A study of the transition from spindles to spike and wave discharge in feline generalized penicillin epilepsy: EEG features

Earlier work suggested that the epileptic bursts occurring in the form of spike and wave discharges in feline generalized penicillin epilepsy were closely related to spindles. The present study showed that after i.m. penicillin, spindles elicited by single-shock midline thalamic stimulation gradually change into spike and waves. Hybrid forms are often seen during the transition phase. The transformation of spindles into spike and waves initially involves an increase in amplitude and the development of positive phases of spindle waves. Furthermore, every second (or in cats with lesions of the midbrain reticular formation, every second and third) spindle wave is gradually eliminated and replaced by a slow wave. The remaining enhanced spindle wave becomes the spike of the spike and wave complex. In conformity with this development, spectral analysis shows that no gradual frequency shift occurs during this transformation, but that the intraburst frequency decreases by a half or a third in one step from that characteristic of spindles to that typical for spike and waves. Spindle and spike and wave frequencies vary from cat to cat, but the above ratios are constant across animals. The spike and waves of cats with lesions of the midbrain reticular formation resemble those of human generalized epilepsy more closely than those induced in intact animals. A continuous transition from spindles to spikes and wave is thus demonstrable suggesting that spike and wave bursts are elicited by the same thalamocortical volleys which normally induce spindles.     

Effects of changes in cortical excitability upon the epileptic bursts in generalized penicillin epilepsy of the cat.

Previous studies had suggested that the epileptic bursts of feline generalized penicillin epilepsy represent the response of hyperexcitable cortex to thalamocortical volleys normally evoking spindles. If this were the case, it should be possible to convert the epileptic bursts of generalized penicillin epilepsy into spindles by decreasing the excitability of cortical neurons. In cats exhibiting the EEG signs of feline generalized penicillin epilepsy cortical excitability was decreased by hypoxia, by the topical application to the cortex of KCl (inducing spreading depression), barbiturates, GABA, AMP or noradrenaline. During generalized penicillin epilepsy, hypoxia and KCl-induced spreading depression abolished epileptic bursts which were replaced by spindles. When spindles and epileptic complexes occurring in the same animal were compared, a direct correlation between the frequencies of these two rhythms could be demonstrated, that of the epileptic complexes being about half that of the spindle waves. These observations support the hypothesis that the epileptic bursts of feline generalized penicillin epilepsy are induced by thalamocortical volleys normally involved in spindle genesis. Topical cortical applications of barbiturates, GABA, AMP and noradrenaline reduced or inverted the negative spikes of the spike and wave complexes, while augmenting the negative slow waves, or revealing them clearly in instances in which they had been poorly developed. This effect is interpreted as being due to a selective inactivation of the superficial cortical layers. That topical cortical application of barbiturates, GABA, AMP and noradrenaline was capable of transforming into typical spike and wave complex epileptic bursts, which had not previously conformed to this pattern, indicates that the intracortical electrophysiological events of typical and atypical epileptic bursts in feline generalized penicillin epilepsy are fundamentally the same and reflect an alternation between excitatory and inhibitory sequences.     

Transition from spindles to generalized spike and wave discharges in the cat: Simultaneous single-cell recordings in cortex and thalamus

The relationships between the activity of the cortex and that of a “specific” (n. lateralis posterior, LP) and an intralaminar thalamic nucleus (n. centralis medialis, NCM) were studied in the cat during the transition from spontaneous spindles to generalized spike and wave (SW) discharge following i.m. penicillin injection. The EEG and extracellular single-unit activity were recorded in cortex and thalamus during the spindle stage and at different intervals after penicillin until well developed SW discharges were present. Computer-generated EEG averages and histograms of single-unit activity were triggered by either peaks of cortical or thalamic EEG transients or by cortical or thalamic action potentials. In agreement with previous observations, cortical neurons increasingly fired during the spindle wave as it was transformed into the “spike” of the SW complex, while a period of neuronal silence gradually developed as the “wave” of the SW complex emerged. Similar changes developed in the thalamus, particularly in LP, either concurrently with or more often after the onset of the changes in the cortex. Most neurons in NCM, continued to fire randomly even after well developed SWs and rhythmic neuronal discharges had developed in cortex and LP. Only $\text{4}\text{11}$ NCM neurons did ultimately exhibit a rhythmic firing pattern similar to that seen in the cortex and LP. The correlation between cortical and thalamic unit activity was low during spindles, but gradually increased during the development of SW discharges. These data confirm that the cortex is the leading element in the transition from spindles to SWs. Increasingly, in the course of this transition, cortical and thalamic neuronal firing becomes more intimately phase-locked. This mutual interrelationship appears to be more pronounced between cortex and “specific” than intralaminar thalamic nuclei.     

Generalized epilepsy with bilateral synchronous spike and wave discharge. New findings concerning its physiological mechanisms.

A hypothesis for the mechanism of generalized spike and wave discharge in human generalized epilepsy is proposed in the light of findings obtained in feline generalized penicillin epilepsy. It is postulated that generalized bilaterally synchronous spike and wave discharge depends upon a diffuse and relatively mild state of cortical hyperexcitability which increases the responsiveness of cortical neurons. Afferent thalamo-cortical volleys normally involved in the genesis of spindles and recruiting responses are most likely to precipitate spike and wave discharges under these conditions. The spike and wave pattern probably results from the activation of a recurrent intracortical inhibitory pathway which becomes activated when cortical neurons discharge in greater number and more repetitively than is normally the case. During spike and wave discharges a large number of neurons oscillate between short periods of excitation, corresponding to the spike, and longer periods of inhibition, corresponding to the slow wave component of the spike and wave complex. This disrupts the normal transactional processes of cortical neurons which are presumably responsible for mental activity, particularly for the close integration of perception, cognition and voluntary motor responsiveness. The degree of this interference varies greatly and in mild absence seizure it is not justified to speak of "loss of consciousness". The fundamental disturbance in absence seizures brought about by the generalized cortical spike and wave discharges is therefore better regarded as a "clouding of the mind". Loss of consciousness can be said to occur only when the interference with mental activity becomes particularly intense. Loss of consciousness in absence seizures can therefore not be used as an argument in favor of primary involvement of higher brain-stem mechanisms.     

Acute effect of carbamazepine on corticothalamic 5–9‐Hz and thalamocortical spindle (10–16‐Hz) oscillations in the rat

A major side effect of carbamazepine (CBZ), a drug used to treat neurological and neuropsychiatric disorders, is drowsiness, a state characterized by increased slow‐wave oscillations with the emergence of sleep spindles in the electroencephalogram (EEG). We conducted cortical EEG and thalamic cellular recordings in freely moving or lightly anesthetized rats to explore the impact of CBZ within the intact corticothalamic (CT)–thalamocortical (TC) network, more specifically on CT 5–9‐Hz and TC spindle (10–16‐Hz) oscillations. Two to three successive 5–9‐Hz waves were followed by a spindle in the cortical EEG. A single systemic injection of CBZ (20 mg/kg) induced a significant increase in the power of EEG 5–9‐Hz oscillations and spindles. Intracellular recordings of glutamatergic TC neurons revealed 5–9‐Hz depolarizing wave–hyperpolarizing wave sequences prolonged by robust, rhythmic spindle‐frequency hyperpolarizing waves. This hybrid sequence occurred during a slow hyperpolarizing trough, and was at least 10 times more frequent under the CBZ condition than under the control condition. The hyperpolarizing waves reversed at approximately ?70 mV, and became depolarizing when recorded with KCl‐filled intracellular micropipettes, indicating that they were GABA_A receptor‐mediated potentials. In neurons of the GABAergic thalamic reticular nucleus, the principal source of TC GABAergic inputs, CBZ augmented both the number and the duration of sequences of rhythmic spindle‐frequency bursts of action potentials. This indicates that these GABAergic neurons are responsible for the generation of at least the spindle‐frequency hyperpolarizing waves in TC neurons. In conclusion, CBZ potentiates GABA_A receptor‐mediated TC spindle oscillations. Furthermore, we propose that CT 5–9‐Hz waves can trigger TC spindles.     

Laminar analysis of spindles and of spikes of the spike and wave discharge of feline generalized penicillin epilepsy

Intracortical laminar profiles of spindles and spikes of spike and wave complexes in feline generalized penicillin epilepsy were studied using two methods: (i) sequential microelectrode recordings at various cortical depths, and simultaneous recordings at multiple cortical depths using a fine multi-contact electrode. Raw EEG data and EEG epochs averaged with respect to peaks of surface EEG waves were analyzed. Spindles and the spikes of the spike and wave complexes showed similar laminar profiles. This supports the hypothesis that the two are basically the same cortical electrophysiological phenomenon, the spike being a spindle wave enhanced and slightly altered because of the penicillin-induced increased cortical excitability. The latter causes the weight of the thalamic input to shift from superficial to more deep lying synapses. Both surface negative and surface positive phases of spindles and of spikes of spike and wave complexes show similar laminar profiles, those of the former suggesting activation of excitatory synapses in the superficial cortical layers, those of the latter suggesting activation of more deeply located excitatory synapses. The profiles generally conform to the dipole hypothesis of cortical electrogenesis and suggest that spindles and spikes of spike and wave complexes are generated by the same pyramidal neurons, probably through activation of the same sets of synapses. Some inconstant and relatively minor deviations of the laminar profiles from the pattern predicted by the dipole theory of cortical electrogenesis were encountered and are tentatively explained in the light of some of the complexities of the microanatomical organization of mammalian neocortex.     

Laminar field potentials and unit activity in the cortex during visual evoked potentials in feline generalized penicillin epilepsy

Modifications of the visual evoked potential during generalized epilepsy were investigated in feline generalized penicillin epilepsy. Visual evoked potentials and their intracortical profiles were averaged during intraburst periods and during the wave of the spike and wave complex to a fixed latency from the preceding spike. During interburst periods, the evoked potentials showed an increase in the amplitude of the early positive peak and the appearance after a variable latency period of a second consistent peak during the late phase of the evoked potential. Laminar profiles of visual evoked potentials and their current source density analysis compared with the activity of single cortical units suggested an early excitation of neuronal populations at layers II, III and IV, as seen before penicillin, followed by a variable inhibitory period and by a subsequent rebounded excitation at those same levels. In evoked potentials recorded during the wave of the spike and wave complex, the early phase was unchanged and the late positive peak and the corresponding deep sink were greatly reduced or nonexistent, although the rebounded activation of cortical units was still evident. These data support the conclusion that during feline generalized penicillin epilepsy a larger number of cortical neurons are activated and a sequence of excitation-inhibition-excitation, probably involving also subcortical structures, is brought about. Moreover, the inhibitory phase of the spike and wave complex is soon disrupted whenever a consistent sensory stimulus arrives at the cortex.     

Interaction of cortex and thalamus in spike and wave discharges of feline generalized penicillin epilepsy

The transition from spindles to spike and wave (SW) discharges of feline generalized penicillin epilepsy was studied using simultaneous EEG recordings from mutually related cortical and thalamic sites after i.m. injection (350,000 IU/kg) or diffuse cortical application of a weak solution (100–300 IU/hemisphere) of penicillin. Both procedures induced similar changes at cortical and thalamic levels, those in the thalamus developing at the same time or slightly later but nerver earlier than in the cortex. These changes consisted of: (i) amplitude increase of spindles, development of positive phases, and decrease in amplitude, followed by disappearance of every second spindle wave as SW discharges developed; (ii) facilitation, progressive amplitude increase, and increase or development of positive phases of recruiting responses to midline thalamic stimulation. Once SW had developed, a decrease in cortical excitability by cortical application of 15% KCl caused the cortical and thalamic SW discharges to disappear and to be replaced by spindles. These results demonstrate that important changes in thalamic activity occur during the development of cortical SW discharge whether induced by i.m. penicillin or by diffuse cortical application of a weak penicillin solution. Changes in thalamic activity appear to be secondary to changes in cortical activity. Thus, although cortical SWs are triggered by thalamocortical inputs which originally were spindle-inducing, these inputs change after penicillin, and reflect an alteration in thalamic activity imposed by the cortex through corticothalamic volleys. In their turn, they modify the cortical response.     

Reticularis thalami neurons revisited: activity changes during shifts in states of vigilance

This study tested the hypothesis that inhibitory actions are exerted by reticularis thalami (RE) neurons upon thalamocortical neurons. The RE neurons were recorded in the rostral pole and lateral districts of the nucleus, and were activated monosynaptically by cortical volleys. Thalamocortical neurons were identified antidromically in intralaminar and ventrolateral nuclei. During sleep with EEG synchronization, prolonged spike barrages of RE neurons extended over the whole spindle sequences. This result suggests that RE neurons are depolarized throughout spindle oscillations, whereas thalamocortical neurons show, simultaneously, long hyperpolarizations and short rebounds. During waking, parallelism rather than reciprocity was found between RE and thalamocortical neurons. Spontaneous discharge rates almost doubled in RE neurons on arousal from sleep, and the probability of cortically evoked short-latency discharges increased. The increase in spontaneous firing rates of RE neurons during natural arousal is consistent with their short-latency synaptic excitation by stimulating the rostral brain stem reticular formation after chronic degeneration of passing fibers. We suggest that RE cells inhibit GABAergic local-circuit cells, in addition to inhibiting thalamocortical neurons, and that different ratios of inhibitory effects are exerted by RE neurons upon these two cell classes during waking and sleep. We further suggest that, upon arousal, disinhibition of thalamocortical neurons (via the local-circuit neurons) outweighs direct inhibition of the thalamocortical neurons.     

Involvement of cortical, thalamic and midbrain reticular formation neurons in spike and wave discharges: extracellular study in feline generalized penicillin epilepsy

Extracellular activity of single units, simultaneously recorded in cortex, thalamus, and midbrain reticular formation was investigated during feline generalized penicillin epilepsy. The firing activity of neurons recorded in the cortex was invariably and consistently enhanced in coincidence with the positive peak and the positive-negative transient of the "spike" of the spike and wave complex, and it was greatly decreased during the wave. In the nonspecific thalamic nuclei three classes of neurons were identified according to their patterns of activity during the spike and wave complex: (i) neurons behaving like cortical units, (ii) neurons with enhanced firing activity during the wave and a decreased activity during the "spike," and (iii) unmodified neurons. In the nucleus lateralis posterior neurons of the third class were not found. Most midbrain reticular neurons could be classified in the same three classes of the nonspecific thalamic nuclei; however, 11% of those units increased their activity 20 to 30 ms earlier than did the cortical units (class IV). Investigation of the activities of all these neuronal populations immediately prior to a spike and wave discharge showed that the rhythmic cycle of excitation-inhibition commenced earlier in the cortical neurons than in any other subcortical neuron. Moreover, there were some nonspecific thalamic neurons of class II with an inhibitory phase exactly coincident with the activation of class IV midbrain reticular neurons. These data suggest (i) a leading role of cortical neurons in initiating and maintaining a spike and wave burst; (ii) the involvement of a corticothalamocortical circuit in timing the bursts, and (iii) an accessory reticulothalamic loop also involved in regulating the intraburst frequency of the spike and wave complex.     

Propagation of focal cortical epileptiform discharge to the basal ganglia

Single-unit activity was recorded in the caudate and entopeduncular nuclei of cats during penicillin-induced epileptiform discharge from the pericruciate cortex. More than 80% of responsive caudate neurons fired a burst of action potentials after the cortical interictal spikes. An even higher percentage (95%) burst during the clonic phase of electrocorticographic seizures. In the entopeduncular nucleus, approximately 45% of the cells increased their firing rate or burst with the interictal spike and 33% decreased their firing rate after the interictal spike. These results are consistent with the notion that the basal ganglia may act as an important pathway for the spread and generalization of focal epileptic discharge.     

Potentiation and modification of recruiting responses precedes the appearance of spike and wave discharges in feline generalized penicillin epilepsy

Recruiting responses (RR) were evoked by stimulation of nucleus centralis medialis in awake and painlessly immobilized cats. Following the administration of sodium penicillin G (350,000 IU/kg i.m.) and at a time preceding the development of generalized spike-and-wave discharge we observed a strong potentiation of RR in 10 out of 15 experiments (50-200% increase in amplitude). The major feature of wave form modification consisted mainly of a development or increase of positive phases of individual recruiting waves. In between such large amplitude negative-positive recruiting waves a slow negative wave developed. One of every two recruiting waves was often diminished when the preceding recruiting wave had reached considerable amplitude. The changes in the RR were antagonized by barbiturates and by caffeine. In conjunction with previous evidence these results support the hypothesis that spikes of spike-and-wave discharges in FGPE are generated by similar thalamocortical volleys as those creating RR and spindles. They further suggest that the crucial neuronal mechanism underlying this effect of penicillin is a shift in the emphasis from distal apical dendritic thalamocortical synapses on cortical pyramidal neurons to more proximal ones.     

Effects of post-ictal depression on experimental spike and wave discharges

The effects of post-ictal depression on spike and wave (SW) discharges of feline generalized penicillin epilepsy (FGPE) were studied. After tonic-clonic seizures which are not uncommon in FGPE spindle bursts appeared during the post-ictal period. Upon recovery spontaneous and thalamically evoked SW discharges reappeared. Spindles before penicillin and during post-ictal depression showed a similar intraburst frequency (twice that of SW discharges) in the same animal. These findings add further evidence to the notion that any depression of cortical excitability in FGPE leads to replacement of SW by spindles and thus supports the hypothesis that SW discharges occur in hyperexcitable cortex in response to normally spindle-inducing thalamocortical volleys.     

Sleep spindles in humans: insights from intracranial EEG and unit recordings

Sleep spindles are an electroencephalographic (EEG) hallmark of non-rapid eye movement (NREM) sleep and are believed to mediate many sleep-related functions, from memory consolidation to cortical development. Spindles differ in location, frequency, and association with slow waves, but whether this heterogeneity may reflect different physiological processes and potentially serve different functional roles remains unclear. Here we used a unique opportunity to record intracranial depth EEG and single-unit activity in multiple brain regions of neurosurgical patients to better characterize spindle activity in human sleep. We find that spindles occur across multiple neocortical regions, and less frequently also in the parahippocampal gyrus and hippocampus. Most spindles are spatially restricted to specific brain regions. In addition, spindle frequency is topographically organized with a sharp transition around the supplementary motor area between fast (13-15 Hz) centroparietal spindles often occurring with slow-wave up-states, and slow (9-12 Hz) frontal spindles occurring 200 ms later on average. Spindle variability across regions may reflect the underlying thalamocortical projections. We also find that during individual spindles, frequency decreases within and between regions. In addition, deeper NREM sleep is associated with a reduction in spindle occurrence and spindle frequency. Frequency changes between regions, during individual spindles, and across sleep may reflect the same phenomenon, the underlying level of thalamocortical hyperpolarization. Finally, during spindles neuronal firing rates are not consistently modulated, although some neurons exhibit phase-locked discharges. Overall, anatomical considerations can account well for regional spindle characteristics, while variable hyperpolarization levels can explain differences in spindle frequency.     

Firing pattern of neurons in the rostral and ventral part of nucleus reticularis thalami during EEG spindles

The firing pattern of neurons in the rostral and ventral part of nucleus reticularis thalami during cortical EEG spindles was investigated in unanesthetized encéphale isolé cats. Spontaneous spindles as well as those induced by a single thalamic shock were accompanied by an increase in discharge frequency in 97% of the neurons in the rostral pole of the nucleus. In most cases the enhanced firing rate was tonically sustained throughout the duration of the spindles, although phasic bursts at EEG wave frequency were sometimes superimposed on the tonic cellular activation. Suppression of triggered spindles by conditioning fast-frequency stimulation in the mesencephalic reticular formation also abolished the rostral reticularis response. Intracellular recordings revealed a depolarizing shift of small amplitude which was sustained throughout the duration of triggered spindies. The majority of neurons in the ventral part of nucleus reticularis, in contrast, underwent a prolonged hyperpolarizing shift in membrane potential during cortical spindles, sustained for as long as 2 sec and interrupted by depolarizing waves. Both the prolonged membrane hyperpolarization and the depolarizing waves were reduced during the intracellular passage of polarizing currents, suggesting that the former was an inhibitory postsynaptic potential and the latter were disinhibitory potentials. Since neurons in dorsal thalamic nuclei, to which the reticularis axons project, are hyperpolarized concomitantly with cortical spindles, the results are viewed as being in agreement with the hypothesis that, during EEG spindles, neurons in the rostral pole but not in the ventral part of nucleus reticularis exert a tonic inhibitory influence on cells throughout the thalamus.     

Ethosuximide alters intrathalamic and thalamocortical synchronizing mechanisms: a possible explanation of its antiabsence effect

Effects of systemic administration of a single dose (50 mg/kg) of ethosuximide (ESM) on extracellularly recorded thalamic (nucleus centralis lateralis, CL; nucleus reticularis, RE) and cortical neurons and on cortical EEG activity of acute cats, have been studied. In intact animals ESM led to: (a) desynchronization of cortical EEG activity; (b) reduction of cortical recruiting responses to 6 Hz stimulation of nucleus centralis medialis (CeM); (c) increased firing rate of CL units; and (d) reduction of incremental responses (IRs) of CL neurons to CeM stimulation. In midbrain reticular formation (MRF)-lesioned animals, ESM induced: (a) reduction of cortical spindle waves; (b) increment of their intraburst frequency; (c) reduction of the IR of CL neurons to 3 and 6 Hz CeM stimulation; (d) shortening of the inhibitory period following each response; and (e) no increment of spontaneous firing rate of CL units. Moreover, ESM led to important changes in the spontaneous activity of RE neurons: spike barrages, typical of these neurons in MRF-lesioned animals, became less frequent and of longer duration, being also constituted by longer interspike intervals. However, responses of RE neurons to low frequency CeM stimulation, when present, did not show any incremental phenomenon and appeared unchanged after ESM. Responses of cortical neurons to paired stimuli, applied with different interstimulus intervals, to nucleus ventralis posterolateralis or in animals with isolated cortex, to subcortical white matter, disclosed a reduction of the cortical inhibitory period following the response to the conditioning stimulus. These data suggest that ESM exerts a moderate diffuse anti-inhibitory action at both cortical and thalamic levels and an activating effect on MRF, which could also be accomplished through disinhibition. The reduction of the inhibitory phases in thalamic nuclei would alter spontaneous intrathalamic synchronizing mechanisms, leading to a decreased effectiveness of thalamocortical volleys, which are believed to be fundamental for the appearance of cortical spike and wave discharges. This hypothesis would therefore explain the specific efficacy of ESM against absence seizures.     

Study of spindle-spike interactions: features of basal ganglia control

Changes in cortical spindle distribution following penicillin (PCN) injections were studied in feline generalized PCN epilepsy. PCN activation caused no substantial changes in spindle duration, frequency and intraburst frequency, while significant reductions in the amplitude of the negative waves were noted. At the same time combinations of spindle waves and epileptic complexes were recorded with one or more spikes randomly occurring at the beginning, in the middle, or at the end of a spindle envelope. Low frequency stimulation of the caudate nucleus induced a certain degree of enhancement in cortical precruciate spike frequency while high frequency activation of the entopeduncular nucleus caused significant inhibition of cortical spike frequency. The results are discussed in the light of the reciprocal interrelationship between spindles and spikes. Furthermore, the role played by the caudate and the entopeduncular nucleus in the control of the cortico-thalamo-cortical circuit is also emphasized.     

Cortical and thalamic cellular correlates of electroencephalographic burst-suppression

This experimental study on anesthetized cats used intracellular recordings of cortical, thalamocortical and reticular thalamic neurons (n = 54), as well as multi-site extracellular recordings (n = 36), to investigate the cellular cf EEG burst-suppression patterns, defined as alternating wave bursts and periods of electrical silence. Burst-suppression was elicited by the administration of the same or other anesthetic agents upon the background of an already synchronized EEG activity.About 95% of cortical cells entered burst-suppression, in close time-relation with EEG activity, displaying sequences of phasic depolarizing events associated with bursts of EEG waves and an electrical silence of the neuronal membrane during flat EEG epochs. The membrane potential (V_m) hyperpolarized by ≈ 10 mV prior to any EEG change and the slow rhythms reflecting deep stages of anesthesia progressively disorganized with transition to burst-suppression. During flat EEG epochs, the apparent input resistance (tested through short hyperpolarizing current pulses) decreased (range 12–60%) and neuronal responsiveness to orthodromic volleys (tested by thalamic and cortical evoked excitatory postsynaptic potentials) was dramatically reduced. It is proposed that the decreased input resistance is mainly due to an increase in K⁺ conductances.At variance with cortical neurons, only 60–70% of thalamic cells ceased firing before overt EEG burst-suppression and were completely silent during flat periods of EEG activity. The remaining 30–40% of thalamic cells discharged rhythmic (1–4 Hz) spike bursts during periods of EEG silence. This rhythm, within the frequency range of delta waves, is generated in thalamic cells by the interplay between two of their intrinsic currents at critical levels of V_m hyperpolarization. However, with the deepening of burst-suppression, when silent EEG periods became longer than 30 sec, thalamic cells also ceased firing.The assumption that full-blown burst-suppression is achieved through virtually complete disconnection in brain circuits implicated in the genesis of the EEG is corroborated by the revival of normal cellular and EEG activities after volleys setting into action thalamic and cortical networks.     

Neuronal sensitivity to GABA and glutamate in generalized epilepsy with spike and wave discharges

In awake but painlessly immobilized cats the extracellular activity of the same cortical neurons was recorded before and for 2 to 5 h after the injection of penicillin G (350,000 IU/kg, i.m.) during the development of generalized epilepsy with bilaterally synchronous spike and wave discharges. Possible changes in their sensitivity to microiontophoretically applied glutamate and GABA during this period were searched for using computer-generated periejection histograms at intervals of about 30 min. In contrast to reported studies in other models of epilepsy, glutamate excited and GABA depressed virtually all neurons tested during fully developed spike and wave epilepsy. Spike height was not apparently affected either by the amino acids or by the development of epilepsy. Comparison of relative thresholds for the above effects on rhythmical neuronal activity associated with spike and wave discharge versus effects on random neuronal activity during the interburst periods, supported the idea that spikes and waves result from strong excitatory and inhibitory synaptic drives of the neurons. In all neurons until the appearance of spike and wave discharges, changes in the effect of amino acids, if observed, were small and statistically nonsignificant. This suggests that the hyperexcitability of cortical neurons which reportedly leads to the appearance of spike and wave discharges depends on mechanisms other than an increase in sensitivity to glutamate or a desensitization to GABA. Sometimes the sensitivity to GABA decreased later in this experimental model when the very frequent appearance of spike and wave discharges eventually led to EEG tonic-clonic seizures.     

Intracellular recordings in pericruciate neurons during spike and wave discharges of feline generalized penicillin epilepsy

Concurrent EEG and intracellular recordings from pericruciate neurons of cats obtained before and after i.m. injection of penicillin inducing the syndrome of feline generalized penicillin epilepsy (FGPE) characterized by spike and wave (SW) discharge in the EEG, display large excitatory postsynaptic potentials (EPSPs) at the time of the EEG 'spike' which alternate with hyperpolarizing potentials occurring in coincidence with the EEG 'wave' component of the SW complex. The large EPSPs trigger discharges of single or multiple high-frequency action potentials which do not show a progressive decrement in amplitude nor an appreciable increase in duration. These bursts thus differ in some respects from typical paroxysmal depolarization shifts. The hyperpolarizing potentials show an early phase which is reversed by intracellular Cl- injection or diffusion and thus behaves like a classical inhibitory postsynaptic potential (IPSP). The late phase is unaffected by Cl-. Hyperpolarizing potentials of pericruciate neurons induced by antidromic activation of the cerebral peduncle (CP) or by direct cortical stimulation are not altered after i.m. injections of penicillin at doses sufficient to induce generalized SW discharge. The early phase of hyperpolarization both before and after i.m. penicillin is reversed by intracellular Cl- injection or diffusion, the late phase remains unchanged. The early phase thus represents a classical IPSP, which does not appear to be affected by the low brain penicillin concentrations sufficient to induce generalized SW discharge. It is concluded that this form of epileptic discharge cannot be attributed to blockage of phasic (presumably somatic) postsynaptic inhibition by penicillin. These results indicate that to regard all forms of epileptic discharge as the consequence of a blockage of gamma-aminobutyric acid-mediated phasic postsynaptic inhibition acting on the soma represents an unduly restrictive view of epileptogenesis.