criteria and HCs without relevant headache history were included. Initially, factors affecting the experimental setting of testing afterimage latency were determined. Then, afterimage duration was measured in the two study groups (MwA and MwoA) and the HC group. Patient characteristics, intraocular pressure, and relevant comorbid conditions, as well as scales on depressive symptoms (nine-item Patient Health Questionnaire) and headache-specific psychosocial impairment (six-item Headache Impact Test) were recorded. Lastly, the role of different stimulus colors, as well as habituation effects after repeated stimulation, were investigated.

The main study included 174 participants (40 with MwA, 53 with MwoA, and 81 HCs). The duration of the afterimage in patients with MwA was significantly longer than in HCs, at a mean (standard error of the mean [SEM]) of 12.6 (2.6) versus 5.5 ( 0.3) s (p = 0.035), while there was no significant difference between patients with MwoA (mean [SEM] 7.7 [1.6] s; p = 0.510) and HCs. There was also no significant effect of stimulus color on afterimage latency (mean [SEM] red: 8.9 [1.2] s and black: 8.4 [1.2] s).

We found significantly longer afterimage duration in patients with MwA compared to both HCs and patients with MwoA. Furthermore, partially selective stimulation of retinal rods and cones by different stimulus colors had no effect on afterimage duration suggesting a relevant subcortical and/or cortical modulation in migraine aura with increased excitability.

BackgroundMigraine pathogenesis involves both central and peripheral mechanisms. Although calcitonin gene-related peptide monoclonal antibodies have shown efficacy over placebo in migraine prevention, a proportion of individuals with migraine may experience a substantial residual burden while on treatment. Transcranial direct current stimulation is a non-invasive neuromodulation technique that can target central migraine mechanisms and may therefore complement calcitonin gene-related peptide monoclonal antibodies. The present study aimed to assess the efficacy of transcranial direct current stimulation as an adjunctive treatment to calcitonin gene-related peptide monoclonal antibodies in migraine prevention and to investigate its neurophysiological effects.MethodsThis is a multicenter, randomized double-blind, sham-controlled, parallel-group trial including subjects with migraine on treatment with calcitonin gene-related peptide monoclonal antibodies for ≥90 days and with ≥8 monthly migraine days in the last 30 days. Subjects were randomized to active or sham transcranial direct current stimulation. The transcranial direct current stimulation protocol consisted of five daily 20-minute sessions of bilateral cathodal stimulation on the occipital area and anodal stimulation on the M1 area. High-density electroencephalographic recordings were performed before the first and after the last transcranial direct current stimulation session. The primary endpoint was the number of headache days during the 28-day follow-up period controlling for the 28-days baseline value. Secondary endpoints included the number of migraine days during the follow-up period, disability measures and electroencephalographic spectral power. The active and sham groups were compared using analysis of covariance. For clinical outcomes with significant differences between groups, we also ran paired t-tests comparing baseline and follow-up assessment within groups.ResultsThirty participants were randomized (15 to active and 15 to sham group). Headache days during the 28-day follow-up period did not differ significantly between groups (p = 0.560, ηp2 = 0.017). However, participants receiving active transcranial direct current stimulation reported fewer migraine days during follow-up compared to the sham group (p = 0.008, ηp2 = 0.241). Paired t-tests indicated that the active tDCS group reported a reduction in migraine days during the follow-up period compared to baseline (t = 2.557, p = 0.023, Cohen's d = 0.660), while no difference was found in the sham group. Referring to neurophysiological endpoints, active transcranial direct current stimulation induced a significant decrease in delta power at frontal regions compared to sham.ConclusionsThis randomized-controlled trial suggests that transcranial direct current stimulation is a promising potentially effective treatment that may give additional benefits to subjects with migraine who are already on prevention with calcitonin gene-related peptide monoclonal antibodies but who have a substantial residual migraien burden. Combination treatments need to be better explored to provide strategies to further improve benefits of migraine prevention.Trial Registration: NCT05161871 (clinicaltrials.gov).

The association between hypertension and migraine remains unclear.

The aim of this study employ multi-layered evidence chain that revealed the association between hypertension and migraine.

We first strictly included data from the NHANES 1999-2004 population and applied logistic regression, subgroup analysis and RCS to assess the correlation between hypertension, SBP, DBP and migraine. Meanwhile, LDSC and Mendelian randomization were conducted based on the GWAS to determine the causal relationship between hypertension and migraine. Inverse-variance weighted (IVW) was used as the primary method. Sensitivity analysis and Colocalization analysis were performed to confirm the robustness of the results. LDSC validated the genetic correlation between traits. Enrichment analysis revealed their underlying biological mechanisms.

After strict inclusion in NHANES, 10,743 participants were included. The logistic regression showed a significant correlation between hypertension (OR = 1.21 [95% CI, 1.08-1.36], FDR < 0.001)、DBP (OR = 1.01 [95% CI, 1.01-1.02], FDR < 0.001) and migraine. This association did not show significant group differences in subgroup. The MR results further supported the existence of a significant causal relationship between hypertension (OR = 1.77 [95% CI, 1.43-2.30], FDR < 0.001)、DBP (OR = 1.02 [95% CI, 1.01-1.03], FDR < 0.001) and migraine onset. Additionally, the RCS analysis showed a linear relationship (P non-linear = 0.897) between the two. The LDSC result showed a significant genetic correlation between the two (Rg = 0.1092, SE = 0.028, P < 0.001).

The development of migraine caused by hypertension is mainly realized through high DBP.

Headaches and transient neurological symptoms that bear resemblances to clinical manifestations of migraine, especially migraine with aura, are common among patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) or cysteine-altering NOTCH3 genetic variants. However, according to the International Classification of Headache Disorders, Third Edition (ICHD-3), these patients should be diagnosed as headache attributed to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) rather than migraine with or without aura. Although transient focal neurological symptoms are often labeled as migraine aura, these symptoms are often atypical and complicated, and could not easily conform to the criteria for migraine with aura. Besides, the association between migraine and CADASIL could not be supported by population-based genetic studies, and cysteine-altering NOTCH3 genetic variants are not more common among patients with migraine with or without aura compared with non-migraine controls. In addition, the underlying pathophysiology may be different between migraine and CADASIL. Although increased cortical spreading depression (CSD) susceptibility in mice harboring a human pathogenic Notch3 variant is often regarded as supportive evidence for the association, CSD could been seen in conditions other than migraine, such as cerebral ischemia. The role of calcitonin gene-related peptide (CGRP), one of the most important molecules in migraine pathophysiology, in CADASIL patients with migraine-like manifestations is yet to be determined. To sum up, there remain uncertainties whether headache and migraine aura-like manifestations in CADASIL correspond to "ordinary" migraine with or without aura seen in routine clinical practice. Therefore, we are still a number of steps from a firm conclusion about the association between CADASIL and migraine.

Cortical excitability, defined as the cortex's responsiveness to incoming stimuli, is a fundamental concept in neuroscience and a targetable mechanism for controlling brain dysfunctions such as epilepsy, as well as other neurological and psychiatric disorders. In this review, we delineate the boundaries between physiological and pathological excitability, highlighting recent theoretical, experimental, and translational advances relevant to human brain disorders. Specifically, we describe the dynamic regulation of cortical excitability and propose practical means to monitor its known fluctuations as to guide therapeutic interventions.

From a conceptual standpoint, the last decade of research on cortical excitability has benefited from dynamical systems theory, which studies the behavior of nonlinear systems (here, the cortex) and their resilience to perturbations in different conditions (here, variable excitability). We review how fundamental relationships between excitability and resilience were verified in the brain in a series of recent studies. We also review natural fluctuations in cortical excitability, and how these may open windows of vulnerability for the expression of cortical dysfunctions. We then turn to the practicalities of measuring and monitoring cortical excitability, a latent variable that must be actively probed.

Practical means for gauging cortical excitability likely have broad applicability. To enable new developments in clinical practice, a principled design of pharmacological and neurostimulation therapies must leverage current understanding of cortical dynamics.

Migraine with aura is a common neurological disorder. Cortical spreading depression is the hypothetical pathophysiologic correlate, but it has never been directly recorded during migraine in a human. A 32-year-old female with a history of migraine underwent a presurgical workup for comorbid epilepsy. While implanted for stereotactic electroencephalography with 94 electrode contacts across bilateral hemispheres, she experienced a typical migraine with aura. Stereotactic electroencephalography demonstrated low-voltage suppression starting in the left mesial occipital cortex and propagating anteriorly at 3 mm/min, clinically correlating with a contralateral right superior scintillating scotoma and ipsilateral headache. Intracranial stereotactic electroencephalographic recording demonstrated cortical spreading depression during migraine with aura. Our findings add to the body of evidence implicating cortical spreading depression in the pathophysiology of migraine with aura.

Recurrent and intense headache is a well appreciated cardinal feature of migraine, a common and incapacitating neurological disorder. Often, there are associated canonical sensory abnormalities, such as light and sound sensitivity, as well as associated nausea. Given this phenotype of disordered sensory processing and, in a third of patients, the phenomenon called aura accompanying migraine attacks, it has been suggested that the pathophysiology of migraine is likely to involve glutamate, the main excitatory neurotransmitter in the central nervous system (CNS). Glutamate plays a role in nociception, central sensitization, and cortical spreading depression (CSD), three processes that are deemed important in migraine biology. With an emphasis on the therapeutic potential of targeting various glutamate receptors in migraine, this review will discuss the currently available literature and emerging findings on the role of targeting glutamatergic pathways for the treatment of migraine. A thorough literature review was carried out on the functions of both metabotropic glutamate receptors (mGluRs), and the ionotropic glutamate receptors (NMDA, AMPA, and kainate) in migraine pathogenesis. The ever-present need for new treatments, the role of glutamate in the migraine aura phenomenon, and the consequences of monogenic migraine mutations on mediating prolonged, complex, or permanent aura are all discussed, culminating in a suggestion that glutamatergic targeting may hold particular promise in the management of migraine aura. There are plausible roles for metabotropic receptors in regulating pain processing in important migraine-related brain structures, like the thalamus and trigeminal nucleus. Similarly, ionotropic receptors contribute to excitatory neurotransmission and neuronal hyperexcitability. Recent studies have shown preclinical and early clinical results for treatments targeting these receptors, but there are still significant issues with treatment response, including drug transport, side effects, and efficacy. With ongoing and emerging discoveries in the field, there is increasing promise of new migraine medications targeting glutamate receptors. For bench to bedside translation in this area, continued study of the molecular basis of migraine, receptor subtypes, and exploration of potential drug delivery methods are needed.

Attention performance in chronic migraine remains unclear. The present study aimed to explore the pre-attentive detection and attention orienting ability in individuals with chronic migraine (CM) measured by mismatch negativity (MMN) and P3a components and assess their associations with migraine characteristics.

This cross-sectional observational study recruited 25 individuals with episodic migraine (EM), 25 individuals with CM and 25 healthy controls (HC) matched for age, sex, and educational level. The MMN and P3a components were measured using event-related potential (ERPs) tools with auditory oddball paradigms and migraine characteristics were collected.

Individuals with CM exhibited a longer MMN latency (p = 0.010) and a lower P3a amplitude than HC (p = 0.004) and EM (p = 0.002). Correlation analysis showed that P3a amplitude was negatively correlated with headache attack frequency and the Migraine Disability Assessment Scale (MIDAS), Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD) scores.

Individuals with CM showed deficits in pre-attentive detection and attention orientation. Moreover, attention-oriented dysfunction is associated with headache attack frequency, headache-related disability, anxiety and depression.

Migraine, with a prevalence of 14-15% in the world population, is one of the diseases that markedly reduce patients' quality of life. Despite extensive therapeutic tools, the search for substances that may have potential therapeutic properties in migraine patients is still ongoing. Coenzyme Q10 (CoQ10), as a natural and potent antioxidant, appears to be a valuable adjunct in treating and preventing many conditions, such as cardiovascular, metabolic, autoimmune, or neurodegenerative diseases. This review aims to evaluate if CoQ10 can be a potential therapeutic agent in the treatment of migraine. Based on the studies discussed, CoQ10 may have applications in migraine therapy due to its potent anti-inflammatory and oxidative stress-reducing properties. Furthermore, by improving mitochondrial function, CoQ10 can contribute to the energy supply to brain cells, which is particularly important in migraine. Supplementation with CoQ10 in a wide range of doses has resulted in many therapeutic benefits in subjects, including a decrease in the frequency and duration of migraine attacks, a reduction in nausea, a lower maximum pain during an attack, and fewer days with migraine. Therefore, it seems that CoQ10 may be a relevant therapeutic supplement for the treatment and prevention of migraine.

Background/Objectives: Pediatric migraine is a prevalent neurological disorder that significantly impacts children's quality of life, academic performance, and social interactions. Unlike migraines in adults, pediatric migraines often present differently and involve unique underlying mechanisms, making diagnosis and treatment more complex. Methods: This review discusses the clinical phases of pediatric migraine, key trigger factors, sex- and age-related differences, and the role of childhood maltreatment in migraine development. We also discuss episodic syndromes such as cyclic vomiting syndrome, abdominal migraine, benign paroxysmal vertigo, and benign paroxysmal torticollis, along with comorbidities such as psychiatric disorders, sleep disturbances, and epilepsy. Results: The underlying pathophysiological mechanisms for pediatric migraines, including genetic predispositions, neuroinflammation, and gut microbiota dysbiosis, are summarized. Current therapeutic strategies, including conventional and emerging pharmacological treatments, nutraceuticals, and non-pharmacological approaches, are evaluated. Non-pharmacological strategies, particularly evidence-based lifestyle interventions such as stress management, diet, hydration, sleep, exercise, screen time moderation, and cognitive behavioral therapy, are highlighted as key components of migraine prevention and management. The long-term prognosis and follow-up of pediatric migraine patients are reviewed, emphasizing the importance of early diagnosis, and tailored multidisciplinary care to prevent chronic progression. Conclusions: Future research should focus on novel therapeutic targets and integrating gut-brain axis modulation, with a need for longitudinal studies to better understand the long-term course of pediatric migraine.

Migraine patients often experience sensory symptoms called auras accompanying the headaches. Cortical spreading depression (CSD), a slow-propagating wave of neuroglial depolarization followed by hyperpolarization is proposed to be the neurological mechanism underlying these auras. We have previously found that progesterone regulates susceptibility to migraine through progesterone receptor (PR) activation. Here, we determined if PR signaling also regulates susceptibility to CSD. We used gonadally-intact and ovariectomized, estrogen-primed female mice expressing PRs or lacking them in the brain. CSDs were induced with dural application of KCl (1 M) and recorded using saline-filled glass electrodes placed in the cortex. PRs were modulated using agonist segesterone and antagonist RU-486. PR expression in the somatosensory cortex was evaluated using mice expressing a cre recombinase under the control of Pgr promoter, stereotaxically injected with adeno-associated virus (AAV) serotype 9 encoding flexed GFP. PR expression in excitatory or inhibitory neurons and distinctions in the cortical layer-specific expression were determined. The effect of chemogenetic silencing of PR-expressing somatosensory cortical neurons on CSD susceptibility was also evaluated using AAV9 expressing cre-driven hM4Di. PRs were expressed in the excitatory neurons of the somatosensory cortex. Their expression was stronger in layer 4-6 cortical neurons than in layer 2/3 neurons. PR activation increased CSD frequency and accelerated their propagation speed. In contrast, PR antagonism or their genetic deletion suppressed CSDs. Chemogenetic silencing of PR-expressing somatosensory cortical neurons also reduced the CSD frequency. These findings demonstrate the critical role of progesterone-PR signaling in regulating CSD and enhance our understanding of female hormonal regulation of migraine pathophysiological mechanisms.

Prosopagnosia is a neurological phenotype, characterized by the inability to recognize faces, typically resulting from damage or dysfunction in specific brain regions such as the fusiform gyrus. In contrast, migraine is a disease process, a complex neurological disorder with a range of symptoms including severe headache and visual disturbances.

The brain regions involved in migraine and prosopagnosia are located in close proximity to each other, and perhaps as an unsurprising yet rarely reported result of this, there have been several cases of migraineurs, the majority presenting with aura, who manifested prosopagnosia as a symptom during an attack. While rarely reported, the fact that prosopagnosia can occasionally manifest during migraine episodes, particularly during the aura phase, emphasizes the importance of exploring the cortical processes involved in both conditions. This review discusses migraine and prosopagnosia in the context of comorbidity, explores and summarizes current and key historical knowledge on the reported occurrences of prosopagnosia manifesting as a symptom of migraine, and emphasizes the importance of reporting this phenomenon.

While the etiopathology of Parkinson's disease (PD) is complex, mitochondrial dysfunction is established to have a central role. Thus, mitochondria have emerged as targets of therapeutic interventions aiming to slow or modify PD progression. We have previously identified serotonergic 5-HT1F receptors as novel mediators of mitochondrial biogenesis (MB) - the process of producing new mitochondria. Given this, here, we assessed the therapeutic potential of the FDA-approved 5-HT1F receptor agonist, lasmiditan, in a chronic progressive PD model (Thy1-aSyn 'line 61' mice). It was observed that systemic lasmiditan exhibited robust brain penetration and reversed cognitive deficits in young (4-5.5 months old) Thy1-aSyn mice (1mg/kg, every other day). Anxiety-like behavior was also improved while motor function remained unaffected. These behavioral changes were associated with enhanced MB and mitochondrial function, paired with reduced alpha-synuclein aggregation particularly in cortico-hippocampal regions. Furthermore, in older (10-11.5 months old) mice, although the effects were milder, daily lasmiditan administration increased MB and bettered cognitive abilities. In essence, these findings indicate that repurposing lasmiditan could be a potent strategy to address PD-related cognitive decline.

The role of the cerebrovascular system in migraine pathogenesis is critical. Several studies have demonstrated alterations in the regional cerebral blood flow that persist during headache-free intervals. In the present study, we aimed to measure the prefrontal hemodynamic responses to the cognitive task in interictal episodic migraineurs. We enrolled eight migraine patients with aura (mean age 25.75 ± 4.39 years), twelve migraine patients without aura (mean age 28.25 ± 6.59 years), and eleven age- and education-matched healthy subjects. We employed the Victoria Stroop task to assess executive functions, specifically selective attention and inhibitory control. The mean changes in the oxy-Hb, deoxy-Hb and total Hb concentrations during the Stroop interference (incongruent minus neutral) were recorded by functional near-infrared spectroscopy (fNIRS). Our preliminary results indicated that migraine patients with aura had higher reaction time (p = 0.033) and lower prefrontal oxy-Hb activity (p = 0.036) during the Stroop interference compared to healthy subjects. For the left lateral prefrontal cortex, migraine with aura group showed lower oxy-Hb activity than the healthy subjects during the Stroop interference (p = 0.009). However, there were no such differences in the right lateral prefrontal cortex. Additionally, we found a relationship between prefrontal oxygenation and the severity of headaches, the frequency of attacks, and the number of monthly migraine days. We noticed a decrease in prefrontal blood flow in migraine patients with aura, even during the interictal periods. This may indicate that migraine with aura could be a persistent neurovascular uncoupling disorder. Moreover, the reduced oxygen supply to the prefrontal cortex may be associated with impaired frontal lobe functions.

Understanding the neural mechanisms underlying migraine and other primary headache disorders is critical for the development of long-term cures. Magnetoencephalography (MEG), an imaging modality that measures neuronal currents and cortical excitability with high temporal and superior spatial resolution, has been increasingly used in neurological research. Initial MEG studies showed promise in directly recording cortical spreading depression-a cortical correlate of migraine with aura. However, lately MEG technology has highly evolved with greater potential to reveal underlying pathophysiology of migraine and primary headache disorders, and aid in the identification of biomarkers.

To systematically review the use of MEG in migraine and other primary headache disorders and summarize findings.

We conducted a systematic search and selection of MEG studies in migraine and primary headache disorders from inception until June 8, 2023, in Medline, Embase, Cochrane, and Scopus databases. Peer-reviewed English articles reporting the use of MEG for clinical or research purposes in migraine and primary headache disorders were selected.

We found 560 articles and included 38 in this review after screening. Twelve studies investigated resting-state, while others investigated a sensory modality using an evoked or event-related paradigm with a total of 35 cohort and 3 case studies. Thirty-two studies focused exclusively on migraine, while the rest reported other primary headache disorders.

The findings show an evolution of MEG from a 7- to a 306-channel system and analysis evolving from sensor-level evoked responses to more advanced source-level connectivity measures. A relatively few MEG studies portrayed migraine and primary headache disorders as a sensory abnormality, especially of the visual system. We found heterogeneity in the datasets, data reporting standards (due to constantly evolving MEG technology and analysis methods), and patient characteristics. Studies were inadequately powered and there was no evidence of blinding procedures to avoid selection bias in case-control studies, which could have led to false-positive findings. More studies are needed to investigate the affective-cognitive aspects that exacerbate pain and disability in migraine and primary headache disorders.

Although numerous studies have identified associations between socioeconomic, behavioral, dietary, and physical factors and migraine, the causal nature of these relationships has yet to be adequately established.

We utilized 2-sample Mendelian randomization (MR) to elucidate the causal associations of 28 distinct traits for socioeconomic factors, behavioral factors, dietary factors, and physical measurement with migraine. In the univariable MR analysis, the inverse-variance weighted method served as the primary analytic approach. Robustness checks included the Cochran Q test, Egger intercept test, and leave-one-out analysis. A multivariable MR analysis framework was utilized to assess the direct causal impacts of these traits on migraine risk.

The univariable MR analysis analysis revealed that genetic predispositions to higher coffee intake (Odds Ratio (OR) = 0.547; 95% CI = 0.359-0.834; P = 0.005), greater oily fish intake (OR = 0.556; 95% CI = 0.394-0.785; P = 0.001), and higher educational attainment (OR = 0.916; 95% CI = 0.884-0.949; P < 0.001) were associated with reduced migraine risk. In contrast, predispositions to higher poultry intake (OR = 4.690; 95% CI = 1.377-15.977; P = 0.013) and longer mobile phone use (OR = 1.526; 95% CI = 1.080-2.157; P = 0.017) correlated with increased risk. These associations remained consistent in the multivariable MR analysis after adjusting for stroke and particulate matter air pollution.

Our study robustly supports the significant causal roles of specific socioeconomic, behavioral, and dietary factors with physical measurement in the development of migraine. Notably, coffee intake, oily fish intake, and educational attainment appear protective, whereas poultry intake and extensive mobile phone use elevate risk. These insights pave the way for developing targeted preventive strategies for migraine.

Migraine is a complex disorder, and its etiology is not yet fully understood. In the last 40 years, calcitonin gene-related peptide (CGRP) has been central to the understanding of migraine pathophysiology, leading to the development of new molecules targeting the CGRPergic system. These new molecules, such as gepants and monoclonal antibodies, are effective, well-tolerated, and safe, and are approved for clinical use.

By searching multiple electronic scientific databases, this narrative review examined: (i) the role of CGRP in migraine; and (ii) the current knowledge on the effects of CGRPergic antimigraine pharmacotherapies, including a brief analysis of their pharmacodynamic and pharmacokinetic characteristics.

Current anti-CGRPergic medications, although effective, have limitations, such as side effects and lack of antimigraine efficacy in some patients. The existence of patients with medication-resistant migraine may be due to the: (i) complex migraine pathophysiology, in which several systems appear to be deregulated before, during, and after a migraine attack; and (ii) pharmacodynamic and pharmacokinetic properties of antimigraine medications. As envisioned here, although seminal studies support the notion that CGRP plays a key role in migraine headache, the dysfunction of CGRPergic transmission does not seem to be relevant in all cases.

In recent decades, cranial and cervical vascular disorders have become major global health concerns, significantly impacting patients, families, and societies. Headache is a prevalent symptom of these vascular diseases and can often be the initial, primary, or sole manifestation. The intricate relationship between headaches and cranial/cervical vascular disorders poses a diagnostic and therapeutic challenge, with the underlying mechanisms remaining largely elusive. Understanding this association is crucial for the early diagnosis, prevention, and intervention of such conditions. This review aims to provide a comprehensive overview of the clinical features and potential pathogenesis of headaches attributed to cranial and cervical vascular disorders and provide a reference for disease management and a basis for potential pathological mechanisms.

Background/Objectives: Research on calcitonin-gene-related peptide (CGRP) in adult migraine is extensive, but its role in childhood migraine remains unclear. This study aimed to evaluate serum CGRP levels in children experiencing migraine and tension-type headache (TTH) during interictal periods, comparing these levels to age-matched healthy controls. Methods: A total of 66 migraine patients, 59 with TTH, and 53 controls were recruited and stratified by headache onset age: under 7, 7-12, and over 12 years. CGRP levels were quantified using enzyme-linked immunosorbent assay (ELISA). Results: The migraine patients showed significantly higher serum CGRP levels than both the TTH patients and the controls (p < 0.001), with no significant difference between the latter two groups. Among the migraine patients, those without aura (MO) exhibited higher CGRP levels than those with aura (MA). The CGRP levels were lower in the. MA patients whose headaches began between ages 7 and 12 compared to the subjects with MO, while no significant differences were found in the patients whose headaches began after age 12. Conclusions: These findings suggest that elevated serum CGRP is indicative of pediatric migraine, with variations based on migraine type and age of onset. The difference in CGRP in preadolescent migraineurs with and without aura suggest that CGRP levels may vary depending on age and on migraine type.

The neurovascular theory is thought to be one of the main pathological mechanisms of migraine. Locus coeruleus (LC) is a major node in the neurovascular pathway. Exploring the functional network characteristics of LC in migraine without aura (MwoA) patients can help us gain insight into the underlying neural mechanisms in MwoA patients.

In this study, we used resting-state functional magnetic resonance imaging (rsfMRI) and a functional connectivity (FC) approach to explore the functional characteristics of LC in MwoA patients. 17 healthy controls (HCs) and 28 MwoA patients were included in the study. FC was calculated based on rsfMRI data collected by a 3T MRI scanner. General linear model were used to compare whether there were differences in LC brain networks between the two groups. We also utilized logistic regression to explore the role of LC functional networks in the clinical diagnosis of MwoA.

After general linear analysis, MwoA patients displayed increased FC from right LC to the left lingual and calcarine sulcus, as well as to the right frontal medial gyrus/orbit part, when compared with HCs. The results of the logistic regression showed that the LC FC signals were 81% accurate in distinguishing MwoA from the HCs.

Our results demonstrated that patients with MwoA exhibited significant LC FC differences in the brain areas associated with visual and cognitive function. Understanding the changes in the LC brain network in MwoA patients can provide us with new ideas to understand the pathological mechanisms of MwoA.

Migraine is a common disabling conditions which, globally, affects 15.2% of the population. It is the second cause of health loss in terms of years lived with disability, the first among women. Despite being so common, it is poorly recognised and too often undertreated. Specialty centres and neurologists with specific expertise on headache disorders have the knowledge to provide specific care: however, those who do not regularly treat patients with migraine will benefit from a synopsis on the most relevant and updated information about this condition. This paper presents a comprehensive view on the hallmarks of migraine, from genetics and diagnostic markers, up to treatments and societal impact, and reports the elements that identify migraine specific features.

The most relevant hallmark of migraine is that it has common and individual features together. Besides the known clinical manifestations, migraine presentation is heterogeneous with regard to frequency of attacks, presence of aura, response to therapy, associated comorbidities or other symptoms, which likely reflect migraine heterogeneous genetic and molecular basis. The amount of therapies for acute and for prophylactic treatment is really wide, and one of the difficulties is with finding the best treatment for the single patient. In addition to this, patients carry out different daily life activities, and might show lifestyle habits which are not entirely adequate to manage migraine day by day. Education will be more and more important as a strategy of brain health promotion, because this will enable reducing the amount of subjects needing specialty care, thus leaving it to those who require it in reason of refractory condition or presence of comorbidities.

Recognizing the hallmarks of migraine and the features of single patients enables prescribing specific pharmacological and non-pharmacological treatments. Medical research on headaches today particularly suffers from the syndrome of single-disease approach, but it is important to have a cross-sectional and joint vision with other close specialties, in order to treat our patients with a comprehensive approach that a heterogeneous condition like migraine requires.

Migraine is a prevalent neurological disorder, particularly among individuals aged 20-50 years, with significant social and economic impacts. Despite its high prevalence, the pathogenesis of migraine remains unclear. In this review, we provide a comprehensive overview of cortical spreading depolarization/depression (CSD) and its close association with migraine aura, focusing on its role in understanding migraine pathogenesis and therapeutic interventions. We discuss historical studies that have demonstrated the role of CSD in the visual phenomenon of migraine aura, along with modern imaging techniques confirming its propagation across the occipital cortex. Animal studies are examined to indicate that CSD is not exclusive to migraines; it also occurs in other neurological conditions. At the cellular level, we review how CSD is characterized by ionic changes and excitotoxicity, leading to neuronal and glial responses. We explore how CSD activates the trigeminal nervous system and upregulates the expression of calcitonin gene-related peptides (CGRP), thereby contributing to migraine pain. Factors such as genetics, obesity, and environmental conditions that influence the CSD threshold are discussed, suggesting potential therapeutic targets. Current treatments for migraine, including prophylactic agents and CGRP-targeting drugs, are evaluated in the context of their expected effects on suppressing CSD activity. Additionally, we highlight emerging therapies such as intranasal insulin-like growth factor 1 and vagus nerve stimulation, which have shown promise in reducing CSD susceptibility and frequency. By elucidating the molecular and cellular mechanisms of CSD, this review aims to enhance the understanding of migraine pathogenesis and support the development of targeted therapeutic strategies.

Cortical spreading depression (CSD) is an electrophysiologic pathological state in which a wave of depolarization in the cerebral cortex is followed by the suppression of spontaneous neuronal activity. This transient spread of neuronal depolarization on the surface of the cortex is the hallmark of CSD. Numerous investigations have demonstrated that transmembrane ion transport, astrocytic ion clearing and fatigue, glucose metabolism, the presence of certain genetic markers, point mutations, and the expression of the enzyme responsible for the production of various arachidonic acid derivatives that participate in the inflammatory response, namely, cyclooxygenase (COX), all influence CSD. Here, we explore the associations between CSD occurrence in the cortex and various factors, including how CSD is related to migraines, how the glucose state affects CSD, the effect of TBI and its relationship with CSD and glucose metabolism, how different markers can be measured to determine the severity of CSD, and possible connections to oligemia, orexin, and leptin.

The study's objective was to evaluate the functioning of sacculocollic and vestibulomasseteric reflex pathways in individuals with vestibular migraine and migraine.

Seventy-five participants aged 18-50 years were selected for the study. Participants were divided into three groups. Group 1 consisted of 25 healthy individuals, Group 2 consisted of 25 migraine individuals, and Group 3 consisted of 25 individuals with vestibular migraine. Cervical vestibular-evoked myogenic potential (cVEMP) and masseter vestibular-evoked myogenic potential (mVEMP) were recorded using a 500-Hz tone burst stimulus presented at 125 dB peSPL for all participants.

The cVEMP test results showed a delayed p13 and n23 latency for both migraine and vestibular migraine individuals when compared to healthy individuals. Also, the amplitude of the p13-n23 peak was reduced compared to healthy individuals in both migraine and vestibular migraine. Similarly, the mVEMP test results showed a delayed p11 and n21 latency for both migraine and vestibular migraine individuals. No difference was observed in the amplitude of the p11-n21 peak complex between the three groups. Spearman's rho correlation revealed no significant (p > .05) correlation between cervical and masseter VEMP latency and amplitude parameters between healthy, migraine, and vestibular migraine individuals.

The results of the study are suggestive of the pathology of the sacullocollic and vestibulomasseteric reflex pathways in individuals with migraine and vestibular migraine. Individuals with migraine and vestibular migraine should undergo a detailed vestibular evaluation.

Cortical spreading depolarization is one possible pathogenesis of migraine, of which slow neurophysiological change is barely recorded in conventional EEG settings. Using wide-band EEG conditions, we reappraised the features of EEG in migraineurs, including subdelta-band EEG changes.

This retrospective study included 144 patients with migraine. We delineated EEG of focal delta slow (FDS) (1-4 Hz) by time constant (TC) 0.3 s and focal subdelta slow (FSDS) (< 1 Hz) by TC 2 s. Relationships between clinical variables and EEG findings were evaluated.

Of 144 patients, 39 had aura and 105 did not. FSDS and FDS were observed in 38 and 58 patients, respectively. No EEG was recorded during the aura. In multivariate analysis with the phase of migraine, family history, age, and percentage of sleep during EEG recording, the phase of migraine was related to the occurrence of FSDS (postdrome vs interictal, prodrome, and headache respectively (OR = 49.00 [95% CI = 3.89-616.66], 46.28 [2.99-715.78], 32.79 [2.23-481.96], p = 0.0026, 0.0061, 0.011). FDS was clinically unremarkable for differential evaluation.

Wide-band EEG abnormality in migraineurs, i.e., FSDS, can be affected by migraine phase.

Wide-band EEG finding could be a biomarker related to clinical variables in migraines.

One characteristic of migraine is recurrent headache attacks, which are known to be induced by changes in climatic variables such as atmospheric pressure, humidity, and outside temperature. However, the relationship between temperature changes and migraine remains unclear. Therefore, we investigated the relationship between body temperature changes and cortical spreading depression (CSD) using KCl-induced rat models of CSD. We initially induced CSD under controlled conditions at a room temperature of 28°C on an operating table maintained at 37°C. Subsequently, we controlled the operating table temperature to induce a second round of CSD under conditions of either a 10 ± 1% increase or decrease in body temperature. We ensured 1 h rest period between the first and second inductions of CSD. The results indicated that the number of CSDs significantly increased after body temperature elevation (before, 8.8 ± 1.2 times vs. after, 13.4 ± 1.3 times; p = 0.0003). The mean percentage change in cerebral blood flow decreased after body temperature increased (before, 33.1 ± 2.4% vs. after, 18.2 ± 1.4%; p = 0.006). There were no significant changes in CSD after body temperature decreased. The susceptibility of the cortex to CSD may increase under conditions of elevated body temperature.

To examine the unique role of migraine aura in predicting day-to-day levels of headache-related disability.

Migraine symptoms and psychological variables contribute to headache-related disability. Migraine aura may be associated with more severe symptom profiles and increased risk of psychiatric comorbidities, but the impact of aura on daily functioning is unknown. The present study sought to evaluate the role of migraine aura in predicting same-day and subsequent-day migraine-related disability while accounting for demographic, headache, and psychological variables.

This was an observational prospective cohort study among 554 adults with migraine. For each participant, data on migraine symptoms and psychological variables were collected daily for 90 days using the N-1 Headache™ digital app (N = 11,156 total migraine days). Analyses assessed whether the presence of aura predicted daily ratings of migraine-related disability independently of other headache and psychological variables. Given the number of predictors examined, statistical significance was set at p < 0.01.

The mean (standard deviation, range) patient-level Migraine Disability Assessment questionnaire score across days of the migraine episode was 1.18 (1.03, 0-3). Aura was significantly associated with higher disability ratings on all days of the migraine episode (odds ratio [OR] 1.40, 99% confidence interval [CI] 1.13-1.74; p < 0.001). This relationship remained unchanged after adjusting for patient-level variables (OR 1.40, 99% CI 1.13-1.73; p < 0.001) and day-level psychological variables (OR 1.39, 99% CI 1.12-1.73; p < 0.001) but was fully negated after controlling for day-level headache variables (OR 1.19, 99% CI 0.95-1.49; p = 0.039). Aura on the first day of the episode was associated with increased odds of allodynia (OR 1.87, 99% CI 1.22-2.86; p < 0.001), phonophobia (OR 1.62, 99% CI 1.17-2.25; p < 0.001), photophobia (OR 1.89, 99% CI 1.37-2.59; p < 0.001), and nausea/vomiting (OR 1.54, 99% CI 1.17-2.02; p < 0.001) on all days of the episode, but not episode duration (p = 0.171), peak severity (p = 0.098), or any examined psychological variables (sleep duration [p = 0.733], sleep quality [p = 0.186], stress [p = 0.110], anxiety [p = 0.102], or sadness [p = 0.743]).

The presence of aura is predictive of increased headache-related disability during migraine episodes, but this effect is attributable to associated non-pain symptoms of migraine.

Stress is one of the most common precipitating factors in migraine and is identified as a trigger in nearly 70% of patients. Responses to stress include release of glucocorticoids as an adaptive mechanism, but this may also contribute to migraine attacks. Here, we investigated the role of glucocorticoids on stress-induced migraine-like behaviors.

We have shown previously that repeated stress in mice evokes migraine-like behavioral responses and priming to a nitric oxide donor. Metyrapone, mifepristone, and corticosterone (CORT) were used to investigate whether CORT contributes to the stress-induced effects. Facial mechanical hypersensitivity was evaluated by von Frey testing and grimace scoring assessed the presence of non-evoked pain. We also measured serum CORT levels in control, stress, and daily CORT injected groups of both male and female mice.

Metyrapone blocked stress-induced responses and priming in male and female mice. However, repeated CORT injections in the absence of stress only led to migraine-like behaviors in females. Both female and male mice showed similar patterns of serum CORT in response to stress or exogenous administration. Finally, administration of mifepristone, the glucocorticoid receptor antagonist, prior to each stress session blocked stress-induced behavioral responses in male and female mice.

These findings demonstrate that while CORT synthesis and receptor activation is necessary for the behavioral responses triggered by repeated stress, it is only sufficient in females. Better understanding of how glucocorticoids contribute to migraine may lead to new therapeutic opportunities.

Head MRI images of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients during migraine attacks are rare.

Migraine is a neurological disorder characterized by episodes of severe headache. Cortical spreading depression (CSD), the electrophysiological equivalent of migraine aura, results in opening of pannexin 1 megachannels that release ATP and triggers parenchymal neuroinflammatory signaling cascade in the cortex. Migraine symptoms suggesting subcortical dysfunction bring subcortical spread of CSD under the light. Here, we investigated the role of purinergic P2X7 receptors on the subcortical spread of CSD and its consequent neuroinflammation using a potent and selective P2X7R antagonist, JNJ-47965567. P2X7R antagonism had no effect on the CSD threshold and characteristics but increased the latency to hypothalamic voltage deflection following CSD suggesting that ATP acts as a mediator in the subcortical spread. P2X7R antagonism also prevented cortical and subcortical neuronal activation following CSD, revealed by bilateral decrease in c-fos positive neuron count, and halted CSD-induced neuroinflammation revealed by decreased neuronal HMGB1 release and decreased nuclear translocation of NF-kappa B-p65 in astrocytes. In conclusion, our data suggest that P2X7R plays a role in CSD-induced neuroinflammation, subcortical spread of CSD and CSD-induced neuronal activation hence can be a potential target.

Migraine is a complex disorder characterized by episodes of moderate-to-severe, often unilateral headaches and generally accompanied by nausea, vomiting, and increased sensitivity to light (photophobia), sound (phonophobia), and smell (hyperosmia). Photophobia is considered the most bothersome symptom of migraine attacks. Although the underlying mechanism remains unclear, the intrinsically photosensitive retinal ganglion cells (ipRGCs) are considered to be involved in photophobia associated with migraine. In this study, we investigated the association between the sensitivity of ipRGCs and migraines and cortical spreading depression (CSD), which may trigger migraine attacks. The pupillary responses closely associated with the function of ipRGCs in patients with migraine who were irradiated with lights were evaluated. Blue (486 nm) light irradiation elicited a response from ipRGCs; however, red light (560 nm) had no such effect. Melanopsin, a photosensitive protein, phototransduces in ipRGCs following blue light stimulation. Hypersensitivity of ipRGCs was observed in patients with migraine. CSD was more easily induced with blue light than with incandescent light using a mouse CSD model. Moreover, CSD was suppressed, even in the presence of blue light, after injecting opsinamide, a melanopsin inhibitor. The hypersensitivity of ipRGCs in patients with migraine may induce CSD, resulting in migraine attacks.

Migraine has been associated with functional brain changes including altered connectivity and activity both during and between headache attacks. Recent studies established that the variability of the blood-oxygen-level-dependent (BOLD) signal is an important attribute of brain activity, which has so far been understudied in migraine. In this study, we investigate how time-varying measures of BOLD variability change interictally in episodic migraine patients.

Two independent resting state functional MRI datasets acquired on 3T (discovery cohort) and 1.5T MRI scanners (replication cohort) including 99 episodic migraine patients (n3T = 42, n1.5T=57) and 78 healthy controls (n3T = 46, n1.5T=32) were analyzed in this cross-sectional study. A framework using time-varying measures of BOLD variability was applied to derive BOLD variability states. Descriptors of BOLD variability states such as dwell time and fractional occupancy were calculated, then compared between migraine patients and healthy controls using Mann-Whitney U-tests. Spearman's rank correlation was calculated to test associations with clinical parameters.

Resting-state activity was characterized by states of high and low BOLD signal variability. Migraine patients in the discovery cohort spent more time in the low variability state (mean dwell time: p = 0.014, median dwell time: p = 0.022, maximum dwell time: p = 0.013, fractional occupancy: p = 0.013) and less time in the high variability state (mean dwell time: p = 0.021, median dwell time: p = 0.021, maximum dwell time: p = 0.025, fractional occupancy: p = 0.013). Higher uptime of the low variability state was associated with greater disability as measured by MIDAS scores (maximum dwell time: R = 0.45, p = 0.007; fractional occupancy: R = 0.36, p = 0.035). Similar results were observed in the replication cohort.

Episodic migraine patients spend more time in a state of low BOLD variability during rest in headache-free periods, which is associated with greater disability. BOLD variability states show potential as a replicable functional imaging marker in episodic migraine.

New daily persistent headache (NDPH) is a rare primary headache with unclear pathogenesis. Neuroimaging studies of NDPH are limited, and controversy still exists. Diffusion tensor imaging (DTI) is commonly used to study the white matter. However, lacking specificity, the potential pathological mechanisms of white matter microstructural changes remain poorly understood. In addition, the intricacy of gray matter structures impedes the application of the DTI model. Here, we applied an advanced diffusion model of neurite orientation dispersion and density imaging (NODDI) to study the white matter and cortical gray matter microstructure in patients with NDPH.

This study assessed brain microstructure, including 27 patients with NDPH, and matched 28 healthy controls (HCs) by NODDI. The differences between the two groups were assessed by tract-based spatial statistics (TBSS) and surface-based analysis (SBA), focusing on the NODDI metrics (neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF)). Furthermore, we performed Pearson's correlation analysis between the NODDI indicators and clinical characteristics.

Compared to HCs, patients with NDPH had a reduction of density and complexity in several fiber tracts. For robust results, the fiber tracts were defined as comprising more than 100 voxels, including bilateral inferior fronto-occipital fasciculus (IFOF), left superior longitudinal fasciculus (SLF) and inferior longitudinal fasciculus (ILF), as well as right corticospinal tract (CST). Moreover, the reduction of neurite density was uncovered in the left superior and middle frontal cortex, left precentral cortex, and right lateral orbitofrontal cortex and insula. There was no correlation between the NODDI metrics of these brain regions and clinical variables or scales of relevance after the Bonferroni correction.

Our research indicated that neurite loss was detected in both white matter and cortical gray matter of patients with NDPH.

Migraine affects ∼12 % of the worldwide population and is more prevalent in females, which suggests a role of sex hormones in migraine pathophysiology. Most studies have focused on estrogen and progesterone, and the involvement of androgens has been less studied. However, due to the recent advances in androgen interventions, which could advance new androgen-based migraine treatments, it is critical to better understand the role of androgens in migraine. Testosterone, the most studied androgen, was found to have an antinociceptive effect in various animal and human pain studies. Thus, it could also have a protective effect related to lower migraine severity and prevalence. In this review, we discuss studies examining the role of androgens on migraine-related symptoms in migraine animal models. Additionally, we summarize the results of human studies comparing androgen levels between patients with migraine and healthy controls, studies assessing the relationships between androgen levels and migraine severity, and intervention studies examining the impact of testosterone treatment on migraine severity. Many of the studies have limitations, however, the results suggest that androgens may have a minor effect on migraine. Still, it is possible that androgens are involved in migraine pathophysiology in a sub-group of patients such as in adolescents or postmenopausal women. We discuss potential mechanisms in which testosterone, as the main androgen tested, can impact migraine. These mechanisms range from the cellular level to systems and behavior and include the effect of testosterone on sensory neurons, the immune and vascular systems, the stress response, brain function, and mood. Lastly, we suggest future directions to advance this line of research.

Although the relationship between migraine and multiple sclerosis (MS) has been reported, the risk of migraine in MS and neuromyelitis optica spectrum disorder (NMOSD) is unclear. Therefore, this study investigated the risk of migraine in the Korean MS and NMOSD populations.

This study analyzed claims data from 1,492 patients with MS and 1,551 patients with NMOSD based on diagnostic codes in the Korean National Health Insurance Service. Migraine risk was compared with a control group (matched 1:5 for age, sex, and comorbidities) using Cox proportional hazards analysis. Patients aged <20 years and with previous migraine were excluded.

Migraine risk was higher in patients with MS (adjusted hazard ratio [aHR] 1.37; 95% confidence interval [CI]: 1.15-1.62) but did not differ significantly in patients with NMOSD (aHR 1.05; 95% CI: 0.87-1.27) compared to controls. No significant sex-based differences in migraine risk were observed. Patients with NMOSD showed decreasing risk with age (p for interaction = 0.040). Comorbidities like hypertension, diabetes, or dyslipidemia did not significantly alter migraine risk in either group.

The study results revealed an increased risk of migraines in patients with MS but not in patients with NMSOD compared with matched controls.

Migraine, as a prevalent neurologic disorder, involves intricate and yet incompletely elucidated pathophysiological mechanisms. A plethora of research findings underscores the pivotal role played by astrocytes in the progression of migraines. In order to elucidate the current advances and directions in research pertaining to astrocytes in migraines, we conducted bibliometric analysis of relevant literature and visualized the results. Subsequently, we expound upon these findings to contribute to the evolving understanding of the role of astrocytes in migraine pathophysiology.

On November 21, 2023, we conducted a search on Web of Science (WOS), restricting the document type to articles or reviews and language to English. Following a meticulous selection process involving three researchers, we identified the literature to be included in our analysis. Subsequently, we employed Microsoft Office Excel programs, R, VOSviewer, Scimago Graphica, and CiteSpace software to conduct visualization analysis of basic information and trends regarding journals, countries/regions, and influential authors, institutions, keywords, and papers.

As of November 21, 2023, relevant literature has been published in 71 journals across 27 countries/regions. This corpus comprises contributions from 576 authors affiliated with 220 institutions, encompassing 865 keywords and referencing 6065 scholarly articles. CEPHALALGIA stands out as the most influential journal in this field, while authors PIETROBON D and DALKARA T have significant impact. The United States is highly influential, with CNR and UNIV PADUA emerging as highly influential institutions. The predominant category is Neurosciences.

Future investigators may continue to focus on migraines with aura, familial hemiplegic migraine (FHM), and the crucial calcitonin gene-related peptide (CGRP) system. Employing advanced observational techniques, such as imaging, researchers should pay attention to cellular and tissue structures, such as microglia and the trigeminal ganglion, as well as mechanisms involving inflammation and central sensitization. Moreover, animal models are paramount in obtaining high-quality evidence.

Migraine, as a prevalent neurologic disorder, involves intricate and yet incompletely elucidated pathophysiological mechanisms. A plethora of research findings underscores the pivotal role played by astrocytes in the progression of migraines. In order to elucidate the current advances and directions in research pertaining to astrocytes in migraines, we conducted bibliometric analysis of relevant literature and visualized the results. Subsequently, we expound upon these findings to contribute to the evolving understanding of the role of astrocytes in migraine pathophysiology.

On November 21, 2023, we conducted a search on Web of Science (WOS), restricting the document type to articles or reviews and language to English. Following a meticulous selection process involving three researchers, we identified the literature to be included in our analysis. Subsequently, we employed Microsoft Office Excel programs, R, VOSviewer, Scimago Graphica, and CiteSpace software to conduct visualization analysis of basic information and trends regarding journals, countries/regions, and influential authors, institutions, keywords, and papers.

As of November 21, 2023, relevant literature has been published in 71 journals across 27 countries/regions. This corpus comprises contributions from 576 authors affiliated with 220 institutions, encompassing 865 keywords and referencing 6065 scholarly articles. CEPHALALGIA stands out as the most influential journal in this field, while authors PIETROBON D and DALKARA T have significant impact. The United States is highly influential, with CNR and UNIV PADUA emerging as highly influential institutions. The predominant category is Neurosciences.

Future investigators may continue to focus on migraines with aura, familial hemiplegic migraine (FHM), and the crucial calcitonin gene-related peptide (CGRP) system. Employing advanced observational techniques, such as imaging, researchers should pay attention to cellular and tissue structures, such as microglia and the trigeminal ganglion, as well as mechanisms involving inflammation and central sensitization. Moreover, animal models are paramount in obtaining high-quality evidence.

With the global rise in obesity, metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common chronic liver disease. Concurrently, depression is a highly prevalent mental disorder. As the incidence of MASLD and depression continues to increase, a growing body of research indicates a potential association between the two conditions. However, the direction of causality between depression and MASLD remains uncertain. To address this gap, our study utilizes a two-sample Mendelian randomization (MR) approach to explore the bidirectional causal relationship between depression and MASLD.

We extracted single nucleotide polymorphisms (SNPs) associated with depression and MASLD from pooled data of genome-wide association studies (GWAS). A comprehensive assessment of possible causality was also performed. Possible mediating effects of liver enzymes on MASLD were also assessed.

A total of three GWAS pooled data on depression as well as GWAS data related to MASLD and GWAS data on four liver enzymes were used in this study. Our findings indicated a strong causal relationship between depression and MASLD (OR, 1.557; 95% CI, 1.097-2.211; P = 0.016). And we found a mediating effect of gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). ALT 10% (95% CI: 7% - 13%, P< 0.0002). AST, 4.14% (95% CI: 2.34% - 5.94%, P < 0.05). GGT 0.19% (95% CI: 0.15% - 0.22%, P< 0.000000002). However, we did not find a mediating effect of alkaline phosphatase (ALP). Our inverse MR analysis did not reveal any causal relationship between MASLD and depression.

The MR analysis revealed a positive causal relationship between depression and MASLD, while no reverse causal relationship was identified. Liver enzymes may mediate the role between depression and MASLD.

To assess whether systemic lupus erythematosus (SLE) may be genetically causally associated with migraine, including the two primary subtypes: migraine with aura (MWA) and migraine without aura (MWoA).

The association between SLE and migraine has been investigated extensively. Previous studies have shown a higher prevalence of migraine in patients with SLE, although the exact relationship remains unclear. This study investigated the potential causal association between SLE and migraine using the powerful analytical tool of Mendelian randomization (MR).

We performed two-sample MR analysis of publicly available summary statistic datasets using inverse variance-weighted (IVW), weighted median, and MR-Egger methods based on an SLE genome-wide association study (GWAS; 5201 cases; 9066 controls; the exposure frequency is 36.5%) as an exposure and migraine GWAS (15,905 cases; 264,662 controls) in individuals with European ancestry as outcomes, focusing on the two migraine subtypes MWA (6780 cases; 264,662 controls) and MWoA (5787 cases; 264,662 controls). Thepleiotropy and heterogeneity were performed.

We selected 42 single-nucleotide polymorphisms from SLE GWAS as instrumental variables (IVs) for SLE on migraine, and 41 SNP IVs for SLE on MWA or MWoA. The IVW (odds ratio [OR] = 1.01, 95% confidence interval [CI] = [0.99, 1.03], p = 0.271), weighted median (OR = 1.00, 95% CI = [0.97, 1.03], p = 0.914), and MR-Egger (OR = 1.04, 95% CI = [0.99, 1.09], p = 0.153) methods showed no causal effect of SLE on migraine. A causal effect of SLE was observed on MWA (IVW: OR = 1.05, 95% CI = [1.02, 1.08], p = 0.001; weighted median: OR = 1.05, 95% CI = [1.01, 1.10], p = 0.018; MR-Egger: OR = 1.07, 95% CI = [1.01, 1.14], p = 0.035 and pIVW < 0.017 [Bonferroni correction]) but not MWoA (IVW: OR = 0.99, 95% CI = [0.96, 1.02], p = 0.331; weighted median: OR = 0.98, 95% CI = [0.94, 1.03], p = 0.496; MR-Egger: OR = 1.02, 95% CI = [0.95, 1.09], p = 0.652). The results showed no significant pleiotropy or heterogeneity.

Our MR analysis demonstrated the complex relationship between SLE and migraine, suggesting a potential effect of SLE on the risk of MWA but not MWoA. These findings can aid in the development of improved subtype-specific management of migraine in patients with SLE.