Migraine Pain Research Articles

Neuromodulation Techniques for Headache Management.

This narrative review aims to summarize evidence regarding the current utilization and future applications of neuromodulation in patients with headaches, with special attention paid to migraine and chronic cluster headache. A search was conducted in PubMed in August of 2023 to survey the current literature on neuromodulation for the treatment of headache. In total, the search yielded 1989 results, which were further filtered to include only systematic reviews published between 2022 to 2023 to capture the most up-to-date and comprehensive research on this topic. The citation lists of these articles were reviewed to find additional research on neuromodulation and supplement the results presented in this paper with primary literature. Research on the use of neuromodulation for the treatment of headache has predominantly focused on four neuromodulation techniques: peripheral nerve stimulation (PNS), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and spinal cord stimulation (SCS). Outcome measures reported in this article include impact on migraine and headache frequency and/or pain intensity, adverse effects of the neuromodulation technique, and associated costs, when available. We found that neuromodulation has developed utility as an alternative treatment for both chronic cluster headaches and migraines, with a reduction in frequency and intensity of headache most elucidated from the articles mentioned in this review.

Effectiveness of Palmitoylethanolamide (Levagen+) Compared to a Placebo for Reducing Pain, Duration, and Medication Use during Migraines in Otherwise Healthy Participants-A Double-Blind Randomised Controlled Study.

Migraines are a common neurological disorder that generally affects young to middle-aged adults and females more than males. Various treatment options are available; however, these can cause undesirable side effects. Therefore, alternative treatments with minimal side effects are still being investigated. Palmitoylethanolamide (PEA) is a signalling lipid known to have anti-inflammatory and analgesic properties. Previous prophylactic research has reported PEA supplementation to decrease pain associated with migraines. Upon commencement of migraine symptoms, participants were supplemented with either 600 mg of PEA (Levagen+) or a placebo (maltodextrin). Once a dose was taken, participants recorded a visual analogue scale (VAS) for pain every 30 min for 4 h or until the migraine resolved. If the migraine had not resolved 2 h post-dose, participants were instructed to take a second dose. Levagen+ supplementation resolved more headaches after 2- and 8 h, had a lower VAS for pain score at 1.5 and 4 h, and reduced rescue medication use significantly more than a placebo. No adverse events were reported in either group. Overall, PEA was safe and effective in reducing migraine pain, duration, and medication use in an otherwise healthy adult population.

Rebalancing NOX2/Nrf2 to limit inflammation and oxidative stress across gut-brain axis in migraine

Migraine is one of the most common neurological illnesses, and it is characterized by complicated neurobiology. It was confirmed the influence of inflammation and oxidative stress in migraines and also in distal organs such as the intestine. Indeed, the constant bidirectional communication between the Central Nervous System (CNS) and the gastrointestinal (GI) tract, known as the gut-brain axis, has become an attractive target involved in different human disorders. Herein, we explored the role of NADPH oxidase 2 (NOX2) in nitroglycerin (NTG)-induced migraine in mice models to discover the mechanism by which, during migraine attack, oxidative stress is sustained within trigeminal neurons and GI. Considering the inverse relationship between NOX2 and Nrf2, Nrf2 upregulation seems to be a promising approach to decrease NOX2 expression and consequently limit oxidative stress and inflammation spread in neurological and non-neurological diseases. With this aim, we exploited tempol's Nrf2-inducer ability to better understand the involvement of Nrf2/NOX2 axis in migraine and associated GI comorbidities. Behavioral tests confirmed that tempol, in a dose-dependent manner, moderated clinical signs of migraine and abdominal pain. Moreover, we demonstrated that the decrease in migraine-related symptomatology was strongly linked to the modulation of Nrf2/NOX2 signaling pathway in the brain and colon. In the brain, the rebalancing of Nrf2/NOX2 prevented neuronal loss, decreased glia reactivity while inhibiting NF-κB and NLRP3 inflammasome activation. In the colon, Nrf2 upregulation and consequent NOX2 decrease reduced the histological damage, mast cells infiltration as well as tumor necrosis factor (TNF)-α and interleukin (IL)-1β release. Furthermore, the attenuation of inflammation and oxidative stress led to the restoration of the intestinal barrier through TJs replacement. Taken as a whole, data suggested that the regulation of Nrf2/NOX2 balance is a successful way to reduce neurological and related intestinal impairments during migraine and could be of relevance for migraine-like attacks in humans.

Dry eye disease in episodic and chronic migraine: A cross-sectional clinic-based study

Background Dry eye disease (DED) and migraine, two common disorders with public health concerns, may have a bidirectional relationship. Population-based studies have found that migraine patients have higher odds of DED and vice versa. We aimed to evaluate and compare the presence of DED symptoms and objective signs between migraine patients and non-migraine controls. Methods This was a case-control study. We prospectively enrolled 60 consecutive migraine patients (30 episodic and 30 chronic) presenting in the medicine outpatient department, aged 18–65 years, and 60 non-migraine healthy controls visiting the ophthalmology department for refractive errors between February 2019 and June 2021. Consecutive migraine patients and non-migraine healthy controls were assessed in the ophthalmology department at Hindu Rao Hospital, Delhi by the Ocular Disease Surface Index (OSDI) questionnaire for DED symptoms and objectively by measuring tear break-up time (TBUT), Schirmer test (ST), and Fluorescein staining (FS). DED severity was assessed by the Odessey algorithm. Results The mean OSDI score was significantly greater in migraineurs than in controls (31.2 ± 19.8 vs 22.7 ± 15.6; p = 0.010). 45% of migraineurs had DED compared to 18.3% in controls (p = 0.002), whereas 23.3% had severe DED compared to one (1.7%) in the control group (p < 0.001). Migraineurs, compared to controls, had significantly lower mean TBUT (10.1 ± 6.5 s versus 13.4 ± 5.8 s; p = 0.004), higher FS grade (1.57 ± 1.4 versus 0.92 ± 1.2; p = 0.008) and lower ST scores (11.5 ± 5.8 mm versus 14.2 ± 6.2 mm; p = 0.014). Migraineurs with DED, compared with those without DED, had longer migraine disease duration, higher frequency, pain severity, and disability. Compared to episodic migraine, chronic migraine patients had significantly lower TBUT (11.9 ± 5.9 vs 8.3 ± 6.7; p = 0.30) and higher OSDI scores (25.7 ± 20.1 vs 36.8 ± 18.2). Conclusions This study showed that migraine patients had an increased presence of DED and severe DED compared to controls. Further, increased migraine severity and chronicity were associated with increased subjective symptoms and objective signs of DED. Migraine patients with DED were more disabled.CM patients had more DED symptoms and signs.

Atogepant: Mechanism of action, clinical and translational science.

Since the discovery of calcitonin gene-related peptide (CGRP) in 1982, its integral role in migraine pathophysiology, specifically migraine pain, has been demonstrated through cumulative scientific discoveries that have led to the development and approval of migraine-specific therapeutics. Today, eight drugs, including monoclonal antibodies and small molecule CGRP receptor antagonists, known as gepants, have received approval for acute or preventive treatment of migraine. The primary mechanism of these drugs is to block CGRP signaling, thus preventing CGRP-mediated nociception and neurogenic inflammation. Here, we focus on atogepant, a highly potent and selective gepant and the first and only oral medication approved for the preventive treatment of both episodic and chronic migraine in adults. In this article, we summarize the role of CGRP in migraine pathophysiology and the mechanism of action of atogepant. In addition, we provide an overview of atogepant's pharmacology and the key clinical trials and outcomes that have demonstrated the safety and efficacy of atogepant.

Calcitonin gene-related peptide receptor antagonism reduces motion sickness indicators in mouse migraine models.

Migraine and vestibular migraine are disorders associated with a heightened motion sensitivity that provoke symptoms of motion-induced nausea and motion sickness. VM affects ∼3% of adults in the USA and affects three-fold more women than men. Triptans (selective serotonin receptor agonists) relieve migraine pain but lack efficacy for vertigo. Murine models of photophobia and allodynia have used injections of calcitonin gene-related peptide (CGRP) or other migraine triggers, such as sodium nitroprusside (SNP), to induce migraine sensitivities in mice to touch and light. Yet, there is limited research on whether these triggers affect motion-induced nausea in mice, and whether migraine blockers can reduce these migraine symptoms. We hypothesized that systemic delivery of CGRP or SNP will increase motion sickness susceptibility and motion-induced nausea in mouse models, and that migraine blockers can block these changes induced by systemically delivered CGRP or SNP. We investigated two measures of motion sickness assessment [motion sickness index (MSI) scoring and motion-induced thermoregulation] after intraperitoneal injections of either CGRP or SNP in C57BL/6J mice. The drugs olcegepant, sumatriptan and rizatriptan were used to assess the efficacy of migraine blockers. MSI measures were confounded by CGRP's effect on gastric distress. However, analysis of tail vasodilatations as a surrogate for motion-induced nausea was robust for both migraine triggers. Only olcegepant treatment rescued tail vasodilatations. These preclinical findings support the use of small molecule CGRP receptor antagonists for the treatment of motion-induced nausea of migraine, and show that triptan therapeutics are ineffective against motion-induced nausea of migraine.Trial Registration: Not Applicable.

Effects of somatostatin, a somatostatin agonist, and an antagonist, on a putative migraine trigger pathway

ObjectiveTo determine whether somatostatin (SST) could be a cortico-brainstem neurotransmitter involved in producing the headache of migraine. BackgroundThere is evidence to support the idea that a cortico-brainstem-trigeminal nucleus neuraxis might be responsible for producing migraine headache; we have suggested that SST may be one of the neurotransmitters involved. MethodsRats were anesthetised and prepared for recording neurons in either the periaqueductal gray matter (PAG) or nucleus raphe magnus (NRM), as well as the trigeminal nucleus caudalis (TNC). The dura mater and facial skin were stimulated electrically or mechanically. SST, the SST agonist L054264 and the SST antagonist CYN54806 were injected intravenously, by microinjection, or by iontophoresis into the PAG or NRM. Cortical neuronal activity was provoked by cortical spreading depression (CSD) or light flash (LF) and was monitored by recording cortical blood flow (CBF). ResultsIntravenous injection of SST: (a) selectively decreased the responses of TNC neurons to stimulation of the dura, but not skin, for up to 5 h; (b) decreased the ongoing discharge rate of TNC neurons while simultaneously increasing the discharge rate of neurons in either brainstem nucleus and; (c) prevented, or reversed, the effect of CSD and LF on brainstem and trigeminal neuron discharge rates. CSD and LF decreased the discharge rate of neurons in both brainstem nuclei and increased the discharge rate of TNC neurons. These effects were reversed by L054264 and mimicked by CYN54806. Injections of L054264 into the PAG or NRM reduced the response of TNC neurons to dural stimulation and skin stimulation differentially, depending on the nucleus injected. Injections of CYN54806 into either brainstem nucleus potentiated the responses of TNC neurons to dural and skin stimulation, but without a marked differential effect. ConclusionsThese results imply that SST could be a neurotransmitter in a pathway responsible for migraine pain.

Gastrodin alleviates NTG-induced migraine-like pain via inhibiting succinate/HIF-1α/TRPM2 signaling pathway in trigeminal ganglion

BackgroundIncreasing evidence highlights the involvement of metabolic disorder and calcium influx mediated by transient receptor potential channels in migraine; however, the relationship between these factors in the pathophysiology of migraine remains unknown. Gastrodin is the major component of the traditional Chinese medicine Tianma, which is extensively used in migraine therapy. PurposeOur work aimed to explore the analgesic action of gastrodin and its regulatory mechanisms from a metabolic perspective. Methods/resultsAfter being treated with gastrodin, the mice were given nitroglycerin (NTG) to induce migraine. Gastrodin treatment significantly raised the threshold of sensitivity in response to both mechanical and thermal stimulus evidenced by von Frey and hot plate tests, respectively, and decreased total contact numbers in orofacial operant behavioral assessment. We found that the expression of transient receptor potential melastatin 2 (TRPM2) channel was increased in the trigeminal ganglion (TG) of NTG-induced mice, resulting in a sustained Ca2+ influx to trigger migraine pain. The content of succinate, a metabolic biomarker, was elevated in blood samples of migraineurs, as well as in the serum and TG tissue from NTG-induced migraine mice. Calcium imaging assay indicated that succinate insult elevated TRPM2-mediated calcium flux signal in TG neurons. Mechanistically, accumulated succinate upregulated hypoxia inducible factor-1α (HIF-1α) expression and promoted its translocation into nucleus, where HIF-1α enhanced TRPM2 expression through transcriptional induction in TG neurons, evidenced by luciferase reporter measurement. Gastrodin treatment inhibited TRPM2 expression and TRPM2-dependent Ca2+ influx by attenuating succinate accumulation and downstream HIF-1α signaling, and thereby exhibited analgesic effect. ConclusionThis work revealed that succinate was a critical metabolic signaling molecule and the key mediator of migraine pain through triggering TRPM2-mediated calcium overload. Gastrodin alleviated NTG-induced migraine-like pain via inhibiting succinate/HIF-1α/TRPM2 signaling pathway in TG neurons. These findings uncovered the anti-migraine effect of gastrodin and its regulatory mechanisms from a metabolic perspective and provided a novel theoretical basis for the analgesic action of gastrodin.

Analysis of the ocular surface functional unit in episodic migraine

AimMigraine is a chronic neurovascular disease that affects the trigeminovascular system. The purpose of this study was to evaluate corneal subbasal nerve fibers, dendritic cells and to measure tear film parameters in migraine.Patients and methods87 eyes of 44 patients suffering from migraine with a mean age of 33.23 ± 11.41 years were included in our study. 25 age-matched controls (mean age of 30.16 ± 12.59 years; P = 0.162) were recruited. The corneal subbasal plexus and the dendritic cells (DC) were analyzed using in vivo confocal microscopy (Heidelberg Retina Tomograph II Rostock Cornea Module; Heidelberg Engineering GmbH), and the tear film was imaged using LacryDiag (Quantel Medical, France).ResultsRegarding the subbasal nerve fibers of the cornea, none of the examined parameters differed significantly in migraine patients from controls. We found a significant increase in the corneal DC density (P < 0.0001) and DC area (P < 0.0001) in migraine patients compared to healthy volunteers. DC density showed a positive correlation with the monthly attack frequency (r = 0.32, P = 0.041) and the DC area a negative correlation with corneal nerve branch density (r = -0.233, P = 0.039), nerve fiber length (r = -0.232, P = 0.04) and total branch density (r = -0.233, P = 0.039). Using LacryDiag a significant loss of Meibomian gland area could be detected on the superior eyelid (P = 0.005) in migraine.ConclusionsOur results suggest the presence of neuroinflammation in the cornea of migraine patients affecting the peripheral trigeminal system. Dendritic cells surrounding the subbasal plexus may be involved in the activation and modulation of pain in migraine.

The Application of Botulinum Toxin in the Prophylactic Treatment of Migraine

Abstract Introduction: Migraine is a common disorder that affects about 2% of the general population, with a prevalence of 7% in men, 24% in women and 4% in children. Migraine is the fourth most disabling condition among women and the seventh most disabling worldwide. It is characterized by paroxysmal, throbbing headaches, often unilateral, accompanied by hypersensitivity to noise, light, nausea and vomiting. Migraine is divided into episodic and chronic, with chronic meaning headache for at least 15 days a month for more than 3 months, with 8 migraine days. Treatment includes non-pharmacological and pharmacological methods, but often ineffective and fraught with side effects. Chronic migraine can lead to significant disability. Material and methods: The purpose of this article is to discuss the treatment of migraine with botulinum toxin. Information was collected from the English-language databases Google Scholar, Scopus and PubMed. Results :Onabotulinum toxin A, approved for the treatment of migraine, works by blocking acetylcholine release at the synapse level, leading to reversible flaccid paralysis and blocking neurotransmitters such as CGRP. Injection sites include peri-cranial and neck muscles, allowing the toxin to be transported to the meninges and trigeminal ganglion. In recent years, injections near the cranial sutures have been preferred. BTX-A therapy has shown efficacy in reducing the frequency and severity of migraine pain, with fewer side effects compared to topiramate. Side effects, such as hematoma or ptosis, are rare and their frequency decreases with subsequent sessions. The cost of migraine treatment is high, but botulinum toxin reduces headache days and is cost-effective.

Cervical muscle parameters and allodynia in migraine and cervical pain-A controlled study.

Neck pain is common among individuals with migraine, but there is a lack of information of how this comorbidity can be associated with cervical muscle function. This controlled cross-sectional study aimed to compare cervical muscle function, activity, and sensitization in women with migraine, neck pain, both, and neither. This study included women, between 18 and 55 years old, with either episodic migraine with or without aura, without any concomitant headache diagnosis; chronic neck pain, with at least moderate intensity and mild disability; or neither headache nor neck pain. Pain pressure threshold, allodynia, muscle strength, and endurance and cervical muscles activity were evaluated. One hundred subjects, with mean age of 30.4 years old, were stratified by diagnosis (n = 25 per group) and by self-reported pain during tests. Lower endurance during flexion was observed for migraine and neck pain (34s) relative to neck pain alone (45s), migraine (40s), and controls (58s) (p = 0.04). For extensor endurance, means were 142s, 166s, 215s, and 270s, respectively (p < 0.001). Endurance times were impacted by the presence of test-induced pain decreasing about 40%-53% of the performance. Diagnostic groups did not differ significantly in strength (p > 0.05), but all pain groups presented significantly higher proportion of test-induced pain, lower muscle activity during the maximal isometric voluntary contractions, and lower pressure pain thresholds. Patients with migraine, chronic neck pain, and the association of both present altered cervical muscle function and activity. Also, test-induced pain impacts significantly on neck muscles endurance. The diagnosis of migraine and chronic neck pain is associated with altered function and activity of the cervical muscles. However, the test-induced pain had an important contribution to worse cervical muscle endurance. This suggests that the therapeutic approach should focus on de-sensitization of the trigeminal-cervical complex when dealing with the comorbidity of migraine and cervical pain.

Are there network differences between the ipsilateral and contralateral hemispheres of pain in patients with episodic migraine without aura?

Background: We aimed to identify any differences in the structural covariance network based on structural volume and those in the functional network based on cerebral blood flow between the ipsilateral and contralateral hemispheres of pain in patients with episodic migraine without aura.Methods: We prospectively enrolled 27 patients with migraine without aura, all of whom had unilateral migraine pain. We defined the ipsilateral hemisphere as the side of migraine pain. We measured structural volumes on three-dimensional T1-weighted images and cerebral blood flow using arterial spin labeling magnetic resonance imaging. We then analyzed the structural covariance network based on structural volume and the functional network based on cerebral blood flow using graph theory. Results: There were no significant differences in structural volume or cerebral blood flow between the ipsilateral and contralateral hemispheres. However, there were significant differences between the hemispheres in the structural covariance network and the functional network. In the structural covariance network, the betweenness centrality of the thalamus was lower in the ipsilateral hemisphere than in the contralateral hemisphere. In the functional network, the betweenness centrality of the anterior cingulate and paracingulate gyrus was lower in the ipsilateral hemisphere than in the contralateral hemisphere, while that of the opercular part of the inferior frontal gyrus was higher in the former hemisphere.Conclusions: The present findings indicate that there are significant differences in the structural covariance network and the functional network between the ipsilateral and contralateral hemispheres of pain in patients with episodic migraine without aura.

Orofacial Migraine and Other Idiopathic Non-Dental Facial Pain Syndromes: A Clinical Survey of a Social Orofacial Patient Group.

Background: Orofacial pain syndromes (OFPs) are a heterogeneous group of syndromes mainly characterized by painful attacks localized in facial and oral structures. According to the International Classification of Orofacial Pain (ICOP), the last three groups (non-dental facial pain, NDFP) are cranial neuralgias, facial pain syndromes resembling primary headache syndromes, and idiopathic orofacial pain. These are often clinical challenges because the symptoms may be similar or common among different disorders. The diagnostic efforts often induce a complex diagnostic algorithm and lead to several imaging studies or specialized tests, which are not always necessary. The aim of this study was to describe the encountered difficulties by these patients during the diagnostic-therapeutic course. Methods: This study was based on the responses to a survey questionnaire, administered to an Italian Facebook Orofacial Patient Group, searching for pain characteristics and diagnostic-therapeutic care courses. The questionnaire was filled out by patients affected by orofacial pain, who were 18 years and older, using a free online tool available on tablets, smartphones, and computers. Results: The sample was composed of 320 subjects (244F/76M), subdivided by age range (18-35 ys: 17.2%; 36-55 ys: 55.0%; >55 ys 27.8%). Most of the patients were affected by OFP for more than 3 years The sample presented one OFP diagnosis in 60% of cases, more than one in 36.2% of cases, and 3.8% not classified. Trigeminal neuralgia is more represented, followed by cluster headaches and migraines. About 70% had no pain remission, showing persisting background pain (VAS median = 7); autonomic cranial signs during a pain attack ranged between 45 and 65%. About 70% of the subjects consulted at least two different specialists. Almost all received drug treatment, about 25% received four to nine drug treatments, 40% remained unsatisfied, and almost 50% received no pharmacological treatment, together with drug therapy. Conclusion: To the authors' knowledge, this is the first study on an OFP population not selected by a third-level specialized center. The authors believe this represents a realistic perspective of what orofacial pain subjects suffer during their diagnostic-therapeutic course and the medical approach often results in unsatisfactory outcomes.

Neurovascular Compression-Induced Intracranial Allodynia May Be the True Nature of Migraine Headache: an Interpretative Review.

Surgical deactivation of migraine trigger sites by extracranial neurovascular decompression has produced encouraging results and challenged previous understanding of primary headaches. However, there is a lack of in-depth discussions on the pathophysiological basis of migraine surgery. This narrative review provides interpretation of relevant literature from the perspective of compressive neuropathic etiology, pathogenesis, and pathophysiology of migraine. Vasodilation, which can be asymptomatic in healthy subjects, may produce compression of cranial nerves in migraineurs at both extracranial and intracranial entrapment-prone sites. This may be predetermined by inherited and acquired anatomical factors and may include double crush-type lesions. Neurovascular compression can lead to sensitization of the trigeminal pathways and resultant cephalic hypersensitivity. While descending (central) trigeminal activation is possible, symptomatic intracranial sensitization can probably only occur in subjects who develop neurovascular entrapment of cranial nerves, which can explain why migraine does not invariably afflict everyone. Nerve compression-induced focal neuroinflammation and sensitization of any cranial nerve may neurogenically spread to other cranial nerves, which can explain the clinical complexity of migraine. Trigger dose-dependent alternating intensity of sensitization and its synchrony with cyclic central neural activities, including asymmetric nasal vasomotor oscillations, may explain the laterality and phasic nature of migraine pain. Intracranial allodynia, i.e., pain sensation upon non-painful stimulation, may better explain migraine pain than merely nociceptive mechanisms, because migraine cannot be associated with considerable intracranial structural changes and consequent painful stimuli. Understandingmigraine as an intracranial allodynia could stimulate research aimed at elucidating the possible neuropathic compressive etiology of migraine and other primary headaches.

B - 91 Cognition as a Premonitory Symptom of Migraine.

Migraine is often accompanied by premonitory symptoms (neurologic symptoms preceding migraine pain) which serve as "warning signs." Cognition changes are commonly described during the premonitory period (period preceding pain onset). Ecological momentary assessment can be utilized to understand if perceived cognitive changes are a symptom patients use as an indicator of the premonitory period. Participants with episodic migraine were recruited through a large urban health system and online advertising (n = 43). Individuals participated in a three-month, three-times-a-day electronic diary answering questions regarding migraine attack symptoms, including perception of being in a premonitory period, and the presence of premonitory symptoms, including "difficulty thinking or concentrating." The frequency of perceived cognitive difficulties was analyzed during the perceived premonitory period (endorsing "I think I might get a headache") vs. the perceived interictal period (endorsing "I do not anticipate a headache"). Cross tabs evaluated the frequencies of perceived cognitive difficulties during different migraine phases. Participants were predominantly White (n = 33, 76.7%), non-Hispanic (n = 33, 76.7%) women (n = 36, 83.7%). Thirty-three participants endorsed subjective cognitive difficulties at least once during the premonitory phase (n = 33; 76.75%). Difficulty thinking and concentrating was endorsed 35.16% of the time when participates also reported anticipating a headache in the morning and only 8.36% of the time when participants reported not anticipating a headache. Participants perceived cognitive decline as a premonitory symptom. Difficulty concentrating and thinking was endorsed more when participants anticipated getting a headache vs. when not. Assessing subjective cognitive decline as a premonitory symptom can guide individualized interventions for migraine and elucidate the relationship between cognition and migraine.

Deciphering migraine pain mechanisms through electrophysiological insights of trigeminal ganglion neurons

Migraine is a complex neurological disorder that affects millions of people worldwide. Despite extensive research, the underlying mechanisms that drive migraine pain and related abnormal sensation symptoms, such as hyperalgesia, allodynia, hyperesthesia, and paresthesia, remain poorly understood. One of the proposed mechanisms is cortical spreading depression (CSD), which is believed to be involved in the regulation of trigeminovascular pathways by sensitizing the pain pathway. Another mechanism is serotonin depletion, which is implicated in many neurological disorders and has been shown to exacerbate CSD-evoked pain at the cortical level. However, the effects of CSD and serotonin depletion on trigeminal ganglion neurons, which play a critical role in pain signal transmission, have not been thoroughly studied. In this study, we aimed to investigate the association between CSD and serotonin depletion with peripheral sensitization processes in nociceptive small-to-medium (SM) and large (L) -sized trigeminal ganglion neurons at the electrophysiological level using rat models. We divided the rats into four groups: the control group, the CSD group, the serotonin depletion group, and the CSD/serotonin depletion group. We induced CSD by placing KCl on a burr hole and serotonin depletion by intraperitoneal injection of PCPA (para-chlorophenoxyacetic acid). We then isolated trigeminal ganglion neurons from all groups and classified them according to size. Using patch-clamp recording, we recorded the excitability parameters and action potential (AP) properties of the collected neurons. Our results showed that in SM-sized trigeminal ganglion neurons, the CSD-SM and CSD/serotonin depletion groups had a higher positive resting membrane potential (RMP) than the control-SM group (p = 0.001 and p = 0.002, respectively, post-hoc Tukey’s test). In addition, the gap between RMP and threshold in the CSD-SM group was significantly narrower than in the control-SM group (p = 0.043, post-hoc Tukey’s test). For L-sized neurons, we observed prolongation of the AP rising time, AP falling time, and AP duration in neurons affected by CSD (p < 0.05, pairwise comparison test). In conclusion, our study provides new insights into the underlying mechanisms of migraine pain and abnormal somatosensation. CSD and serotonin depletion promote the transmission of pain signals through the peripheral sensitization process of nociceptive small-to-medium-sized trigeminal ganglion neurons, as well as nociceptive and non-nociceptive large-sized trigeminal ganglion neurons.

Can upper cervical manual therapy affect the blink reflex in subjects with migraine and neck pain?

ABSTRACT Background Neck pain is a common complaint among migraineurs possibly due to the anatomic connections between cervical and trigeminal afferents in the trigeminocervical complex (TCC). Manual therapy (MT) is used in the management of headache disorders, with demonstrable neurophysiological effects. The blink reflex (BR) is one method of analyzing neurophysiological effects in headache patients. The purpose of this study was to investigate the effect of upper cervical spine MT on BR in subjects with migraine and neck pain. Methods & Materials Twenty subjects were assigned to a medication plus MT (MedMT) group (n = 10) and medication plus sham MT (sham MT) group (n = 10). After random assignment, all patients underwent testing for the BR (R1, R2, R2c responses). Then, subjects in group MedMT and group sham MT received either 4 sessions of MT or sham MT to the upper cervical spine. After completion of the intervention, BR testing was repeated. Results There were no significant differences in both side R1 latency between group MT and group sham MT (P > 0.050). For both sides, R2 latencies were significantly prolonged in MedMT group compared with sham MT group (P < 0.050). Subjects in MedMT group showed significant prolongation in right and left R2c latency compared with sham MT group (P < 0.050). Discussion The present study demonstrated that upper cervical MT affected trigeminal nociceptive neurotransmission in subjects with migraine and neck pain as reflected by changes in the BR. The increase in BR late response latencies of BR indicates an inhibitory effect of upper cervical spine MT on the TCC in these subjects. Trial Registration: The trial design was registered at the Iranian Registry of Clinical Trials (IRCT ID: IRCT20160621028567N2, url: https://www.irct.ir/) before the first patient was enrolled.

Migraine as a Disease Associated with Dysbiosis and Possible Therapy with Fecal Microbiota Transplantation.

Migraine is a painful neurological condition characterized by severe pain on one or both sides of the head. It may be linked to changes in the gut microbiota, which are influenced by antibiotic use and other factors. Dysbiosis, which develops and persists as a result of earlier antibiotic therapy, changes the composition of the intestinal flora, and can lead to the development of various diseases such as metabolic disorders, obesity, hematological malignancies, neurological or behavioral disorders, and migraine. Metabolites produced by the gut microbiome have been shown to influence the gut-brain axis. The use of probiotics as a dietary supplement may reduce the number and severity of migraine episodes. Dietary strategies can affect the course of migraines and are a valuable tool for improving migraine management. With fecal microbiota transplantation, gut microbial restoration is more effective and more durable. Changes after fecal microbiota transplantation were studied in detail, and many data help us to interpret the successful interventions. The microbiological alteration of the gut microflora can lead to normalization of the inflammatory mediators, the serotonin pathway, and influence the frequency and intensity of migraine pain.

Mechanisms of initiation of cortical spreading depression

BackgroundThere is increasing evidence from human and animal studies that cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura and a trigger of migraine pain mechanisms. The mechanisms of initiation of CSD in the brain of migraineurs remain unknown, and the mechanisms of initiation of experimentally induced CSD in normally metabolizing brain tissue remain incompletely understood and controversial. Here, we investigated the mechanisms of CSD initiation by focal application of KCl in mouse cerebral cortex slices.MethodsHigh KCl puffs of increasing duration up to the threshold duration eliciting a CSD were applied on layer 2/3 whilst the membrane potential of a pyramidal neuron located very close to the site of KCl application and the intrinsic optic signal were simultaneously recorded. This was done before and after the application of a specific blocker of either NMDA or AMPA glutamate receptors (NMDARs, AMPARs) or voltage-gated Ca2+ (CaV) channels. If the drug blocked CSD, stimuli up to 12–15 times the threshold were applied.ResultsBlocking either NMDARs with MK-801 or CaV channels with Ni2+ completely inhibited CSD initiation by both CSD threshold and largely suprathreshold KCl stimuli. Inhibiting AMPARs with NBQX was without effect on the CSD threshold and velocity. Analysis of the CSD subthreshold and threshold neuronal depolarizations in control conditions and in the presence of MK-801 or Ni2+ revealed that the mechanism underlying ignition of CSD by a threshold stimulus (and not by a just subthreshold stimulus) is the CaV-dependent activation of a threshold level of NMDARs (and/or of channels whose opening depends on the latter). The delay of several seconds with which this occurs underlies the delay of CSD initiation relative to the rapid neuronal depolarization produced by KCl.ConclusionsBoth NMDARs and CaV channels are necessary for CSD initiation, which is not determined by the extracellular K+ or neuronal depolarization levels per se, but requires the CaV-dependent activation of a threshold level of NMDARs. This occurs with a delay of several seconds relative to the rapid depolarization produced by the KCl stimulus. Our data give insights into potential mechanisms of CSD initiation in migraine.

D2 dopamine receptor-mediated mechanisms of dopaminergic system modulation in in vivo and in vitro experimental models of migraine.

The dopaminergic system is implicated in the pathophysiology of migraine. However, the underlying mechanisms remain unclear. We explored the effects and mechanisms of dopaminergic system modulation in the in vivo and in vitro rat models of migraine. Dopaminergic agonist apomorphine, D2 receptor antagonists metoclopramide and haloperidol and 5-HT3 receptor antagonist ondansetron alone and together were tested in nitroglycerin-induced migraine model, in vivo. Likewise, the combinations of drugs were also tested on basal calcitonin gene-related peptide (CGRP) release in vitro hemiskull preparations. Mechanical allodynia was tested by von Frey filaments. CGRP concentrations in trigeminovascular structures and in vitro superfusates and c-Fos levels in the brainstem were determined by enzyme-linked immunosorbent assay. Meningeal mast cells were evaluated with toluidine blue staining. Apomorphine further enhanced nitroglycerin-induced mechanical allodynia, brainstem c-fos expression, trigeminal ganglion and brainstem CGRP concentrations and meningeal mast cell degranulation, in vivo. Haloperidol completely antagonised all apomorphine-induced effects and also alleviated changes induced by nitroglycerin without apomorphine. Metoclopramide and ondansetron partially attenuated apomorphine- or nitroglycerin-induced effects. A combination of haloperidol and ondansetron decreased basal CGRP release, in vitro, whereas the other administrations were ineffective. Apomorphine-mediated dopaminergic activation exacerbated nitroglycerin-stimulated nociceptive reactions by further enhancing c-fos expression, CGRP release and mast cell degranulation in strategical structures associated with migraine pain. Metoclopramide partially attenuated the effects of apomorphine, most likely because it is also a 5-HT3 receptor antagonist. Haloperidol with pure D2 receptor antagonism feature appears to be more effective than metoclopramide in reducing migraine-related parameters in dopaminergic activation- and/or NTG-induced migraine-like conditions.