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Vagus nerve stimulation for epilepsy: A review of central mechanisms

Vagus nerve stimulation for epilepsy: A review of central mechanisms Website: www.surgicalneurologyint.com In a previous paper, the anatomy and physiology of the vagus nerve was discussed DOI: in an attempt to explain which vagus nerve fibers and branches are affected by 10.4103/2152-7806.103015 clinically relevant electrical stimulation. This companion paper presents some of Quick Response Code: vagus nerve stimulation’s putative central nervous system mechanisms of action by summarizing known anatomical projections of vagal afferents and their effects on brain biogenic amine pathways and seizure expression. Key Words: Locus coeruleus, norepinephrine, raphe nuclei, serotonin, vagus nerve stimulation, seizures INTRODUCTION This year marks the fifteenth anniversary of the U.S. Food and Drug Administration’s approval of VNS as a The first epilepsy patient was implanted with a vagus treatment for medication-refractory seizures. Despite the passing years and the advent of several promising nerve stimulation (VNS) system by Penry and Dean in [38] neuromodulation technologies, such as deep brain 1988. Since then, VNS has been implanted in more stimulation and trigeminal nerve stimulation, VNS today than 50,000 patients. VNS is considered a low-risk remains the only FDA-approved device-related therapy for surgery with few complications. The surgery involves epilepsy. Several theories exist regarding the therapeutic the placement of helical electrodes on the left cervical mechanisms of VNS, but it is certain that activation of vagus nerve, with intermittent stimulation provided by vagal afferents through electrical stimulation influences a remarkably small neurocybernetic prosthesis implanted seizure-related circuitry within the brain. subcutaneously in the upper chest. Most patients are stimulated at 20-30 Hz, with a stimulation cycle of 30 To understand how stimulation of the vagus nerve seconds on, and 5 minutes off. Clinical trials demonstrate reduces or eliminates seizure activity, an understanding of that 20-40% of patients achieve greater than 50% the peripheral anatomy and physiology of the vagus nerve [17,51] reduction in seizure frequency in the first year of use. and its central afferent projections is critical. Previously, [12,35] This number increases with time, while the number we reviewed the peripheral aspects of VNS in seizure [28] of concomitant antiepileptic drugs necessary to maintain attenuation. This companion review will focus on the [48] satisfactory seizure control after VNS decreases. anatomy and physiology of the hindbrain and midbrain S255 SNI: Stereotactic 2012, Vol 3, Suppl 4 - A Supplement to Surgical Neurology International as they relate to putative mechanisms of VNS-induced hypoglossi (PrH). Areas previously reported to project seizure suppression. to the LC (such as the NTS, central nucleus of the amygdala, frontal cortex, dorsal raphe nucleus, and ventral AFFERENT VAGUS NERVE PROJECTIONS tegmentum) were labeled only when tracers were injected into either the pericoerulear or central gray regions. The cervical vagus nerve is composed of afferent These results were confirmed using electrophysiological sensory and efferent motor fibers in a rough 4-to-1 means. Stimulation of the LC resulted in antidromic activation of Pgi and PrH neurons; however, stimulation ratio, respectively. The nucleus of the solitary tract, or of the LC did not antidromically activate neurons in nucleus tractus solitarius (NTS), is the recipient of most [2] other structures. afferent sensory fibers, but the vagus also sends ipsilateral projections to the area postrema, dorsal motor nucleus Further work has demonstrated that cell bodies residing of the vagus, nucleus ambiguus, medullary reticular in the LC proper have an extensive dendritic network formation, and the spinal trigeminal nucleus. [45] in the pericoerulear region. Therefore, areas that do The NTS is an important processing and relay center not project directly into the LC proper still influence for a variety of vital functions, so in addition to these LC activity either indirectly, through the Pgi or PrH, or vagal projections, it also integrates inputs from the directly, through projections into the pericoerulear region. glossopharyngeal, facial, and trigeminal nerves, and Fiber tracts emanating from the LC form an extensive [5] numerous brain regions. Studies indicate that the network of noradrenergic projections throughout the brain sensory afferents innervate the NTS in a topographic [24,30,50] and spinal cord. The largest pathway, the dorsal distribution, with the vagus nerve terminating ipsilaterally bundle (DB), leaves the LC and ascends through the central in both the rostral portions of the medial NTS and the tegmental tract. Along its course through the hypothalamus, [25,44] caudal portion of the lateral NTS. The vagus projects the DB merges with the medial forebrain bundle (MFB) [5,25] bilaterally to the caudal portion of the medial NTS. and projects to most parts of the telencephalon and The NTS, in turn, sends monosynaptic projections to diencephalon. The DB provides essentially all of the diffuse regions of the brain. The rostral portion of the noradrenergic innervation to the hippocampus and parts NTS sends axons to the facial, trigeminal, and hypoglossal of the neocortex. A second ascending pathway is the dorsal periventricular tract, a component of the dorsal longitudinal nuclei, while the caudal extent projects to the dorsal [37] fasciculus, projecting to medial and midline thalamic, motor nucleus of the vagus and nucleus ambiguus. pretectal, and hypothalamic regions. The descending fibers The NTS also sends fibers to the parabrachial nucleus, arising from the LC project to the spinal cord through pons, and the respiratory and cardiovascular centers [9] the ventral funiculus to innervate the dorsal and ventral located on the ventral surface of the medulla. [39] Importantly, monoamine nuclei in the brainstem, the horns. Another descending pathway enters the superior locus coeruleus (LC) and the raphe nuclei, receive direct cerebellar peduncles and terminates in the cerebellum, [2,52] mainly on Purkinje cells. Depending on the recipient and/or indirect projections from the NTS. Forebrain structure, LC projections can release norepinephrine and limbic structures also receive NTS projections, and neuropeptides from classical synaptic terminals or including the bed nucleus of the stria terminalis, [4] from non-classical synaptic varicosities. This latter type paraventricular, dorsomedial, and arcuate hypothalamic provides a distribution method capable of influencing large nuclei, preoptic and periventricular thalamic nuclei, and [20,42] central amygdaloid nucleus. regions of the brain, emphasizing the neuromodulatory nature of norepinephrine. LOCUS COERULEUS Effects of vagus nerve stimulation on the locus coeruleus Anatomy [47] Takigawa and Mogenson were the first researchers to The LC contains about 1,500 neurons per side in the systematically examine the effects of peripheral nerve rat and about 12,000 neurons in humans. The LC is the stimulation on LC activity. They found in rats that the [11] A6 nucleus as designated by Dahlstom and Fuxe and majority of LC neurons are transiently inhibited by VNS this designation is still used in the current literature on (for approximately 50 msec), followed by a much longer the LC. The nucleus designated as A4 by Dahlstrom [16] excitation phase. Groves and colleagues also found [11] and Fuxe is now considered to be a caudal extension that VNS increased LC activity up to 24% above baseline [30] of A6. [36] rates. Naritoku and others have also shown the Using discrete injections of retrograde tracers into the induction of c-fos in the LC following VNS, indicating [2] LC proper, Aston-Jones and colleagues found heavily VNS-induced LC activation. All of these studies involved labeled cells only in the nucleus paragigantocellularis acute VNS only, but chronic VNS also has profound (Pgi) and the perifascicular area of the nucleus prepositus effects on the LC. S258 SNI: Stereotactic 2012, Vol 3, Suppl 4 - A Supplement to Surgical Neurology International [13] Dorr and Debonnel implanted rats with a clinical The major descending serotonergic projection to the system and provided VNS at clinically relevant spinal cord arises from the caudal raphe cell groups. parameters, including cycling of 30 sec on/5 min off, for These bulbospinal pathways innervate the dorsal horn up to 90 days. Acute VNS (1 hour) produced a modest (substantia gelatinsoa), the intermediolateral cell column [49] increase in LC activity of approximately 33% above in the thoracic region, and the ventral horn. The baseline, but chronic VNS (beginning at 3 days and cerebellum appears to receive its serotonergic innervation [6] lasting up to 90 days) produced substantial and prolonged from the DRN, MRN, raphe obscures, and raphe pallidus. activation of LC neurons double that of baseline. These fibers apparently reach the cerebellum through the middle cerebellar peduncle. The deep cerebellar nuclei and While such studies show that VNS increases LC the cerebellar cortex both receive serotonergic innervation, activity, it is equally important to demonstrate that VNS [26,27] but apparently from separate neurons. also increases downstream release of norepinephrine. Using microdialysis during acute VNS in rats, several Effects of vagus nerve stimulation on studies have demonstrated significant increases in the dorsal raphe nucleus [18] norepinephrine levels in the neuropil of the amygdala, Using the same methods described above for the LC, [41,43] [14,43] hippocampus, and the prefrontal cortex. [13] Dorr and Debonnel found increased DRN activity, nearly double that of baseline activity, when VNS was RAPHE NUCLEI given chronically (>14 days). Acute VNS (<3 days) had little to no effect on DRN neurons. Interestingly, this Anatomy same group demonstrated that the LC must remain [31] Unlike the LC, which has a rather restricted afferent intact in order for VNS to affect DRN activity. As innervation, the raphe nuclei receive projections from before, chronic VNS doubled DRN activity; however, a vast number of areas found throughout the brain, when the LC was lesioned with DSP-4, VNS no longer including the LC. While a small number of studies had any effect on DRN activity. have reported direct neuronal connections between [1,19] the NTS and the dorsal raphe nucleus (DRN), ANTIEPILEPTIC EFFECTS OF electrophysiological studies have cast doubt on a NOREPINEPHRINE AND SEROTONIN monosynaptic NTS-to-DRN connection (see below), and there are no studies suggesting direct projections from The central noradrenergic and serotonergic pathways the NTS to any other raphe nuclei. represent diffusely projecting systems that are capable of influencing the entire neuraxis, from the cerebral cortex The serotonergic neurons in the raphe nuclei, not to the spinal cord. Norepinephrine and serotonin exert unlike the noradrenergic neurons in the LC, represent their effects through numerous receptor subtypes, giving a diffusely projecting system that innervates virtually rise to a great diversity of action. all areas of the CNS from the cortex to the spinal cord. In general, the rostral group of raphe neurons There is a vast literature showing that the noradrenergic provides innervation to the forebrain (telencephalon and and serotonergic neurons of the brain exert antiepileptic diencephalon), while the caudal group innervates the effects in a wide variety of seizure models. Pharmacological brainstem and spinal cord. This kind of polarity, where treatments that increase the concentration of the rostral nuclei are entirely ascending and the caudal norepinephrine or serotonin at their receptors produce nuclei are descending in their projections, is rather anticonvulsant effects, while treatments that decrease the unique and characteristic of the serotonergic system. The [7,15,21-23,32,33,40,46] concentration have proconvulsant effects. ascending projections are predominantly from the DRN Given the evidence for anatomical connections between and median raphe nuclei (MRN). The DRN contains the NTS and the LC and raphe nuclei, it seems reasonable the largest number of serotonergic neurons in the brain, to hypothesize that the antiepileptic effects of VNS are whereas the MRN contains the second largest number. mediated through norepinephrine and/or serotonin. While there is a great deal of overlap in the targets of Norepinephrine as a mediator of the ascending serotonergic neurons, there is also significant topographical organization of these systems. For example, antiepileptic effects of vagus nerve stimulation the DRN provides the serotonergic innervation to the Several studies indicate that the LC is a critical structure striatum while the MRN provides the vast majority of in the seizure-suppressing effects of VNS. In the first of serotonergic projections into the hippocampus. The these experiments, the LC was bilaterally lesioned in rats neocortex receives innervation from both the DRN and with 6-hydroxydopamine, while other groups received a [29] MRN. Like the striatum, the substantia nigra receives sham lesion. Two weeks later, seizures were induced its serotonergic innervation from the DRN with a highly through maximal electroshock (MES). Soon thereafter, topographic projection from the DRN innervating specific a cuff electrode was surgically implanted on the left [10,34] areas of the substantia nigra. cervical vagus nerve. The next day, the rats were given S259 SNI: Stereotactic 2012, Vol 3, Suppl 4 - A Supplement to Surgical Neurology International another MES test while receiving VNS. VNS given to the acute and chronic VNS, and abolish VNS-induced seizure sham control group strongly reduced seizure severity from suppression when lesioned. Further work can surely be pretest levels. VNS given to the lesioned group, however, done to determine if other mechanisms of action also did not significantly affect seizure severity. contribute to VNS’s antiepileptic effects, but there is already sufficient evidence that, at a minimum, elucidates In a second experiment, rats were implanted with bilateral some mechanisms of action. cannulae aimed at the LC. As before, seizures were induced with MES, and the rats were then implanted REFERENCES with a left cervical cuff electrode. The next day, in half of the animals, the LC was acutely inactivated with an 1. Aghajanian GK, Wang RY. Habenular and other midbrain raphe afferents infusion of the sodium-channel blocker, lidocaine, while demonstrated by a modified retrograde tracing technique. Brain Res the other half received saline. Both groups were then 1977;122:229-42. 2. Aston-Jones G, Shipley MT, Chouvet G, Ennis M, van Bockstaele E, Pieribone tested with MES while receiving VNS. The next day, V, et al. Afferent regulation of locus coeruleus neurons: Anatomy, physiology animals that had received lidocaine were infused with and pharmacology. Prog Brain Res 1991;88:47-75. saline, and vice versa, and the test was repeated, thus 3. Ben-Menachem E, Hamberger A, Hedner T, Hammond EJ, Uthman BM, Slater J, allowing a within-group comparison. VNS significantly et al. Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures. Epilepsy Res 1995;20:221-7. reduced seizure severity following saline infusion. 4. Beaudet A, Descarries L. The monoamine innervation of rat cerebral cortex: However, inactivation of the LC with lidocaine prevented Synaptic and nonsynaptic axon terminals. Neuroscience 1978;3:851-60. [29] VNS from significantly attenuating MES seizures. 5. Beckstead RM, Morse JR, Norgren R. The nucleus of the solitary tract in the monkey: Projections to the thalamus and brain stem nuclei. J Comp Neurol More recently, VNS was shown to reduce the severity 1980;190:259-82. of a seizure induced by pilocarpine infused into the rat 6. Bishop GA, Ho RH. The distribution and origin of serotonin immunoreactivity hippocampus. When SKF-86466, an α2-adrenoreceptor in the rat cerebellum. Brain Res 1985;331:195-208. antagonist, was also infused into the hippocampus, this 7. Browning RA. The role of neurotransmitters in electroshock seizure models. [41] In: Neurotransmitters and epilepsy. Jobe PC, Laird HE, editors. Clifton, New VNS-induced seizure suppression was abolished. Jersey: The Humana Press; 1987. p. 277-320. 8. Browning RA, Clark KB, Naritoku DK, Smith DC, Jensen RA. Loss of Serotonin as a mediator of the antiepileptic anticonvulsant effect of vagus nerve stimulation in the pentylenetetrazol effects of vagus nerve stimulation seizure model following treatment with 6-hydroxydopamine or The evidence that VNS suppresses seizures through 5,7-dihydroxytryptamine. Soc Neurosci Abstr 1997;23:2424. activation of the serotonin-containing neurons in the 9. Bystrzycka EK, Nail BS. Brain stem nuclei associated with respiratory, cardiovascular, and other autonomic functions. In: Hindbrain and spinal cord. raphe nuclei is less extensive than the evidence linking Paxinos G, editor. New York: Academic Press; 1985. p. 95-110. norepinephrine release by the LC. In an early clinical 10. Corvaja N, Doucet G, Bolam JP. Ultrastructure and synaptic targets of the [3] study, Ben-Menachem and colleagues measured levels raphe-nigral projection in the rat. Neuroscience 1993;55:417-27. of neurotransmitters or their metabolites in the cerebral 11. Dahlstrom A, Fuxe K. Evidence for the existence of monoamine-containing spinal fluid of patients receiving VNS for seizures. They neurons in the central nervous system. I. Demonstration of monoamines in cell bodies of brainstem neurons. Acta Physiol Scand Suppl 1964;62 Suppl found a 33% increase in 5-HIAA levels, a marker for 232:S1-55. serotonin activity, following VNS. Animal studies have 12. DeGiorgio CM, Schachter SC, Handforth A, Salinsky M, Thompson J, Uthman B, also supported a role for serotonin in the antiepileptic et al. Prospective long-term study of vagus nerve stimulation for the treatment effects of VNS. While VNS is capable of suppressing of refractory seizures. Epilepsia 2000;41:1195-200. 13. Dorr AE, Debonnel G. Effect of vagus nerve stimulation on serotonergic and pentylenetetrazole (PTZ)-induced seizures in rats, those noradrenergic transmission. J Pharmacol Exp Ther 2006;318:890-8. antiepileptic effects are abolished when serotonergic 14. Follesa P, Biggio F, Gorini G, Caria S, Talani G, Dazzi L, et al. Vagus nerve neurons are destroyed with 5,7-dihydroxytryptamine stimulation increases norepinephrine concentration and the gene expression [8] (5,7-DHT), a selective serotonin neurotoxin. of BDNF and bFGF in the rat brain. Brain Res 2007;1179:28-34. 15. Giorgi FS, Pizzanelli C, Biagioni F, Murri L, Fornai F. The role of norepinephrine in epilepsy: From the bench to the bedside. Neurosci Biobehav Rev CONCLUSIONS 2004;28:507-24. 16. Groves DA, Bowman EM, Brown VJ. Recordings from the rat locus coeruleus Most clinical papers describing the antiepileptic effects of during acute vagal nerve stimulation in the anaesthetised rat. Neurosci Lett VNS begin with the statement, “The precise therapeutic 2005;379:174-9. 17. Handforth A, DeGiorgio CM, Schachter SC, Uthman BM, Naritoku DK, mechanisms of action remain to be elucidated.” Given Tecoma ES, et al. Vagus nerve stimulation therapy for partial-onset seizures: the preponderance of evidence described herein regarding A randomized active-control trial. Neurology 1998;51:48-55. the relationship between VNS, the LC, and the DRN, 18. Hassert DL, Miyashita T, Williams CL. The effects of peripheral vagal nerve we believe this statement is misleading. While certainly stimulation at a memory-modulating intensity on norepinephrine output in the basolateral amygdala. Behav Neurosci 2004;118:79-88. not the only possible mediators of VNS-induced seizure 19. Herbert H, Saper CB. Organization of medullary adrenergic and noradrenergic suppression, the LC and DRN undoubtedly play projections to the periaqueductal gray matter in the rat. J Comp Neurol prominent roles. Both have widespread projections to 1992;315:34-52. the brain and spinal cord, release neuromodulators with 20. Jean A. The nucleus tractus solitarius: Neuroanatomic, neurochemical and robust antiepileptic effects, are known to be activated by functional aspects. Arch Int Physiol Biochim Biophys 1991;99:A3-52. S258 SNI: Stereotactic 2012, Vol 3, Suppl 4 - A Supplement to Surgical Neurology International 21. Jobe PC, Laird HE. Neurotransmitter abnormalities as determinants of 38. Penry JK, Dean JC. Prevention of intractable partial seizures by intermittent seizure susceptibility and intensity in the genetic models of epilepsy. Biochem vagal stimulation in humans: Preliminary results. Epilepsia 1990;31Suppl Pharmacol 1981;30:3137-44. 2:S40-3. 22. Jobe PC, Mishra PK, Browning RA, Wang C, Adams-Curtis LE, Ko KH, et al. 39. Proudfit HK, Clark FM. The projections of locus coeruleus neurons to the Noradrenergic abnormalities in the genetically epilepsy-prone rat. Brain Res spinal cord. Prog Brain Res 1991;8:123-41. Bull 1994;35:493-504. 40. Przegalinski E. Monoamines and the pathophysiology of seizure disorders. 23. Jobe PC, Reigel CE, Mishra PK, Dailey JW. Neurotransmitter abnormalities In: Frey HH, Janz D, editors. Antiepileptic drugs. Berlin: Springer-Verlag; 1985. as determinants of seizure predisposition in the genetically epilepsy-prone p. 101-37. rat. In: Neurotransmitters, seizures, epilepsy III. Nistico G, et al. editors. New 41. Raedt R, Clinckers R, Mollet L, Vonck K, El Tahry R, Wyckhuys T, et al. York: Raven Press; 1986. p. 387-97. Increased hippocampal noradrenaline is a biomarker for efficacy of vagus nerve stimulation in a limbic seizure model. J Neurochem 2011;117:461-9. 24. Jones MT, Moore RY. Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study. Brain Res 1977;127:23-53. 42. Ricardo JA, Koh ET. Anatomical evidence of direct projections from the 25. Kalia M, Sullivan JM. Brainstem projections of sensory and motor components nucleus of the solitary tract to the hypothalamus, amygdala, and other of the vagus nerve in the rat. J Comp Neurol 1982;211:248-64. forebrain structures in the rat. Brain Res 1978;153:1-26. 43. Roosevelt RW, Smith DC , Clough RW, Jensen RA, Browning RA. 26. Kerr CW, Bishop GA. Topographical organization in the origin of serotoninergic projections to different regions of the cat cerebellar cortex. Increased extracellular concentrations of norepinephrine in cortex and J Comp Neurol 1991;304:502-15. hippocampus following vagus nerve stimulation in the rat. Brain Res 27. Kitzman PH, Bishop GA. The origin of serotonergic afferents to the cat’s 2006;1119:124-32. 44. Rutherfurd SD, Widdop RE, Sannajust F, Louis WJ, Gundlach AL. Expression cerebellar nuclei. J Comp Neurol 1994;340:541-50. 28. Krahl SE. Vagus nerve stimulation for epilepsy: A review of the peripheral of c fos and NGFI A messenger RNA in the medulla oblongata of the mechanisms. Surg Neurol Int 2012;3 Suppl 1:S47-52. anaesthetized rat following stimulation of vagal and cardiovascular afferents. 29. Krahl SE, Clark KB, Smith DC, Browning RA. Locus coeruleus lesions Brain Res Mol Brain Res 1992;13:301-12. 45. Shipley MT, Fu L, Ennis M, Liu W, Aston-Jones G. Dendrites of locus coeruleus suppress the seizure-attenuating effects of vagus nerve stimulation. Epilepsia neurons extend preferentially into two pericoerulear zones. J Comp Neurol 1998;39:709-14. 30. Lindvall O, Bjorklund A. Organization of catecholamine neurons in the 1996;365:56-68. rat central nervous system. In: Iverson LL, Iversen SD, Snyder SH, editors. 46. Snead OC 3rd. On the sacred disease: The neurochemistry of epilepsy. Int Rev Neurobiol 1983;24:93-180. Chemical pathways in the brain. Handbook of psychopharmacology. New 47. Takigawa M, Mogenson GJ. A study of inputs to antidromically identified York: Plenum Press; 1978. p. 139-231. 31. Manta S, Dong J, Debonnel G, Blier P. Optimization of vagus nerve stimulation neurons of the locus coeruleus. Brain Res 1977;135:217-30. parameters using the firing activity of serotonin neurons in the rat dorsal 48. Tatum WO, Johnson KD, Goff S, Ferreira JA, Vale FL. Vagus nerve stimulation and drug reduction. Neurology 2001;56:561-3. raphe. Eur Neuropsychopharmacol 2009;19:250-5. 49. Tork I. Anatomy of the serotonergic system. Ann N Y Acad Sci 1990;600:9-35. 32. Maynert EW. The role of biochemical and neurohumoral factors in the laboratory evaluation of antiepileptic drugs. Epilepsia 1969;10:145-62. 50. Ungerstedt U. Stereotaxic mapping of the monoamine pathways in the rat 33. Maynert EW, Marczynski TJ, Browning RA. The role of neurotransmitters in brain. Acta Physiol Scand Suppl 1971;367:1-48. 51. Vagus Nerve Stimulation Study Group. A randomized controlled trial of the epilepsies. Adv Neurol 1975;13:79-147. chronic vagus nerve stimulation for treatment of medically intractable 34. Molliver ME. Serotonergic neuronal systems: What their anatomic organization tells us about function? J Clin Psychopharmacol 1987;7 Suppl 6:3S-23. seizures. Neurology 1995;45:224-30. 35. Morris GL 3rd, Mueller WM. Long-term treatment with vagus nerve 52. Van Bockstaele EJ, Peoples J, Telegan P. Efferent projections of the nucleus of the solitary tract to peri-locus coeruleus dendrites in rat brain: Evidence for stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation a monosynaptic pathway. J Comp Neurol 1999;412:410-28. Study Group E01-E05. Neurology 1999;53:1731-5. 36. Naritoku DK, Terry WJ, Helfert RH. Regional induction of fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve. Epilepsy Res 1995;22:53-62. Disclaimer: The authors of this paper have received no outside 37. Norgren R. Projections from the nucleus of the solitary tract in the rat. funding, and have nothing to disclose. Neuroscience 1978;3:207-18. S259 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Surgical Neurology International Pubmed Central

Vagus nerve stimulation for epilepsy: A review of central mechanisms

Surgical Neurology International , Volume 3 (Suppl 4) – Oct 31, 2012

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Abstract

Website: www.surgicalneurologyint.com In a previous paper, the anatomy and physiology of the vagus nerve was discussed DOI: in an attempt to explain which vagus nerve fibers and branches are affected by 10.4103/2152-7806.103015 clinically relevant electrical stimulation. This companion paper presents some of Quick Response Code: vagus nerve stimulation’s putative central nervous system mechanisms of action by summarizing known anatomical projections of vagal afferents and their effects on brain biogenic amine pathways and seizure expression. Key Words: Locus coeruleus, norepinephrine, raphe nuclei, serotonin, vagus nerve stimulation, seizures INTRODUCTION This year marks the fifteenth anniversary of the U.S. Food and Drug Administration’s approval of VNS as a The first epilepsy patient was implanted with a vagus treatment for medication-refractory seizures. Despite the passing years and the advent of several promising nerve stimulation (VNS) system by Penry and Dean in [38] neuromodulation technologies, such as deep brain 1988. Since then, VNS has been implanted in more stimulation and trigeminal nerve stimulation, VNS today than 50,000 patients. VNS is considered a low-risk remains the only FDA-approved device-related therapy for surgery with few complications. The surgery involves epilepsy. Several theories exist regarding the therapeutic the placement of helical electrodes on the left cervical mechanisms of VNS, but it is certain that activation of vagus nerve, with intermittent stimulation provided by vagal afferents through electrical stimulation influences a remarkably small neurocybernetic prosthesis implanted seizure-related circuitry within the brain. subcutaneously in the upper chest. Most patients are stimulated at 20-30 Hz, with a stimulation cycle of 30 To understand how stimulation of the vagus nerve seconds on, and 5 minutes off. Clinical trials demonstrate reduces or eliminates seizure activity, an understanding of that 20-40% of patients achieve greater than 50% the peripheral anatomy and physiology of the vagus nerve [17,51] reduction in seizure frequency in the first year of use. and its central afferent projections is critical. Previously, [12,35] This number increases with time, while the number we reviewed the peripheral aspects of VNS in seizure [28] of concomitant antiepileptic drugs necessary to maintain attenuation. This companion review will focus on the [48] satisfactory seizure control after VNS decreases. anatomy and physiology of the hindbrain and midbrain S255 SNI: Stereotactic 2012, Vol 3, Suppl 4 - A Supplement to Surgical Neurology International as they relate to putative mechanisms of VNS-induced hypoglossi (PrH). Areas previously reported to project seizure suppression. to the LC (such as the NTS, central nucleus of the amygdala, frontal cortex, dorsal raphe nucleus, and ventral AFFERENT VAGUS NERVE PROJECTIONS tegmentum) were labeled only when tracers were injected into either the pericoerulear or central gray regions. The cervical vagus nerve is composed of afferent These results were confirmed using electrophysiological sensory and efferent motor fibers in a rough 4-to-1 means. Stimulation of the LC resulted in antidromic activation of Pgi and PrH neurons; however, stimulation ratio, respectively. The nucleus of the solitary tract, or of the LC did not antidromically activate neurons in nucleus tractus solitarius (NTS), is the recipient of most [2] other structures. afferent sensory fibers, but the vagus also sends ipsilateral projections to the area postrema, dorsal motor nucleus Further work has demonstrated that cell bodies residing of the vagus, nucleus ambiguus, medullary reticular in the LC proper have an extensive dendritic network formation, and the spinal trigeminal nucleus. [45] in the pericoerulear region. Therefore, areas that do The NTS is an important processing and relay center not project directly into the LC proper still influence for a variety of vital functions, so in addition to these LC activity either indirectly, through the Pgi or PrH, or vagal projections, it also integrates inputs from the directly, through projections into the pericoerulear region. glossopharyngeal, facial, and trigeminal nerves, and Fiber tracts emanating from the LC form an extensive [5] numerous brain regions. Studies indicate that the network of noradrenergic projections throughout the brain sensory afferents innervate the NTS in a topographic [24,30,50] and spinal cord. The largest pathway, the dorsal distribution, with the vagus nerve terminating ipsilaterally bundle (DB), leaves the LC and ascends through the central in both the rostral portions of the medial NTS and the tegmental tract. Along its course through the hypothalamus, [25,44] caudal portion of the lateral NTS. The vagus projects the DB merges with the medial forebrain bundle (MFB) [5,25] bilaterally to the caudal portion of the medial NTS. and projects to most parts of the telencephalon and The NTS, in turn, sends monosynaptic projections to diencephalon. The DB provides essentially all of the diffuse regions of the brain. The rostral portion of the noradrenergic innervation to the hippocampus and parts NTS sends axons to the facial, trigeminal, and hypoglossal of the neocortex. A second ascending pathway is the dorsal periventricular tract, a component of the dorsal longitudinal nuclei, while the caudal extent projects to the dorsal [37] fasciculus, projecting to medial and midline thalamic, motor nucleus of the vagus and nucleus ambiguus. pretectal, and hypothalamic regions. The descending fibers The NTS also sends fibers to the parabrachial nucleus, arising from the LC project to the spinal cord through pons, and the respiratory and cardiovascular centers [9] the ventral funiculus to innervate the dorsal and ventral located on the ventral surface of the medulla. [39] Importantly, monoamine nuclei in the brainstem, the horns. Another descending pathway enters the superior locus coeruleus (LC) and the raphe nuclei, receive direct cerebellar peduncles and terminates in the cerebellum, [2,52] mainly on Purkinje cells. Depending on the recipient and/or indirect projections from the NTS. Forebrain structure, LC projections can release norepinephrine and limbic structures also receive NTS projections, and neuropeptides from classical synaptic terminals or including the bed nucleus of the stria terminalis, [4] from non-classical synaptic varicosities. This latter type paraventricular, dorsomedial, and arcuate hypothalamic provides a distribution method capable of influencing large nuclei, preoptic and periventricular thalamic nuclei, and [20,42] central amygdaloid nucleus. regions of the brain, emphasizing the neuromodulatory nature of norepinephrine. LOCUS COERULEUS Effects of vagus nerve stimulation on the locus coeruleus Anatomy [47] Takigawa and Mogenson were the first researchers to The LC contains about 1,500 neurons per side in the systematically examine the effects of peripheral nerve rat and about 12,000 neurons in humans. The LC is the stimulation on LC activity. They found in rats that the [11] A6 nucleus as designated by Dahlstom and Fuxe and majority of LC neurons are transiently inhibited by VNS this designation is still used in the current literature on (for approximately 50 msec), followed by a much longer the LC. The nucleus designated as A4 by Dahlstrom [16] excitation phase. Groves and colleagues also found [11] and Fuxe is now considered to be a caudal extension that VNS increased LC activity up to 24% above baseline [30] of A6. [36] rates. Naritoku and others have also shown the Using discrete injections of retrograde tracers into the induction of c-fos in the LC following VNS, indicating [2] LC proper, Aston-Jones and colleagues found heavily VNS-induced LC activation. All of these studies involved labeled cells only in the nucleus paragigantocellularis acute VNS only, but chronic VNS also has profound (Pgi) and the perifascicular area of the nucleus prepositus effects on the LC. S258 SNI: Stereotactic 2012, Vol 3, Suppl 4 - A Supplement to Surgical Neurology International [13] Dorr and Debonnel implanted rats with a clinical The major descending serotonergic projection to the system and provided VNS at clinically relevant spinal cord arises from the caudal raphe cell groups. parameters, including cycling of 30 sec on/5 min off, for These bulbospinal pathways innervate the dorsal horn up to 90 days. Acute VNS (1 hour) produced a modest (substantia gelatinsoa), the intermediolateral cell column [49] increase in LC activity of approximately 33% above in the thoracic region, and the ventral horn. The baseline, but chronic VNS (beginning at 3 days and cerebellum appears to receive its serotonergic innervation [6] lasting up to 90 days) produced substantial and prolonged from the DRN, MRN, raphe obscures, and raphe pallidus. activation of LC neurons double that of baseline. These fibers apparently reach the cerebellum through the middle cerebellar peduncle. The deep cerebellar nuclei and While such studies show that VNS increases LC the cerebellar cortex both receive serotonergic innervation, activity, it is equally important to demonstrate that VNS [26,27] but apparently from separate neurons. also increases downstream release of norepinephrine. Using microdialysis during acute VNS in rats, several Effects of vagus nerve stimulation on studies have demonstrated significant increases in the dorsal raphe nucleus [18] norepinephrine levels in the neuropil of the amygdala, Using the same methods described above for the LC, [41,43] [14,43] hippocampus, and the prefrontal cortex. [13] Dorr and Debonnel found increased DRN activity, nearly double that of baseline activity, when VNS was RAPHE NUCLEI given chronically (>14 days). Acute VNS (<3 days) had little to no effect on DRN neurons. Interestingly, this Anatomy same group demonstrated that the LC must remain [31] Unlike the LC, which has a rather restricted afferent intact in order for VNS to affect DRN activity. As innervation, the raphe nuclei receive projections from before, chronic VNS doubled DRN activity; however, a vast number of areas found throughout the brain, when the LC was lesioned with DSP-4, VNS no longer including the LC. While a small number of studies had any effect on DRN activity. have reported direct neuronal connections between [1,19] the NTS and the dorsal raphe nucleus (DRN), ANTIEPILEPTIC EFFECTS OF electrophysiological studies have cast doubt on a NOREPINEPHRINE AND SEROTONIN monosynaptic NTS-to-DRN connection (see below), and there are no studies suggesting direct projections from The central noradrenergic and serotonergic pathways the NTS to any other raphe nuclei. represent diffusely projecting systems that are capable of influencing the entire neuraxis, from the cerebral cortex The serotonergic neurons in the raphe nuclei, not to the spinal cord. Norepinephrine and serotonin exert unlike the noradrenergic neurons in the LC, represent their effects through numerous receptor subtypes, giving a diffusely projecting system that innervates virtually rise to a great diversity of action. all areas of the CNS from the cortex to the spinal cord. In general, the rostral group of raphe neurons There is a vast literature showing that the noradrenergic provides innervation to the forebrain (telencephalon and and serotonergic neurons of the brain exert antiepileptic diencephalon), while the caudal group innervates the effects in a wide variety of seizure models. Pharmacological brainstem and spinal cord. This kind of polarity, where treatments that increase the concentration of the rostral nuclei are entirely ascending and the caudal norepinephrine or serotonin at their receptors produce nuclei are descending in their projections, is rather anticonvulsant effects, while treatments that decrease the unique and characteristic of the serotonergic system. The [7,15,21-23,32,33,40,46] concentration have proconvulsant effects. ascending projections are predominantly from the DRN Given the evidence for anatomical connections between and median raphe nuclei (MRN). The DRN contains the NTS and the LC and raphe nuclei, it seems reasonable the largest number of serotonergic neurons in the brain, to hypothesize that the antiepileptic effects of VNS are whereas the MRN contains the second largest number. mediated through norepinephrine and/or serotonin. While there is a great deal of overlap in the targets of Norepinephrine as a mediator of the ascending serotonergic neurons, there is also significant topographical organization of these systems. For example, antiepileptic effects of vagus nerve stimulation the DRN provides the serotonergic innervation to the Several studies indicate that the LC is a critical structure striatum while the MRN provides the vast majority of in the seizure-suppressing effects of VNS. In the first of serotonergic projections into the hippocampus. The these experiments, the LC was bilaterally lesioned in rats neocortex receives innervation from both the DRN and with 6-hydroxydopamine, while other groups received a [29] MRN. Like the striatum, the substantia nigra receives sham lesion. Two weeks later, seizures were induced its serotonergic innervation from the DRN with a highly through maximal electroshock (MES). Soon thereafter, topographic projection from the DRN innervating specific a cuff electrode was surgically implanted on the left [10,34] areas of the substantia nigra. cervical vagus nerve. The next day, the rats were given S259 SNI: Stereotactic 2012, Vol 3, Suppl 4 - A Supplement to Surgical Neurology International another MES test while receiving VNS. VNS given to the acute and chronic VNS, and abolish VNS-induced seizure sham control group strongly reduced seizure severity from suppression when lesioned. Further work can surely be pretest levels. VNS given to the lesioned group, however, done to determine if other mechanisms of action also did not significantly affect seizure severity. contribute to VNS’s antiepileptic effects, but there is already sufficient evidence that, at a minimum, elucidates In a second experiment, rats were implanted with bilateral some mechanisms of action. cannulae aimed at the LC. As before, seizures were induced with MES, and the rats were then implanted REFERENCES with a left cervical cuff electrode. The next day, in half of the animals, the LC was acutely inactivated with an 1. Aghajanian GK, Wang RY. Habenular and other midbrain raphe afferents infusion of the sodium-channel blocker, lidocaine, while demonstrated by a modified retrograde tracing technique. Brain Res the other half received saline. Both groups were then 1977;122:229-42. 2. Aston-Jones G, Shipley MT, Chouvet G, Ennis M, van Bockstaele E, Pieribone tested with MES while receiving VNS. The next day, V, et al. Afferent regulation of locus coeruleus neurons: Anatomy, physiology animals that had received lidocaine were infused with and pharmacology. Prog Brain Res 1991;88:47-75. saline, and vice versa, and the test was repeated, thus 3. Ben-Menachem E, Hamberger A, Hedner T, Hammond EJ, Uthman BM, Slater J, allowing a within-group comparison. VNS significantly et al. Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures. Epilepsy Res 1995;20:221-7. reduced seizure severity following saline infusion. 4. Beaudet A, Descarries L. The monoamine innervation of rat cerebral cortex: However, inactivation of the LC with lidocaine prevented Synaptic and nonsynaptic axon terminals. Neuroscience 1978;3:851-60. [29] VNS from significantly attenuating MES seizures. 5. Beckstead RM, Morse JR, Norgren R. The nucleus of the solitary tract in the monkey: Projections to the thalamus and brain stem nuclei. J Comp Neurol More recently, VNS was shown to reduce the severity 1980;190:259-82. of a seizure induced by pilocarpine infused into the rat 6. Bishop GA, Ho RH. The distribution and origin of serotonin immunoreactivity hippocampus. When SKF-86466, an α2-adrenoreceptor in the rat cerebellum. Brain Res 1985;331:195-208. antagonist, was also infused into the hippocampus, this 7. Browning RA. The role of neurotransmitters in electroshock seizure models. [41] In: Neurotransmitters and epilepsy. Jobe PC, Laird HE, editors. Clifton, New VNS-induced seizure suppression was abolished. Jersey: The Humana Press; 1987. p. 277-320. 8. Browning RA, Clark KB, Naritoku DK, Smith DC, Jensen RA. Loss of Serotonin as a mediator of the antiepileptic anticonvulsant effect of vagus nerve stimulation in the pentylenetetrazol effects of vagus nerve stimulation seizure model following treatment with 6-hydroxydopamine or The evidence that VNS suppresses seizures through 5,7-dihydroxytryptamine. Soc Neurosci Abstr 1997;23:2424. activation of the serotonin-containing neurons in the 9. Bystrzycka EK, Nail BS. Brain stem nuclei associated with respiratory, cardiovascular, and other autonomic functions. In: Hindbrain and spinal cord. raphe nuclei is less extensive than the evidence linking Paxinos G, editor. New York: Academic Press; 1985. p. 95-110. norepinephrine release by the LC. In an early clinical 10. Corvaja N, Doucet G, Bolam JP. Ultrastructure and synaptic targets of the [3] study, Ben-Menachem and colleagues measured levels raphe-nigral projection in the rat. Neuroscience 1993;55:417-27. of neurotransmitters or their metabolites in the cerebral 11. Dahlstrom A, Fuxe K. Evidence for the existence of monoamine-containing spinal fluid of patients receiving VNS for seizures. They neurons in the central nervous system. I. Demonstration of monoamines in cell bodies of brainstem neurons. Acta Physiol Scand Suppl 1964;62 Suppl found a 33% increase in 5-HIAA levels, a marker for 232:S1-55. serotonin activity, following VNS. Animal studies have 12. DeGiorgio CM, Schachter SC, Handforth A, Salinsky M, Thompson J, Uthman B, also supported a role for serotonin in the antiepileptic et al. Prospective long-term study of vagus nerve stimulation for the treatment effects of VNS. While VNS is capable of suppressing of refractory seizures. Epilepsia 2000;41:1195-200. 13. Dorr AE, Debonnel G. Effect of vagus nerve stimulation on serotonergic and pentylenetetrazole (PTZ)-induced seizures in rats, those noradrenergic transmission. J Pharmacol Exp Ther 2006;318:890-8. antiepileptic effects are abolished when serotonergic 14. Follesa P, Biggio F, Gorini G, Caria S, Talani G, Dazzi L, et al. Vagus nerve neurons are destroyed with 5,7-dihydroxytryptamine stimulation increases norepinephrine concentration and the gene expression [8] (5,7-DHT), a selective serotonin neurotoxin. of BDNF and bFGF in the rat brain. Brain Res 2007;1179:28-34. 15. Giorgi FS, Pizzanelli C, Biagioni F, Murri L, Fornai F. The role of norepinephrine in epilepsy: From the bench to the bedside. Neurosci Biobehav Rev CONCLUSIONS 2004;28:507-24. 16. Groves DA, Bowman EM, Brown VJ. Recordings from the rat locus coeruleus Most clinical papers describing the antiepileptic effects of during acute vagal nerve stimulation in the anaesthetised rat. Neurosci Lett VNS begin with the statement, “The precise therapeutic 2005;379:174-9. 17. Handforth A, DeGiorgio CM, Schachter SC, Uthman BM, Naritoku DK, mechanisms of action remain to be elucidated.” Given Tecoma ES, et al. Vagus nerve stimulation therapy for partial-onset seizures: the preponderance of evidence described herein regarding A randomized active-control trial. Neurology 1998;51:48-55. the relationship between VNS, the LC, and the DRN, 18. Hassert DL, Miyashita T, Williams CL. The effects of peripheral vagal nerve we believe this statement is misleading. While certainly stimulation at a memory-modulating intensity on norepinephrine output in the basolateral amygdala. Behav Neurosci 2004;118:79-88. not the only possible mediators of VNS-induced seizure 19. Herbert H, Saper CB. Organization of medullary adrenergic and noradrenergic suppression, the LC and DRN undoubtedly play projections to the periaqueductal gray matter in the rat. J Comp Neurol prominent roles. Both have widespread projections to 1992;315:34-52. the brain and spinal cord, release neuromodulators with 20. Jean A. The nucleus tractus solitarius: Neuroanatomic, neurochemical and robust antiepileptic effects, are known to be activated by functional aspects. Arch Int Physiol Biochim Biophys 1991;99:A3-52. S258 SNI: Stereotactic 2012, Vol 3, Suppl 4 - A Supplement to Surgical Neurology International 21. Jobe PC, Laird HE. Neurotransmitter abnormalities as determinants of 38. Penry JK, Dean JC. Prevention of intractable partial seizures by intermittent seizure susceptibility and intensity in the genetic models of epilepsy. Biochem vagal stimulation in humans: Preliminary results. Epilepsia 1990;31Suppl Pharmacol 1981;30:3137-44. 2:S40-3. 22. Jobe PC, Mishra PK, Browning RA, Wang C, Adams-Curtis LE, Ko KH, et al. 39. Proudfit HK, Clark FM. The projections of locus coeruleus neurons to the Noradrenergic abnormalities in the genetically epilepsy-prone rat. Brain Res spinal cord. Prog Brain Res 1991;8:123-41. Bull 1994;35:493-504. 40. Przegalinski E. Monoamines and the pathophysiology of seizure disorders. 23. Jobe PC, Reigel CE, Mishra PK, Dailey JW. Neurotransmitter abnormalities In: Frey HH, Janz D, editors. Antiepileptic drugs. Berlin: Springer-Verlag; 1985. as determinants of seizure predisposition in the genetically epilepsy-prone p. 101-37. rat. In: Neurotransmitters, seizures, epilepsy III. Nistico G, et al. editors. New 41. Raedt R, Clinckers R, Mollet L, Vonck K, El Tahry R, Wyckhuys T, et al. York: Raven Press; 1986. p. 387-97. Increased hippocampal noradrenaline is a biomarker for efficacy of vagus nerve stimulation in a limbic seizure model. J Neurochem 2011;117:461-9. 24. Jones MT, Moore RY. Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study. Brain Res 1977;127:23-53. 42. Ricardo JA, Koh ET. Anatomical evidence of direct projections from the 25. Kalia M, Sullivan JM. Brainstem projections of sensory and motor components nucleus of the solitary tract to the hypothalamus, amygdala, and other of the vagus nerve in the rat. J Comp Neurol 1982;211:248-64. forebrain structures in the rat. Brain Res 1978;153:1-26. 43. Roosevelt RW, Smith DC , Clough RW, Jensen RA, Browning RA. 26. Kerr CW, Bishop GA. Topographical organization in the origin of serotoninergic projections to different regions of the cat cerebellar cortex. Increased extracellular concentrations of norepinephrine in cortex and J Comp Neurol 1991;304:502-15. hippocampus following vagus nerve stimulation in the rat. Brain Res 27. Kitzman PH, Bishop GA. The origin of serotonergic afferents to the cat’s 2006;1119:124-32. 44. Rutherfurd SD, Widdop RE, Sannajust F, Louis WJ, Gundlach AL. Expression cerebellar nuclei. J Comp Neurol 1994;340:541-50. 28. Krahl SE. Vagus nerve stimulation for epilepsy: A review of the peripheral of c fos and NGFI A messenger RNA in the medulla oblongata of the mechanisms. Surg Neurol Int 2012;3 Suppl 1:S47-52. anaesthetized rat following stimulation of vagal and cardiovascular afferents. 29. Krahl SE, Clark KB, Smith DC, Browning RA. Locus coeruleus lesions Brain Res Mol Brain Res 1992;13:301-12. 45. Shipley MT, Fu L, Ennis M, Liu W, Aston-Jones G. Dendrites of locus coeruleus suppress the seizure-attenuating effects of vagus nerve stimulation. Epilepsia neurons extend preferentially into two pericoerulear zones. J Comp Neurol 1998;39:709-14. 30. Lindvall O, Bjorklund A. Organization of catecholamine neurons in the 1996;365:56-68. rat central nervous system. In: Iverson LL, Iversen SD, Snyder SH, editors. 46. Snead OC 3rd. On the sacred disease: The neurochemistry of epilepsy. Int Rev Neurobiol 1983;24:93-180. Chemical pathways in the brain. Handbook of psychopharmacology. New 47. Takigawa M, Mogenson GJ. A study of inputs to antidromically identified York: Plenum Press; 1978. p. 139-231. 31. Manta S, Dong J, Debonnel G, Blier P. Optimization of vagus nerve stimulation neurons of the locus coeruleus. Brain Res 1977;135:217-30. parameters using the firing activity of serotonin neurons in the rat dorsal 48. Tatum WO, Johnson KD, Goff S, Ferreira JA, Vale FL. Vagus nerve stimulation and drug reduction. Neurology 2001;56:561-3. raphe. Eur Neuropsychopharmacol 2009;19:250-5. 49. Tork I. Anatomy of the serotonergic system. Ann N Y Acad Sci 1990;600:9-35. 32. Maynert EW. The role of biochemical and neurohumoral factors in the laboratory evaluation of antiepileptic drugs. Epilepsia 1969;10:145-62. 50. Ungerstedt U. Stereotaxic mapping of the monoamine pathways in the rat 33. Maynert EW, Marczynski TJ, Browning RA. The role of neurotransmitters in brain. Acta Physiol Scand Suppl 1971;367:1-48. 51. Vagus Nerve Stimulation Study Group. A randomized controlled trial of the epilepsies. Adv Neurol 1975;13:79-147. chronic vagus nerve stimulation for treatment of medically intractable 34. Molliver ME. Serotonergic neuronal systems: What their anatomic organization tells us about function? J Clin Psychopharmacol 1987;7 Suppl 6:3S-23. seizures. Neurology 1995;45:224-30. 35. Morris GL 3rd, Mueller WM. Long-term treatment with vagus nerve 52. Van Bockstaele EJ, Peoples J, Telegan P. Efferent projections of the nucleus of the solitary tract to peri-locus coeruleus dendrites in rat brain: Evidence for stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation a monosynaptic pathway. J Comp Neurol 1999;412:410-28. Study Group E01-E05. Neurology 1999;53:1731-5. 36. Naritoku DK, Terry WJ, Helfert RH. Regional induction of fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve. Epilepsy Res 1995;22:53-62. Disclaimer: The authors of this paper have received no outside 37. Norgren R. Projections from the nucleus of the solitary tract in the rat. funding, and have nothing to disclose. Neuroscience 1978;3:207-18. S259

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