Inhibition of Experimental Seizures After Vagal Stimulation

Epilepsia, 33(6): 1005-1012, 1992 Raven Press, Ltd., New York 0 International League Against Epilepsy

Inhibition of Experimental Seizures in Canines by Repetitive Vagal Stimulation

Jacob Zabara

Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A.

Summary: Repetitive electrical stimulation of the canine cervical vagus nerve interrupts or abolishes motor seizures induced by strychnine and tremors induced by pentylenetetrazol (PTZ). Tremors were defined as rhythmic alternating contractions of opposing muscle groups, exerting much less force than seizure contractions. Seizures were induced by injection boluses of strychnine or PTZ at 1- to 4-min intervals until sustained muscle activity was observed electromyographically (EMG). Vagal stimulation terminated seizures in 0.5-5 s. There were prolonged periods with no spontaneous EMG activity after stimulation. The period of protection was approximately four

times the stimulation period. The antiseizure actions of vagal stimulation were not altered by transection of the vagus distal to the stimulating electrode. Optimal stimulus parameters were estimated: strength, -20 V (electrode resistance 1-5 0); frequency 20-30 Hz; duration, -0.2 ms. These data suggest that the antiseizure effects derive from stimulation of small-diameter afferent unmyelinated fibers in the vagus nerve. These results may form the basis of a new therapeutic approach to epilepsy. Key Words: Electrical stimulation-Epilepsy-Pentylene- tetrazol-Seizures-Strychnine-Dogs-Vagus nerve.

Inhibition of motor activity by activation of visceral vagal afferents was first reported by Schweitzer and Wright (1937) and was later con- firmed by Paintal(1973). Identification of vagal projections to the cerebellum (Dell and Olson, 1951; Sobusiak et a!., 1971; Hennemann and Rubia, 1978), cortex (Bailey and Bremer, 1938; Siegfried, 1961; Aubert and Egros, 1963; O'Brien et al., 1971), brainstem (Grastyan et al., 1952; Kimehiko-Too and Dussardier, 1963; Padel and Dell, 1965), thala- mus (Juhasz et al., 1985), and hippocampus (Serkov and Bratus, 1970) followed. Stimulation of vagal afferent fibers was also shown to cause profound changes in the EEG (Zanchetti et al., 1952; Garnier and Aubert, 1964; Chase and Nakamura, 1968; Varbanova, 1972) and that low-voltage vagal stimulation significantly reduced EEG spiking of a cortical epileptic focus caused by topical application of strychnine (Stoica and Tudor, 1967, 1968). More- over, y-aminobutyric acid (GABA), considered a primary inhibitory neurotransmitter, was observed in brain areas of vagal innervation (D'Amelio et al., 1987). These observations suggest that stimulation

Received March 1989; revision accepted June 1992. Address correspondence and reprint requests to Dr. J. Zabara

at Department of Physiology, Temple University School of Med- icine, 3223 N. Broad St., Philadelphia, PA 19140, U.S.A.

of vagal afferents might prevent, reduce, or terminate spontaneous seizures.

Preliminary results from clinical trials (Penry and Dean, 1990; Wilder, 1990) of vagal stimulation from implanted electrodes, given in accordance with the Neurocybernetic Prosthesis (NCP"; Cyberonics, Webster, TX, U.S.A.), provide strong indications that vagal stimulation is effective in reducing complex partial seizures in patients who are refractory to drug therapy. The experimental basis for this therapy was a series of studies of the effects of cervical vagal stimulation on motor seizures or tremors induced in dogs. The details of this work, hereto- fore published only in abstract form (Zabara, 1985a,b, 1987), are reported. The aim of these studies was to determine the ranges of stimulus parameters (amplitude, repetition, frequency, and duration) that produce antiseizure activity and, if possi- ble, to estimate the optimum stimulus parameters.

METHODS

Twenty dogs, 10 male and 10 female, of mixed breed weighing between 10 and 22 kg were anesthe- tized with a-chloralose (Chloralose, Sigma Chemi-

* Zabara J . Neurocybernetic Prosthesis. U.S. Patent 4,702,254-1987; U.S. Patent 4,867,164-1989.

1005

1006 J . ZABARA

cal, St. Louis, MO, U.S.A.) 100 mg/kg intrave- nously (i.v.). An indwelling catheter was then placed in the right femoral vein for administration of strychnine or pentylenetetrazol (PTZ; Knoll Phar- maceutical, Whippany, NJ, U.S.A.) to induce seizure or tremor, respectively, and for supplemental anesthesia as dictated by the needs of the dog throughout the experimental trials. For this study, tremors were defined as rhythmic alternating contractions of opposing muscle groups, exerting much less force than seizure contractions. The dogs were cared for in compliance with the Principles of Lab- oratory Animal Care (National Society for Medical Research, U.S.A.) and the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, Bethesda, MD, U.S.A.).

Electrode application The cervical vagus nerve was exposed high in the

neck between the branching points of the superior pharyngeal and recurrent nerves. Care was taken to eliminate excessive connective tissue and to avoid drying of the nerve. Electrical stimulation was applied to the nerve through either a cuff (Stein et al., 1977; Hoffer et al., 1981) or hook electrodes. The nerve cuff, consisting of stainless-steel braided-wire electrodes embedded in silicone rubber or Teflon, maintains interelectrode separation and contact of the electrodes with the cervical vagus nerve so that the geometry of current is relatively constant for repeated stimulation. The cylindrical cuff was posi- tioned parallel to the vagus nerve with the opening facing ventrally, and the nerve was slipped into the cuff through the opening. Two wire hook electrodes slipped under the nerve and pulled away from sur- rounding tissue were used for biphasic stimulation.

Monitoring Pressure in the right femoral artery was recorded

with a P23AC transducer (Grass Instrument, Quincy, MA, U.S.A.). The electrocardiogram (ECG) was recorded through pin electrodes inserted under the skin. Seizure activity was recorded by electromyography (EMG) with electrode pairs inserted in both gastrocnemius muscles. Respira- tion was recorded through a pressure cuff wrapped around the dogs abdomen or thorax and connected to a PT5A transducer (Grass). All variables were charted on a polygraph (Grass).

A functional monitor based on a respiratory response to cervical vagal stimulation, charted on the same polygraph, was used as an initial control pro- cedure to assure effective activation of inhibitory neurons in the appropriate nerve bundle. Stimula- tion of the cervical vagus produces a respiratory pattern resembling hyperventilation (Rice and Joy,

1947), a mild increase in the frequency of respiration. During the initial phase of the experiment after anesthesia was induced and before strychnine or PTZ was injected, stimulation parameters were adjusted in each dog to produce this respiratory response.

Stimulation parameters The electrical stimulus was delivered from the

pulse generator through lightweight, flexible, braided stainless-steel wire. To test the integrity of the electrodes, the impedance of each contact was measured at 30 Hz with a Grass impedance meter (Grass). Impedance values were steady and in the range of 1-5 R. Square pulses were applied at 15-100 V, 20-150 Hz; brief stimulus pulses (0.2-2 ms) were used to minimize electrode polarization. From Ohms law, currents were in the range of 3-100 mA, most likely in the range of 5-35 mA. Ranges for the threshold of effect in stopping seizures were then deter- mined by steadily increasing the voltage until an increase in respiratory response to cervical vagal stimulation (described above) was obtained and verified.

Stimulation trials In all trials, stimulation was started 1-3 min after

initial signs of seizure were observed on the EMG recording. After each stimulation trial, seizure activity was allowed to return spontaneously or, if it did not recur within 30 min, was again induced.

Strychnine seizures were produced by injecting 0.2-0.5 ml 1% solution of strychnine in distilled water through a catheter in the femoral vein at 1- to 4-min intervals until initial seizure activity was observed on the EMG recording; e.g., the convulsion shown in Fig. 1 resulted from 0.5-ml injections of strychnine at 0, 3.5, 7.4, 9.8, 11.8, 14.8, and 16.7 min. Individual convulsive twitches began after the last injection and climaxed in a high-frequency con- tinuously occurring seizure after 14.2 min. Repeti- tive vagal stimulation was then started. Latency from initiation of stimulation to cessation of the seizure episode was recorded for each trial. In one dog that received strychnine, a ramp-down was used to terminate stimulation: one of the stimulus parameters (amplitude, frequency, or duration) was gradually reduced (four trials) to determine whether an off effect, a myoclonic jerk occurring at termination of stimulation, could be diminished. In another dog, a ramp-up of one of the stimulus parameters was performed (four trials) to determine if latency in seizure suppression could be reduced. In two dogs that received strychnine, three trials were performed; the vagus nerve was then transected distal to the stimulating electrodes to determine if this would abolish seizure suppression.

Epilepsia, Vol. 33, No. 6, 1992

VAGAL INHIBITION OF SEIZURES 1007

1A RESPIRATION

TIME

EMG 1

EMG 2

EKG - 1 MIN STIMULATION STIMULATION

ON OFF

1B

RESPIRATION

TIME

EMGl--

EMG 2

- 1 MIN PTZ was administered at relatively small doses to

induce tremors, but not seizures, in two dogs. A 0.1% solution of PTZ in distilled water was pre- pared: 0.2-0.5 ml solution was injected through a catheter in the femoral vein at 1 - to 4-min incre- ments until tremor was observed on the EMG recording. Brief, repetitive stimulus trains were applied for -30 s each (three trials in each dog). In three dogs that had spontaneous tremors apparently due to chloralose induction, the effects of vagal stimulation were tested (one trial in each dog) before strychnine was administered.

Because of potential injury to the dogs from the movement generated by seizure activity, each dog was loosely restrained in a supine position on a dog- board resting on top of a long rectangular table. The momentum of the seizure was dissipated by movement of the dog-board along the top of the table.

RESULTS

Strychnine produced sustained tonic-clonic seizures lasting a20 min. PTZ in the relatively low doses administered produced tremors in the two dogs so tested. In three dogs, spontaneous tremors occurred, apparently due to chloralose induction. The hyperventilatory response to vagal stimulation (described above) was quite consistent and was used as a reliable indication that the stimulating current was activating the fiber groups in the cervical vagus nerves that cause inhibition of motor seizures.

FIG. 1. Termination of strychnine-induced seizure activity by repetitive stimulation of the vagus nerve. A: Stimulation (60 Hz, 0.6 ms, 40 V) continued for a total duration of 4 min. Time intervals are in seconds. EMG 1, electromyogram from the left gastrocnemius; EMG 2, from the right gastrocnemius muscle. Heart beat (electrocardiogram) and respiration ceased temporarily at onset of stimulation. 8: Continuation of record shown in A. A 10.25-min interval occurred between the end of the recording shown in A and the start of the recording shown in B. Seizure activity was absent for a total duration of 20 min; i.e., during 4-min stimulation and for 16 min after stimulation. Seizure activity resumed near the end of the record.

Effect of vagal stimulation on strychnine-induced seizure activity

The intent of this study was to define the ranges of stimulus parameters that produce antiseizure activity and to estimate optimum values of the parameters. An ongoing seizure was clearly identified in the polygraph recordings based on the massive excursions of all monitors during seizure activity. Re- petitive stimulation was started 1-3 min after the initial signs of a seizure were detected. Seizures could be either interrupted or terminated by repetitive stimulation of the cervical vagus (Figs. 1-3). Transection of the vagus nerve distal to the electrodes had no observable effect on seizure suppression.

The recordings in Fig. 1 show that the time between the start of vagal stimulation and cessation of seizure activity was short:

1008 J. ZABARA

FIG. 2. A strychnine-induced seizure was observed as massive excursions in all channels. At stimulation onset (150 Hz, 0.8 ms, 90 V), seizure frequency decreased, and the seizure terminated in 4 s. A slow but steady decrease in respiration and heart rate (electrocardiogram) was apparent after initiation of stirnulation. Beyond the end of this record, stimulation continued for a total duration of 6.33 min. The seizure continued to be sup- pressed during this period and for 17 min more after st imulat ion was stopped (not shown). The total period of seizure absence was 23.33 min; after this period, seizure immediately returned in full strength and frequency.

STIMULATION

Apparently, therefore, vagal stimulation did not merely coincide with the spontaneous end of the seizure.

During seizures, the limb excursions appeared to remain at a constant level. Thus, either the limb excursions in the seizure appeared to occur in full intensity or they did not occur at all, as in a threshold phenomenon.

After suppression, the seizure did not recur immediately after stimulus termination, but rather after a variable period of time that was directly re- lated to stimulation duration (Fig. 1). In several cases, a delay of 4 min to seizure recurrence occurred for each 1 min of stimulation; e.g., after a 4-min stimulation period there was a 16-min hiatus before a seizure occurred (Fig. 1). Typically, application of stimulus trains produced long-term control of seizures and, after several sequential stimulation periods, seizures did not recur. In such cases, after a 30-min interval, another injection of strychnine was given to continue the experimental trials.

Heart and respiratory function (Figs. 1-4) were not impaired during seizures or vagal stimulation.

- .5MIN Rarely, there was a brief hiatus in the heart beat at onset of stimulation (Fig. lA), but the heart rate quickly stabilized.

Threshold for antiseizure effect of vagal stimulation A wide range of stimulus voltages, durations, and

frequencies were used in an attempt to define the optimal stimulus parameters for seizure suppression (Table 1). There were two main categories: stimulation that abolished seizures, and stimulations that reduced the frequency of clonic jerks 250%. The data show that the antiseizure effects of vagal stimulation were maximum at stimulation frequencies 230 Hz, and stimulus voltages a20 V are independent of duration of stimuli over the range used (0.2-2 ms). In addition, some evidence shows that stimulation frequencies 280 Hz are less effective than 60 Hz.

Off effect At cessation of stimulation, an off effect consist-

ing of one or several myoclonic jerks occurred in some trials (Fig. 1A). This effect could be prevented

I STIMULATION

ON

- .5 MIN

FIG. 3. A strychnine-induced seizure was observed as high-frequency excursions in all channels. Seizure frequency was greatly reduced immediately as stimulation (100 Hz, 0.8 ms, 85 V) started and abruptly terminates within 14 s of stimulus onset. This delay in seizure termination can be reduced to less than a second by a ramp-up in stimulus parameters. Stim- ulation continued beyond the end of this recording for a total duration of 4.67 min. After st imulat ion was stopped, the seizure did not return for a 21-min period (not shown). The time scale in this recording is the same as that in Fig. 2.

Epilepsia, Vol. 33, No. 6 , 1992


FIG. 4. A pentylenetetrazol- induced, preseizure tremor is evident in the electromyogram (EMG) tracings. Stimulation (70 RESPIRATION^^^^^^^^^^^^^ t 7 r P - 1

first black rectangle on the time trace and ended at the second black rectangle The tremors

and were absent for -85 s, well past cessation of stimulation.

both limb muscles almost si- multaneously and gradually increased in amplitude.

T---"-

_ _ _ _. -~ ~ Hz, 0.6 ms, 70 V) began at the TIME- - - r --

EMG 1- I_.- -

STIMULATION t - 1 MIN OFF

t stopped at onset of stimulation EMG 2-

STIMULATION Thereafter, tremors returned in ON

by a ramp-down in stimulation parameters, e.g., by reducing either the stimulus voltage or pulse width to zero in 10 s rather than terminating the stimulus abruptly. The brief, myoclonic jerk at cessation of stimulation shown in Fig. 1A is the same size as a single oscillation of the dog's limbs during a seizure episode. The seizure consisted of a high-frequency repetition of virtually identical jerks. These discrete movements are not distinguishable in the recording. The myoclonic jerk at the end of stimulation appeared to be a breakthrough of the seizure, an off effect, indicating that the full-blown seizure would have recurred at this time if it were not for a slowly developing and decaying inhibitory effect of the stimulation (Fig. 1B).

Effect of vagal stimulation on PTZ-induced subthreshold seizures (tremors)

Tremor induced with PTZ also was controlled by vagal stimulation in the two dogs so tested (Fig. 4). The tremors were observed on EMG recordings from the left and right gastrocnemius muscles. With initiation of stimulation, the tremors stopped and did not reappear for -55 s after stimulation was terminated. When the tremors returned, they usually did so with slowly increasing magnitude. Sei- zures, in contrast, recurred in their full magnitude. The level of voltage necessary to produce the inhibitory effect on tremors was usually less than that required to control seizures. Figure 4 shows that the prestimulation EMG 1 was greater than poststimu- lation; the reverse was true for EMG 2.

Three other dogs had spontaneous tremors, pre- sumably as a result of the chloralose anesthesia (Fig. 5) . Repetitive, brief stimulations were performed (Fig. 5 ) , but there was no discernible effect until the tremors stopped abruptly soon after the end of the last burst of stimuli. The tremors may have been terminated by a persistent inhibitory effect that was incremented by each burst of stimulation until it was strong enough to suppress the tremors. The data are not sufficient, however, to elimi-

nate the possibility that the tremors disappeared spontaneously at this time by coincidence.

DISCUSSION

Our results provide direct evidence that repetitive electrical stimulation of the vagus nerve in the neck can interrupt or terminate strychnine-induced seizures and PTZ-induced tremors in dogs. This inhibitory effect is not affected by transection of the vagus nerve distal to the stimulating site. Bilateral vagal stimulation produces no measurably greater effect than does unilateral stimulation, and right or left vagal stimulation is equally effective in controlling motor seizures (J. Zabara, unpublished observations, 1990). There appears to be a common site or mechanism which either vagal nerve bundle can activate equally to prevent seizures and which can be maximally activated by input from either vagal nerve. In previous studies (Chase and Nakamura, 1967; Chase et al., 1968), vagal stimulation-induced EEG changes appeared to be equivalent over both cortexes. These observations indicate that cervical vagal impulses develop bilateral activity in the brain.

Another consistent finding was that the inhibitory effects of repetitive vagal stimulation persist for a considerable time after termination of stimulation. A rough rule of thumb is that seizures are sup- pressed for a period four times as long as the duration of the stimulation; e.g., in the seizure shown in Fig. 1, stimulation duration was 4 min and seizure activity did not reappear for 16 min more. It is also true that seizures are terminated within several seconds after start of stimulation. These two findings indicate the presence of at least two components of the inhibitory process: a rapidly rising and decaying component (time scale of seconds) and a slowly rising and decaying component (time scale of many minutes).

The results of this study of canine seizures have been corroborated in experiments in other animals. Chronic focal seizures induced in monkeys with


1010 J . ZABARA

TABLE 1. Effect of vagal stimulation on seizures in relation to stimulation frequency, voltage, and pulse

width: 100% (category A ) or 50% (category B) seizure decrease"

Seizure decrease"

(%I

Stimulation frequency

(HzI

Category A 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50

Category B

150 100 100 100 100 80 80 80 80 80 70 60 60 60 60 60 60 60 60 60 60 40 40 30

100 100 I00 100 100 80 80 80 80 80 80 80 60 60 60 60 60 60 60 60 60 20

V __

90 85 60 40 10 70 70 30 20 15 80 60 60 40 50 50 50 50 95 95

100 100 30 80

80 80

100 20 80 60 50 60 15 15 15 15 10 10 10 10 10 15 10 10 10 20

Pulse width (ms)

0.8 0.8 1 .0 0.3 0.2 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.8 0.6 0.6 0.6 0.6 0.2 0.2 0.3 0.3 0.6

1 .0 1 .0 0.5 0.2 0.2 0.5 0.5 0.6 0.2 0.6 0.6 0.6 2.0 2.0 2.0 2.0 2.0 0.6 0.6 0.6 0.2 0.2

~

a Experimental trial results: The aim of these studies was to find the ranges of stimulus parameters that produce antiseizure activity. In the 100% reduction category (A), the seizure was completely stopped during the stimulation period and usually for a period of time after the end of stimulation. In the 50% reduction category (B), the average frequency of clonic jerks was reduced >50% during the stimulation period. The parameters in these studies were 4 to 200 Hz, 1-100 V, and 0.2-2 ms, thus demon- strating a relatively wide range of parameter effectiveness. The trials were presented as a series of decreasing stimulation frequencies, with associated voltages and pulse widths.

alumina gel were then tested for the effects of repetitive vagal stimulation on seizure frequency. In two monkeys, seizures were abolished; the intersei- zure intervals became invariable in the remaining two monkeys (Lockard and Congdon, 1986; Lock- ard et al., 1990). Anticonvulsant effects of cervical vagal stimulation were also observed in seizures induced in rats with PTZ, 3-mercaptoproprionic acid, and maximal electroshock (Woodbury and Wood- bury, 1990, 1991).

Fiber types involved and estimation of optimum stimulus parameters

Apparently two different fiber groups exist, with opposite effects on the EEG (Garnier and Aubert, 1964; Chase and Nakamura, 1968). Stoica and Tu- dor (1967, 1968) observed significantly reduced EEG spiking of a cortical epileptic focus caused by strychnine with low-voltage stimulation of the cervical vagus, and obtained increased spiking with high-voltage stimulation. They concluded that this dual effect may result from activation of different categories of fibers.

Chase et al. (1967) investigated the refractory periods of the nerve groups in the cervical vagus of cats. Increases in stimulus voltage led to excitation of fiber groups with successively higher thresholds and slower conduction velocities. When the voltage and duration of the stimulus were adjusted to excite fibers submaximally in a specific fiber group, an increase in the frequency of stimulation >20/s resulted in a reduction in spike amplitude. The data in Table 1 indicate the types of nerve fibers that produce the antiseizure effect and a preliminary estimate of the optimum stimulus parameters.

Stimulus amplitude Antiseizure effects appear to plateau at or below

20 V. Electrode impedances ranged from 1 to 5 R at 30 Hz. Taking the middle value, the current flow at 20 V was -7 mA (range 4-20 mA). This is a high value, indicating that the inhibitory fibers have small diameters and thus high thresholds. This is consistent with the findings of Woodbury and Woodbury (1990), who concluded that stimulation of small unmyelinated (C) fibers produced the antiseizure effect. For comparison, the values used in studies in humans are usually 0.5-2.0 mA (Ham- mond et al., 1990; Penry and Dean, 1990).

Stimulus frequency Maximum antiseizure effects were obtained at

>20-Hz frequencies, with some indication that >60-Hz frequencies reduce the effect. This finding again suggests that the inhibitory influence is car-



EMG 1- --__rc

EMG 2 2

- .5 MIN ried on small-diameter fibers that cannot sustain im- pulse frequencies 260 Hz. Probably only unmyelinated fibers fit this category.

Stimulus duration Stimulus durations between 0.2 and 2 ms had no

detectable effect on the strength of the antiseizure effect. This result is useful because it is important to minimize average current flow through the electrodes. At any frequency, the average current increases directly with duration; hence, the shortest pulse that does not decrease the antiseizure effect should be used. Thus, the optimum stimulus duration is -0.2 ms.

The data indicate that small unmyelinated nerve fibers must be stimulated to produce an antiseizure effect. The optimum stimulus parameters estimated from the data shown in Table 1 are: stimulus frequency 20-30 Hz, stimulus strength 10-20 V, and stimulus duration -0.2 ms.

Long-term suppression of seizures has been observed in patients implanted with the NCP for cervical vagal stimulation (Hammond et al., 1990; Penry and Dean, 1990; Wilder et al., 1991). Their results are consistent with the results of the present study.

Acknowledgment: I thank Drs. J. Walter Woodbury and Dixon Woodbury for reading the manuscript and making valuable suggestions for revision.

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FIG. 5. Effects of vagal stimulation on spontaneous leg tremors. These are prominent in electromyogram (EMG) 2 tracings. Stimulation periods are indicated by black rectangles on the time trace. At the end of several brief periods of stimulation (60 Hz, 1 .O ms, 15 V), the tremors terminated and did not return.

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(SUPPI 2):S7-20.

&SUME

La stimulation Clectrique rCpCtCe du nerf vague cervical chez le chien interrompt ou abolit les crises motrices induites par la strychnine et les tremblements induits par pentylenetCtrazol (PTZ). Ces tremblements sont dCfinis comme des contractions alternantes rythmiques de groupes musculaires opposCs, exer- Eant une force bien infkrieure B celle des contractions critiques. Les crises ont CtC induites par des bolus dinjections de strychnine ou de PTZ a intervalles de 1 a 4 minutes, jusquh obtention sur IEMG dune activitC musculaire soutenue. La stimulation

vagale a interrompu les crises en 0.5 a 5.0 secondes. De longues pCriodes sans activite EMG spontanee ont CtC observees apres stimulation. La ptriode de protection ttait denviron 4 fois la periode de stimulation. Lactivite anti-crise de la stimulation vagale na pas CtC modifiCe par la transection du vague distale a ltlectrode de stimulation. Les parametres optimaux de stimulation ont CtC estimes comme suit : intensit6 environ 20 volts (resistance de IClectrode de 1 a 5 Kohm); frtquence 20 2 30 Hz; durCe environ 0.2 rns. Ces donnCes suggbrent que les effets anti- crises proviennent de la stimulation des fibres amytliniques af- fkrentes de petit diametre du nerf vague. Ces rCsultats peuvent constituer une base pour une nouvelle approche thkrapeutique de lepilepsie.

(P. Genton, Marseille)

ZUSAMMENFASSUNG

Die repetitive Stimulation des zervikalen N. vagus bei Nagern unterbricht oder bringt motorische durch Strychnin erzeugte An- falle sowie durch Pentylentetrazol (PTZ) erzeugten Tremor zum Verschwinden. Tremor wurde definiert als rhythmische alterni- erende Kontraktion von antagonisierenden Muskelgruppen mit weniger Kraftentfaltung als bei Antfallen. Die Anfalle wurden durch Bolusinjektion von Strychnin oder PTZ in 1 4 Minuten Intervallen bis zu anhaltender Muskelaktivitat im EMG erzeugt. Die Vagusstimulation beendete die Anfalle in 0.5 bis 5.0 Sek. Es gab verlangerte Perioden ohne spontanes EMG nach der Stimu- lation. Die Protektionsdauer betrug ungefahr das Vierfache der Stimulationsperiode. Die antikonvulsive Wirkung der Valguss- timulation wurde durch Transektion des Vagus distal zur Stim- uluselektrode nicht verandert. Als optimaler Stimulusparameter wurde geschatzt: Reizstarke 20 Volt (Elektrodenwiderstand 1-5 kOhm); Frequenz 20 bis 30 Hz; Reizdauer 0,2 ms. Die Daten zeigen, daR die antikonvulsive Wirkung von der Stimulation kleinkalibriger afferenter, unmyelinierter Vagusfasern herruhrt. Die Ergebnisse konnen vielleicht die Grundlage eines neuen therapeutischen Ansatzes bei Epilepsie sein.

(C. K. Benninger, Heidelberg)


Documents

Inhibition of Experimental Seizures After Vagal Stimulation