Migraine-like Symptoms Research Articles

Reversible Perfusion Changes during Acute Attacks in Glucose Transporter Type 1 Deficiency Syndrome: A Pediatric Case Series.

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is an uncommon condition represented by an infantile-onset disorder, frequently arising from heterozygous mutations in the SLC2A1 gene. Individuals with GLUT1-DS may present with early-onset seizures (typically manifesting before 4 years of age), developmental delay, and complex movement disorders. In fewer cases, stroke-like events or hemiplegic migraine-like symptoms are also reported, defined by unilateral paresis affecting 1 side of the body and/or one-half of the face, occasionally accompanied by speech impairment. Currently, the pathomechanism underlying these acute transient clinical manifestations is poorly understood. MR imaging studies performed in the absence of acute manifestations frequently reveal nonspecific imaging signs associated with this syndrome. We present findings obtained using the arterial spin-labeling technique for perfusion imaging and MRA during the acute onset of stroke-like episodes in a series of 4 pediatric patients with GLUT1-DS. We observed reversible hypoperfusion in the left hemisphere and associated reversible attenuation of distal MCA branches on MRA. A notable association between unilateral cerebral hypoperfusion and transient crossed cerebellar diaschisis was evident on perfusion maps as well.

Field-testing the explicit diagnostic criteria for transient ischemic attack: a diagnostic accuracy study.

Explicit diagnostic criteria for transient ischemic attack (TIA) (EDCT) have been recently proposed based on the assumption, that a migraine aura-like symptom is not typical for a TIA. However, migraine-like symptoms have been unexpectedly frequent in patients with confirmed ischemic stroke. This cross-sectional study aimed to field-test the EDCT to distinguish transient neurological symptoms caused by cerebral infarction from those caused by migraine aura. The sensitivity, specificity, positive and negative predictive values of the EDCT score were calculated in samples of patients with (i) transient symptoms caused by cerebral infarction confirmed by imaging and (ii) patients with migraine with aura diagnosed according to the International Classification of Headache Disorders 3rd edition. Sensitivity, specificity, positive and negative predictive values of the original and modified EDCT were calculated, as well as area under the curve adjusted for age and sex using the logistic regression method. The study population included 59 patients with cerebral infarction and 324 patients with migraine with aura. The median age of the stroke group was 72 (IQR 61-81) and of the migraine group 39 (IQR 29-53). There were 36 (61%) men in the stroke group and 221 (68%) women in the migraine group. For the detection of TIA with imaging-proven cerebral infarction, the original EDCT had a sensitivity of 90% (95%CI 79-96), a specificity 77% (95%CI 72-82), a positive predictive value of 42% (95%CI 33-51), and the negative predictive value 98% (95% CI 95-99). For the modified EDCT, the sensitivity was 81% (95%CI 69-90), the specificity 97% (95%CI 94-98), the positive predictive value 81% (95%CI 69-90), and the negative predictive value 97% (95%CI 94-98). The original and modified EDCT criteria miss up to 1 of 10 and 1 of 5 patients, respectively, with transient symptoms due to cerebral infarction. However, the modified EDCT criteria are more specific but less sensitive in detection of ischemic events. The optimal combination of clinical markers to reliably distinguish TIA from migraine aura remains to be found.

Headache and Visual Aura Outcomes After Stereotactic Radiosurgery for Patients With Occipital Lobe Arteriovenous Malformations: A Single-Center Retrospective Cohort Study.

Patients with brain arteriovenous malformations (BAVMs) sometimes experience migraine-like chronic headaches. Reportedly, this symptom is common in occipital lobe BAVMs; however, the exact prevalence has not been clarified, and the details of visual auras have been scarcely reported. Furthermore, no comprehensive studies exist on the improvement of migraine associated with visual auras in occipital lobe BAVMs after stereotactic radiosurgery (SRS). Therefore, this study investigated the prevalence of headache with visual aura in patients with occipital lobe BAVMs and evaluated the impact of SRS on preexisting symptoms. As a single-center retrospective cohort study, a total of 104 patients with occipital lobe BAVMs treated with SRS from 1990 to 2024 were analyzed. Pre-SRS and post-SRS symptoms of headache and visual aura were documented. The outcomes measured were headache severity, frequency, aura characteristics, and BAVM obliteration rates. Of the 104 patients, 41 (39%) reported chronic headache pre-SRS, and 37 (36%) experienced migraine with visual aura. Compared with pre-SRS, 90% (28/31) of the patients experienced a >50% reduction in headache severity and frequency at a median follow-up of 11 months, and 89% (25/28) experienced a >50% reduction in aura frequency. Complete headache remission was achieved in 35% (13/31) of patients. Complete obliteration of BAVMs was confirmed in 75% (76/102) of the patients at a median of 33 months. A smaller nidus volume was associated with both complete headache remission and BAVM obliteration, whereas age and sex were not significant predictors of headache outcome. Patients with occipital lobe BAVMs frequently experience migraine-like headaches with visual aura, which may be more prevalent than in the general population. SRS for occipital lobe BAVMs could not only achieve favorable BAVM obliteration with minimal adverse effects but also significantly improve migraine-like symptoms, including visual aura, particularly in patients with smaller nidus volumes.

Brain-wide mapping of c-Fos expression in nitroglycerin-induced models of migraine

BackgroundMigraine is a neurological disorder characterized by complex, widespread, and sudden attacks with an unclear pathogenesis, particularly in chronic migraine (CM). Specific brain regions, including the insula, amygdala, thalamus, and cingulate, medial prefrontal, and anterior cingulate cortex, are commonly activated by pain stimuli in patients with CM and animal models. This study employs fluorescence microscopy optical sectioning tomography (fMOST) technology and AAV-PHP.eB whole-brain expression to map activation patterns of brain regions in CM mice, thus enhancing the understanding of CM pathogenesis and suggesting potential treatment targets.MethodsBy repeatedly administering nitroglycerin (NTG) to induce migraine-like pain in mice, a chronic migraine model (CMM) was established. Olcegepant (OLC) was then used as treatment and its effects on mechanical pain hypersensitivity and brain region activation were observed. All mice underwent mechanical withdrawal threshold, light-aversive, and elevated plus maze tests. Viral injections were administered to the mice one month prior to modelling, and brain samples were collected 2 h after the final NTG/vehicle control injection for whole-brain imaging using fMOST.ResultsIn the NTG-induced CMM, mechanical pain threshold decreased, photophobia, and anxiety-like behavior were observed, and OLC was found to improve these manifestations. fMOST whole-brain imaging results suggest that the isocortex-cerebral cortex plate region, including somatomotor areas (MO), somatosensory areas (SS), and main olfactory bulb (MOB), appears to be the most sensitive area of activation in CM (P < 0.05). Other brain regions such as the inferior colliculus (IC) and intermediate reticular nucleus (IRN) were also exhibited significant activation (P < 0.05). The improvement in migraine-like symptoms observed with OLC treatment may be related to its effects on these brain regions, particularly SS, MO, ansiform lobule (AN), IC, spinal nucleus of the trigeminal, caudal part (Sp5c), IRN, and parvicellular reticular nucleus (PARN) (P < 0.05).ConclusionsfMOST whole-brain imaging reveals c-Fos + cells in numerous brain regions. OLC improves migraine-like symptoms by modulating brain activity in some brain regions. This study demonstrates the activation of the specific brain areas in NTG-induced CMM and suggests some regions as a potential treatment mechanism according to OLC.Graphical

Paeonol and glycyrrhizic acid in combination ameliorate the recurrent nitroglycerin-induced migraine-like phenotype in rats by regulating the GABBR2/TRPM8/PRKACA/TRPV1 pathway

Ethnopharmacological relevancePaeonol (PAE) and glycyrrhizic acid (GLY) are predominate components of 14 blood-entering ones of Piantongtang No. 1, which is a traditional Chinese medicine prescription for chronic migraine with minimal side effects. Both paeonol and glycyrrhizic acid exhibit analgesic, neuroprotective and anti-inflammatory properties individually. Our previous research has highlighted their combined effect (PAE + GLY) in ameliorating migraine symptoms. However, there are not yet any studies exploring the mechanism of action of PAE + GLY in the treatment of migraine. Aim of the studyThis research aimed to determine the mechanism of PAE + GLY in ameliorating the recurrent nitroglycerin-induced migraine-like phenotype in rats. Materials and methodsUsing a nitroglycerin-induced migraine model via subcutaneous injection in the neck, we evaluated the effect of PAE + GLY on migraine-like symptoms. Behavioural tests and biomarkers analysis were employed, alongside transcriptome sequencing (RNA-seq). Mechanistic insights were further verified utilising reverse transcription quantitative PCR (RT-qPCR), Western blot (WB), ELISA and immunofluorescence (IF) techniques. ResultsFollowing treatment with PAE + GLY, hyperalgesia threshold and 5-hydroxytryptamine (5-HT) levels increased, and migraine-like head scratching, histamine and calcitonin gene-related peptide (CGRP) levels were reduced. RNA-Seq experiments revealed that PAE + GLY upregulated the expression of Glutamate decarboxylase 2 (GAD2) and γ-aminobutyric acid type B receptor subunit 2 (GABBR2) genes. This upregulation activated the GABAergic synapse pathway, effectively inhibiting migraine attacks. Further validation demonstrated an increase in γ-aminobutyric acid (GABA) content in cerebrospinal fluid post PAE + GLY treatment, coupled with increased expression of dural GAD2, GABBR2 and transient receptor potential channel M8 (TRPM8). Consequently, this inhibited the expression of dural cAMP-dependent protein kinase catalytic subunit alpha (PRKACA) and transient receptor potential channel type 1 (TRPV1), subsequently downregulating p-ERK1/2, p-AKT1, IL-1β and TNF-α. ConclusionsOur findings underscore that PAE + GLY ameliorates inflammatory hyperalgesia migraine by upregulating inhibitory neurotransmitters and modulating the GABBR2/TRPM8/PRKACA/TRPV1 pathway.

A role of NLRP3 and MMP9 in migraine progression: a systematic review of translational study.

Migraines affect one billion individuals globally, with a higher occurrence among young adults and women. A significant survey in the United States indicated that 17.1% of women and 5.6% of men suffer from migraines. This study seeks to investigate the potential connection between NLRP3 and MMP9 in migraine pathology. The research involved searching databases such as PubMed, Scopus, Science Direct, Google Scholar, and Proquest, with the search concluding on March 31, 2024. Following PRISMA guidelines, PICO data were collected, focusing exclusively on animal models induced by Nitroglycerine (10 mg/kg), while excluding clinical studies. The study, originally registered in Prospero Reg. No. CRD42022355893, conducted bias analysis using SYRCLE's RoB tool and evaluated author consensus using GraphPad v9.5.1. Out of 7,359 search results, 22 papers met the inclusion criteria. Inter-rater reliability among reviewers was assessed using Cohen's kappa statistics. This review summarizes 22 preclinical studies on Nitroglycerin (NTG), NLRP3, MMP9, and related biomarkers in migraine. They reveal that NTG, especially at 10 mg/kg, consistently induces migraine-like symptoms in rodents by activating NLRP3 inflammasome and stimulating proinflammatory molecule production. https://www.crd.york.ac.uk/prospero/, CRD42022355893.

Two Puzzling Cases of Headache: A Case Series

AbstractMigraine and epilepsy are important causes of morbidity in adolescents and young adults. Mostly the diagnosis is readily made by using the predefined criteria. However, in extremely rare cases, children who present with typical symptoms of migraine with aura or familial hemiplegic migraine might have an underlying etiology of epilepsy. We hereby present the case of two children who presented with migraine-like symptoms but on detailed workup revealed an underlying epilepsy. Both patients responded to antiepileptic medications. These cases highlight the importance of a detailed history and comprehensive investigation plan for such patients to prevent erroneous diagnosis and migraine prophylaxis.

Levcromakalim provokes an acute rapid-onset migraine-like phenotype without inducing cortical spreading depolarization

BackgroundMigraine headache attacks and accompanying sensory augmentation can be induced by several agents including levcromakalim (LVC), that is also capable of provoking aura-like symptoms in migraineurs. We investigated whether single LVC injection causes acute migraine-like phenotype in rats and induces/modulates cortical spreading depolarization (CSD), a rodent model of migraine aura.MethodsWistar rats were administered LVC (1 mg/kg, i.p.) and compared to control (CTRL, vehicle, i.p.) and nitroglycerin (NTG, 10 mg/kg, i.p.) groups. Von Frey filaments were used to examine the periorbital and hind paw mechanical allodynia. Dark–light box (DLB), elevated plus maze (EPM), and open field arena (OFA) were used to evaluate light sensitivity and anxiety-related behaviors. The effects of LVC on CSD parameters, somatosensory evoked potentials, and baseline dural EEG (electroencephalography) were investigated. Possible CSD-induced c-fos expression was studied with Western Blot. Blood–brain barrier integrity in cortex was examined with Evans blue assay.ResultsLVC and NTG administration robustly reduced periorbital mechanical thresholds in rats and induced anxiety-like behaviors and photophobia within 30 and 120 min, respectively. LVC induced migraine-like phenotype recovered in 2 h while NTG group did not fully recover before 4 h. Both LVC and NTG did not provoke DC (direct current) shift, EEG alterations or cortical c-fos expression characteristic to CSD. LVC did not induce de novo CSD and affect KCl (potassium chloride)-induced CSD parameters except for an increase in propagation failure. However, NTG significantly increased both CSD susceptibility and propagation failure. Somatosensory evoked potential (SSEP) configurations were not altered in both LVC and NTG groups, but SSEP latencies were prolonged after CSD. Acute LVC or NTG injection did not increase cortical BBB permeability.ConclusionsSingle LVC administration induced the fastest manifestation and recovery of acute migraine-like phenotype which was not mediated by CSD waves in the cerebral cortex. We suppose LVC triggered rapid-onset migraine-like symptoms are probably related to functional alterations in the trigeminal nociceptive system and K+ channel opening properties of LVC. Understanding the neurobiological mechanisms of this nociceptive window, may provide a novel target in migraine treatment.

Repeated gentle handling or maternal deprivation during the neonatal stage increases adult male rats' baseline orofacial pain responsiveness

ObjectiveEarly life experiences have been found to have a long-lasting effect on brain development in adult life. The purpose of this study was to determine whether neonatal manipulation could alter orofacial pain responsiveness in adult rats MethodsIn the first 21 days of life, male rats were exposed to gentle handling or maternal deprivation (MD) procedures to establish models of handled and MD rats, respectively. The rats were assigned to three of the following experimental groups at the age of two months: intra-dental capsaicin (100 µg), intra-lip formalin (50 µL), and repeated nitroglycerin (NTG) (5 mg/rat/ip) infusion. In addition, there were three drug vehicle groups and three groups that received capsaicin, formalin, or NTG without prior handling or MD procedures. The behaviors were recorded following the pain induction. ResultsSpontaneous pain behaviors in the first phase of formalin test was significantly increased in MD (p < 0.01) and handled rats in comparison with the vehicle group (p < 0.05). The second-phase data showed that formalin-induced spontaneous pain behaviors was increased in rats- treated with MD as compared to either vehicle or handled+formalin groups (p < 0.001). Capsaicin-induced dental pulp nociception was increased in the MD group in comparison with the capsaicin (p < 0.001) and capsaicin+handled (p < 0.001) groups. Moreover, NTG-induced migraine-like behaviors symptoms were increased in the MD group as compared to control and handled groups (p < 0.05). ConclusionsIn this study neonatal gentle handling or MD treatment increased orofacial pain in adulthood, showing early life experiences permanent effects on the development of trigeminal circuits in the brain.

2-Deoxyglucose alleviates migraine-related behaviors by modulating microglial inflammatory factors in experimental model of migraine.

Targeting metabolic pathways has emerged as a new migraine treatment strategy as researchers realize the critical role metabolism plays in migraine. Activated inflammatory cells undergo metabolic reprogramming and rely on glycolysis to function. The objective of this study was to investigate the glycolysis changes in the experimental model of migraine and the effect of glycolysis inhibitor 2-Deoxy-D-glucose (2-DG) in the pathophysiology of migraine. We used a rat model of migraine that triggered migraine attacks by applying inflammatory soup (IS) to the dura and examined changes in glycolysis. 2-DG was used to inhibit glycolysis, and the effects of 2-DG on mechanical ectopic pain, microglial cell activation, calcitonin gene-related peptides (CGRP), c-Fos, and inflammatory factors induced by inflammatory soup were observed. LPS stimulated BV2 cells to establish a model in vitro to observe the effects of 2-DG on brain-derived neurotrophic factor (BDNF) after microglia activation. In the experimental model of migraine, key enzymes involved in glycolysis such as phosphofructokinase platelet (PFKP), hexokinase (HK2), hypoxia inducible factor-1α (HIF-1α), lactate dehydrogenase (LDH) and pyruvate kinase (PKM2) were expressed in the medullary dorsal horn. While the expression of electronic respiratory transport chain complex IV (COXIV) decreased. There were no significant changes in glucose 6-phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway. The glycolysis inhibitor 2-DG alleviated migraine-like symptoms in an experimental model of migraine, reduced the release of proinflammatory cytokines caused by microglia activation, and decreased the expression of CGRP and c-Fos. Further experiments in vitro demonstrated that glycolysis inhibition can reduce the release of Iba-1/proBDNF/BDNF and inhibit the activation of microglia. The migraine rat model showed enhanced glycolysis. This study suggests that glycolytic inhibitor 2-DG is an effective strategy for alleviating migraine-like symptoms. Glycolysis inhibition may be a new target for migraine treatment.

Tension-Type Headache in Children and Adolescents.

In pediatric neurology, tension-type headache (TTH) represents a very common type of primary headache during the pediatric age. Despite the high prevalence of TTH, this diagnosis is often underestimated in childhood, with relevant difficulties in the differential diagnosis of TTH from secondary and primary headache manifestations. Even among primary headaches, a clinical overlap is not so infrequent in children: migraine attacks could present tension headache-like features while tension-type headaches may display migraine-like symptoms as well. Several variables play a role in the complex trajectory of headache evolution, such as hormonal changes during adolescence, triggers and genetic and epigenetic factors. The trajectories and outcomes of juvenile migraine and TTH, as well as the transition of one form to the other, have been investigated in several long-term prospective studies. Thus, the aim of this paper is to review the current literature on the differential diagnosis workout of TTH in pediatrics, the possible outcomes during the developmental age and the appropriate therapeutic strategies. Indeed, TTH represents a challenging diagnostic entity in pediatrics, both from a clinical and a therapeutic point of view, in which early diagnosis and appropriate treatment are recommended.

Migraine aura-like symptoms at onset of stroke and stroke-like symptoms in migraine with aura.

Background and objectivesIn general, suddenly occurring neurological deficits, i.e., negative neurological symptoms, are considered symptoms of focal cerebral ischemia, while positive irritative symptoms with gradual onset are viewed as the characteristics of migraine aura. Nevertheless, cortical spreading depolarization, the pathophysiological basis of migraine aura, has also been observed in acute ischemic stroke. The aim of our study was to determine the frequency of migraine aura-like symptoms at ischemic stroke onset and stroke-like symptoms in migraine with aura.MethodsWe interviewed 350 consecutive patients with ischemic stroke and 343 with migraine with aura using a structured questionnaire. Stroke diagnosis was confirmed by imaging, and migraine with aura was diagnosed according to the current criteria of the International Headache Society. Patients with wake-up strokes or severe cognitive deficits that precluded a useful interview were excluded from the study.ResultsSeventy-eight patients with stroke (22.3%) reported visual symptoms, 145 (41.4%) sensory symptoms, 197 (56.3%) a paresis, and 201 patients (57.4%) more than one symptom, compared to 326 migraine patients with aura (95%) with visual symptoms (P < 0.001), 175 (51%) with sensory symptoms (p = 0.011), 50 (14.6%) with paresis (P < 0.001), and 211 (61.5%) with more than one symptom (p = 0.27). Among patients with stroke, migraine-like symptoms were frequent: 36 patients (46.2%) with visual disturbance and 78 (53.8%) with sensory symptoms experienced irritative sensations. Paresis-onset in stroke lasted longer than 5 min in 43 patients (21.8%). Spreading of sensory and motor symptoms occurred in 37 (25.5%) and 37 (18.8%) patients, respectively. Stroke-like negative symptoms in migraine with aura occurred in 39 patients (12%) with visual symptoms, in 55 (31.4%) with sensory symptoms, and paresis appeared suddenly in 14 patients (28%). More than one symptom in succession occurred in 117 patients with stroke (58.2%) and in 201 migraine with aura patients (95.3%; P < 0.001).ConclusionMany patients with stroke experience migraine-like symptoms at stroke onset, and many migraine with aura patients have stroke-like symptoms. Though overall the symptom frequencies of the two groups are significantly different, clarifying the differential diagnosis in an individual patient requires additional history elements, physical findings, or results of ancillary investigations.

HCN2 Ion Channels Drive Pain in Rodent Models of Migraine.

Migraine is believed to be initiated by neuronal activity in the CNS, that triggers excitation of nociceptive trigeminal ganglion (TG) nerve fibers innervating the meninges and thus causes a unilateral throbbing headache. Drugs that precipitate or potentiate migraine are known to elevate intracellular levels of the cyclic nucleotides cAMP or cGMP, while anti-migraine treatments couple to signaling pathways that reduce cAMP or cGMP, suggesting an involvement of these cyclic nucleotides in migraine. Members of the HCN ion channel family are activated by direct binding of cAMP or cGMP, suggesting in turn that a member of this family may be a critical trigger of migraine. Here, we show that pharmacological block or targeted genetic deletion of HCN2 abolishes migraine-like pain in three rodent migraine models (in both sexes). Induction of migraine-like pain in these models triggered expression of the protein C-FOS, a marker of neuronal activity, in neurons of the trigeminocervical complex (TCC), where TG neurons terminate, and C-FOS expression was reversed by peripheral HCN2 inhibition. HCN2 block in vivo inhibited both evoked and spontaneous neuronal activity in nociceptive TG neurons. The NO donor glyceryl trinitrate (GTN) caused an increase in cGMP in the TG in vivo Exposing isolated TG neurons to GTN caused a rightward shift in the voltage dependence of HCN currents and thus increased neuronal excitability. This work identifies HCN2 as a novel target for the development of migraine treatments.SIGNIFICANCE STATEMENT Migraine is believed to be initiated by localized excitability of neurons within the CNS, but the most disturbing symptom, the characteristic throbbing migraine headache pain, is widely agreed to be caused by activity in afferent pain-sensitive (nociceptive) nerve fibers of the trigeminal nerve. Using a variety of preclinical models of migraine, we identify the HCN2 ion channel as the molecular source of trigeminal hyperexcitability in migraine and we show that pharmacological or genetic inhibition of HCN2 can relieve migraine-like pain symptoms. The work highlights the HCN2 ion channel as a potential pharmacological target for the development of novel analgesics effective in migraine.

CGRP Administration Into the Cerebellum Evokes Light Aversion, Tactile Hypersensitivity, and Nociceptive Squint in Mice.

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 tests was done to assess preclinical behaviors that are surrogates of migraine-like symptoms. 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. Moreover, significant responses to CGRP were seen in the open field assay, von Frey test, and automated squint assay, indicating anxiety, tactile hypersensitivity, and spontaneous pain, respectively. Interestingly, CGRP injection caused significant anxiety and spontaneous pain responses only in female mice, and a more robust tactile hypersensitivity in female mice. No detectable effect of CGRP on gait was observed in either sex. These results suggest that CGRP injection in the MN causes light aversion 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-like hypersensitivity.

Does fructose have a protective role on migraine?-experimental evidence in a rat model of metabolic syndrome under omega-3 supplementation.

BackgroundMigraine is a highly disabling disease, for which current therapies are limited to symptom alleviation. There is compelling evidence linking migraine with metabolic disorders, but the causal relationship is not clear. Omega-3 (n-3) fatty acids have anti-inflammatory properties, with clear benefits in metabolic disorders, but its effects on migraine remains to be tested. We hypothesized that fructose-induced metabolic syndrome could aggravate migraine by increasing neuroinflammation and that n-3 treatment could mitigate it.MethodsMale Wistar rats were used. Animals that received 10% high fructose diet (HFD) or tap water were subdivided into two additional groups: with or without n-3 supplementation. Fifteen days before euthanasia, each group was subdivided into two additional groups: with or without nitroglycerin (NTG)-induced migraine.ResultsHFD lessened the migraine-like painful symptoms, as indicated by decreased grimace scores, which paralleled with reduced CGRP and leptin serum levels, increased hypothalamic CGRP, and decreased hypothalamic adiponectin and IL-6. There was a recovery of body and adipose tissue weight, besides a reduction of crown-like structures (CLS) in the inguinal adipose tissue. N-3 supplementation had no effect on NTG-related pain, but it decreased body and adipose tissue weight of HFD and tap water NTG-injected rats. N-3 improved NTG-related affective behavior and inflammatory parameters in tap water NTG-injected rats, with decreased hypothalamic TNF, serum CGRP and inguinal adipose-tissue CLS.ConclusionsHFD relieved NTG-induced pain, possibly due to decreased energy expenditure, minimizing migraine energy needs. N-3 exhibited favorable effects regarding affective behavior and central and peripheral inflammation, irrespective of HFD.

Altered brain network functional connectivity patterns in patients with vestibular migraine diagnosed according to the diagnostic criteria of the Bárány Society and the International Headache Society

BackgroundVestibular migraine (VM) is considered one of the most common causes of episodic central vestibular disorders, the mechanism of VM is currently still unclear. The development of functional nuclear magnetic resonance (fMRI) in recent years offers the possibility to explore the altered functional connectivity patterns in patients with VM in depth. The study aimed to investigate altered patterns of brain network functional connectivity in patients with VM diagnosed based on the diagnostic criteria of the Bárány Society and the International Headache Society, and hope to provide a scientific theoretical basis for understanding whether VM is a no-structural central vestibular disease, i.e., functional central vestibular disease with altered brain function.MethodsSeventeen patients with VM who received treatment in our hospital from December 2018 to December 2020 were enrolled. Eight patients with migraine and 17 health controls (HCs) were also included. Clinical data of all patients were collected. Blood pressure, blood routine tests and electrocardiography were conducted to exclude other diseases associated with chronic dizziness. Videonystagmography, the vestibular caloric test, the video head impulse test and vestibular-evoked myogenic potentials were measured to exclude peripheral vestibular lesions. MRI was utilized to exclude focal lesions and other neurological diseases. All subjects underwent fMRI. The independent component analysis was performed to explore changes in intra- and inter-network functional connectivity in patients with VM.ResultsAmong 17 patients with VM, there were 7 males and 10 females with an average age of 39.47 ± 9.78 years old. All patients had a history of migraine. Twelve (70.6%) patients had recurrent spontaneous vertigo, 2 (11.7%) patients had visually induced vertigo, and 3 (17.6%) patients had head motion-induced vertigo. All 17 patients with VM reported worsening of dizziness vertigo during visual stimulation. The migraine-like symptoms were photophobia or phonophobia (n = 15, 88.2%), migraine-like headache (n = 8, 47.1%), visual aura during VM onset (n = 7, 41.2%). 5 (29.4%) patients with VM had hyperactive response during the caloric test, and 12 (70.6%) patients had caloric test intolerance. Eleven (64.7%) patients had a history of motion sickness. Totally 13 independent components were identified. Patients with VM showed decreased functional connectivity in the bilateral medial cingulate gyrus and paracingulate gyrus within sensorimotor network (SMN) compared with HCs. They also showed weakened functional connectivity between auditory network (AN) and anterior default mode network (aDMN) compared with HCs, and enhanced functional connectivity between AN and the salience network (SN) compared with patients with migraine.ConclusionPatients with vestibular migraine showed obvious altered functional connectivity in the bilateral medial cingulate gyrus and paracingulate gyrus within the SMN. The median cingulate and paracingulate gyri may be impaired, the disinhibition of sensorimotor network and vestibular cortical network may result in a hypersensitivity state (photophobia/phonophobia). Altered functional connectivity between AN and DMN, SN may lead to increased sensitivity to vestibular sensory processing.

Exogenous Hsp70 attenuates nitroglycerin-induced migraine-like symptoms in mice.

Although the connection between heat shock protein 70 (HSP70) and vestibular migraine is not clear, HSP70 is neuroprotective in other scenarios. This study aimed to investigate the potential of exogenous HSP70 for treating migraine-like symptoms in a mouse model of nitroglycerin (NTG)-induced migraine. HSP70 levels were assessed in patients with vestibular migraine and healthy individuals by ELISA. Migraine was induced in mice by NTG, and HSP70 expression was examined in the trigeminal nucleus caudalis (TNC) tissue of mice treated with NTG and NTG together with exogenous HSP70. The effects of exogenous HSP70 on migraine-like symptoms were assessed through behavioral assays. Finally, the impact of HSP70 on oxidative stress and NF-κB signaling in mice with migraine was investigated. Serum HSP70 in patients with vestibular migraine was significantly lower than that of healthy individuals. NTG administration significantly suppressed HSP70 expression in mouse TNC tissue, which was reversed by exogenous HSP70. HSP70 alleviated NTG-induced mechanical hypersensitivity, light aversion, and anxiety-like behavior. Finally, exogenous HSP70 suppressed NTG-induced oxidative stress and NF-κB signaling. Our study suggests that exogenous HSP70 may be a potential therapy for alleviating migraine symptoms and our promising finding warrants further investigation of HSP70 for clinical application.NEW & NOTEWORTHY The study suggests that exogenous HSP70 may be a potential therapy for alleviating migraine symptoms and our promising finding warrants further investigation of HSP70 for clinical application.

Discovery of tetrahydropalmatine and protopine regulate the expression of dopamine receptor D2 to alleviate migraine from Yuanhu Zhitong formula

BackgroundMigraine is the third most common disease worldwide, leading to severely decreased quality of life for the patients. In spite of great efforts endeavored in pharmacological and nonpharmacological therapeutic strategies for treating migraine, the outcome is rather disappointing in terms of efficacy. Compelling evidence shows that the expression level of dopamine receptor D2 (DRD2) plays an essential role in progression of migraine. PurposeTo explore potential therapeutical possibilities, the attention was paid to Yuanhu Zhitong formula (YHZTF), which is a classical traditional Chinese medicine prescription frequently applied to relieve pain. The aim of this study was to identify the promising compounds derived from YHZTF with anti-migraine effects and investigate the underlying molecular mechanism. MethodsThe high-resolution mass spectrometry and molecular networking were performed for comprehensive chemical profiling of YHZTF. Network pharmacology was used to generate herbal-component-target-pathway network. Based on the pathway enrichment analysis, the active substances of anti-migraine and the potential molecular mechanism were further determined by performing animal experiments combined with molecular docking strategy. ResultsIn total, 31 substances were identified in YHZTF, including alkaloids such as tetrahydropalmatine and protopine. The analysis of herbal-component-target-pathway network suggests that the alkaloid substances (e.g. tetrahydropalmatine and protopine) from YHZTF target dopamine receptors, thus can be linked to neuroactive ligand-receptor interaction pathways. In a nitroglycerin-induced migraine animal model, pretreatment with tetrahydropalmatine or protopine substantially lessened the aberrant migraine-like symptoms. The results of molecular docking analysis showed that tetrahydropalmatine and protopine had strong affinities to dopamine receptor D2 (DRD2). Using RT-qPCR, the investigators found that DRD2 was significantly down-regulated at the mRNA level in brain tissues of tetrahydropalmatine and protopine-treated group compared to the control group. ConclusionCollectively, the results provide reliable evidence showing that the active substances tetrahydropalmatine and protopine from YHZTF lessens migraine symptoms in an in vivo mouse model suggestively via regulating expression of DRD2. These findings shed light on novel therapeutic strategies and targets to treat migraine using natural products.

Orexin one receptors within the basolateral amygdala are involved in the modulation of cognitive deficits associated with a migraine-like state in rats

ABSTRACT Objectives This study explored the possible role of orexin one receptors (Orx1R) in the basolateral amygdala (BLA) on the modulation of nitroglycerin (NTG)-induced migraine-like symptoms. In addition, pain-induced subsequent alteration in learning and memory competence was evaluated in the adult male Wistar rats. Methods The rats were given NTG (5 mg/kg, i.p.) every two days (for nine-day) to induce a migraine-like state. The migraine animals were treated with intra-BLA infusion of an Orx1R antagonist SB 334,867 (10, 20, and 40 nM/rat) or its vehicle DMSO. The NTG-induced migraine symptoms were recorded for 90 min. Spatial and passive avoidance performances were assessed by Morris water maze (MWM) and shuttle box tasks, respectively. Results In comparison with control, NTG produced significant migraine-like symptoms characterized by a decrease in cage climbing and an increase in head-scratching, freezing, and facial grooming behavior. Intra-BLA infusion of SB 334,867 (40 nM/rat) significantly decreased cage climbing and increased facial grooming responses in NTG-treated rats. Moreover, all administrated doses of SB 334,867 increased NTG-evoked head-scratching and freezing behavior. Besides, NTG impaired learning and memory performances in both tests, which were exaggerated by post-injection of SB 334,867 (40 nM/rat). Conclusions Overall, the data provided an emerging role for the orexin system within BLA in the modulation of cognitive decline comorbid with migraine in rats.

CGRP induces migraine-like symptoms in mice during both the active and inactive phases

BackgroundCircadian patterns of migraine attacks have been reported by patients but remain understudied. In animal models, circadian phases are generally not taken into consideration. In particular, rodents are nocturnal animals, yet they are most often tested during their inactive phase during the day. This study aims to test the validity of CGRP-induced behavioral changes in mice by comparing responses during the active and inactive phases.MethodsMale and female mice of the outbred CD1 strain were administered vehicle (PBS) or CGRP (0.1 mg/kg, i.p.) to induce migraine-like symptoms. Animals were tested for activity (homecage movement and voluntary wheel running), light aversive behavior, and spontaneous pain at different times of the day and night.ResultsPeripheral administration of CGRP decreased the activity of mice during the first hour after administration, induced light aversive behavior, and spontaneous pain during that same period of time. Both phenotypes were observed no matter what time of the day or night they were assessed.ConclusionsA decrease in wheel activity is an additional clinically relevant phenotype observed in this model, which is reminiscent of the reduction in normal physical activity observed in migraine patients. The ability of peripheral CGRP to induce migraine-like symptoms in mice is independent of the phase of the circadian cycle. Therefore, preclinical assessment of migraine-like phenotypes can likely be done during the more convenient inactive phase of mice.