274

Electroencephalography and Clinical Neurophysiology, 1979, 46:274--289

© Elsevier/North-Holland Scientific Publishers, Ltd.

EFFECTS OF CHANGES IN CORTICAL EXCITABILITY UPON THE EPILEPTIC BURSTS IN GENERALIZED PENICILLIN EPILEPSY OF THE CAT 1,2 P. GLOOR, A. PELLEGRINI 3 and G.K. KOSTOPOULOS Department of Neurology and Neurosurgery, McGill University, and Montreal Neurological Institute, Montreal, P.Q. H3A 2B4 (Canada) (Accepted for publication: July 3, 1978)

Previous studies (Gloor et al. 1977; Quesney et al. 1977) had suggested that the epileptic bursts in generalized penicillin epilepsy of the cat are closely related to spindles. This conclusion was based on the observation that single shock and low frequency thalamic stimulations which, in a normal cat, trigger spindles or induce recruiting responses are the most p o t e n t stimuli capable of eliciting generalized epileptic bursts in cats having received a large intramuscular dose of penicillin, or in which a weak penicillin solution had been applied diffusely to the cerebral cortex of both hemispheres. The epileptic bursts characteristic of feline generalized penicillin epilepsy may thus represent the response of hyperexcitable cortex to thalamocortical volleys normally evoking spindles. If this hypothesis is correct, it should be possible in this syndrome to convert the epileptic bursts into spindles by decreasing the excitability of the cortex. The present study was undertaken to test this hypothesis.

Methods Acute experiments were carried out in 50 cats. The surgical, anesthetic, analgesic and 1 This work was supported by Research Grant MT3140 of the Medical Research Council of Canada. 2 Address reprint requests to Dr. P. Gloor. 3 Present address: Clinica Neurologica dell'UniversitY, Via Giustiniani 1, 35100 Padua, Italy.

recording procedures are those described previously by Quesney et al. (1977). Generalized penicillin epilepsy was induced by intramuscular injection of 300,000--400,000 IU/kg of Sodium Penicillin G. Methods used to reduce cortical excitability included systemic hypoxia, and the topical application to the cortex of compounds known to exert a depressant effect upon neuronal function, such as KC1 (which induces spreading depression), gamma-aminobutyric acid (GABA), pentobarbital (Nembutal), thiopental sodium (Pentothal), adenosine monophosphate (AMP) and noradrenaline. (For documentation on the neural depressant action of AMP see Phillis and Kostopoulos (1975) and Kostopoulos and Phillis (1977).) Hypoxia was induced by letting the animal breathe a mixture of 2% oxygen in nitrogen or pure nitrogen for a few minutes. The gases were administered through a positive pressure Bird Mark 14 respirator connected to the endotracheal tube used to ventilate the gallamine-paralyzed animals. KC1 in a 15% solution was applied to the cortex either locally with a small, square-shaped (2 m m × 2 mm) filter paper, or more diffusely in small drops from the tip of a hypodermic needle. For topical application to the cortex, 1% and 5% buffered solutions of GABA, and 0.1% and 0.5% buffered solutions of pentobarbital and thiopental sodium were prepared and warmed to 37°C before being applied to the exposed cortex on large pieces of filter paper covering portions of 2--3 gyri. AMP and nor-

CORTICAL EXCITABILITY IN PENICILLIN EPILEPSY adrenaline were applied under one electrode with a small filter paper, 3 mm in diameter, using an unbuffered 0.1 M solution of 5'-adenosine m o n o p h o s p h a t e or an unbuffered 0.5 M solution of noradrenaline.

Results

After i.m. injection of penicillin, generalized bilaterally synchronous bursts of epileptic activity appeared over b o t h hemispheres of the t y p e previously described b y Prince and Farrell (1969), Gloor and Testa (1974) and Quesney et al. (1977). These bursts at times exhibited a fairly typical 3--5 c/sec spike and wave pattern; at others t h e y consisted of 3--7 c/sec bursts of high voltage diphasic or triphasic sharp waves or spikes alternating with small surface negative or positive slow waves. These slow waves were sometimes absent and replaced by a flat stretch of EEG record between spikes having the duration of the missing slow waves (Fig. 8C, L ASS).

(I) Hypoxia H y p o x i a was induced in 11 cats. The changes induced by h y p o x i a in cats before t h e y were given penicillin were the same as those reported b y Sugar and Gerard (1938) and by Naquet and Fernandez-Guardiola (1960, 1961}. They are shown in Fig. 1. The EEG during the hypoxic period was characterized b y an initial desynchronization of the background activity which lasted for 2--3 min. This was followed b y a sudden appearance of slow waves in the delta frequency band upon which low voltage spindles were sometimes superimposed. After a few seconds, the record became fiat, b u t was interrupted b y high voltage spindles consisting of negative waves which occurred, often asynchronously, over the t w o hemispheres (Fig. 1B). When the animal was allowed to breathe normal air again, slow waves reappeared during the early recovery phase. In some animals these were associated with an intense r e b o u n d of

275 high voltage spindle activity superimposed u p o n the slow waves lasting a few seconds, after which the normal background activity reappeared (Fig. 1C). When the same experiment was repeated during generalized penicillin epilepsy (Fig. 2), the initial desynchronization of the EEG was not always present, b u t when it was, the epileptic bursts disappeared for its duration. During the slow wave phase of hypoxia, instead of the low voltage spindles seen at this stage in normal animals, epileptic bursts reappeared which sometimes had a more typical spike and wave morphology than the initial ones (Fig. 2B). However, when the EEG became flat, the epileptic bursts were replaced by spindles which looked identical to those seen in normal animals during this phase of hypoxia as is shown in Figs. 2C, D and 3. In 2 cats, immediately after they were allowed to breathe normal air again, there was a r e b o u n d of epileptic bursts at the time when spindle rebound had occurred in b o t h of these animals before they had received penicillin (Fig. 3C, compare with Fig. 1 taken from the same cat). During this rebound the epileptic bursts tended to assume a more typical spike and wave form than before hypoxia. Most of the cats, however, showed a depression of epileptic activity after the hypoxic period which could last for several minutes, even though the background activity had already returned to normal. When the epileptic activity reappeared, it often assumed a multiple spike pattern of the t y p e seen in generalized tonic-clonic convulsions.

(II) Topical cortical application of neural depressants It is evident that even if hypoxia reduces cortical excitability, it is difficult to determine when and to what extent subcortical structures are also affected. In order to induce a more selective depression of cortical excitability, c o m p o u n d s k n o w n to be neural depressants were applied directly and locally to the cerebral cortex. KCl-induced spreading depression. In 18

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animals, a 15% KC1 solution was topically applied to a small area of the cortex (4 mm 2, at a distance of a b o u t 3--4 mm from the closest recording electrode}. In 3 other animals a mild mechanical injury to the brain was produced b y inserting a 22-gauge needle into the cortex during generalized penicillin epilepsy. We had accidentally observed that spreading depression could be elicited in this manner, probably in response to deformation of the cortex as reported by Kub~t (1977}. In most anh=nals both methods induced a marked voltage depression of the cortical background activity on the side o f KC1 application or mechanical injury. The voltage of the epileptic bursts was first also reduced; they then disappeared completely and were replaced b y small spindles (Fig. 4) consisting predominantly of negative waves (Fig. 5). The

spindles were most evident during recovery from spreading depression. The spindles did n o t occur synchronously with the epileptic bursts remaining on the intact side. The epileptic activity of the hemisphere contralateral to the KC1 application remained unaffected, except for an inconstant, transient decrease in the amplitude and number of epileptic bursts early during the course of spreading depression (Fig. 4B and C). Subsequent application of KC1 to the second hemisphere led to total elimination of the epileptic bursts and to their replacement b y spindles occurring asynchronously in the two hemispheres (Fig. 4D). During recovery from spreading depression the spindles increased in amplitude as the voltage of the background activity increased. Then, after an interval varying from a few minutes to more than an hour, the epileptic

Fig. 1. EEG changes induced in a normal cat with'hypoxia. A: before hypoxia, animal awake. B: 3 min after beginning of hypoxia: flat EEG with superimposed spindles. C: 30 sec after breathing normal air again: spindle rebound. Abbreviations in this and the following figures are as follows: ASS, anterior suprasylvian gyrus; MES, middle ectosylvian gyrus; ML, mid portion of lateral gyrus; MSS, middle suprasylvian gyms; PS, posterior sigmoid gyrus; PSS, posterior suprasylvian gyrus; OCC REF, occipital reference; R, right; L, left; (A), anterior; (P), posterior.

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Fig. 4. Effects o f KCl-induced spreading depression on epileptic bursts. A : c o n t r o l recording in a cat with generalized penicillin epilepsy ( 3 8 0 , 0 0 0 I U / k g o f penicillin i . m . ) s h o w i n g epileptic bursts. B: 2 rain after applicat i o n o f 15% KCI to small area of c o r t e x in the right lateral gyrus. Flat E E G with superimposed spindles. S o m e depression o f activity is also seen in the contralateral hemisphere. C: 8 rain later. Spreading depression begins to recover. T h e r e are spindles on the side o f the recovering spreading depression and typical epileptic bursts on the contralateral side. T h e t w o o c c u r asynchronously. D: 16 rain later. 15% KCI has n o w also been applied to a small area o f c o r t e x o f the left h e m i s p h e r e 6 rain prior to thi~ recording. Bilateral spreading depression which, on the right, is in the progress o f recovery. A s y n c h r o n o u s spindles on b o t h sides.

activity returned at a time when the background activity had fully recovered. In some experiments, a clear transition phase b e t w e e n pure spindle activity and epileptic bursts was seen, individual bursts exhibiting a combination of spindle waves and epileptic complexes (Fig. 5). Usually such a burst started o u t with epileptic complexes and ended with a sequence of spindle waves. When epileptic activity had fully recovered, spindles were no longer present. In 6 animals, spreading depression was n o t associated with the appearance of spindle bursts, b u t in these cats the epileptic activity recovered quickly and, in some, epileptic bursts never disappeared completely. In 4 animals, 15% KC1 was applied diffusely

to the cortex of one hemisphere. In these experiments, a very marked depression of electrical activity appeared in a widespread manner over the cortex treated with KC1. The epileptic bursts disappeared completely for a variable time, b u t no spindles were seen. As the epileptic activity began to recover, the epileptic bursts on the side of the KC1 application differed from those seen before KC1 had been applied (Fig. 6) and resembled those seen after topical barbiturate, GABA, AMP or noradrenaline application (see below). However, the negative waves had a much lower amplitude than those obtained with the topical application of these compounds.

Topical application of barbiturates, GABA, AMP and noradrenaline. Barbiturates were

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Fig. 5. Changes in the morphology of bursts during recovery from KCl-induced spreading depression in a cat with generalized penicillin epilepsy (350,000 IU/kg of penicillin i.m.). Typical epileptic bursts before KCl-induced spreading depression are replaced by spindles during spreading depression (7 rain after KCI). This is followed by transitional forms between spindles and epileptic bursts, the epileptic morphology becoming more prominent as time progresses (9, 17 and 21 min after KC1).

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