Convulsive Discharges Research Articles

Effect of the compound GIZH -290 and levetiracetam on epileptic activity in rat brain structures on EEG models of bemegrid-induced seizures

The effect of levetiracetam (a derivative of 4-phenylpyrrolidone) and its original analog, the compound GIZH-290, on primary generalized epileptic activity (EpA) in rat brain structures (sensorimotor cortex, dorsal hippocampus-CA3 field and lateral hypothalamus field) on EEG models of bemegridinduced seizures was studied. It was found that EpA, after the introduction of bemegrid, appears in 1–2 minutes in the form of prolonged generalized high-amplitude discharges and is registered within 3 hours. GIZH-290 (5 mg/kg, intraperitoneal, 15 minutes after bemegrid) causes a significant (p < 0.05) decrease in the number of epileptic discharges in the cortex and at the level of the trend in the hippocampus, which is accompanied by a decrease in the amplitude of the Epi-discharges. Levetiracetam at a dose of 200 mg / kg does not significantly change the severity of paroxysmal activity (the number of convulsive discharges and their duration) caused by bemegrid.

Coherence and Phase Analysis of Theta Oscillations in the Septohippocampal System during Generation of Convulsive Activity

Changes in the interactions of the hippocampus and medial septal area in the theta range (4–8 Hz) during the generation of convulsive activity in electrical kindling were studied in conscious guinea pigs. Overall electrical activity (EEG)was analyzed by wavelet transformation. Decreases in the coherence of theta oscillations recorded in both structures were seen during generation of convulsive discharges. Phase analysis showed that the phase-leading structure at the initial stage of epileptogenesis was the medial septal area; however, after formation of the pathological focus, the medial septal area lagged the hippocampus in phase. These data may contribute to our understanding of the mechanisms of development of temporal epilepsy.

Protective Effects of the CB1 Receptor Agonist WIN 55.212-2 during Development of Seizure Activity in the Brain in Models of Temporal Epilepsy in Vivo

The effects of intracerebral intraventricular administration of the nonselective cannabinoid CB1 receptor WIN 55.212-2 (1 μM, 2 μl) on seizure activity were studied in conscious guinea pigs. Changes in local field potential and convulsive discharges evoked by electrical stimulation of the perforant path were recorded simultaneously in the hippocampus, entorhinal cortex, medial septal area, and amygdala after prior administration of WIN 55.212-2 or the organic solvent DMSO. In 80% of tests, WIN 55.212-2 was found to block the development of seizure activity. Repeated injections of agonist for 30 days increased the amplitude of local field potentials and the power of the theta rhythm in all structures recorded. Administration of kainic acid provoked status epilepticus in control animals, while status epilepticus did not arise in guinea pigs given daily agonist injections for 25–30 days. The possible mechanisms of the protective effects of WIN 55.212-2 are discussed.

Activation of the Glutamatergic System of the Medial Septal Area Accelerates Epileptogenesis

The effects of injection of L-glutamate into the medial septal area on epileptogenesis associated with stimulation of the perforant pathway were studied in conscious guinea pigs. EEG field potentials were recorded in the hippocampus and medial septal area in the initial state and on formation of epileptic foci in animals given physiological saline (controls) or L-glutamate (glutamate group) into the medial septal area. Administration of glutamate enhanced the theta rhythm in both structures. During kindling in animals given glutamate, there was significantly earlier onset of the convulsive state and secondary epileptiform discharges than in controls. As the epileptic focus formed, sharp weakening of theta oscillations was seen in all animals, though onset was much earlier in the glutamate group. The correlation between the hippocampal and septal EEG decreased sharply in animals given glutamate, while changes in controls were minor. These results are of value in deciphering the mechanisms of temporal epilepsy.

Convulsive Activity in the Electroencephalogram in Rats Sensitive and Tolerant to Pentylenetetrazol Kindling

Studies on rats divided into two groups with different sensitivities on the basis of manifest convulsive activity in response to pentylenetetrazol kindling showed that both "tolerant" and "sensitive" rats showed convulsive discharges on EEG traces. However, as compared with values in "tolerant" rats, the number of convulsive discharges in "sensitive" rats was 60% greater, convulsive discharges occurred 45 sec later, and had a duration in the first 45 post-injection minutes which was 70% longer. There was no difference between the mean durations of convulsive discharges in the two groups. The EEG frequency power peak in "tolerant" rats was more marked than that in "sensitive" animals, and was located at 7.2 Hz. These data led to the conclusion that pentylenetetrazol kindling induces epileptic activity on the EEG in rats independently of whether or not the animals showed behavioral seizures, though there were significant differences in measures of this activity in "sensitive" and "tolerant" rats.

Landau‐Kleffner syndrome: 50 years after

Landau‐Kleffner syndrome: 50 years after

Correlational Relationships Between the Hippocampus and Medial Septal Area and Their Changes During Epileptogenesis

EEG traces were recorded from the hippocampus and medial septal area of conscious guinea pigs in control conditions and on repeated stimulation of the perforant path. Changes in the correlations of activity in these structures during stimulation-evoked convulsions (a model of acute epilepsy) and during the process of epileptogenesis (a model of chronic epilepsy) were analyzed. A high correlation between baseline activity in the hippocampus and medial septal area seen in control conditions decreased sharply with the appearance of acute and chronic convulsions. Kindling led to hippocampus-independent generation of field convulsive discharges in the medial septal area. During kindling, there was a gradual disintegration of activity in the hippocampus and septum, which provides evidence for impairment of the operation of the septo-hippocampal network during epileptogenesis.

Pathophysiological aspects of Landau-Kleffner syndrome: From the active epileptic phase to recovery

In their original description of the syndrome of “acquired aphasia with convulsive disorder,” Landau and Kleffner (1957) suggested “that persistent convulsive discharges in brain tissue largely concerned with linguistic communication result in the functional ablation of these areas for normal linguistic behavior.” In further case studies, the observation of continuous epileptic discharges in electroencephalograms (EEGs) recorded during sleep agreed with this early suggestion. Although several group studies emphasized the almost parallel fluctuation of aphasic disorders and EEG abnormalities, the causal relationship between epileptiform EEG discharges and the language defect remains a matter of debate. Another subject of discussion concerns the outcome of aphasia after recovery of epilepsy that typically occurs at the beginning of adolescence. In the Landau-Kleffner syndrome (LKS), the prognosis of aphasia varies in a manner opposite that observed after structural lesions of the left hemisphere. To further elucidate the pathophysiological basis of aphasia and its poor outcome in LKS, this chapter reexamines five clinical studies of LKS with particular emphasis on electrophysiological and metabolic findings and their relationship to neuropsychological deficits. The data presented and discussed covers a follow-up period extending for each case from the active period to the late recovery phase of epilepsy lasting from 7 to 15 years. The chapter summarizes the clinical histories and neuropsychological findings gathered during the period when the children were aphasic and epileptic and after recovery and focuses on the experimental data supporting focal or regional cerebral dysfunction underlying this particular acquired childhood aphasia.

Autoregressive Modeling of the Eeg in Systemic Kainic Acid-Induced Epileptogenesis

Background activity as well as three kinds of bilateral epileptiform discharges, recorded from the cerebral cortex and hippocampus of freely behaving rats treated with intravenous kainic acid (KA), were analysed by the directed transfer function (DTF) method within multivariate autoregressive modeling of the EEG. This method reveals statistical influence (flow of activity) between brain regions at different frequencies. There was no significant influence between rhythms in different brain regions in the background EEG. Early after KA administration, low frequency rhythms (< 10 Hz) in the frontal cortex began to lead slow rhythms in other areas and high frequency rhythms (20–60 Hz), possibly gamma oscillations, intensified in the hippocampus. In spike-wave discharges, frontal cortex led both low and high frequency rhythms. Initially during generalised non-convulsive discharges, slow rhythms originated from frontal cortex and high frequency rhythms from hippocampus while later, slow rhythms as well, often arose from hippocampus. During the convulsive discharge, the flow of activity of dominant slow rhythms repeatedly changed between hippocampus and neocortex, with more frequent dominance of the hippocampus, while hippocampus continued to lead high frequency rhythms. We conclude that KA-induced epileptiform discharges are cortical and hippocampal events, specifically that the frontal cortex is early to express low frequency rhythms and the hippocampus, high frequency rhythms. More generally, the findings suggest that epileptiform discharges result from interacting rhythms of different frequencies that arise from different structures, and that gamma oscillations possibly contribute to widespread synchronisation during some forms of epileptogenesis.

Cortical and subcortical spreading depression in rats produced by focused ultrasound

Steady potential shifts produced by focused ultrasond were recorded in the cerebral cortex, hippocampus, thalamus, and caudate nucleus. Impulses of 50–100 msec duration were presented at a frequency of 5 and 10 Hz. Negative steady potential shifts were produced in each of the structures investigated, which gradually increased during rhythmic electrical reaction to reach −3 to −7 mV within 10–30 sec, often succeeded by a wave of spreading depression (SD). In each structure analyzed amplitude of SD waves measured 20–30 mV, lasting 30–40 sec in the cortex, the caudate nucleus and the thalamus, and 80–120 sec in the hippocampus. In unanesthetized and lightly anesthetized animals SD waves were on occasions the precursors of convulsive discharges forming under the action of focused ultrasound. Ultrasound at threshold doses proved ineffective for 5–7 min after the occurrence of an SD wave, but again evoked repeated SD waves once the refractory period had ended. Accordingly, local effects produced by focused ultrasound can result in functional blockage of the brain structures due to cortical and subcortical spreading depression.

Action of opiate peptides and narcotic analgesics on the cerebral cortex

The chronic experiments on freely moving cats have shown that the opiate peptides, FK33--824 (Tyr--D--Ala--Gly--MePhe--Met(o)--ol) and tetrapeptide (Tyr--D--Ala--Gly--Phe--NH2), as well as the narcotic analgesics, morphine, phentanyl and pentazocine in doses close to analgesic ones, suppress the recovery cycles of primary responses (PR) in the second somatosensory and associative zones of the brain cortex, recorded at paired stimulation of the fibres of thalamo-cortical radiation (TCR). In larger doses these agents slightly increase PR recorded at single stimulation of TCR, provoke the convulsive discharges on EEG and motor excitation of the animals. Naloxon eliminates all the mentioned effects of the tested opiate peptides and narcotic analgesics.

Heart rate changes in convulsive and nonconvulsive neonatal apnea

One hundred twelve apneic spells of at least 4 seconds' duration were monitored in 15 neonates; 77 episodes were associated with convulsive discharges on the electroencephalogram and 35 were not. Convulsive apnea did not occur in conjunction with bradycardia. Nonconvulsive apnea of less than 20 seconds' duration occurred in the presence of variable heart rates, but nonconvulsive apnea of 20 seconds or longer was nearly always associated with bradycardia.

Inhibition and facilitation of antidromically identified tubero-infundibular neurones following stimulation of the median eminence in the rat.

1. Stimulation of the median eminence of female rats inhibited the spontaneous firing of antidromically identified tubero-infundibular units. Some units could be inhibited by stimuli subthreshold for the antidromic spike. A conditioning stimulus of subthreshold intensity for the antidromic spike also delayed or abolished the invasion of the soma and dendrites of the same unit by antidromic action potentials evoked by a suprathreshold stimulus given 2-10 msec later. 2. Although strychnine (0-2 mg/kg, i.v.) did not significantly alter the inhibition evoked by stimulation of the median eminence, it was abolished by picrotoxin (2-6 mg/kg, iv.). 3. In seven of the fifty-seven identified units examined stimulation of the median eminence facilitated the spontaneous firing. However, after an i.v. injection of picrotoxin the facilitory response was observed in thirty-seven of the forty-six units tested. Post-stimulus time histograms obtained from the same unit before and after an injection of picrotoxin demonstrated that the latency and duration of the facilitation did not always coincide with that of the inhibition. 4. After an injection of picrotoxin the field potential evoked by antidromic stimulation of the median eminence consisted of a small positive wave followed by a negative wave. Frequently the negative wave of the field potential was accompanied by a convulsive discharge. The latency of the negative wave appears to be identical to that of the facilitation seen in nearby single units. 5. The facilitation evoked by antidromic stimulation in the presence of picrotoxin was blocked by an i.v. injection of alpha-methyl-p-tyrosine (250 or 375 mg/kg). None of the nine units sampled from rats pre-treated with alpha-methyl-p-tyrosine injected twice I.P. (250 mg/kg for each) were facilitated by stimulation of the median eminence following I.V. picrotoxin, while eight of the eleven units sampled from control rats pre-treated with L-tyrosine could be facilitated by antidromic stimulation. 6. These results suggest that tuber-infundibular neurosecretory neurones are inhibited and facilitated by neural pathways which could involve the axon collaterals of the neruosecretory neurones which project to the external layer of the median eminence. It is also suggested that GABA-releasing neurones mediate the inhibition and catecholaminergic neurones are involved in the facilitory pathways. Presumably the facilitation is normally masked by the activity of the GABA-releasing neurones.

Generalized penicillin epilepsy in the cat: Effects of intracarotid and intravertebral pentylenetetrazol and amobarbital injections

Generalized penicillin epilepsy in the cat produced by large intramuscular injections of penicillin is characterized by clinical and EEG features resembling human myoclonic petit mal (Prince and Farrell 1969). The similarities between this feline form of epilepsy and human generalized corticoreticular (centrencephalic) epilepsy were further documented in this study. Such similarities are also found with regard to the responses of the generalized paroxysmal discharges to intracarotid and intravertebral injections of pentylenetetrazol and amobarbital. These responses in the cat were studied both in acute experiments and in chronically prepared freely moving animals with indwelling arterial catheters. The catheterization and intra-arterial injection techniques were designed to ensure that normal cerebral hemodynamics were preserved under these experimental conditions. Unilateral intracarotid pentylenetetrazol injections produced a bilateral activation of the generalized epileptiform discharges. Intravertebral pentylenetetrazol diminished, and in chronic animals invariably eliminated spontaneous generalized epileptiform activity. Unilateral intracarotid amobarbital injection produced either an ipsilateral or bilateral diminution of paroxysmal discharges, or an ipsilateral activation. The responses of the generalized epileptiform discharge to intravertebral amobarbital depended upon the unspecific electrocorticographic response induced by the drug: with EEG desynchronization induced by intravertebral amobarbital generalized epileptiform discharges were diminished or arrested: with EEG synchronization they were increased. It was concluded that the origin of the convulsive discharges in this animal model is most likely cortical. Brain-stem structures, however, exert a powerful influence upon these discharges: increased desynchronizing drive of brain-stem reticular origin markedly reduces or even eliminates them; conversely a reduction in ascending reticular drive markedly promotes their occurence. It is proposed that similar mechanisms are at work in human generalized corticoreticular epilepsy.

Patterns of cortical population discharges during metrazol-induced seizures in cats

1. 1. Discharges of neuronal populations were recorded, together with the electrocorticogram (ECoG), in various areas of the cortex and in the pyramidal tract simultaneously, throughout Metrazol-induced seizures in curarized cats. Quantitative evaluation of the level of neuronal discharge was deduced from sequential numbering of multi-unit spikes recorded during the course of a seizure. 2. 2. The organization of cortical cell discharges during Metrazol-induced seizures presented a constant pattern in which three stages could be distinguished: (a) initial paroxysmal bursts at increasing level; (b) tonic discharge maintained for a few seconds at maximal level; (c) clonic bursts of high level recurring until the abrupt end of the seizure. 3. 3. The convulsive discharges of pyramidal tract fibres followed the same pattern. They were similar to and synchronous with those of motor cortex neurones. It was therefore assumed that the population explored in the motor cortex consisted mostly of pyramidal cells. 4. 4. The same general pattern of neuronal ictal discharges was found in the different cortical areas examined, with high variability in occurrence and accuracy of synchronization. 5. 5. The relationship between convulsive ECoG waves and neuronal activity varied according to whether the discharge was phasic or tonic in character. During the first and the third stages of the seizure a clear correlation appeared between the paroxysmal bursts and surface-positive waves. Interruption of cell discharges during surface-negative waves was less constant. Tonic discharges bore no clear relation to the concomitant ECoG waves.

Effects of general stimulant drugs on the electrical responses of isolated slabs of cat's cerebral cortex.

1. In the neuronally isolated cortex of the cat, local application of bemegride, picrotoxin, nikethamide, caffeine and strychnine facilitated the surface positive response of the isolated cortex and lowered the stimulus threshold for this response. Excepting nikethamide, they all produced convulsive discharge in the isolated cortex unrelated to the applied stimulus.2. Local application of glutamate to the cortex produced spreading depression, which was sometimes preceded by spontaneous positive bursting.3. In contrast to the "general depressants" which produce a relatively consistent pattern of effects on the electrical responses of isolated cortex, the "general stimulants", although they all have excitatory effects on isolated cortex, each produced a greatly different type of electrical response in the isolated cortex, suggesting that several different mechanisms of action are responsible for their effects.

Effects of general depressant drugs on the electrical responses of isolated slabs of cat's cerebral cortex

1. In the neuronally isolated cortex of the cat, local application of diphenhydramine, promethazine, gammahydroxybutyrate, gammabutyrolactone, gamma aminobutyric acid, hyoscine and pethidine, and the intravenous injection of diazepam and meprobamate depressed or abolished the surface negative and surface positive response to direct stimulation and raised the stimulus threshold of the positive burst response. These effects were the same as previously demonstrated for general and local anaesthetics on the same preparation.2. Chlorpromazine produced a similar depression in small concentrations but caused spontaneous activity in higher concentrations.3. In contrast to local application, pethidine when given by intravenous injection in a high dose produced convulsant activity in the isolated cortical slab. The possibility was suggested that the convulsant activity was produced by a metabolite of pethidine.4. The results of this investigation suggest that the central depression produced by a number of structurally unrelated drugs is indicative of an anaesthetic-like property of these drugs.

Synchronization characteristics of paroxysmal EEG activity

1. 1. Direct superimposition of highly resolved potential contours was capable of only first order measurements. 2. 2. Cross-correlations of contemporaneous potentials were made in an attempt to achieve a higher order of precision measurement. 3. 3. Using both types of measurement it was shown that physiological cortical visual system activities, in both man and cat, were closely synchronized following retinal stimulation. 4. 4. Convulsive discharges, even when primarily involving the visual system in man, showed a marked variability in the time of occurrence of measurable elements of the potential discharge derived from homologous regions of the head. 5. 5. These latter measurements suggested that the convulsive discharge was a contingent, adventitious action superimposed on the passive electrical characteristics of the anatomical network.

Steady potential of cerebellar cortex. Results of direct, olivo- and ponto-cerebellar activation

Evoked responses were recorded from cerebellar cortex in 68 cats. Surface records were compared with those from graded depths of penetration. Potentials were either evoked directly by surface stimulation or by stimuli applied to the inferior olive or pericruciate cortex for activation of the cerebro-ponto-cerebellar path. Single stimuli and 1 sec trains at 6/sec and 20/sec were used. As evoked by a single shock, the early component of each record shows a somewhat different configuration but is usually diphasic in character. With vertical penetration of cortex this early diphasic potential inverts at 0.3–0.4 mm, corresponding to the position of Purkinje cell somata. All such records also show a slow negativity which follows upon the early diphasic complex. Upon repetitive stimulation the slow components summate to produce a prolonged negative shift which significantly outlasts the stimulus period. Such shifts also reverse to positive upon penetration of the electrode below the level of the Purkinje somata. The evidence suggests that the shift is principally a summation of the slow negativities which are attributed to EPSPs arising along the Purkinje dendritic arborization. Differences were noted between the olivocerebellar responses of vermis and paramedian lobule, the latter being closely akin in form and dispersion to that which is seen in the cerebro-ponto-cerebellar activation. Convulsive activity was elicited from stimulation of the two afferent sources, but not from stimulation at the cerebellar surface. These discharges were relatively prolonged (about 10 min), showed a significant post-ictal depression, and were notable for the magnitude of the negative SP shift which accompanies the train of convulsive discharge.

Eurosurgical aspects of epilepsy: physiological sleep as a means for focalizing EEG epileptic discharges.

The EEGs of a group of epileptic patients with no clear signs of lateralization either in the clinical history and examination, the clinical seizure pattern, the radiological examinations, or the repeated standard EEG recordings, were registered during nocturnal physiological sleep. The appearance of clearcut focal epileptic discharges was observed during sleep in most of the patients who when awake had normal EEG or bilateral inconstantly synchronous abnormalities; no focal abnormality was found in patients showing bilateral constantly synchronous convulsive discharges during wakefulness. The possible application of these findings in the selection of patients for surgical treatment of their epilepsy is discussed.