A study of the transition from spindles to spike and wave discharge in feline generalized penicillin...

EXPERIMENTAL NEUROLOGY 73, 55-77 (1981)

A Study of the Transition from Spindles to Spike and Wave Discharge in Feline Generalized Penicillin

Epilepsy: Microphysiological Features

GEORGE KOSTOPOULOS, PIERRE GLOOR, ANDREA PELLEGRINI, AND JEAN GOTMAN’

Montreal Neurological Institute, McGill University, MontGal, Quibec H3A 284, Canada

Received September 8, 1980; revision received November 25. 1980

The microphysiological features underlying the evolution of spike and wave discharge from spindles in feline generalized penicillin epilepsy were investigated using extracellular microelectrode recordings. Action potentials generated by single cortical neurons were related to the EEG features of the transition from spindles to spike and waves using statistical methods of analysis on a computer. The probability of an action potential being discharged by a spindle wave was weak. It progressively increased after penicillin during the transformation of the spindle wave into the spike of the spike and wave complex. As this occurred, periods of decreased firing probability coinciding with the slow wave of the spike and wave complex developed immediately after each period of enhanced firing probability. The spike and wave pattern was thus characterized by a remarkable oscillation between periods of increased excitation of cortical neurons corresponding to the spike, and periods of markedly decreased firing probability corresponding to the wave of the spike and wave complex. This was associated with increased synchronization of discharge of neighboring cortical neurons. We propose that the transformation of spindles to spike and waves is the consequence of a single feature: increased excitability of cortical neurons to spindle-inducing thalamocortical volleys. Under those conditions cortical cells discharge action potentials more consistently with each thalamocortical volley. Because of this the high threshold intracortical recurrent inhibitory pathway is recruited into the discharging process and induces recurrent periods of powerful inhibition of cortical neurons.

Abbreviations: EEG-electroencephalogram; UT-unit-triggered; WT-wave-triggered; IPSP, EPSP-inhibitory, excitatory postsynaptic potential; a.p.-action potential.

’ This work was supported by grant MT-3140 awarded by the Medical Research Council of Canada to Dr. Gloor. Drs. Kostopoulos and Gotman are MRC Scholars. Dr. Pellegrini’s present address is Clinica Neurologica dell’ Universitl, Via Giustiniani 1.35100 Padova, Italy. Technical assistance by Mrs. S. Schiller and Mr. E. Puodziunas is greatly appreciated.

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OOl4-4886/81/070055-23$02.00/O Copyright 0 1981 by Academic Press. Inc. All rights of reproduction in any form reserved.

56 KOSTOPOULOS ET AL.

INTRODUCTION

The preceding paper (2 1) dealt with the electroencephalographic (EEG) features of the transition from spindles to spike and wave discharge in cats which had received a large i.m. injection of penicillin. Two main observations were made in that study: (i) Under the influence of penicillin, the transition from spindles to spike and waves occurs as a continuous process in which the initial change is that the initially monophasic negative spindle waves increase in amplitude and acquire positive phases. The progressive increase of mainly positive phases transforms the spindle waves into the spikes2 of the spike and wave complexes. (ii) This transformation affects every second or, in cats with mesencephalic lesions, every second and third spindle wave, while there is a progressive elimination of the intervening spindle waves which reduces the intraburst frequency to about one-half or one-third of the original spindle frequency. This reduced frequency is that of the fully developed spike and wave rhythm, the slow waves of the spike and wave complex replacing the eliminated spindle wave(s).

In the light of earlier work from this laboratory (17) the hypothesis was proposed that spike and wave discharge evolved from spindles as a result of an increase in the excitability of cortical neurons caused by penicillin. Under these conditions the number of action potential discharges occurring in response to spindle-inducing thalamocortical volleys was thought to increase and to lead to a more effective recruitment of intracortical inhibitory neurons into the discharging process resulting in the generation of powerful widespread cortical inhibitory postsynaptic potentials (IPSPs) capable of suppressing the excitation of cortical neurons during their duration. The oscillation between increased excitation and inhibition of cortical neurons was assumed to be expressed in the surface EEG by the spike and wave rhythm ( 16).

In the experiments reported in this paper we attempted to test some of the postulates of this hypothesis by studying with extracellular microelectrodes the changes the activities of single cortical neurons undergo as spindles are transformed into spike and wave complexes, Preliminary results of these studies were reported in abstract form (20).

METHODS

The experiments were carried out on 43 cats; 14 of these were conducted in the same animals and concurrently with the EEG studies described in the previous paper (21) to which the reader is referred for details on an- esthetic, surgical, and EEG recording techniques.

* In this paper “spike” always refers to the EEG spike of the spike and wave complex and is not to be confused with action potential.

FROM SPINDLES TO SPIKE AND WAVE DISCHARGE 57

For extracellular single-cell recordings tungsten microelectrodes (tip about 1 pm, exposed for 5 pm, resistance 2 5 MQ) were used. The recording arrangement was that described by Ball et al. (2) (Fig. 1): a ring-shaped small plate rested on the cortex to suppress its pulsations without inducing ischemia. This plate contained an annular electrode surrounding its central l-mm-wide opening and served to record the surface EEG. The microelectrode was lowered through the central opening into the cortex from which the intracortical EEG and extracellular unit activity was recorded. According to the criteria of Bishop et al. (4), the recorded extracellular action potentials were generated by neuronal somata. Most of the recordings were from the middle suprasylvian gyrus. The electrophysiologic data recorded with the extracellular microelectrode were filtered with a band- pass of 0.5 to 5 kHz for the analysis of unit activity. The same data as well as the surface EEG were also filtered with a band-pass of 0.1 to 100 Hz. The three sets of data were stored on magnetic tape. In addition the surface EEG from several areas of the cortex was recorded in the manner described in the preceding paper (21) in order to verify that the epileptic discharges were generalized.

Computer Analysis

The two main methods of analysis were those described by Ball et al. (2) with some modifications. After analog to digital conversion, all data were analyzed off-line on a PDP-12 computer. The digitizing frequency varied from 100 to 800 Hz; that most frequently used was 400 Hz.

Before describing the methods of analysis, some terms must be defined: (i) a “session” is a continuous, unbroken period of time (usually 3 min) during which data were collected for a specific computer analysis (EEG average, or unit histogram); (ii) “segment” refers to particular periods of

Intracortical EEG

Neuronal activity

FIG. 1. Diagram of the recording arrangement and typical example of raw data. WD- amplitude window discriminator, A/D-analog to digital conversion of raw data for analysis. (Negativity is up in this and all subsequent figures).


time (several seconds) within a session which were selected for analysis, because the EEG at that time exhibited specific features such as spindles, spike and waves, or interburst activity. Segments were selected for analysis by identifying one of the specific features in the surface EEG. The computer then produced EEG averages or unit histograms for sets of homologous segments within a session; (iii) “epoch” is the time interval in relation to significant events (action potentials or peaks of EEG waves) for which the computer was programmed to produce an EEG average or unit histogram. An epoch usually encompassed 1 s before and 1 s after the significant event.

Unit-Triggered (UT) EEG Averages. This analysis served to demonstrate whether the unit discharge was statistically related to the surface EEG. During a session or segment each action potential triggered the computer to store a 2-s-long epoch of concurrently recorded EEG data, i.e., 1 s before and 1 s after this event. Sometimes the duration of the epoch was only 1 s. Depending on the firing rate of the neuron, EEG averages for as many as 2000 action potentials generated by the same neuron could be computed. The length of the recorded sessions or segments and the neuronal firing rate during these periods were calculated.

Wave-Triggered (WT) Unit Histogram. These were obtained by selecting surface EEG transients of specific morphology, averaging both the surface and intracortical EEGs, and plotting a time histogram of the unit activity associated with a selected wave with time zero at the peak of the wave. This analysis gave a measure of the firing probability of a neuron in relation to specific EEG features. The histogram covered an epoch of 1 to 5 s with the peak of the transient falling at its midpoint. The data were normalized to represent instantaneous firing rate expressed as action potentials per second. The computer also calculated the mean neuronal firing rate for the entire session as well as that for any chosen period of time within the time window of the histogram.

Cross Correlograms. In a few instances in which the discharges of two neurons were recorded simultaneously by the same microelectrode and could be distinguished by their different amplitudes, the cross-correlation function of their firing was computed.

RESULTS

Using these computational methods, the statistical relationship between neurons and spindles as they were progressively transformed into spike and wave discharges were studied in 43 acute experiments. Both spontaneous spindles and spindles evoked by single shocks applied to the midline of the thalamus were studied. The transformation of spindles to spike and wave activity was induced by the i.m. injection of 350,000 IU/kg sodium pen-


icillin G which was administered some time after a base-line recording during the spindle state had been obtained.

Three methods were used to ensure the presence of spindles: in 25 experiments 2 to 3 mg/kg thiopental was injected i.v. 1 h prior to penicillin injection; in 10 experiments a small dose of thiopental (1 mg/kg/h, i.v.) was infused continuously; and in eight a lesion was made in the midbrain reticular formation [for coordinates see preceding paper (21)]. Single shocks to the midline thalamus delivered regularly every 10 s consistently elicited spindle bursts before i.m. penicillin application in the last two groups, but did so less consistently in the first group.

All neurons studied were in the middle suprasylvian gyrus, mostly in its deep layers (mean depth, 1050 pm; range, 100 to 2300 pm). Many of these neurons responded to midline thalamic stimuli at long and variable latencies (30 to 50 ms). These responses were either enhanced by or appeared only with low-frequency (5 to 10 cycles per second) thalamic stimulations which elicited recruiting responses.

Visual inspection of the raw EEG and unit data did not reveal a clear relationship between the two phenomena. Units tended to fire more frequently during spindles or spike and wave bursts than between such bursts, but this was not always evident (Fig. 1). Some clustering of unit firing in relation to the spike and wave discharges was often noted.

The relationship between the EEG and the unit discharges was, however, very clearly revealed by computing UT EEG averages and WT unit histograms. This report is primarily based on the study of 23 of 134 neurons whose activity could be studied continuously during the entire 2- to 5-h transition period from spindles to spike and waves. Some results are also presented from the study of other neurons recorded only during spindles or during spike and wave activity.

Unit-Triggered EEG Averages during the Transition from Spindles to Spike and Waves. Like Ball et al. (2), we found that averaging the surface or the intracortical EEG 1 s before and 1 s after a cortical action potential often produced one or a series of averaged EEG waves with a peak near time zero (Figs. 2 and 3). The frequency of the repetitive averaged EEG waves was that of spindles.

During the transition of spindles to spike and waves under the influence of penicillin, three main changes were noted: (i) a progressive increase in the amplitude of the UT EEG average, (ii) a gradual development or increase of the positive phases of these EEG averages, and (iii) a change of the predominant frequency of the averaged EEG from that characteristic for spindles to about one-half, or (for cats with a mesencephalic lesion) one-third of this value, i.e., to that characteristic for the spike and wave


Epicortical EEG Introcortical EEG

FIG, 2. Unit-triggered EEG averages at successive stages of transition from spindles to spike and waves induced after i.m. penicillin administration by single stimuli to the nucleus centralis medialis of the thalamus recorded by surface and intracortical electrodes. First samples taken 1 h before penicillin when the cat, after a single injection of 2 mg/kg thiopental, was drowsy and thalamic stimuli evoked spindles. After penicillin, spindles were gradually transformed into spike and wave bursts. The action potentials used to trigger the computer were generated by the same neuron 1241 pm deep in the suprasylvian gyrus for the entire duration of the experiment. Each sample represents the EEG average triggered by 1000 action potentials. Vertical bars at time 0 of the averages: 20 WV, duration 2 s. Numbers indicate time after penicillin. Duration of recording sessions about 3 min.

FIG. 3. Unit-triggered EEG averages before and after the administration of penicillin selectively computed for burst (spindles or spike and wave) and interburst segments. Cat drowsy in response to continuous i.v. infusion of 1 mg/kg/h thiopental. Single stimuli applied to the nucleus centralis medialis first induced spindles. After penicillin this response was gradually transformed into spike and wave bursts at a time when spontaneous spike and waves also appeared (74’ after penicillin). The UT EEG averages in the left column are selectively derived from segments consisting of bursts (spindles or spike and waves). The UT EEG averages in the right column are derived from segments recorded between bursts selected from the same recording session from which burst segments had been collected (the summed length of the segments for each average was at least 40 s). Calibration as in Fig. 2.

discharges (Figs. 2, 3). No intermediate frequencies between those of spindles and of spike and waves appeared during this transition.

The amplitude increase of the averaged surface and intracortical UT EEGs was severalfold that of the mean of the original spindle activity


(Figs. 2, 3). This amplitude increase of the UT EEG averages was out of proportion to the increase in the amplitude of the bursts in the raw EEG from which the averages were computed, as well as to that of the EEG averages in the WT unit histograms computed for the same data. This indicates a closer coupling of the firing of the unit with the EEG transients. It most likely resulted from a more consistent firing of the unit in relation to these EEG transients.

Analyzing burst and interburst segments separately, as in Fig. 3, showed that the bursts were predominantly responsible for the shape of the averages seen in the analysis of the data of entire sessions, consisting of both burst and interburst periods. Before penicillin and during the early period after penicillin, a statistical relationship between unit firing and the EEG existed only for the bursts (Fig. 3, +lO’, +49’, +74’), but later, some time after the emergence of spike and wave activity, when the interburst EEG began to exhibit some slow waves without spikes, there also appeared some relationship between the unit discharge and the EEG for interburst segments (Fig. 3, right column, +94’). The relationship was always less prominent than for the burst segments. The UT EEG averages in animals with lesions of the reticular formation were more complicated because the EEG even after spike and waves had developed still contained some spindles as well as delta waves for which Ball et al. (3) also demonstrated a statistical relationship with unit discharge.

The development or increase of the positive phases of the EEG averages under the influence of penicillin mirrored the development of positive phases in the raw data described in the preceding paper (21).

Wave- Triggered Unit Histograms during the Transition from Spindles to Spike and Waves. Because the statistical sampling process in the method of UT EEG averaging is contingent on the occurrence of unit discharge which by its very nature is dependent on an excitatory event, this type of analysis is incapable of revealing whether or not certain EEG features could be related to processes which reduce the firing probabiity of cortical neurons, such as inhibition. This information is, however, readily provided by WT unit histograms which were therefore used to reanalyze the data reported in the preceding section.

Wave-triggered unit histograms showed that before penicillin only a weak or no definite association existed between cortical action potential discharge and spindle waves (Figs. 4, 5A). Thalamocortical volleys gen- erating spindle waves were therefore not very effective in exciting these cortical neurons to the point of eliciting action potentials. After penicillin their effectiveness increased: the probability of action potential discharge related to spindle waves steadily grew, the cell attaining its highest firing probability some time after the negative peak of spindle waves, coincident


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FIG. 4. Wave-triggered unit histograms from 10 successive 3-min long recording sessions before (“spindles”) and at indicated times after penicillin administration. Same data as those of Fig. 1 of preceding paper (21). All bursts were evoked by single stimuli applied to the nucleus centralis medialis except in the last session (+3 h IO’) where the bursts were spontaneous. Continuous infusion of thiopental throughout the experiment (1 mg/kg/h). Upper: average of epicortical EEG, lower: histogram of the activity of a single neuron (depth: 900 pm). All histograms were triggered by the peaks of negative transients of spindle waves or spikes of spike and wave bursts (including transitional forms) appearing in the epicortical EEG. Time span covered by histogram: 1 s. Vertical bar: 450 pV for EEG average. Vertical


with a shallow positivity (Fig. 4, +32’; Fig. 5, +15’). An overall increase in the background firing level sometimes developed slightly before that or at the same time (Fig. 4, +23’). These changes occurred when the spindle waves increased in amplitude and began to change from type II into type I spindles of Spencer and Brookhart (35) by developing increasingly prominent positive phases. These initially tended to follow, but later mostly preceded, the negative phases. When WT histograms were computed separately for the two types of spindles occurring during the same recording session, it could be shown that cells fired preferentially with type I spindles, even before penicillin (Fig. SB). As the spindle wave grew into the spike of the spike and wave complex some time after penicillin (Fig. 4, +2 h 36’, +3 h 10’; Fig. 5A, +60’), the probability of single-cell discharge attained its peak. The maximum firing probability at that time often had increased by 200 to 300% (Fig. 7A, compare left with middle).

The initial increase in firing probability which occurred after penicillin with every spindle wave as it progressively assumed a type I form was associated with or followed by another development: after each of these

scales along histograms: firing rate in action potentials (a.p.)/s as indicated by numbers on the top of the scale. [Note differences in scale due to normalization of histograms for the different number of transients used to produce them (80 to IYO)]. Bin width: 5 ms. Arrows indicate average firing rate of the neuron for each recording session. Note the increased probability of this neuron to fire with spindle waves as they were transformed into the spikes of the spike and wave complexes. Periods of decreased firing probability developed after those of increased excitation and correspond to the slow wave component of the spike and wave complex.

FIG. 5. Wave-triggered unit histograms recorded during the transition of spindles to spike and waves in two different experiments: A and B. Upper and middle traces in all WT unit histograms are averages of surface and intracortical EEGs, respectively (depth 900 pm for A and 1100 pm for B). Bursts were evoked by single-shock stimulation applied to the nucleus centralis medialis in cats receiving a continuous infusion of thiopental (1 mg/kg/h). The number of transients averaged in each session varied between 100 and 200; the histograms were normalized. Time after penicillin injection indicated above each WT unit histogram in A. W: transient (spindle or spike); the duration of W was arbitrarily demarcated by a pointer on the terminal screen as shown on top of the averaged EEGs by small vertical bars to the left and right of the vertical bar indicating time 0. The firing rates in a.p./s was computed for W: single transients; B: bursts; and S: entire recording session. The scales on the left of the histograms in A and B indicate instantaneous firing rate of the neuron in a.p./s. The overall firing rate during the entire recording session is indicated by an arrow on the right of each histogram. It is markedly reduced for the cell in B after spike and wave discharge has developed, most likely because this cell showed no increase in excitation with the spike, but profound inhibition after it. Time covered by histograms: 2 s in A; 1 s in B. WT unit histograms of A were computed from all spindle waves appearing in a session; in B separate histograms were computed for type II (first WT unit histogram) and for type I spindles (second WT unit histogram) occurring in the same recording session before penicillin injection. Note that the cell tends to fire only with type I spindles.

KOSTOPOULOS ET AL.

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FIG. 6. WT unit histograms of positive-negative and negative-positive spikes of spike and wave complexes. The histograms were computed for spikes occurring during the same recording period. Top: example of one of the analyzed spike and wave bursts showing both types of spikes. The highest incidence of firing of the neuron always coincided with the steepest segment of the EEG spike. Vertical line: time 0 for averages and histograms. Time span of histograms: 500 ms. Scale on the left of histograms: firing rate (a.p./s). Bin width: 2.5 ms. Arrows: average firing rate.

FIG. 7. A-three wave-triggered unit histograms from the same recording session 4 h 50’ after penicillin administration. Left: triggered from positive peaks of spikes of spike and wave


periods of increased excitation, initially only brief periods of diminished firing probability developed. These became, however, more pronounced and longer with time (Fig. 4, +50’-+3 h 10’; Fig. 5A, +45’, +60’). Increasingly the curves of the histograms clearly dipped below the level of the average background firing rate for progressively longer intervals. Finally, at the time when the averaged surface EEG clearly espoused the frequency pattern of the spike and wave rhythm (Fig. 4, +2 h 36’; Fig. 5A +60’), the decrease in firing probability intermittently attained zero and often lasted for 200 to 250 ms which coincided with the slow waves of the spike and wave complexes. The most characteristic feature of the fully developed spike and wave pattern was in fact this remarkable oscillation between increased firing probability at the time of the spike and decreased probability of firing at the time of the slow-wave component of the spike and wave complex (Fig. 4, +3 h 10’; Fig. 6, Fig. 7A, left, and B). The overall firing rate for the entire recording session often decreased again at that time, undoubtedly as a consequence of the repeated occurrence of the relatively long periods of transient reduction in firing probability. When the WT unit histograms early after penicillin administration had shown a periodic fluctuation of firing probability which espoused the spindle frequency, the period doubled its length at the time of the emergence of the spike and wave rhythm in the EEG (Fig. 5A).

As the spindle wave changed into the spike of the spike and wave complex, the timing of maximum firing probability of the cell changed from a point coinciding with a shallow positivity after the peak of the negative spindle wave (Fig. 4 +32’ -1 h 20’; Fig. 5A, +15’) to one corresponding to a larger positivity preceding the negative phase of the spike of the spike and wave complex (Fig. 4, +2 h 36’, +3 h 10’; Fig. 5A, +60’). At an intermediate stage the histogram sometimes exhibited a double-peak profile (Fig. 4, +2 h 5’): the earlier of the two firing maxima corresponding to that typical for spike and waves, the later to that typical for spindles. Both for type I spindles and spikes the maximum firing probability always occurred at a point close to the steepest segment of the slope connecting the

discharges; middle: with random triggering indicating average firing rate; right: triggered during the interburst EEG from peaks between slow negative waves. Upper and middle: surface and intracortical (depth: 1320 pm) EEG averages, respectively. B-wave-triggered unit histograms from three different neurons (depth: 1268, 1280, and 900 pm for left, middle, and right, respectively). The histograms were triggered from the positive peaks of the first spikes of spike and wave bursts appearing in the surface EEG. Number of samples: 11, 19, and 20, respectively, for left, middle, and right. Note rhythmic behavior of neurons precedes onset of spike and wave discharge in the EEG. Vertical bars-300 rV for surface EEG averages and 600 NV for the intracortical ones. Time span of histograms: 2 s except for B, left: 5 s. Vertical scales to the left of histograms: firing rate (full scale: 20 a.p./s). Arrows: average firing rate.


negative with the positive maxima of EEG transients, irrespective of whether the initial peak was negative or positive (Fig. 5B, Fig. 6). For type I spindles negative-positive sequences were most common; for spikes of spike and waves the reverse sequence prevailed.

Exceptionally with the emergence of spike and wave activity, a cell developed very prominent periods of decreased firing probability without any preceding increase at the time of the spike (Fig. 5B). However, whenever the neuron fired, it did so during the spike phase only. The firing pattern during spike and wave activity was thus typical, but in this case it was not achieved through the twin development of increased firing probability during the spike and decreased firing probability during the wave, but only through a marked development of the latter.

The mean firing rate of most cells was increased during spike and wave bursts compared with their average firing rate for an entire recording session (70% of cells; mean increase 80%, range 2 to 300%), for some, however, it was decreased (30% of cells; mean decrease 23%, range 5 to 41 o/o). During the spike and wave bursts the rate consistently increased for neurons which had fired slowly between bursts and decreased for neurons showing a high background firing rate. The major change in neuronal activity during generalized spike and wave bursts as opposed to interburst periods and to spindles was in the structured rhythmic pattern of firing (Fig. 5B, +109’; Fig. 7A, left) rather than in the overall firing rate. This rhythmic firing pattern was typical for nearly all neurons and lasted for the duration of the spike and wave bursts; it sometimes even started before their onset when no surface expression of this change was as yet visible (Fig. 7B, middle and right). Although some cells fired weakly or not at all during the spike, we never found cells that fired preferentially during the wave. Our sample was, however, biased in favor of large neurons.

In the advanced stages of penicillin action, when the interburst activity was also altered, WT unit histograms triggered by the troughs between slow waves occurring in the interburst intervals showed a reduction of the firing probability during the slow waves and only a mild increase during the small positive transients preceding or following them (Fig. 7A, right).

Increase in Probability of Action Potential Discharge Associated with Spindles and Spikes during Transformation of Spindles into Spike and Waves. From the UT EEG averages and the WT unit histograms it appears likely that what lies at the core of the transformation from spindles to spike and wave activity is an increase in the number of action potentials fired by neurons in response to a thalamocortical volley normally eliciting a spindle wave. This change must be distinguished from a possible general and unspecific increase in unit firing rate caused by penicillin. Some of the numerical values used for measuring neuronal firing rate and its changes


are presented under the histograms of Fig. 5A. For the cell shown in this figure, all firing rates, those for the sessions (S), those for the bursts (B), as well as those for the spindle waves or their presumed equivalents, the spikes of the spike and wave complex (W), initially increased after penicillin. Later, however, the values for the sessions (S) and for the bursts (B) decreased again, probably because of the marked diminution of firing probability which developed during the wave component of the spike and wave complex. The value W for the firing rate during the spindle wave or the spike of the spike and wave complex, showed no significant late decrease, hence the continuous progressive increase in the difference between W and B throughout the transformation of spindles into spike and waves, a finding that was obtained in all experiments. Throughout the experiment W exhibited values at least twice as high as those for S.

Pooled data on firing rates obtained from 16 neurons in the spindle state before, and in the spike and wave state after penicillin administration are plotted in the bar graphs of Fig. 8. The average firing rate of these 16 neurons increased slightly following the development of spike and wave discharge after penicillin administration, but this increase was not statistically significant. Also the firing rate during spike and wave bursts was higher than during the preceding spindle bursts. To compare directly the firing rate specifically associated with spindle waves and their equivalents, the spikes of the spike and wave complexes, the following computation was carried out: first the average duration of spindle waves and the maximum duration of spikes were determined by dividing the respective sums of the durations of spindle and of spike and wave bursts measured during a recording session by the intraburst frequency of spindles or spike and waves, respectively. From these values and the known firing rate during the respective bursts we determined the average number of action potentials that the neurons fired in association with individual spindle waves and spikes. This value probably underestimates the firing rate during spikes, because the duration of the spike is so much shorter than that of the slow waves. The third pair of columns in Fig. 8 shows that the neurons fired at least twice as many action potentials during a spike than during a spindle wave. The difference between the average number of action potentials per spindle wave and that of action potentials per spike was statistically significant and reflected a change induced by penicillin which was seen in almost every experiment, as the graph on the right side of Fig. 8 shows: all points are to the right of the diagonal, except for one (the data on this neuron are shown in Fig. 5B). This indicates that in 15 of 16 neurons, the firing rate associated with spikes was higher than the firing rate associated with spindle waves from which they had developed.

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Spike and Wave Discharge. The change from spindle into spike and wave activity was associated with an increased synchronization of the activities of neighboring neurons, as was shown in experiments in which the microelectrode happened to record action potentials generated by two neurons situated close to each other (Figs. 9 and 10). Cross correlograms in addition to UT EEG averages and WT unit histograms were used to analyze the data. Before penicillin administration there was a minimal degree of correlation between the activities of the two neurons (Fig. 9A, lower), or between their activities and the surface EEG (Fig. 9A, upper). When spike and wave discharges had developed the activities of the two neurons had become highly correlated, mainly during the spike and wave bursts (Fig. 9C, lower), but also to a lesser degree during the interburst period (Fig. 9B, lower). The cross correlogram of the activities of the two neurons

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A E FIG. 9. Correlation of the activities of two neurons recorded by the same microelectrode

(depth of 1.1 mm) and of the surface EEG. Raw data (upper half) and results of computer analyses (lower half) are compared for periods before and after the development of generalized spike and wave discharge. A, B, and C (upper): unit-triggered (UT) EEG averages triggered by neuron 1; A, B, and C (lower): cross correlograms of units 1 and 2. A-before penicillin administration. B-after penicillin, selective analysis of interburst segments (one such segment extends between the first two arrows shown on top of the epicortical EEG). C-after penicillin, selective analysis of segments with spike and wave bursts (as between second and third arrows shown at top of the EEG). Both averages and cross correlograms show I-s epochs. Vertical bars in UT EEG averages: 50 pV. The vertical scale on the left of the cross correlogram in A indicates action potentials of unit 2 per bin (I bin = 2.5 ms) and applies to all three cross correlograms. The vertical scale on the right of each crosscorrelogram represents the value of correlation (range 0 to 100%). N, = number of action potentials of unit 1 encountered in the indicated time. Note the increased synchronization of the activities of the two neurons during spike and wave discharge after penicillin.


during spike and wave discharge (Fig. 9C, lower) showed a periodicity corresponding to the frequency of the spike and wave discharge seen in the raw data and in the UT EEG averages.

In cats with lesions of the midbrain reticular formation in which com- monly spindles and spike and wave complexes coexisted side by side, it could be shown that the increased synchronization of cells was predominantly tied to the spike and wave pattern (Fig. 10). For at a time at which both spindles and spike and waves were present in the EEG, the cross

A Spindles Spike and Wave

i.co.20- Unit 1 Lbahbhw- d--

Interburst Spindles Spike and Wave

FIG. 10. Synchronization of neuronal discharge during spike and waves. Action potential discharges of two neurons (units 1 and 2) were recorded by the same microelectrode (depth 1010 rm) in a cat with a lesion of the midbrain reticular formation. After penicillin administration the discharges of both neurons and their relationship to the EEG which at that time exhibited both spindles and spike and wave bursts were analyzed for 3 min. A-wave-triggered (WT) unit histograms of the two neurons triggered by the negative peaks of 57 spindle waves (left column) and the positive peaks of 62 spikes of spike and waves (right column). e.co.- epicortical EEG, i.co.-intracortical EEG at 1010 pm. Scales on the left of the histograms apply to both columns and indicate firing rate in a.p./s. Arrows: average firing rate for recording session. W indicates the firing rate of unit 2 in a.p./s calculated for the duration of a spindle wave or spike as indicated by the two vertical lines in the histogram. Averages and histograms are for 0.62 s. B- cross correlograms for units 1 and 2 during interburst periods, spindles, and spike and waves. Scale on the left of B for all three cross correlograms: a.p./bin for unit 2 (one bin = 2.5 ms) normalized with respect to the firing rate of unit 1; left correlogram: seven interburst segments of spindle bursts (cumulative duration 10 s); middle correlogram: 13 segments of spindle bursts (cumulative duration IO s); right correlogram: 14 segments of spike and waves (cumulative duration 20 s). Note that the synchronization of the two neurons is prominent only during spike and wave bursts and modest or nearly absent during spindle and interburst segments, respectively, even though all samples were taken at the same time after penicillin injection.


correlogram showed a high correlation of firing of the two cells during spike and wave bursts only. There was modest correlation during spindles and a minimal one between bursts. In relation to spindle waves one of these cells fired nearly at random, whereas the other moderately increased its firing probability. However, during spike and wave bursts both cells markedly increased their firing probability with the spike and were nearly silent during the wave (WT unit histograms of Fig. 10).

DISCUSSION

Microphysiological Characteristics of the Spindle Stage

Wave-triggered unit histograms have shown that there is only a weak association between action potential discharges of cortical neurons and spindle waves, particularly for the type II spindles of Spencer and Brook- hart (35). These findings are in accord with intracellular recordings reported by Creutzfeldt et al. (5, 6) who showed that many excitatory postsynaptic potentials (EPSPs), which sum to produce spindle waves, elicit only a subliminal excitation of cortical neurons without inducing action potentials.

The WT unit histograms of type II spindles also disclosed no evidence of inhibition and, in the case of type I spindles, only weak and short-lasting periods of decreased firing probability. This too agrees well with the findings of Creutzfeldt et al. (5, 6) who rarely found IPSPs in intracellular recordings of cortical neurons during spindles. Jasper and Stefanis (19) showed that hyperpolarizations sometimes alternated with depolarizations in intracellular recording during spindle activity. These presumed IPSPs were not only inconstant and small, but often also short compared with the more powerful and longer-lasting IPSPs (which may attain 300 ms) often seen in cortical neurons under other conditions (22, 32, 33).

The spindle state microphysiologically is therefore characterized by (i) the prevalence of a weak excitatory drive with a low probability of effective synaptic transfer at the cortical level and (ii) by the absence or weakness of inhibitory processes.

Microphysiological Characteristics of the Transition from Spindles to Spike and Wave Activity Induced by Penicillin

Increased Excitation of Cortical Neurons. Development of or an increase in the positive phases of spindle waves, i.e., a shift toward an increasing predominance of type I spindles, is the first change in the transition from spindles to spike and waves occurring after penicillin. Both UT EEG averages and WT unit histograms suggest that this change is associated with


an increased probability of EPSPs, summing into spindle waves, becoming supraliminal and thus capable of initiating action potentials. The increase in the amplitude of the UT EEG averages exceeding that of the raw EEG during the transformation of spindles to spike and waves is suggestive of this. The following considerations bear this out: UT EEG averages demonstrate an association in time between extracellularly recorded action potentials and certain EEG waves (2, 45). This does not imply, however, a direct causal relationship between the two phenomena; rather the two events are associated because each is causally related to a third event, depolarization of cortical neurons, usually EPSPs which algebraically sum to produce EEG waves. For a detectable wave to arise in a UT EEG average two conditions must be met: (i) a certain degree of synchronization of depolarizations of many neurons must occur, and (ii) some of these depolarizations must be supraliminal to elicit the action potential discharges which trigger the computer. We suggest that the progressive increase in amplitude of the UT EEG average which accompanied the evolution of spike and waves from spindles (Fig. 3, left column) indicates an increased effectiveness of both conditions, because the amplitude of the EEG, a measure of the first condition, increased by only 30 to 60% (peak- to-peak amplitudes of spindles versus spikes of spike and wave complexes, e.g., EEG averages in Fig. 4 and 5), whereas the corresponding UT EEG averages increased by 100 to 300%. An increased statistical relationship between the EEG and unit discharges had already been demonstrated earlier in feline generalized epilepsy by Wray and Hablitz (45), but their method did not clearly differentiate between the respective contributions of burst versus nonburst EEG segments within the same recording period.

Wave-triggered histograms demonstrate more directly that spindle-inducing thalamocortical volleys become more effective in eliciting action potential discharge by cortical neurons (Figs. 4, 5): cells which showed only a minimal or no clear tendency to fire in relation to spindle waves, increasingly did so after penicillin administration, and this increase in firing probability continued to augment until the spindles had been transformed into spike and wave complexes. Ultimately the probability for cortical neurons to discharge in relation to spindle waves more than doubled as the latter evolved into the spikes of the spike and wave complexes (Fig. 8). If one accepts the homology of spindle waves with the spikes of spike and wave complexes, the intracellular data of Creutzfeldt et al. (5, 6) on spindles, and those of Fisher and Prince ( 14) on spike and waves, are in agree- ment with this interpretation. The latter showed that EPSPs consistently increased above the firing threshold during the spike, often eliciting more than one action potential per EPSP. The conclusion that penicillin en- hances the effectiveness of thalamocortical volleys in exciting cortical neu-


rons also agrees with extracellular ( 12) and intracellular studies (42) using microiontophoretic application of penicilin to cortical neurons.

Development of Recurrent Periods of Reduced Firing Probability. Wave-triggered unit histograms showed that as cortical neurons began to discharge more consistently in relation to spindle waves, each period of increased firing probability was followed by longer periods of markedly decreased firing probability, which in the fully developed spike and wave stage often attained zero and remained at this level for more than 200 ms. These periods of reduced firing probability were associated with the slow wave of the spike and wave complex in accord with the observations of Pollen et al. (29) and Steriade (37) on other models. These periods of reduced firing probility were the most consistent and striking feature of the microphysiology of the spike and wave pattern and exceptionally even developed without any increase in firing probability during the spike (Fig. 5B). The periods of reduced firing probability always developed either after or concurrently with, but never before the increase in firing probability associated with the spindle wave evolving into the spike. We therefore wish to propose that the development of these periods of reduced firing probability are most likely attributable to a powerful activation of the recurrent intracortical inhibitory pathway, first demonstrated physiologically by Phil- lips (28) and Stefanis and Jasper (36) for which Szentagothai (38, 39) proposed an anatomic substrate.

Alternative explanations implicating more complex inhibitory systems, possibly involving even the thalamus, are conceivable, but we prefer the simpler explanation of activation of the recurrent intracortical inhibitory pathway for the following reasons:

(i) It is the most parsimonious explanation for the development of recurrent periods of reduced excitability which are contingent upon the development of an increased discharge rate of cortical neurons preceding them. According to Creutzfeldt et al. (5, 6), single action potential discharges triggered by EPSPs during spindle waves are practically never followed by IPSPs. When IPSPs do occur, they are preceded by high- frequency clusters of more than one action potential. Thus the cortical inhibitory interneuron whose excitation is contingent upon preceding cortical nerve cell discharge must have a relatively high threshold and requires temporal and/or spatial summation to be sufficiently excited to discharge action potentials in its turn. Such conditions of increased temporal and spatial summation are likely to occur after penicillin, because (a) cortical neurons begin to discharge more consistently with each spindle-inducing thalamocortical volley, and (b) because the discharges of neighboring neurons increasingly become synchronized.

(ii) The rich intracortical branching of the intracortical inhibitory path-


way proposed by Szentagothai (38, 39), would explain why even the few neurons which do not show an increased excitation with the spike, yet undergo profound inhibition with the slow wave of the spike and wave complex, and why every cortical neuron showed an inhibitory pause during the wave component of the spike and wave complex.

The recruitment of cortical recurrent inhibition could also explain the disappearance of every second (or second and third) spindle wave in the course of the transformation of spindles into spike and waves (21). The question is whether short-circuiting of the membrane during IPSPs could sufficiently reduce the amplitude of the EPSPs summating to form every second spindle wave and thus effectively eliminate them from the EEG. This explanation appears, however, far fetched and probably is only par- tially true. A reduction in the amplitude of every second spindle wave could be attributed to such a mechanism; a complete abolition is more difficult to accept. The complete elimination of every second spindle wave most likely results from changes in the thalamic firing pattern which develop secondarily after the emergence of cortical spike and wave discharge (13, 3 1). This problem is now under investigation in our laboratory.

The proposed important role of recurrent intracortical inhibition in spike and wave genesis may seem to be difficult to reconcile with recent evidence demonstrating that penicillin antagonizes inhibition ( 1, 26, 40, 44), either because it acts as a GABA antagonist (7, 10, 23, 24) or because it reduces chloride conductance ( 11, 18, 27, 43). In fact it has been argued that the epileptogenic action of penicillin could be explained solely on the basis of its antiinhibitory effect. If this were the case it would be difficult to un- derstand how a profound increase in cortical inhibition as postulated for spike and wave discharge could result, even indirectly, from the action of penicillin. However, Macon and King (25) recently showed that at low concentration penicillin exerts an excitatory action that seems to be in- dependent of its antiinhibitory effect. We know that during feline generalized penicillin epilepsy, the penicillin concentration in the cortex is indeed low (30). Even at higher concentrations the excitatory action of penicillin can probably not be entirely attributed to its antiinhibitory effect (8, 9, 15, 41). It appears likely that, at least under the conditions in which the cortical penicillin concentration is low, pyramidal cells respond more vig- orously to thalamocortical volleys not because they are less inhibited, but because of some increase in the effectiveness of synaptic excitation.

Increased Synchronization of Neurons during Spike and Wave Discharge

The cross correlograms of the activities of two neurons recorded simultaneously showed increased synchronization of their firing during spike and


wave discharge. In the case in which spindles and spike and waves coexisted at the same time after penicillin in a cat with a lesion of the midbrain reticular formation, it became particularly clear that this increased synchronization was tied to the spike and wave pattern and did not reflect an unspecific effect of the penicillin action.

CONCLUSIONS

The main conclusions we draw from this study are that (i) in feline generalized penicillin epilepsy, spike and wave discharge directly evolves from spindles, and (ii) this transformation can be attributed to a diffuse increase in the excitability of cortical neurons. Under this condition the response of cortical neurons to spindle-inducing thalamocortical volleys is transformed into an oscillation between increased excitation and increased inhibition by virtue of inherent physiological and structural properties of cerebral cortex. Inhibition is thought to result from increased excitation of cortical neurons through secondary recruitment of the relatively high- threshold recurrent intracortical inhibitory pathway which during spindles is rarely activated. The oscillation of neuronal activity between enhanced excitation and enhanced inhibition is reflected in the EEG as spike and wave discharge.

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