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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 sei- zures
induced by strychnine and tremors induced by pen- tylenetetrazol
(PTZ). Tremors were defined as rhythmic alternating contractions of
opposing muscle groups, ex- erting 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 stimula-
tion terminated seizures in 0.5-5 s. There were prolonged periods
with no spontaneous EMG activity after stimula- tion. 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 stimu- lus parameters were
estimated: strength, -20 V (elec- trode 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 unmy- elinated 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
pro- jections 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 af- ferent 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 stim- ulation significantly reduced EEG spiking
of a cor- tical 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 termi- nate
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 com- plex 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 cer- vical 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 stud- ies was to determine the ranges of
stimulus param- eters (amplitude, repetition, frequency, and dura-
tion) 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 sei- zure 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 con- tractions
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
ap- plied 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 in-
serted 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 re- sponse 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 respira- tion. During
the initial phase of the experiment after anesthesia was induced
and before strychnine or PTZ was injected, stimulation parameters
were ad- justed in each dog to produce this respiratory re-
sponse.
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 thresh- old
of effect in stopping seizures were then deter- mined by steadily
increasing the voltage until an in- crease in respiratory response
to cervical vagal stim- ulation (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 ac- tivity 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 wa- ter through a catheter in
the femoral vein at 1- to 4-min intervals until initial seizure
activity was ob- served 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 sei- zure episode was
recorded for each trial. In one dog that received strychnine, a
ramp-down was used to terminate stimulation: one of the stimulus
parame- ters (amplitude, frequency, or duration) was gradu- ally
reduced (four trials) to determine whether an off effect, a
myoclonic jerk occurring at termi- nation of stimulation, could be
diminished. In an- other dog, a ramp-up of one of the stimulus
param- eters was performed (four trials) to determine if la- tency
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
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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 re- cording.
Brief, repetitive stimulus trains were ap- plied 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) be- fore
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
move- ment of the dog-board along the top of the table.
RESULTS
Strychnine produced sustained tonic-clonic sei- zures 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 strych- nine-induced seizure activity by
repetitive stimulation of the va- gus nerve. A: Stimulation (60 Hz,
0.6 ms, 40 V) continued for a total duration of 4 min. Time in-
tervals are in seconds. EMG 1, electromyogram from the left
gastrocnemius; EMG 2, from the right gastrocnemius mus- cle. Heart
beat (electrocardio- gram) and respiration ceased temporarily at
onset of stimula- tion. 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 ac- tivity and to estimate
optimum values of the param- eters. An ongoing seizure was clearly
identified in the polygraph recordings based on the massive ex-
cursions 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 repet- itive stimulation of the cervical vagus (Figs.
1-3). Transection of the vagus nerve distal to the elec- trodes had
no observable effect on seizure suppres- sion.
The recordings in Fig. 1 show that the time be- tween the start
of vagal stimulation and cessation of seizure activity was
short:
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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 fre- quency decreased, and the seizure ter- minated
in 4 s. A slow but steady de- crease in respiration and heart rate
(electrocardiogram) was apparent af- ter 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; af- ter this period, seizure immediately re- turned 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 thresh- old phenomenon.
After suppression, the seizure did not recur im- mediately after
stimulus termination, but rather af- ter 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 oc- curred
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, appli- cation 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 suppres- sion (Table 1). There were
two main categories: stimulation that abolished seizures, and
stimula- tions that reduced the frequency of clonic jerks 250%. The
data show that the antiseizure effects of vagal stimulation were
maximum at stimulation fre- quencies 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 effec- tive 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 ex- cursions in all channels. Seizure fre- quency
was greatly reduced immedi- ately as stimulation (100 Hz, 0.8 ms,
85 V) started and abruptly terminates within 14 s of stimulus
onset. This de- lay in seizure termination can be re- duced 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
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VAGAL INHIBITION OF SEIZURES 1009
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 in-
creased 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 ap-
peared 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 usu- ally did so with slowly increasing magnitude.
Sei- zures, in contrast, recurred in their full magnitude. The
level of voltage necessary to produce the inhib- itory 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 per- formed (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 ef- fect that was incremented
by each burst of stimula- tion until it was strong enough to
suppress the trem- ors. 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 repeti- tive electrical
stimulation of the vagus nerve in the neck can interrupt or
terminate strychnine-induced seizures and PTZ-induced tremors in
dogs. This in- hibitory 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 control- ling motor seizures (J. Zabara,
unpublished obser- vations, 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 dura- tion
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 sec- onds 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 ris- ing 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
Epilepsia, Vol. 33, No. 6 , 1992
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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 fre-
quencies, with associated voltages and pulse widths.
alumina gel were then tested for the effects of re- petitive
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 in- duced 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 cer- vical 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 pe- riods 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 re- sulted in a reduction in
spike amplitude. The data in Table 1 indicate the types of nerve
fibers that pro- duce the antiseizure effect and a preliminary
esti- mate 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 an-
tiseizure 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-
Epilepsia, Vol. 33, No. 6 , 1992
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VAGAL INHIBITION OF SEIZURES 1011
EMG 1- --__rc
EMG 2 2
- .5 MIN ried on small-diameter fibers that cannot sustain im-
pulse frequencies 260 Hz. Probably only unmyelin- ated 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 elec- trodes. At any frequency, the
average current in- creases directly with duration; hence, the
shortest pulse that does not decrease the antiseizure effect should
be used. Thus, the optimum stimulus dura- tion 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
fre- quency 20-30 Hz, stimulus strength 10-20 V, and stimulus
duration -0.2 ms.
Long-term suppression of seizures has been ob- served in
patients implanted with the NCP for cer- vical 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.
REFERENCES Aubert ML, Egros J. Projections du nerfvague sur le
neocortex
du chat. J Physiol 1963;2:109. Bailey P, Bremer F. A sensory
cortical representation of the
vagus nerve. J Neurophysiol 1938;1:405-12. Chase MH, Nakamura Y.
Cortical and subcortical EEG patterns
of response to afferent abdominal vagal stimulation: neuro-
graphic correlates. Physiol Behav 1968;3:605-10.
Chase MH, Nakamura Y, Clemente CD. Afferent vagal stimu- lation:
neurographic correlates of induced EEG synchroniza- tion and
desynchronization. Brain Res 1967;5:23649.
DAmelio FE, Mehler WR, Gibbs MA, et al. Immunocytochem- ical
localization of glutamic acid decarboxylase (GAD) and
glutaminesynthetase (GS) in the area postrema of the cat. Light and
electron microscopy. Brain Res 1987;410:232-44.
Dell P, Olson R. Projections secondaires mesencephaliques,
di-
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.
encephaliques et amygdaliennes des afferences viscerales va-
gales. C R Soc Biol (Paris) 1951;145:1088-91.
Garnier L , Aubert M. Modifications delelectroencephalo- gramme
du chat consecutives a la stimulation du nerf vague. C R Soc Biol
(Paris) 1964;158:2405-8.
Grastyan E, Hasznos T, Lissak L. Activation of the brain stem
activating system by vegetative afferents. Acta Physiol Scand Sci
Hung 1952;3:102-22.
Hammond EJ, Ramsay ER, Uthman BM, Reid SA, Wilder BJ. Vagus
nerve stimulation in humans: neurophysiological stud- ies and
electrophysiological monitoring. Epilepsia 1990;31
Hennemann HE, Rubia FJ. Vagal representation in the cerebel- lum
of the cat. Pflugers Arch 1978;375:119-23.
Hoffer JA, Loeb GE, Pratt CA. Single unit conduction velocities
from averaged nerve cuff electrode records in freely moving cats. J
Neurosci Methods 1981;4:211-25.
Juhasz G , Detari L, Kukorelli T. Effects of hypnogenic vagal
stimulation on thalamic neuronal activity in cats. Bruin Res Bull
1985;15:437-41.
Kimehiko-Too T, Dussardier M. Convergence sur les cellules de la
formation reticulaire bulbaire dafferences vagales et daf- ferences
des membres. .I Physiol 1963;2: 179.
Lockard JS, Congdon WC. Effects of vagal stimulation on sei-
zure rate in monkey model. Epilepsia 1986;27:626.
Lockard JS, Congdon WC, DuCharme LL. Feasibility and safety of
vagal stimulation in monkey model. Epilepsia 1990;31(suppl
2):S20-7.
OBrien JH, Pimpaneau A, Albe-Fessard D. Evoked cortical re-
sponses to vagal, laryngeal and facial afferents in monkeys under
chloralose anaesthesia. Electroencephalogr Clin Neu- rophysiol 197
1 ;3 1 :7-20.
Padel Y, Dell P. Effets bulbaires et reticulaires des
stimulation- sendormantes du tronc vago-aortique. J Physiol (Paris)
1965;
Paintal AS. Vagal sensory receptors and their reflex effects.
Physiol Rev 1973;53:159-227.
Penry JK, Dean JC. Prevention of intractable partial seizures by
intermittent vagal stimulation in humans: preliminary results.
Epilepsiu 1990;3 l(suppl 2): S40-4.
Rice HV, Joy MS. Modifications of respiratory movements by vagal
stimulation. A m J Physiol 1947;149:24-42.
Schweitzer A, Wright S. Effects on the knee jerk of stimulation
of the central end of the vagus and of various changes in the
circulation and respiration. J Physiol 1937;88:459-75.
Serkov FN, Bratus NV. Electrical responses of the hippocampus to
stimulation of the vagus nerve. In: Rusinov VS, ed. Elec-
trophysiology of the central nervous system. New York: Ple- num,
1970;391402.
Siegfried J. Topographie des projections corticales du nerf
vagus chez le chat. Helv Physiol Pharmacol Acta 1961;19:269-78.
Sobusiak T, Zimny R, Matlosz Z. Primary glossopharyngeal and
vagal afferent projection into the cerebellum in the dog. J
Hirnforsch 1971;13:117-34.
Stein RB, Nichols TR, Jhamandas J, et al. Stable long-term re-
cordings from cat peripheral nerves. Brain Res 1977;128:21- 38.
(SUPPI 2):S51-9.
57: 269-70.
Epilepsia, Vol. 33, No. 6 , 1992
-
1012 J . ZABARA
Stoica I, Tudor I. Effects of vagus afferents on strychninic
focus of coronal gyrus. Rev Roum Neurol 1967;4:287-95.
Stoica I, Tudor I. Vagal trunk stimulation influences on
epileptic spiking focus activity. Rev Roum Neurol
1968;5:203-10.
Varbanova A. The role of the rhythmic vagal impulses in the
appearance of paroxysmal EEG activity (in English). Izv lnst Fiziol
(Sofiya) 1972;14:63-83.
Wilder BJ, ed. Vagus nerve stimulation for the control of epi-
lepsy. Epilepsia 1990;31(suppl 2):S140.
Wilder BJ, Uthman BM, Hammond EJ. Vagal stimulation for control
of complex partial seizures in medically refractory epileptic
patients. PACE 1991 ;14: 108-15.
Woodbury DM, Woodbury JW. Effects of vagal stimulation and
experimentally induced seizures in rats. Epilepsia 1990;3 1
Woodbury JW, Woodbury DM. Vagal stimulation reduces the severity
of maximal electroshock seizures in intact rats: use of a cuff
electrode for stimulating and recording. PACE 1991; 14:94-107.
Zabara J. Control of hypersynchronous discharge in epilepsy.
Electroencephalogr Clin Neurophysiol 1985a ;6 1 : 162.
Zabara J . Time course of seizure control to brief, repetitive
stirn- uli. Epilepsia 1985b;26: 5 18.
Zabara J. Controlling seizures by changing GABA receptor sen-
sitivity. Epilepsia 1987;28:604.
Zanchetti A, Wang SC, Moruzzi G. The effect of vagal stimula-
tion on the EEG pattern of the cat. Electroencephalogr Clin
Neurophysiol 1952;4:357-61.
(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 strych- nine 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 va-
gale na pas CtC modifiCe par la transection du vague distale a
ltlectrode de stimulation. Les parametres optimaux de stimula- tion
ont CtC estimes comme suit : intensit6 environ 20 volts (re-
sistance 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)
Epilepsia, Vol. 33, No. 6 , 1992