Sinais clínicos da migrânea vestibular em adolescentes / Clinical signs of vestibular migraine in adolescents / Signos clínicos de la migraña vestibular em adolescentes

Introdução: A migrânea é um tipo de cefaleia primária incapacitante que, quando associada a crises de vertigem, configura-se migrânea vestibular. Objetivo: Verificar quais as principais manifestações clínicas da migrânea vestibular em adolescentes. Métodos: Trata-se de uma revisão integrativa da literatura, cujas buscas foram executadas nas bases de dados eletrônicas PubMed/Medline, Scientific Electronic Library Online (SciELO), e Portal da Biblioteca Virtual em Saúde (BVS), em junho de 2022. Foram incluídas publicações entre o ano 2012 e o mês de junho de 2022; estudos observacionais e ensaios clínicos envolvendo seres humanos, nos quais o objetivo fosse avaliar indivíduos com idades entre 12 e 19 anos com diagnóstico de migrânea vestibular e verificar suas principais manifestações clínicas nessa população. Resultados: Todos os estudos mencionaram um maior percentual de meninas nas amostras, porém a diferença entre os sexos para os diferentes diagnósticos não foi avaliada em todas as pesquisas. Conclusão: Verificou-se, com a presente revisão, que as manifestações clínicas da migrânea na adolescência são semelhantes às da população adulta. (AU)

Introduction: Migraine is a disabling type of primary headache that, when associated with vertigo attacks, constitutes vestibular migraine. Objective: To investigate the main clinical findings of vestibular migraine in adolescents. Methods: This is an integrative literature review, with searches conducted in the electronic databases PubMed/Medline, Scientific Electronic Library Online (SciELO), and the Virtual Health Library Portal (BVS) in June 2022. Publications from the year 2012 to June 2022 were included; observational studies and clinical trials involving human subjects, in which the objective was to assess individuals aged 12 to 19 years diagnosed with vestibular migraine and investigate their main clinical findings in this population. Results: All studies mentioned a higher percentage of girls in the samples; however, the difference between sexes for different diagnoses was not assessed in all studies. Conclusion: With this review, it was found that the clinical findings of migraine in adolescence are similar to those in the adult population. (AU)

Introducción: La migraña es em tipo de dolor de cabeza adolescente incapacitante que, cuando se dolesc em ataques de vértigo, constituye la migraña vestibular. Objetivo: Investigar las principales manifestaciones clínicas de la migraña vestibular em adolescentes. Métodos: Se trata de em revisión integradora de la literatura, em búsquedas realizadas em las bases de datos electrónicas PubMed/Medline, Scientific Electronic Library Online (SciELO) y el Portal de la Biblioteca Virtual em Salud (BVS) em junio de 2022. Se incluyeron publicaciones desde el año 2012 hasta junio de 2022; dolescê observacionales y ensayos clínicos que involucraran a sujetos humanos, en los cuales el objetivo fuera evaluar adolescentes de 12 a 19 años en diagnóstico de migraña vestibular e investigar sus principales manifestaciones clínicas em esta población. Resultados: Todos los adolescentes mencionaron en mayor porcentaje de niñas en las muestras; sin embargo, la diferencia entre los sexos para diferentes diagnósticos no fue evaluada en todos los adolescentes. Conclusión: En esta revisión, se descobrió que las manifestaciones clínicas de la migraña en la dolescência son similares a las de la población adulta. (AU)

The role of TRP ion channels in migraine and headache.

Migraine afflicts more than 10% of the general population. Although its mechanism is poorly understood, recent preclinical and clinical evidence has identified calcitonin gene related peptide (CGRP) as a major mediator of migraine pain. CGRP, which is predominantly expressed in a subset of primary sensory neurons, including trigeminal afferents, when released from peripheral terminals of nociceptors, elicits arteriolar vasodilation and mechanical allodynia, a hallmark of migraine attack. Transient receptor potential (TRP) channels include several cationic channels with pleiotropic functions and ubiquitous distribution in various cells and tissues. Some members of the TRP channel family, such as the ankyrin 1 (TRPA1), vanilloid 1 and 4 (TRPV1 and TRPV4, respectively), and TRPM3, are abundantly expressed in primary sensory neurons and are recognized as sensors of chemical-, heat- and mechanical-induced pain, and play a primary role in several models of pain diseases, including inflammatory, neuropathic cancer pain, and migraine pain. In addition, TRP channel stimulation results in CGRP release, which can be activated or sensitized by various endogenous and exogenous stimuli, some of which have been proven to trigger or worsen migraine attacks. Moreover, some antimigraine medications seem to act through TRPA1 antagonism. Here we review the preclinical and clinical evidence that highlights the role of TRP channels, and mainly TRPA1, in migraine pathophysiology and may be proposed as new targets for its treatment.

Visual snow syndrome, the spectrum of perceptual disorders, and migraine as a common risk factor: A narrative review.

OBJECTIVE: The aim of this narrative review is to explore the relationship between visual snow syndrome (VSS), migraine, and a group of other perceptual disorders. BACKGROUND: VSS is characterized by visual snow and additional visual and nonvisual disturbances. The clinical picture suggests a hypersensitivity to internal and external stimuli. Imaging and electrophysiological findings indicate a hyperexcitability of the primary and secondary visual areas of the brain possibly due to an impairment of inhibitory feedback mechanisms. Migraine is the most frequent comorbidity. Epidemiological and clinical studies indicate that other perceptual disorders, such as tinnitus, fibromyalgia, and dizziness, are associated with VSS. Clinical overlaps and parallels in pathophysiology might exist in relation to migraine. METHODS: We performed a PubMed and Google Scholar search with the following terms: visual snow syndrome, entoptic phenomenon, fibromyalgia, tinnitus, migraine, dizziness, persistent postural-perceptual dizziness (PPPD), comorbidities, symptoms, pathophysiology, thalamus, thalamocortical dysrhythmia, and salience network. RESULTS: VSS, fibromyalgia, tinnitus, and PPPD share evidence of a central disturbance in the processing of different stimuli (visual, somatosensory/pain, acoustic, and vestibular) that might lead to hypersensitivity. Imaging and electrophysiological findings hint toward network disorders involving the sensory networks and other large-scale networks involved in the management of attention and emotional processing. There are clinical and epidemiological overlaps between these disorders. Similarly, migraine exhibits a multisensory hypersensitivity even in the interictal state with fluctuation during the migraine cycle. All the described perceptual disorders are associated with migraine suggesting that having migraine, that is, a disorder of sensory processing, is a common link. CONCLUSION: VSS, PPPD, fibromyalgia, and chronic tinnitus might lie on a spectrum of perceptual disorders with similar pathophysiological mechanisms and the common risk factor migraine. Understanding the underlying network disturbances might give insights into how to improve these currently very difficult to treat conditions.

Involvement of TRPM2 in the Neurobiology of Experimental Migraine: Focus on Oxidative Stress and Apoptosis.

Excessive Ca2+ influx and mitochondrial oxidative stress (OS) of trigeminal ganglia (TG) have essential roles in the etiology of migraine headache and aura. The stimulation of TRPM2 channel via the generation of OS and ADP-ribose (ADPR) induces pain, inflammatory, and oxidative neurotoxicity, although its inhibition reduces the intensity of pain and neurotoxicity in several neurons. However, the cellular and molecular effects of TRPM2 in the TG of migraine model (glyceryl trinitrate, GTN) on the induction of pain, OS, apoptosis, and inflammation remain elusive. GTN-mediated increases of pain intensity, apoptosis, death, cytosolic reactive oxygen species (ROS), mitochondrial ROS, caspase -3, caspase -9, cytosolic Ca2+ levels, and cytokine generations (TNF-α, IL-1ß, and IL-6) in the TG of TRPM2 wild-type mouse were further increased by the TRPM2 activation, although they were modulated by the treatments of GSH, PARP-1 inhibitors (PJ34 and DPQ), and TRPM2 blockers (ACA and 2APB). However, the effects of GTN were not observed in the TG of TRPM2 knockout mice. The current data indicate that the maintaining activation of TRPM2 is not only important for the quenching OS, inflammation, and neurotoxicity in the TG neurons of mice with experimental migraine but also equally critical to the modulation of GTN-induced pain.

Was it something I ate? Understanding the bidirectional interaction of migraine and appetite neural circuits.

Migraine attacks can involve changes of appetite: while fasting or skipping meals are often reported triggers in susceptible individuals, hunger or food craving are reported in the premonitory phase. Over the last decade, there has been a growing interest and recognition of the importance of studying these overlapping fields of neuroscience, which has led to novel findings. The data suggest additional studies are needed to unravel key neurobiological mechanisms underlying the bidirectional interaction between migraine and appetite. Herein, we review information about the metabolic migraine phenotype and explore migraine therapeutic targets that have a strong input on appetite neuronal circuits, including the calcitonin gene-related peptide (CGRP), the pituitary adenylate cyclase-activating polypeptide (PACAP) and the orexins. Furthermore, we focus on potential therapeutic peptide targets that are involved in regulation of feeding and play a role in migraine pathophysiology, such as neuropeptide Y, insulin, glucagon and leptin. We then examine the orexigenic - anorexigenic circuit feedback loop and explore glucose metabolism disturbances. Additionally, it is proposed a different perspective on the most reported feeding-related trigger - skipping meals - as well as a link between contrasting feeding behaviors (skipping meals vs food craving). Our review aims to increase awareness of migraine through the lens of appetite neurobiology in order to improve our understanding of the earlier phase of migraine, encourage better studies and cross-disciplinary collaborations, and provide novel migraine-specific therapeutic opportunities.

Primary headaches among gender dysphoric female-to-male individuals: A cross-sectional survey on gender transition experience.

OBJECTIVE: To investigate the frequency, attack characteristics, and treatment experiences of migraine and tension-type headache (TTH) among gender dysphoric female-to-male (FtM) participants as well as in relation to psychiatric comorbidities and real-life experience that relates to being transgender in Turkey. BACKGROUND: There are only a few publications to date on transgender individuals with headache. Further studies to understand the distinctive needs might provide better management. METHODS: A total of 88 gender dysphoric FtM individuals (mean (SD) age: 24.8 (5.7) years) were included on a voluntary basis in this cross-sectional survey. Each participant filled out the questionnaire form that elicited items on sociodemographic characteristics, Gender Identity Transition Inventory, Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Headache Questionnaire. RESULTS: Overall, 32/88 (36.4%; 95% confidence interval [CI]: 27.0%-47.0%) participants were diagnosed with migraine, and 36/88 (40.9%; 95% CI: 31.5%-52.3%) participants were diagnosed with TTH. High rates of unemployment, smoking, and social drinking were observed in our sample compared with the general population in Turkey. The three-item ID migraine screener was positive in 20.5% (18/88 patients) of our population. Patients with migraine in comparison with patients with TTH had statistically significantly higher BDI [12.0 (1-50) vs. 7.0 (0-33); p = 0.013] and BAI [13 (1-48) vs. 5 (0-22); p = 0.016] scores, longer headaches in the past month [median 3 vs. 1 day; p < 0.001], higher Numerical Rating Scale scores for headache severity [7 (2-10) vs. 5 (1-9), p < 0.001], and higher likelihood of menstruation acting as a triggering factor [8/32 patients (25.0%) vs. 0/36 patients (0.0%); p = 0.001] as well as increased rates of previously given diagnosis by a physician [15/32 patients (46.9%) vs. 4/36 patients (11.1%); p < 0.001], a greater number of neuroimaging tests being performed [12/32 patients (37.5%) vs. 3/36 patients (9.1%); p = 0.012], and a higher rate of emergency room utilization [7/32 patients (21.9%) vs. 1/36 patients (2.8%); p = 0.039] for headache. CONCLUSIONS: In the FtM transgender population we investigated, migraine and TTH were quite common. The screening and early recognition of comorbid migraine, as well as the comorbid depression and anxiety, seem to be important in gender dysphoric FtM individuals. Further studies are needed to better understand the potential interaction of migraine with comorbid psychiatric disorders and the prevalence of headache types and gender-affirmative hormone treatment outcomes in the transgender population.

Symptomatic migraine: A systematic review to establish a clinically important diagnostic entity.

OBJECTIVE: To determine if a clinical presentation indistinguishable from migraine can occur due to an underlying condition or pathology, that is, "symptomatic migraine." BACKGROUND: It is currently not clear whether migraine truly can be caused by an underlying condition or pathology. Characterization of the etiology and clinical features of possible symptomatic migraine is of significant clinical importance and further may help elucidate the pathophysiology of migraine. METHODS: We devised operational diagnostic criteria for "symptomatic migraine" and "possible symptomatic migraine" requiring strong evidence for a causal relation between underlying cause and migraine symptoms adhering strictly to diagnostic criteria. PubMed was searched for case reports of symptomatic migraine from inception to March 2020. Only articles published in English or German were included. No restrictions were placed on study design. Relevant references in the articles were also included. Papers were systematically reviewed by two independent reviewers for detailed clinical features of migraine as well as the proposed underlying conditions and the effects of treatment of these conditions. RESULTS: Our search retrieved 1726 items. After screening, 109 papers comprising 504 cases were reviewed in detail. Eleven patients with migraine with aura (MWA) fulfilled our working criteria for symptomatic migraine, and 39 patients fulfilled our criteria for possible symptomatic migraine. The most common etiologies of symptomatic migraine were arteriovenous malformations, carotid stenosis, dissection or aneurysm, brain infarctions, meningioma, and various intra-axial tumors. CONCLUSIONS: Symptomatic MWA, indistinguishable from idiopathic MWA, may occur due to cortical lesions or microembolization. We found no clear evidence supporting the existence of symptomatic migraine without aura although we did identify possible cases. Our findings are limited by the available literature, and we suggest that prospective studies are needed.

Stroke-Like Migraine Attacks After Radiation Therapy (SMART) Syndrome: A Comprehensive Review.

PURPOSE OF REVIEW: SMART syndrome is a delayed complication of cranial irradiation that can be misconstrued as tumor recurrence or some other intracranial neurological disease. Recognition of this clinical syndrome is imperative as it can obviate the need for invasive diagnostic testing and can provide reassurance to both the patient and their loved ones. RECENT FINDINGS: SMART syndrome is generally considered a reversible clinical syndrome; however, neurological deficits may become permanent. Pathophysiology of SMART syndrome may involve cerebrovascular autoregulation impairment, neuronal dysfunction leading to trigeminovascular system impairment and/or cortical spreading depression, and seizures. In addition to MRI brain with gadolinium, other imaging modalities, such as CT perfusion, MR perfusion, MR spectroscopy, and FDG PET/CT, aid in arriving to the diagnosis sooner. Patients should also undergo electroencephalogram in order to promptly identify and treat seizures. There are currently no clear guidelines on how to effectively treat SMART syndrome, but treatment may involve anti-seizure medication, anti-hypertensives, anti-platelet, and steroid therapy. This review provides a comprehensive understanding of the clinical characteristics of SMART syndrome from presentation to diagnostic evaluation. We also discuss radiographic features and treatment strategies for this rare disease. With increased radiotherapy utilization, prompt clinical recognition of SMART syndrome and further development of a comprehensive diagnostic approach to SMART syndrome utilizing newer radiographic modalities as well as treatment algorithms to effectively treat this clinical condition will be imperative.

Discovery of Selective Pituitary Adenylate Cyclase 1 Receptor (PAC1R) Antagonist Peptides Potent in a Maxadilan/PACAP38-Induced Increase in Blood Flow Pharmacodynamic Model.

Inhibition of the pituitary adenylate cyclase 1 receptor (PAC1R) is a novel mechanism that could be used for abortive treatment of acute migraine. Our research began with comparative analysis of known PAC1R ligand scaffolds, PACAP38 and Maxadilan, which resulted in the selection of des(24-42) Maxadilan, 6, as a starting point. C-terminal modifications of 6 improved the peptide metabolic stability in vitro and in vivo. SAR investigations identified synergistic combinations of amino acid replacements that significantly increased the in vitro PAC1R inhibitory activity of the analogs to the pM IC90 range. Our modifications further enabled deletion of up to six residues without impacting potency, thus improving peptide ligand binding efficiency. Analogs 17 and 18 exhibited robust in vivo efficacy in the rat Maxadilan-induced increase in blood flow (MIIBF) pharmacodynamic model at 0.3 mg/kg subcutaneous dosing. The first cocrystal structure of a PAC1R antagonist peptide (18) with PAC1R extracellular domain is reported.

Evidence that blood-CSF barrier transport, but not inflammatory biomarkers, change in migraine, while CSF sVCAM1 associates with migraine frequency and CSF fibrinogen.

OBJECTIVE: Our objective is to explore whether blood-cerebrospinal fluid (CSF) barrier biomarkers differ in episodic migraine (EM) or chronic migraine (CM) from controls. BACKGROUND: Reports of blood-brain barrier and blood-cerebrospinal fluid barrier (BCSFB) disruption in migraine vary. Our hypothesis is that investigation of biomarkers associated with blood, CSF, brain, cell adhesion, and inflammation will help elucidate migraine pathophysiology. METHODS: We recruited 14 control volunteers without headache disorders and 42 individuals with EM or CM as classified using the International Classification of Headache Disorders, 3rd edition, criteria in a cross-sectional study located at our Pasadena and Stanford headache research centers in California. Blood and lumbar CSF samples were collected once from those diagnosed with CM or those with EM during two states: during a typical migraine, before rescue therapy, with at least 6/10 level of pain (ictal); and when migraine free for at least 48 h (interictal). The average number of headaches per month over the previous year was estimated by those with EM; this enabled comparison of biomarker changes between controls and three headache frequency groups: <2 per month, 2-14 per month, and CM. Blood and CSF biomarkers were determined using antibody-based methods. RESULTS: Antimigraine medication was only taken by the EM and CM groups. Compared to controls, the migraine group had significantly higher mean CSF-blood quotients of albumin (Qalb : mean ± standard deviation (SD): 5.6 ± 2.3 vs. 4.1 ± 1.9) and fibrinogen (Qfib mean ± SD: 1615 ± 99.0 vs. 86.1 ± 55.0). Mean CSF but not plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) levels were significantly higher in those with more frequent migraine: (4.5 ng/mL ± 1.1 in those with <2 headache days a month; 5.5 ± 1.9 with 2-14 days a month; and 7.1 ± 2.9 in CM), while the Qfib ratio was inversely related to headache frequency. We did not find any difference in individuals with EM or CM from controls for CSF cell count, total protein, matrix metalloproteinase-9, soluble platelet-derived growth factor receptor ß, tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-6, IL-8, IL-10, or C-reactive protein. CONCLUSIONS: The higher Qalb and Qfib ratios may indicate that the transport of these blood-derived proteins is disturbed at the BCSFB in persons with migraine. These changes most likely occur at the choroid plexus epithelium, as there are no signs of typical endothelial barrier disruption. The most striking finding in this hypothesis-generating study of migraine pathophysiology is that sVCAM-1 levels in CSF may be a biomarker of higher frequency of migraine and CM. An effect from migraine medications cannot be excluded, but there is no known mechanism to suggest they have a role in altering the CSF biomarkers.

Slowly repeated evoked pain (SREP) as a central sensitization marker in episodic migraine patients.

Migraine headache is a pain condition characterized by severe and recurrent unilateral head pain. Among other mechanisms, central pain sensitization processes seem to be involved in the disorder. An experimental protocol based on slowly repeated evoked pain (SREP) has been shown to indicate pain sensitization in fibromyalgia patients and differentiate these patients from healthy individuals and rheumatoid arthritis patients. This study examined SREP sensitization in migraine patients and explored its potential usefulness as a central sensitization marker. The SREP protocol was administered to 40 episodic migraine (EM) patients not currently experiencing a headache and 40 healthy controls. SREP consisted of a series of 9 suprathreshold painful pressure stimuli of 5 s duration and a 30 s interstimulus interval. SREP sensitization was indexed by the increase in pain ratings across the stimuli. Pain threshold, pain tolerance and temporal summation of pain were also assessed. SREP sensitization was observed in EM, but not in healthy individuals (p < .001). SREP differentiated between EM and healthy individuals with up to 75% diagnostic accuracy. Pain threshold, pain tolerance and temporal summation of pain did not show significant discriminative ability. An SREP index value of 0.5 was the most sensitive cut-off for detecting central pain sensitization when prioritizing diagnostic sensitivity (0.88). Results provide evidence for SREP as a possible central sensitization marker with potential clinical utility in migraine patients. Inclusion of SREP in Quantitative Sensory Testing protocols may enhance the assessment of altered pain modulation in different pain conditions.

An outlook on the trigeminovascular mechanisms of action and side effects concerns of some potential neuropeptidergic antimigraine therapies.

Introduction: In addition to serotonin (5-hydroxytryptamine; 5-HT) and other (neuro)mediators, the role of neuropeptides in migraine pathophysiology is relevant. Indeed, while some molecules interfering with calcitonin gene-related peptide (CGRP) transmission have recently been approved for clinical antimigraine use, other neuropeptides with translational use are in the pipeline. Among others, hypothalamic neuropeptides such as pituitary adenylate cyclase-activating peptide (PACAP), oxytocin (OT), and orexins stand out as potential novel targets to treat this neurovascular disorder. Areas covered: Based on the aforementioned findings, the present review: (i) summarizes the current knowledge on the role of the above neuropeptides in the trigeminovascular system, and migraine pathophysiology; and (ii) discusses some issues related with the mechanisms of action and side effects concerns that could be elicited when targeting the CGRPergic, PACAPergic, oxytocinergic and orexinergic systems. Expert opinion: Specific antimigraine pharmacotherapies have evolved from the enhancement of serotonergic 5-HT1B/1D/1F transmission to the use of compounds interacting with neuropeptidergic systems. Canonically, neuropeptides cause an array of complex intracellular mechanisms that, after modifying neuronal and/or vascular transmission, result in antimigraine action and also potential side effects. Furthermore, due to the chemical nature of some molecules targeting the above neuropeptidergic transmission (e.g., monoclonal antibodies, peptides), there are some limiting pharmacokinetics issues.

The effects of two different intensities of aerobic training protocols on pain and serum neuro-biomarkers in women migraineurs: a randomized controlled trail.

OBJECTIVES: We have a weak understanding of how aerobic training may influence migraine, and the optimal parameters for exercise regimens as migraine therapy are not clear. The objectives of this study were to assess, first, effects of two different intensities of aerobic exercise on migraine headache indices; second, serum neuro-biomarker in women migraineurs. METHODS: A total of 45 non-athlete female migraine patients were selected by a neurologist and randomly divided into three groups: control (CON), moderate-intensity aerobic training (MOD T), and high-intensity aerobic training (HIGH T). Before and after the training protocol, body composition factors, migraine pain indices, VO2max, and serum Adenylate-Cyclase Activating Polypeptide (PACAP) and Substance P (SP) were measured. Exercise training protocol includes two different intensities of aerobic exercise: Moderate (13-15 Borg Scale, 60-80% HRmax) and High (15-17 Borg Scale, 65-95% HRmax). RESULTS: Moderate-intensity aerobic training (MOD T) reduced headache intensity, frequency, and duration in women with migraine (p < 0.001, for all). Also, high-intensity aerobic training (HIGH T) reduced headache intensity, frequency, and duration (p < 0.001, for all). However, for headache intensity and duration, MOD T was effective rather than HIGH T (p < 0.001; p ≤ 0.05, respectively). In addition, neither MOD T nor HIGH T could not alter PACAP and SP contents (p = 0.712; p = 0.249, respectively). CONCLUSIONS: Our results demonstrated that either MOD T or HIGH T could modify migraine pain indices but neither MOD T nor HIGH T could not alter the PACAP and SP contents in women with migraine.

Latest Insights into the Pathophysiology of Migraine: the ATP-Sensitive Potassium Channels.

PURPOSE OF REVIEW: Migraine remains a challenging condition to treat, thus highlighting the need for a better understanding of its molecular mechanisms. This review intends to unravel a new emerging target in migraine pathophysiology, the adenosine 5'-triphosphate-sensitive K+ (KATP) channel. RECENT FINDINGS: KATP channel is a common denominator in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) mediated intracellular cascades, both of which are involved in migraine. Intravenous infusion of KATP channel opener, levcromakalim, provoked migraine attack associated with dilation of extracerebral arteries in all persons with migraine. Preclinical and clinical studies implicate KATP channels in migraine initiation. KATP channel is a novel therapeutic target for the acute and preventive treatment of migraine. Future studies are warranted to provide a better understanding of the role of KATP channel subgroups in migraine.

Estrogen receptors α, ß and GPER in the CNS and trigeminal system - molecular and functional aspects.

BACKGROUND: Migraine occurs 2-3 times more often in females than in males and is in many females associated with the onset of menstruation. The steroid hormone, 17ß-estradiol (estrogen, E2), exerts its effects by binding and activating several estrogen receptors (ERs). Calcitonin gene-related peptide (CGRP) has a strong position in migraine pathophysiology, and interaction with CGRP has resulted in several successful drugs for acute and prophylactic treatment of migraine, effective in all age groups and in both sexes. METHODS: Immunohistochemistry was used for detection and localization of proteins, release of CGRP and PACAP investigated by ELISA and myography/perfusion arteriography was performed on rat and human arterial segments. RESULTS: ERα was found throughout the whole brain, and in several migraine related structures. ERß was mainly found in the hippocampus and the cerebellum. In trigeminal ganglion (TG), ERα was found in the nuclei of neurons; these neurons expressed CGRP or the CGRP receptor in the cytoplasm. G-protein ER (GPER) was observed in the cell membrane and cytoplasm in most TG neurons. We compared TG from males and females, and females expressed more ER receptors. For neuropeptide release, the only observable difference was a baseline CGRP release being higher in the pro-estrous state as compared to estrous state. In the middle cerebral artery (MCA), we observed similar dilatory ER-responses between males and females, except for vasodilatory ERß which we observed only in female arteries. CONCLUSION: These data reveal significant differences in ER receptor expression between male and female rats. This contrasts to CGRP and PACAP release where we did not observe discernable difference between the sexes. Together, this points to a hypothesis where estrogen could have a modulatory role on the trigeminal neuron function in general rather than on the acute CGRP release mechanisms and vasomotor responses.

The role of acupuncture in the treatment of chronic pain.

Acupuncture is a practice based on traditional Chinese medicine, in which needles are used to restore the body's internal balance. Recently, there has been growing interest in the use of acupuncture for various pain conditions. Acupuncture's efficacy in five pain conditions-low back pain (LBP), migraines, fibromyalgia, neck pain, and abdominal pain-was evaluated in this evidence-based, comprehensive review. Based on the most recent evidence, migraine and fibromyalgia are two conditions with the most favorable outcomes after acupuncture. At the same time, abdominal pain has the least evidence for the use of acupuncture. Acupuncture is efficacious for reducing pain in patients with LBP, and for short-term pain relief for those with neck pain. Further research needs to be done to evaluate acupuncture's efficacy in these conditions, especially for abdominal pain, as many of the current studies have a risk of bias due to lack of blinding and small sample size.

Serum CGRP, VIP, and PACAP usefulness in migraine: a case-control study in chronic migraine patients in real clinical practice.

Calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypetide-38 (PACAP-38) have relevant roles in migraine pathophysiology. Their serum levels have been proposed as biomarkers for migraine. Our aim was to assess their diagnostic value in real clinical practice in a cohort of chronic migraine (CM), episodic migraine (EM) and healthy controls (HC). We recruited subjects with CM, EM and HC at two medical centers. Blood samples were drawn under fasting conditions in the interictal period, immediately centrifuged and stored at - 80 ºC. Serum levels were determined by ELISA. Neuropeptide levels, the effect of preventatives, correlations with clinical and demographic variables, and their diagnostic value were studied among clinical categories. 296 age- and sex-matched subjects (101 CM, 98 EM and 97 HC) were included. All three neuropeptide serum levels were higher in CM [median and IQ for CGRP = 18.023 pg/ml (14.4-24.7); VIP = 121.732 pg/ml (48.72-186.72) and PACAP = 204.931 pg/ml (101.08-597.64)] vs EM [CGRP = 14.659 pg/ml (10.29-17.45); VIP = 75.603 pg/ml (28.722-107.10); and PACAP = 94.992 pg/ml (65.77-128.48)] and vs HC [CGRP = 13.988 pg/ml (10.095-17.87); VIP = 84.685 pg/ml (35.32-99.79), and PACAP = 103.142 pg/ml (59.42-123.97)]. Using multinomial modeling, only VIP (OR 1.011, 95% CI 1.003-1.018, p = 0.005) and PACAP (OR 1.003, 95% CI 1.001-1.005, p = 0.002) increased the risk for CM, but not for EM. CGRP did not predict CM or EM. This model could correctly classify only 62/101 (61.38%) of CM, 75/98 (76.53%) of EM, and 5/97 (4.12%) of HC [globally 147/296 (49.8%)]. Individually, PACAP performed the best for classifying clinical categories [global accuracy 150/296 (50.67%)]. In CM, neuropeptide levels were higher in those OnaBT-treated than in no-treated patients. Although interictal serum CGRP and VIP were higher in CM than both EM or HC, their utility to discriminate migraine categories was low. Contrary to other studies, PACAP serum levels were also higher in CM than in EM or HC and had more discriminative capability to distinguish CM from EM and HC. Further investigation is needed for determination technique standardization.

Deficiency in the function of inhibitory interneurons contributes to glutamate-associated central sensitization through GABABR2-SynCAM1 signaling in chronic migraine rats.

The occurrence of pain has always been closely related to a break in the balance between excitatory and inhibitory systems, and the internal relationship between these two systems has not been studied in the pathogenesis of chronic migraine (CM). In this study, we explored how inhibitory interneurons specifically modulate the glutamate-induced hyperexcitability in the periaqueductal gray (PAG) of CM rats. The CM model was established by repeated dural infusion of inflammatory soup (IS) in rats. Then, Baclofen, a gamma-aminobutyric acid type B receptor (GABABR) agonist; CGP35348, a GABABR antagonist; H89, a protein kinase A (PKA) inhibitor; and 8-Bromo-cAMP, a PKA agonist, were applied by intraventricular injection to investigate the detailed CM mechanism. Our results showed that GABABR2 mRNA and protein levels were significantly downregulated (P < .01) in the PAG of CM rats. Similarly, gamma-aminobutyric acid (GABA) and its synthetase glutamate decarboxylase 65/67 (GAD65/67) seriously decreased (P < .01), implying a deficit in the function of inhibitory interneurons in the PAG of CM rats. Afterward, the application of Baclofen and H89 alleviated the IS-evoked hyperalgesia and extenuated vesicular glutamate transporter 2 (VGLUT2), glutamate, calcitonin gene-related peptide (CGRP), and c-Fos expression by regulating the GABABR2/PKA/SynCAM1 pathway in the PAG of CM rats, while the application of CGP35348 and 8-Bromo-cAMP exactly exerted the opposite effect. Importantly, CGP35348 induced an elevation of CGRP, and VGLUT2 expression was relieved by H89. These data suggest that the loss in the function of inhibitory interneurons contributes to glutamate-associated central sensitization through the GABABR2/PKA/SynCAM1 pathway in the PAG of CM rats.

Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) with monoclonal antibodies in migraine prevention: a brief review.

INTRODUCTION: Interest is growing in the role of pituitary adenylate cyclase-activating polypeptide (PACAP) and its specific PAC1 receptor in migraine and in their antagonism as a strategy for migraine prevention. AREAS COVERED: We discuss and critically evaluate (i) the evidence of the role of PACAP in migraine pathophysiology and (ii) the first clinical trials in migraine prophylaxis with monoclonal antibodies AMG 301 and ALD1910 which act against PAC1 and PACAP38 respectively. We examined PubMed, Scopus, and ClinicalTrials.gov electronic databases to examine the relevant material. EXPERT OPINION: There is much proof of the ability of PACAP to cause migraine, but there is limited evidence that blocking PACAP or PAC1 receptor can prevent migraine. However, the potential of anti-PACAP antibodies in migraine prophylaxis is high. Theoretically, if these antibodies block the activation of the trigeminovascular system, they will prevent the onset of migraine attacks. There are still knowledge gaps in the role of PACAP in migraine and the risk/benefit ratio of anti-PACAP antibodies must be carefully studied.

A Comprehensive Review of Surgical Treatment of Migraine Surgery Safety and Efficacy.

BACKGROUND: Recent clinical experience with migraine surgery has demonstrated both the safety and the efficacy of operative decompression of the peripheral nerves in the face, head, and neck for the alleviation of migraine symptoms. Because of the perceived novelty of these procedures, and the paranoia surrounding a theoretical loss of clinical territory, neurologists have condemned the field of migraine surgery. The Patient Safety Subcommittee of the American Society of Plastic Surgeons ventured to investigate the published safety track record of migraine surgery in the existing body of literature. METHODS: A comprehensive review of the relevant published literature was performed. The relevant databases and literature libraries were reviewed from the date of their inception through early 2018. These articles were reviewed and their findings analyzed. RESULTS: Thirty-nine published articles were found that demonstrated a substantial, extensively replicated body of data that demonstrate a significant reduction in migraine headache symptoms and frequency (even complete elimination of headache pain) following trigger-site surgery. CONCLUSIONS: Migraine surgery is a valid method of treatment for migraine sufferers when performed by experienced plastic surgeons following a methodical protocol. These operations are associated with a high level of safety. The safety and efficacy of migraine surgery should be recognized by plastic surgeons, insurance companies, and the neurology societies.