EXPERIMENTAL

NEUROLOGY

46, 418-431 (1975)

Effects of Projected Cortical Epileptiform Discharges Neuronal Activities in Ventrobasul Thalamus of the Cat: lctal Discharge MICHAEL

J. GUTNICK

Department

of Neurology, Medicine, St&or&

AND DAVID

on

A. PRINCE

Stanford University School of Califo&a 94305

Received July 24, 1974; revision received September

25, 1974

Extracellular recordings were made from neurons in nucleus ventralis posterolateralis during projected ictal discharges from penicillin foci in cat posterior sigmoid cortex. During the initial phase of the clectrographic seizure,spike generation in the thalamic nucleus was suppressed. Excitatory effects became prominent during the tonic phase of the ictal episode when rhythmic firing of ventralis posterolateralis neurons occurred. During the clonic phase of the seizure, thalamic cells generated prolonged high frequency bursts of spikes which might begin before the onset of the surface paroxysm. Analysis of interval histograms and autocorrelograms of spike discharges in some thalamocortical relay cells during the clonic phase of the seizure suggested that both orthodromic and antidromic spike generation occurred. The findings together with those from previous studies suggest that the excitability of intracortical axons of thalamocortical relay cells increases as the ictal episode develops and spontaneous bursts originate in these axons and antidromically invade the cell body. Burst generation in thalamocortical relay cells during ictal episodes, and shifts from inhibitory to excitatory behavior in these units during a seizure would provide a powerful positive feedback to the epileptogenic focus. Propagation of bursts throughout the arborizations of thalamocortical fibers to presynaptic terminals would result in a marked increase in excitatory synaptic impingement, and a synchronization of neumnal activity which characterizes the ictal episode.

INTRODUCTION The electroencephalographic manifestations of focal epileptiform discharges are generally described in terms of interictal and ictal stages (1). IThese experiments were supported in part by USPHS grant NS 06477 from the NINDS (D.A.P.) and USPHS postdoctoral fellowship 42766 to M.J.G. We gratefully acknowledge the advice of Dr. Donald Perkel who assisted in the spike-train analysis shown in Figs. 6 and 7 and the secretarial assistance of Ms. Pamela Vario. Dr. Gutnick’s present address is: Experimental Neurology Laboratory, The Hebrew University-Hadassah Medical School, Jerusalem, Israel. 418 Copyright All right.9

0 1975 by Academic Press, I c. of rqmduction in any form r e& wed.

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Single paroxysmal discharges (epileptiform “spikes” of the electroencephalographer) are a classical sign of focal epileptogenesis that may not be associated with behavioral changes. Transitions between these spontaneous or triggered interictal discharges and self sustained tonic-clonic electrographic-clinical “ictal episodes,” occur regularly in human and experimental epilepsy. The changes in cortical cellular activities which underlie this transition have been extensively studied (e.g., 3, 4, 9, 18, 30). In the present report, we describe the activities of neurons in the specific thalamic nucleus ventralis posterolateralis during seizure development in a focus situated in the functionally related region of the somato-sensory cortex. We have previously reported that orthodromic projection of interictal discharge from such a focus produces prolonged inhibition of neurons in ventralis posterolateralis but at the same time leads to the generation of bursts of impulses which originate in the intracortical axons of thalamocortical relay cells and invade thalamic cell bodies (12-14). As we shall demonstrate, during the transition to ictal activity there is a change in the activities of thalamic units so that inhibition gives way to intense excitation and an increase occurs in the excitability of presynaptic terminals within the cortical focus which leads to generation of prolonged trains of impulses in these elements. The observations reported here support the hypothesis that the antidromic spikes which invade cell bodies of thalamocortical relay neurons during interictal events and ictal episodes may play a significant role in facilitating the transition between interictal and ictal activity and maintaining cortical seizure discharge.

METHODS Experiments were performed on 26 adult cats anesthetized with a single intravenous dose of sodium pentobarbital. Surgical procedures and techniques for stimulation and recording have been reported elsewhere (14). Epileptogenic foci were made by application of a gel-foam pledget moistened with buffered aqueous Na penicillin G (250,000 pm/ml) to the pial surface. Seizures usually developed late in the course of an experiment, when the animal was recovering from the anesthetic and the cortical penicillin focus had been active for several hours. The criteria for identification of units in nucleus ventralis posterolateralis are described elsewhere (2, 14). Samples of the spontaneous and ictal activities of four thalamocortical relay cells were subjected to spike-train analysis. The technical and theoretical aspects of the calculations have been described by Perkel, Gerstein and Moore (22). Unit data were digitalized using an IBM 1800 computer, and calculations were performed with an IBM 360/67 computer.

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RESULTS Corticothalunzic Axons. Recordings in ventrobasal thalamus from corticothalamic axons whose cell bodies of origin were presumably located within the epileptogenic focus revealed that seizure discharge was projected to the thalamus in the form of high frequency bursts of spikes which were timelocked to surface events. Activities in these axons during ictal episodes closely paralleled those of cortical neurons described by Matsumoto and Ajmone-Marsan (18). A typical extracellular recording from one such element, identified by criteria described in a previous paper (14), is shown in Fig. 1. The sinusoidal oscillations of the electrocorticogram EEG which characterized the tonic phase of the ictal episode were accompanied in these fibers by the generation of short, rhythmic bursts of action potentials (Fig. lA, following second dot). During the clonic phase of the seizure, sequences of bursts were recorded during each complex paroxysmal EEG wave (Fig. lB, C). No spikes were ever recorded from corticothalamic axons at the conclusion of the ictal episode, during the period of postictal depression of the EEG (Fig. 1C). Field Potentials. Figure 2 shows an example of the field potentials generated in the thalamic nucleus during the course of projected ictal discharge. During each interictal discharge a negative wave with superimposed spikes was recorded in ventralis posterolateralis (Fig. 2A) . The tonic phase of the seizure was accompanied by low voltage rhythmic oscillations in the thalamus (Fig. ZA, second half of line). During each subsequent clonic surface discharge, large negative potentials with superimposed unit activity were recorded (Fig. ZB, C). Orthodromic Efects on Ventralis Posterolateralis Neurons. Extracellular recordings were obtained from 53 neurons during projected seizure dis-

FIG. 1. Activities of a corticothalamic axon during an ictal episode. Dots in A indicate the direct cortical stimuli which triggered the seizure. In this and the following four figures, upper traces are from the cortical surface at the site of the focus, and lower traces are from nucleus ventralis posterolateralis. Polarity: upper trace, positivity down; lower trace, positivity up.

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FIG. 2. Field potentials in ventrobasal thalamaus during an ictal episode. Dots in A indicate the direct cortical stimuli which triggered the seizure. In all traces, positivity is down.

charges ; all of these were cells that showed evidence of inhibition during interictal events (Fig. 3A ; also ref. 14). Certain features of the patterns of neuronal activity during projected ictal sequences were similar in all recordings. These are illustrated in Figs. 3, 4 and 5. At the onset of the ictal episode, spike generation in thalamic neurons was either entirely suppressed or considerably decreased in frequency (Fig. 3A ; Fig. 4A, end of segment). This effect waned gradually as brief bursts of impulses were generated coincident with surface oscillations (Figs. 3B and 4B). The excitatory effects became more prominent and during the clonic phase the thalamic cells generated prolonged, high frequency spike bursts (Figs. 3D-I; 4C-E; 5b-d). The time of onset of these bursts relative to the onset of the surface epileptiform potentials varied unsystematically throughout the clonic period. It was quite common for repetitive firing to begin in a thalamic neuron up to 15 msec before the earliest detectable deflection in the surface recording (e.g., first burst of Fig. 3E ; first and third bursts of Fig. 3G). Although intracellular recordings were not obtained from ventralis posterolateralis neurons during ictal episodes, it was possible to draw inferences about intracellular events from the extracellular characteristics of clonic bursts. In the neuron illustrated in Fig. 3, each clonic burst was characterized by a rapid attenuation of impulse amplitudes and a gradual increase in interspike intervals. The decrease in spike heights was least prominent during the relatively low-frequency bursts (2OO/sec) which occurred early in the clonic phase (Fig. 3D) and was most marked during the bursts of higher frequency such as those shown in Fig. 3F-I (up to 550/set). These findings suggest that bursts of spikes in this cell were generated by large EPSPs. As the clonic phase of the seizure progressed, the synaptic depolarizations presumably grew larger, causing an increase in the impulse frequency while leading to progressive diminution of spike amplitudes. This interpretation is supported by recent intracellular record-

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FIG. 3. Activities of a neuron in nucleus during an ictal episode. Dots in A and B indicate the direct cortical stimuli which triggered the seizure. Numbers refer to the number of seconds which have elapsed since the first stimulus in A. Polarities as in Fig. 1.

ings from neurons in n. ventralis lateralis during cortical ictal episodes (29). Evidence regarding the origin of clonic bursts was also obtained by statistically analyzing representative spike trains sampled from the activities of thalamic neurons before and during an ictal episode. Figure 6 shows the interval histograms (A) and autocorrelogram (B) corresponding to preseizure spontaneous burst activity in a thalamocortical relay cell, The interval distribution is narrow and has a modal value of 1 to 2 msec, indicating that spontaneous firing frequencies were usually greater than SOO/sec. The autocorrelogram, which plots the probability of encountering any impulse in a train as a function of time after a given spike and thus uncovers any cyclic pattern of neuronal firing from background “noise,” shows rapid fall-off from an early peak. This indicates that the high frequency spontaneous firing was restricted to short bursts. The interval histogram

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FIG. 4. Activities of a thalamocortical relay neuron during a spontaneous ictal episode. Underlined portions are shown at an expanded sweep speed in Fig. 5. Polarities as in Fig. 1.

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from the ictal spike train (Fig. 6C) is similar in form to the spontaneous distribution, and has an identical mode of l-2 msec. The corresponding autocorrelogram (Fig. 6D) also has a shape that is basically similar to that of the spontaneous train, although the longer clonic burst duration is reflected by a more gradual declining slope. These similarities in firing pattern are consistent with the hypothesis that in this cell spontaneous spikes and clonic ictal bursts were generated at the same locus of impulse initiation, and that under both conditions, spikes arose from synaptic depolarizations of the thalamic cell body. Antidromic Efects on Ventralis Posterolateralis Neurons. Several thalamocortical relay cells showed evidence of antidromic invasion of impulses from their cortical axons during ictal episodes; activities of one such neuron are illustrated in Figs. 4 and 5. At the transition to seizure (Fig. 4A), as interictal events become more frequent and afterdischarges began to develop, they were accompanied by the generation of spike bursts in this cell. These were quite similar to the interictal antidromic bursts previously described (12, 14) in that they showed a characteristic’ late onset relative to the onset of surface events, and had extremely regular interspike intervals of 6.5-8 msec (Fig. Sa, first burst).

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During the clonic phase of the seizure, two distinct types of spike trains were recorded from this cell. Brief bursts, characterized by high frequency spike firing and rapid attenuation of spike amplitudes (second and third bursts of Fig. 5a; initial few spikes of Fig. S-d), were similar to those seen during spontaneous interictal activity (see below) and were probably generated as a result of synaptic depolarization of the cell body. These short bursts usually occurred just before or immediately after the long trains of impulses which were characterized by lower spike frequencies and the absence of progressive spike amplitude attenuation. Interspike intervals were extremely constant throughout such long burst trains (Fig. 5b-d) ; this lack of frequency variation makes it unlikely that these bursts were generated by graded depolarization of the thalamocortical relay cell body. Moreover, when longer interspike intervals did occur, they were multiples of the basic interval. Thus, in Fig. 5c, the intervals between spikes “A” and “B,” between “C” and “D” and between “E” and “F” are all 5 msec, while the “B’‘-“C” interval is 10 msec and the “D’‘--“E” interval is 15 msec. This suggests that spike generation at the recording site failed in an all-or-none manner without disturbing the basic rhythm of the spike train. This is the pattern that would be expected if these impulses were recorded as they antidromically invaded the cell body from the axon, and individual spikes within a burst failed to propagate past points of low safety factor along the antidromic pathway ( 12, 14). The suggestion that the bursts in the neuron of Figs. 4 and 5 were not generated in the thalamic cell body is supported by the analysis shown in Fig. 7. The interval histogram and autocorrelogram for the spontaneous (preictal) activity in this cell (Fig. 7A, B) are identical to those in Fig. 6A, B. However, during clonic ictal activity, the interval histogram (Fig. 7C) shows an overwhelming preponderance of intervals at 4 to 6 msec. The peaks in the corresponding autocorrelogram (Fig. 7D), which occur at 6, 12, and 18 msec, demonstrate the periodic tendency of this activity. This rhythm is superimposed on a pattern similar to that of preictal activity, as is indicated by the peak in the interval distribution at 1 to 2 msec. The enlarged section of the interval histogram (Fig. 7C. inset), although representing only a small sample of the total number of intervals, clearly shows peaks at multiples of the mode, again suggesting that long interspike intervals reflect a failure of impulse invasion rather than a failure of impulse initiation. These findings suggest the presence of at least two zones of spike generation for this thalamocortical relay cell during the clonic phase of an ictal episode, one of which may be in the intracortical axon, as is the case during interictal discharges (12). The a,ntidromic bursts which accompanied clonic ictal discharges differed from those recorded during interictal events (12, 14) in three ways: a) the onset of clonic bursts was variable relative to the onset of surface

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FIG. 7. Interspike interval histograms (A, C) and autocorrelograms (B, D) for spike trains recorded from the thalamocortical relay neuron in Figs. 4 and 5. A, B: Preseizure spontaneous activity. C, D: Bursting during the clonic phase of the ictal episode. Inset in C is a magnification of the interval distribution at 8-20 msec. Note scaling difference betweenA, B and C, D.

epileptiform potentials, and on occasion antidromic spikes were recorded in the thalamus before any deflection could be observed in the cortical recordings (Fig. 5b) ; b) in most instances, a clonic antidromic burst was preceded by a brief orthodromic burst; c) interspike intervals were shorter in clonic bursts (4-6 msec) than in interictal bursts (6.5-8 msec) . Since these differences could be demonstrated in the same neuron during the two different activity states (compare Fig. 5a with Fig. 5b-d) , it is apparent that they were related directly to changes in the excitability of thalamocortical terminals. End of the Ictal Episode. In the waning stagesof a seizure, clonic epileptiform discharges becameless frequent, and ventralis posterolateralis neurons began to fire spontaneously in the prolonged periods between bursts (Figs. 3H-I and 4E). Thalamic neurons thus did not show signs of postictal depression (Figs. 31 and 4E). DISCUSSION These data indicate that the projection of epileptiform discharge during the course of a cortical ictal episode results in a characteristic sequenceof

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neuronal events in the specific thalamic nucleus which closely resembles the behavior reported for cortical neurons in the “inhibitory surround” of neurons within the focus itself (18). the focus (26) and for “passive” Thus, as a seizure progresses, more and more cells are recruited to active participation in the epileptogenic process, until the “focal” epileptic neuronal aggregate has become enlarged to include wide areas of the cortex and functionally related regions of the thalamus. During the early stages of a seizure, orthodromic activities in VPL cells are depressed. This effect is probably mediated by the same corticothalamic pathway which produces postsynaptic inhibition in these neurons during cortical interictal events (13, 14). As the seizure continues, there appears to be a gradual shift in the balance between inhibitory and excitatory corticofugal influences, and thalamic neurons begin to fire high frequency spike bursts coincident with surface paroxysmal waves. Evidence is presented which indicates that in most cases, these bursts are generated at the thalamic cell body, where they arise from membrane depolarizations that are probably synaptic in origin (but see below). Since paroxysmal orthodromic bursts in thalamic neurons were always associated with cortical epileptiform potentials, it seems likely that the corticofugal barrage is the major synaptic driving force for clonic repetitive firing in these cells. However, whereas burst onset in corticothalamic axons is timelocked to surface events (Fig. lB, C), bursts in ventralis posterolateralis neurons are not. This suggests that the excitability of thalamic neurons is also influenced by activity in local thalamic circuits during a seizure. One possible modulating effect might be the generation or recurrent IPSPs of variable durations following the bursts in thalamocortical relay cells (2). This could have an effect on the timing of burst generation in thalamic neurons activated by a subsequent epileptiform corticofugal volley. Such inhibitory modulation might also be produced by propagation of the epileptiform discharge to other structures which, in turn, projected to the ventrobasal thalamus. Maekawa and Purpura (17) have demonstrated that stimulation of the nonspecific, medial thalamic nuclei can produce weak inhibitory effects in ventralis posterolateralis neurons. Since thalamocortical relay neurons project back to the cortical focus, the finding that bursts in these cells often begin earlier than surface epileptiform potentials (Fig. 3) suggests that clonic cortical paroxysms may at times be triggered by preceding discharges in ventralis posterolateralis. Thus the driving site for continuing ictal discharges might shift back and forth from cortex to thalamus at various times during the seizure. This would be true only if EEG potentials accurately reflect the onset of corticofugal discharge. If the size of the epileptogenic cortical neuronal population involved in an ictal episode were large and variable (18, 25)) and if the EEG was not a good index of the activities of deeper lying

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neurons responsible for the output of the cortex (8, 24, 27)) it would be possible for corticothalamic discharges to always lead excitation in thalamocortical neurons even though the recorded cortical surface potentials appeared to follow some thalamic cell bursts. Our data indicate that in addition to the orthodromic changes in ventrobasal thalamic neurons described above, the initiation of an ictal episode may also be accompanied by spike generation in the cortical terminals of thalamocortical axons as has been clearly demonstrated for these cells during interictal events (12, 14). Although relatively few of the neurons studied showed evidence of axonal generation and antidromic invasion of spikes during ictus, this phenomenon may have been more common and gone undetected in cases where the axon and the soma of a single thalamocortical relay neuron acted as simultaneous spike ge’nerators, causing antidromic and orthodromic bursts to collide somewhere along the thalamocortical pathway. Since orthodromic firing rates are usually higher, the antidromic impulses would not reach the site of the microelectrode. Figures 4 and 5 show that the excitability of presynaptic terminals in the focus, as indicated by the generation of antidromic spike bursts, begins to increase just before the onset of the seizure, when interictal discharges become more frequent. As the seizure progresses, the characteristics of the ictal antidromic bursts begin to differ from the characteristics of bursts which occur during the interictal period (12, 14). During the clonic phase, interspike intervals within bursts become shorter and the bursts no longer show a characteristic late onset relative to the cortical surface waves. These changes suggest an even greater enhancement of axonal excitability. During ictal episode discharge, the antidromic bursts are almost always preceded by orthodromic volleys suggesting repetitive firing in the axon terminals may be triggered by orthodromic impulses. A similar phenomenon has been reported for several preparations, such as phenylethylaminetreated lobster neuromuscular system ( 11) and many types of nerves treated with the poisons, DDT and Allethrin (21). In these instances, orthodromic impulses cause repetitive axonal discharge because of a drug-induced disturbance in the normal conductance mechanisms which underlie the action potential. In the case of the epileptogenic focus, the mechanisms leading to “backfiring” are not known. One possibility is that the normally hyperpolarizing spike afterpotential in the terminal reverses to a depolarizing one in the face of a large and sustained increase in the extracellular concentration of I(+ (see below). Orthodromic triggering of repetitive discharge in thalamocortical terminals might explain the results of cortical intracellular studies which show that in neurons of the focus, EPSPs evoked by thalamic stimulation are enhanced during ictus (3). In previous papers (12, 14), we suggested that the generation of antidromic spikes during interictal discharges may be related to the large,

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epilepsy-related increases in the extracellular concentration of K+ in the focus that have been inferred from intracellular recordings in cortical glial cells (5, 23, 28, 30) and have now been demonstrated by direct measurement with K+-sensitive electrodes (7, 15, 19, 20, 25). The present findings further support this hypothesis, since the sequence of changes in axonal excitability during the development of an ictal episode parallels the buildup of intracortical [K+] o which occurs during seizures (7, 19). We should point out however that other substances capable of depolarizing terminals may be released during seizures and that the evidence implicating an increase in [K+] 0 in antidromic burst generation is very indirect. It has been proposed (5, 10, 16, 30, 31) that the accumulation of K+ plays a causal role in the transition from interictal discharge to seizures. Our observations suggest that during this transition and [K+10 elevation, presynaptic terminals within the cortical focus depolarize to the point that they begin to generate spikes. This may be a potent mechanism for providing the powerful, synchronous excitatory drives necessary to initiate the regenerative ictal episode. Since the axons of the thalamic neurons that we studied constitute the major afferent pathway to the cortical cells which comprise the epileptogenic neuronal aggregate, the shift from inhibitory to excitatory behavior in nucleus ventralis posterolateralis during a seizure represents the activation of a powerful positive feedback loop to the focus. Our findings indicate that during an ictal episode, high frequency bursts of impulses are generated in the thalamocortical relay cell body or in its cortical axon, or both. Propagation of these impulses throughout the numerous cortical branches of the thalamocortical fibers to presynaptic terminals would result in synchronous release of large amounts of neurotransmitter onto the neurons of the cortical focus and account, in part, for the marked increase in excitatory synaptic impingement and synchronization of neuronal activity which characterizes the ictal episode (3, 6, 18). REFERENCES 1. 2.

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