1,721,261 research outputs found
Dissecting out migraine complexity through comprehensive analysis of allodynia
No full textThis scientific commentary refers to ‘Nitroglycerine triggers triptan-responsive cranial allodynia and trigeminal neuronal hypersensitivity’, by Akerman et al. (doi:10.1093/brain/awy313)
Headache in 2021: clinical, biological, and genetic advances
No full textIn the past decade, the strenuous efforts of the scientific community have substantially advanced our understanding of primary headaches. This research has promoted the development of novel disease-specific treatments, such as monoclonal antibodies and small molecules targeting the calcitonin gene-related peptide (CGRP) pathway, and agonists of the 5-HT1F receptor. However, despite these major advances, primary headaches still constitute a challenge for clinicians and a major burden for patients and society.
Among primary headaches, chronic migraine is the leading cause of disability and economic burden. Chronic migraine is defined by the recurrence of 15 or more headache days per month, with at least 8 days with a migraine phenotype, for at least 3 months. This definition assumes that the cutoff of 15 days adequately separates two different subtypes of migraine: episodic (less aggressive and burdensome) and chronic (more severe and disabling). Ishii and colleagues1 have now challenged the validity of the 15-day cutoff by showing that patients with 8–14 monthly headache days (ie, high-frequency episodic migraine) endure a similar loss of productivity, due to absenteeism, presenteeism, depression, and anxiety, as do patients with 15–23 monthly headache days. This observation is a clarion call to extend allocation of health-care and research resources to subtypes of migraine that have previously been thought of as less burdensome.
In the International Classification of Headache Disorders (ICHD-3), primary headaches are framed according to their phenotypical manifestations, while almost no consideration is given to their neurobiological determinants. This apparently oversimplified approach has been validated within the Finnish Migraine Genome Project, where the main ICHD-3 categories were remarkably correlated with a polygenic risk score.2 The association with polygenic risk showed two striking features: first, it intensified across the proposed categories, being weaker in non-migraine headache and probable migraine, and becoming stronger in migraine without aura, migraine with aura, and hemiplegic migraine; and second, it was linked to specific migraine features—namely, the presence of nausea or vomiting, longer headache duration, and higher headache intensity. Altogether, these findings demonstrate a link between the ICHD-3 categories and biological mechanisms. They represent a steppingstone towards the development of a more individualised approach to the management of primary headaches based on two powerful tools: the ICHD-3 classification and polygenic risk score.
Further advances in genetics were provided by a large cohort study (comprising 860 patients with hemiplegic migraine) that clarified the genotype–phenotype connection between autosomal dominant mutations in PRRT2 and hemiplegic migraine. PRRT2 mutations were present in 12 (7·4%) of 163 patients with hemiplegic migraine who previously tested negative for CACNA1A, ATP1A2, and SCN1A mutations, and in 18 (2·6%) of 697 patients who had not previously had genetic testing. PRRT2 mutations accounted for 18 (17%) of 103 pathogenic variants identified in this latter group. In 16 of 30 patients, hemiplegic migraine was the only clinical manifestation, but other phenotypes included epilepsy, cognitive impairment, sleep disturbances, and movement disorders.3 PRRT2 mutations lead to altered neuronal excitability, mainly through dysregulation of transmembrane calcium and sodium channels.4 Hemiplegic migraine is a rare migraine subtype, but unveiling the functional correlates of PRRT2 mutations might also shed light on novel pathways involved in less rare forms of migraine.
In the context of migraine biomarkers, Alpuente and colleagues5 assessed CGRP concentrations in saliva over 30 days in 49 patients with episodic migraine, thus capturing changes during the different phases of attacks. Patients had higher CGRP concentrations interictally than did healthy controls. CGRP concentrations further increased slightly in the pre-ictal phase, increased more markedly during a genuine migraine attack, and then reverted to baseline values after the attack resolved. Even more interestingly, a subset of patients with episodic migraine did not have increased saliva CGRP concentrations, suggesting the existence of a non-CGRP-dependent migraine phenotype. Meanwhile, Al-Karagholi and colleagues6 showed, in patients with migraine, that the activation of a downstream cellular pathway, based on ATP-sensitive potassium channel opening, was able to induce a migraine attack in 14 (82%) of 17 patients. Of note, aura symptoms fulfilling ICHD-3 criteria were present in up to 60% (10 of 17) of patients who had migraine with aura, possibly providing the first model for the study of the aura phase in humans under well-controlled conditions.
Cluster headache is a highly disabling and relatively rare primary headache, characterised by attacks of unilateral and excruciating pain associated with ipsilateral cranial autonomic symptoms and restlessness. Typically manifesting with active periods during which recurring attacks devastate patients’ quality of life, cluster headache is an enigmatic disorder whose pathophysiology is highly elusive. Occurrence in families suggests a genetic predisposition, but previous studies have not shown any such association. In 2021, two genome-wide association studies identified seven loci associated with cluster headaches.7, 8 Two pivotal observations strongly suggest that these loci might be risk loci for cluster headache: four loci were individually identified by both study groups in the two different cohorts; and five loci were not previously described in other primary headache disorders. Although not conclusive, these studies are a starting point for better understanding the genetic profile of cluster headache as well as the mechanisms of the disease.
Notwithstanding relentless scientific advances, further research is still needed as too few people with primary headaches receive adequate care,9 and treatment resistance and refractoriness remain untackled issues.10 The findings summarised here show the importance of identifying solid clinical, biological, and genetic biomarkers for primary headaches—a crucial step for recognition of these diseases and for improving their management globally.
RDI has received speaker honoraria for oral presentations from Eli-Lilly. CT has received fees for advisory boards or scientific lecturing from Allergan/AbbVie, Eli Lilly, Lundbeck, Novartis, and TEVA; and institutional payments for clinical trials from Allergan/AbbVie, Eli Lilly, Novartis Lundbeck, and TEVA
Effects of the intrastriatal administration of selective dopaminergic agonists on Fos expression in the rat brain
No full textLasmiditan: an additional therapeutic option for the acute treatment of migraine
No full textIntroduction: Migraine is currently listed as the second cause of ‘years lived with disability’ and the sixth cause of global disability. Despite the burden associated to the disease, availability of specific drugs is still limited. Areas covered: The authors have evaluated lasmiditan, the first ‘ditan’ approved by the Food and Drugs Administration in 2019, from a global perspective: basic chemistry, pharmacodynamic and pharmacokinetic profiles, efficacy in migraine as a 5-HT1F receptor selective agonist, tolerability and clinical safety, and impact on migraine-related disability. Our evaluation considered original papers and review articles published from 2010 to 2020. Expert opinion: Available data point to the efficacy of lasmiditan in reducing migraine pain and the most bothersome symptoms within 2 hours from oral administration. Moreover, lasmiditan has a positive effect on migraine-related disability. Its side effects mostly reflect an involvement of the central nervous system or the vestibular system, while cardiovascular side effects are rare and mild. Lasmiditan can be safely prescribed in patients who have failed non-steroid anti-inflammatory drugs or triptans or with cardiovascular risk factors. Caution is advised in frequent users, due to lack of reliable data on its abuse potential. Further data are necessary to determine the usability of lasmiditan in particular populations, e.g. children and adolescents, pregnancy
The endocannabinoid system and migraine.
No full textThe recently discovered endocannabinoid system (ECS), which includes endocannabinoids and the proteins that metabolize and bind them, has been implicated in multiple regulatory functions both in health and disease. Several studies have suggested that ECS is centrally and peripherally involved in the processing of pain signals. This finding is corroborated by the evidence that endocannabinoids inhibit, through a cannabinoid type-1 receptor (CB1R)-dependent retrograde mechanism, the release of neurotransmitters controlling nociceptive inputs and that the levels of these lipids are high in those regions (such as sensory terminals, skin, dorsal root ganglia) known to be involved in transmission and modulation of pain signals. In this review we shall describe experimental and clinical data that, intriguingly, demonstrate the link between endocannabinoids and migraine, a neurovascular disorder characterized by recurrent episodic headaches and caused by abnormal processing of sensory information due to peripheral and/or central sensitization. Although the exact ECS-dependent mechanisms underlying migraine are not fully understood, the available results strongly suggest that activation of ECS could represent a promising therapeutical tool for reducing both the physiological and inflammatory components of pain that are likely involved in migraine attacks
Functional changes of the basal ganglia circuitry in Parkinson's disease. Prog Neurobiol. 2000 Sep;62(1):63-88.
No full textChronic migraine and Botulinum Toxin Type A: Where do paths cross?
No full textMigraine is a highly prevalent and disabling disorder accounted among the primary headaches. It is the expression of a complex, and not yet fully understood, pathophysiology involving the sensitization of peripheral and central nociceptive pathways. In this review we succinctly illustrate the molecular, anatomical, and functional abnormalities underlying the migraine attack that are relevant for understanding in more depth the neurobiology behind the therapeutic effect of Botulinum Toxin Type A (BoNT-A). BoNT-A has proved effective in several neurological conditions and, more recently, also in chronic migraine. Its antimigraine mechanism of action was initially thought to be limited to the periphery and interpreted as an inhibitory activity on the processes associated to the local release of neuropeptides, with subsequent induction of peripheral sensitization. Increasing experimental evidence has become available to suggest that additional mechanisms are possibly involved, including the direct/indirect inhibition of sensitization processes in central nociceptive pathways
Electrokinesiographic Study of Oropharyngeal Swallowing in Neurogenic Dysphagia
No full textElectrokinesiographic study of swallowing (EKSS) can be useful for the assessment of patients with suspected or overt neurogenic dysphagia. EKSS consists of multichannel recording of the electromyographic (EMG) activity of the suprahyoid/submental muscle complex (SHEMG), the EMG activity of the cricopharyngeal muscle (CPEMG), and the laryngopharyngeal mechanogram (LPM). The LPM is an expression of the mechanical changes that the laryngopharyngeal structures undergo during the pharyngeal phase of swallowing. This method allows detailed evaluation of the magnitude, duration and temporal relations of the different events that characterize oropharyngeal swallowing, and thus in-depth exploration both of physiological deglutition mechanisms and of pathophysiological features of swallowing in neurogenic dysphagia. Furthermore, EKSS can guide dysphagia treatment strategies, allowing identification of optimal solutions for single patients. For instance, CPEMG recording can identify incomplete or absent relaxation of the upper esophageal sphincter during the pharyngeal phase of swallowing, thus suggesting a therapeutic approach based on botulinum toxin injection into the cricopharyngeal muscle. More recently, the ‘shape’ of SHEMG and the reproducibility of both SHEMG and LPM over repeated swallowing acts have been implemented as novel electrokinesiographic parameters. These measures could be valuable for straightforward non-invasive investigation of dysphagia severity and response to dysphagia treatment in clinical practice
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