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Cenk Ayata - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic implications of Cortical Spreading Depression models in migraine.
Progress in brain research, 2020Co-Authors: Tsubasa Takizawa, Cenk Ayata, Shih-pin ChenAbstract:Migraine is among the most common and disabling neurological diseases in the world. Cortical Spreading Depression (CSD) is a wave of near-complete depolarization of neurons and glial cells that slowly propagates along the cortex creating the perception of aura. Evidence suggests that CSD can trigger migraine headache. Experimental models of CSD have been considered highly translational as they recapitulate migraine-related phenomena and have been validated for screening migraine therapeutics. Here we outline the essential components of validated experimental models of CSD and provide a comprehensive review of potential modulators and targets against CSD. We further focus on novel interventions that have been recently shown to suppress CSD susceptibility that may lead to therapeutic targets in migraine.
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Cortical Spreading Depression Denotes Concussion Injury
Journal of neurotrauma, 2018Co-Authors: James P. Bouley, Cenk Ayata, David Y. Chung, Robert H. Brown, Nils HenningerAbstract:Abstract Cortical Spreading Depression (CSD) has been described after moderate-to-severe traumatic brain injury (TBI). It is uncertain, however, whether CSD occurs after mild, concussive TBI and wh...
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Vagus nerve stimulation inhibits Cortical Spreading Depression.
Pain, 2016Co-Authors: Shih-pin Chen, Katharina Eikermann-haerter, De Morais Al, Tao Qin, Zheng Y, Homa Sadeghian, Fumiaki Oka, Bruce J. Simon, Cenk AyataAbstract: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.
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oxcarbazepine does not suppress Cortical Spreading Depression
Cephalalgia, 2011Co-Authors: Ulrike Hoffmann, Chiho Kudo, Ergin Dilekoz, Cenk AyataAbstract:Background: Cortical Spreading Depression is the electrophysiological substrate of migraine aura, and may trigger headache. Recently, chronic treatment with five migraine prophylactic drugs was sho...
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Oxcarbazepine does not suppress Cortical Spreading Depression.
Cephalalgia : an international journal of headache, 2010Co-Authors: Ulrike Hoffmann, Chiho Kudo, Ergin Dilekoz, Cenk AyataAbstract:BACKGROUND Cortical Spreading Depression is the electrophysiological substrate of migraine aura, and may trigger headache. Recently, chronic treatment with five migraine prophylactic drugs was shown to suppress Cortical Spreading Depression, implicating Spreading Depression as a common therapeutic target in migraine prophylaxis. MATERIALS AND METHODS In order to assess the negative predictive value of Spreading Depression susceptibility as a preclinical drug screening tool, we tested oxcarbazepine, an anti-epileptic ineffective in migraine prophylaxis. Valproate served as the positive control. Cortical Spreading Depression susceptibility was measured in rats using topical KCl or electrical stimulation. RESULTS Oxcarbazepine did not suppress Spreading Depression either after a single dose or after daily treatment for 5 weeks. As previously shown, valproate suppressed Spreading Depression susceptibility after chronic dosing, while a single dose was ineffective. CONCLUSIONS These data provide further support for Spreading Depression as a relevant target in migraine prophylaxis, and demonstrate the predictive utility of employed Spreading Depression models.
Shih-pin Chen - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic implications of Cortical Spreading Depression models in migraine.
Progress in brain research, 2020Co-Authors: Tsubasa Takizawa, Cenk Ayata, Shih-pin ChenAbstract:Migraine is among the most common and disabling neurological diseases in the world. Cortical Spreading Depression (CSD) is a wave of near-complete depolarization of neurons and glial cells that slowly propagates along the cortex creating the perception of aura. Evidence suggests that CSD can trigger migraine headache. Experimental models of CSD have been considered highly translational as they recapitulate migraine-related phenomena and have been validated for screening migraine therapeutics. Here we outline the essential components of validated experimental models of CSD and provide a comprehensive review of potential modulators and targets against CSD. We further focus on novel interventions that have been recently shown to suppress CSD susceptibility that may lead to therapeutic targets in migraine.
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vagus nerve stimulation inhibits Cortical Spreading Depression exclusively through central mechanisms
Pain, 2020Co-Authors: Andreia Morais, David Y. Chung, Rubem Carlos Araújo Guedes, Tao Qin, Bruce J. Simon, Tzuting Liu, Homa Sadhegian, Damla Yagmur, Rosangela Mendes Da Silva, Shih-pin ChenAbstract:Experimental and clinical data strongly support vagus nerve stimulation (VNS) as a novel treatment in migraine. Vagus nerve stimulation acutely suppresses Cortical Spreading Depression (CSD) susceptibility, an experimental model that has been used to screen for migraine therapies. However, mechanisms underlying VNS efficacy on CSD are unknown. Here, we interrogated the central and peripheral mechanisms using VNS delivered either invasively (iVNS) or noninvasively (nVNS) in male Sprague-Dawley rats. Cortical Spreading Depression susceptibility was evaluated 40 minutes after the stimulation. iVNS elevated the electrical CSD threshold more than 2-fold and decreased KCl-induced CSD frequency by 22% when delivered to intact vagus nerve. Distal vagotomy did not alter iVNS efficacy (2-fold higher threshold and 19% lower frequency in iVNS vs sham). By contrast, proximal vagotomy completely abolished iVNS effect on CSD. Pharmacological blockade of nucleus tractus solitarius, the main relay for vagal afferents, by lidocaine or glutamate receptor antagonist CNQX also prevented CSD suppression by nVNS. Supporting a role for both norepinephrine and serotonin, CSD suppression by nVNS was inhibited by more than 50% after abrogating norepinephrinergic or serotonergic neurotransmission alone using specific neurotoxins; abrogating both completely blocked the nVNS effect. Our results suggest that VNS inhibits CSD through central afferents relaying in nucleus tractus solitarius and projecting to subCortical neuromodulatory centers providing serotonergic and norepinephrinergic innervation to the cortex.
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Vagus nerve stimulation inhibits Cortical Spreading Depression.
Pain, 2016Co-Authors: Shih-pin Chen, Katharina Eikermann-haerter, De Morais Al, Tao Qin, Zheng Y, Homa Sadeghian, Fumiaki Oka, Bruce J. Simon, Cenk AyataAbstract: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.
Rubem Carlos Araújo Guedes - One of the best experts on this subject based on the ideXlab platform.
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vagus nerve stimulation inhibits Cortical Spreading Depression exclusively through central mechanisms
Pain, 2020Co-Authors: Andreia Morais, David Y. Chung, Rubem Carlos Araújo Guedes, Tao Qin, Bruce J. Simon, Tzuting Liu, Homa Sadhegian, Damla Yagmur, Rosangela Mendes Da Silva, Shih-pin ChenAbstract:Experimental and clinical data strongly support vagus nerve stimulation (VNS) as a novel treatment in migraine. Vagus nerve stimulation acutely suppresses Cortical Spreading Depression (CSD) susceptibility, an experimental model that has been used to screen for migraine therapies. However, mechanisms underlying VNS efficacy on CSD are unknown. Here, we interrogated the central and peripheral mechanisms using VNS delivered either invasively (iVNS) or noninvasively (nVNS) in male Sprague-Dawley rats. Cortical Spreading Depression susceptibility was evaluated 40 minutes after the stimulation. iVNS elevated the electrical CSD threshold more than 2-fold and decreased KCl-induced CSD frequency by 22% when delivered to intact vagus nerve. Distal vagotomy did not alter iVNS efficacy (2-fold higher threshold and 19% lower frequency in iVNS vs sham). By contrast, proximal vagotomy completely abolished iVNS effect on CSD. Pharmacological blockade of nucleus tractus solitarius, the main relay for vagal afferents, by lidocaine or glutamate receptor antagonist CNQX also prevented CSD suppression by nVNS. Supporting a role for both norepinephrine and serotonin, CSD suppression by nVNS was inhibited by more than 50% after abrogating norepinephrinergic or serotonergic neurotransmission alone using specific neurotoxins; abrogating both completely blocked the nVNS effect. Our results suggest that VNS inhibits CSD through central afferents relaying in nucleus tractus solitarius and projecting to subCortical neuromodulatory centers providing serotonergic and norepinephrinergic innervation to the cortex.
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Cortical Spreading Depression: A Model for Studying Brain Consequences of Malnutrition
Handbook of Behavior Food and Nutrition, 2011Co-Authors: Rubem Carlos Araújo GuedesAbstract:This chapter focuses on the worldwide problem of the neurological impact of nutritional deficiency and how to electrophysiologically study it by analyzing the changes in brain electrical activity. The electrophysiological phenomenon known as Spreading Depression of the Cortical electrical activity or simply “Cortical Spreading Depression” is briefly presented. This phenomenon is an interesting and remarkable reaction produced by the brain gray-matter in response to electrical, mechanical, or chemical stimulation of one point of the tissue. Experimental data on Cortical Spreading Depression obtained under conditions of severe and moderate malnutrition, as well as under favorable nutritional conditions early in life (“overnutrition”) are described and possible underlying mechanisms are discussed. Changes in the propagation features of this phenomenon under normal and altered nutritional conditions are reviewed and confronted with changes studied under the effect of non-nutritional (environmental, hormonal, and pharmacological) factors in studies on developing and adult animals. Over the last two decades, data from several laboratories including ours, on an impressive number of experiments, have shown that the propagation velocity of Cortical Spreading Depression constitutes a good indicator of alterations induced by malnutrition or by other conditions that influence brain developmental and physiological properties. The description of the experimental conditions studied is made in a simple manner and pertinent literature is presented concisely, enabling nonspecialists to understand the text easily. The experimental findings strongly support the conclusion that Cortical Spreading Depression is a useful and interesting tool to electrophysiologically investigate the effects of nutritional changes on brain development and function, enabling also analyzing the interaction between the effects of nutritional and non-nutritional factors.
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Caffeine/nutrition interaction in the rat brain: Influence on latent inhibition and Cortical Spreading Depression.
European journal of pharmacology, 2010Co-Authors: Márlison José Lima De Aguiar, Cilene Rejane Ramos Alves De Aguiar, Rubem Carlos Araújo GuedesAbstract:Caffeine, like malnutrition, can produce behavioral and electrophysiological alterations. However, the interaction of both factors remains unclear. Here this interaction has been studied in male Wistar rats previously malnourished during the lactation period by feeding their dams the "regional basic diet" of Northeast Brazil, containing about 8% protein, predominantly from vegetable sources (RBD(8)). At 70-75days of life, a subset of the pups was treated intraperitoneally with 30mg/kg caffeine for 4days while being tested according to the behavioral model of latent inhibition. Another group was subjected to an electrophysiological recording of the phenomenon known as Cortical Spreading Depression, and the effects of caffeine injected during the recording session were evaluated. Caffeine did not affect Cortical Spreading Depression, but antagonized latent inhibition in both the RBD(8)-malnourished rats and in the well-nourished control group fed a chow diet with 22% protein. This effect of caffeine was not seen in malnourished rats fed a protein-supplemented RBD (protein increased to 22% by increasing the proportion of foodstuffs from vegetable origin; RBD(22) group), suggesting that the amino acid imbalance of this diet may modulate the caffeine effects on latent inhibition. The results indicate a differential effect of caffeine in the latent inhibition behavioral model, as compared to the Cortical Spreading Depression phenomenon, and this effect is influenced by the early nutritional status of the animal. We suggest that caffeine may modulate dopaminergic subCortical receptors participating in attention processes, but does not interact at the Cortical level, in a way that would affect Cortical Spreading Depression.
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Analysis of signal fluctuations of Cortical Spreading Depression: Preliminary findings
Physica A: Statistical Mechanics and its Applications, 2010Co-Authors: Rosângela S. Do Nascimento, Rubem Carlos Araújo Guedes, Luiz Henrique Gama Dore De Araújo, Renato Barros Moraes, Catão T.f. Barbosa, Romildo De Albuquerque Nogueira, Tatijana StosicAbstract:In this work, we apply Detrended Fluctuation Analysis (DFA) to study the dynamics of electrical Cortical activity in rats during the phenomenon of Cortical Spreading Depression (CSD), as well as the periods before and after this phenomenon. The characteristic of CSD is reduced electrical activity that occurs and spreads in the cerebral cortex after the application of electrical, chemical or mechanical stimulus. Our results show that the electrocorticogram signal shows long range temporal correlations and scaling behavior, except during the pre-CSD burst phase (significant increase of amplitude provoked by stimulus).
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effects of transcranial direct current stimulation coupled with repetitive electrical stimulation on Cortical Spreading Depression
Experimental Neurology, 2007Co-Authors: Felipe Fregni, Manuella B. Oliveira, David Liebetanz, Katia Montesilva, Angela A Santos, Michael A Nitsche, Alvaro Pascualleone, Rubem Carlos Araújo GuedesAbstract:We have recently shown that two techniques of brain stimulation - repetitive electrical stimulation (ES) (that mimics transcranial magnetic stimulation) and transcranial direct current stimulation (tDCS) - modify the velocity of Cortical Spreading Depression (CSD) significantly. Herein we aimed to study the effects of these two techniques combined on CSD. Thirty-two Wistar rats were divided into four groups according to the treatment: sham tDCS/sham ES, sham tDCS/1 Hz ES, anodal tDCS/1 Hz ES, cathodal tDCS/1 Hz ES. Our findings show that 1 Hz ES reduced CSD velocity, and this effect was modified by either anodal or cathodal tDCS. Anodal tDCS induced larger effects than cathodal tDCS. Hereby CSD velocity was actually increased significantly after anodal tDCS/1 Hz ES. Our results show that combining two techniques of brain stimulation can modify significantly the effects of ES alone on Cortical excitability as measured by the neurophysiological parameter of Cortical Spreading Depression and therefore provide important insights into the effects of this new approach of brain stimulation on Cortical activity.
Rami Burstein - One of the best experts on this subject based on the ideXlab platform.
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migraine pathophysiology anatomy of the trigeminovascular pathway and associated neurological symptoms Cortical Spreading Depression sensitization and modulation of pain
Pain, 2013Co-Authors: Rodrigo Noseda, Rami BursteinAbstract:Scientific evidence supports the notion that migraine pathophysiology involves inherited alteration of brain excitability, intracranial arterial dilatation, recurrent activation, and sensitization of the trigeminovascular pathway, and consequential structural and functional changes in genetically susceptible individuals. Evidence of altered brain excitability emerged from clinical and preclinical investigation of sensory auras, ictal and interictal hypersensitivity to visual, auditory, and olfactory stimulation, and reduced activation of descending inhibitory pain pathways. Data supporting the activation and sensitization of the trigeminovascular system include the progressive development of cephalic and whole-body cutaneous allodynia during a migraine attack. In addition, structural and functional alterations include the presence of subCortical white mater lesions, thickening of Cortical areas involved in processing sensory information, and Cortical neuroplastic changes induced by Cortical Spreading Depression. Here, we review recent anatomical data on the trigeminovascular pathway and its activation by Cortical Spreading Depression, a novel understanding of the neural substrate of migraine-type photophobia, and modulation of the trigeminovascular pathway by the brainstem, hypothalamus and cortex.
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activation of the migraine pain pathway by Cortical Spreading Depression do we need more evidence
Cephalalgia, 2012Co-Authors: Michael A. Moskowitz, Dan Levy, Rodrigo Noseda, Rami BursteinAbstract:This is a commentary on article Fioravanti B, Kasasbeh A, Edelmayer R, Skinner DP Jr, Hartings JA, Burklund RD, De Felice M, French ED, Dussor GO, Dodick DW, Porreca F, Vanderah TW. Evaluation of cutaneous allodynia following induction of Cortical Spreading Depression in freely moving rats. Cephalalgia. 2011Jul;31(10):1090-100.
Chiho Kudo - One of the best experts on this subject based on the ideXlab platform.
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Anesthetic effects on susceptibility to Cortical Spreading Depression.
Neuropharmacology, 2012Co-Authors: Chiho Kudo, Midori Toyama, Aiji Boku, Hiroshi Hanamoto, Yoshinari Morimoto, Mitsutaka Sugimura, Hitoshi NiwaAbstract:Cortical Spreading Depression (CSD) is a transient neuronal and glial depolarization and disruption of membrane ionic gradients that propagates slowly across the cerebral cortex. Recent clinical and experimental evidence has implicated CSD in the pathophysiology of migraines and neuronal injury states. In the current study, we examined the influence of four different anesthetics (propofol, dexmedetomidine, isoflurane, pentobarbital) on CSD susceptibility in a KCl application animal model. We found that isoflurane and dexmedetomidine suppressed CSD frequency, and tended to reduce the CSD propagation speed. Our data suggest that these anesthetics may be therapeutically beneficial in preventing CSD in diverse neuronal injury states.
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oxcarbazepine does not suppress Cortical Spreading Depression
Cephalalgia, 2011Co-Authors: Ulrike Hoffmann, Chiho Kudo, Ergin Dilekoz, Cenk AyataAbstract:Background: Cortical Spreading Depression is the electrophysiological substrate of migraine aura, and may trigger headache. Recently, chronic treatment with five migraine prophylactic drugs was sho...
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Oxcarbazepine does not suppress Cortical Spreading Depression.
Cephalalgia : an international journal of headache, 2010Co-Authors: Ulrike Hoffmann, Chiho Kudo, Ergin Dilekoz, Cenk AyataAbstract:BACKGROUND Cortical Spreading Depression is the electrophysiological substrate of migraine aura, and may trigger headache. Recently, chronic treatment with five migraine prophylactic drugs was shown to suppress Cortical Spreading Depression, implicating Spreading Depression as a common therapeutic target in migraine prophylaxis. MATERIALS AND METHODS In order to assess the negative predictive value of Spreading Depression susceptibility as a preclinical drug screening tool, we tested oxcarbazepine, an anti-epileptic ineffective in migraine prophylaxis. Valproate served as the positive control. Cortical Spreading Depression susceptibility was measured in rats using topical KCl or electrical stimulation. RESULTS Oxcarbazepine did not suppress Spreading Depression either after a single dose or after daily treatment for 5 weeks. As previously shown, valproate suppressed Spreading Depression susceptibility after chronic dosing, while a single dose was ineffective. CONCLUSIONS These data provide further support for Spreading Depression as a relevant target in migraine prophylaxis, and demonstrate the predictive utility of employed Spreading Depression models.
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Gabapentin suppresses Cortical Spreading Depression susceptibility
Journal of Cerebral Blood Flow and Metabolism, 2010Co-Authors: Ulrike Hoffmann, Chiho Kudo, Ergin Dilekoz, Cenk AyataAbstract:Cortical Spreading Depression (CSD) is an intense depolarization wave implicated in the pathophysiology of brain injury states and migraine aura. As Cav2.1 channels modulate CSD susceptibility, we tested gabapentin, which inhibits Cav2.1 through high-affinity binding to its α2δ subunit, on CSD susceptibility in anesthetized rats. Gabapentin, 100 or 200 mg/kg, elevated the electrical threshold for CSD and diminished recurrent CSDs evoked by topical KCl, when administered 1 hour before testing. With its favorable safety and tolerability profile, gabapentin may have a role in suppression of injury depolarizations in stroke, intracranial hemorrhage, and traumatic brain injury.
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Cortical Spreading Depression and estrogen.
Headache: The Journal of Head and Face Pain, 2007Co-Authors: Katharina Eikermann-haerter, Chiho Kudo, Michael A. MoskowitzAbstract:Cortical Spreading Depression (CSD) is an electrophysiological phenomenon characterized by a wave of excitation followed by inhibition. The aura phase that precedes migraine headache in about 20-30% of migraineurs shares overlapping characteristics with CSD. Studies of rare autosomal-dominant forms of migraine with aura provide strong evidence that the threshold for evoking CSD and aura are related to neuronal excitability. Although the relationship between CSD and migraine without aura is not completely understood, the molecular abnormalities that predispose to migraine with aura illustrate the importance of physiologic events associated with neuronal hyperexcitability, and provide a basis for understanding a more generalized view of migraine.
