Search

EEG power changes in anaesthetized and conscious rats were studied (under repeated experiments) in wide frequency band (0.1-200 Hz) during cortical spreading depression wave (SD). In anaesthetized rats the decrease of EEG spectral power was shown through all diapasons under consideration. The most pronounced decay of the EEG power was marked in the 30-40 Hz band (27.3 ± 18.5, p = 2.46 x 10-(11)). In other frequency ranges the power decrease was less but its significance remained high. In conscious rats the simultaneous decay of the EEG power from 20 to 100 Hz range was also the most informative index of SD wave. The maximum power loss was found for band 30-40 Hz (11.2 ± 7.8, p = 2.55 x 10(-7)). It was shown that besides of EEG power decay the development of SD wave was characterized by the appearance of high frequency activity in front of SD and at the end of it. The increase of high-frequency activity in front of SD wave appeared in the ipsilateral hemisphere and moved along the cortex with the velocity of the SD wave itself. However the bursts of high frequency activity at the end of unilateral SD occurred simultaneously in both hemispheres and lasted 1.5-2.5 min. Findings contribute to detection of SD wave on basis of EEG spectral analysis.

EEG aftereffects of spreading depression waves were studied in waking rabbits in chronic experiments by spectral coherence analysis. Experiments were divided in two groups: early (from the first to the third-fourth experiments) and late (fifth-tenth experiments). During the early experimental series, unilateral persistent EEG changes consisting in an increase in the delta- and beta-band power with a simultaneous depression of the gamma-band activity were observed in the ipsilateral to SD hemisphere. In addition, interhemispheric coherence between symmetrical cortical points decreased. During the late experimental series, a generalized bilateral increase in the power of the delta and beta activity was demonstrated with a rise in coherence in the beta band. This generalized activity occurred cyclically and was distinct during a long period of time (2-3 hours) after propagation of a single SD wave. Such kind of cyclical activity blocked the propagation of subsequent SD waves in the neocortex of a waking rabbit and decreased the probability of recurrent wave origin up to a complete cessation of wave generation. Thus, a cortical SD wave provoked the appearance of synchronized beta oscillations in the EEG, which in turn actively influenced the properties of recurrent waves.

The EEG spectral analysis applied to electrical brain activity of rabbits in the state of animal hypnosis revealed a 2-4-fold increase in the power of the sigma frequency band (12-17 Hz) and a 1.5-2-fold decrease in the gamma frequency (especially 40-70 Hz) in addition to well-known growth of delta (0.3-3 Hz) and reduction of theta activity (4-8 Hz). The changes were more prominent in the frontal cortex areas. The influence of hypnotic state on cortical gamma activity pharmacologically augmented by ketamine injection was analyzed. Administration of subanesthetic ketamine doses led to behavioral locomotor excitation of an animal accompanied by a long-lasting (up to 2 h) increase in the gamma electrical activity. If the animal hypnosis was induced after the ketamine injection, it resulted in an almost instant reorganization of the spectral power. The slow-wave power increased and the gamma-power decreased to the baseline levels. Thus, the animal hypnosis eliminated the reorganization of cortical rhythmicity produced by ketamine, which suggests a stabilizing and, to a certain extent, protective function of this kind of hypnosis in the states of behavioral locomotion and stress.

Reflection of cortical waves of spreading depression in changes in high-frequency gamma activity was shown to improve significantly in conditions of bipolar recording of brain electrical activity. Intense suppression of the EEG gamma range (37-47 Hz) was seen in all cortical areas studied at the moment of onset of waves of spreading depression. The drop in the power of EEG gamma activity had clear leading and trailing fronts, allowing the passage time of the wave to be evaluated in each cortical area, as well as the sequence of propagation. Waves of spreading depression were characterized by normal, i.e., sequential movements across the cortex, only in the first 3-4 experiments. When experiments were continued, there were changes in the latent period and distortions of the propagation sequence. In some cases, waves of spreading depression responded to standard injections of KCl by developing rapidly (0.5-2 min) over the whole of the dorsal surface of the neocortex. More frequently, the wave was delayed (to 6-9 min) was completely blocked in some areas of the cortex. Different types of mild convulsive activity could accompany both the rapid propagation of waves across the cortex and inhibition of wave development. In most cases, there were no electrophysiological signs of changes in neocortical excitability. However, alterations to the spatial characteristics of waves of spreading depression and the spontaneous appearance of repeated waves provided evidence of changes in the functional state of the brain. Overall, EEG spectral analysis in conscious rabbits allowed analysis of spreading depression both in cases of sequential propagation across the cortex and in cases of atypical modes of development of this phenomenon.

It was shown that the manifestation of the SD phenomenon in dynamics of the cortical high-frequency gamma activity is rather prominent after bipolar interpretation of the common reference electrode derivations, i.e. when the modeling of the bipolar signal on the base of monopolar EEG recordings is used. The SD wave was accompanied by significant decrease in the power of the EEG gamma band (37-47 Hz) in all observed cortical areas. A curve of decline of gamma activity power had distinct fore and back fronts, so the time of SD appearance in different cortex areas and it's spread succession could be well determined. In the long-term experiments SD waves were characterized by normal (i.e. successive) spread through the cortex mainly in initial three-four experiments. In the subsequent tests latency of SD waves in different cortex areas changed and disturbance of propagation became obvious. Sometimes SD arose rapidly (due 0.5-2 min) on the whole dorsal neocortical surface, when the standard injection of the KCI was done. In the most of experiments the delay of the SD wave appearance was prolonged till 6-9 min or no SD wave occur at some cortical regions. Week epileptiform activity could conduct abnormalities in the SD. In many instances electrophysiological signs of the cortical excitability changes were absent. However the modified spatial SD characteristic and spontaneous occurrence of the repeated. SD waves indicated the increased functional inhomogeneities of the neighboring cortical areas. So, spectral EEG analysis in awake rabbits made it possible to characterize the SD wave both in case of its normal propagation through the cortex and in unusual forms of this reaction.

Spreading depression can arise spontaneously in convulsions, migraine attacks, vascular lesions, and other pathological brain states. However, the methodological complexity of recording a direct current potential in the neocortex in humans and conscious animals significantly limits studies of the functional consequences of spreading depression. The present report describes a detailed analysis of the EEG dynamics at the moment of development of spreading depression waves and identifies specific signs allowing spreading depression to be recorded without recording changes in the direct current potential. At the moment of arrival of spreading depression, the interhemisphere equilibrium is highly disturbed because of large decreases in high-frequency activity. The time parameters of the dynamics of the gamma-1 and gamma-2 ranges were the most informative features of the development of spreading depression waves. Increases in power in the delta range developed with some delay on the background of a deep inhibition of high-frequency activity and are in essence a consequence of spreading depression. The encephalographic criteria of spreading depression waves identified here can significantly simplify the detection of this phenomenon both in experimental and clinical conditions in a number of pathological brain states.

A spreading depression (SD) can spontaneously develop in seizures, attacks of migraine, vascular disorders and other pathological states of the brain. However, problems in technique of recording the DC-potential in the neocortex of humans and waking animals substantially restrict the possibilities of studying functional consequences of the SD. In this article, the EEG pattern was studied in detail at the moment of the SD development. Specific features were revealed, which make it possible to detect the SD without recording shifts of the DC-potential. At the moment of the SD arrival, the interhemispheric balance drastically disturbs because of a strong decrease in the high-frequency activity. By the time indices, the course of the suppression of the gammal and gamma2 EEG frequencies is the most reliable symptom of the SD wave development. The EEG spectral power in the delta band increases with a certain delay in reference to the deep depression of the high-frequency activity and is, in essence, an SD aftereffect. The found EEG signs of an SD wave can substantially simplify the identification of this phenomenon both in experiment and clinical conditions in certain pathological states of the brain.

Effects of a single wave of the cortical spreading depression (SD) on the ECoG of a waking rabbit was studied with chronically implanted intracortical calomel and silverball epidural electrodes. DC potential shifts and integral electrical activity were recorded monopolary in reference to a nasal-bone electrode. ECoG spectral analysis (FFT) showed that an SD wave was accompanied by a suppression of the neocortical activity in a broad frequency range (0.25-80 Hz). However, the SD-related ECoG depression was a rather short phenomenon (5-7 min) as compared to a following rebound effect, i.e., persistent (1.5-2 h) unilateral exaltation of bioelectrical activity. The spectral power in the delta (6-14 fold) and beta bands (2-6-fold) increased, whereas the high-frequency activity (40-80 Hz) remained suppressed. Similar changes in the contralateral neocortex were poorly pronounced or absent; this resulted in a strong interhemispheric asymmetry. It is suggested that (1) exaltation of the delta activity after SD wave is related not only to a dendrite swelling and changes in the extracellular space structure but to increase in synaptic transmission efficiency, probably, by the type of anoxic potentiation, (2) activation of some subcortical structures by the mechanism of their release from the inhibitory neocortical control is an additional factor of the augmentation of the delta and spindle-like beta activity after an SD wave, and (3) the long-term attenuation of the high-frequency gamma activity is a result of its strong suppression during the SD and its reciprocal relations with the exalted delta activity.

Cortical negative DC potential shifts were studied on two experimental models: focal cortical ischemia provoked by a photothrombotic occlusion of the distal part of the middle cerebral artery (dMCA) and a combination of systemic hypoxia induced by bilateral ligation of the common carotid arteries (temporary ligation of the left artery and permanent ligation of the right one) with breathing with 0.5% carbon monoxide (CO). The perifocal ischemic depolarization (ID) after the dMCA thrombosis was found to reach 28-33 mV and then gradually decline during 80 min to a certain residual level about 5 mV. Spontaneous depolarization didn't occur during hypoxia but it was easily provoked in one or both hemispheres by the waves of the cortical spreading depression (SD). The amplitude of hypoxic depolarization (HD) didn't exceed 20 mV, was remarkably stable during hypoxic condition (more than 60 min) and returned to the baseline level within 20-30 min after the cessation of CO breathing and releasing of the left carotid artery. Despite the similar durations of the ID and HD, their functional consequences differed greatly. The ID led to a damage of the nervous tissue as evidenced by a reduction of the SD amplitude (to 20-25%) and biphasic change in persistent negative potential (PNP) evoked by the SD wave alone. The 1.5-2-fold increase in the PNP amplitude in the perifocal region was the most prominent outcome of the ID. In contrast to the ID, the SD and PNP characteristics were unchanged after the HD. Such a discrepancy between the ID and HD can be related with their different origin. The results suggest that the HD is produced by blood-brain barrier processes associated with the intensive vasospasm and vasogenic edema. Besides these phenomena, the other well-known factors such as a disturbance of permeability of neuronal membranes, glutamatemediated exitotoxicity, and tissue destruction determine the ID noxious influences.

The functional consequences of spreading depression (SD) during the evolution of ischemic damage was studied in two models: focal cortical ischemia induced by photothrombosis of the middle cerebral artery (MCA) and systemic hypoxia induced by 0.8% carbon monoxide (CO). These studies showed that cortical waves of SD, arising spontaneously during MCA thrombosis and after arterial occlusion delayed thrombus formation and promoted the establishment of a collateral blood supply in the perifocal zone of ischemic lesions. The underlying mechanism consisted of episodes of intense vasodilation at the decay phase of every wave of SD. Respiration of 0.8% CO increased the blood carboxyhemoglobin level to 50-60%. In lightly anesthetized rats (pentobarbital 20 mg/kg), cortical and subcortical spontaneous waves of SD were transformed into stable hypoxic depolarization, leading to death of 60% of the animals or severe lesions of the central nervous system, in 20% of animals. Increases in the level of anesthesia (50 mg/kg anesthetic) prevented the spontaneous appearance of SD during long-lasting exposure to CO. In these conditions, experimentally induced waves of SD demonstrated that the hippocampus has a high sensitivity to moderate levels of hypoxia. The duration of hypoxic depolarization of the hippocampus, provoking a single SD wave, reached 30-60 min. Selective neuron damage in field CA1 was seen 30 days after hypoxia. Additionally, the left hippocampus of rats frequently showed profound morphological lesions in the form of "granules." Cerebrolysine (2.5 ml/kg daily for 10 days) completely prevented the formation of these lesions.

A model of acute carbon monoxide poisoning combined with spreading depression (SD) induced metabolic stress was used to examine the protective effects of cerebrolysin (CL) on the development of electrophysiological, behavioral and morphological signs of hypoxic damage. Capillary electrodes were implanted into the neocortex and hippocampus of anesthetized rats which were then exposed for 90 min to breathing of 0.8% to 0.5% CO, while 3 to 4 waves of cortical and hippocampal SD were elicited by microinjections of 5% KCl. Duration of SD-provoked depolarization of cerebral cortex and hippocampus was noted. Nine and 18 to 19 days later propagation of SD waves was recorded with the same electrodes and decrease of their amplitude was used as an index of brain damage which was significant in the hippocampus but not in the cortex. CL-treatment (2.5 ml/kg per day) started after CO administration and continued for 14 days significantly improved hippocampal recovery manifested by increased amplitude of SD waves. Behavioral tests performed 10 and 20 days after CO poisoning in the Morris water maze revealed better performance (escape latency 7 s) in the CL-treated than in untreated animals (14 s). Morphological analysis showed marked damage in the hippocampus consonant with electrophysiological and behavioral findings in the same animals. No apparent histological damage was found in rats exposed to CO inhalation alone without the additional SD-provoked depolarization. It is concluded that chronic CL-treatment enhances recovery of hippocampal tissue after hypoxic damage of intermediate severity., (Copyright 1999 Elsevier Science B.V.)

The role of spreading depression (SD) in the development of ischemic brain damage in rats was studied in two models: focal cortical ischemia provoked by a photothrombotic occlusion of the middle cerebral artery (MCA) and systemic hypoxia induced by breathing with 0.8% carbon monoxide (CO). Spontaneous cortical SD waves occurring during illumination were found to delay the irreversible MCA occlusion. Thrombosis was probably prevented by episodes of striking vasodilation and hyperemia lasting for 1-2 min and accompanying every SD wave. The SD-induced hyperemia after permanent MCA occlusion seems to improve the oxygen supply of the penumbra zone. During hypoxia induced by one-hour respiration with 0.8% CO, COHb saturation of the blood reached 50-60%. SD waves occurred in different brain regions of lightly anesthetized rats (pentobarbital, 20 mg/kg) changed under the above conditions into prolonged depolarizations (HDs) which led to a substantial increase in animals' mortality (60%). The SDs evoked in the cortex and hippocampus of deeply anesthetized rats (pentobarbital, 50 mg/kg) showed that hippocampus became highly vulnerable by CO hypoxia. Duration of the SD-provoked HDs often reached 30-60 min after a single SD wave. Decreased cell density was found in CA1 area of the hippocampus 20-30 days after the CD-enhanced CO hypoxia. Cerebrolysin (2.5 ml/kg daily, during 10 days) prevented from severe hippocampal injury (formation of granulomas) usually seen in the left hemisphere of rats not treated with cerebrolysin.

The persistent negative potential (PNP) developed after a single wave of cortical spreading depression (SD) in the cortex, hippocampus, thalamus, and caudate nucleus. The PNP lasted for about 3-4 hours, its amplitude was 6-7 mV in the ipsilateral and 3-4 mV in the contralateral structures. After development of bilateral primary cortical SD waves the amplitudes of the respective PNP were summed up and reached 9-11 mV. However, after the repeated waves of cortical SD produced with 15-30-min intervals, the PNP level remained unchanged. We think that the PNP is an electrographic manifestation of the well known persistent vasoconstriction after a single wave of cortical SD. It seems to be related with reticular activation due to functional decortication.

The effect of neuroprotective drugs on the early and late electrophysiological manifestations of photothrombotic occlusion of distal branches of middle cerebral artery was studied in rats treated with MK-801 and Cerebrolysin (CL). DC potentials were recorded from the irradiated cortex (ischemic core), from the adjacent penumbra zone and from remote intact cortex. Irradiation elicited after a few minutes of spontaneous spreading depression (SD) waves followed during 10-15 min by focal ischemic depolarization (FID) developing in the irradiated cortex and spreading into the perifocal areas. While the core FID amplitude reached about 30 mV and decayed during subsequent 2 h to 10-13 mV, FID in the penumbra zone was broken by periods of partial repolarization and returned during 30-90 min almost to baseline. At the same time, generation of spontaneous SD waves almost stopped. MK-801 (0.5 mg/kg, i.p., 45 min after ischemia) blocked SD waves, but did not shorten penumbra FID, the decay of which was slowed down to the rate found in the ischemic core. CL treatment (2.5 ml/kg, i.p. , 1 h after ischemia) did not influence FID in the acute phase of the experiment, but its 10-day administration facilitated post-ischemic recovery indicated by higher amplitude of evoked SD waves penetrating into the former penumbra zone. Morphological examination showed that the volume of total and partial necrosis was increased in the MK-801 group and marginally reduced in the CL group. It is suggested that the absence of the SD-induced hyperperfusion episodes in MK-801-treated rats may accelerate perifocal thrombotization in this model of focal ischemia., (Copyright 1998 Elsevier Science B.V.)

Activity and distribution of protein kinase C (PKC) in the rat cerebral cortex was correlated with the development of spreading depression. When the 'waves' of the slow potential shift, induced by topical application of concentrated KCl solutions, were allowed to spread over the cerebral cortex for 10 min, both cytosolic and particulate fractions of the enzyme were increased to 169% and 143%, respectively, of the control values obtained from the contralateral, relatively intact hemicortex. When the enzyme activities were correlated with development of a single slow potential shift, it appeared that in the cortical area fully depolarized (under the maximum of negativity), the respective values were 175% and 157%. One min after recovery of the single wave of spreading depression both cytosolic and particulate fractions continued to rise up to 218% and 239%, respectively. During 5 min of recovery both the cytosolic and particulate fractions fell to 71% and 57%, respectively, of control levels. Even at 10 min the cytosolic enzyme was still decreased to 80%. At 20 min no difference between control and experimental values was found (soluble, 111%; particulate, 96%). The results are discussed in the context of data obtained in a few studies dealing with depolarization-induced changes of PKC in vitro.

Slow potential recording was used for long-term monitoring of the penumbra zone surrounding an ischemic region produced by middle cerebral artery (MCA) occlusion in adult hooded rats (n = 32). Four capillary electrodes (El-E4) were chronically implanted at 2-mm intervals from AP -3, L 2 (El) to AP 0, L 5 (E4). Spontaneous or evoked slow potential waves of spreading depression (SD) were recorded during and 4 h after a 1-h MCA occlusion and at 2- to 3-day intervals afterward for 3 weeks. Duration of the initial focal ischemic depolarization was maximal at E4 and decreased with distance from the focus. SD waves in the penumbra zone were high at El and E2, low and prolonged at E3, and almost absent at E4. Amplitude of elicited SD waves was further reduced 3 days later and slowly increased in the following week. Cortical areas displaying marked reduction of SD waves in the first days after MCA occlusion either remained low or showed substantial (60%) recovery, the probability of which decreased with the duration of the initial focal ischemic depolarization and increased with the distance from the focus. It is concluded that the outcome of ischemia monitored by long-term SD recovery in the perifocal region can be partly predicted from the acute signs of MCA occlusion.

Character of spreading depression (SD) wave propagation was studied on two-dimensional model of excitable tissue. It was shown that strips with diminished density of active elements were of different permeability for the waves depending on their front orientation and curvature. When triggered near the border with a rarefied strip the wave could not penetrate through it and the effect of wave "sliding" along this strip was observed. In several-compartment model imitating the diffusely connected cortico-striatal system of the rat brain the sequence of events was determined by a primary focus position. In this model a single stimulus could provoke not only one wave but re-entry waves and reverberators. Described mechanism of repetitive waves generation in inhomogeneous tissue allow to interpret unusual SD wave consequences observed in electrophysiological experiments.

Spreading depression (SD) in the cortex and the caudate nucleus induced by 40 mg/kg i.p. pentylenetetrazole (PTZ) injection was studied in awake rats with implanted carbon electrodes. It was shown that spontaneous bilateral occurrence of cortical SD was the most probable and had an effective inhibitory influence on seizures after the first PTZ application. Penetration of cortical SD waves into the caudate nucleus and their return to the cortex substantially prolonged the anticonvulsive effects of SD. In the course of daily repeated PTZ injections the cortico-caudate SD propagation reduced progressively being accompanied by a decrease of efficiency of its inhibitory effect and interictal spike activity intensification. Similar restriction of SD propagation was observed without any seizure manifestations under the conditions of daily cortical electrical stimulation (without systemic drug treatment). So, reducing the cortico-caudate SD incidence during PTZ kindling is rather the cause of seizure facilitation than its consequence.

Subconvulsive dosages (40 mg/kg) of intraperitoneally applied pentylenetetrazol (PTZ) elicit, after a latency of 1 min, slow potential waves of spreading depression (SD) in the thalamus and 20 s later also in the cerebral cortex of rats. The PTZ-induced SD waves appear only exceptionally in the caudate nucleus and hippocampus. Repeated daily application of 40 mg/kg PTZ elicits kindling of epileptic phenomena manifested by increasing incidence of high-amplitude spikes in the EEG, myoclonic jerks and minimal and later maximal generalized seizures but by decreasing incidence of cortical SD. It is concluded that kindled epileptic activity interferes with the generation of SD waves the reduced incidence of which may contribute to the development of more severe forms of epilepsy.

Cortical spreading depression (SD) may produce some symptoms of the aura of classical migraine but it is less probable that it can account for the headache. The aversiveness of SD was examined in unanesthetized rats. In Exp. 1, rats with implanted cortical cannulae were confined in the dark compartment of the step-through apparatus and repeated waves of SD were elicited in one hemisphere. After two such training sessions the rats did not evince passive avoidance of the compartment associated with cortical SD. In Exp. 2, thirsty rats with implanted hippocampal electrodes were trained to drink from two different spouts A and B. Hippocampal SD was elicited when the animal was drinking from spout A but not from spout B. Drinking was interrupted shortly after appearance of the SD wave and gradually recovered over the subsequent 10 min, but up to ten spout A-SD pairings did not change the animal's preference for spout A. It is concluded that cortical or hippocampal SD has no immediate or delayed aversive consequences.

Behavioral manifestations of spreading depression (SD) were compared with SD electrophysiological characteristics in these structures. Carbon electrodes were suitable for recording DC slow potential changes in freely moving animal. It was shown that short (0.1 s) high-frequency (200 Hz) electrical stimulation of thalamus and hippocampus with intensity 50-300 microA easily triggered SD wave in these structures in narcotized and awake rats. The threshold of SD occurrence in dorsal hippocampus was the same or sometimes lower than that of the primary afterdischarge. Penetrating SD into ventral hippocampus provoked long latency seizure discharge and wet-dog shakings in awake rats. Intensity of locomotor activity accompanying bilateral hippocampal SD exceeded orienting response significantly. Contrary to hippocampus, thalamic SD was usually subseizure and unilateral phenomenon and had a clear tranquil effect on the rat locomotor activity. It was found that the rats didn't change the compartment preference after 20-45 SD waves in the thalamus or in the hippocampus.

About 40% of spreading depression (SD) waves elicited from the parieto-occipital cortex of anesthetised rats penetrated through the temporal lobe structures (amygdala) into the caudate nucleus. Almost 70% of these SD waves did not terminate in the caudate but returned to the cortex and spread through it toward the site of SD initiation. Longer cortico-caudate (5.9 +/- 0.1 min) than caudate-cortical (4.7 +/- 0.2 min) conduction times suggest that SD enters and leaves caudate through routes of different length. SD waves elicited by KCl microinjection into the caudate reached frontal and parieto-occipital cortical electrodes with latencies indicating that the transit point is 5 mm closer to the rostral than to the caudal electrode. The region best satisfying this condition corresponds to rostral claustrum. The directionally biased SD conduction through the transit zone provides a re-entry path for cortico-caudate-cortical SD propagation and forms thus a natural reverberator the small dimensions of which preclude generation of repetitive SD waves.

Parameters of electrical stimulation (ES) of the rats cerebral cortex which synaptically induced spreading depression (SD) in deep structures were found. The thalamic SD was regularly triggered by short (0.02-0.05 s) high-frequency (200-500 Hz) ES of the parietal cortical surface. In this case the EEG control showed the absence of any seizure activity in the cortical and subcortical structures. Nembutal (20-40 mg/kg) raised the SD thresholds, but did not prevent the short-latency thalamic SD. The ES of the parietal cortex was not sufficiently effective for SD synaptic excitation in the hippocampus and caudate nucleus. In contrast to the thalamic SD, the hippocampal one was accompanied by the episodes of epileptiform activity at certain SD phases. Thus, the low subseizure threshold of the synaptically triggered cortical and subcortical SD should be taken into account when biological purpose of the SD is discussed.

Penetration of cortical spreading depression (SD) into epileptic foci established in the cerebral cortex by penicillin or Metrazol and into electrically stimulated cortical regions was studied in anaesthetized rats. SD suppressed the activity of penicillin foci with low rates of interictal discharge (0.3 Hz) but did not invade more active foci (1 Hz) or foci triggered by electrical stimulation (1-3 Hz). Metrazol foci did not block SD propagation unless stimulated at 6-10 Hz. Repetitive direct cortical responses elicited by 0.05-0.1 msec pulses blocked SD propagation when applied at 6-10 Hz for 5-20 min. The SD blockade covered an area 3-5 mm in diameter around the bipolar stimulating electrodes. The block outlasted the stimulation for several minutes but was fully reversible. New stimulation reinstated the SD blockade after a shorter latency and at lower stimulus intensities and rates. Interaction of the blocked cortical area and SD resulted in anomalous SD propagation, characterized by reentry or circle waves, returning through or around the stimulated region to the recovered cortex. The dynamics of the onset and offset of blocking suggests that SD propagation is prevented by enhanced K+ reabsorption which rapidly removes the K+ ions penetrating the stimulated area from the SD wave front. The interactive phenomena, particularly SD circulation around an epileptic focus, may account for periodic changes of ictal and interictal activity found in some types of focal epilepsy.

Epileptic foci were established by application of Na-penicillin on the exposed parietal cortex of rats (n = 66) anesthetized with pentobarbital. Spikes appearing after a brief (greater than 30s) spontaneous interruption of the interictal discharge were sometimes followed by a spike-triggered spreading depression (STSD) wave, which blocked the activity of the focus for several min. The first recovering spike induced another STSD and repetitive STSD generation continued for up to 20 cycles, with a median cycle duration of 6 min. STSDs appeared more regularly after postictal depression induced by electrical stimulation of the focus or of the symmetrical brain area, and could also be elicited by SD waves evoked by microinjection of 5% KCl into extrafocal cortical regions. An ongoing STSD cycle was interrupted when another penicillin focus in the contralateral hemisphere started to trigger the focal discharge during relative SD refractoriness. STSD waves were observed in 42% of the animals. Attempts to elicit STSD were successful in 70% when the interictal discharge rate was low (less than 10/min) but mostly failed with higher discharge rates (greater than 30/min). It is suggested that STSD is generated when an isolated epileptic spike appears at the level of decreased potassium clearance and that repetitive STSDs are produced by synaptically and metabolically mediated interaction between focal discharge and spreading depression.

Shifts of steady potentials (SP) in the cerebral cortex of rats were studied during formation of stationary excitation foci by low-frequency electric stimulation and application of penicillin. The dynamics of SP shifts reflects summary effect of depolarization and hyperpolarization processes, actively involved in each cycle of excitation. As a result of functional heterogeneity of different cortical areas, a spontaneously appearing wave of spreading depression (SD) may be transformed into a spiral wave, actively influencing the dynamics of excitation resulting from direct stimulation of the cortex. The cause of long-term inhibition of paroxysmal activity foci may be repeated generation of slow negative waves of SD persisting in conditions of rapid restoration of cortical ability to conduct SD.

Properties of cortical spreading depression (SD) were studied at different phases of cyclic excitation occurring in the rat neocortex under low-frequency electrostimulation. SD waves appeared in the cortex spontaneously or were elicited by KCL microinjection. It is shown that the state preventing penetration of SD waves into the stimulated area (blockade of SD) developed during each cycle of excitation. The spatial extent of the SD blockade depended on the degree of excitation generalization over cerebral cortex. After the end of excitation the ability of the stimulated cortical area to conduct SD waves restored. In the intervals between the excitation cycles the SD waves duration was on the average half as long as before stimulation. The development of SD blockade during active phase and restoration of SD waves in the intervals confirms a hypothesis that K+-Na+ pump activation prevents the propagation of SD.

Blockade of the spread depression [SD] in chemically or electrically stimulated areas of the cerebral cortex was analyzed in a series of experiments performed in 40 curarized, locally anaesthetised rats. Longlasting stimulation of the cerebral cortex (0.5 to 1.7 mA, 6 Hz, 0.1 ms) elicited recurrent episodes of enhanced evoked potentials propagating to remote cortical areas [Co], the caudate nucleus [Cd], the hippocampus [Hi] and the thalamus [Th] and was accompanied by marked slow potential shifts (4-6 mV amplitude, 2-3 min duration, at 2-5 min intervals]. The projected discharge interfered with SD initiation and propagation in all the examined structures. The SD blockade was most pronounced during the episodes and almost absent in the intervals between them. The block was manifested by reduced amplitude and duration of the slow potential of SD. Pentobarbital [20 mg/kg] suppressed the recurrent discharges and eliminated the corresponding SD blockade. Recurrent excitability changes induced by Cd and Th stimulation elicited similar effects but the threshold was higher in Cd and Th than in Co. SD was less effectively blocked by the projected discharge than by stimulation of the same structure, particularly in the vicinity of the recording electrodes, where the blockade could be observed even under pentobarbital. The SD blockade outlasted stimulation by a considerably longer period of time in Th (about 10 min) than in the Cd (about 3 min). The onset of stimulation and the projected episodes sometimes elicited SD waves but SD blockade prevailed with continued stimulation. The present findings support the hypothesis that excessive neural activity increases the potassium clearance and thus prevents the autoregenerative accumulation of potassium ions, mediating SD propagation.

Spreading depression (SD) elicited in the cerebral cortex of anaesthetized rats does not penetrate into epileptic foci (penicillin) or cortical regions subjected to repetitive electrical stimulation (6--10 Hz, 0.05--0.01 msec). The extent of the SD block, monitored by the absence of the slow potential change and preservation of spontaneous and evoked EEG activity, can be varied in certain limits by changing the stimulus parameters. When the diameter of the block in the parietal cortex is reduced at a time when its temporal boundary is circumvented by an SD wave, propagating in the rostral direction, a strip of cortical tissue between the block and sagittal sulcus is opened for SD which spreads through this route from the frontal to the occipital cortex and starts reverberating around the block. Other methods for eliciting SD reverberation employ removal of an additional block in a section of the circular pathway and directionally biased propagation around the stimulation point. SD reverberation lasting for at least 3 cycles was observed 109 times (median number of completed cycles 5.2, average cycle duration 4.4 +/- 0.1 min). It is suggested that SD reverberation around an epileptic focus can account for slow oscillations of ictal and interictal discharge and for recurrent seizures.

The role played by synaptic phenomena in the initiation of Leão's spreading depression (SD) was examined in 30 rats anaesthetized with pentobarbital. SD was elicited by a train of 8 electrical pulses (0.1-0.3 msec, 10 Hz) applied through bipolar electrodes to the exposed cortical surface. The slow potential waves of SD were recorded from the stimulated site and from a remote cortical area. Threshold stimulus intensity (40 V) was increased above 80 V when low frequency stimulation (0.3 Hz, 10 V) was applied through the same electrodes. SD penetration into the stimulated area was blocked with higher stimulus rates (3-10 Hz) and intensities (20 V). Systemic application of the pyrrolopyrimidine drug BE 58-271 decreased SD threshold from 40 V to 7 V and reduced also the intensity and frequency of stimulation inducing the SD blockade. Similar effects were obtained with local application of 2 microliters of 10(-3) M 4-amino-pyridine to the stimulated cortex. The SD threshold was reduced from 40 V to 5 V, probably by prolonged depolarization of axon terminals and increased output of transmitters. Estimation of SD threshold revealed a biphasic effect of locally applied penicillin: an initial threshold decrease which gradually changed with the development of regular interictal discharge into a threshold increase and eventual SD blockade. It is concluded that sudden synaptic activation of cerebral cortex elicits SD whereas prolonged continuous stimulation decreases SD susceptibility, probably by enhancing the K+ clearance.

Cyclic discharges occurring during prolonged low-frequency electric stimulation of the cortical surface were studied in the rat neocortex by means of K+ selective microelectrodes. Duration of excitation cycles and intervals between them depended on the parameters of stimulation. Surface potential shift reached 4-5 mV and [K+]0 increased to 8-10 mM. The cyclic excitation process was not self-sustained and stopped just after the current was switched off. Small doses of nembutal (10-20 mg/kg) increased both the threshold for the cyclic process onset and duration of the intervals between the active phases. Higher nembutal doses (30-40 mg/kg) abolished cyclic excitation for 2-3 hours. This model of cyclic discharges is supposed to be useful for investigation of the mechanism of seizure activity and of the effect of antiepileptic drugs.

The failure to elicit cortical spreading depression (SD) under ketamine anesthesia has been examined in 25 rats. SD was elicited by microinjection of K+ acetate (1 microliter, 0.15 mol/l) into the cerebral cortex and monitored by recording the accompanying slow-potential waves. I.p. injection of ketamine HCl (50 mg/kg) elicited after 5-10 min blockade of SD propagation lasting 30-40 min. SD penetration into a cortical area superfused with 10(-4) and 10(-3) mol/l ketamine was partly or completely blocked, respectively. Systemic ketamine doses eliciting SD blockade only slightly reduced spontaneous activity of cortical units recorded with carbon fiber microelectrodes and did not increase but rather decreased the rate of K+ removal from a KCl pool (30 microliters, 40 mmol/l) contacting a 12.5 mm2 area of exposed cortical surface. The results indicate that the ketamine-induced SD blockade is due neither to epileptic activity nor to enhanced active transport of ions but rather to interference with chemically gated ionic channels and/or to stabilization of postsynaptic membranes.

Properties of the cortical spreading depression (SD) were studied at different parameters of the electrical stimulation (ES) of the rat brain. The ES consists of 10 pulses with the frequency from 10 to 200 Hz. Thus, the seizure activity, usually complicating SD, did not appear. With an increase of the ES frequency SD thresholds decreased from 30-40 to 5-10 V. Suprathreshold ES significantly broadened the SD focus. Secondary synaptic SD foci were regularly triggered in the stimulating and contralateral hemisphere as well. Long-term changes in the cortical excitability following the high-frequency ES resulted in a decrease of SD latencies and thresholds. These changes have shown the active role of synaptic events in SD triggering.

Spreading depression (SD) was elicited in rats anesthetized with pentobarbital by a train of 8 electrical pulses (0.1 ms, 10 Hz) applied to parietal cortex. Local application of 50 micrograms of D-ala2-metenkephalinamide (DAME) on the stimulated area evoked one or two SD waves followed by an increase of SD threshold from 40 V to 90 V. This effect could be partly prevented by naloxone (1 mg/kg i.p.) and reversed by local application of 4-aminopyridine (10(-3) M, 2 microliters), which reduced SD threshold to 5 and 20 V in normal and DAME-treated cortex, respectively. It is argued that DAME exerts an inhibitory effect on cortical neurons and that the initial SD facilitation is due to initial blockade of inhibitory neurons in the superficial cortical layers.

Steady potential shifts produced by focused ultrasound were recorded in the cerebral cortex, hippocampus, thalamus and caudate nucleus of the rat. Impulses of 50-100 ms duration were presented with frequency 5 and 10 Hz. Negative slow potential shifts gradually increased up to 3-7 mV during 10-30 s and were often followed by the spreading depression (SD) waves. In every analyzed structure the SD amplitude reached 20-30 mV; the SD duration in the cortex, caudate nucleus and thalamus was 30-40 s while in the hippocampus it was 80-120 s. Seizures initiated by the ultrasound influence proceded in some cases the SD. Threshold ultrasound doses were not effective for 5-7 min after every the SD wave but at the end of the refractory period they became effective again. So, local influence of the focused ultrasound may result in functional blockade of the brain structures due to the cortical and subcortical spreading depression.