The chemical neuroanatomy of vagus nerve stimulation

Journal of Chemical Neuroanatomy 42 (2011) 288–296

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Journal of Chemical Neuroanatomy journal homepage: www.elsevier.com/locate/jchemneu

Review

The chemical neuroanatomy of vagus nerve stimulation Riccardo Ruffoli a, Filippo S. Giorgi b, Chiara Pizzanelli b, Luigi Murri b, Antonio Paparelli a, Francesco Fornai a,c,* a

Department of Human Morphology and Applied Biology, University of Pisa, Via Roma 55, 56100 Pisa, Italy Department of Neurosciences, Section of Neurology, University of Pisa, Via Roma 55, 56100 Pisa, Italy c I.R.C.C.S. I.N.M. Neuromed Pozzilli (IS), Italy b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 19 October 2010 Received in revised form 30 November 2010 Accepted 4 December 2010 Available online 16 December 2010

In this short overview a reappraisal of the anatomical connections of vagal afferents is reported. The manuscript moves from classic neuroanatomy to review details of vagus nerve anatomy which are now becoming more and more relevant for clinical outcomes (i.e. the therapeutic use of vagus nerve stimulation). In drawing such an updated odology of central vagal connections the anatomical basis subserving the neurochemical effects of vagal stimulation are addressed. In detail, apart from the thalamic projection of central vagal afferents, the monoaminergic systems appear to play a pivotal role. Stemming from the chemical neuroanatomy of monoamines such as serotonin and norepinephrine the widespread effects of vagal stimulation on cerebral cortical activity are better elucidated. This refers both to the antiepileptic effects and most recently to the beneficial effects of vagal stimulation in mood and cognitive disorders. ß 2010 Elsevier B.V. All rights reserved.

Keywords: Vagus nerve Serotonin Norepinephrine Monoamine Locus coeruleus Raphe nuclei

Contents 1.

2. 3. 4.

The vagus nerve revisited . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Origin and peripheral course . . . . . . . . . . . . . . . . . . . . . 1.1. The functional components . . . . . . . . . . . . . . . . . . . . . . 1.2. The background of vagus nerve stimulation. . . . . . . . . . . . . . . Fiber types and the electrical stimulation of the vagus nerve . The neurochemical consequences of vagus nerve stimulation References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. The vagus nerve revisited 1.1. Origin and peripheral course The vagus nerve, once named pneumogastric nerve, is the tenth and the longest of the cranial nerves. Its name derives from Latin root, ‘‘wandering’’, as consequence of its long course, from the brain stem to the abdomen. The vagus nerve arises from the medulla and possesses numerous rootlets, between the inferior olive and the inferior cerebellar peduncle, in series with the

* Corresponding author at: Department of Human Morphology and Applied Biology, University of Pisa, Via Roma 55, 56100 Pisa, Italy. Tel.: +39 050 2218611; fax: +39 050 2218628. E-mail address: [email protected] (F. Fornai). 0891-0618/$ – see front matter ß 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jchemneu.2010.12.002

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glossopharyngeal nerve above and the accessory nerve (Wiles et al., 2007). The rootlets form a single trunk, which leaves the skull crossing the subarachnoid space and passing outwards the jugular foramen. Within the jugular foramen the vagus nerve shows a small enlargement, the jugular (or superior) ganglion. Just below the jugular foramen, the nerve expands again to form its nodose (or inferior) ganglion, which is larger and longer (Ramachandra et al., 2005). After the exit from the jugular foramen, the vagus nerve descends in the neck within the carotid sheath, and it lies in the dihedral angle behind the internal carotid artery and the internal jugular vein, to form the vasculo-nervous axis of the neck. At the level of the nodose ganglion, the vagus nerve gives off pharyngeal branches, which join the pharyngeal branches of the glossopharyngeal nerve and superior cervical sympathetic ganglion to form the pharyngeal plexus. At the same level, the vagus nerve gives off the superior laryngeal nerve, coursing beneath the carotid

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artery to the larynx. The superior (or cervical) cardiac branches arise from the vagus, along its cervical course, or in some cases from the superior laryngeal nerve, and give off upper and lower branches. The upper branches communicate with the cardiac branches of the sympathetic system and they can be tracked down to the deep part of the cardiac plexus. The lower branch arises at the root of the neck, just above the first rib. In particular, the branch from the right vagus passes in front, or aside, of the innominate artery and proceeds to the deep part of the cardiac plexus. The branch from the left vagus runs down across the left side of the arch of the aorta, and joins the superficial part of the cardiac plexus. The vagus nerve then continues at the root of the neck. At this level the right and left vagus nerve present important anatomical differences in their course which are noticeable for the functional surgery intended to stimulate the vagus nerve. On the right side, the nerve passes in front of the first part of the subclavian artery and enters the thoracic cavity, giving off the right inferior (or recurrent) laryngeal nerve. The inferior (or thoracic) cardiac branches, on the right side, arise from the trunk of the vagus, as it lies by the side of the trachea, and from its recurrent nerve. Then, the right vagus descends by the right side of the trachea to the back of the pulmonary root. Here, the vagus nerve breaks up into numerous branches, which constitute the right posterior pulmonary plexus. From the lower part of this plexus the right vagus nerve descends as two cords on the esophagus, and divides to form, with branches from the corresponding cords of the opposite nerve, the esophageal plexus. Below, these branches are collected into a single cord which descends on the posterior surface of the esophagus and, through the esophageal opening of the diaphragm, enters the abdomen. Here, this cord distributes to the posterior surface of the stomach, joining the left side of the celiac plexus, and sending fibers to the lienal plexus. On the left side, the vagus enters the thoracic cavity between the left common carotid and subclavian arteries, behind the left innominate vein. Then, the vagus passes in front of the aortic arch, giving off the left inferior (or recurrent) laryngeal nerve at the lower border of aortic arch. The inferior (or thoracic) cardiac branches, on the left side, arise from the recurrent nerve only, when it winds around the arch of the aorta. These cardiac branches end in the deep part of the cardiac plexus. Then, the left vagus nerve descends behind the root of the left lung, breaks up into numerous branches forming the left posterior pulmonary plexus. From the lower part of this plexus, two cords descend on the esophagus, and divide to form, with branches from the opposite nerve, the esophageal plexus. Below, these branches are collected into a single cord, which runs along the back of the esophagus, enters the abdomen, and it spreads to the stomach, joining the left side of the celiac plexus, and sending

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filaments to the lienal plexus. These concepts of gross anatomy need to be appreciated in order to understand the significance of side-specificity of monolateral vagus nerve stimulation. 1.2. The functional components Embryologically the vagus nerve represents the nerve of the 4th branchial arch. Although it is composed of about 80% afferent sensory fibers carrying information to the brain from the head, neck, thorax, and abdomen, the vagus nerve has both afferent and efferent components (Foley and DuBois, 1937; Agostoni et al., 1957). The vagus nerve contains ‘‘A-fibers’’, ‘‘B-fibers’’ and ‘‘Cfibers’’, so defined in accordance to the classification that subdivides the peripheral nerve fibers according to their conduction velocity, which, in myelinated fibers, is proportional to their size (Erlanger and Gasser, 1937). The types of fibers which form the vagus nerve play different physiological roles. In particular, the vagal A-fibers are the largest and myelinated fibers and carry afferent visceral information and motor input. The vagal B-fibers are small and myelinated fibers carrying parasympathetic input. Finally, the vagal C-fibers are small and unmyelinated and carry afferent visceral information. Moreover, the vagal fibers are connected to four nuclei located in the brain medulla: the spinal nucleus of the trigeminal nerve, the nucleus of the solitary tract (NST), the nucleus ambiguus (NA), the dorsal motor nucleus of the vagus nerve (DMN) (see Table 1). General visceral afferent component: The vagus nerve carries general visceral afferents (GVA) from thoracic, abdominal viscera and from aortic baroreceptors and chemoreceptors of the aortic arch. These afferents play a crucial role in the reflex regulation of respiratory, digestive and cardiovascular functions. The cell bodies of the primary sensory neurons are located in the nodose ganglion and transmit to the caudal part of the NST. This portion of the nucleus is an important center for the regulation of visceral, cardiovascular and respiratory functions. In fact, NST sends input to vasomotor interneurons in the caudal ventrolateral medulla which are involved in the control of blood pressure. NST also controls motoneurons of the NA innervating striate muscles involved in swallowing, and vagal parasympathetic premotor neurons controlling heart rate (Fig. 1) (Nieuwenhuys et al., 2008). In particular, short pathways connect the NST with cardiomotor neurons in DMN, slowing down the heart rate (Nieuwenhuys et al., 2008). The caudal part of the NST also projects to the periaqueductal grey, and to the visceral nuclei in the spinal cord, mediating visceral sensation (Nieuwenhuys et al., 2008). Vagal GVA fibers also constitute the afferent limb of the Hering–Breuer reflex. Sensory endings of the smaller bronchia carry input to the

Table 1 Functional components of the vagus nerve. Type of fibers

Origin

Innervation territories

Central destination

Afferent components General somatic afferent fibers

Jugular (superior) ganglion

Posterior wall of external auditory meatus and posterior portion of external surface of tympanic membrane Hypopharynx, larynx, trachea, lungs, esophagus, abdominal viscera, aortic baro- and chemoreceptors, dura mater in the posterior fossa Taste receptors from epiglottic area

Spinal trigeminal nucleus

General visceral afferent fibers

Nodose (inferior) ganglion

Special visceral afferent fibers

Nodose (inferior) ganglion

Nucleus of the solitary tract (caudal part)

Nucleus of the solitary tract (cranial part)

Type of fibers

Origin

Innervation territories

Efferent components Efferent special visceral (or branchiomotor) fibers

Nucleus ambiguus

Muscles of pharynx and larynx, striated muscle fibers in the esophagus Thoracic and abdominal viscera

Efferent general visceral (visceral motor or parasympathetic) fibers

Dorsal motor nucleus

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Fig. 1. Diagram of the principal efferent projections of the nucleus of the solitary tract (Legend: NST, nucleus of the solitary tract; BNST, bed nucleus of the stria terminalis; VPM, ventral posteromedial nucleus of the thalamus; DMN, dorsal motor nucleus of the vagus nerve; NA, nucleus ambiguus; PAG, periaqueductal grey). NST connects to the brain medulla to control blood pressure and the expiratory center, which represents the efferent limb of the Hering–Breuer reflex. NST projects to DMN and NA parasympathetic pregangliar neurons influencing cardiac activity. Moreover, NST reaches NA for the innervation of striate muscles involved in swallowing and heart rate. NST also projects to the periaqueductal grey and visceral nuclei of the spinal cord, mediating visceral sensation. Efferent pathways reach the BNST, from which they are relayed to the amygdala. Inputs from NST reach the cerebral cortex via the parabrachial complex and the VPM.

NST by vagal GVA fibers, at an increasing rate as the lung are inflated. Then, these inputs are relayed from the NST to the expiratory center situated in the reticular formation of brain medulla. The most abundant pathways ascending from the interoceptive portion of the NST reach the forebrain, in particular the bed nucleus of the stria terminalis (Fig. 1) (Ricardo and Koh, 1977; Ricardo, 1983; Nieuwenhuys et al., 2008). The bed nucleus of the stria terminalis projects substantially to the amygdala, along the ventral ‘‘amygdalofugal’’ pathway, ends mainly in the central and medial nuclei (Nauta, 1961; Coolen and Wood, 1998; Nieuwenhuys et al., 2008). Moreover, through the vagus nerve information concerning the internal body reaches the neocortex. In fact, the vagal sensory information from the thoracic and abdominal viscera is carried out to the NST and, after further synaptic connections with the parabrachial complex and the ventral posteromedial nucleus of the thalamus (VPM), reaches the viscerosensory portion of the insular cortex (Fig. 1) (Saper, 2002). The latter is an area strongly interconnected with paralimbic structures, including the amygdala and the hippocampus (Nieuwenhuys et al., 2008). Special visceral afferent component: Vagal fibers supply taste buds of the epiglottis. These special visceral afferents (SVAs) are mediated by unipolar cells situated in the nodose ganglion. The central processes of these neuronal cells end in the rostral, gustatory, portion of the NST. This portion of the NST gives rise to an uncrossed ascending pathway ending in VPM (Beckstead et al., 1980). Finally, the VPM projects to the gustatory cortex, which is located in the rostral, granular cortex of the insula and the inner frontal operculum (Pritchard et al., 1986). General somatic afferent component: The vagus nerve carries general somatic afferents (GSAs) for general sensation from the lower part of the pharynx, larynx, trachea, bronchi, esophagus, concha of the external ear, posterior wall of external auditory meatus, tympanic membrane, and dura lying the posterior cranial fossa (Kiernan, 2009). The cell bodies of GSA are located in the jugular ganglion and their central processes terminate in the spinal trigeminal nucleus. However, the sensory neurons for pain arising

in thoracic and abdominal viscera are located in the dorsal root ganglia of the thoracic and upper lumbar spinal nerves and are associated only with the sympathetic nervous system (Kiernan, 2009). General visceral efferent component: The vagus nerve is the most caudal cranial nerve participating in the preganglionic parasympathetic system. Preganglionic parasympathetic fibers constitute the general visceral efferent (GVE) fibers of the vagus nerve and arise from DMN. The DMN is a neuronal column situated in the medulla and extending beneath the vagal triangle in the floor of the fourth ventricle, by which the vagus nerve innervates essentially all the thoracic and abdominal organs, including the gastrointestinal tract as far as the lienal flexure. As for all parasympathetic nerves, the fibers arising from DMN do not innervate directly peripheral organs, but end on a second set of neurons in parasympathetic ganglia close to or in the walls of the organs. From the parasympathetic ganglia, the postganglionic neurons travel to the cardiovascular, respiratory, and gastrointestinal systems. Other preganglionic parasympathetic neurons are located near and among the NA, which is a motor nucleus located ventromedial to the spinal nucleus of the trigeminal nerve, in the central tegmentum throughout the medulla. The NA can be subdivided into an external formation containing preganglionic parasympathetic neurons, and a dorsal, branchiomotor division, corresponding to the NA strictly so-called (Nieuwenhuys et al., 2008). Axons from the parasympathetic portion of the NA terminate in small ganglia associated with the cardiac muscle, with cardio-inhibitory effect (Massari et al., 1995; Gatti et al., 1996, 1997). In particular, the sinoatrial ganglion, the atrioventricular (AV) ganglion, and the cranioventricular ganglion are the major intracardiac ganglia having a selective influence on heart rate, AV conduction, or left ventricular contractility, respectively (Massari et al., 1995; Gatti et al., 1996, 1997; for a review, Salo et al., 2006). Functional experiments documented the corresponding cardiac effects obtained after microinjections of sodium glutamate (GLU) in different sites of NA (Fig. 2) (Massari et al., 1995; Gatti et al., 1996). In particular, it has been found that: (i) GLU microinjections

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Fig. 2. Different portions of the ventrolateral nucleus ambiguus influence different cardiac activities. Microinjection of sodium glutamate (GLU) into the rostral ventrolateral nucleus ambiguus (VL-NA) causes selectively a negative dromotropic effect. GLU microinjection into the intermediate ventrolateral NA causes both negative chronotropic and negative dromotropic effects. GLU microinjection into the caudal ventrolateral NA causes selectively negative chronotropic effect.

into the rostral ventrolateral NA caused a selective negative dromotropic effect; (ii) GLU microinjections into the intermediate ventrolateral NA caused both negative chronotropic and dromotropic effects; (iii) GLU microinjections into the caudal ventrolateral NA caused a selective negative chronotropic effect (Fig. 2). Recently it was indicated that GVE from the NA participate with DMN to provide the vagal fibers which control the human cardiac muscle (Kiernan, 2009). Special visceral efferent component: The vagus nerve carries also special visceral efferent (SVE) fibers innervating striate muscles, in particular the branchiomotor muscles deriving from the 4th branchial. The efferent fibers belong to motoneurons located in dorsal division of the NA and supply muscles of the soft palate, pharynx (except the stylopharyngeus muscle, which is supplied by the NA, but through the glossopharyngeal nerve), larynx, and the striate fibers of the upper part of the esophagus. Interestingly, the NA receives most sensitive fibers from the spinal trigeminal nucleus and NST, leading stimuli from respiratory and digestive tracts. These sensory stimuli to the NA represent the afferent limb of crucial reflex activities, such as gagging, coughing, and vomiting. In particular, the NA, like the NST, the spinal trigeminal nucleus, and DMN, receives afferent fibers from the area postrema, which is a medullary structure having a role in vomiting and nausea (McKinley et al., 2004). 2. The background of vagus nerve stimulation The vagus nerve stimulation (VNS) was proposed in late 19th for the treatment of epilepsy by the American neurologist Corning (1882, 1883). This was based on the idea that seizures may be due to alterations in cerebral blood flow. Accordingly, seizures were previously associated with facial flushing and bounding carotid and cranial pulse as an excess of cerebral blood flow (Parry, 1792). In keeping with this, it was reported that the decrease of cerebral blood flow following manual compression of the carotid arteries was effective in reducing seizures (Parry, 1792, 1811, 1825). In the 19th century the carotid compression as useful therapeutic treatment of seizures was considered by several authors, as reported by the same Corning (1882), who proposed that an excess of blood flow affected the cerebral cortex. As reported by Lanska (2002), in 1884 Corning was the first to use compression of the carotid arteries in concomitance with the electrical transcutaneous stimulation of the vagus nerve, in order to slow the heart rate and to decrease the cardiac output, and also the sympathetic cervical nerves, to constrict the cerebral vasculature (Corning, 1884). In 1938 a renewed interest on the electrical VNS was based on the misinterpretation that peripheral stimulation of the vagus nerve via alterations in peripheral organs might indirectly affect brain

cortical activity by producing a fall of blood pressure as a depressor reflex through the right vagus nerve (Bailey and Bremer, 1938). From their observations, however, they concluded that their experiments did not support the hypothesis of a direct inhibitory action by vagus nerve on the cerebral cortex (Bailey and Bremer, 1938). This fallacy was likely to be due to a lack of knowledge of the different effects induced by different electrical pattern of vagal stimulation. In fact, these authors could not observe classic alterations in the sleep waking cycle during VNS (Bailey and Bremer, 1938). It was only in 1952, that a clear demonstration of the seminal role of central vagal afferents in modulating directly cortical activity emerged. In fact, using an elegant experimental approach Zanchetti et al. (1952) investigated the effects of vagal afferent stimulation on the EEG pattern of the cat. For this purpose, an experimental model was set up to record cortical potentials during afferent vagal stimulation in vagotomized ‘‘ence´phale isole´’’ ruling out changes in systemic blood pressure (Zanchetti et al., 1952). The results documented that: (i) using a broad range of frequency of stimulation of the vagus nerve (2–300 Hz) produced EEG desynchronization; (ii) these high frequency of stimulation were also suppressing epileptic activity recorded in the cortex following focal strychnine application; (iii) these effects were depending on the range of stimulation frequencies. The alteration of cortical activity was directly due to vagal afferents and not to secondary effects in blood pressure since: (i) it was not observed if the proximal end of the vagus nerve had been tied; (ii) in ‘‘ence´phale isole´’’ preparation these findings were not associated with changes in blood pressure (Zanchetti et al., 1952). Therefore, Zanchetti et al. (1952) demonstrated, for the first time, that cortical effects of the vagal nerve stimulation are neurogenic, where vagal effects are likely to reach the cortex via subcortical associative mechanisms. This latter assumption was supported by previous studies, from the same research team, showing that: (i) the electrical stimulation of the ascending reticular system abolishes cortical synchronization (Moruzzi and Magoun, 1949; Starzl et al., 1951); (ii) seizures produced by focal strychnine are blocked by stimulation of the ascending reticular system (Arduini and Lairy-Bounes, 1952); (iii) nuclei belonging to the rostral (‘‘meso-diencephalic’’) reticular formation (i.e. reticular regions of the midbrain, as well as the thalamus), are activated following electrical stimulation of the vagus nerve (Dell and Olson, 1951). Grastyan and his collaborators (1952) confirmed that vagus nerve affects the cerebral cortex via the reticular activating system of the brain stem. Later on Chase et al. (1966a,b, 1967) detailed the various effects induced by different electrical patterns of VNS. In particular, they found that stimulation of the vagus nerve with frequencies higher than 70 Hz induced EEG synchronization. In contrast, stimulation at frequencies lower

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than 70 Hz caused EEG desynchronization. Moreover, they found that cerebral cortex and thalamic nuclei were affected with considerable delay, while the hippocampal cortex responded much faster (a potential explanation for these time differences will be provided later in the review, dealing with direct connections of monoamine with hippocampal allocortex). Similarly, Stoica and Tudor (1967, 1968) documented variability of the effects of VNS upon strychnine-induced seizures depending on the strength of the stimulus. In more recent years, a clinical potential for the VNS in the control of epilepsy was suggested by Zabara (1985a,b). In particular, it was shown that, in canine models, VNS had an antiepileptic effect preventing the onset or stopping ongoing seizure induced by strychnine, and clones induced by pentylenetetrazol. Moreover, Lockard et al. (1990), in an aluminagel monkey model, and Woodbury and Woodbury (1990, 1991), in murine models, showed that VNS decreases frequency and severity of seizure. In particular, Woodbury and Woodbury (1990, 1991) stated that VNS appears to act via release of large quantities of the inhibitory mediators GABA and glycine in the brainstem and cerebral cortex and suggested that antiepileptic potency of VNS was directly related to the fraction of vagal Cfibers stimulated. However, it has been recently reported that the destruction of peripheral C-fibers does not alter subsequent VNSinduced seizure suppression in rats (Krahl et al., 2001). The first descriptions of implants of VNS device in humans for the treatment of drug-resistant epilepsy appeared in the literature in the early 1990s (Penry and Dean, 1990; Terry et al., 1990, 1991). Experimental studies carried out in animal models added further interesting knowledge about the role of the electric VNS in therapy of seizures. In fact, Zabara (1992) hypothesized that VNS had also a long-lasting inhibition that increased with continued periods of stimulation to prevent seizures in dogs. More recently McLachlan (1993) investigated the effects of electrical stimulation of the vagus nerve on focal interictal spikes produced by penicillin and EEG secondarily generalized seizures induced by pentylenetetrazol in rats. This study demonstrated that VNS is a potent but nonspecific method to reduce cortical epileptiform activity, likely through an indirect effect mediated by the reticular activating system. This latter finding confirmed what originally found forty years before by Zanchetti et al. (1952). Recently, VNS has been found to affect significantly spike and wave discharge incidence in two rodent models mimicking epilepsy in humans, such as the Genetic Absence Epilepsy Rats of Strasbourg and Fast Rats (Dedeurwaerdere et al., 2006). More recently, it has been shown that VNS exerts a powerful acute anticonvulsant effects on spontaneous seizures occurring in rats which had been previously submitted to full electrical kindling of the amygdala, i.e. in a model of spontaneous focal limbic seizures (Rijkers et al., 2010). In particular, this VNS-treated kindled rat model has been proposed as clinically relevant since it affects limbic seizures which are most responsive to VNS in epilepsy patients (Rijkers et al., 2010). Taking into account all these experimental data, a variety of clinical trials were performed leading in July 1997 the U.S. Food and Drug Administration (FDA) to approve the use of VNS, as an adjunctive treatment for partial onset seizures refractory to antiepileptic medications in adults and adolescents aged at least 12 years. VNS exerts significant effects on several different types of seizures, which bear anatomical and neurophysiological substrates very different from each other. Furthermore, the anticonvulsant effect has been constantly observed in animal species very far phylogenically from one another, such as primates, rats, dogs, cats and humans (see above). These latter observations suggest that a powerful anticonvulsant mechanism, affecting different parts of the brain and subclasses of neurons, and highly preserved throughout phylogenesis, is likely to underline VNS-related anticonvulsant effects. As repeatedly

suggested in this, and other papers, locus coeruleus (LC) appears, with this respect, as a very good candidate. 3. Fiber types and the electrical stimulation of the vagus nerve Myelination of the human vagus nerve begins between 14 and 17 weeks postconception (pc) and the number of myelinated fibers augments from about 5000 at 26 weeks pc to as many as 40,000, the adult value, at 10 weeks after birth (Wozniak and O’Rahilly, 1981; Sachis et al., 1982). In the cat, the afferent component in the cervical tract of the vagus nerve includes myelinated A- and Bfibers, and unmyelinated C-fibers, conveying sensory information from a number of organs, such as the heart, lungs, liver, and much of the digestive tract (Foley and DuBois, 1937). In particular, the most numerous are the afferent C-fibers, accounting in fact for 65– 80% of the total number of the fibers. Considering the range of stimulation parameters, the vagal Afibers have the lowest amplitude-duration threshold required for VNS to excite action potentials (ranging from 0.02 to 0.2 mA). The B-fibers have higher excitation thresholds (ranging from 0.04 to 0.6 mA), whereas the highest excitation thresholds (more than 2.0 mA) belong to the narrow, unmyelinated C-fibers (for a review, Groves and Brown, 2005). For clinical use of the vagal stimulation, the frequencies range from 20 to 30 Hz as frequencies of 50 Hz and above caused major irreversible damage to the vagal nerve (for a review, Groves and Brown, 2005). Significantly different responses in EEG recordings can be evoked by the stimulation of the different fibers of the vagus (Chase et al., 1966b). In fact, the recruitment of the A- and B-fibers by a weak stimulation of the vagus causes a synchronization of the EEG; by contrast a higher stimulation recruiting also C-fibers causes an EEG desynchronization. Animal models of epilepsy from anesthetized rats suggest that the most important fibers mediating the anti-seizure effect of VNS are Cfibers maximally recruited by high-level stimulation (Woodbury and Woodbury, 1990). However, the destruction of C-fibers by capsaicin administered subcutaneously in awake rats has no effect on subsequent VNS-induced seizure suppression, indicating that activation of vagal C-fibers could not be necessary for VNS-induced seizure suppression (Krahl et al., 2001). Moreover, therapeutic VNS appears to be sub-threshold for vagal C-fibers, suggesting that seizure suppression results from activation of vagal A- and B-fibers (Banzett et al., 1999). 4. The neurochemical consequences of vagus nerve stimulation In the last decades the electrical stimulation of the vagus nerve has become the most widely used non-pharmacological treatment for refractory epilepsy (Treiman, 2010). More recently, VNS has been applied also to treat mood and cognitive disorders, from major depressive disorder to Alzheimer’s disease (for a review, Beekwilder and Beems, 2010). One potential mechanism underlying the effects of VNS on seizures and mood is the alteration of norepinephrine (NE) release by projections of solitary tract to the LC (Henry, 2002). The NST is a large nuclear complex, situated in the dorsal tegmentum (for a review, Koutcherov et al., 2004). In humans and experimental mammals, the NST receives input from the solitary tract, a heavily myelinated fiber bundle that extends from the level of the facial nucleus in the caudal pons to the spinomedullary junction. In the adult brain, the solitary tract is composed of nerve fibers carrying the special visceral afferent and general visceral afferent inputs from the corresponding components of the seventh, ninth and tenth nerves (Kiernan, 2009). However, the NST receives also a variety of somatic and visceral sensory afferent projections from several other sources, such as the spinal cord (e.g., via spinosolitary tract), several brainstem structures (e.g., area post-

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rema, periaqueductal grey, parabrachial nucleus, Ko¨lliker-Fuse nucleus) and cerebral structures (e.g., regions of the hypothalamus and central nucleus of the amygdala) (Henry, 2002; Nieuwenhuys et al., 2008). Moreover, the NST projects the sensory information to different areas of the brain, including the amygdala, cerebellum, hypothalamus, thalamus, parabrachial nucleus, raphe nuclei, and LC (Henry, 2002; Nieuwenhuys et al., 2008). Moreover, in humans the NST fiber trajectories have been revealed with postmortem horseradish peroxidase tracing method (Ruggiero et al., 2000). In particular, three major bundles were described: (i) a prominent trans-tegmental system of axons through the intermediate reticular zone; (ii) a medial system across the dorsomedial reticular formation toward the dorsal medullary raphe; and (iii) a system projecting ventrally toward the nucleus gigantocellularis (Ruggiero et al., 2000). Thus, the vagus nerve is projecting sensory information via NST to NE and serotonin (5-HT) systems (Fig. 1) which are associated with the regulation of mood, anxiety, emotion and seizure activity. Interestingly, it has been found that changes in GABA-ergic and glutamatergic transmission in the NST can regulate the susceptibility to seizures (Walker et al., 1999). In particular, an increase in GABA transmission or a decrease in glutamate transmission in the rat NST reduces susceptibility to limbic motor seizures evoked by systemic and focal bicuculline and systemic pentylenetetrazol. It is noteworthy that the activation of LC following VNS implies a direct effect on the cerebral cortex based on the widespread connections produced by the in numerous varicosities of LC axons. The LC represents the largest group of NE neurons in the human

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brain. LC has a crucial role for vigilance, particularly focused or selective attention and behavioral flexibility or scanning attentiveness (Halliday, 2004). The LC is unsurpassed in the divergence and ubiquity of its projections through the central nervous system. In fact, virtually all levels of the central nervous system are innervated by LC, being it the sole NE innervation of the cerebral and cerebellar cortices. The projections rising from the LC do not need to relay within thalamic nuclei and produce a faster effect on EEG activity (this might explain the short time delay reported above). Interestingly, the projections rising from the LC possess diffuse varicosities which determine a marked paracrine influence on innervated structures (Giorgi et al., 2004). Such an effect becomes seminal when examining the allocortex of the limbic system where the presence of NE is far in excess compared with isocortical area. For such a reason it was proposed that the regulation of cortical synchronization within allocortex is more dependent on monoaminergic control than thalamic afferents (Giorgi et al., 2004). Strikingly, the most remarkable effects due to VNS as an antiepileptic treatment are related to limbic seizures (Giorgi et al., 2004). In contrast to this extraordinary divergence, the major inputs to LC are found in the nucleus paragigantocellularis (PGi) and the perifascicular area of the nucleus prepositus hypoglossi (PrH), two structures both located in the rostral medulla (Fig. 3) (Ennis and Aston-Jones, 1988, 1989; Aston-Jones et al., 1991; Halliday, 2004). Then, the vagal afferents are relayed from NST to the LC through disynaptic pathways: one via fibers containing excitatory amino acids from the nucleus paragigantocellularis, and one via inhibitory fibers containing GABA from the

Fig. 3. Additional efferent pathway from the nucleus of the solitary tract. (A) Vagal inputs are relayed from the nucleus of the solitary tract (NST) to locus coeruleus via two disynaptic pathways: one excitatory from the nucleus paragigantocellularis (Pgi), and one inhibitory from the nucleus prepositus hypoglossi (PrH). Norepinephrine neurons (NE) of the locus coeruleus project to the cerebral cortex and to the dorsal raphe nucleus (DRN). (B) The vagus nerve stimulation (VNS) increases the firing rate of NE neurons of the locus coeruleus and, indirectly, of 5-HT neurons of DRN. (C) The excitatory action of VNS on 5-HT neurons in the DRN is prevented by the selective lesion of NE neurons in LC following administration of the selective NE-ergic toxin DSP-4.

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nucleus prepositus hypoglossi (Fig. 3) (Ennis and Aston-Jones, 1988, 1989; Aston-Jones et al., 1991; Halliday, 2004). The strong connection between VNS and LC had been elucidated and implicated in the anti-nociceptive effects of VNS in rat (Ren et al., 1990). However, LC has shown also to play a key role in the circuitry necessary for the anticonvulsant effects mediated by VNS. The first evidence for a prominent role of LC in the anticonvulsant effects of VNS dates back to 1998, when Krahl and colleagues demonstrated that, in rats, the anticonvulsant effect of VNS is blocked by a previous LC lesion (Krahl et al., 1998). A huge amount of data exist concerning the role of NE in seizures and epilepsy. In particular, it appears that the activity of LC is critical in limiting the spreading and duration of seizures since a damage to LC neurons is able to convert sporadic seizures into status epilepticus (Giorgi et al., 2004). This seizure-modifying effect appears to be bound to the activity of LC neurons on cortical excitability via modulation of synaptic plasticity and memory (Giorgi et al., 2003, 2004, 2006; Pizzanelli et al., 2009). In fact, recent data obtained by out research team demonstrated that LC is critical in modulating epilepsyrelated plasticity-dependent gene expression (Giorgi et al., 2008). This LC-dependent synaptic plasticity might subserve a variety of effects described following VNS such as antidepressant effect, cognitive enhancement, improvement of memory (for a review see Giorgi et al., 2004) as well as the bizarre time window which exists in the temporal pattern of VNS. In fact, if one considers that VNS produces a stimulation-dependent EEG desynchronization, then it is expected that the efficacy of VNS on cortical activity lasts up to the time of stimulation of the vagus nerve. However, this is not the case since epileptic patients undergo VNS intermittently and independently from ongoing seizures such as taking an antiepileptic drug. If one assumes that VNS via LC activation modifies the plasticity of the epileptic circuitry then it is expected that the duration of cortical changes produced by VNS are long-lasting. Conversely a lesion to LC should produce a long-lasting brain hyperexcitability (Giorgi et al., unpublished data). The NST also projects to raphe nuclei (Fig. 3), which are distributed among midline reticular neurons from the inferior medulla through the mesencephalon and are the major source of 5-HT in the brain (Nieuwenhuys et al., 2008). A study carried out to evaluate the influence of VNS on depressed mood in epilepsy patients showed that VNS is associated with significant positive mood effects. Furthermore, such mood improvements are independent of effects on seizure activity and persist up to 6 months (Elger et al., 2000). As demonstrated in a variety of functional neuroimaging studies with positron emission tomography, single photon emission computed tomography, and functional magnetic resonance imaging, VNS causes immediate and longer-term changes in brain regions with vagus innervation and which have been implicated in depression, as well as in epilepsy (for a review, Chae et al., 2003). Results from an electrophysiological investigation about the effect of VNS on serotonin and norepinephrine transmission in rat brain showed increased firing rate of 5-HT and NE neurons after VNS treatments (Dorr and Debonnel, 2006). In particular, the firing rates of both 5HT and NE neurons increase as length of treatment increases. In fact, the basal firing rates in the dorsal raphe nucleus (DRN) and LC were significantly increased after long-term treatments with VNS, whereas after short-term VNS treatments firing rates were significantly higher for LC (at 1 h and 3 days). Moreover, no significant differences in dose response curves for 5-HT1A somatodendritic and alpha-2 adrenergic autoreceptors were noticed between long-term VNS and controls. As the LC, but not the DRN, receives direct inputs from the NST (Van Bockstaele et al., 1999), it has been postulated that VNS may act initially and/or predominantly on the LC, and indirectly with the DRN via afferents from the LC (Dorr and Debonnel, 2006). The concomitance of substantial increase in neurotransmission for both neurotrans-

mitters and no decrease in sensitivity for 5-HT1A receptors has been suggested as a possible new mechanism of an antidepressant action mediated by VNS (Dorr and Debonnel, 2006). An electrophysiologic study has recently elucidated the role of 5-HT neurons in the mechanism of action of VNS in rat brain (Manta et al., 2009). VNS increased the firing activity and the pattern of NE neurons in LC and subsequently those of 5-HT neurons in DRN, likely as a cascade effect via alpha-1 postsynaptic adrenoceptors (Fig. 3) (Manta et al., 2009). In particular, animals treated with VNS for 90 days showed the percentage of NE neurons displaying burst more than doubled compared with controls rats. Moreover, the burst length increased by 110% and the mean number of spikes per burst increased by 80%. After 90 days of VNS, the percentage of 5-HT neurons discharging in burst increased to 32% from a value of 20% in controls. In addition, it was found that the stimulatory effect of VNS on 5-HT neuronal firing was indirect and likely mediated by activation of the NE system. In fact, the selective lesion of NE neurons in LC following administration of the selective NE-ergic toxin DSP-4 prevented completely the enhancing action of VNS on 5-HT neuron firing activity in the DRN (Fig. 3) (Manta et al., 2009). Considering that the vagal afferents are relayed from NST to the LC through two disynaptic excitatory and inhibitory pathways, it has been suggested that VNS facilities the excitatory pathway to the LC neurons more than the inhibitory one, acting first on the LC and then indirectly on 5-HT neurons in the DRN (Manta et al., 2009). Recently the efficacy of VNS therapy for intractable depression has been confirmed by recent clinical investigations (Schlaepfer et al., 2008; Bajbouj et al., 2010). After 1 year of VNS, patients with treatment-resistant depression showed significant reduction in clinical severity of depression, as evidenced by the increases in the clinical response and remission rates, which respectively reached 53% and 33% in the 28-item Hamilton Rating Scale for Depression (HRSD28) score (Schlaepfer et al., 2008). In patients underwent VNS for 2 years, the HRSD28 scores documented that the patients fulfilling the response criteria were 53.1% and those who fulfilling the remission criteria were 38.9% (Bajbouj et al., 2010). On July 15, 2005, the VNS Therapy System received final premarket approval application by the FDA for ‘‘adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to 4 or more adequate antidepressant treatments’’ (U.S. Food and Drug Administration, 2005). Ethical statement Conflict of interest: None of the authors has actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work. Submission declaration: The present article has not been published previously and it is not under consideration for publication elsewhere, its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere including electronically in the same form, in English or in any other language, without the written consent of the copyright-holder. Contributors: Each author declare his or her individual contribution to the article: all authors have materially participated to the article preparation and have approved the final article. References Agostoni, E., Chinnock, J.E., De Daly, M.B., Murray, J.G., 1957. Functional and histological studies of the vagus nerve and its branches to the heart, lungs and abdominal viscera in the cat. J. Physiol. 135, 182–205.

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