The Journal of Headache and Pain

IntroductionEpisodic migraine is reflected by cyclic changes in behaviour and cortical processing. We aimed to identify how Functional connectivities change over the entire migraine cycle. MethodsBy using longitudinal neuroimaging and a whole-brain connectivity analysis approach, we tested 12 episodic migraine patients across 82 FMRI recordings during spontaneous headache attacks with Follow-up measurements over the pain-free interval without any external stimulation. ResultsWe Found that Functional connectivities linearly increased over the interictal interval. In the prodromal phase, we observed the strongest connections between the anterior agranular insula and the posterior orbitofrontal cortex with sensory, motor, and cingulate areas. The strengths of the connections dropped during the headache. Peak connectivity during the prodromal phase and its collapse during the headache can be regarded as a mechanism of normalising cortical processing. ConclusionsThe strongest connections during the ictal phase of the migraine cycle may contribute to the variety of symptoms of migraine attacks including headache, sensory hypersensitivity, and autonomous symptoms. We speculate about a malfunction at the molecular level in agranular frontal and insular regions, which needs to be addressed in subsequent studies. Article highlightsO_LIWe investigated functional connectivities over an entire migraine cycle. C_LIO_LIWe found cycle-related connectivity changes for two proximate agranular regions. C_LIO_LIThe prodromal increase and the collapse of connectivity during the headache may reflect normalising cortical processing. C_LI

BackgroundA system of lymphatic vessels has been recently characterized in the meninges, with a postulated role in cleaning the brain via cerebral fluid drainage. As meninges are the origin site of migraine pain, we hypothesized that malfunctioning of the lymphatic system should affect the local trigeminal nociception. To test this hypothesis, we studied nociceptive and inflammatory mechanisms in the meninges of K14-VEGFR3-Ig mice lacking the meningeal lymphatic system. MethodsWe recorded the spiking activity of meningeal afferents and estimated the local mast cells infiltration, calcitonin gene-related peptide (CGRP) and cytokine levels (basal and stimulated), as well as the dural trigeminal innervation in freshly-isolated hemiskull preparations from K14-VEGFR3-Ig (K14) or wild type C57BL/6 mice (WT). ResultsWe found that the meningeal level of CGRP and of the pro-inflammatory cytokines IL12-p70 and TNF (implicated in migraine) were reduced in the meninges of K14 mice. On the contrary, in the meninges of K14 mice, we found an increased level of the mast cell activator MCP-1 and, consistently, a larger number of dural mast cells. The other migraine-related pro-inflammatory cytokines did not differ between the two genotypes. The patterns of trigeminal innervation in meninges remained unchanged and we did not observe alterations in basal or ATP-induced nociceptive firing in the meningeal afferents. ConclusionsIn summary, the lack of meningeal lymphatic system does not induce migraine-like nociceptive state per se, but leads to a new balance between pro- and antiinflammatory factors implicated in migraine mechanisms.

Migraine is a prevalent and disabling brain disorder characterized by recurrent headache attacks alternating with pain-free periods. Patients with migraine exhibit altered brain activation in response to experimental nociceptive stimuli compared to healthy controls, suggesting impaired pain inhibition mechanisms. However, the relevance of these alterations to the underlying pathophysiology of migraine attacks remains unclear. To explore this relationship, we propose a novel pain imagery paradigm aimed to induce brain activation patterns associated with migraine attacks specifically during pain-free. The task required patients to alternate between imagining a severe migraine attack and being headache free, while healthy controls imagined severe physical head pain (e.g., toothache) and pain relief. We collected fMRI data from 14 episodic migraine without aura patients in the interictal phase and 15 healthy controls performing this task. Both patients and controls activated pain-related brain areas during imagery of pain relative to pain relief. Moreover, controls also activated the medial pain system associated with pain inhibition and attentional modulation of pain via top-down pathways. In contrast, patients significantly deactivated these areas, namely the anterior cingulate cortex and dorsolateral prefrontal cortex. Collectively, our findings indicate altered functioning of pain networks in migraine patients, suggesting a disease-related dysregulation of pain inhibition. Eventually, the proposed attack imagery paradigm may provide a promising alternative to studies of pain mechanisms in migraine research.

Opioids are regularly prescribed for migraine and can result in medication overuse headache and dependence. We recently showed that pituitary adenylate cyclase activating polypeptide (PACAP) is upregulated following opioid administration or in a model of chronic migraine. The goal of this study was to determine if PACAP was a link between opioid use and headache chronification. We tested the effect of PACAP-PAC1 receptor inhibition in novel models of opioid-exacerbated migraine pain and aura; and examined the co-expression between mu opioid receptor (MOR), PAC1, and PACAP in headache-associated brain and peripheral regions. To model opioid exacerbated migraine pain, mice were injected daily with morphine (10 mg/kg) or vehicle for 11 days. On days 3,5,7,9, and 11 they also received the known human migraine trigger nitroglycerin (0.1 mg/kg) or vehicle. To model opioid exacerbated aura, mice were treated with vehicle or morphine twice daily for 4 days (20 mg/kg on days 1-3, 40 mg/kg on day 4), a well-established paradigm for causing opioid-induced hyperalgesia. On day 5 they underwent cortical spreading depression, a physiological correlate of migraine aura. The effect of the PAC1 inhibitor, M65 (0.1 mg/kg), was tested in these models. Fluorescent in situ hybridization was used to investigate the expression of MOR, PAC1, and PACAP. Only mice treated with combined morphine and nitroglycerin developed chronic cephalic allodynia (n=18/group). M65 reversed this hypersensitivity (n=9/group). Morphine significantly increased the number of CSD events (n=8-9/group); and M65 decreased this exacerbation by morphine (n=8-12/group). PAC1 and/or PACAP were highly co-expressed with MOR, and varied by region (n=6/group). MOR and PACAP were co-expressed in the trigeminal ganglia, while MOR and PAC1 receptor showed near complete overlap in the trigeminal nucleus caudalis and periaqueductal gray. The cortex showed similar cellular co-expression between MOR-PACAP and MOR-PAC1. These results show that opioids facilitate the transition to chronic headache through induction of PACAPergic mechanisms. Antibodies or pharmacological agents targeting PACAP or PAC1 receptor may be particularly beneficial for the treatment of opioid-induced medication overuse headache.

ObjectiveTo determine whether induction of migraine-like symptoms in mice by calcitonin gene-related peptide (CGRP) requires activation of the posterior thalamic nuclei (PoT) in the brain.BackgroundPrevious research found that both optical activation of the PoT and injection of CGRP into the PoT are sufficient to induce light aversive behavior in mice. The PoT is well known as a sensory integration center of light and pain signals in the brain. However, whether this region is required for touch hypersensitivity and light aversion following peripheral administration of CGRP was not known.MethodsThe PoT was injected in two strains of mice, inbred C57BL/6J and outbred CD-1, with viral vectors expressing inhibitory chemogenetic Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). The inhibitory DREADDs were activated by systemic intraperitoneal (ip) injection of two designer drugs, clozapine N-oxide (CNO) and DREADD agonist compound 21 (C21). We used ip injection of CGRP to induce migraine-like phenotypes and tested whether we could rescue these phenotypes by bilateral chemogenetic inhibition of the PoT. The light/dark assay was used to measure light aversive behavior (a surrogate for photophobia) and the plantar von Frey assay to measure hindpaw touch sensitivity (a surrogate for extracephalic allodynia).ResultsWe successfully induced light aversive and hindpaw touch hypersensitivity phenotypes in mice using ip injections of CGRP. Activation of the inhibitory DREADDs in the PoT using ip CNO (5 mg/kg) was sufficient to partially rescue the touch hypersensitivity phenotype, but with off target effects in the control mice. Lowering the CNO dose to 1 mg/kg alleviated off target effects but was insufficient to rescue the touch hypersensitivity phenotype. On the other hand, C21 (1 mg/kg) fully rescued the touch hypersensitivity phenotype without any off target effects. Treatment with C21 also partially rescued the light aversion phenotype. These results were consistent across both C57BL/6J and CD-1 mouse strains.ConclusionInhibition of the PoT fully rescues CGRP-induced touch hypersensitivity and partially rescues light aversion in mice, indicating that the PoT is necessary for touch hypersensitivity and partially necessary for light aversive behaviors. These data suggest the PoT is part of a central network that receives peripheral CGRP-induced signals and thus could be harnessed for future targeted therapeutics for migraine.Plain language summaryThe posterior thalamus is a central brain region that contributes to migraine pathophysiology when stimulated. In this study, we asked if inhibition of this brain region could alleviate migraine-like phenotypes in mice. We found that inhibition of the posterior thalamus fully rescues touch hypersensitivity and partially rescues light aversive behavior, suggesting that the posterior thalamus is necessary for migraine pathophysiology and could offer a potential therapeutic target for migraine.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSWe aimed to assess the impact of pain catastrophizing, measured using the Italian version of the Pain Catastrophizing Scale (PCS), on the clinical response of patients with chronic migraine to anti-CGRP monoclonal antibodies combined with a multidisciplinary approach, including psychological treatment. Methods25 Outpatients from SS. Antonio e Biagio e Cesare Arrigo headache clinic randomly assigned to receive Galcanezumab, Erenumab, or Fremanezumab. Their clinical response was evaluated over six months using various measures, including reducing the number of days with migraine per month, and quality of life using Headache Impact Test (HIT 6), MIgraine Disability Assessment Score questionnaire (MIDAS), and Becks Inventory Scale (BDI II) scales to assess comorbid depression. ResultsWe established a strong correlation between HIT 6 and PCS, with coefficients of 0.81 and 0.88 at T1 and T2, respectively. Furthermore, we found no significant correlation between PCS and the other scales, such as MIDAS, as with any pharmacological therapies. ConclusionThis study aims to clearly define the impact of a multidisciplinary approach including a psychological follow-up on a particular clinical phenotype of chronic migraines and their tendency to catastrophize, but more extended data are needed.

BackgroundMigraine is a disorder of severe, recurrent headaches and debilitating sensory, cognitive and affective symptoms, often triggered by stress. Early life stress in childhood has been shown to increase the likelihood of migraine in adulthood in humans. Calcitonin-gene relate peptide (CGRP) has been shown to reliably and acutely induce migraine or migraine-like behavior in both humans and rodent models. Here we investigate the impact of early life stress and CGRP on migraine-related neural circuitry, as well as the impact of early life stress on CGRP-mediated migraine-like activity in order to better understand the mechanisms by which early life stress predisposes neural circuitry to migraine brain activity. MethodsWe implemented an early life stress paradigm in the outbred strain of mice, CD1. We evaluated the impact of peripheral CGRP on migraine-like behavior and employed multi-site in vivo neurophysiology in freely behaving mice. A changepoint analysis was used to dissect differences in individual CGRP-induced responses. ResultsWe found that early life stress exacerbated migraine-related behavioral and network physiology. CGRP alone caused disruptions in neural oscillatory activity across a network of brain regions including the anterior cingulate cortex (ACC), amygdala (AMY), thalamus (Po, VPM, and MDthal), and parabrachial nucleus (PBN). We found that power across the network was lowered within 10 minutes of peripheral CGRP exposure, which was sustained for [~]40-50 min. Coherence was mostly disrupted in amygdalar brain region pairings, and took on a shorter timecourse, with partial rescue of these responses by migraine abortive, sumatriptan. We found that early life stress exacerbated most of these responses, especially AMY-thalamic coherence pairings, although early life stress in the absence of CGRP demonstrated no impact on the network overall. We further identified individual mice with brain-network activity hypersusceptible to migraine. ConclusionsOur findings demonstrate that early life stress confers vulnerability to migraine, simultaneously impacting behavior and brain network activity responses to peripheral CGRP.

Both enhanced motion-induced nausea and increased static imbalance are observed symptoms in migraine and especially vestibular migraine (VM). Motion-induced nausea and static imbalance were investigated in a mouse model, nestin/hRAMP1, expressing elevated levels of human RAMP1 which enhances CGRP signaling in the nervous system, and compared to non-affected littermate controls. Behavioral surrogates such as the motion- induced thermoregulation and postural sway center of pressure (CoP) assays were used to assess motion sensitivity. Nausea readouts revealed that the nestin/hRAMP1 mouse exhibit an increased sensitivity to CGRPs effects at lower doses compared to unaffected controls. In addition, the nestin/hRAMP1 mice exhibit a higher dynamic range in postural sway than their wildtype counterparts, along with increased sway observed in nestin/hRAMP1 male mice that was not present in male unaffected controls. Results from migraine blocker experiments were challenging to interpret, but the data suggests that olcegepant is incapable of reversing CGRP-induced or endogenous alterations in the nestin/hRAMP1 mice, while rizatriptan was ineffective in both the nestin/hRAMP1 and control mice. The results indicate that overexpression of hRAMP1 leads to heightened endogenous CGRP signaling. Results also suggest that both olcegepant and rizatriptan are ineffective in reducing nausea and sway in this hypersensitive CGRP mouse model. This study suggests that the hypersensitive nestin/hRAMP1 mouse may serve as a model for difficult to treat cases of migraine that exhibit increased motion sensitivity.

BackgroundMigraine is typically precipitated by unaccustomed changes in ones internal state and/or external environment. Migraine symptoms largely involve increased, noxious, awareness of bodily changes and external stimuli. Links have been proposed between migraine and interoception (sensing and interpreting internal states), but direct evidence is limited. MethodsUnmedicated, otherwise healthy, age-matched female participants were grouped by migraine tendency: control (no unprovoked headaches, n=19); low-frequency (<=3 migraines/month, n=20); high-frequency (>=4 migraines/month, n=19). Interoception was assessed, interictally, with standardised questionnaires such as MAIA-2 and a widely used heartbeat counting task. ResultsThe notable significant questionnaire-based difference was in the noticing, not distracting domain of the MAIA-2; controls were least likely to continue activities despite experiencing physical discomfort, and high-frequency migraineurs most likely. Follow-up questioning clarified that this behaviour related predominantly to migraine-related symptoms. The heartbeat task found no differences in accuracy, but lower confidence in the low-frequency migraine group than the control and high-frequency groups. ConclusionsWe suggest that low interoceptive confidence is a risk factor for migraine, whilst amplification of interoceptive signals caused by migraine restores this confidence, but at the price of migraines disabling symptoms. Self-reported tendency to deliberately ignore physical discomfort, including that caused by migraine, may result in more migraine attacks.

Moderate to severe head pain is a hallmark of recurring migraine attacks. However, it is challenging to study patients during spontaneous attacks and most research on the brain mechanisms of pain in migraine patients has been limited to the processing of painful stimuli between attacks. Here, we hypothesize that the experience of a migraine attack extends beyond the response to painful stimuli and is associated with specific impairments of the salience network (SN), which integrates sensory, emotional and cognitive information in relation to salient stimuli. To test this hypothesis, we analysed the SN dynamics of a group of patients with episodic migraine in three distinct conditions: at rest during a spontaneous migraine attack (ictal phase); while performing an imagery task aiming to elicit the experience of a previous attack, during the interictal phase; and at rest, during the interictal phase. For comparison, we also studied a group of healthy controls in three matching conditions, including rest as well as an imagery task of a (non-migraine) head pain experience. We collected functional magnetic resonance imaging (fMRI) data and used a dynamic functional connectivity (dFC) analysis to examine the temporal features of the SN from a total of 78 samples. Compared to healthy controls, the SN had a significantly shorter lifetime in patients during the pain imagery task, but not during a migraine attack or interictal resting state. Our results support the disruption of the SN in migraine, and indicate that pain imagery may be a useful paradigm for isolating the emotional and cognitive aspects of pain and investigating SN dynamics.

Despite migraine being one of the top five most prevalent childhood diseases, a lack of knowledge about pediatric migraine limits effective treatment strategies; standard adult pharmaceutical therapies are less effective in children and can carry undesirable side-effects. Non-pharmacological therapies have shown some success in adults; however, to appropriately apply these in children we need to understand pediatric migraines underlying biology. One theory is that migraine results from an imbalance in cortical excitability. Magnetic resonance spectroscopy (MRS) studies show changes in GABA and glutamate levels (the primary inhibitory and excitatory neurotransmitters in the brain, respectively) in multiple brain regions. Although there is indirect evidence of abnormal excitability in pediatric migraine, GABA and glutamate levels have yet to be assessed. The purpose of this study was to measure levels of GABA and glutamate in the thalamus, sensorimotor cortex and visual cortex of children with migraine using MRS. We found that children with migraine and aura had significantly lower glutamate levels in the visual cortex as compared to control children, opposite to results seen in adults. Additionally, we found significant correlations between metabolite levels and migraine characteristics; higher GABA levels were associated with a higher migraine burden. We also found that higher glutamate in the thalamus and higher GABA/Glx ratios in the sensorimotor cortex were associated with duration since diagnosis, i.e., having migraines longer. Lower GABA levels in the sensorimotor cortex were associated with being closer to their next migraine attack. Together this indicates that GABA and glutamate disturbances occur early in migraine pathophysiology and emphasizes that evidence from adults with migraine cannot be immediately translated to paediatric sufferers. This highlights the need for further mechanistic studies of migraine in children, to aid in the development of more effective treatments.

ObjectiveTo characterize the role of the amygdala in episodic (EM) and chronic (CM) migraine, we evaluated amygdala volumes, functional connectivity (FC), and associations with clinical and affective measures. MethodsEighty-eight patients (44 with EM and 44 age- and sex-matched patients with CM) completed anatomical and resting-state functional MRI scans. Amygdala volumes and resting-state FC to three core large-scale cognitive control networks (default mode (DMN), salience (SN), central executive (CEN)) were compared between groups. Associations between amygdala volume and FC, measures of headache severity (frequency and intensity), and cognitive-affective measures (depression, anxiety, pain catastrophizing) were evaluated. ResultsCompared to EM, patients with CM had larger amygdala volume bilaterally. Headache frequency and intensity were associated with increased left and right amygdala volume, and depression was associated with increased right amygdala volume. Patients with CM also demonstrated increased left amygdala FC with the DMN, which across patients was related to headache frequency. Left amygdala FC to the SN was correlated with headache intensity while right amygdala FC to the CEN was correlated with pain catastrophizing. ConclusionOur findings reveal increased amygdala volume and FC with large-scale neurocognitive networks in patients with CM compared to EM. Aberrant amygdala volume and FC measures were associated with increased migraine severity, depression, and pain catastrophizing, pointing to a link between emotion and pain in migraine. Our findings provide novel insights into amygdala involvement in chronic migraine and may inform future interventions aimed at preventing the progression of both headache and its negative cognitive-affective symptoms.

The neuropeptide calcitonin gene-related peptide (CGRP) is a major player in migraine pathophysiology. Previous preclinical studies demonstrated that intracerebroventricular administration of CGRP caused migraine-like behaviors in mice, but the sites of action in the brain remain unidentified. The cerebellum has the most CGRP binding sites in the central nervous system and is increasingly recognized as both a sensory and motor integration center. The objective of this study was to test whether the cerebellum, particularly the medial cerebellar nuclei (MN), might be a site of CGRP action. In this study, CGRP was directly injected into the right MN of C57BL/6J mice via a cannula. A battery of behavioral tests was done to assess migraine-like behaviors. CGRP caused light aversion measured as decreased time in the light zone even with dim light. The mice also spent more time resting in the dark zone, but not the light, along with decreased rearing and transitions between zones. These behaviors were similar for both sexes. In contrast, significant responses to CGRP were seen only with female mice in the open field assay, von Frey test, and automated squint assay, indicating anxiety, tactile hypersensitivity, and spontaneous pain, respectively. In male mice, the responses had the same trend as females but did not reach statistical significance. No detectable effect of CGRP on gait was observed in either sex. These results suggest that CGRP in the MN causes light aversion in males, while in females, light aversion is accompanied by increased anxiety, tactile hypersensitivity, and spontaneous pain. A caveat is that we cannot exclude contributions from other cerebellar regions in addition to the MN due to diffusion of the injected peptide. These results reveal the cerebellum as a new site of CGRP actions that may contribute to migraine pathophysiology and possibly its prevalence in females.

BackgroundMigraine patients show choroid plexus (CP) changes, impairing the blood-CSF barrier. The CP regulates circadian rhythms, but links between CP circadian genes and migraine are unexplored. ObjectiveThis study examined CP circadian gene transcriptome changes in a chronic migraine rat model versus controls to identify migraine-related pathways. DesignChronic migraine model: Sprague Dawley rats (3 females, 3 males) received nitroglycerine (NTG) every other day for 9 days; controls (3 females, 3 males) got saline. CP from the 4th ventricle was collected 2 hours post-final injection for RNAseq. MethodsMigraine Behavior: Von Frey hair tests on days 1, 5, and 9, pre- and 2 hours post-NTG/saline injection, assessed basal and NTG-induced pain thresholds. RNAseq & Analysis: Differentially expressed genes (p < 0.05, fold change > 1) were identified. GO, KEGG, and Reactome enrichment analyses evaluated circadian gene expression changes. ResultsO_LINTG group showed reduced basal and NTG-induced pain thresholds on days 1, 5, and 9. C_LIO_LIFemales had more upregulated genes (MT2A, SLC7A11), males upregulated ZBTB16, S100A8. SLC7A11, SCG2, GRIA1 showed inverse regulation (up in females, down in males). C_LIO_LICircadian gene expression altered: 10 genes upregulated (e.g., SERPINE1, MAPK9, ATF4), 13 downregulated (e.g., PER2, DBP, EZH2). Sex-specific differences: females (FBXL12, GPR157), males (NKX2-1, ATF4, CLOCK). C_LIO_LIGO/KEGG analyses revealed significant enrichment of circadian rhythm-related pathways, insulin resistance, and inflammatory response processes, with sex-specific differences: females showed HIF-1 signaling and hemoglobin-related pathways, while males exhibited arachidonic acid and leukotriene production. C_LI ConclusionCP transcriptomics in the rat migraine model revealed sex-specific gene regulation, with females upregulating antioxidant genes (MT2A, SLC7A11) and males upregulating inflammatory factors (ZBTB16, S100A8), alongside circadian disruption (e.g., SERPINE1 upregulated, PER2 downregulated). Pathway analyses indicate enriched circadian rhythms, HIF-1 signaling (females), inflammatory processes (males), lipid metabolism (PPAR), and heme signaling, highlighting sex-specific and circadian targets for migraine therapy.

Chronic low back pain (CLBP) is the leading cause of disability worldwide. Structural abnormalities in the lumbar region rarely account for the pain symptoms observed. In contrast, the brain plays a central role in chronic pain, with several studies suggesting that chronic pain may result from the persistence of pain memories and/or the inability to extinguish these memories following an initial inciting injury. Previous research has reported a reduction in grey matter density (GMD) in CLBP patients, as measured by magnetic resonance imaging (MRI). Notably, lower GMD has been observed in patients with moderate to severe CLBP who are undergoing prescribed pharmacological treatments. However, it remains unclear whether these differences in GMD could be associated with a less severe condition. This study aimed to investigate whether GMD is altered in a cohort with mild to moderate CLBP symptoms, and who have not been prescribed pharmacological treatments. To achieve this, we acquired T1-weighted MRI scans from 25 healthy controls (HC) and 27 untreated individuals with mild to moderate CLBP. Scans were taken at baseline, 2 months, and 4 months after baseline. GMD analysis was carried out using the FMRIB Software. Our results consistently showed higher GMD in the CLBP group compared to HC. These findings suggest that the observed alterations in GMD may be related to the condition itself, and can occur even in patients with milder symptoms and better physical function, without the influence of opioids, anticonvulsants, or antidepressants. Given that our participants differ from those typically studied in the literature, our results imply that they may be in a distinct brain state relative to the condition. Further research is needed to elucidate the underlying biological mechanisms and confirm whether these brain alterations are indeed a characteristic feature of CLBP.

IntroductionMedical students are vulnerable group to migraine, one of the most common type of headache worldwide. The aim of the present study was to determine the prevalence of migraine and related disability among medical students of Bangladesh. MethodsThis cross-sectional study was conducted among 1327 students from six medical colleges Bangladesh during March 2021 through a self-administered online survey. ID Migraine scale and MIDAS scale were used to screen migraine and migraine related disability respectively. Frequency distribution, and Chi-square test, t-test along with multiple logistic regressions model were used to determine the prevalence and associated factors of migraine respectively. ResultsThe overall prevalence of migraine among the participants was 19%. The prevalence was higher among females (27%) than males (8%). Female sex (aOR 4.11, 95% CI 2.79-6.03) and poor sleep quality (aOR 2.07, 95% CI 1.48-2.91) were identified as independent risk factors of migraine. More than 90% migrainures reported to suffer from moderate to severe headache. Nausea was most commonly reported associated symptom (83.5%) followed by photophobia (72%) and vomiting (53%). Self-reported mental stress (55%), irregular sleep (49%), noise (30.5%), and usage of electronic device (30.5%) were most commonly reported triggering factor of migraine attack. More than half of the sufferers reported severe migraine related disability (MIDAS score [&ge;] 21). ConclusionsThe prevalence of migraine among medical students of Bangladesh is alarmingly high. Frequent migraine attacks and severe intensity of headache cause a substantial level of disability among the sufferers. Cautious avoidance of the triggering factors through appropriate interventions and prophylactic medication can mitigate the negative impact of migraine as well as improve the quality of life.

Patients with myofascial pain in the head and neck area report widespread and referred pain, including headache. Existing preclinical models fail to replicate this clinical phenotype; therefore, we aimed to develop animal models mimicking referred pain phenomenon and investigate whether referred pain leads to gene plasticity at the referred sites. We modeled masticatory myalgia by stimulation of either the masseter (MM) or temporal muscle (TM) in mice. MM and TM were stimulated with a single high-dose injection of Collagenase-type II (Col), repetitive low-dose Col injections, repetitive gentle MM stimulation, or single or repetitive forceful mouth opening. Referred pain was assessed by measuring mechanical hypersensitivity in the periorbital area (representing headache-like behavior) and another masticatory muscle. Stimulation of the MM, whether through single or repetitive Col injections or mouth opening, produced inconsistent, short-lasting (1-2 days) headache-like behavior in both males and females. In contrast, stimulation of the TM, using different paradigms, triggered mechanical hypersensitivity in both the MM and the periorbital area. Referred headache-like behavior lasted longer in females compared to males, while referred myalgia in the MM was pronouncer in males. The referred pain in the MM and periorbital areas triggered by TM stimulation was associated with significant gene plasticity in the MM and dura mater. Transcriptional changes in the MM following Col injection into the TM resembled those observed after direct MM injections. Presented data imply that referred pain modeled by TM stimulation could be accounted by nociceptive signaling from multiple local sites involved in this referred pain network.

AO_SCPLOWBSTRACTC_SCPLOWThere is growing evidence that migraine is associated with attentional abnormalities, both during and outside migraine attacks, which would impact the cognitive processing of sensory stimulation. However, these attention alterations are poorly characterized and their neurophysiological basis is still unclear. Nineteen migraineurs without aura and nineteen healthy participants were recruited to perform a task which used visually-cued auditory targets and distracting sounds to evaluate conjointly top-down and bottom-up attention mechanisms. Magnetoencephalography (MEG) signals were recorded. We investigated anticipatory alpha activity (power increase and decrease) and distractor-induced gamma activity as markers for top-down (inhibition and facilitation) and bottom-up attention, respectively. Compared to healthy participants, migraineurs presented a significantly less prominent alpha power increase in visual areas in anticipation of the auditory target, indexing a reduced inhibition of task-irrelevant visual areas. However, there was no significant group difference regarding the alpha power decrease in the relevant auditory cortices in anticipation of the target, nor regarding the distractor-induced gamma power increase in the ventral attention network. These results in the alpha band suggest that top-down inhibitory processes in the visual cortices are deficient in migraine but there is no clear evidence supporting a disruption of top-down facilitatory attentional processes. This relative inability to suppress irrelevant sensory information may be underlying the self-reported increased distractibility and contribute to sensory disturbances in migraine.

Abstract Background/HypothesisMonoclonal antibodies targeting calcitonin gene-related peptide (CGRP mAbs) are effective drugs for migraine prevention. Worsening of symptoms following their discontinuation challenges their consideration as disease-modifying migraine drugs (DMMD). This study investigates whether changes in sensory processing and cortical network efficiency under CGRP mAb treatment. Methods22 patients suffering episodic migraine (21 female, 46.2{+/-}13.8 years) and 22 age-/gender-matched controls received visual and somatosensory evoked potentials (VEPs, SSEPs) assessments, and quantitative electroencephalography (qEEG). Patients were investigated before (V0),after three months (V3), and headache characteristics additionally followed-up at 6 and 12 months, of treatment with CGRP mAbs. Controls were assessed only once. ResultsFacilitation of VEP at V0 in patients shifted to habituation at V3 following treatment with CGRP mAbs ({Delta}slope: -0.37{+/-}0.83, p=0.03). VEP habituation at V3 did not differ from controls. SSEPs were equally attenuated in patients and controls throughout the study. QEEG parameters in patients indicated impaired network efficiency at V0 that normalized at V3, and were unlike evoked potential studies correlated with six and twelve month outcomes. Conclusion/ InterpretationImproved cortical network efficiency and sensory processing suggests disease-modifying effects of CGRP mAbs with delayed clinical effects on headache. Relapse after withdrawal may reflect insufficient central adaptation in some patients.

Migraine is a prevalent and disabling neurological disorder, characterized by difficulties in regulating headache activity, sensory processing, and cognitive-emotional states. Brain entropy quantifies the complexity of neural dynamics, where reduced entropy may reflect diminished neural adaptability, but its assessment with fMRI in migraine remains limited. Here, we examined alterations in brain entropy and their associations with clinical burden, attack timing, and symptomatology. Resting-state fMRI data were acquired from adults with episodic migraine, chronic migraine, and healthy controls. Following standard preprocessing, voxel-wise sample entropy was computed, and group differences were assessed using ANCOVA with age and sex as covariates. Associations with clinical burden and symptom measures were examined within affected regions. In chronic migraine, attack timing-related changes in entropy were further explored, and the largest Lyapunov exponent (LLE) was estimated to characterize chaotic dynamics underlying attack-related complexity changes. Migraine patients showed reduced entropy in sensory, attentional, and default mode regions compared to controls, most pronounced in chronic migraine. Lower entropy correlated with greater headache frequency and longer illness duration. In chronic migraine, entropy relatively increased during attacks in multisensory integration regions and was associated with positive and elevated LLEs, indicating partially restored complexity with weakly chaotic dynamics. Patients experiencing phonophobia and nausea also exhibited increased entropy in multisensory and default mode regions. Our findings demonstrate widespread reductions in brain entropy in migraine, reflecting impaired neural adaptability, whereas attacks may transiently restore complexity partially through chaotic dynamics. These results advance understanding of migraine pathophysiology and highlight potential targets for therapeutic intervention. Highlights- Migraine is marked by reduced brain entropy across sensory, attentional and default mode regions, which correlates with disease burden. - Reduced entropy reflects constrained neural adaptability within affected regions. - Migraine attacks transiently restore entropy, suggesting partial recovery of neural adaptability. - Positive and elevated Lyapunov exponents indicate a shift toward weakly chaotic dynamics during attacks. - Symptoms such as phonophobia and nausea are linked to increased entropy in multisensory integration and default mode regions.