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At least 19 recordsLinked to original sources
PubMed1981

Phosphorylation of cerebral cortex proteins during spreading cortical depression.

Spreading cortical depression induced by the topical application of 25 % KC1 onto on hemisphere of the rat brain produced an increase in 32P radioactivity in the proteins of the microsomal [+39 %] and membrane [+21 %] fraction of the affected hemicortex compared with the intact contralateral hemicortex; conversely, radioactivity in the cytosol fraction fell by 19 %, while in the mitochondrial fraction it remained the same. The results are evaluated from the aspects of a possible difference in the response of cAMP-dependent and cAMP-independent protein phosphorylation to the depolarization of cortical cells in vivo.

Animals↗
PubMed1996

A dipole model for spreading cortical depression.

Spreading Cortical Depression (SCD) is the hyper-excitation, followed by extreme suppression of spontaneous electrical activity in the cortex. This work models SCD propagation using current dipoles to represent excitable pyramidal cells. An area of cortex, either gyrus or sulcus, supporting SCD is represented by surface dipoles oriented perpendicular to the surface. Magnetic fields created by these individual surface dipoles are calculated using the Biot-Savart law. We have assumed a plane volume conductor to represent the sulcus to simplify the mathematical derivation. The sources included in cortical surface area of 10(-4)mm2 is represented by a signal dipole. The magnetic field arising from the entire excited area of the cortex is obtained by summing the fields due to these individual dipoles. The simulated waveforms suggest that the shapes, amplitudes, and durations of the SCD signals depend on the size of the active area of cortex involved in SCD, as well as the location and orientation of the detector. Using this dipole model, we are able to simulate the Large Amplitude Waves (LAWs) similar to those observed by Barkley et al. (1990) while measuring spontaneous activity from migraine headache patients using the assumption that these LAWs arise from propagation of SCD across a sulcus. The shape of the simulated LAW waveform is strongly influenced by the relationships between the detector location and orientation, the propagation direction of the SCD wave, and the orientation of the sulcus.

Cerebral Cortex↗
PubMed1997

Possible mechanism of c-fos expression in trigeminal nucleus caudalis following cortical spreading depression.

Cortical spreading depression (CSD) is characterized by a transient, reversible depression of EEG activity which advances across the cortical surface at a velocity of 2-5 mm/min. CSD was originally linked to the aura phase of migraine, but recently also to migraine headache. The theory is that CSD activates meningeal trigeminal C-fibers causing neurogenic inflammation and pain (Moskowitz, M.A., Nozaki, K. and Kraig, R.P., Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms, J. Neurosci., 13 (1993) 1167-1177). The present study is an examination of the proposed link between CSD elicited in rats and activation of trigeminal nerve fibers. Multiple CSDs were elicited unilaterally for 1 h by KCl injections (1 M, 5 microliters) into the right hemisphere, while NaCl (1 M, 5 microliters) was injected into the left as control. After an additional 1 h the animals were sacrificed and trigeminal activation assessed by the expression of c-fos in trigeminal nucleus caudalis (TNC) using immunohistochemistry. The correlation between the number of CSDs and the extent of c-fos expression was determined. In addition the effect of sumatriptan (0.3 mg/kg) and morphine (3 mg/kg) given i.v. 30 min before elicitation of CSD was evaluated. CSD caused increased c-fos expression in lamina I and II of TNC where C-fibers, end, the response being greater ipsilaterally. Morphine, but not sumatriptan, reduced c-fos expression in both the ipsilateral and contralateral TNC by 71% (P < 0.05 and P = 0.19, respectively), confirming that nociceptors have been activated. No positive correlation was seen between the number of CSDs and the extent of c-fos expression in TNC. Instead we observed a positive, linear correlation between the number of KCl injections and the extent of c-fos expression in TNC (correlation coefficient r = 0.709, P < 0.05). We suggest that the C-fiber activation observed is caused by hyperosmolar KCl/NaCl and not CSD. Hence, our results do not support the hypothesis of Moskowitz et al. (Moskowitz, M.A., Nozaki, K. and Kraig, R.P., Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms, J. Neurosci., 13 (1993) 1167-1177) which links CSD with migraine headache.

Animals↗
PubMed1994

Modeling cortical spreading depression.

Cortical spreading depression is a wave of electrical silence and biochemical changes that spreads across the cerebral cortex. Recently there has been a growing recognition that it may be an important pathophysiological event in a number of neurological disorders. In this paper, we describe a reaction-diffusion model of the extracellular potassium changes that are a central part of this process. Simulations with the model show that an appropriate stimulus evokes a moving wave of increased potassium with many similarities to that seen experimentally. The resultant model is a useful computational tool for future study of the effects of spreading depression on the cortex.

Computer Simulation↗
PubMed1976

Cortical afterdischarges during Leao's cortical spreading depression.

Cortical spreading depression (CSD) has been employed in unanesthetized curarized rats, in order to analyse the role of the cerebral cortex in the generation of epileptic self-sustained parozysms produced by direct cortical electrical stimulation. CSD was preferred because it is reversible and may be repeated several times in the same animal. CSD evoked in the hemisphere contralateral to the stimulated cortex decreased the duration of the afterdischarge by 40% and modified its form and amplitude both at the cortical and reticular levels. The possible role of cortical and subcortical structures in the development of after-discharges is discussed.

Animals↗
PubMed2000

Characterization of optical intrinsic signals and blood volume during cortical spreading depression.

Cortical spreading depression (CSD) was imaged in vivo in a rodent model with optical intrinsic signals (OIS). This is the first study to identify a triphasic OIS response and to characterize the rate and timing of the response. The initial OIS phase had a highly uniform wavefront, which spread at a rate characteristic of CSD, 3.5 mm/min. Later phases were more diffuse and inhomogeneous. Blood volume changes, measured with intravascular fluorescent dye, correlated in time and location with the later phases of OIS response. This suggests that the inhomogeneity of the late OIS response may be due to complex residual hemodynamic contributions, as opposed to underlying cortical circuitry.

Animals↗
PubMed2002

Multiwavelength optical intrinsic signal imaging of cortical spreading depression.

Cortical spreading depression (CSD) is an important disease model for migraine and cerebral ischemia. In this study, we exploit the high temporal and spatial resolution of optical imaging to characterize perfusion-dependent and -independent changes in response to CSD and to investigate the etiology of reflectance changes during CSD. In this experiment, we characterized the optical response to CSD at wavelengths that emphasize perfusion-related changes (610 and 550 nm), and we compared these results with 850 nm and blood volume data. Blood volume changes during CSD were recorded using an intravascular fluorescent dye, Texas Red dextran. We observed triphasic optical signals at 850 and 550 nm characterized by spreading waves of increased, decreased, then increased reflectance (Fig. 1) which expanded at a rate of approximately 3-5 mm/min. The signal at 610 nm had a similar initial phase, but the phase 2 response was slightly more complex, with a parenchymal decrease in reflectance but a vascular increase in reflectance. Reflectance values decreased in phase three. Blood volume signals were delayed relative to the optical intrinsic signals and corresponded temporally to phases 2 and 3. This is the first study to characterize optical imaging of intrinsic signal responses to CSD, in vivo, at multiple wavelengths. The data presented here suggest that changes in light scattering precede perfusion responses, the blood volume increase (phase 2) is accompanied by a reduction in deoxyhemoglobin, and the blood volume decrease (phase 3) is accompanied by an increase in deoxyhemoglobin. Previous studies have suggested the oligemia of spreading depression was a result of decreased metabolic demand. This study suggests that during the oligemic period there is a greater reduction in oxygen delivery than in demand.

Animals↗
PubMed2003

Effects of the nitric oxide donor, DEA/NO on cortical spreading depression.

Cortical spreading depression (CSD) is a transient disruption of local ionic homeostasis that may promote migraine attacks and the progression of stroke lesions. We reported previously that the local inhibition of nitric oxide (NO) synthesis with Nomega-nitro-L-arginine methyl ester (L-NAME) delayed markedly the initiation of the recovery of ionic homeostasis from CSD. Here we describe a novel method for selective, controlled generation of exogenous NO in a functioning brain region. It is based on microdialysis perfusion of the NO donor, 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA/NO). As DEA/NO does not generate NO at alkaline pH, and as the brain has a strong acid-base buffering capacity, DEA/NO was perfused in a medium adjusted at alkaline (but unbuffered) pH. Without DEA/NO, such a microdialysis perfusion medium did not alter CSD. DEA/NO (1, 10 and 100 microM) had little effect on CSD by itself, but it reversed in a concentration-dependent manner the effects of NOS inhibition by 1 mM L-NAME. These data demonstrate that increased formation of endogenous NO associated with CSD is critical for subsequent, rapid recovery of cellular ionic homeostasis. In this case, the molecular targets for NO may be located either on brain cells to suppress mechanisms directly involved in CSD genesis, or on local blood vessels to couple flow to the increased energy demand associated with CSD.

Animals↗
PubMed2000

Pharmacological investigation into the involvement of nitric oxide in K+-induced cortical spreading depression.

Cortical spreading depression (CSD) is a transient, local disruption of cellular ionic homeostasis that propagates slowly across the cerebral cortex. As previous data have suggested a possible link between nitric oxide (NO) formation and CSD, we have examined whether CSD is suppressed by local inhibition of NO synthesis with 7-nitroindazole (7-NINA), a compound which may have a greater selectivity for the neuronal NO synthase isoform. Multifunctional microdialysis probes were implanted in the cortex of halothane-anaesthetised rats, and used for (1) elicitation of repetitive CSD by perfusion of 160 mM K+ through the probe, (2) recording of CSD as a negative shift of the extracellular direct current (DC) potential, and (3) perfusion of 7-NINA before and during CSD elicitation. Elicitation of CSD was moderately inhibited by 1 mM 7-NINA in the perfusion medium, as shown in one treated group (n=8) by a significant reduction of both number (from 5.1+/-0.4 to 3.6+/-0.4; P<0.05) and cumulative DC negativity (from 16.4+/-0.7 mV x min to 13.3+/-0.9 mV x min; P<0.01). However, effective concentrations of 7-NINA were at least 100-fold higher than its Ki for the target enzyme in vitro, the moderate inhibition of CSD by 7-NINA was not reversed by the NO precursor, L-arginine, and the amplitude of the K+-induced sustained DC potential negative shift was also reduced significantly by 7-NINA (from 27.9+/-0.9 mV to 23.9+/-1.2 mV; P<0.05). These data do not support the hypothesis that NO formation contributes to the elicitation of CSD by high extracellular K+. The finding that 7-NINA reduced the intensity of K+-induced depolarisation may be relevant to previous investigations that used this drug to examine the role of NO in the modulation of K+-induced neurotransmitter release.

Animals↗
PubMed1991

Integration of neocortical embryonal grafts with the neocortex of host rats examined by Leao's spreading cortical depression.

Cortical spreading depression (SD) was used to assess the density and organization of neural elements in neocortical transplants and their connectivity with the host brain. Embryonal neocortex (E14) was transplanted into cavities in the frontoparietal cortex of 3-month-old rats. SD elicited in the cortex of anesthetized host rats (n = 12) 3 to 8 months after transplantation did not penetrate into the grafts. SD could be elicited in large transplants but did not propagate to the surrounding host neocortex. Spontaneous unit activity in the transplants was affected by SD elicited in the neocortex of the host rats anesthetized with urethane. Most units (n = 49) displayed excitatory-inhibitory (52%) or inhibitory (29%) reactions, whereas purely excitatory reactions were less frequent (8%). The results suggest that the packing density of neurons in the transplant can support SD but that the conditions at the graft-host boundary (glial scar, scarcity of neurons) stop SD propagation. High reactivity of the graft neurons to SD in the host neocortex indicates that afferentation from the host brain represents an important, predominantly excitatory contribution to the spontaneous activity of the transplant.

Animals↗
PubMed2002

Modeling the spreading cortical depression wavefront.

Spreading cortical depression (SCD) is a wave of depolarization that spreads across the cortex at 2-5 mm/min and is followed by a 5-10 minute reduction in EEG activity. It is assumed that SCD is involved in the pathophysiology of migraine. We present a new model and a visualization technique for the spread of excitation on realistic brain surfaces. The usefulness of the technique is demonstrated on a rat brain that had been segmented from a three-dimensional magnetic resonance image data set. With the help of this methodology it is possible to create specific patient models to better understand the mechanisms of SCD.

Animals↗
PubMed1969

Amino acid incorporation into rat brain proteins during spreading cortical depression.

Unilateral spreading cortical depression was elicited by applying potassium chloride solutions to the dura of conscious, freely moving rats. Incorporation of (3)H-leucine into soluble cortical proteins was decreased in the depressed hemisphere relative to the control side, while soluble brainstem proteins from both sides had the same specific activity. Various subfractions of soluble cortical proteins were affected to equal degrees.

Amino Acids↗
PubMed1999

Effect of cortical spreading depression on activity of trigeminovascular sensory neurons.

The effect of cortical spreading depression, a proposed initiating event for migraine pain, on cortical blood flow (laser Doppler method) and on the spontaneous firing rate and stimulus-evoked responses of trigemino-cervical neurons with craniovascular input was studied in 17 neurons in 8 cats anesthetized with chloralose. Cortical spreading depression, induced via cortical pinprick injury, produced an initial wave of cortical hyperemia (243+/-57% of control) and a later and smaller phase of oligemia (96+/-4% of control). Neither the basal discharge rate (6.7+/-1.7 sec(-1)) nor the evoked responses to electrical stimulation of the superior sagittal sinus (4.1+/-0.8 discharges per stimulus) of upper cervical spinal cord neurons was altered over periods of up to 2 h following one, two, or three waves of spreading cortical depression. We conclude that a small number of episodes of cortical spreading depression is not capable of activating C2 cervical spinal cord craniovascular sensory neurons in the cat.

Animals↗
PubMed2000

Effects of cortical spreading depression on cortical blood flow, impedance, DC potential, and infarct size in a rat venous infarct model.

A cortical venous infarction model has been evaluated as to the degree of regional flow reduction and by studying effects of cortical spreading depression (CSD). Two adjacent cortical veins were occluded photochemically with rose bengal and fiberoptic illumination. Seven rats served to demonstrate effects on regional cortical blood flow using laser Doppler scanning. In 36 rats local CBF, DC potential, and brain tissue impedance were measured continuously for 75 min after vein occlusion. No, 3, or 10 CSD waves were induced by potassium chloride injection during the initial 75 min. Rats were compared for spontaneous CSDs; baseline local CBF, CBF, and impedance response to CSD; and infarct volume. Seventy-five minutes after vein occlusion regional cortical flow in a 3.5x7-mm window was reduced to 34.3+/-13.2%. At 45% of the 840 measured locations in 7 rats flow was <40% baseline and at 27.3% <30%, indicating a widespread penumbra territory. During the initial 75 min 2.1+/-1.1 spontaneous CSDs were observed. There was a positive correlation between the number of spontaneous CSDs seen acutely and infarction volume after 5 days. Moreover, brain injury was significantly increased in the group with 10 KCl-induced CSDs. A reduced 1CBF response and an overshooting tissue impedance change during CSD were predictors of ischemic damage. This study demonstrates a CSD-related growth of the venous infarct. Second, the data indicate that flow after two-vein occlusion resembles that seen under penumbra conditions, allowing for studies of damage mechanisms responsible for infarct growth.

Acute Disease↗
PubMed1991

The 21-aminosteroid antioxidant tirilazad mesylate, U-74006F, blocks cortical hypoperfusion following spreading depression.

Cortical spreading depression (SD) has been implicated in the pathophysiology of classical migraine headache and cerebral ischemia. A reduction in cerebral blood flow (CBF), mimicking that seen during the aura and headache phase of migraine, is typically observed following SD in the rat. This phenomenon may also play a role in potentiating ischemic brain damage. In the present study, brief cortical exposure to 1 M KCl produced a marked suppression of EEG amplitude which persisted 20 min in the rat. Upon normalization of the EEG, cortical blood flow declined 20-30% and remained low for at least 2 h. Treatment with a 1 mg/kg i.v. dose of the 21-aminosteroid antioxidant tirilazad mesylate (U-74006F), 2 min following KCl application, completely blocked the hypoperfusion while leaving the magnitude and duration of the EEG suppression and mean arterial pressure unchanged. Tirilazad mesylate is a potent inhibitor of oxygen radical-mediated lipid peroxidation both in vitro and in vivo. Thus, based on present results, an oxygen radical hypothesis is proposed to account for the SD-induced cerebral hypoperfusion.

Animals↗
PubMed1970

Lack of coincidence between neural and behavioral manifestations of cortical spreading depression.

The presence of cortical spreading depression is typically inferred from the presence of hypesthesia. The electrocorticogram and slow-potential change were recorded during cortical spreading depression and it was found that hypesthesia remained long after the cortex recovered from neural depression. Hypesthesia, therefore, is an unreliable indicant of cortical spreading depression; if cortical spreading depression is used as a research tool, neural activity must be monitored. These data offer a special problem for memory transfer studies.

Animals↗
PubMed1985

On the possible relation of spreading cortical depression to classical migraine.

During the first 1 to 2 h of the classical migraine attack a hypoperfusion develops which starts in the posterior part of the brain and progresses anteriorly at a rate of 2-3 mm/min. The hypoperfusion stops at primary sulci outlining major cortical macro- and microstructural changes, but seems not to be inhibited by other changes of the cortical architecture. The low flow regions are cortical and the low flow persists for 4-6 h, until the attack abates. Regions of hyperperfusion are either minor or non-existent. A similar behavior characterizes the velocity and mode of evolution of a cortical spreading depression, a transient perturbation of cortical neuronal function which has profound and long-lasting influence on the cortical blood flow. This paper briefly summarizes the arguments which have been put forward in recent years suggesting that spreading depression is a pathogenetic mechanism of migraine.

Animals↗
PubMed2001

Cortical spreading depression in migraine.

Cortical spreading depression (CSD) is associated with a dramatic failure of brain ion homeostasis as well as efflux of excitatory amino acids from nerve cells and increased energy metabolism. There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine. This paper will, based on the experience related to the detection of CSD in humans, discuss pitfalls and possible strategies for detection of CSD in man. Development of reliable methods for detection of CSD in humans will determine the extent to which the large body of experimental findings from animal studies of CSD can be applied to the investigation and treatment of human brain disease. The paper is based on the experience that has been gained from two decades of studies of CSD in relation to clinical neurological diseases.

Animals↗