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Extracellular ATP activates inflammasome and triggers the release of multiple cytokines in various immune cells, a process primarily mediated by P2X7 receptors. However, the expression and functional properties of P2X7 receptors in native mast cells in tissues such as meninges where migraine pain originates from have not been explored. Here we report a novel model of murine cultured meningeal mast cells and using these, as well as easily accessible peritoneal mast cells, studied the mechanisms of ATP-mediated mast cell activation. We show that ATP induced a time and dose-dependent activation of peritoneal mast cells as analyzed by the uptake of organic dye YO-PRO1 as well as 4,6-diamidino-2-phenylindole (DAPI). Both YO-PRO1 and DAPI uptake in mast cells was mediated by the P2X7 subtype of ATP receptors as demonstrated by the inhibitory effect of P2X7 antagonist A839977. Consistent with this, significant YO-PRO1 uptake was promoted by the P2X7 agonist 2',3'-O-(benzoyl-4-benzoyl)-ATP (BzATP). Extracellular ATP-induced degranulation of native and cultured meningeal mast cells was shown with Toluidine Blue staining. Taken together, these data demonstrate the important contribution of P2X7 receptors to ATP-driven activation of mast cells, suggesting these purinergic mechanisms as potential triggers of neuroinflammation and pain sensitization in migraine.
Learn More >Cluster headache (CH) is the most severe primary headache condition. Its pathophysiology is multifaceted and incompletely understood. This review brings together the latest neuroimaging and neuropeptide evidence on the pathophysiology of CH.
Learn More >It remains unknown whether migraine headache has a progressive component in its pathophysiology. Quantitative MRI may provide valuable insight into abnormal changes in the migraine interictum and assist in identifying disrupted brain networks. We carried out a data-driven study of structural integrity and functional connectivity of the resting brain in migraine without aura. MRI scanning was performed in 36 patients suffering from episodic migraine without aura and 33 age-matched healthy subjects. Voxel-wise analysis of regional brain volume was performed by registration of the T1-weighted MRI scans into a common study brain template using the tensor-based morphometry (TBM) method. Changes in functional synchronicity of the brain networks were assessed using probabilistic independent component analysis (ICA). TBM revealed that migraine is associated with reduced volume of the medial prefrontal cortex (mPFC). Among 375 functional brain networks, resting-state connectivity was decreased between two components spanning the visual cortex, posterior insula, and parietal somatosensory cortex. Our study reveals structural and functional alterations of the brain in the migraine interictum that may stem from underlying disease risk factors and the "silent" aura phenomenon. Longitudinal studies will be needed to investigate whether interictal brain changes are progressive and associated with clinical disease trajectories.
Learn More >Migraines with aura have been associated with suicide in adolescents and young adults, but the association between suicide and migraine frequency has not been determined. This study investigated suicidal ideation and suicide attempts among patients with varying frequencies of migraines, with and without auras. This cross-sectional study analyzed 528 patients aged between 20 and 60 years from a headache outpatient clinic in Taiwan. All patients completed a set of questionnaires, including a demographic questionnaire, the Migraine Disability Assessment questionnaire, the Hospital Anxiety and Depression Scale, the Beck Depression Inventory, and the Pittsburgh Sleep Quality Index. Suicide risk was evaluated by self-reported lifetime suicidal ideation and attempts. Patients were divided into low-frequency (1-4 days/month), moderate-frequency (5-8 days/month), high-frequency (9-14 days/month), and chronic (≥15 days/month) migraine groups. The association between migraine frequency and suicidality was investigated using multivariable linear regression and logistic regression. The rates of suicidal ideation and suicide attempts were the highest for chronic migraine with aura (ideation: 47.2%; attempts: 13.9%) and lowest in migraine-free controls (2.8%). Migraine frequency was an independent risk factor for suicidal ideation and attempts in patients with aura (both < 0.001), but not in patients without auras. Migraine aura and depression were associated with higher risks of suicidal ideation and suicide attempts in patients with migraine. High migraine frequency has a correlation with high suicide risk in patients who experience an aura, but not in other patients with migraine.
Learn More >Migraine is a common neurological disorder that afflicts up to 15% of the adult population in most countries, with predominance in females. It is characterized by episodic, often disabling headache, photophobia and phonophobia, autonomic symptoms (nausea and vomiting), and in a subgroup an aura in the beginning of the attack. Although still debated, many researchers consider migraine to be a disorder in which CNS dysfunction plays a pivotal role while various parts of the trigeminal system are necessary for the expression of associated symptoms.Treatment of migraine has in recent years seen the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are now approved for use in frequent episodic and in chronic migraine. CGRP-related therapies offer considerable improvements over existing drugs, as they are the first to be designed specifically to act on the trigeminal pain system: they are more specific and have little or no adverse effects. Small molecule CGRP receptor antagonists, gepants, are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (Eptinezumab, Fremanezumab, and Galcanezumab) or the CGRP receptor (Erenumab) effectively prevent migraine attacks. The neurobiology of CGRP signaling is briefly summarized together with key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatments.
Learn More >By definition, post-traumatic headache (PTH) attributed to mild traumatic brain injury (mTBI) is not associated with brain structural abnormalities that are seen on routine clinical inspection of brain images. However, subtle brain structural abnormalities, as well as functional abnormalities, detected via research imaging techniques yield insights into the pathophysiology of PTH. The objective of this manuscript is to summarize published findings regarding research imaging of the brain in PTH attributed to mTBI. For this narrative review, PubMed was searched using the terms "post-traumatic headache" or "post-concussion headache" and "imaging" or "magnetic resonance imaging" or "research imaging" or "positron emission tomography". Articles were chosen for inclusion based on their relevance to the topic. Ten articles were ultimately included within this review. The studies investigated white matter tract integrity and functional connectivity in acute PTH, structural measures, white matter tract integrity, cerebral blood flow, and functional connectivity in persistent PTH (PPTH), and proton spectroscopy in both acute and persistent PTH. The articles demonstrate that acute and persistent PTH are associated with abnormalities in brain structure, that acute and persistent PTH are also associated with abnormalities in brain function, that it might be possible to predict the persistence of PTH using brain imaging findings, and that there are differences in imaging findings when comparing PTH to healthy controls and when comparing PTH to migraine. Although it is not entirely clear if the imaging findings are directly attributable to PTH as opposed to the underlying TBI or other post-TBI symptoms, correlations between the imaging findings with headache frequency and headache resolution suggest a true relationship between the imaging findings and PTH. PTH attributed to mTBI is associated with abnormalities in brain structure and function that can be detected via research imaging. Additional studies are needed to determine the specificity of the findings for PTH, to differentiate findings attributed to PTH from those attributed to the underlying TBI and coexistent post-TBI symptoms, and to determine the accuracy of imaging findings for predicting the development of PPTH.
Learn More >Peripheral mechanisms of primary headaches such as a migraine remain unclear. Meningeal afferents surrounded by multiple mast cells have been suggested as a major source of migraine pain. Extracellular ATP released during migraine attacks is a likely candidate for activating meningeal afferents via neuronal P2X receptors. Recently, we showed that ATP also increased degranulation of resident meningeal mast cells (Nurkhametova et al., 2019). However, the contribution of ATP-induced mast cell degranulation in aggravating the migraine pain remains unknown. Here we explored the role of meningeal mast cells in the pro-nociceptive effects of extracellular ATP. The impact of mast cells on ATP mediated activation of peripheral branches of trigeminal nerves was measured electrophysiologically in the dura mater of adult wild type (WT) or mast cell deficient mice. We found that a spontaneous spiking activity in the meningeal afferents, at baseline level, did not differ in two groups. However, in WT mice, meningeal application of ATP dramatically (24.6-fold) increased nociceptive firing, peaking at frequencies around 10 Hz. In contrast, in mast cell deficient animals, ATP-induced excitation was significantly weaker (3.5-fold). Application of serotonin to meninges in WT induced strong spiking. Moreover, in WT mice, the 5-HT3 antagonist MDL-7222 inhibited not only serotonin but also the ATP induced nociceptive firing. Our data suggest that extracellular ATP activates nociceptive firing in meningeal trigeminal afferents via amplified degranulation of resident mast cells in addition to direct excitatory action on the nerve terminals. This highlights the importance of mast cell degranulation via extracellular ATP, in aggravating the migraine pain.
Learn More >Chronic headache (headache ≥15 days/month) is a leading cause of disability. Illness perception, beliefs and cognitive models are likely central for patient understanding of their chronic pain condition and are associated with treatment outcome. However, these factors are insufficiently described in chronic headache.
Learn More >Migraine is one of the most prevalent neurological disorders among all age groups including the elderly, but the incidence and prevalence of migraine tend to decrease with age. The clinical phenotype of migraine also appears to be different in the elderly patient group in comparison to the younger patient group, with elderly migraine appearing to be more often bilateral and associated with what has become known as "late-life migraine accompaniments. Furthermore, difficulty in the differentiation of migraine from vascular insults such as transient ischemic attacks and amyloid angiopathy and other multiple comorbidities, polypharmacy and age-related changes in pharmacodynamics and pharmacokinetics makes treatments for this cohort challenging but necessary, especially given the worldwide increase in life expectancy, and likelihood of migraine continuing to be a major personal and public health problem.
Learn More >Progressive muscle relaxation (PMR) is an under-utilized Level A evidence-based treatment for migraine prevention. We studied the feasibility and acceptability of smartphone application (app)-based PMR for migraine in a neurology setting, explored whether app-based PMR might reduce headache (HA) days, and examined potential predictors of app and/or PMR use. In this single-arm pilot study, adults with ICHD3 migraine, 4+ HA days/month, a smartphone, and no prior behavioral migraine therapy in the past year were asked to complete a daily HA diary and do PMR for 20 min/day for 90 days. Outcomes were: adherence to PMR (no. and duration of audio plays) and frequency of diary use. Predictors in the models were baseline demographics, HA-specific variables, baseline PROMIS (patient-reported outcomes measurement information system) depression and anxiety scores, presence of overlapping pain conditions studied and app satisfaction scores at time of enrollment. Fifty-one patients enrolled (94% female). Mean age was 39 ± 13 years. The majority (63%) had severe migraine disability at baseline (MIDAS). PMR was played 22 ± 21 days on average. Mean/session duration was 11 ± 7 min. About half (47%) of uses were 1+ time/week and 35% of uses were 2+ times/week. There was a decline in use/week. On average, high users (PMR 2+ days/week in the first month) had 4 fewer days of reported HAs in month 2 vs. month 1, whereas low PMR users (PMR < 2 days/week in the first month) had only 2 fewer HA days in month 2. PROMIS depression score was negatively associated with the log odds of using the diary at least once (vs. no activity) in a week (OR = 0.70, 95% CI = [0.55, 0.85]) and of doing the PMR at least once in a week (OR = 0.77, 95% CI = [0.68, 0.91]). PROMIS anxiety was positively associated with using the diary at least once every week (OR = 1.33, 95% CI = [1.09, 1.73]) and with doing the PMR at least once every week (OR = 1.14 [95% CI = [1.02, 1.31]). In conclusion, about half of participants used smartphone-based PMR intervention based upon a brief, initial introduction to the app. App use was associated with reduction in HA days. Higher depression scores were negatively associated with diary and PMR use, whereas higher anxiety scores were positively associated.
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