Occurrence Of Spreading Depression Research Articles

Activity dependence of spreading depression in the locust CNS.

Spreading depression (SD) is associated with large changes in extracellular ion concentrations and can be induced by impairing mechanisms of K(+) ion homeostasis. We tested activity dependence of SD in the locust model of ouabain-induced SD in the metathoracic ganglion. Wind activation of thoracic circuitry resulted in small increases of K(+) concentration that took 5-10 s to be cleared from the extracellular space. In the presence of the Na(+)/K(+)-ATPase inhibitor ouabain, wind stimulation every 30 s halved the latency to the first SD event and increased its duration. Wind stimulation was able to trigger the first event, suggesting that local activity could determine the origin of successive SD events. Perfusion with calcium-free saline blocked neural activity in the ganglion and prevented the occurrence of ouabain-induced SD. We conclude that ouabain-induced SD in the locust CNS is strongly dependent on the existing level of neural activity.

Neurovascular regulation is critical for metabolic recovery from spreading depression.

This scientific commentary refers to ‘Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma’ by Hinzman et al. (doi:10.1093/awu241). Long after Leao’s 1944 description of spreading depression in rabbit neocortex, scepticism remained over whether this phenomenon could be evoked or observed in the human brain (Somjen, 2001). Although many investigations have been carried out into the initiation, occurrence and spread of spreading depression, the mechanisms of ionic current flow underlying depolarization, and treatment paradigms (Pietrobon and Moskowitz, 2014), it is only recently that recording and imaging techniques have been able to confirm the occurrence of spreading depression in damaged human cortex, particularly in conditions involving trauma, subarachnoid haemorrhage, stroke, and possibly migraine headache with aura (Lauritzen et al. , 2011; Eikermann-Haerter et al. , 2012; Woitzik et al. , 2013). The intense depolarization and loss of ionic gradients in large volumes of brain tissue experiencing spreading depression means that significant substrate and metabolic capacity is required to generate energy for cell recovery (Somjen, 2001). If this metabolic need is unmatched by substrate supply (through neurovascular induction of increased blood flow), then propagation of brain damage can occur (Hossmann, 1994). In this issue of Brain , Hinzman and colleagues report a critical deficit in neurovascular coupling when spreading depression occurs near a traumatic brain lesion, in which decreased blood flow occurs in response to spreading depression (i.e. inverse neurovascular coupling) instead of increased blood flow, limiting the brain’s ability to meet the intense metabolic demand (Hinzman et al. , 2014). Although Hinzman and colleagues’ combined blood flow and electrocorticographic (ECoG) recording techniques only effectively worked in 5 of 24 patients, the spectrum of enhanced versus inverted neurovascular coupling in these five patients provides us with excellent examples of how proximity to a developing brain …

Real-time optical diagnosis of the rat brain exposed to a laser-induced shock wave: observation of spreading depolarization, vasoconstriction and hypoxemia-oligemia.

Despite many efforts, the pathophysiology and mechanism of blast-induced traumatic brain injury (bTBI) have not yet been elucidated, partially due to the difficulty of real-time diagnosis and extremely complex factors determining the outcome. In this study, we topically applied a laser-induced shock wave (LISW) to the rat brain through the skull, for which real-time measurements of optical diffuse reflectance and electroencephalogram (EEG) were performed. Even under conditions showing no clear changes in systemic physiological parameters, the brain showed a drastic light scattering change accompanied by EEG suppression, which indicated the occurrence of spreading depression, long-lasting hypoxemia and signal change indicating mitochondrial energy impairment. Under the standard LISW conditions examined, hemorrhage and contusion were not apparent in the cortex. To investigate events associated with spreading depression, measurement of direct current (DC) potential, light scattering imaging and stereomicroscopic observation of blood vessels were also conducted for the brain. After LISW application, we observed a distinct negative shift in the DC potential, which temporally coincided with the transit of a light scattering wave, showing the occurrence of spreading depolarization and concomitant change in light scattering. Blood vessels in the brain surface initially showed vasodilatation for 3–4 min, which was followed by long-lasting vasoconstriction, corresponding to hypoxemia. Computer simulation based on the inverse Monte Carlo method showed that hemoglobin oxygen saturation declined to as low as ∼35% in the long-term hypoxemic phase. Overall, we found that topical application of a shock wave to the brain caused spreading depolarization/depression and prolonged severe hypoxemia-oligemia, which might lead to pathological conditions in the brain. Although further study is needed, our findings suggest that spreading depolarization/depression is one of the key events determining the outcome in bTBI. Furthermore, a rat exposed to an LISW(s) can be a reliable laboratory animal model for blast injury research.

Peri-infarct temporal changes in intrinsic optical signal during spreading depression in focal ischemic rat cortex

The changes of intrinsic optical signals (IOS) are one of the important parameters of spreading depression (SD). The relationship between cerebral blood flow (CBF) and IOS can provide useful information for understanding the role of SD in neurological disorders. Here, we combined laser speckle imaging (LSI), intrinsic optical signal imaging (IOSI), and electrophysiological recording techniques to study the effect of CBF before the occurrence of SD on the spatiotemporal characteristics of IOS related to SD in a ministroke model. Four kinds of temporal pattern of changes in IOS were observed at cortical locations with different level of the CBF before the occurrence of SD. The results indicate that in the surrounding of micro-infarcts, SD-associated IOS vary as a function of blood flow rate, suggesting that the characteristics of IOS during SD might reflect blood flow rates.

Epidemiology and clinical characteristics of headache comorbidity with epilepsy in children and adolescents

Purpose : To assess the prevalence and characteristics of headache comorbidity with epilepsy in children and adolescents in a specialty epilepsy clinic. Methods : Two hundred twenty nine consecutive patients attending the Chosun University Hospital Pediatric Epilepsy Clinic (mean age 10.0±4.1 years, range 4-17, M:F ratio 1.1:1.0) were interviewed with a standardized headache questionnaire. Headache was classified according to the International Classification of Headache Disorders, 2nd Edition and epilepsy was classified according to the International League Against Epilepsy. Disability was assessed using pediatric migraine disability assessment (PedMIDAS). Results : Of the 229 epilepsy patients, 86 (37.6%) had co-morbid headache. Of the headache patients, 64 (74.4%) had migraine (65.6%- migraine without aura, 20.3% - migraine with aura, 14.1% - probable migraine). The mean headache frequency was 7.2±8.4 per month, mean duration was 2.2±4.0 hours, mean severity was 5.2±2.2 out of 10, and mean PedMIDAS score was 13.0±35.4. The proportion of females was not higher in epilepsy with headache patients (48.8%) compared to epilepsy patients alone (48.0%). In the patients with migraine, 48.4% had complex partial seizures, 17.2% had simple partial seizures, and 34.4% had generalized seizures (P=0.368). A postictal association of migraine was reported in 18.8% with 17.2% reporting a preictal headache, and 7.8% reporting an ictal headache. Conclusion : The prevalence of headache in pediatric epilepsy is higher than that in general pediatric population, suggesting a co-morbidity of headache in epilepsy patients with migraine being the most frequent headache disorder. Altered cerebral excitability resulting in an increased occurrence of spreading depression may explain the headache comorbidity with epilepsy. Further studies are needed to assess the etiology of this co-morbidity as well as assess the frequency, duration, severity and disability response to antiepileptic drugs.

Protective effect of ifenprodil against spreading depression in the mouse entorhinal cortex.

In the brain, spreading depression (SD) is characterized by a large extracellular DC shift, a massive failure of ion homeostasis and a transient cessation of neuronal function. Clinically, SD is believed to be involved in various neurological disorders including migraine and cerebrovascular diseases. The propagation of cortical SD requires the release of glutamate, and N-methyl-D-aspartate (NMDA) receptors play a crucial role in this process. Here, we have isolated the NMDA receptor-mediated component of extracellularly recorded field excitatory postsynaptic potentials (fEPSPs) in layers 2-3 of the entorhinal cortex of murine brain slices. In the absence of GABAA and AMPA receptor-mediated synaptic transmission, stimulation of layer 6 afferents every 15-90 s elicited spontaneous SD on average within 18.5 min after the start of the stimulation. In the presence of ifenprodil, an NR2B receptor subunit-selective NMDA receptor antagonist, the occurrence of SD was nearly abolished. Our results are consistent with an important role of NR2B subunits in triggering SD in the entorhinal cortex.

Anomalous statistics in turbulence, financial markets and other complex systems

Spreading depression (SD) is a dynamic wave phenomenon occurring in all gray matter regions of the central nervous systems (CNS). It is characterized by a sudden breakdown of neuronal activity and accompanied by a massive influx and efflux of ions across the membrane of neurons. The retina is a constituent of the CNS in which one can easily observe the dynamic behavior of the SD wave fronts, because SD changes the optical properties of the tissue. There is ample evidence that SD belongs to the self-organization processes due to the coupling of reaction with diffusion in excitable medium. It is assumed that the occurrence of SD is associated with some neurological symptoms of migraine with aura. A frequently reported aura symptom is a traveling visual blind region (scotoma) with a preceding figure of scintillating line segments. The characteristic form and development of the scotoma suggests that the underlying phenomenon is a wave propagating through the primary visual cortex, most likely the cortical spreading depression. In this article we discuss similarities between SD waves and the migraine aura on the basis of properties of reaction-diffusion waves known from other excitable media. In particular, the propagation velocities, the shape and the dynamics of the waves are compared with each other. We find that the assumption of the neuronal tissue to be in a state of only weak excitability explains some properties of the migraine aura, such as the confined appearance and its propagation with a stable velocity.

Unique profile of spreading depression in a primate model.

Spreading depression (SD) is considered to play a role in pathologic conditions of humans such as in the evolution of ischemic brain injury and migraine aura. Because many studies have demonstrated spreading hypoperfusion in patients with migraine and persistent hypoperfusion in nonprimate animal models of SD, these changes in cerebral blood flow (CBF) were regarded as an epiphenomenon of SD. However, there is no direct evidence of the occurrence of SD in primates. The authors attempted to elicit SD by applying 3.3 mol/L potassium chloride to the cerebral cortex of nine male cynomolgus monkeys. The CBF was monitored by positron emission tomography in five animals. Propagated direct-current shifts were found by the two neighboring microelectrodes only in one animal. The direct-current wave propagated at a speed of 4 mm/min and its amplitude was 20 mV, being consistent with the SD findings. Except in one animal with 6 SD episodes, SD waves were recorded infrequently at the rostral site (none in three animals, once in three, and twice in two). Focal hyperemia accompanied SD. Neither spreading hypoperfusion nor persistent hypoperfusion was found. These unique features of SD in primates raise a doubt as to whether the role of SD in nonprimate animals is the same as that in stroke and migraine in humans.

Effects of atropine on refractive development, dopamine release, and slow retinal potentials in the chick.

Atropine has previously been found to suppress visually induced myopia both in animals and humans. The mechanism of its action is unclear. We have studied its retinal effects in an in vitro preparation, using the retina-pigment epithelium-choroid complex of the chick eye. In vivo, deprivation myopia was induced by translucent goggles. Atropine solution was injected into the vitreous at two-day intervals. Dopamine release from the retina following atropine injection in vivo and from the in vitro retina preparation was quantified by HPLC-EC. In vitro preparations of the isolated chick retina-pigment epithelium-choroid were superfused with atropine. Light-induced potentials (local ERG), slow standing potentials from the retinal pigment epithelium/neural retina, and extracellular potassium concentrations were recorded. In line with previous findings, intravitreal injections of atropine (25 microg, 250 microg) reduced deprivation myopia in a dose-dependent manner. Atropine increased the release of the neurotransmitter dopamine into the superfusate in vitro at 100-500 microM and into the vitreous in vivo at 250 microg. Before an increase was measured in the vitreous, the retinal dopamine content was elevated. In concentrations equivalent to the intravitreal concentration to suppress myopia in vivo (200-800 microM), atropine induced spreading depression (SD) in the in vitro preparation. In contrast, muscarinic agonists, acetylcholine and pilocarpine, did not induce SD. Atropine reduced the ERG b- and d-wave, led to damped oscillations of RPE potentials, and reversed the ERG c-wave. Atropine suppressed myopia only at doses at which severe nonspecific side effects were observed in the retina. Atropine seems to intrude massively into the vital functions of the retina as indicated by the occurrence of SD. We conclude that atropine, by inducing SD, boosts neurotransmitter release from cellular stores, which may cancel out a presumed retinal signal that controls eye growth and through this, myopia.

The Role of Postlesion Seizures and Spreading Depression in the Upregulation of Glial Fibrillary Acidic Protein mRNA after Entorhinal Cortex Lesions

Unilateral lesions of the entorhinal cortex have been shown to lead to dramatic increases in GFAP mRNA levels in denervated zones in the hippocampus and dentate gyrus and sometimes (but not always) in nondenervated zones in the contralateral hippocampus and dentate gyrus. The variable distribution of the increases in GFAP mRNA expression suggests that the events which trigger changes in GFAP mRNA levels occur to a variable extent in individual animals. The companion paper characterizes two candidate triggering events: spreading depression (SD) that occurs to a variable extent at the time of the lesion and recurrent seizures that occur during the early postlesion interval. The goal of the present study was to evaluate whether individual differences in the extent or spatial distribution of lesion-induced increases in GFAP mRNA are related to the occurrence of either SD or seizures. We quantified the increases in GFAP mRNA levels in individual animals that had been monitored physiologically to define the incidence of SD and postlesion seizures. The results revealed that the quantitative extent of the increases in GFAP mRNA in denervated zones and was not related to either SD or postlesion seizures. The increases in GFAP mRNA in nondenervated zones also were not related to episodes of spreading depression that occurred at the time of lesion production but were related to the spontaneous seizures that developed during the first 24 h postlesion after the animals had recovered from the surgical anesthesia. Taken together, these data indicate that physiological events that occur during the early postlesion interval can play an important role in determining the pattern and extent of altered cellular gene expression in response to an injury.

Endogenous adenosine exerts inhibitory effects upon the development of spreading depression and glutamate release induced by microdialysis with high K + in rat hippocampus

Spreading depression (SD) is known to be involved in the N-methyl- D-aspartate receptor-mediated neuronal damage. In urethane-anesthetized rats, we examined the release of adenosine and glutamate during SD induced by microdialysis of high K + perfusate through the hippocampal CA1 area. The effects of endogenous adenosine upon SD were studied by applying an adenosine antagonist, theophylline (1 mM) and by a simultaneous application of adenosine uptake blockers, dipyridamole (DPR) (100 μM) and nitrobenzylthioinosine (NBI) (50 μM). The dialysates were sampled every 5 or 10 min and analyzed by HPLC. SD was identified by flattening of background EEG and disappearance of population spikes recorded from the pyramidal cell layer of CA1 area by a glass microelectrode. Adenosine and glutamate release was enhanced significantly in association with the occurrence of SD. Theophylline increased the release of glutamate and the incidence of SD and decreased the latency of the SD occurrence. DPR + NBI decreased the release of glutamate and the occurrence of SD, but increased extracellular adenosine concentration. The effects of DPR + NBI were blocked by application of a selective antagonist of adenosine Al receptor, 8-cyclopentyl-l,3-dipropylxanthine (DPCPX, 0.1 μM). These findings suggest that endogenous adenosine exerts inhibitory influences upon the development of SD and the glutamate release through the Al receptor in rat hippocampus.

The role of electrode size on the incidence of spreading depression and on cortical cerebral blood flow as measured by H2 clearance.

Cerebral blood flow was measured by the H2 clearance method 30 and 60 min after the implantation of 300, 250, 125, or 50 microns diameter platinum-iridium electrodes 2 mm deep into the right parietal cortex of normothermic, normocarbic halothane-anesthetized rats. Another group of animals had 50 microns electrodes inserted 1 mm. In all animals, the presence or absence of a wave of spreading depression (SD) was noted at the time of implantation, with recordings made with glass micropipettes. H2 flow values were compared with those measured in gray matter from the same anatomical region (but from different rats), using [3H]nicotine. The incidence of SD ranged from 60% following insertion of 300 microns electrodes to 0% with 50 microns electrodes. H2 clearance flows also varied with electrode size, from 77 +/- 21 ml 100 g-1 min-1 (mean +/- standard deviation) with 300 microns electrodes to 110 +/- 31 and 111 +/- 16 ml 100 g-1 min-1 with 125 and 50 microns electrodes, respectively (insertion depth of 2 mm). A CBF value of 155 +/- 60 ml 100 g-1 min-1 was obtained with 50 micron electrodes inserted only 1 mm. Cortical gray matter blood flow measured with [3H]nicotine was 154 +/- 35 ml 100 g-1 min-1. When the role of SD in subsequent flow measurements was examined, there was a gradual increase in CBF between 30 and 60 min after electrode insertion in those animals with SD, while no such change was seen in rats without SD.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of K +-conductance-blocking substances on the occurrence of retinal spreading depression

Retinal spreading depression (SD) has been thought to be generated by an abnormal increase in [K +] 0 in the inner plexiform layer. When a retina isolated from bullfrog was immersed in a medium conditioned for SD (low Cl − Ringer's solution), spontaneous SDs periodically occurred at a fixed interval in the dark. The effect of K +-conductance blocking substances (Ba 2+, Cs +, TEA and 4-AP) on the occurrence of SD was studied using the concomitant changes in the field potential (spreading depression potential; SDP) as an index. These substances increased the frequency of occurrence and decreased the amplitude of the potential. According to the Müller cell theory of SDP, an increase in [K +] 0 depolarizes the Müller cells and the resulting extracellular current generates the potential changes. Since the small amplitude of the SDP reflects the decreased K + current, it may be said that the K +-buffering capacity of the Müller cells was partially reduced by the substances and that the frequency of the SD occurrence consequently increased in order to clear accumulating [K +] 0 from neurons with the decreased buffering capacity. The present results lend a good support to the current Müller cell theory for the occurrence of SDP.

Ion channel involvement in hypoxia-induced spreading depression in hippocampal slices

Rat hippocampal tissue slices were made hypoxic in control medium and in medium containing the ion channel blockers tetraethylammonium (TEA), 4-aminopyridine (4-AP), or tetrodotoxin (TTX). Postsynaptic evoked potentials, extracellular DC potential V ec , and in some experiments extracellular potassium concentration [K +] o were monitored in stratum pyramidale of the CA1 region. TEA (10 mM) decreased the latency of hypoxia-induced spreading depression (SD), and reduced the amplitudes of the changes in V ec and [K +] o. 4-AP (50 μM) also decreased the latency of SD but had no effect on the V ec shift. In most slices, TTX (1 μM) increased SD latency but had no effect on the V ec shift. In some slices, TTX blocked the occurrence of SD.

Cholinergic modulation of epileptiform activity in the developing rat neocortex

The effects of carbachol on picrotoxin-induced epileptiform activity and membrane properties of neurons in the developing rat neocortex were examined in an in vitro slice preparation. Intracellular recordings were obtained in layer II–III neurons of slices prepared from rats 9–21 days of age. Epileptiform activity in 9- to 14-day-olds consisted of a sharply rising, sustained (10–30 s) membrane depolarization with superimposed action potentials. Bath application of carbachol (5–50 μM) raised the threshold for evoking epileptiform activity but, when such responses were evoked, their underlying depolarizations were increased in amplitude. Orthodromic stimulation in slices from 15- to 21-day-old animals evoked a prolonged epileptiform burst response that triggered an episode of spreading depression (SD). Carbachol reduced epileptiform responses and suppressed the occurrence of SD. It did not significantly affect the resting membrane potential or the height of the action potential but decreased the rheobase current needed to evoke an action potential and increased the input resistance. All effects of carbachol were antagonized by atropine (1 μM). These results indicate that carbachol has both pre- and postsynaptic effects in the developing neocortex and can significantly modulate neuronal excitability in the immature nervous system.

Involvement of GABA and ACh in retinal spreading depression: effects of "low calcium-high magnesium" solutions.

Experiments have been performed on isolated chick retinas to demonstrate the participation of gabaergic and cholinergic systems in spreading depression (SD). Gamma-aminobutyric acid (GABA) and acetylcholine (ACh) were measured in the effluent solution of superfused retinas. The influence of changes in the concentration of calcium/magnesium on the release of these neurotransmitters was studied. GABA and ACh are released in the superfusate of retinas during SD. Such release was observed during experimental periods longer than 2 h during which SD was elicited regularly at 15-20 min intervals. Decreasing calcium concentration from 1.0 to 0.5 mM and simultaneously increasing magnesium from 1.0 to 2.0-4.0 mM led to a decrease in GABA and ACh release during SD. Variations in light-scattering and increases in potassium concentration, usually occurring during SD, also decreased when superfusing with low calcium/high magnesium solutions. Lowering calcium concentration to 0.5 mM and increasing magnesium to 2.0 mM eventually turned the tissue refractory to SD. Sometimes a magnesium concentration of 2.0 mM was not effective in blocking SD. However, this blockage could be attained by increasing the concentration of magnesium to 4.0 mM. The effects of low calcium - high magnesium solutions on GABA and ACh release during SD suggests that the release of the substances is at least partially due to synaptic activity. It is not yet possible to establish whether GABA and ACh release is essential for the occurrence of SD. Nevertheless such release suggest that these neurotransmitters could influence the characteristics of SD manifestations in the retina.

Spreading depression is not associated with neuronal injury in the normal brain

This study was performed in order to evaluate whether waves of spreading depression (SD) induces irreversible neuronal injury. SD was elicited by topical application of 3 M KCl to the exposed cortex for 4–5 h and the resulting change of the cortical electrical potential showing the occurrence of SD, was recorded by glass microelectrodes. Histological examination of cerebral cortex revealed no signs of neuronal injury outside the area of KCl application as examined after 4 days recovery. The results indicate that recurrent waves of SD do not induce irreversible neuronal injury in the otherwise normal rat brain.

Electroencephalographic spreading depression and concomitant behavioral changes induced by intrahippocampal injections of ACTH1–24 andd-Ala2-met-enkephalinamide in the rat

ACTH1–24 (0.5or10 μg≜ 0.17or3.45nmol) andd-Ala2-Met-enkephalinamide (DAME; 10 μg≜ 17.05nmol) were injected unilaterally into the hippocampus of freely moving rats to examine their effects on EEG activity, DC potentials and behavior. In 85% of the rats DAME elicited spreading depression (SD) with epileptiform discharges preceding and following the wave of SD. The following behavioral changes were recorded. DAME- and KCl-induced SD were accompanied by an increase in locomotor activity and wet-dog shaking behavior, which occurred only during the period of SD. After a wave of SD induced by DAME a biphasic pattern of activity, consisting of an initial depression in locomotion followed by hyperactivity, appeared in 59% of the rats.ACTH1–24 elicited SD in 13% of the rats tested. Neither the dosage of ACTH1–24 nor the strain of rats influenced the occurrence of SD and the incidence of ACTH-induced grooming behavior. SD induced by KCl also resulted in excessive grooming comparable to that induced by ACTH1–24. In the case of KCl-induced SD, grooming began directly after the injection of KCl and was frequently interrupted by short periods of locomotion. ACTH-induced grooming had a later onset and episodes of stretching and yawning were observed. It can be concluded that the behavioral effects of the injection of DAME are unspecific responses to SD and seizure activity. However, ACTH-induced grooming is not solely a byproduct of SD, since it occurred also in the absence of SD.

Spreading EEG Depression in Chickens

LEÃO (1944) reported originally the depression of spontaneous electrical activity of the cerebral cortex, caused by electrical or mechanical stimulation, in rabbits, and he designated this response as “spreading depression.” Spreading depression (SD) accompanied by a slow potential change of the cortex has been reported in many mammalia (Marshall, 1959). In lower vertebrates, similar phenomenon has been observed in the retina of the toad (Gouras, 1958). In pigeons, Leão (1944) also mentioned the occurrence of SD, and recently Bureš et al. (1960) have reported this phenomenon in pigeons using slow potential changes as the main indicator of SD. We have observed a similar phenomenon of SD on EEG of chicks and adult chickens as herein reported.Forty White Leghorn cocks, aged 3 to 8 months old, and sixteen male White Leghorn chicks, 1 to 23 days after hatching, were used. The bird was fixed to the stereotaxic apparatus under nembutal…