- Email: [email protected]
Vagus nerve stimulation inhibits harmaline-induced tremor
Brain Research 1011 (2004) 135 – 138 www.elsevier.com/locate/brainres
Short communication
Vagus nerve stimulation inhibits harmaline-induced tremor Scott E. Krahl a,b,*, Fredricka C. Martin a, Adrian Handforth a,c a
Research and Development Service, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA b Division of Neurosurgery, University of California, Los Angeles, Los Angeles, CA 90025, USA c Neurology Service, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA Accepted 23 March 2004 Available online 27 April 2004
Abstract Excessive olivo-cerebellar burst-firing occurs during harmaline-induced tremor. This system receives rich sensory inputs, including visceral. We hypothesized that electrical vagus nerve stimulation (VNS) would suppress harmaline tremor, as measured with digitized motion power in the rat. Cervical vagus nerve stimulation suppressed power in the 8 – 12-Hz tremor range by 40%, whereas sham stimulation was ineffective. This study raises the possibility that activation of various sensory modalities, as well as visceral, may reduce tremor. Published by Elsevier B.V. Theme: Motor systems and sensorimotor integration Topic: Control of posture and movement Keywords: Tremor; Harmaline; Essential tremor; Vagus nerve stimulation; Electrical stimulation
Harmaline-induced tremor is an experimental animal model that shares features with human essential tremor. Harmaline tremor has a similar frequency to that of essential tremor, and occurs with posture and kinesis. Harmaline tremor can be suppressed by drugs utilized clinically for essential tremor, including beta-adrenoceptor blockers [17] and benzodiazepines [12]. Both harmaline tremor and essential tremor are inhibited by ethanol [7,19], and both display increased energy metabolism in the cerebellum [2,25]. Evidence suggests an abnormality in inferior olive (IO) function in essential tremor [5]. Harmaline is believed to induce tremor experimentally via its effects on IO, especially the medial accessory IO [4]. These cells normally fire at 0.25 –2 Hz; harmaline increases this to 4– 10 Hz [4,21] and induces large cell groups to fire in rhythmic hypersynchrony [14]. Via climbing fibers, rhythmic firing is propagated to Purkinje neurons, especially in the vermis [4,14], then to the deep cerebellar nuclei [1], which in turn drive other portions of the motor system [1], culminating in tremor [23]. * Corresponding author. VA Greater Los Angeles Healthcare System, Bldg. 114, Suite 217, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA. Tel.: +1-310-268-3352; fax: +1-310-268-4811. E-mail address: [email protected] (S.E. Krahl). 0006-8993/$ - see front matter. Published by Elsevier B.V. doi:10.1016/j.brainres.2004.03.021
Physiological studies have indicated that the IO and cerebellum are responsive to visceral sensory stimuli through the splanchnic nerve [18]. IO cell firing rate is also affected by afferent vagus nerve activation. Electrical vagus nerve stimulation (VNS) elicits cerebellar-evoked potentials via IO climbing fibers [10,22]. Because IO neuronal firing rate is affected by vagal visceral inputs, it may be expected that vagal activation may disrupt the olivary hypersynchronous rhythmic firing that underlies harmaline tremor. Accordingly, we hypothesized that VNS would suppress harmaline-induced tremor in the rat. In this report, we tested this hypothesis utilizing digital motion quantitation. Fifteen adult male 300 –350 g Long-Evans rats (Harlan, San Diego, CA) were housed singly with ad libitum food and water access in a 12/12-h light/dark cycle. Procedures were approved by the institutional animal care and use committee, and conformed to the U.S. Animal Welfare Act. Under ketamine/xylazine (75:15 mg/kg) anaesthesia, the left cervical vagus nerve was exposed and a cuff electrode placed around it. Leads were tunneled subcutaneously to a connector cemented to the dorsal skull [13]. Two days after surgery, each animal’s VNS leads were connected to a constant current stimulator (A-M Systems,
136
S.E. Krahl et al. / Brain Research 1011 (2004) 135–138
Fig. 1. Spectral analysis of movement during pre-harmaline baseline (dark line) and after harmaline administration (light line) in an example rat. Motion power, which is directly related to mass and acceleration acting on a strain gauge, and expressed as mV2, was sampled at 0.03-Hz bandwidths over 10 min. A moving-average smoothing function was applied to generate interpretable spectra. Data were collected from 0 to 17 Hz. The increase in motion power between 8 and 12 Hz corresponds to harmalineinduced tremor.
Everett, WA). Habituation to the tremor monitor chamber for 20 min preceded data collection. Pre-harmaline baseline motion activity was collected for 10 min. Tremor was then induced with harmaline (30 mg/kg, i.p.), and another 10 min of motion data collected. On completion of this harmaline tremor pre-stimulation condition, VNS or sham stimulation was initiated. Continuous VNS consisted of 20-Hz, 0.5-ms charge-balanced biphasic pulses delivered at a 0.5-mA current intensity. Sham-stimulated animals were connected in an identical fashion, but did not receive current. Motion data during VNS or sham stimulation were collected for 10 min. The stimulation lead was connected to a covered relay switch that was set by one of the investigators to route current either to the vagus nerve or to a shunt. The assignment of animals to VNS or sham stimulation was randomized, with the order of randomization determined prior to the experiment. The technician performing the experiment had no knowledge of the relay setting and was thus blinded to the treatment condition. At the end of each experiment, the blinded technician judged whether each animal received active stimulation, based on observations of the tremor response. The tremor monitor chamber consisted of a metal platform resting on a strain gauge (Columbus Instruments, Columbus OH) surrounded by a Plexiglas cage. The strain gauge was connected to an electrical amplifier (Grass Instruments, Quincy, MA) that transmitted data to a computer acquisition system (DataWave Technologies, Boulder, CO). This system digitized data into spectral power analyses using the fast Fourier transformation (FFT) method. This
method calculates ‘‘power’’, a function of both the frequency and force of the rats’ movements within the cage. Previously reported studies [20,24] and our own preliminary data determined that most harmaline-induced tremor is expressed within the 8 – 12-Hz frequency range. Rats not treated with harmaline express low motion power in this range. Thus, the total power between 8 and 12 Hz was used as a measure of tremor severity. VNS suppresses pentylenetetrazol (PTZ)-induced seizures in rats [13]. This property was employed to assess the viability of the surgical preparation in each subject. At least 24 h after the tremor experiment, continuous VNS, using the same parameters described above, was initiated, and PTZ administered 30 s later (60 mg/kg, i.p.). VNS was continued another 15 min, during which the highest seizure severity attained was scored on a 0– 6 rating scale [13]. At least 48 h later, rats were given PTZ without VNS. Tremor data were discarded from two animals that did not demonstrate a seizure severity reduction of at least 50% with VNS compared to the no-VNS PTZ seizure condition. Spectral analysis during pre-harmaline baseline demonstrated relatively uniform moderate motion power in the 0– 17-Hz range, as depicted by the example in Fig. 1. Harmaline induced a marked increase in the 8 – 12-Hz range, corresponding to observed tremor, and contrasting with the low power in this range during non-tremor baseline (Fig. 1). VNS reduced harmaline-associated 8 – 12 Hz motion power by 40% ( p < 0.05, Student’s t-test), indicating suppression of harmaline-induced tremor by VNS. In contrast,
Fig. 2. Mean motion power (mV2) in the 8- to 12-Hz bandwidth in six sham- and seven VNS-stimulated rats during pre-harmaline baseline (Base), harmaline pre-stimulation (Harm), and harmaline sham- or VNS stimulation treatment (Treat) conditions; each condition lasted 10 min. Means F S.E.M. are shown. *p < 0.05, Student’s t-test as compared to harmaline prestimulation condition.
S.E. Krahl et al. / Brain Research 1011 (2004) 135–138
sham stimulation caused no significant change in 8– 12-Hz motion power, indicating that harmaline-induced tremor was not changed by sham stimulation (Fig. 2). Sham stimulation resulted in three out of six rats demonstrating increased tremor and three showing decreased tremor. Of the seven rats in the treated group, two had increased, and five had decreased, tremor following VNS. Detachment of a lead led to unblinding of the observer to the condition of one sham-stimulated animal. For the remaining rats, the blinded observer correctly judged the treatment condition based on tremor change in five of the seven VNS- and four of the five sham-stimulated animals ( p < 0.05, Chi-square). In summary, we tested the hypothesis that VNS suppresses tremor in the harmaline model by using a randomized parallel-group design, with blinding of the observer to the treatment condition. Digital quantitation of motion power in the 8 –12-Hz tremor range was analyzed. The viability of the preparation was validated by checking whether VNS suppressed PTZ-induced seizures. These results demonstrate that VNS significantly reduces harmaline-associated 8– 12-Hz motion power. The degree of reduction, 40%, was comparable to the 50% reduction reported with different methodology [8]. In addition, this degree of tremor reduction was comparable to the 50% reduction of accelerometry-measured tremor in a pilot feasibility clinical study of VNS for essential tremor [9]. Stimulation of vagal afferents presumably desynchronizes the rhythmic hypersynchronous burst-firing within the olivo-cerebellar system that underlies harmaline tremor. The anatomic route by which VNS suppresses tremor is not known, but several anatomic projection systems are candidate pathways. Vagal afferents have been reported to project directly to IO [6]. The main target of vagal afferents is the solitary nucleus complex, and most of these projection are bilateral [11]. The lateral solitary subnucleus reportedly projects to the medial accessory IO [15], although there is some disagreement on this point [3]. The nucleus of the solitary tract may also influence the IO and cerebellum indirectly via effects on brainstem nuclei. For example, VNS increases locus coeruleus cell firing [16]. The locus coeruleus has been found to be essential for the anti-seizure effect of VNS [13]. Electrical stimulation of the locus coeruleus suppresses harmaline tremor [26]; thus, VNS may suppress tremor via this mechanism. Vagal afferents comprise only a small portion of all sensory afferents to the olivocerebellar system. The partial efficacy of VNS in reducing tremor raises the interesting possibility that activation of other sensory modalities may be as effective or more effective in suppressing tremor.
Acknowledgements This study was supported by grants from Cyberonics and the U.S. Department of Veterans Affairs (AH and SEK). The
137
authors gratefully acknowledge the technical assistance of Shayani Senanayake.
References [1] C. Batini, J.F. Bernard, C. Buisseret-Delmas, M. Conrath-Verrier, G. Horcholle-Bossavit, Harmaline-induced tremor: II. Unit activity correlation in the interpositorubral and oculomotor systems of cat, Exp. Brain Res. 42 (1981) 383 – 391. [2] C. Batini, C. Buisseret-Delmas, M. Conrath-Verrier, Harmaline-induced tremor: I. Regional metabolic activity as revealed by [14C]2deoxyglucose in cat, Exp. Brain Res. 42 (1981) 371 – 382. [3] R.M. Beckstead, J.R. Morse, R. Norgren, The nucleus of the solitary tract in the monkey: projections to the thalamus and brain stem nuclei, J. Comp. Neurol. 190 (1980) 259 – 282. [4] J.F. Bernard, C. Buisseret-Delmas, C. Compoint, S. Laplante, Harmaline induced tremor: III. A combined simple units, horseradish peroxidase, and 2-deoxyglucose study of the olivocerebellar system in the rat, Exp. Brain Res. 57 (1984) 128 – 137. [5] H. Boecker, A.J. Wills, A. Ceballos-Baumann, M. Samuel, P.D. Thompson, L.J. Findley, D.J. Brooks, The effect of ethanol on alcohol-responsive essential tremor: a positron emission tomography study, Ann. Neurol. 39 (1996) 650 – 658. [6] J.L. Fitzakerley, G.E. Lucier, Connections of a vagal communicating branch in the ferret: II. Central projections, Brain Res. Bull. 20 (1988) 479 – 486. [7] J.H. Growdon, B.T. Shahani, R.R. Young, The effect of alcohol on essential tremor, Neurology 25 (1975) 259 – 262. [8] A. Handforth, S.E. Krahl, Suppression of harmaline-induced tremor in rats by vagus nerve stimulation, Mov. Disord. 16 (2001) 84 – 88. [9] A. Handforth, W.G. Ondo, S. Tatter, G.W. Mathern, R.K. Simpson, F. Walker, J.P. Sutton, J.P. Hubble, J. Jankovic, Effect of vagus nerve stimulation on essential tremor, Neurology 54 (Suppl. 3) (2000) 238. [10] H.E. Hennemann, F.J. Rubia, Vagal representation in the cerebellum of the cat, Pflugers Arch. 375 (1978) 119 – 123. [11] M. Kalia, M.-M. Mesulam, Brain stem projections of sensory and motor components of the vagus complex in the cat: II. Laryngeal, tracheobronchial, pulmonary, cardiac, and gastrointestinal branches, J. Comp. Neurol. 193 (1980) 467 – 508. [12] K. Kawanishi, Y. Hashimoto, M. Fujiwara, Y. Kataoka, S. Ueki, Pharmacological characteristics of abnormal behavior induced by harmine with special reference to tremor in mice, J. Pharmacobio-Dyn. 4 (1981) 520 – 527. [13] S.E. Krahl, K.B. Clark, D.C. Smith, R.A. Browning, Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation, Epilepsia 39 (1998) 709 – 714. [14] R. Llinas, R.A. Volkind, The olivo-cerebellar system: functional properties as revealed by harmaline-induced tremor, Exp. Brain Res. 18 (1973) 69 – 87. [15] A.D. Loewy, H. Burton, Nuclei of the solitary tract: efferent projections to the lower brain stem and spinal cord of the cat, J. Comp. Neurol. 181 (1978) 421 – 449. [16] S.D. Moore, P.G. Guyenet, An electrophysiological study of the forebrain projection of nucleus commissuralis; preliminary identification of presumed A2 catecholaminergic neurons, Brain Res. 263 (1983) 211 – 222. [17] V. Paul, Involvement of h2-adrenoceptor blockade and 5-hydroxytryptamine mechanism in inhibition of harmaline-induced tremors in rats, Eur. J. Pharmacol. 122 (1986) 111 – 115. [18] J. Perrin, J. Crousillat, Response of single units in the inferior olive nucleus to stimulation of the splanchnic afferents in the cat, J. Auton. Nerv. Syst. 2 (1980) 15 – 22. [19] M.S. Rappaport, R.T. Gentry, D.R. Schneider, V.P. Dole, Ethanol effects on harmaline-induced tremor and increase of cerebellar cyclic GMP, Life Sci. 34 (1984) 49 – 56.
138
S.E. Krahl et al. / Brain Research 1011 (2004) 135–138
[20] K. Semba, B.R. Komisaruk, Neural substrates of two different rhythmical vibrissal movements in the rat, Neuroscience 12 (1984) 761 – 774. [21] S.E. Stratton, J.F. Lorden, Effect of harmaline on cells of the inferior olive in the absence of tremor: differential response of genetically dystonic and harmaline-tolerant rats, Neuroscience 41 (1991) 543 – 549. [22] G. Tong, L.T. Robertson, J. Brons, Vagal and somatic representation by the climbing fiber system in lobule V of the cat cerebellum, Brain Res. 552 (1991) 58 – 66. [23] M. Weiss, Rhythmic activity of spinal interneurons in harmaline-trea-
ted cats. A model for olivo-cerebellar influence at the spinal level, J. Neurol. Sci. 54 (1982) 341 – 348. [24] J.P. Welsh, B. Chang, M.E. Menaker, S.A. Aicher, Removal of the inferior olive abolishes myoclonic seizures associated with a loss of olivary serotonin, Neuroscience 82 (1998) 879 – 897. [25] A.J. Wills, I.H. Jenkins, P.D. Thompson, L.J. Findley, D.J. Brooks, A positron emission tomography study of cerebral activation associated with essential and writing tremor, Arch. Neurol. 52 (1995) 299 – 305. [26] M. Yamazaki, C. Tanaka, S. Takaori, Significance of central noradrenergic system on harmaline induced tremor, Pharmacol. Biochem. Behav. 10 (1979) 421 – 427.
Short communication
Vagus nerve stimulation inhibits harmaline-induced tremor Scott E. Krahl a,b,*, Fredricka C. Martin a, Adrian Handforth a,c a
Research and Development Service, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA b Division of Neurosurgery, University of California, Los Angeles, Los Angeles, CA 90025, USA c Neurology Service, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA Accepted 23 March 2004 Available online 27 April 2004
Abstract Excessive olivo-cerebellar burst-firing occurs during harmaline-induced tremor. This system receives rich sensory inputs, including visceral. We hypothesized that electrical vagus nerve stimulation (VNS) would suppress harmaline tremor, as measured with digitized motion power in the rat. Cervical vagus nerve stimulation suppressed power in the 8 – 12-Hz tremor range by 40%, whereas sham stimulation was ineffective. This study raises the possibility that activation of various sensory modalities, as well as visceral, may reduce tremor. Published by Elsevier B.V. Theme: Motor systems and sensorimotor integration Topic: Control of posture and movement Keywords: Tremor; Harmaline; Essential tremor; Vagus nerve stimulation; Electrical stimulation
Harmaline-induced tremor is an experimental animal model that shares features with human essential tremor. Harmaline tremor has a similar frequency to that of essential tremor, and occurs with posture and kinesis. Harmaline tremor can be suppressed by drugs utilized clinically for essential tremor, including beta-adrenoceptor blockers [17] and benzodiazepines [12]. Both harmaline tremor and essential tremor are inhibited by ethanol [7,19], and both display increased energy metabolism in the cerebellum [2,25]. Evidence suggests an abnormality in inferior olive (IO) function in essential tremor [5]. Harmaline is believed to induce tremor experimentally via its effects on IO, especially the medial accessory IO [4]. These cells normally fire at 0.25 –2 Hz; harmaline increases this to 4– 10 Hz [4,21] and induces large cell groups to fire in rhythmic hypersynchrony [14]. Via climbing fibers, rhythmic firing is propagated to Purkinje neurons, especially in the vermis [4,14], then to the deep cerebellar nuclei [1], which in turn drive other portions of the motor system [1], culminating in tremor [23]. * Corresponding author. VA Greater Los Angeles Healthcare System, Bldg. 114, Suite 217, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA. Tel.: +1-310-268-3352; fax: +1-310-268-4811. E-mail address: [email protected] (S.E. Krahl). 0006-8993/$ - see front matter. Published by Elsevier B.V. doi:10.1016/j.brainres.2004.03.021
Physiological studies have indicated that the IO and cerebellum are responsive to visceral sensory stimuli through the splanchnic nerve [18]. IO cell firing rate is also affected by afferent vagus nerve activation. Electrical vagus nerve stimulation (VNS) elicits cerebellar-evoked potentials via IO climbing fibers [10,22]. Because IO neuronal firing rate is affected by vagal visceral inputs, it may be expected that vagal activation may disrupt the olivary hypersynchronous rhythmic firing that underlies harmaline tremor. Accordingly, we hypothesized that VNS would suppress harmaline-induced tremor in the rat. In this report, we tested this hypothesis utilizing digital motion quantitation. Fifteen adult male 300 –350 g Long-Evans rats (Harlan, San Diego, CA) were housed singly with ad libitum food and water access in a 12/12-h light/dark cycle. Procedures were approved by the institutional animal care and use committee, and conformed to the U.S. Animal Welfare Act. Under ketamine/xylazine (75:15 mg/kg) anaesthesia, the left cervical vagus nerve was exposed and a cuff electrode placed around it. Leads were tunneled subcutaneously to a connector cemented to the dorsal skull [13]. Two days after surgery, each animal’s VNS leads were connected to a constant current stimulator (A-M Systems,
136
S.E. Krahl et al. / Brain Research 1011 (2004) 135–138
Fig. 1. Spectral analysis of movement during pre-harmaline baseline (dark line) and after harmaline administration (light line) in an example rat. Motion power, which is directly related to mass and acceleration acting on a strain gauge, and expressed as mV2, was sampled at 0.03-Hz bandwidths over 10 min. A moving-average smoothing function was applied to generate interpretable spectra. Data were collected from 0 to 17 Hz. The increase in motion power between 8 and 12 Hz corresponds to harmalineinduced tremor.
Everett, WA). Habituation to the tremor monitor chamber for 20 min preceded data collection. Pre-harmaline baseline motion activity was collected for 10 min. Tremor was then induced with harmaline (30 mg/kg, i.p.), and another 10 min of motion data collected. On completion of this harmaline tremor pre-stimulation condition, VNS or sham stimulation was initiated. Continuous VNS consisted of 20-Hz, 0.5-ms charge-balanced biphasic pulses delivered at a 0.5-mA current intensity. Sham-stimulated animals were connected in an identical fashion, but did not receive current. Motion data during VNS or sham stimulation were collected for 10 min. The stimulation lead was connected to a covered relay switch that was set by one of the investigators to route current either to the vagus nerve or to a shunt. The assignment of animals to VNS or sham stimulation was randomized, with the order of randomization determined prior to the experiment. The technician performing the experiment had no knowledge of the relay setting and was thus blinded to the treatment condition. At the end of each experiment, the blinded technician judged whether each animal received active stimulation, based on observations of the tremor response. The tremor monitor chamber consisted of a metal platform resting on a strain gauge (Columbus Instruments, Columbus OH) surrounded by a Plexiglas cage. The strain gauge was connected to an electrical amplifier (Grass Instruments, Quincy, MA) that transmitted data to a computer acquisition system (DataWave Technologies, Boulder, CO). This system digitized data into spectral power analyses using the fast Fourier transformation (FFT) method. This
method calculates ‘‘power’’, a function of both the frequency and force of the rats’ movements within the cage. Previously reported studies [20,24] and our own preliminary data determined that most harmaline-induced tremor is expressed within the 8 – 12-Hz frequency range. Rats not treated with harmaline express low motion power in this range. Thus, the total power between 8 and 12 Hz was used as a measure of tremor severity. VNS suppresses pentylenetetrazol (PTZ)-induced seizures in rats [13]. This property was employed to assess the viability of the surgical preparation in each subject. At least 24 h after the tremor experiment, continuous VNS, using the same parameters described above, was initiated, and PTZ administered 30 s later (60 mg/kg, i.p.). VNS was continued another 15 min, during which the highest seizure severity attained was scored on a 0– 6 rating scale [13]. At least 48 h later, rats were given PTZ without VNS. Tremor data were discarded from two animals that did not demonstrate a seizure severity reduction of at least 50% with VNS compared to the no-VNS PTZ seizure condition. Spectral analysis during pre-harmaline baseline demonstrated relatively uniform moderate motion power in the 0– 17-Hz range, as depicted by the example in Fig. 1. Harmaline induced a marked increase in the 8 – 12-Hz range, corresponding to observed tremor, and contrasting with the low power in this range during non-tremor baseline (Fig. 1). VNS reduced harmaline-associated 8 – 12 Hz motion power by 40% ( p < 0.05, Student’s t-test), indicating suppression of harmaline-induced tremor by VNS. In contrast,
Fig. 2. Mean motion power (mV2) in the 8- to 12-Hz bandwidth in six sham- and seven VNS-stimulated rats during pre-harmaline baseline (Base), harmaline pre-stimulation (Harm), and harmaline sham- or VNS stimulation treatment (Treat) conditions; each condition lasted 10 min. Means F S.E.M. are shown. *p < 0.05, Student’s t-test as compared to harmaline prestimulation condition.
S.E. Krahl et al. / Brain Research 1011 (2004) 135–138
sham stimulation caused no significant change in 8– 12-Hz motion power, indicating that harmaline-induced tremor was not changed by sham stimulation (Fig. 2). Sham stimulation resulted in three out of six rats demonstrating increased tremor and three showing decreased tremor. Of the seven rats in the treated group, two had increased, and five had decreased, tremor following VNS. Detachment of a lead led to unblinding of the observer to the condition of one sham-stimulated animal. For the remaining rats, the blinded observer correctly judged the treatment condition based on tremor change in five of the seven VNS- and four of the five sham-stimulated animals ( p < 0.05, Chi-square). In summary, we tested the hypothesis that VNS suppresses tremor in the harmaline model by using a randomized parallel-group design, with blinding of the observer to the treatment condition. Digital quantitation of motion power in the 8 –12-Hz tremor range was analyzed. The viability of the preparation was validated by checking whether VNS suppressed PTZ-induced seizures. These results demonstrate that VNS significantly reduces harmaline-associated 8– 12-Hz motion power. The degree of reduction, 40%, was comparable to the 50% reduction reported with different methodology [8]. In addition, this degree of tremor reduction was comparable to the 50% reduction of accelerometry-measured tremor in a pilot feasibility clinical study of VNS for essential tremor [9]. Stimulation of vagal afferents presumably desynchronizes the rhythmic hypersynchronous burst-firing within the olivo-cerebellar system that underlies harmaline tremor. The anatomic route by which VNS suppresses tremor is not known, but several anatomic projection systems are candidate pathways. Vagal afferents have been reported to project directly to IO [6]. The main target of vagal afferents is the solitary nucleus complex, and most of these projection are bilateral [11]. The lateral solitary subnucleus reportedly projects to the medial accessory IO [15], although there is some disagreement on this point [3]. The nucleus of the solitary tract may also influence the IO and cerebellum indirectly via effects on brainstem nuclei. For example, VNS increases locus coeruleus cell firing [16]. The locus coeruleus has been found to be essential for the anti-seizure effect of VNS [13]. Electrical stimulation of the locus coeruleus suppresses harmaline tremor [26]; thus, VNS may suppress tremor via this mechanism. Vagal afferents comprise only a small portion of all sensory afferents to the olivocerebellar system. The partial efficacy of VNS in reducing tremor raises the interesting possibility that activation of other sensory modalities may be as effective or more effective in suppressing tremor.
Acknowledgements This study was supported by grants from Cyberonics and the U.S. Department of Veterans Affairs (AH and SEK). The
137
authors gratefully acknowledge the technical assistance of Shayani Senanayake.
References [1] C. Batini, J.F. Bernard, C. Buisseret-Delmas, M. Conrath-Verrier, G. Horcholle-Bossavit, Harmaline-induced tremor: II. Unit activity correlation in the interpositorubral and oculomotor systems of cat, Exp. Brain Res. 42 (1981) 383 – 391. [2] C. Batini, C. Buisseret-Delmas, M. Conrath-Verrier, Harmaline-induced tremor: I. Regional metabolic activity as revealed by [14C]2deoxyglucose in cat, Exp. Brain Res. 42 (1981) 371 – 382. [3] R.M. Beckstead, J.R. Morse, R. Norgren, The nucleus of the solitary tract in the monkey: projections to the thalamus and brain stem nuclei, J. Comp. Neurol. 190 (1980) 259 – 282. [4] J.F. Bernard, C. Buisseret-Delmas, C. Compoint, S. Laplante, Harmaline induced tremor: III. A combined simple units, horseradish peroxidase, and 2-deoxyglucose study of the olivocerebellar system in the rat, Exp. Brain Res. 57 (1984) 128 – 137. [5] H. Boecker, A.J. Wills, A. Ceballos-Baumann, M. Samuel, P.D. Thompson, L.J. Findley, D.J. Brooks, The effect of ethanol on alcohol-responsive essential tremor: a positron emission tomography study, Ann. Neurol. 39 (1996) 650 – 658. [6] J.L. Fitzakerley, G.E. Lucier, Connections of a vagal communicating branch in the ferret: II. Central projections, Brain Res. Bull. 20 (1988) 479 – 486. [7] J.H. Growdon, B.T. Shahani, R.R. Young, The effect of alcohol on essential tremor, Neurology 25 (1975) 259 – 262. [8] A. Handforth, S.E. Krahl, Suppression of harmaline-induced tremor in rats by vagus nerve stimulation, Mov. Disord. 16 (2001) 84 – 88. [9] A. Handforth, W.G. Ondo, S. Tatter, G.W. Mathern, R.K. Simpson, F. Walker, J.P. Sutton, J.P. Hubble, J. Jankovic, Effect of vagus nerve stimulation on essential tremor, Neurology 54 (Suppl. 3) (2000) 238. [10] H.E. Hennemann, F.J. Rubia, Vagal representation in the cerebellum of the cat, Pflugers Arch. 375 (1978) 119 – 123. [11] M. Kalia, M.-M. Mesulam, Brain stem projections of sensory and motor components of the vagus complex in the cat: II. Laryngeal, tracheobronchial, pulmonary, cardiac, and gastrointestinal branches, J. Comp. Neurol. 193 (1980) 467 – 508. [12] K. Kawanishi, Y. Hashimoto, M. Fujiwara, Y. Kataoka, S. Ueki, Pharmacological characteristics of abnormal behavior induced by harmine with special reference to tremor in mice, J. Pharmacobio-Dyn. 4 (1981) 520 – 527. [13] S.E. Krahl, K.B. Clark, D.C. Smith, R.A. Browning, Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation, Epilepsia 39 (1998) 709 – 714. [14] R. Llinas, R.A. Volkind, The olivo-cerebellar system: functional properties as revealed by harmaline-induced tremor, Exp. Brain Res. 18 (1973) 69 – 87. [15] A.D. Loewy, H. Burton, Nuclei of the solitary tract: efferent projections to the lower brain stem and spinal cord of the cat, J. Comp. Neurol. 181 (1978) 421 – 449. [16] S.D. Moore, P.G. Guyenet, An electrophysiological study of the forebrain projection of nucleus commissuralis; preliminary identification of presumed A2 catecholaminergic neurons, Brain Res. 263 (1983) 211 – 222. [17] V. Paul, Involvement of h2-adrenoceptor blockade and 5-hydroxytryptamine mechanism in inhibition of harmaline-induced tremors in rats, Eur. J. Pharmacol. 122 (1986) 111 – 115. [18] J. Perrin, J. Crousillat, Response of single units in the inferior olive nucleus to stimulation of the splanchnic afferents in the cat, J. Auton. Nerv. Syst. 2 (1980) 15 – 22. [19] M.S. Rappaport, R.T. Gentry, D.R. Schneider, V.P. Dole, Ethanol effects on harmaline-induced tremor and increase of cerebellar cyclic GMP, Life Sci. 34 (1984) 49 – 56.
138
S.E. Krahl et al. / Brain Research 1011 (2004) 135–138
[20] K. Semba, B.R. Komisaruk, Neural substrates of two different rhythmical vibrissal movements in the rat, Neuroscience 12 (1984) 761 – 774. [21] S.E. Stratton, J.F. Lorden, Effect of harmaline on cells of the inferior olive in the absence of tremor: differential response of genetically dystonic and harmaline-tolerant rats, Neuroscience 41 (1991) 543 – 549. [22] G. Tong, L.T. Robertson, J. Brons, Vagal and somatic representation by the climbing fiber system in lobule V of the cat cerebellum, Brain Res. 552 (1991) 58 – 66. [23] M. Weiss, Rhythmic activity of spinal interneurons in harmaline-trea-
ted cats. A model for olivo-cerebellar influence at the spinal level, J. Neurol. Sci. 54 (1982) 341 – 348. [24] J.P. Welsh, B. Chang, M.E. Menaker, S.A. Aicher, Removal of the inferior olive abolishes myoclonic seizures associated with a loss of olivary serotonin, Neuroscience 82 (1998) 879 – 897. [25] A.J. Wills, I.H. Jenkins, P.D. Thompson, L.J. Findley, D.J. Brooks, A positron emission tomography study of cerebral activation associated with essential and writing tremor, Arch. Neurol. 52 (1995) 299 – 305. [26] M. Yamazaki, C. Tanaka, S. Takaori, Significance of central noradrenergic system on harmaline induced tremor, Pharmacol. Biochem. Behav. 10 (1979) 421 – 427.