Self-sustained After-discharges Research Articles

Role of intrinsic burst firing, potassium accumulation, and electrical coupling in the elevated potassium model of hippocampal epilepsy.

Perfusing rat hippocampal slices with high-K+ (7.5 mM) saline induced brief population bursts originating in CA3 at 0.5-1 Hz and spreading synaptically into CA1. In 42% of the slices the brief bursts evoked in CA1 gave way every 0.5-2 s to sustained ictal (or seizure) episode with tonic and clonic components. Paired intra- and extracellular recordings in the CA1 pyramidal layer were used to characterize the synaptic and nonsynaptic mechanisms generating the brief and sustained epileptiform events. The interictal, tonic, or clonic primary burst response in CA1 comprised a spindle-shaped, tight cluster (170-180 Hz) of five to seven population spikes. Bursts evoked between sequential seizures (interictal bursts) were initially small and progressively increased in size. Concurrently, basal extracellular K+ concentration ([K+]o] increased from 6.5 to 7.5 mM. The tonic event emanated from a large primary burst and comprised prolonged (> 1 s), self-sustained afterdischarge, associated with a rise in [K+]o to 12 mM. Bursts generated during the subsequent [K+]o decline (clonic bursts) also were large and followed by some afterdischarge. They became small during [K+]o undershoot to 6.5 mM. Intrinsically burst firing pyramidal cells (PCs) were recruited before or at the very onset of the primary population burst and fired repetitively during its course. Nonbursters were recruited > or = 10 ms after the beginning of the primary burst and fired, on average, only one spike. The PCs depolarized during the primary burst and subsequent afterdischarge. The primary depolarizing shift was larger in bursters than in nonbursters. Both bursters and nonbursters fired repetitively, albeit intermittently, during tonic and clonic afterdischarge. Throughout the interictal-ictal cycle intracellular spikes were time-locked to population spikes, indicating that PCs fire in tight synchrony. Differential recording of transmembrane potentials unmasked rapid (4-7 ms) transmembrane depolarizing potentials of up to 10 mV, coincident with population spikes. We conclude that in the high-K+ model of hippocampal epilepsy, the local generation of population bursts in CA1 is led by intrinsic bursters, which recruit and synchronize other PCs by synaptic, electrical, and K(+)-mediated excitatory interactions. The cycling between interictal, tonic, and clonic events appears to result from feedback interactions between neuronal discharge and [K+]o.

Action of clonazepam and clorazepate on cortical self-sustained after-discharges in the rat.

Self-sustained after-discharges (SSADs) induced by electric stimulation of the sensorimotor cortex in rats exhibited under control conditions a significant progressive prolongation with repeated stimulations. Clonazepam not only blocked this increase in duration but it suppressed and/or abolished SSADs in a dose-dependent manner. Clorazepate in the lowest dose used (10 mg/kg) did not change SSADs. The two higher doses (25 and 50 mg/kg) blocked the prolongation of the 4th SSAD, i.e. this effect had a relatively long latency.

Postsynaptic neuronal response of a cat sensorimotor cortex during evoked and self-sustained rhythmic "spike and wave" activity

Intracellular correlates of complex sets of rhythmic cortical "spike and wave" potentials evoked in sensorimotor cortex and of self-sustained rhythmic "spike and wave" activity were examined during acute experiments on cats immobilized by myorelaxants. Rhythmic spike-wave activity was produced by stimulating the thalamic relay (ventroposterolateral) nucleus (VPLN) at the rate of 3 Hz; self-sustained afterdischarges were recorded following 8–14 Hz stimulation of the same nucleus. Components of the spike and wave afterdischarge mainly correspond to the paroxysmal depolarizing shifts of the membrane potential of cortical neurons in length. After cessation of self-sustained spike and wave activity, prolonged hyperpolarization accompanied by inhibition of spike discharges and subsequent reinstatement of background activity was observed in cortical neurons. It is postulated that the negative slow wave of induced spike and wave activity as well as slow negative potentials of direct cortical and primary response reflect IPSP in more deep-lying areas of the cell bodies, while the wave of self-sustained rhythmic activity is due to paroxysmal depolarizing shifts in the membrane potential of cortical neurons.

Deep prepyriform cortex kindling and its relation to amygdala kindling in the rat

Kindling of the deep prepyriform cortex (DPC), a recently identified sensitive site to chemoconvulsants, was compared to kindling of the amygdala in rats. Although the two kindled sites were very similar in their initial responses, electroencephalographic changes during kindling stimulation, kindling seizure development, and growth of afterdischarge, they differed in that the deep prepyriform cortex showed a significantly lower final threshold, a significantly higher frequency of afterdischarge and a significantly shorter latency to bilateral forelimb clonus than the amygdala. Significant bidirectional transfer was found during secondary kindling of either of the two sites, suggesting a close interrelation between them. Rhythmic synchronous discharge was directly induced in the deep prepyriform cortex by ipsilateral amygdala stimulation, but not in the amygdala by ipsilateral cortical stimulation. Local application of both muscimol (0.45 n M) and 2-amino-5-phosphonovaleric acid (25 n M) into the cortical site reduced the afterdischarge duration of amygdala-kindled seizures by approximately 20% without changing the type or duration of the motor seizure. We suggest that the deep prepyriform cortex is “downstream” from the amygdala in the preferential routes of afterdischarge propagation, and that, although the deep prepyriform cortical neurocircuits of GABA and excitatory amino acids may be involved in the maintenance of amygdala-kindled, self-sustained afterdischarge, they are not essential in the expression of amygdala-kindled motor convulsions.

Localization of the origin of self-sustained afterdischarges (SSADs) in the rat: I. The spike-and-wave type of SSAD.

The genesis of the thalamocortical self-sustained afterdischarge (SSAD) composed of spike-and-wave (S + W) rhythm was studied in adult male albino rats. Under control conditions, rhythmic electrical stimulation of the specific somatosensory nucleus of the thalamus always elicited type S + W SSAD. An electrolytic lesion of the nonspecific thalamic nuclei did not prevent generation of type S + W SSAD, while stimulation of the ventrobasal complex evoked both type S + W SSAD and another type of SSAD composed of large waves with superimposed fast activity. Elimination of the cortex (by suction or spreading depression) ipsilateral to the stimulated thalamus completely suppressed any possibility of the formation of type S + W SSAD; elimination of the contralateral cortex did not affect it. Our results suggest that the cortex is the decisive factor in the genesis of S + W rhythm, while the thalamus markedly influences the conditions of its formation.

Number of synaptic vesicles in rat cortex immediately after cessation of the self-sustained afterdischarge during kindling.

The sensorimotor area of rat cerebral cortex was subjected to repetitive electrical stimulation at 10-min intervals; this led to progressive lengthening of self-sustained afterdischarges (SSADs). At 50-60 s after cessation of the third SSAD the brains of the animals were perfused transaortally with fixing fluid, and a quantitative electron microscopic analysis of type I synapses in the second cortical layer of the sensorimotor area of the contralateral hemisphere was carried out. In a zone 0.1 micron wide adjacent to the presynaptic membrane in the active zone, the number of synaptic vesicles (converted to the number per 0.01 micron2 area) in the experimental animals fell by 64.6%. In a zone of the same width 0.1 micron distant from the presynaptic membrane, it fell by 67.6%. The mean absolute synaptic vesicle count per presynaptic bag section fell by 66.6%. The number of synapses showing signs of exocytosis rose in the experimental animals from 3.8 to 5.9%, while the number with clearly demonstrable exocytosis rose from 0.7 to 11.4%. The proportion of synapses with signs of (clearly demonstrable) endocytosis rose from 2.8% (2.1%) in the controls to 7.1% (3.7%) in the experimental rats. In the experimental and control animals we demonstrated complex vesicle formation in 4.3 and 3.8%, respectively, of the synapses and dense-cored vesicles in 7.7 and 2.8%, respectively, of the synapses. We consider changes in the number and formation of synaptic vesicles to be signs of exhaustion of the synapses caused by the previous epileptic seizure, which simultaneously activates mechanisms of vesicle formation.

Ontogenetic development of rhythmic thalamo-cortical phenomena in the rat

MAREŠ, P., D. MAREŠOVÁ, S. TROJAN AND J. FISCHER. Ontogenetic development of rhythmic thalamo-cortical phenomena in the rat. BRAIN RES. BULL. 8(6) 765–769 1982.—Three rhythmic cortical phenomena (rhythmic afterdischarges, incremental responses and self-sustained after-discharges formed by spike-and-wave rhythm) were elicited by electrical stimulation of thalamic nuclei during ontogenesis in rats. All three phenomena could be recorded for the first time at the age of 12 days and they matured until the 18th postnatal day. Possible explanation for the delayed development of these rhythmic thalamo-cortical phenomena in comparison with single thalamo-cortical responses are discussed.

Changes in the excitability of rat cerebral cortex after a self-sustained after-discharge

Changes in the duration of the cortical self-sustained after-discharge (SSAD) were studied in relation to the preceding SSAD in adult rats. An ‘excitability cycle’ could be constructed by means of different intervals between the end of the first SSAD and the beginning of subsequent electrical stimulation of the sensorimotor cortex. During short intervals (30, 60 and 120 sec) the second SSAD was significantly shorter than the first. No significant differences were found with intervals of 3 and 5 min; all longer intervals, except 120 min, resulted in significant prolongation of the second SSAD. The possibility of elicitation of the second SSAD also increased with increasing intervals, demonstrating thus the presence of a ‘refractory period’. The results with manifold stimulation demonstrated the rather complicated nature of the changes of excitability during post-ictal periods.

Number of synaptic vesicles in the rat somatosensory cortex after repetitive electrical stimulation prolonging self-sustained after-discharges.

The sensorimotor area of the cerebral cortex of rats was repetitively electrically stimulated (8 Hz for sec) at 10-min intervals, inducing a gradual prolongation of self-sustained after-discharges (SSADs). At 10 min after termination of the third SSAD, the animals were perfused with a fixation solution. The homotopic area of the contralateral hemisphere was examined in the electron microscope. In the II cortical layer, the agranular synaptic vesicles in type I synapses (after Gray) were counted close to the synaptic cleft. The number of synaptic vesicles was significantly increased in the experimental animals.

The ontogenesis of cortical self-sustained after-discharges in rats.

An ontogenetic development of cortical self-sustained after-discharges (SSADs) was studied in acute experiments on 98 male albino rats aged from 9 days to adulthood. Rhythmic electrical stimulation of one cortical sensorimotor area regularly elicited SSADs formed by spike-and-wave complexes starting from the postnatal day 15. Frequency of these complexes increased from 2.0 to 2.5 cycles/s in 15- and 18-day-old rats to 3.0 to 4.0 cycles/s in older animals. In younger animals SSADs were better expressed in the stimulated sensorimotor than in the visual area of both hemispheres, whereas in older rats the SSADs were fully generalized. The SSADs became longer with increasing age. A highly significant prolongation of the SSADs was seen in all age groups with repeated stimulations; this finding is discussed as a possible form of kindling.

Interhemispheric field potentials, spreading depression and kindling

The incidence of spreading depression, which was elicited by interhemispheric stimulation, increased with prolonged duration and strength of individual pulses and with longer stimulus trains. In the first trial spreading depression appeared in one-third of the experiments, in two-thirds it was activated by repeated stimulus trains. Both the activated and the first trial spreading depression were preceded by alternation of the interhemispheric response and often by self-sustained afterdischarges. All the phases of the interhemispheric response patterns contained inhibitory components either in the form of phasic focal polarizing waves of the evoked and self-sustained field potentials or giant slow spreading depolarizations. The stimulation parameters determine whether a permanent increase of excitability prevails, as in Goddard's kindling procedures, or whether inhibitory patterns, described in this paper, result from the stimulation.

Ceiling of stimulus induced rises in extracellular potassium concentration in the cerebral cortex of cat

Levels of extracellular potassium activity (a K) during repetitive electrical stimulation were measured with ion sensitive microelectrodes in the somatosensory cortex of the cat to determine maximum values (‘ceiling’ levels) under different experimental conditions. The maximal values of a K were 10.2 mequiv./1 during stimulation of the cortical surface (CS) or of the nucleus ventroposterolateralis thalami (VPL) and during selfsustained afterdischarges (SAD). Similarly, peak values were 6.5 mequiv./1 for the nucleus ventrolateralis anterior and 4 mequiv./1 for the nucleus centromedianus as well as for the nucleus cuneatus. The rise in a K during a test stimulus with constant intensity and frequency was inversely related to the level of a K produced by a preceding stimulation. Also rise in a K during SAD was smaller when it started from an enhanced level of a K. During repetitive stimulation of CS or VPL a rise in a K was not observed when a K was increased to levels above 10 mequiv./1 by superfusion with potassium enriched solutions. An electrophoretically evoked K + test signal was reduced between 10 and 48% when applied during stimulus induced increased levels of a K. Stimulus induced potassium changes could become negative when a K was increased to levels above 7 mequiv./1 by local electrophoresis, while the stimulus induced increase in neuronal discharge rate did not disappear or reverse. Amplitudes of ECoG and local evoked potentials were reduced as a K increased during stimulation or superfusion. It is suggested that the ceiling in its steady state is maintained by an active K + uptake mechanism which balances extra releases of K +. Decreased release of K + at increased levels of a K may in addition limit the rise in a K.

Interneuronal epileptic discharges related to spike-and-wave cortical seizures in behaving monkeys

Micro-electrode recordings of unit firing and local slow waves from the precentral motor cortex of chronically implanted, sitting macaque monkeys disclosed the occurrence, during drowsiness, of focal epileptic events with the typical pattern of 3/sec spike-and-wave discharges, lasting 5–17 sec and associated with tonic eye movements. The seizures appeared either spontaneously or as self-sustained afterdischarges following protracted single shock stimulation (0.5–1/sec) or repetitive shocks (8–10/sec) to the specific thalamic nuclei. The depth-recorded spike-and-wave discharges were poorly reflected—and in some instances failed to appear—at the cortical surface. Long-axoned neurons were identified by their antidromic invasion following pes pedunculi stimulation, while interneurons were recognized from their peculiar spontaneous bursting firing and high-frequency spike barrages evoked by pes pedunculi and/or specific thalamic stimulation. The EEG components of focal spike-and-wave discharges were closely associated with the epileptic firing of interneurons. Commonly, they discharged long barrages during the depth-negative “spike” component of epileptic EEG complexes, with progressive spike inactivation; afterwards, the spike potentials partially recovered their amplitude the first part of the depth-positive “wave” component and, finally, interneurons stopped firing completely and exhibited synaptic unresponsiveness during the trough of the “wave”. A single interneuron, likely belonging to a different type, discharged spike clusters towards the peak of the “wave”. The uniformity of seizure initiation and development in different neuronal pools and the focal character of cortical 3/sec spike-and-wave seizures related to epileptic interneuronal discharges are discussed. The “spike” is viewed as reflecting extracellularly the synchronous and powerful depolarization of excitatory interneurons, which set in motion inhibitory Golgi II elements responsible for the subsequent, long lasting “wave”.

Effects of septal after-discharges on switch-off behavior motivated by hypothalamic stimulation in cats.

Summary The cats with chronic electrodes were trained to perform switch-off behavior motivated by hypothalamic stimulation. The performance of switch-off behavior was investigated during septal after-discharges. Results were following: 1. In all cases, as soon as the self-sustained amygdaloid after-discharges appeared cats could not perform switch-off behavior. 2. They could not perform switch-off behavior just after the septal after-discharges originated in the dorsal or lateral septum appeared. We came a conclusion that effects of septal after-discharges on switch-off behavior might relate to the stimulating point in the septum.