Data of ascending cortical vein occlusion induced spreading depression.
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ABSTRACT:
SUBMITTER: Donmez-Demir B
PROVIDER: S-EPMC5997957 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC4943574 | biostudies-literature
Project description:Cortical spreading depression (CSD) is associated with migraine, stroke, and traumatic brain injury, but its mechanisms remain poorly understood. One of the major features of CSD is an hour-long silencing of neuronal activity. Though this silencing has clear ramifications for CSD-associated disease, it has not been fully explained. We used in vivo whole-cell recordings to examine the effects of CSD on layer 2/3 pyramidal neurons in mouse somatosensory cortex and used in vitro recordings to examine their mechanism. We found that CSD caused a reduction in spontaneous synaptic activity and action potential (AP) firing that lasted over an hour. Both pre- and postsynaptic mechanisms contributed to this silencing. Reductions in frequency of postsynaptic potentials were due to a reduction in presynaptic transmitter release probability as well as reduced AP activity. Decreases in postsynaptic potential amplitude were due to an inhibitory shift in the ratio of excitatory and inhibitory postsynaptic currents. This inhibitory shift in turn contributed to the reduced frequency of APs. Thus, distinct but complementary mechanisms generate the long neuronal silence that follows CSD. These cellular changes could contribute to wider network dysfunction in CSD-associated disease, while the pre- and postsynaptic mechanisms offer separate targets for therapy.
| S-EPMC6317285 | biostudies-literature
Project description:We analyzed the metabolic response to cortical spreading depression that drastically increases local energy demand to restore ion homeostasis. During single and multiple cortical spreading depressions in the rat cortex, we simultaneously monitored extracellular levels of glucose and lactate using rapid sampling microdialysis and glucose influx using 18 F-fluorodeoxyglucose positron emission tomography while tracking cortical spreading depression using laser speckle imaging. Combining the acquired data with steady-state requirements we developed a mass-conserving compartment model including neurons and glia that was consistent with the observed data. In summary, our findings are: (1) Early breakdown of glial glycogen provides a major source of energy during increased energy demand and leaves 80% of blood-borne glucose to neurons. (2) Lactate is used solely by neurons and only if extracellular lactate levels are >80% above normal. (3) Although the ratio of oxygen and glucose consumption transiently reaches levels <3, the major part (>90%) of the overall energy supply is from oxidative metabolism. (4) During cortical spreading depression, brain release of lactate exceeds its consumption suggesting that lactate is only a circumstantial energy substrate. Our findings provide a general scenario for the metabolic response to increased cerebral energy demand.
| S-EPMC5094298 | biostudies-literature
Project description:Cortical spreading depression is a slowly propagating wave of near-complete depolarization of brain cells followed by temporary suppression of neuronal activity. Accumulating evidence indicates that cortical spreading depression underlies the migraine aura and that similar waves promote tissue damage in stroke, trauma, and hemorrhage. Cortical spreading depression is characterized by neuronal swelling, profound elevation of extracellular potassium and glutamate, multiphasic blood flow changes, and drop in tissue oxygen tension. The slow speed of the cortical spreading depression wave implies that it is mediated by diffusion of a chemical substance, yet the identity of this substance and the pathway it follows are unknown. Intercellular spread between gap junction-coupled neurons or glial cells and interstitial diffusion of K(+) or glutamate have been proposed. Here we use extracellular direct current potential recordings, K(+)-sensitive microelectrodes, and 2-photon imaging with ultrasensitive Ca(2+) and glutamate fluorescent probes to elucidate the spatiotemporal dynamics of ionic shifts associated with the propagation of cortical spreading depression in the visual cortex of adult living mice. Our data argue against intercellular spread of Ca(2+) carrying the cortical spreading depression wavefront and are in favor of interstitial K(+) diffusion, rather than glutamate diffusion, as the leading event in cortical spreading depression.
| S-EPMC4816793 | biostudies-literature
Project description:A migraine is a recurring neurological disorder characterized by unilateral, intense, and pulsatile headaches. In one-third of migraine patients, the attacks are preceded by a visual aura, such as a slowly-propagating scintillating scotoma. Migraine aura is thought to be a result of the neurovascular phenomenon of cortical spreading depression (SD), a self-propagating wave of depolarization that spreads across the cerebral cortex. Several animal experiments have demonstrated that cortical SD causes intracranial neurogenic inflammation around the meningeal blood vessels, such as plasma protein extravasation and pro-inflammatory peptide release. Cortical SD has also been reported to activate both peripheral and central trigeminal nociceptive pathways. Although several issues remain to be resolved, recent evidence suggests that cortical SD could be the initial trigger of intracranial neurogenic inflammation, which then contributes to migraine headaches via subsequent activation of trigeminal afferents.
| S-EPMC5562594 | biostudies-other
Project description:Spreading depression (SD) is a slowly propagating wave of neuronal and glial depolarization lasting a few minutes, that can develop within the cerebral cortex or other brain areas after electrical, mechanical or chemical depolarizing stimulations. Cortical SD (CSD) is considered the neurophysiological correlate of migraine aura. It is characterized by massive increases in both extracellular K? and glutamate, as well as rises in intracellular Na? and Ca²?. These ionic shifts produce slow direct current (DC) potential shifts that can be recorded extracellularly. Moreover, CSD is associated with changes in cortical parenchymal blood flow. CSD has been shown to be a common therapeutic target for currently prescribed migraine prophylactic drugs. Yet, no effects have been observed for the antiepileptic drugs carbamazepine and oxcarbazepine, consistent with their lack of efficacy on migraine. Some molecules of interest for migraine have been tested for their effect on CSD. Specifically, blocking CSD may play an enabling role for novel benzopyran derivative tonabersat in preventing migraine with aura. Additionally, calcitonin gene-related peptide (CGRP) antagonists have been recently reported to inhibit CSD, suggesting the contribution of CGRP receptor activation to the initiation and maintenance of CSD not only at the classic vascular sites, but also at a central neuronal level. Understanding what may be lying behind this contribution, would add further insights into the mechanisms of actions for "gepants", which may be pivotal for the effectiveness of these drugs as anti-migraine agents. CSD models are useful tools for testing current and novel prophylactic drugs, providing knowledge on mechanisms of action relevant for migraine.
| S-EPMC3728002 | biostudies-literature
Project description:Cortical spreading depression (CSD) is associated with severe hypoperfusion in mice. Using minimally invasive multimodal optical imaging, we show that severe flow reductions during and after spreading depression are associated with a steep decline in cerebral metabolic rate of oxygen. Concurrent severe hemoglobin desaturation suggests that the oxygen metabolism becomes at least in part supply limited, and the decrease in cortical blood volume implicates vasoconstriction as the mechanism. In support of oxygen supply-demand mismatch, cortical nicotinamide adenine dinucleotide (NADH) fluorescence increases during spreading depression for at least 5?minutes, particularly away from parenchymal arterioles. However, modeling of tissue oxygen delivery shows that cerebral metabolic rate of oxygen drops more than predicted by a purely supply-limited model, raising the possibility of a concurrent reduction in oxygen demand during spreading depression. Importantly, a subsequent spreading depression triggered within 15?minutes evokes a monophasic flow increase superimposed on the oligemic baseline, which markedly differs from the response to the preceding spreading depression triggered in naive cortex. Altogether, these data suggest that CSD is associated with long-lasting oxygen supply-demand mismatch linked to severe vasoconstriction in mice.
| S-EPMC3272607 | biostudies-literature
Project description:We found novel types of parenchymal functional magnetic resonance imaging (fMRI) signals in the rat brain during large increases in metabolism. Cortical spreading depression (CSD), a self-propagating wave of cellular activation, is associated with several pathologic conditions such as migraine and stroke. It was used as a paradigm to evoke transient neuronal depolarization leading to enhanced energy consumption. Activation of CSD was investigated using spin-lock (SL), diffusion, blood oxygenation level-dependent and cerebral blood volume fMRI techniques. Our results show that the SL-fMRI signal is generated by endogenous parenchymal mechanisms during CSD propagation, and these mechanisms are not associated with hemodynamic changes or cellular swelling. Protein phantoms suggest that pH change alone does not explain the observed SL-fMRI signal changes. However, increased amounts of inorganic phosphates released from high-energy phosphates combined with pH changes may produce SL- power-dependent longitudinal relaxation in the rotating frame (R??) changes in protein phantoms that are similar to those observed during CSD, as seen before in acute ischemia under our experimental conditions. This links SL-fMRI changes intimately to energy metabolism and supports the use of the SL technique as a new, promising functional approach for noninvasive imaging of metabolic transitions in the active or pathologic brain.
| S-EPMC4013757 | biostudies-literature
Project description:Spreading depolarizations (SDs) are classically thought to be associated with spreading depression of cortical activity. Here, we found that SDs in patients with subarachnoid hemorrhage produce variable, ranging from depression to booming, changes in electrocorticographic activity, especially in the delta frequency band. In rats, depression of activity was characteristic of high-potassium-induced full SDs, whereas partial superficial SDs caused either little change or a boom of activity at the cortical vertex, supported by volume conduction of signals from spared delta generators in the deep cortical layers. Partial SDs also caused moderate neuronal depolarization and sustained excitation, organized in gamma oscillations in a narrow sub-SD zone. Thus, our study challenges the concept of homology between spreading depolarization and spreading depression by showing that SDs produce variable, from depression to booming, changes in activity at the cortical surface and in different cortical layers depending on the depth of SD penetration.
| S-EPMC10676372 | biostudies-literature
Project description:ObjectiveThe aim of this study was to determine if the non-convulsant delta-opioid receptor (DOR) agonist, KNT-127, could inhibit migraine-associated endpoints.BackgroundThe DOR has been identified as a therapeutic target for migraine. However, the development of delta agonists is limited as some ligands have seizurogenic properties, which may be related to their ability to induce receptor internalization. While both pro- and non-convulsant delta agonists can reduce migraine-associated allodynia, only the proconvulsant agonist, SNC80, has been shown to decrease cortical spreading depression (CSD). It is unclear if the ability of delta agonists to modulate cortical activity is related to the same signaling mechanisms that produce proconvulsant effects.MethodsThe effects of the non-convulsant delta agonist, KNT-127, were examined. Repetitive CSD was induced in female C57BL6/J (n = 6/group) mice by continuous application of KCl and the effect of KNT-127/vehicle (Veh) on both local field potentials and optical intrinsic signals was determined. To assess the effect of KNT-127 on established chronic migraine-associated pain, male and female C57BL6/J mice were treated with nitroglycerin (NTG; 10 mg/kg, ip) every other day for 9 days and tested with KNT-127 (5 mg/kg, sc) or Veh on day 10 (n = 6/group). DOR-enhanced green fluorescent protein mice (n = 4/group) were used to confirm the internalization properties of KNT-127 in the trigeminal ganglia, trigeminal nucleus caudalis, and somatosensory cortex.ResultsKNT-127 inhibited CSD events (t(10) = 3.570, p = 0.0051). In addition, this delta agonist also reversed established cephalic allodynia in the NTG model of chronic migraine (F(1, 20) = 12.80, p < 0.01). Furthermore, KNT-127 caused limited internalization of DOR in key migraine processing regions.ConclusionsThis study shows that the antimigraine effects of DOR agonists can be separated from their proconvulsant effects. This data provides valuable information for the continued development of delta agonists for the treatment of migraine.
| S-EPMC8082730 | biostudies-literature