Spreading depression (SD) is an intense and prolonged depolarization in the central nervous systems from insect to man. It is implicated in neurological disorders such as migraine and brain injury. ...Here, using an in vivo mouse model of focal neocortical seizures, we show that SD may be a fundamental defense against seizures. Seizures induced by topical 4-aminopyridine, penicillin or bicuculline, or systemic kainic acid, culminated in SDs at a variable rate. Greater seizure power and area of recruitment predicted SD. Once triggered, SD immediately suppressed the seizure. Optogenetic or KCl-induced SDs had similar antiseizure effect sustained for more than 30 min. Conversely, pharmacologically inhibiting SD occurrence during a focal seizure facilitated seizure generalization. Altogether, our data indicate that seizures trigger SD, which then terminates the seizure and prevents its generalization.
Background
Non-invasive vagus nerve stimulation (nVNS) is a proven treatment for cluster headache and migraine. Several possible mechanisms of action by which nVNS mitigates headache have been ...identified.
Methods
We conducted a narrative review of recent scientific and clinical research into nVNS for headache, including findings from mechanistic studies and their possible relationships to the clinical effects of nVNS.
Results
Findings from animal and human studies have provided possible mechanistic explanations for nVNS efficacy in headache involving four core areas: Autonomic nervous system functions; cortical spreading depression inhibition; neurotransmitter regulation; and nociceptive modulation. We discuss how overlap and interplay among these areas may underlie the utility of nVNS in the context of clinical evidence supporting its safety and efficacy as acute and preventive therapy for both cluster headache and migraine. Possible future nVNS applications are also discussed.
Conclusion
Significant progress over the past several years has yielded valuable mechanistic and clinical evidence that, combined with the excellent safety and tolerability profile of nVNS, suggests that it should be considered a first-line treatment for both acute and preventive treatment of cluster headache, an effective option for acute treatment of migraine, and a highly relevant, practical option for migraine prevention.
Background/aim
Certain constituents in migraine food triggers and non-steroidal anti-inflammatory drugs (NSAIDs) inhibit sulfotransferases (SULTs) that detoxify drugs/chemicals and play role in the ...metabolism of neurotransmitters. We aimed to dissect SULT1A1 modulation of CSD susceptibility and behavior in an in vivo experimental model using hesperidin, a SULT1A1 inhibitor found in citrus fruits (known migraine triggers) and mefenamic acid (SULT1A1 inhibitor), an NSAID to simulate medication overuse.
Methods
Hesperidin was used as SULT1A1 inhibitor found in citrus fruits, known migraine triggers and mefenamic acid (NSAID), another SULT1A1 inhibitor, was used to induce MO in rats. The groups were; 1) Hesperidin (ip) or its vehicle-DMSO (ip) 2) Chronic (4 weeks) mefenamic acid (ip) or its vehicle (ip) 3) Chronic mefenamic acid+hesperidin (ip) or DMSO (ip). CSD susceptibility was evaluated and behavioral testing was performed. SULT1A1 enzyme activity was measured in brain samples.
Results
Single-dose of hesperidin neither changed CSD susceptibility nor resulted in any behavioral change. Chronic mefenamic acid exposure resulted in increased CSD susceptibility, mechanical-thermal hypersensitivity, increased head shake, grooming and freezing and decreased locomotion. Single dose hesperidin administration after chronic mefenamic acid exposure resulted in increased CSD susceptibility and mechanical-thermal hypersensitivity, increased freezing and decreased locomotion. SULT1A1 enzyme activity was lower in mefenamic acid and mefenamic acid+hesperidin groups compared to their vehicles.
Conclusion
Mefenamic acid and hesperidin have synergistic effect in modulating CSD susceptibility and pain behavior. Sulfotransferase inhibition may be the common mechanism by which food triggers and NSAIDs modulate migraine susceptibility. Further investigations regarding human provocation studies using hesperidin in migraine patients with medication overuse are needed.
Vagus nerve stimulation has recently been reported to improve symptoms of migraine. Cortical spreading depression is the electrophysiological event underlying migraine aura and is a trigger for ...headache. We tested whether vagus nerve stimulation inhibits cortical spreading depression to explain its antimigraine effect. Unilateral vagus nerve stimulation was delivered either noninvasively through the skin or directly by electrodes placed around the nerve. Systemic physiology was monitored throughout the study. Both noninvasive transcutaneous and invasive direct vagus nerve stimulations significantly suppressed spreading depression susceptibility in the occipital cortex in rats. The electrical stimulation threshold to evoke a spreading depression was elevated by more than 2-fold, the frequency of spreading depressions during continuous topical 1 M KCl was reduced by ∼40%, and propagation speed of spreading depression was reduced by ∼15%. This effect developed within 30 minutes after vagus nerve stimulation and persisted for more than 3 hours. Noninvasive transcutaneous vagus nerve stimulation was as efficacious as direct invasive vagus nerve stimulation, and the efficacy did not differ between the ipsilateral and contralateral hemispheres. Our findings provide a potential mechanism by which vagus nerve stimulation may be efficacious in migraine and suggest that susceptibility to spreading depression is a suitable platform to optimize its efficacy.
An accurate and efficient statistical method for repeated measures analysis and selection of scion/rootstock combinations (SRC) is a fundamental prerequisite for genetic progress in ‘Tahiti’ acid ...lime breeding. Thus, this work aimed: (i) to evaluate the applicability and efficiency of random regression models in the analysis of repeated measures and (ii) to apply a selection index to recommend SRC of ‘Tahiti’ acid lime, associating vegetative and productive traits. Between July 2017 and January 2019, 24 SRC of ‘Tahiti’ acid lime were evaluated for vegetative and productive traits over eight measurements. The random regression model (RRM) was compared with a repeatability model (REP). The variance components were estimated via residual maximum likelihood. The predicted genotypic values were predicted via the best linear unbiased prediction. The genotypic values (for REP) and the areas below the genotypic trajectories (for RRM) were used as input for the additive index aiming for simultaneous selection. The three best-performing genotypes were selected, considering a selection percentage equal to 12.5%. Models based on random regression and repeatability showed the same selected genotypes, even though, there were changes in the ranking. The random regression model allows the prediction of genotypic values for genotypes that were not evaluated in the field being advantageous for genetic evaluation of ‘Tahiti’ acid lime. The selection index based on the REP and RRM models indicated that the recommended SRC for propagation and planting are Iconha/
’Riverside’ citrandarin
, CNPMF5059/
’Riverside’ citrandarin
and Itarana/
Swingle citrumelo
.
•Bayesian inference models demonstrate to be useful for Tahiti lime genetic selection.•Multitrait and multiharvest strategy represented a possibility to breed genotypes.•Repeatability model is ...successfully applied under Bayesian framework.•Models with diagonal residual variance are indicated for Tahiti lime trait assessment.•Tahiti lime genotypes selected are promising accounting for the main crop traits.
Fruit breeding programs demand substantial investment for the development and selection of superior genotypes. Thus, statistical methods that allow a reliable genetic evaluation should be preferred. The present study aimed to estimate genetic parameters and genotypic values through the Markov chain Monte Carlo algorithm and perform the selection of Tahiti acid lime genotypes, based on a multitrait index. Twenty-four Tahiti acid lime genotypes were evaluated, from July 2017 to January 2019, for their vegetative, productive, and physical-chemical traits. Repeatability models with different residual variance structures were tested. The Deviance information criterion (DIC) was used to select the best model and test the significance of the random effects. A multiple trait index was used to identify superior genotypes, closely with the ideotype. According to DIC, models with diagonal residual variance structure presented best fit. Heritability estimates presented a downward trend through the harvests. Mean selective accuracies were moderate to very high (0.50≤r˜g^g) for all traits, which indicates high reliability in the genotype ranking. Desirable gains for all traits were achieved by the multitrait index. The Bayesian inference was adequate for the genetic evaluation; and the multitrait index allowed an efficient genetic selection.
Cortical spreading depolarization (CSD) induces pro-inflammatory gene expression in brain tissue. However, previous studies assessing the relationship between CSD and inflammation have used invasive ...methods that directly trigger inflammation. To eliminate the injury confounder, we induced CSDs non-invasively through intact skull using optogenetics in Thy1-channelrhodopsin-2 transgenic mice. We corroborated our findings by minimally invasive KCl-induced CSDs through thinned skull. Six CSDs induced over 1 h dramatically increased cortical interleukin-1β (IL-1β), chemokine (C-C motif) ligand 2 (CCL2), and tumor necrosis factor-α (TNF-α) mRNA expression peaking around 1, 2 and 4 h, respectively. Interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) were only modestly elevated. A single CSD also increased IL-1β, CCL2, and TNF-α, and revealed an ultra-early IL-1β response within 10 min. The response was blunted in IL-1 receptor-1 knockout mice, implicating IL-1β as an upstream mediator, and suppressed by dexamethasone, but not ibuprofen. CSD did not alter systemic inflammatory indices. In summary, this is the first report of pro-inflammatory gene expression after non-invasively induced CSDs. Altogether, our data provide novel insights into the role of CSD-induced neuroinflammation in migraine headache pathogenesis and have implications for the inflammatory processes in acute brain injury where numerous CSDs occur for days.
Combining longitudinal data and statistical models from perennial crops enabled us to estimate the optimum number of measures (harvests), implying accurate discrimination of superior genotypes in ...those crops. Herein, the goal of this study was to determine the optimum number of harvests based on yield traits and recommend a superior graft/rootstock combination (GRC) for Citrus latifolia Tanaka. Twenty-four GRCs of 'Tahiti' acid lime were evaluated from July 2017 to August 2018 for fruit yield per plant (FYP), number of fruits per plant (NFP), and longitudinal (LFD) and transversal fruit diameter (TFD). The experimental design was a randomized complete block with 4 replications. The experimental unit consisted of three individuals, totalling 244 individuals. The GRCs were composed of (i) two hybrids that were used as rootstock, citrumelo ‘Swingle’ (Citrus paradisi x Poncirus trifoliata) and cintrandarin ‘Riverside’ (Citrus sunki x Poncirus trifoliata); and (ii) 12 different C. latifolia genotypes that were used as grafts: Bello Fruit, Eledio, Iconha, Itarana, Santa Rosa, Bearss lime, CNPMF 01, CNPMF 02, CNPMF 2001, CNPMF 5059, BRS Passos, and Persian 58. Mixed models were employed to estimate the variance components. The optimum number of harvests was determined based on selective efficiency values above 0.9. The estimated repeatability coefficients presented values of 0.14 (LFD), 0.16 (TFD), 0.36 (FYP), and 0.38 (NFD). Based on the results, four harvests were able to choose genotypes based on FYP and NFP, whereas LFD and TFD were considered inefficient traits for recommending superior GRCs.
Abstract The objective of this work was to estimate the genetic parameters and to evaluate the genotypic diversity of 12 'Tahiti' acid lime (Citrus latifolia) genotypes grafted onto two rootstocks. ...The experiment was carried out from July 2017 to January 2019, in the municipality of São Mateus, in the state of Espírito Santo, Brazil. Vegetative (stem diameter, canopy projection diameter, and plant height), productive (yield and fruit number), and fruit quality (fruit diameter, soluble solids content, and juice yield) traits were determined. A mixed model was used to estimate heritability and repeatability coefficients, as well as to predict clonal values. Scion diversity was determined through the standardized mean difference of Euclidean distances, and genotypes were clustered by modified Tocher. Clustering quality and trait importance were evaluated using the principal component analysis (PCA). Genotypic variance was observed, which is indicative of the possibility of selection of superior genotypes. The Tocher method showed the presence of three clusters, which is in alignment with the PCA results. The multivariate analyses allows of the selection and the recommendation of superior 'Tahiti' acid lime genotypes.
Resumo O objetivo deste trabalho foi estimar os parâmetros genéticos e avaliar a diversidade genética de 12 genótipos de lima ácida 'Tahiti' (Citrus latifolia) enxertados em dois porta-enxertos. O experimento foi conduzido de julho de 2017 a janeiro de 2019, no município de São Mateus, no estado de Espírito Santo, Brasil. Foram mensuradas características vegetativas (diâmetro de caule, diâmetro de projeção de copa e altura de planta), produtivas (rendimento e número de frutos) e de qualidade de frutos (diâmetros de fruto, teor de sólidos solúveis e rendimento de suco). Utilizou-se modelo misto para estimar os coeficientes de herdabilidade e repetibilidade, bem como predizer os valores genéticos. A diversidade entre os enxertos foi obtida por meio da diferença da distância euclidiana média padronizada, e os genótipos foram agrupados pelo método de Tocher modificado. A qualidade do agrupamento e a importância dos caracteres foi avaliada pela análise de componentes principais (ACP). Observou-se variabilidade genética, o que indica a possibilidade de seleção de genótipos superiores. O método de Tocher mostrou a presença de três grupos de genótipos, o que foi congruente com os resultados da ACP. O uso de técnicas multivariadas permite a seleção e a recomendação de genótipos superiores de lima ácida 'Tahiti'.
Although ascorbic acid (AA) is an antioxidant, under certain conditions it can facilitate oxidation, which may underlie the opposite actions of AA on brain excitability in distinct seizure models. ...Here, we investigated whether chronic AA administration during brain development alters cortical excitability as a function of AA dose, as indexed by cortical spreading depression (CSD) and by the levels of lipid peroxidation-induced malondialdehyde. Well-nourished and early-malnourished rats received per gavage 30, 60, or 120 mg/kg/d of AA, saline, or no gavage treatment (naïve group) at postnatal days 7–28. CSD propagation and malondialdehyde levels were analyzed at 30–40 days. Confirming previous observations, CSD velocities were significantly higher in the early-malnourished groups than in the well-nourished groups. AA dose was important: 30 mg/kg/d AA decelerated CSD and reduced malondialdehyde levels, whereas 60 mg/kg/d and 120 mg/kg/d accelerated CSD and augmented malondialdehyde levels compared with the corresponding saline and naïve groups. Our findings reinforce previous suggestion that AA acts as an antioxidant in the brain when administered at low doses, but as a prooxidant at high doses, as indicated by CSD propagation and malondialdehyde levels.
•We treated developing rats chronically with 3 different doses of ascorbic acid (AA).•We measured cortical spreading depression (CSD) parameters.•In addition, we measured brain malondialdehyde (MDA) levels.•Low and high AA doses respectively decreased and increased CSD and MDA levels.•Data suggest antioxidant and prooxidant actions of low and high AA, respectively.
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