Feline Generalized Penicillin Epilepsy Research Articles

Corticothalamic 5-9 Hz oscillations are more pro-epileptogenic than sleep spindles in rats.

Absence-related spike-and-wave discharges (SWDs) occur in the thalamocortical system during quiet wakefulness or drowsiness. In feline generalized penicillin epilepsy, SWDs develop from sleep spindles. In contrast, in genetic absence epilepsy rats from Strasbourg (GAERS), SWDs develop from wake-related 5-9 Hz oscillations, which are distinct from spindle oscillations (7-15 Hz). Since these two oscillation types share common frequency bands and may contribute to SWD genesis, it is important to compare their thalamic cellular mechanisms. Under neuroleptic analgesia, in GAERS and control non-epileptic rats barbiturates abolished both SWDs and 5-9 Hz oscillations but increased the incidence of spindle-like oscillations. Within the thalamocortical circuit 5-9 Hz oscillations occurred more coherently than spindle-like oscillations. Intracellular events associated with 5-9 Hz and spindle-like oscillations were distinctively different in both thalamic relay and reticular neurons. In both cell types, SWDs and 5-9 Hz oscillations emerged from a significantly more depolarized membrane potential than spindle-like oscillations. In relay neurons, 5-9 Hz oscillations were mainly characterized by a rhythmic depolarization, which occurred during a tonic hyperpolarization and which could trigger an apparent low-threshold Ca2+ potential, whereas spindle-like oscillations were characterized by a rhythmic hyperpolarization. In reticular cells, SWDs and 5-9 Hz oscillations occurred during a tonic hyperpolarization, whereas spindle-like oscillations occurred during a long-lasting depolarizing envelope. The difference in the intracellular events between 5-9 Hz and spindle-like oscillations and similarities between 5-9 Hz oscillations and SWDs indicate that in GAERS, 5-9 Hz oscillations are more pro-epileptogenic than spindle-like oscillations. In conclusion, the present study strongly supports the hypothesis that SWDs in GAERS are generated by a wake-related corticothalamic resonance, and not by sleep-related, hypersynchronous, spindle-like activity originating in the thalamus.

Spike-and-wave discharges of absence seizures as a transformation of sleep spindles: the continuing development of a hypothesis

Objectives: This review aims to offer a critical account of recent scientific developments relevant to the hypothesis which Pierre Gloor proposed in the 1970s for the generation of spike and wave discharges (SWDs) of primary generalized absence seizures. Results: According to this hypothesis SWDs develop in the same circuits, which normally generate sleep spindles, by an initially cortical transformation of one every two or more spindle waves to a ‘spike’ component of SWDs, while the next one or more spindle waves are eliminated and replaced by a slow negative wave. This hypothesis was based on experiments in feline generalized penicillin epilepsy showing the possibility of transition from spindles to SWDs, when cortical neurons become hyper-responsive to thalamocortical volleys, which normally induce spindles, and thus engage feedback cortical inhibition, rebound excitation, recurrent intracortical dissemination of excitation during the ‘spike’ and strong excitation of thalamus for further augmentation of a brain wide synchronous oscillation. In the 1980s, electrophysiological studies in vitro and in vivo revealed the basic features of spindle rhythm generation by neurons in nucleus reticularis thalami and thalamocortical-corticothalamic oscillatory reverberations. Conclusions: In the light of this knowledge, experimental studies in several genetic and pharmacological animal models of absence seizures, clinical observations and theoretical studies in computer models have considered, tested, modified and challenged this hypothesis. It may still be found useful in the era of dynamic digital EEG analysis of SWDs and its current sources.

Feline generalized penicillin epilepsy.

Feline generalized penicillin epilepsy represents an experimental model of generalized spike-and-wave discharges occurring during clinical absence attacks. Spike-and-wave discharges of feline generalized penicillin epilepsy also have a pharmacological profile that is similar to that encountered in human absence attacks. Studies on the respective roles played by the thalamus and cortex in the generation of spike-and-wave discharges indicate that both structures are important in the elaboration of such generalized activity. Moreover, GABAA-mediated, intracortical inhibitory mechanisms are preserved and eventually enhanced at a time when generalized spike-and-wave discharges of feline generalized penicillin epilepsy are recorded. A preservation of GABA-mediated mechanisms in pure absence epilepsy might explain the differences in prognostic outlook that characterizes this type of epilepsy from seizures in which GABAergic mechanisms break down (e.g., generalized convulsive and partial epileptic attacks).

Effects of cortical stimulation on epileptic activity in feline generalized penicillin epilepsy

We analyzed peri-ictal electrocorticography below 70 Hz by a semiautomatic quantitative method. Thirty-four patients with medically intractable temporal lobe epilepsy underwent chronic electrocorticography using subdural electrodes. The resection extent of cortices with maximum amplitude activities were compared between seizure outcome groups. In detected activity significantly related to seizure outcome, we analyzed waveforms with automated waveform amplitude analysis. Mann–Whitney U tests were used. Mean follow-up duration was 49.7 ± 18.2 months. The resection extents of maximum amplitude activities in theta bands during the period between −10 and −5 s from the ictal onset were significantly different between seizure outcome groups (adjusted p = 0.01, the Benjamini–Hochberg correction). Delta, alpha and beta bands were related to seizure outcome only without multiple comparison corrections (unadjusted p = 0.02, 0.03 and 0.04). Waveform peak amplitudes greater than 200 μV tended to be more common in the seizure free group than in the non-seizure-free group (unadjusted p = 0.06). Waveform peak amplitudes greater than 350 μV were significantly more common in the cortical dysplasia type I group than in the hippocampal sclerosis group (unadjusted p = 0.03). The resection of theta band activities during the preictal period was most important for good seizure outcome in temporal lobe epilepsy.

Unilateral topical cortical application of penicillin: electrographic aspects. A new complement to an old model.

In 7 cats 800 IU of penicillin were applied diffusely over one hemisphere on the exposed neocortex. After 40 min all animals showed bilateral and synchronous burst discharges with a higher amplitude at the hemisphere where the penicillin had been applied. These data fill a gap in the literature concerning feline generalized penicillin epilepsy, in which penicillin is applied bilaterally on the exposed neocortex.

Inhibitory control by substantia nigra of generalized epilepsy in the cat

Previous investigations have shown that the basal ganglia may exert a regulating influence on cortical epilepsy. Stimulation of the caudate nucleus enhances cortical penicillin (PCN) spikes. Stimulation of globus pallidus internus reduces cortical spike frequency. Since the substantia nigra pars reticulata (SNpr) seems to have an inhibitory action on the ventro-anterior (VA) and ventro-lateral (VL) thalamic nuclei and thalamic neurones send an excitatory influence to the cortex, we undertook an investigation to study nigral influence on cortical epilepsy induced by PCN. Experiments were conducted on encéphale isolé cats in which steady interictal activity was induced by means of parenteral PCN administration (feline generalized PCN epilepsy). Variations occurring in cortical PCN spikes following activation of either pars compacta (SNpc) or SNpr were analyzed. Electrical stimulation of SNpc reduced spike frequency and amplitude in 19% of the total number of stimulations; SNpr stimulation significantly inhibited cortical spikes, especially in the precruciate gyrus, in 80% of cases. The experimental findings constitute an electrophysiological feature of the control exerted by SNpr on the thalamo-cortical re-exciting loop. A putative preferential role of SNpr in the regulation of abnormal phenomena involving the neocortex is emphasized.

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.

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 theEEG ‘spike’ which alternate with hyperpolarizing potentials occuring 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 penduncle (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 blockade of γ-aminobutyric acid-mediated phasic postsynaptic inhibition acting on the soma represents an unduly restrictive view of epileptogenesis.

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. More-over, the inhibitory phase of the spike and wave complex is soon disrupted whenever a consistent sensory stimulus arrives at the cortex.

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.

Intracortical inhibitory mechanisms are preserved in feline generalized penicillin epilepsy

Intracortical inhibition elicited by direct cortical stimulation or by stimulation of the cerebral peduncle, the latter inducing recurrent inhibition of cortical neurons, is not significantly affected by intramuscular injection of penicillin sufficient for inducing the syndrome of feline generalized penicillin epilepsy characterized by generalized spike and wave (SW) discharges in the EEG. This raises to four the number of paradigms of presumably postsynaptic inhibition resistant to penicillin concentrations sufficient to produce generalized SW discharges, a form of epileptic discharge which thus cannot be attributed to blockage of the forms of intracortical postsynaptic inhibition so far tested.

Differential participation of some ‘specific’ and ‘non-specific’ thalamic nuclei in generalized spike and wave discharges of feline generalized penicillin epilepsy

Extracellular single unit and electroencephalographic (EEG) activity during generalized spike and wave discharges (SW) induced by i.m. penicillin was recorded simultaneously in the cortex, in a ‘specific’ thalamic nucleus (n. lateralis posterior, LP) and in some ‘non-specific’ thalamic nuclei (n. centralis medialis, NCM; n. centrum medianum, CM; n. centralis lateralis, CL) Computer-generated EEG averages and histograms of single unit activity were triggered by either peaks of EEG transients or action potentials. The time at which cortical neurons (66/66) were most likely to fire was during the ‘spike’ of the SW complex while absence of firing was the rule during the ‘wave’. Most LP neurons (23/26) showed a similar pattern, 3 cells firing preferentially during the ‘wave’. In NCM only 17 of 39 neurons fired during the ‘spike’, 8 of 39 neurons during the ‘wave’ while the others showed no change in their firing pattern during SWs. Twenty-six of 30 CM and 20 of 24 CL neurons fired during the ‘spike’ of SW; the other cells in these nuclei did not change their firing pattern during SWs. When present, rhythmic fluctuations in firing linked to SW discharge were less prominent in these ‘non-specific’ thalamic nuclei than in cortex and LP. Furthermore, participation of NCM, CM and CL neurons in the SW rhythm occurred only after neurons in cortex and LP had become involved in it. Thus, as is the case for cortical neurons, the main firing pattern of thalamic cells during SWs consists of an oscillation between ‘excitation’ during the ‘spike’ and ‘inhibition’ during the ‘wave’ of the SW complex. However, the coupling between cortical and thalamic neuronal firing is less intimate for cells of the ‘non-specific’ thalamic nuclei than for a ‘specific’ nucleus such as LP. Thus, at least some ‘specific’ thalamic nuclei are more intimately involved in the mechanism of SW discharge than the midline intralaminar nuclei.

Behavioral alterations associated with generalized spike and wave discharges in the EEG of the cat

Instrumental conditioning procedures demonstrated that in feline generalized penicillin epilepsy (FGPE) the cat's ability to respond to sensory (visual or auditory) stimuli was selectively impaired during penicillin-induced generalized spike and wave (SW) discharge. Responsiveness between SW bursts remained unimpaired. Most often the performance deficit consisted of a total absence of a learned response to stimuli presented during SW bursts or, if such a response occurred, reaction times were on the average significantly longer than to stimuli presented between SW bursts. Stimuli falling in the middle of a SW burst were associated with the highest likelihood of response failure. Spontaneous motor performance which was not contingent on any stimulus was also impaired during SW discharge. Response failure during SW bursts is either attributable to a cognitive defect or to motor impairment associated with temporary amnesia. Impairment of motor performance unassociated with amnesia or a cognitive defect was sometimes present during SW discharge, as evidenced by failure to carry out a motor response or to complete it until the SW burst was over. These deficits are similar to those seen in human absence attacks associated with generalized SW discharge. These observations thus support the validity of FGPE as an acceptable model of human primary generalized epilepsy.

Enhanced response of cortical neurons to thalamic stimuli precedes the appearance of spike and wave discharges in feline generalized penicillin epilepsy

Peristimulus time histograms of extracellularly recorded action potential discharges of cortical neurons in response to single shock and/or repetitive stimulation of 'specific' and 'non-specific' nuclei of the thalamus were studied after i.m. penicillin injection during a period corresponding to that of the development of spike and wave (SW) discharges of feline generalized penicillin epilepsy (FGPE). After i.m. penicillin cortical neurons displayed an enhancement of both the excitatory and 'inhibitory' phases of their responses to single shock stimulation of n. centralis medialis (NCM). This increase was even more pronounced for responses induced by repetitive stimulation of NCM at the frequencies inducing typical recruiting responses. These changes always preceded the appearance of SW discharges. Changes of the responses of cortical neurons to single shock and repetitive stimulation of 'specific' thalamic nuclei after penicillin were weak and inconsistent, although when observed were characterized by an enhancement of both excitatory and 'inhibitory' phases. The latter appeared not to decrease after i.m. penicillin. These data suggest that the appearance of SW discharges of FGPE is closely related to an increased responsiveness of cortical neurons to thalamocortical volleys arising from the so-called 'non-specific' nuclei. This facilitation of the recruiting process is accompanied by an increase of both excitatory and 'inhibitory' phases of the cortical neuronal responses induced by the volleys.

An analysis of penicillin-induced generalized spike and wave discharges using simultaneous recordings of cortical and thalamic single neurons.

To study the relationship between cortical and thalamic single-neuron activity during spike and wave (SW) discharge of feline generalized penicillin epilepsy (FGPE), extracellular single-unit and local electroencephalogram (EEG) activity were recorded simultaneously from pairs of neurons, one located in the cortex of the middle suprasylvian gyrus (MSS), the other in the dorsal thalamic nuclei (n. lateralis posterior or pulvinar). These two areas are anatomically and functionally closely interrelated. Computer-generated EEG averages and histograms of single-unit activity triggered by either peaks of cortical or thalamic EEG transients or by cortical or thalamic action potentials (aps) showed that cortical neurons in the MSS fired at the time of the spike of the SW complex, while at the time of the wave they became silent. Two populations of thalamic neurons also fired maximally during the spike of SW discharge, but they differed in the precise timing of their firing in relation to that of the simultaneously recorded cortical neuron. The first group of thalamic neurons tended to fire 5-45 ms before the cortical neuron. Of these 28 neurons, 9 were antidromically and 2 orthodromically activated by cortical stimulation. The neurons of the second group tended to fire 0-45 ms after the cortical neuron. Cortical stimulation activated 15 of these 19 neurons orthodromically and 2 antidromically. A third and smaller population of thalamic neurons (n = 8) increased its firing probability during the wave of the SW complex and decreased it during the spike. In 74% of the pairs of neurons the cyclic alternation of excitation and "inhibition" associated with SW activity appeared in the cortex by 1-3 cycles earlier than in the thalamus. This was most common when the thalamic neuron of the pair reached its peak firing probability before the simultaneously recorded cortical neuron. In 11 pairs of neurons the same rhythmic alternation of excitation and "inhibition" of neuronal firing was seen in both the cortex and thalamus during SW discharges evoked by single-shock stimulation of nucleus centralis medialis. These data demonstrate that both cortical and thalamic neurons participate in the SW firing pattern of FGPE by undergoing periods of mutually phase-locked cyclic alternations of excitation and "inhibition" at the frequency of the EEG SW rhythm. Although the initial steps leading to generalized SW discharge in FGPE take place in the cortex, the thalamus soon becomes entrained in the SW rhythm.(ABSTRACT TRUNCATED AT 400 WORDS)

Participation of cortical recurrent inhibition in the genesis of spike and wave discharges in feline generalized penicillin epilepsy

Cortical recurrent inhibition (RI) evoked in pericruciate cortex by antidronic stimulation of the cerebral peduncle (CP) was studied in normal cats and in cats exhibiting the signs of feline generalized penicillin epilepsy (FGPE) following the i.m. injection of penicillin. Two measures of RI evoked by antidromic CP stimulation were used: (i) the averaged focal potential in the pericruciate gyrus: and (ii) the duration of the suppression or diminution of extracellularly recorded action potential (ap) discharge of antidromically activated pericruciate neurons measured in peristimulus time histograms (PSTHs). After i.m. injection of 350,000 IU/kg of penicillin RI remained preserved as long as only generalized spike and wave (SW) discharges appeared in the EEG, although in 5/17 neurons a modest to moderate reduction in the duratuon of RI occurred once SW discharges had appeared in the EEG. This inconstant reduction was probably not caused by a direct anti-inhibitory action of penicillin, but is a consequence of the increased number of ap discharges curtailing RI. At the small concentrations of penicillin existing in brain in FGPE its anti-inhibitory action evident with larger concentrations cannot be demonstrated. When focal or generalized tonic-clonic (T-C) seizured occurred, RI was reduced in slightly more than half of the instances for a few minutes before the onset of these seizures. This suggests that the transition from SW discharge to T-C seizure may be caused by a breakdown of RI.

Certains aspects de la physiologie et de la pathophysiologie des fuseaux chez le chat

Spindles are a thalamocortical rhythm entirely dependent upon a thalamic mechanism. Generators of cortical spindle waves are the pyramidal neurons of the cortex. A positive statistical relationship exists between postsynaptic excitatory events of these neurons and spindle waves, but there is no significant association with inhibitory postsynaptic events. The excitatory synaptic coupling between thalamocortical fibers and cortical neurons implicated in the genesis of spindles is weak, but increases considerably after i.m. injection of penicillin which induces a transformation of spindles into generalized spike and wave discharges (feline generalized penicillin epilepsy). The bursts of increased discharges of pyramidal neurons after penicillin recruit the recurrent intracortical inhibitory pathway. There results from this an oscillation between phases of increased excitability and phases of diminished excitability which correspond respectively to the spike and to the slow wave component of the spike and wave complex. In its turn the cortex imposes this pattern of discharge upon the thalamus which brings about a close coupling of cortical and thalamic neuronal discharges during spike and wave activity.

Feline generalized penicillin epilepsy: changes of glutamic acid and taurine parallel the progressive increase in excitability of the cortex.

A coinciding temporal sequence of electrophysiological and biochemical correlates of developing generalized penicillin epilepsy in cats may indicate a "cause and effect" relationship between the two phenomena. After intramuscular injection of penicillin, in the pre-epileptic state prior to the onset of spike-and-wave discharge, the cortical content of glutamic acid decreases. This change occurs when an increased amplitude of visual evoked potentials in association cortex heralds the approach of spike-and-wave activity. The decrease of glutamic acid and that of aspartic acid occur in parallel with an almost stoichiometric increase of glutamine, gamma-aminobutyric acid (GABA), or both, while taurine levels in the pre-epileptic state remain near normal. As the pre-epileptic progresses to the epileptic state, characterized by generalized 4-5 cycles/s spike-and-wave discharges, a failure of the glial capture mechanisms for taurine and glutamate appears to occur, since both amino acids are lost from the tissue and glutamine levels fall while GABA levels are maintained or become elevated but increasingly at the expense of aspartic acid. A presumed increase in interstitial glutamic acid concentration possibly in combination with subsequent failure of GABA inhibition appears the most plausible explanation for the increasing hyperexcitability during the development of feline generalized penicillin epilepsy.

Role of the thalamus in generalized penicillin epilepsy: Observations on decorticated cats

Experiments in bilaterally and unilaterally decorticated cats determined whether or not the thalamus plays a primary role in the production of spike and wave (SW) discharge in feline generalized penicillin epilepsy (FGPE). In bilaterally decorticated cats an i.m. dose of penicillin sufficient to induce FGPE in intact cats did not change thalamic spindles appreciably; it failed to induce thalamic SWs or any other form of epileptic activity in the decorticated thalamus. Low-frequency spindles bearing some resemblance to SWs were often seen in the nucleus lateralis posterior (LP) before penicillin administration and showed some slight increase thereafter. This may have some bearing on earlier evidence suggesting that the thalamocortical sector comprising the LP and suprasylvian gyrus plays a leading role in the elaboration of SWs in FGPE. In unilaterally decorticated cats the SW discharges in the intact hemisphere were associated with lower voltage synchronous discharges in the decorticated thalamus which persisted after transection of the massa intermedia or of the mesencephalic reticular formation, but disappeared after section of the anterior commissure. This pathway thus seemed to be responsible for transmitting rhythmic activity at the SW frequency from the intact hemisphere to the decorticated thalamus. These findings support earlier conclusions that the development of generalized SW discharge in FGPE primarily depends on a change in cortical excitability, even though a thalamic trigger is essential. Thalamic SW activity appearing in intact animals after penicillin thus seems to be imposed upon the thalamus by the cortex.

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 discharges 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.