1 INTRODUCTION

Migraine is a disabling neurological disorder estimated to affect at least one in ten individuals worldwide.1 Though characteristically presenting as a headache lasting several hours, symptoms often vary from person to person. Typically, there are four phases that the disorder's episodes typically follow. Firstly, a prodromal phase serves as a warning of an upcoming episode. In this phase, an individual may exhibit an altered or irritable mood, depression, hyperphotosensitivity, and hyperosmia. Next there is an aura phase whereby the patient experiences perceptual disturbances. These are most commonly visual disturbances such as scotomas. Symptoms may also include dizziness, numbness, auditory disturbances, and temporary aphasia. However, it should be noted that aura is not specific to migraine and is experienced in other headache syndromes, albeit in varying proportions, such as up to 23% in cluster headache.2-4 The third phase is characterized by a severe pulsatile headache often accompanied by nausea, photophobia, osmophobia, and phonophobia. Finally, a hangover-like postdromal phase occurs as the body recovers from the episode. Postdromal symptoms often include soreness, tiredness, malaise, and impairments in cognition. The disorder is further complicated by some patients presenting with headache without aura, and others with aura in the absence of headache.

The International Headache Society defines chronic migraine (CM) as “headache occurring on 15 or more days per month for more than three months, which, on at least 8 days per month, has the features of migraine headache.”5 Headache symptoms occurring for 0–14 days per month is subsequently classified as episodic migraine (EM). Pharmacological treatment options for CM are diverse and include: acetaminophen, triptans, topiramate, valproate, propranolol, amitriptyline, candesartan, and riboflavin. If there's a lack of response to first-line oral medications, further treatment options include: greater occipital nerve block, occipital nerve stimulation, cognitive behavioral therapy to help with stress management, transcranial magnetic stimulation, acupuncture, and intramuscular botulinum toxin (BoTox) injections. Following successful clinical trials, three monoclonal antibodies targeting CGRP signaling have been FDA-approved as novel migraine therapies: erenumab,6-8 fremanezumab,9, 10 and galcanezumab.11-13

BoTox is an exotoxin produced by the gram-positive rod bacterium Clostridium botulinum. During the agent's initial use in aesthetic medicine to reduce facial muscle tone, simultaneous findings of reduced headaches in patients14-16 sparked an interest in utilizing the agent as a potential migraine therapy. Clinical trials on the efficacy of the “A” serotype of the toxin (BTX-A) for the treatment of migraine soon followed, the most notable being the PRE-EMPT studies.17, 18 The pair of placebo-controlled phase 3 clinical trials showed a significant reduction from baseline in the frequency of both headache days and migraine days in CM patients. Additionally, BTX-A therapy showed a reduction in Headache Impact Test (HIT-6) scores and the cumulative total of headache hours on headache days. The HIT-6 is a six point questionnaire designed to be a reliable and efficient assessment of the impact of headaches in migraine patients.19, 20 In 2010, BTX-A received FDA approval for the treatment of CM. Recent meta-analyses have shown 3-month courses of BTX-A to reduce migraine frequency in CM patients by 1.5621 and 2.022 days/month.

2 METHOD

A literature search was performed using EMBASE, PubMed, and Cochrane's Central Register of Controlled Trials (CENTRAL) using key search terms: “migraine pathophysiology”, “migraine transformation,” “GWAS migraine,” “migraine risk factors,” “chronic migraine,” “migraine chronification,” “pathogenesis of chronic migraine,” “migraine transformation,” “chronic migraine risk factors,” “botulinum toxin,” “botulinum toxin mechanism,” “BTX,” “botulinum toxin and migraine,” “botulinum toxin and chronic migraine.” Following the removal of duplicates, the literature search was filtered out for conference abstracts, correspondence articles, and narrative reviews. Abstracts were screened for their relevance to the mechanisms and processes underlying migraine pathophysiology, CM transformation, and the action of BTX-A. Furthermore, abstracts were excluded for inappropriate study design (such as non-blinded studies or those without control groups), interventions other than intramuscular BTX-A, and/or outcomes beyond the scope of this review. Subsequently, full-text articles were assessed for pre-set eligibility criteria relating to recent study dates, citations per paper, impact factor of journals published in, and appropriate sample sizes for statistical power and ≥95% confidence in analysis. Additionally, articles were filtered for content redundancy and literature on pediatric populations was excluded. A further two articles were included after a manual search, the resulting reference list was included this following narrative review.

3 MIGRAINE PATHOPHYSIOLOGY

Migraine was long attributed to heightened blood flow to the brain; however, both intracranial and extracranial vasodilation have been shown to not play a primary role in migraine pathophysiology.23 Presently, migraine is seen as a disorder of altered thresholds which, when low, result in susceptibility to a migraine attack. As summarized in Figure 1, there are three leading models as to how this reduced threshold arises.

Brain structures implicated in models of migraine: Trigeminal afferent circuitry (pink) and descending modulatory circuitry (blue). Also note the thalamic nuclei which have been implicated in central sensitisation

3.1 Hyperactivity of trigeminal afferents

Nociceptive information from the face and meninges is relayed to higher cortical areas via trigeminal afferents which secrete the potent neuropeptides substance P and calcitonin gene-related peptide (CGRP). Elevated CGRP levels have been shown to be a strong biomarker for migraine during the interictal stage between episodes.24 These trigeminal afferents enter the trigeminal ganglion and synapse in the spinal trigeminal nucleus (STN) within the medulla oblongata. From here information is relayed to thalamic nuclei and then onto multiple higher processing areas. Pathways from the ventral posteromedial thalamic nucleus to the primary somatosensory cortex (S1) explain painful responses during migraine. While, circuitry from the pulvinar on towards the primary visual cortex (V1) may suggest a mechanism behind visual symptoms in migraine, such as scintillating scotomas. Additionally, fMRI studies have also shown increased activity within trigeminal nuclei and the dorsal pons during migraine attacks.25

Hyperactivity of the trigeminal system has been suggested to have two separate neuroanatomical origins, each corresponding to different stages of migraine episodes. Development of prodromal symptoms and aura has been linked to a heightened brain state due to a self-propagating wave of neuronal and glial depolarization across the cerebral cortex, known as cortical spreading depression (CSD). This increases activity of the trigeminovasular system and stimulates Substance P and CGRP release (neurogenic inflammation) in the meninges and cutaneous nerve ends. Substance P and CGRP activate Neurokinin-1 receptors, thereby inducing mast cell degranulation and histamine-mediated arteriolar vasodilation.26 Trigeminal neural afferents innervating meningeal vasculature exhibit increased responses to prostaglandins (PGI2), serotonin, and histamine.27 CSD also increases permeability of the blood–brain Barrier (BBB) by increasing activity of matrix metallopeptidases (MMPs), a family of zinc endopeptidases. MMPs, most notably MMP-2 and MMP-9, cleave extracellular matrix proteins and activate proinflammatory cytokines. This disrupts endothelial tight junctions and astrocytic end-feet at the BBB, causing plasma protein extravasation (PPE).28 In vitro and in vivo mouse assays have shown Substance P, CGRP, and the potently vasoactive peptide Adrenomedullin to further potentiate this PPE.29 Together, these processes cause local edema, erythema, and activation of trigeminal afferents, resulting in the main migraine attack and postdromal symptoms.

This model is supported by trigeminal nerve lesioning significantly reducing PPE within the middle meningeal artery.30 Additionally, intravenous infusions of human Adrenomedullin induces more frequent and more intense migraine attacks in migraine patients.31 Furthermore, MMP activity has been shown to be raised in migraine patients with and without aura, especially in those with hyperinsulinemia and atherogenic lipid disturbances secondary to migraine.32 The ratio of MMP-9 to its physiological inhibitor, Tissue Inhibitor of MetalloProteases-1 (TIMP-1), is significantly raised in patients suffering from migraine without aura compared to those with aura, potentially suggesting a difference in pathogenesis between the two conditions.33 Pharmacological MMP inhibitors may offer a novel treatment for migraine, akin to the success had by CGRP/CGRPR antibodies.6-13

3.2 Impaired inhibitory pain networks

Contrastingly, efferent circuitry has also been hypothesized to be the root of migraine pathogenesis. Ascending information of noxious stimuli is modulated by a descending inhibitory pain network. Optogenetic studies have shown this system to originate in the prefrontal cortex (PFC) projecting caudally via the nucleus accumbens (NAc) and periaqueductal grey matter (PAG).34 The pathway that descends via the rostral ventromedial medulla (RVM) modulating activity within dorsal horn spinal structures, including the STN. In this model, increased nociceptive stimuli from repetitive migraine episodes results in increased activity of descending inhibitory pain networks. Release of neuromodulators such as Nitric Oxide may then lead to oxidative stress and consequent loss of pain modulation, hence reducing the threshold for future episodes. Additionally, Iron homeostasis within the PAG has been observed to be impaired with repetitive migraine episodes.35 This was hypothesized to result in dysfunctional modulation of the Trigeminovascular nociceptive system.

3.3 Central sensitization

A third model centers around a state of allodynia due to central sensitization. This may be due to increased excitability of thalamic nuclei. This is supported by many pharmacological interventions for migraine being known to have modulatory effects on the thalamus, namely Valproate, Topiramate and Anti-CGRP.36-38 Contrastingly, interventions for acute migraine may also lead to central centralization, resulting in transformation to CM. Continuous dosing of medications for acute migraine relief, such as triptans, has been shown cause cutaneous allodynia.39 Overuse of such medications has also been shown to lead to a heightened susceptibility to cortical spreading depression.40

4 TRANSFORMATION TO CHRONIC MIGRAINE

The transformation rate of EM to CM is approximately 3% per year.41 Non-modifiable risk factors for this progression include: female sex (F/M ratio of 3:1), low socioeconomic status, and being unmarried.42 Prevalence peaks during in the third and fifth decades of life for both sexes.43 Modifiable risk factors for this progression include: ineffective EM management,44 obesity,45 high caffeine intake,46 snoring and sleep apnea,47 depression,48 stressful life events,49 gastrointestinal disorders,50 and cutaneous allodynia.51 This is supported by CM patients compared to EM patients significantly more commonly reporting psychiatric co-morbidities, such as depression, chronic pain, and anxiety,52 as well as asthma and sleep-disordered breathing.53 Recent meta-analysis has identified headache frequency of ≥10 days per month to be a significant predictor of EM to CM transformation.54 Furthermore, having a household income above $50k a year was identified as a protective factor.

The significance of medication overuse in CM transformation remains elusive. Animal studies have shown daily sumatriptan use to result in central sensitization and subsequent cutaneous allodynia39 as well as a lowered cortical spreading depression threshold and subsequent increased activation of the trigeminal nucleus caudalis.55 While medication overuse is also often cited as a modifiable precipitator of CM transformation, it should be noted that high frequency of attacks has been shown to be a key risk factor for CM,56 and so any correlation with medication overuse may occur secondary to this.

One model suggests that risk factors of CM, such as headache frequency, obesity, and psychiatric disorders, may result in an increasingly sustained activity of the Trigeminovascular pathway,53 thus interictal cutaneous allodynia may be in-fact a biomarker of this trigeminal sensitization rather than being a risk factor for transformation itself. Conversely, CM progression has been attributed to increased strength of corticothalamic connections resulting in early response sensitization and late habituation.57

Eight single-nucleotide polymorphisms (SNPs) have been found during genome-wide association study (GWAS) to be significantly associated with CM and high frequency migraines.58 These included rs858745 in the calcitonin receptor-like (CALCRL) gene, rs2956 in the calcitonin-gene related peptide (CALCA) gene, and rs5742912 in the sodium channel, non-voltage-gated 1 alpha subunit (SCNN1A) gene. Epigenetic regulation has also been implicated in CALCA gene expression in rat and human cell lines and cultured rat trigeminal ganglia glia.59

5 BTX-A ADMINISTRATION

There are multiple paradigms for injection sites for BTX-A administration; however, a commonly used protocol is based on the PRE-EMPT studies.17, 18 As shown in Figure 2, thirty one injections are made symmetrically into muscle sites which overlay key nerves in the head and neck. Facial sites include one within the procerus muscle, two within the Corrugator supercilii muscles, and four within the frontalis muscles. It is likely that the intramuscular injections diffuse through the muscular tissue and act on adjacent nerves; the supraorbital and supratrochlear nerves have especially been shown to be closely associated with these structures.60, 61 Furthermore, Corrugator Supercilii muscle resection has been shown to cause significant migraine headache improvement, possibly via decompression of the underlying nerves.62 Laterally, there are eight sites in the Temporalis muscles, with auriculotemporal and zygomaticotemporal nerves running along nearby. Posteriorly, there are six sites in the occipitalis muscles, adjacent to the Greater Occipital and Lesser Occipital nerves. Four in the cervical paraspinal muscle group, through which the Third Occipital nerve runs through. And finally, six sites in the Trapezius muscle, which overlies surrounding Supraclavicular nerves.

Diagram of intramuscular injection sites as per the PRE-EMPT protocol. (17-18) 155 U Botox® is divided into 31 sites, each containing a 5 U dose. Four sites in the Frontalis muscles (pink). Two sites in the Corrugator Supercilii (blue). One site in the Procerus (purple). Eight sites in the Temporalis muscles (light green). Six sites in the Occipitals muscles (yellow). Four sites in the Cervical Paraspinal muscle group (red). And six sites in the Trapezius muscle (dark green)

The PRE-EMPT protocol also introduced two different dosing approaches: “fixed-site” and “follow-the-pain,” both of which involve the dilution of each 100 U vile of BTX-A with 2ml of normal saline to produce a solution with a concentration of 5 U/0.1 mL.63 In the former approach, a minimum dose of 155 U is divided into 5 U individual injections, administered to the 31 aforementioned sites. Up to eight further injections may also be administered under the “follow-the-pain” approach, totaling an additional 40 U dose on top of the initial 155 U. These eight additional doses are made at the discretion of the clinician and may only be applied as follows: two sites within the temporalis, two within the occipitalis, and four within the trapezius muscles.

6 MECHANISM OF BOTOX ACTION 6.1 Inhibition of neurotransmitter exocytosis

Normally when an action potential propagates down an axon, the bouton is depolarized thereby opening and activating voltage gated calcium channels, resulting in calcium ion influx. These calcium ions then bind to the C2 domain on synaptotagmin, a Soluble N-ethylmaleimide sensitive factor Attachment protein REceptor (SNARE) protein. This stimulates neurotransmitter vesicles to migrate towards membrane where there is then binding of other SNARE proteins: Synaptobrevin with Syntaxin and Synaptosomal Nerve-Associated Protein 25 (SNAP25). This leads to the fusion of the vesicle with the neuronal membrane. Neurotransmitter is exocytosed and diffuses into the synaptic cleft and binds to, and activates, a receptor on post synaptic membrane.

As summarized in Figure 3, BTX-A binds to the synaptic vesicle protein (SV2) receptor64 on presynaptic neurons and is endocytosed into vesicles. The light chain (LC) subunit then dissociates and enters the neuronal cytosol where it proteolytically cleaves SNAP25, a Soluble N-ethylmaleimide sensitive factor Attachment protein REceptor (SNARE), thereby preventing vesicular fusion with the membrane, inhibiting the release of neurotransmitter into the synaptic cleft. Other serotypes of BoTox cleave other snare proteins, namely Synaptobrevin and Syntaxin.

Diagram of Botulinum Toxin's interference with synaptic neurotransmission. (A) Action potential of ionic current propagates down the axon towards the bouton. (B): Arrival of an action potential depolarises the membrane, in turn opening and activating voltage gated calcium channels and leading to calcium influx. (C) Calcium ions bind to C2 domain on synaptotagmin (pink), stimulating neurotransmitter vesicles to migrate towards membrane. (D) Binding of SNARE proteins: Synaptobrevin (red) to Synaptosomal Nerve-Associated Protein 25 (SNAP25 - green) and Syntaxin (blue) leads to fusion of vesicle with membrane and exocytosis of neurotransmitter. (E) Neurotransmitter diffuses into synaptic cleft and binds to, and activates, receptor on post synaptic membrane (in this example, causing ionic influx thus depolarising the post synaptic neuron). (F) BTX-a binds to SV2 receptor on presynaptic neuron and is endocytosed into vesicles. (G) Light chain (LC) subunit dissociates and enters cytosol of neuron. (H) BTX-A LC subunit proteolytically cleaves SNARE proteins. Serotypes (A and E) cleave SNAP25, (B,D,F, and G) cleave with Synaptobrevin, and (C) cleaves with Syntaxin. The mechanism of action of the (H) serotype is currently unknown

This inhibition of neurotransmitter exocytosis explains observations of botulinum toxin serotypes in Formalin-induced nociceptive animal studies to inhibit the release of glutamate,65 CGRP,66 and Substance P.67 Reduced transmission of glutamate and these neuropeptides within C-fibers may explain local anti-inflammatory and analgesic properties of BoTox. The toxin has also been shown to undergo axonal transport, both retrograde68 and anterograde.69 Therefore, BTX-A may reduce transmission of these neurotransmitters within the trigeminal ganglia via transport as per the neuroanatomical connections shown in Figure 1. However, this mechanism of BTX-A may not be this clear cut, especially as the toxin has been reported to inhibit up to 90% of calcium-dependent dopamine, noradrenaline, and acetylcholine release.70

6.2 Anti-inflammatory effects

Substance P is known to induce histamine and serotonin release from both peripheral71 and brain72 mast cells. Furthermore, trigeminal sensory fiber stimulation, at intensities below those reported to stimulate unmyelinated C fibers, has been shown to promote mast cell secretion and degranulation in dura mater.73 CGRP also induces mast cell degranulation within the dura,74 as well as having potent cerebral vasodilatory effects.75 As BTX-A is known to modulate the release of these neuropeptides, the toxin likely has downstream effects in reducing neurogenic inflammation, a key process in the chronification of migraine. This is further supported by the toxin locally reducing pain, skin temperature, erythema, and edema.76 Furthermore, direct inhibition of mast cell degranulation by BTX-A has been shown to reduce rosacea-associated skin inflammation.77

BTX-A has been observed to have further anti-inflammatory properties via inhibiting intracellular signaling pathways in microglia, such as NF-B, ERK1/2, P38, and NOS2.78 BTX-A treatment also reduces inflammation within arthritic rat knee joints, reducing joint destruction and binding of interleukin-1β (IL-1β) and anti-ionized calcium-binding adaptor molecule 1 (Iba-1) antibodies.79 BTX-A suppresses chronic constriction injury induced up-regulation of pro-nociceptive interleukins (IL-18 and IL-1β) and increases expression of anti-nociceptive interleukins (IL-10 and IL-1RA) in the dorsal root ganglion.80 By inactivating the Rho signaling cascade, BoTox reduces IL-8/CXCR1 signaling.81 BTX-A therefore may play a key role in reducing inflammatory processes in chronic migraine, especially as the disorder is associated with the up-regulation of the pro-inflammatory genes CCL8 and TLR2 and down-regulation of genes that suppress inflammation and differentiation of immune cells, namely IL-10RA and CSF1R.82 However, it should also be noted that the toxin has been suggested to cause flu-like symptoms associated with raised levels of the pro-inflammatory cytokines eotaxin, an eosinophil chemotactic protein, IL-8, and Monocyte Chemotactic Protein-1 (MCP-1).83 Additionally, 3D X-ray imaging has shown high dose BTX-A (6 UI) to cause rat muscle tissue damage and subsequent reductions in stride length. Genetic analysis of these samples revealed significant up-regulation of genes encoding interleukin 6, collagen type 1 (COL1A1), myosin heavy chain IIA (MHCIIA), matrix metallopeptidase 2 (MMP-2), transforming growth factor beta 1 (TGF-β1), and myosin heavy chain IIX (MHCIIX).84

6.3 Ion channel regulation

BTX-A has also been shown to inhibit SNARE dependent membrane insertion of peripheral receptors such as transient receptor potential cation channel subfamily V member 1 (TRPV1) within C-fibers, thereby reducing capsaicin-induced pain.85 This reduction in TRPV1 expression has also been shown to occur in fibers in the trigeminal ganglion, especially those that that receive projections from the dura mater, upon peripheral BTX-A administration to ophthalmic divisions of the ganglion.86 TRPV1 receptors are understood to play a significant role in central sensitization and subsequent hyperalgesia and allodynia.87 CSD has been found to activate meningeal macrophages and dendritic cells that are in close proximity to neuronal axons expressing TRPV1.88 Therefore, suggesting a potential mechanism whereby neurogenic inflammatory processes within CM stimulate these nociceptors.

Other ion channels whose expression is down-regulated by BTX-A include TRPA1,89 TRPM8,90 and P2X3.91 Agonism of TRPA1 by acrolein stimulates CM phenotypes in rat models.92 BTX-A has also been shown to down-regulate TRPA1 in the DRG to attenuate chronic pruritus.93 BTX-A attenuates menthol's cold-sensitizing effects in TRPM8-expressing fibers by reducing vesicular fusion.90 Multiple GWAS have implicated TRPM8 SNP rs10166942 in migraine.94 Interestingly, expression of this variant has been shown to “follow a latitudinal cline” and be more prevalent in Eurasian populations.95 This may explain the increased prevalence of CM in European countries, especially those with high latitude and colder climates such as Norway, where higher levels of thermoregulation are required.96 BTX-A also reduces P2X3 over-expression and neuropathic pain in animal L5 ventral root transections.91

7 CLINICAL IMPLICATIONS

Migraine is a relatively common, disabling and debilitating condition. There is a need to best understand the pathophysiology of the condition to optimize treatment options. This is most pertinent in CM where headache lasting 15 or more days per month for more than 3 months has a significantly detrimental impact on a patient's activities of daily living. Important risk factors for transformation to chronic migraine include having a female sex, high headache frequency, psychiatric co-morbidities, obesity, and low socioeconomic status. Therefore, patients matching these demographics should be routinely screened for individual likelihood of transformation to CM, and offered prophylactic BTX-A therapy if their migraine symptoms are unresponsive to several first-line pharmacological interventions. Medication overuse should also be identified by clinicians as a possible indicator of upcoming transformation to CM.

There is currently no specific diagnostic test for migraine. Diagnosis remains through the clinical judgment of practitioners. Migraine diaries may aid this process to identify frequency of headache attacks, any concomitant symptoms, and patterns of potential triggers. Furthermore, questionnaires such as the “HIT-6” help to quantify the impact of headaches in migraine patients. It is important to exclude key differential diagnoses such as trigeminal neuralgia and tension headache. Though not fully specific nor sensitive to migraine, there is typically a characteristic progression of: Prodromal symptoms (eg, mood changes, depression, and sensory hypersensitivity), Aura (sensory disturbances), the Main Attack phase (with a pulsatile headache), and a final Postdromal phase (often featuring malaise and cognitive impairment). However, presentation of migraine can be varied, making diagnosis and prognosis difficult. fMRI studies have had success in identifying increased activity within brainstem nuclei during migraine episodes. Furthermore, several genes (notably CALCA, CALCRL, SCNN1A, CCL8, and TLR2) have been associated with transformation to CM. These two advancements may offer novel, individualized medicine investigations to better diagnose the condition and focus BTX-A treatment to those of greatest potential benefit.

Patient outcomes are improved by a greater understanding of the mode of action of BTX-A and mapping this onto known CM pathophysiology. This refines protocols of administration, dosing strategies, and awareness of adverse effects and drug interactions, thereby enhancing patient outcomes. With multiple comorbidities, including depression, asthma, and sleep disordered breathing, advances in the understanding of BTX-A treatment for CM have a multidisciplinary benefit to patient care. A mechanism via blockade of neurotransmitter exocytosis appears to succinctly explain therapeutic benefit in aesthetic medicine; however, these effects are insufficient to fully explain the effect of the toxin in CM.

Anti-inflammatory properties of the agent also act to reduce neurogenic inflammation, most notably by increasing levels of the anti-nociceptive factors IL-6, IL-10 and IL-1RA. Chronic neuropathic pain (CNP) is a very complex and difficult condition to treat, often with poor patient outcomes. The condition affects a broad range of patients: from metastatic pain, to Guillain–Barré syndrome, and diabetic neuropathy. Neurogenic inflammation is associated with CNP,97 and animal models have shown IL-10 to reduce this inflammation and subsequently improve mechanical allodynia in painful diabetic neuropathy,98 possibly suggesting a role for BTX-A in the treatment of CNP. BTX-A also regulates ion channel insertion in fibers of the trigeminal ganglion, suggesting particular benefit of the therapy for CM patients presenting with hyperalgesia and allodynia.

8 CONCLUSIONS

Migraine is likely caused by increased activity within the trigeminovascular nociceptive system. Threshold changes within this system may be due to both intrinsic hyperexcitability (secondary to cortical spreading depression and neurogenic inflammation) and impaired modulation by descending inhibitory pain networks. Allodynia in migraine can be attributed to a state of central sensitization due to increased excitability of thalamic nuclei. The mechanism of transformation to chronic migraine remains unclear, but key risk factors include sex (female), headache frequency, psychiatric comorbidities, obesity, and low socioeconomic status. BTX-A acts via inhibiting snare-mediated processes such as neurotransmitter exocytosis and membrane receptor insertion. By attenuating neuropeptidergic signaling, the toxin directly reduces both nociceptive signaling and neurogenic inflammation. Additionally, BTX-A downregulates the expression of several receptors, most notably TRPV1 which is implicated in cortical spreading depression, a possible mechanism behind the prodromal symptoms of migraine and aura development.

CONFLICT OF INTERESTS

None.

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