Epilepsia, 33(6): 1013-1 020, 1992 Raven Press, Ltd., New York 0 International League Against Epilepsy
Electrophysiological Studies of Cervical Vagus Nerve Stimulation in Humans: I. EEG Effects Edward J. Hammond, Basim M. Uthman, *Steven A. Reid, and B. J. Wilder Neurology Service and *Neurosurgery Section, Department of Veterans Affairs Medical Center, Gainesville, Florida, U . S . A .
~
Summary: Evidence from studies of experimental animals indicates that electrical stimulation of the vagus nerve alters EEGs under certain stimulus parameters. We report EEG effects of electrical stimulation of the vagus nerve in 9 patients with medically intractable seizures as part of a clinical trial of chronic vagal stimulation for control of epilepsy. The mechanism of action of the vagal antiepileptic effect is unknown, and we believed that analysis of electrophysiologic effects of vagal nerve stim-
ulation would help elucidate the brain areas affected. The left vagus nerve in the neck was stimulated with a programmable implanted stimulator. Stimulation at various stimulus frequencies and amplitudes had no noticeable effect on EEG activity whether the patient was under general anesthesia, awake, or asleep, but vagus nerve stimulation may interrupt ongoing ictal EEG activity. Key Words: Vagus nerve-Electrical stimulation-Electroencephalogram.
Stimulation of the vagus nerve in experimental animals can cause profound changes in the EEG (Zanchetti et al., 1952; Chase et al., 1967, 1968; Chase and Nakamura, 1968), and vagal stimulation can markedly decrease EEG spiking of a cortical epileptogenic focus caused by topical or systemic administration of strychnine (Stoica and Tudor, 1967, 1968; Zabara, 1985). Woodbury and Woodbury (1990) showed that vagal stimulation has an antiepileptic effect in several different animal models of epilepsy. For this reason, we conducted a controlled clinical trial of chronic vagus nerve stimulation in medically intractable patients (Hammond et al., 1990; Uthman et al., 1990; Wilder et al., 1991). Because the mechanism of the antiepileptic effect of vagus nerve stimulation is unknown, we believed that a study of brain areas that appear to be affected by vagus nerve stimulation would help elucidate the neural mechanism of this effect. For this reason, we studied not only the EEG under waking, sleeping, and anesthetized conditions, but also the scalp topography of the vagus nerve evoked potential and the effects of vagus nerve stimulation on various evoked potentials. We now describe the EEG ef-
fects; a subsequent article (Hammond et al., 1992) deals with evoked activity.
Received December 1991 ; revision accepted March 1992. Address correspondence and reprint requests to Dr. E. J. Hammond at Neurology Service (127), Veterans Affairs Medical1 Center, Gainesville, FL, 32608-1 197, U.S.A.
METHODS AND MATERIALS We studied nine patients aged 21-58 years who had medically intractable complex seizures. All patients gave written informed consent for participation in the study. The Cyberonics (Houston, TX, U .S.A.) model 100, an implantable, programmable pulse generator that delivers electrical signals to the vagus nerve, was implanted subcutaneously (s.c.) in the upper chest (Fig. 1). A bipolar stimulation lead (Fig. 2) was tunneled S.C. from the pulse generator to the left vagus nerve (Reid, 1990). The impedence of the stimulating electrode-nerve interface was 800-1,000 R in each patient. The system can be programmed with an IBM-compatible personal computer, interface unit, and software. The pulse width, output current, duty cycle, and signal frequency may be adjusted noninvasively . Sixteenchannel EEGs were recorded with an electroencephalograph (Grass Instruments, Quincy, MA, U.S.A.), and Fourier analysis of EEG signals was performed with a Cadwell 8400 (Kennewick, WA, U.S.A.) analysis system. For quantitative EEG analysis, the power spectrum of each EEG signal was obtained by means of fast Fourier transformation. The frequency span of this analysis was from 1013
1014
E. J . HAMMOND ET A L .
1 to 20 Hz, and the duration of each analyzed epoch was 30 s. Some additional analyses were made using 10-s epochs. RESULTS Effects on normal EEG rhythms Vagus stimulation (at stimulus frequencies of 1, 5 , 10, and 50 Hz) had no effect on the EEG of awake or anesthetized patients (Figs. 3-5). Fourieranalysis EEGs also confirmed the lack of any noticeable effect (Figs. 6 and 7). EEG during sleep was studied in all-night recordings stored on a laser disk. During sleep, each patient was studied at 50Hz stimulation, but no effects on EEG were apparent. Effects on interictal epileptiform activity There were no obvious effects of stimulation on iterictal EEG activity in 2 patients with long bursts of epileptiform sharp activity (Figs. 8 and 9). Many bursts obtained during several recording sessions
FIG. 2. Bipolar stimulating electrode that is wrapped around the vagus nerve in our patients. The electrode is shown wrapped around a piece of plastic tubing.
Epilepsia, Vol. 33, No. 6, 1992
(with various stimulus rates) were carefully examined. No changes in burst duration or morphology could be detected when the bursts occurred spontaneously during stimulation of the vagus nerve. Similarly, vagal stimulation did not appear to alter either the waveform or frequency of occurrence of interictal temporal lobe spiking. This was studied acutely in 2 patients with frequent (-Us) spiking; interictal spiking during vagal stimulation continued unchanged. Similarly, in the other patients with occasional interictal epileptiform EEG abnormalities, no changes were apparent after chronic (weeks Or months) stimulation. Another patient showed long
1015
VAGUS NERVE STIMULATION: EFFECTS ON EEG
bursts of unilateral temporal theta activity; vagal stimulation did not alter this activity. Effects on ictal epileptiform activity Vagus nerve stimulation at onset of the seizures in 1 patient abruptly terminated the behavioral and EEG seizure activity (Fig. 10). This phenomenon was repeated twice. In another patient who experi-
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FIG. 5. Vagus nerve stimulation on EEG during stage II sleep in patient C04, a 32-year-old man with complex partial and secondarily generalized seizures receiving carbamazepine. A: No stimulus, B: 50 Hz, 1 mA, 250-ps stimulus. Normal sleep spindle is shown.
enced auras, the stimulator was manually activated by the patient at onset of the aura. Bilateral rhythmical delta activity was abruptly terminated before any epileptiform activity was noted. In this type of study, the time interval between experiencing an aura and development of EEG epileptiform patterns is an important variable. Some patients whose complex partial seizures began with an aura reported that they were able to abort seizure evolution and that no effect on the seizure was noted if the stimulator was activated too late. We ourselves activated the device in 3 patients who were well into a seizure, but noted no EEG or behavioral effect. Epilepsia, Vol. 33, No. 6, 1992
E . J . HAMMOND ET A L .
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nection in the region of the nucleus of the solitary tract and the area postrema. Presumably, synchronized bursts of potentials could then be dispersed to widespread areas of the brain. The effect of vagal stimulation in experimental animals most relevant to this study is modulation of EEG activity. Depending on the stimulus parameters, vagal stimulation in animals can produce EEG synchronization or desynchronization. High-frequency vagal stimulation can produce orbitofrontal cortex EEG fast activity (Bailey and Bremer, 1938). In cats, stimulation of the vagus produces EEG desynchronization and blocks sleep spindle occurrence during slow wave sleep (Zanchetti et al., 1952). Stimulation of the nucleus of the solitary tract at low frequencies (1-16 Hz) produces EEG synchronization, whereas at high frequencies (>30 Hz), stimulation results in EEG desynchronization (Magnes et al., 1961). Zanchetti et al. (1952) re-
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FIG. 6. Compressed spectral arrays taken from four recording sites (Fz,T3, 01, 02) referred to linked ears. Patient is awake with eyes closed. Vertical lines at left indicate time when vagus nerve stimulator is turned on. Patient CO1 is a 58-year-old man with complex partial and secondarily generalized seizures receiving phenytoin and carbamazepine. A: Stimulus frequency l/s (3.0 mA, 250-ps pulse width). B: Stimulus frequency 1O/s (3.0 mA, 250-ps pulse width).
Effects on hyperventilation-induced EEG slowing Balzamo et al. (1991) showed that in anesthetized cats, vagal afferents played a major role in producing the EEG responses to hyperventilation. They indicated that the EEG effects of vagal stimulation could be related to a desynchronizing effect and postulated that in humans vagal stimulation could counteract the effects of hyperventilation. We studied effects of vagal stimulation on hyperventilationinduced EEG changes in 4 patients but noted no obvious effect (visual analysis). Figure 11 shows EEG slowing persisting unabated during vagal stimulation. DISCUSSION As the diffuse projections Of the Of the Solitary tract suggest, stimulation of Vagd afferents could profound effects on CNS function. the vagus potentials conducted along the afferent fibers to the first synaptic conEpilepsia, Vol. 33, N o . 6 , 1992
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FIG. 7. Compressed spectral arrays. Recording conditions were similar to those of patient described in legend to Fig. 6. Patient C07, a 37-year-old man with simple partial, complex partial, and secondarily generalized seizures was receiving phenytoin and carbamazepine. A: Stimulus frequency l/s (2.0 mA, 250-ps pulse width). B: Stimulus frequency 1O/s (2.0 mA, 250-ps pulse width).
VAGUS NERVE STIMULATION: EFFECTS ON EEG
ported that the EEG response to afferent cervical vagus nerve stimulation was one of cortical activation. Grastyan et al. (1952) reported the same result, but in contrast to Zanchetti et al. (1952) described the occasional appearance of cortical spindles and slow waves when the vagus nerve was stimulated. Diverse results have been reported by other investigators (Bonvallet and Sigg, 1958; Garnier and Aubert, 1964). In our studies, vagal stimulation did not appear to block the appearance of sleep spindles (Fig. 5). Balzamo and colleagues (Balzamo and Jammes, 1990; Balzamo et al., 1990) stimulated the vagus nerve in anesthetized cats and made epidural recordings from many cortical locations. They noted that EEG rhythms recorded on the posterior sigmoid cortex could be changed by either repetitive electrical stimulation of all vagal afferents, chemical activation of vagal C fibers, or selective mechanical stimulation of lung receptors. These changes were characterized by depressed spontaneous background rhythms resembling desynchronization, by lengthening of intervals between spindles, and/or by alterations in EEG spindle pattern. Most of these changes caused by vagal stimulation occurred in 70/s frequencies (with stimulus amplitude s 3 V) induced EEG synchronization. This response was indistinguishable from the EEG patterns typically observed during
1017
spontaneous slow-wave sleep in cats. In their studies, EEG spindles and slow waves developed from a desynchronized background with a latency of 1040 s. Vagal stimulation had no effect if the EEG was previously synchronized. If the stimulating intensity was raised to >3 V and delivered at a rate of >70/s, the result was cortical desynchronization. Vagal-induced EEG synchronization or desynchronization appeared to be bilaterally symmetric. Chase et al. (1967) suggested that the factors determining the nature of the EEG response to vagal stimulation might not be the stimulation parameters themselves but rather the differential activation of specific fiber groups in the vagus nerve. They compared vagus nerve compound action potentials with
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FIG. 9. lnterictal epileptiform EEG activity recorded during ongoing vagal nerve stimulation. Stimulus parameters 2.0 mA, 250-ks pulse width at 1O/s in patient C05, a 29-year-old man with complex partial and secondarily generalized seizures receiving phenytoin and carbamazepine. Epilepsia, Vol. 33, No. 6, 1992
VAGUS NERVE STIMULATION: EFFECTS ON EEG \
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FIG. 11. Hyperventilation-induced EEG slowing during vagal stimulation. Slowing appeared to continue unchanged during stimulation. A: Stimulus parameters 2 mA, 250 ps, at 20/s in patient C 0 3 (clinical details are given in legend to Fig. 3). 6: Stimulus parameters 1 mA, 250-ps at 1O/s in patient M05, an 18-year-old woman with simple and complex partial seizures.
manuscript preparation and Charlotte Mixon for figure preparation.
REFERENCES Bailey P, Bremer F. A sensory cortical representation of the vagus nerve. J Neurophysiol 1938;1:405-12. Balzamo E, Gayan-Ramirez G, Jammes Y. Pulmonary vagal sensory afferents and spontaneous EEG rhythms in the cat sensorimotor cortex. J Auton Nerv System 1990;30:149-58. Balzamo E, Jammes Y . Vagal afferents and EEG rhythms in the S1 area in anesthetized cats: similarities between responses
1019
to electrical and chemical (phenyldiguanide) stimulations. Arch Int Physiol Biochim 1990;97:483-92. Balzamo E, Gayan-Ramirez G, Jammes Y . Quantitative EEG changes under various conditions of hyperventilation in sensorimotor cortex of the anaesthetized cat. Electroencephalogr Clin Neurophysiol 1991;78:15945. Bonvallet M, Sigg B. Etude electrophysiologique des afferentes vagales au niveau de leur penetration dans le bulbe. J Physiol (Lond) 1958;50:63-74. Chase MH, Nakamura Y , Clemente CD. Afferent vagal stimulation: neurographic correlates of induced EEG synchronization and desynchronization. Brain Res 1967;5:23649. Chase MH, Nakamura Y. Cortical and subcortical EEG patterns of response to afferent abdominal vagal stimulation: neurographic correlates. Physiol Behav 1968;3:605-10. Chase MH, Sterman MB, Clemente CD. Cortical and subcortical patterns of response to afferent vagal stimulation. Exp Neurol 1968;16:3W9. Garnier L, Aubert M. Modifications de I'electroencephalogramme du chat consecutives a la stimulation du nerf vague. C R Soc Biol (Paris) 1964;158:2405-8. Grastyan E , Hasznos T, Lissa KL. Activation of the brainstem activating system by vegetative afferents. Acta Physiol Scand Sci 1952;3:102-22. Hallin RG, Torebjork HE. Activity in unmyelinated nerve fibers in man. Fahn S , Calne DB, Shoulson I, et al., eds. Experimental therapeutics of movement disorders. 1974:19-27. (Advances in neurology; vol 37.) Hammond EJ, Uthman BM, Wilder BJ, Reid SA. Vagus nerve stimulation in humans: neurophysiological studies and electrophysiological monitoring. Epilepsia 1990;31(suppl 2): s51-9. Hammond EJ, Uthman BM, Reid SA, Wilder BJ. Electrophysiological studies of cervical vagus nerve stimulation in humans: 11. Evoked potentials. Epilepsia 1992;33:1021-8. Hoffman HH, Kuntz A. Vagus nerve components. Anat Rec 195732755 1-67. Magnes J , Moruzzi G , Pompeiano 0. Synchronization of the EEG produced by low frequency electrical stimulation of the region of the solitary tract. Arch Ital Biol 1961;99:33-67. Mei N, Condamin M, Boyer A. The composition of the vagus nerve in the cat. Cell Tissue Res 1980;209:423-31. Paintal AS. Vagal afferent fibers. Ergehn Physiol 1963;52:74156. Puizillout JJ, Gambarelli F. Electrophysiological and morphological properties of type C vagal neurons in the nodose ganglion of the cat. J Auton Nerv Syst 1989;29:49-58. Reid SA. Surgical technique for implantation of the neurocybernetic prosthesis. Epilepsia 1990;31(suppl 2):S38-9. Santamaria J, Chiappa KH. The EEG of drowsiness in normal adults. J Clin Neurophysiol 1987;4:327-82. Stoica I, Tudor I. Effects of vagus afferents on strychninic focus of coronal gyms. 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. Uthman BM, Wilder BJ, Hammond EJ, Reid SA. Efficacy and safety of vagus nerve stimulation in patients with complex partial seizures. Epilepsia 1990;3l(suppl 2):544-50. Wilder BJ, Uthman BM, Hammond EJ. Vagal stimulation for control of complex partial seizures in medically refractory epileptic patients. PACE 1991 ;14:108-1 5. Woodbury DM, Woodbury JW. Effects of vagal stimulation on experimentally induced seizures in rats. Epilepsia 1990;31 (SUPPI2):S7-19. Zabara J . Peripheral control of hypersynchronous discharge in epilepsy. Electroencephalogr Clin Neurophysiol 1985;61: S162. Zanchetti A, Wang SC, Moruzzi G. The effect of vagal stimulation on the EEG pattern of the cat. Electroencephalogr Clin Neurophysiol 1952;4:357461. Epilepsia, Vol. 33, No. 6, 1992
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E. J . HAMMOND ET AL. RkSUME
ZUSAMMENFASSUNG
Les rtsultats d’Ctudes effectukes en exptrimentation animale indiquent que la stimulation tlectrique du nerf vague modifie l’tlectroenctphalogramme (EEG) lorsque certains parametres de stimulation sont respectts. Les auteurs rapportent les effets sur 1’EEG d’une stimulation Blectrique du nerf vague chez 9 patients prtsentant des crises rebelles aux traitements, cette etude fait partie d’un essai clinique d’une stimulation vagale chronique pour le contr8le de l’tpilepsie. Le mtcanisme d’action antitpileptique d e la stimulation vagale n’est pas connu, et les auteurs ont pens6 que l’analyse des effets electrophysiologiques de la stimulation vagale pourraient aider B mieux cerner les zones c t rCbrales concernkes. Une stimulation du nerf vague gauche au niveau du cou a t t t effectute au moyen d’un stimulateur implant6 programmable. L a stimulation B diffkrentes frkquences et amplitudes n’a pas eu d’effets notables sur I’activitt EEG, indtpendamment de la situation du patient (anesthtsie gtnkrale, veille, sommeil). Cependant, la stimulation du nerf vagal peut interrompre une activitt EEG critique en cours.
Aus tierexperimentellen Untersuchungen geht hervor, daR die elektrische Vagusstimulation bei bestimmten Stimulusparametern das EEG andert. Wir berichten uber EEG-Wirkungen der elektrischen Vagusstimulation bei 9 Patienten mit therapierefraktaren Anfallen als Teil eines klinischen Versuchs zur Epilepsiebehandlung mit chronischer Vagusstimulation. Die Wirkungsweise des antiepileptischen Effektes ist unbekannt, und wir dachten, daB die Analyse der elektrophysiologischen Wirkung der Vagusstimulation zur Bestimmung der beteiligten Hirnareale beitragen kann. Die Stimulation des linken N . vagus im Nacken wurde mit einem programmierbaren implantierten Stimulator vorgenommen. Die Stimulation rnit verschiedenen Frequenzen und Amplituden hatte keine merkbare Wirkung auf das EEG, unabhangig davon, ob die Patienten anaesthesiert, wach oder im Schlaf waren. Trotzdem ist es moglich, daB eine Vagusstimulation auftretende iktale EEG-Aktivitat unterbrechen kann.
(P. Genton, Mumeilk)
(C. K. Benninger, Heidelherg)
Epilepsia, Vol. 33, NO. 6 , 1992
Electrophysiological Studies of Cervical Vagus Nerve Stimulation in Humans: I. EEG Effects Edward J. Hammond, Basim M. Uthman, *Steven A. Reid, and B. J. Wilder Neurology Service and *Neurosurgery Section, Department of Veterans Affairs Medical Center, Gainesville, Florida, U . S . A .
~
Summary: Evidence from studies of experimental animals indicates that electrical stimulation of the vagus nerve alters EEGs under certain stimulus parameters. We report EEG effects of electrical stimulation of the vagus nerve in 9 patients with medically intractable seizures as part of a clinical trial of chronic vagal stimulation for control of epilepsy. The mechanism of action of the vagal antiepileptic effect is unknown, and we believed that analysis of electrophysiologic effects of vagal nerve stim-
ulation would help elucidate the brain areas affected. The left vagus nerve in the neck was stimulated with a programmable implanted stimulator. Stimulation at various stimulus frequencies and amplitudes had no noticeable effect on EEG activity whether the patient was under general anesthesia, awake, or asleep, but vagus nerve stimulation may interrupt ongoing ictal EEG activity. Key Words: Vagus nerve-Electrical stimulation-Electroencephalogram.
Stimulation of the vagus nerve in experimental animals can cause profound changes in the EEG (Zanchetti et al., 1952; Chase et al., 1967, 1968; Chase and Nakamura, 1968), and vagal stimulation can markedly decrease EEG spiking of a cortical epileptogenic focus caused by topical or systemic administration of strychnine (Stoica and Tudor, 1967, 1968; Zabara, 1985). Woodbury and Woodbury (1990) showed that vagal stimulation has an antiepileptic effect in several different animal models of epilepsy. For this reason, we conducted a controlled clinical trial of chronic vagus nerve stimulation in medically intractable patients (Hammond et al., 1990; Uthman et al., 1990; Wilder et al., 1991). Because the mechanism of the antiepileptic effect of vagus nerve stimulation is unknown, we believed that a study of brain areas that appear to be affected by vagus nerve stimulation would help elucidate the neural mechanism of this effect. For this reason, we studied not only the EEG under waking, sleeping, and anesthetized conditions, but also the scalp topography of the vagus nerve evoked potential and the effects of vagus nerve stimulation on various evoked potentials. We now describe the EEG ef-
fects; a subsequent article (Hammond et al., 1992) deals with evoked activity.
Received December 1991 ; revision accepted March 1992. Address correspondence and reprint requests to Dr. E. J. Hammond at Neurology Service (127), Veterans Affairs Medical1 Center, Gainesville, FL, 32608-1 197, U.S.A.
METHODS AND MATERIALS We studied nine patients aged 21-58 years who had medically intractable complex seizures. All patients gave written informed consent for participation in the study. The Cyberonics (Houston, TX, U .S.A.) model 100, an implantable, programmable pulse generator that delivers electrical signals to the vagus nerve, was implanted subcutaneously (s.c.) in the upper chest (Fig. 1). A bipolar stimulation lead (Fig. 2) was tunneled S.C. from the pulse generator to the left vagus nerve (Reid, 1990). The impedence of the stimulating electrode-nerve interface was 800-1,000 R in each patient. The system can be programmed with an IBM-compatible personal computer, interface unit, and software. The pulse width, output current, duty cycle, and signal frequency may be adjusted noninvasively . Sixteenchannel EEGs were recorded with an electroencephalograph (Grass Instruments, Quincy, MA, U.S.A.), and Fourier analysis of EEG signals was performed with a Cadwell 8400 (Kennewick, WA, U.S.A.) analysis system. For quantitative EEG analysis, the power spectrum of each EEG signal was obtained by means of fast Fourier transformation. The frequency span of this analysis was from 1013
1014
E. J . HAMMOND ET A L .
1 to 20 Hz, and the duration of each analyzed epoch was 30 s. Some additional analyses were made using 10-s epochs. RESULTS Effects on normal EEG rhythms Vagus stimulation (at stimulus frequencies of 1, 5 , 10, and 50 Hz) had no effect on the EEG of awake or anesthetized patients (Figs. 3-5). Fourieranalysis EEGs also confirmed the lack of any noticeable effect (Figs. 6 and 7). EEG during sleep was studied in all-night recordings stored on a laser disk. During sleep, each patient was studied at 50Hz stimulation, but no effects on EEG were apparent. Effects on interictal epileptiform activity There were no obvious effects of stimulation on iterictal EEG activity in 2 patients with long bursts of epileptiform sharp activity (Figs. 8 and 9). Many bursts obtained during several recording sessions
FIG. 2. Bipolar stimulating electrode that is wrapped around the vagus nerve in our patients. The electrode is shown wrapped around a piece of plastic tubing.
Epilepsia, Vol. 33, No. 6, 1992
(with various stimulus rates) were carefully examined. No changes in burst duration or morphology could be detected when the bursts occurred spontaneously during stimulation of the vagus nerve. Similarly, vagal stimulation did not appear to alter either the waveform or frequency of occurrence of interictal temporal lobe spiking. This was studied acutely in 2 patients with frequent (-Us) spiking; interictal spiking during vagal stimulation continued unchanged. Similarly, in the other patients with occasional interictal epileptiform EEG abnormalities, no changes were apparent after chronic (weeks Or months) stimulation. Another patient showed long
1015
VAGUS NERVE STIMULATION: EFFECTS ON EEG
bursts of unilateral temporal theta activity; vagal stimulation did not alter this activity. Effects on ictal epileptiform activity Vagus nerve stimulation at onset of the seizures in 1 patient abruptly terminated the behavioral and EEG seizure activity (Fig. 10). This phenomenon was repeated twice. In another patient who experi-
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FIG. 5. Vagus nerve stimulation on EEG during stage II sleep in patient C04, a 32-year-old man with complex partial and secondarily generalized seizures receiving carbamazepine. A: No stimulus, B: 50 Hz, 1 mA, 250-ps stimulus. Normal sleep spindle is shown.
enced auras, the stimulator was manually activated by the patient at onset of the aura. Bilateral rhythmical delta activity was abruptly terminated before any epileptiform activity was noted. In this type of study, the time interval between experiencing an aura and development of EEG epileptiform patterns is an important variable. Some patients whose complex partial seizures began with an aura reported that they were able to abort seizure evolution and that no effect on the seizure was noted if the stimulator was activated too late. We ourselves activated the device in 3 patients who were well into a seizure, but noted no EEG or behavioral effect. Epilepsia, Vol. 33, No. 6, 1992
E . J . HAMMOND ET A L .
1016
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nection in the region of the nucleus of the solitary tract and the area postrema. Presumably, synchronized bursts of potentials could then be dispersed to widespread areas of the brain. The effect of vagal stimulation in experimental animals most relevant to this study is modulation of EEG activity. Depending on the stimulus parameters, vagal stimulation in animals can produce EEG synchronization or desynchronization. High-frequency vagal stimulation can produce orbitofrontal cortex EEG fast activity (Bailey and Bremer, 1938). In cats, stimulation of the vagus produces EEG desynchronization and blocks sleep spindle occurrence during slow wave sleep (Zanchetti et al., 1952). Stimulation of the nucleus of the solitary tract at low frequencies (1-16 Hz) produces EEG synchronization, whereas at high frequencies (>30 Hz), stimulation results in EEG desynchronization (Magnes et al., 1961). Zanchetti et al. (1952) re-
IO/sec STIMULUS
n
01
l/SeC STIMULUS
FIG. 6. Compressed spectral arrays taken from four recording sites (Fz,T3, 01, 02) referred to linked ears. Patient is awake with eyes closed. Vertical lines at left indicate time when vagus nerve stimulator is turned on. Patient CO1 is a 58-year-old man with complex partial and secondarily generalized seizures receiving phenytoin and carbamazepine. A: Stimulus frequency l/s (3.0 mA, 250-ps pulse width). B: Stimulus frequency 1O/s (3.0 mA, 250-ps pulse width).
Effects on hyperventilation-induced EEG slowing Balzamo et al. (1991) showed that in anesthetized cats, vagal afferents played a major role in producing the EEG responses to hyperventilation. They indicated that the EEG effects of vagal stimulation could be related to a desynchronizing effect and postulated that in humans vagal stimulation could counteract the effects of hyperventilation. We studied effects of vagal stimulation on hyperventilationinduced EEG changes in 4 patients but noted no obvious effect (visual analysis). Figure 11 shows EEG slowing persisting unabated during vagal stimulation. DISCUSSION As the diffuse projections Of the Of the Solitary tract suggest, stimulation of Vagd afferents could profound effects on CNS function. the vagus potentials conducted along the afferent fibers to the first synaptic conEpilepsia, Vol. 33, N o . 6 , 1992
lO/sec STIMULUS
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e
e
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FIG. 7. Compressed spectral arrays. Recording conditions were similar to those of patient described in legend to Fig. 6. Patient C07, a 37-year-old man with simple partial, complex partial, and secondarily generalized seizures was receiving phenytoin and carbamazepine. A: Stimulus frequency l/s (2.0 mA, 250-ps pulse width). B: Stimulus frequency 1O/s (2.0 mA, 250-ps pulse width).
VAGUS NERVE STIMULATION: EFFECTS ON EEG
ported that the EEG response to afferent cervical vagus nerve stimulation was one of cortical activation. Grastyan et al. (1952) reported the same result, but in contrast to Zanchetti et al. (1952) described the occasional appearance of cortical spindles and slow waves when the vagus nerve was stimulated. Diverse results have been reported by other investigators (Bonvallet and Sigg, 1958; Garnier and Aubert, 1964). In our studies, vagal stimulation did not appear to block the appearance of sleep spindles (Fig. 5). Balzamo and colleagues (Balzamo and Jammes, 1990; Balzamo et al., 1990) stimulated the vagus nerve in anesthetized cats and made epidural recordings from many cortical locations. They noted that EEG rhythms recorded on the posterior sigmoid cortex could be changed by either repetitive electrical stimulation of all vagal afferents, chemical activation of vagal C fibers, or selective mechanical stimulation of lung receptors. These changes were characterized by depressed spontaneous background rhythms resembling desynchronization, by lengthening of intervals between spindles, and/or by alterations in EEG spindle pattern. Most of these changes caused by vagal stimulation occurred in 70/s frequencies (with stimulus amplitude s 3 V) induced EEG synchronization. This response was indistinguishable from the EEG patterns typically observed during
1017
spontaneous slow-wave sleep in cats. In their studies, EEG spindles and slow waves developed from a desynchronized background with a latency of 1040 s. Vagal stimulation had no effect if the EEG was previously synchronized. If the stimulating intensity was raised to >3 V and delivered at a rate of >70/s, the result was cortical desynchronization. Vagal-induced EEG synchronization or desynchronization appeared to be bilaterally symmetric. Chase et al. (1967) suggested that the factors determining the nature of the EEG response to vagal stimulation might not be the stimulation parameters themselves but rather the differential activation of specific fiber groups in the vagus nerve. They compared vagus nerve compound action potentials with
,?lA-BT
T6-A2.,
% -L -
1 sec
AWAKE -50
HI STIMULUS
FIG. 9. lnterictal epileptiform EEG activity recorded during ongoing vagal nerve stimulation. Stimulus parameters 2.0 mA, 250-ks pulse width at 1O/s in patient C05, a 29-year-old man with complex partial and secondarily generalized seizures receiving phenytoin and carbamazepine. Epilepsia, Vol. 33, No. 6, 1992
VAGUS NERVE STIMULATION: EFFECTS ON EEG \
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FIG. 11. Hyperventilation-induced EEG slowing during vagal stimulation. Slowing appeared to continue unchanged during stimulation. A: Stimulus parameters 2 mA, 250 ps, at 20/s in patient C 0 3 (clinical details are given in legend to Fig. 3). 6: Stimulus parameters 1 mA, 250-ps at 1O/s in patient M05, an 18-year-old woman with simple and complex partial seizures.
manuscript preparation and Charlotte Mixon for figure preparation.
REFERENCES Bailey P, Bremer F. A sensory cortical representation of the vagus nerve. J Neurophysiol 1938;1:405-12. Balzamo E, Gayan-Ramirez G, Jammes Y. Pulmonary vagal sensory afferents and spontaneous EEG rhythms in the cat sensorimotor cortex. J Auton Nerv System 1990;30:149-58. Balzamo E, Jammes Y . Vagal afferents and EEG rhythms in the S1 area in anesthetized cats: similarities between responses
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to electrical and chemical (phenyldiguanide) stimulations. Arch Int Physiol Biochim 1990;97:483-92. Balzamo E, Gayan-Ramirez G, Jammes Y . Quantitative EEG changes under various conditions of hyperventilation in sensorimotor cortex of the anaesthetized cat. Electroencephalogr Clin Neurophysiol 1991;78:15945. Bonvallet M, Sigg B. Etude electrophysiologique des afferentes vagales au niveau de leur penetration dans le bulbe. J Physiol (Lond) 1958;50:63-74. Chase MH, Nakamura Y , Clemente CD. Afferent vagal stimulation: neurographic correlates of induced EEG synchronization and desynchronization. Brain Res 1967;5:23649. Chase MH, Nakamura Y. Cortical and subcortical EEG patterns of response to afferent abdominal vagal stimulation: neurographic correlates. Physiol Behav 1968;3:605-10. Chase MH, Sterman MB, Clemente CD. Cortical and subcortical patterns of response to afferent vagal stimulation. Exp Neurol 1968;16:3W9. Garnier L, Aubert M. Modifications de I'electroencephalogramme du chat consecutives a la stimulation du nerf vague. C R Soc Biol (Paris) 1964;158:2405-8. Grastyan E , Hasznos T, Lissa KL. Activation of the brainstem activating system by vegetative afferents. Acta Physiol Scand Sci 1952;3:102-22. Hallin RG, Torebjork HE. Activity in unmyelinated nerve fibers in man. Fahn S , Calne DB, Shoulson I, et al., eds. Experimental therapeutics of movement disorders. 1974:19-27. (Advances in neurology; vol 37.) Hammond EJ, Uthman BM, Wilder BJ, Reid SA. Vagus nerve stimulation in humans: neurophysiological studies and electrophysiological monitoring. Epilepsia 1990;31(suppl 2): s51-9. Hammond EJ, Uthman BM, Reid SA, Wilder BJ. Electrophysiological studies of cervical vagus nerve stimulation in humans: 11. Evoked potentials. Epilepsia 1992;33:1021-8. Hoffman HH, Kuntz A. Vagus nerve components. Anat Rec 195732755 1-67. Magnes J , Moruzzi G , Pompeiano 0. Synchronization of the EEG produced by low frequency electrical stimulation of the region of the solitary tract. Arch Ital Biol 1961;99:33-67. Mei N, Condamin M, Boyer A. The composition of the vagus nerve in the cat. Cell Tissue Res 1980;209:423-31. Paintal AS. Vagal afferent fibers. Ergehn Physiol 1963;52:74156. Puizillout JJ, Gambarelli F. Electrophysiological and morphological properties of type C vagal neurons in the nodose ganglion of the cat. J Auton Nerv Syst 1989;29:49-58. Reid SA. Surgical technique for implantation of the neurocybernetic prosthesis. Epilepsia 1990;31(suppl 2):S38-9. Santamaria J, Chiappa KH. The EEG of drowsiness in normal adults. J Clin Neurophysiol 1987;4:327-82. Stoica I, Tudor I. Effects of vagus afferents on strychninic focus of coronal gyms. 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. Uthman BM, Wilder BJ, Hammond EJ, Reid SA. Efficacy and safety of vagus nerve stimulation in patients with complex partial seizures. Epilepsia 1990;3l(suppl 2):544-50. Wilder BJ, Uthman BM, Hammond EJ. Vagal stimulation for control of complex partial seizures in medically refractory epileptic patients. PACE 1991 ;14:108-1 5. Woodbury DM, Woodbury JW. Effects of vagal stimulation on experimentally induced seizures in rats. Epilepsia 1990;31 (SUPPI2):S7-19. Zabara J . Peripheral control of hypersynchronous discharge in epilepsy. Electroencephalogr Clin Neurophysiol 1985;61: S162. Zanchetti A, Wang SC, Moruzzi G. The effect of vagal stimulation on the EEG pattern of the cat. Electroencephalogr Clin Neurophysiol 1952;4:357461. Epilepsia, Vol. 33, No. 6, 1992
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E. J . HAMMOND ET AL. RkSUME
ZUSAMMENFASSUNG
Les rtsultats d’Ctudes effectukes en exptrimentation animale indiquent que la stimulation tlectrique du nerf vague modifie l’tlectroenctphalogramme (EEG) lorsque certains parametres de stimulation sont respectts. Les auteurs rapportent les effets sur 1’EEG d’une stimulation Blectrique du nerf vague chez 9 patients prtsentant des crises rebelles aux traitements, cette etude fait partie d’un essai clinique d’une stimulation vagale chronique pour le contr8le de l’tpilepsie. Le mtcanisme d’action antitpileptique d e la stimulation vagale n’est pas connu, et les auteurs ont pens6 que l’analyse des effets electrophysiologiques de la stimulation vagale pourraient aider B mieux cerner les zones c t rCbrales concernkes. Une stimulation du nerf vague gauche au niveau du cou a t t t effectute au moyen d’un stimulateur implant6 programmable. L a stimulation B diffkrentes frkquences et amplitudes n’a pas eu d’effets notables sur I’activitt EEG, indtpendamment de la situation du patient (anesthtsie gtnkrale, veille, sommeil). Cependant, la stimulation du nerf vagal peut interrompre une activitt EEG critique en cours.
Aus tierexperimentellen Untersuchungen geht hervor, daR die elektrische Vagusstimulation bei bestimmten Stimulusparametern das EEG andert. Wir berichten uber EEG-Wirkungen der elektrischen Vagusstimulation bei 9 Patienten mit therapierefraktaren Anfallen als Teil eines klinischen Versuchs zur Epilepsiebehandlung mit chronischer Vagusstimulation. Die Wirkungsweise des antiepileptischen Effektes ist unbekannt, und wir dachten, daB die Analyse der elektrophysiologischen Wirkung der Vagusstimulation zur Bestimmung der beteiligten Hirnareale beitragen kann. Die Stimulation des linken N . vagus im Nacken wurde mit einem programmierbaren implantierten Stimulator vorgenommen. Die Stimulation rnit verschiedenen Frequenzen und Amplituden hatte keine merkbare Wirkung auf das EEG, unabhangig davon, ob die Patienten anaesthesiert, wach oder im Schlaf waren. Trotzdem ist es moglich, daB eine Vagusstimulation auftretende iktale EEG-Aktivitat unterbrechen kann.
(P. Genton, Mumeilk)
(C. K. Benninger, Heidelherg)
Epilepsia, Vol. 33, NO. 6 , 1992
