Vagal Tone: Effects on Sensitivity, Motility, and Inflammation

Neurogastroenterology & Motility Neurogastroenterol Motil (2016) 28, 455–462 doi: 10.1111/nmo.12817

MINI-REVIEW

Vagal tone: effects on sensitivity, motility, and inﬂammation

B. BONAZ,*,† V. SINNIGER*,† & S. PELLISSIER†,‡

*University Clinic of Hepato-Gastroenterology, University Hospital, Grenoble, France †Stress and Neuro-Digestive Interactions, Inserm U1216, University Grenoble Alpes, Institute of Neurosciences, Grenoble, France ‡Department of Psychology, LIP/PC2S, Savoie University, Chambery, France

Key Points • The vagus nerve is involved in the control of gastrointestinal sensitivity, motility and inﬂammation. • A low vagal tone, as assessed by heart rate variability, is a marker of autonomic dysfunction that might favor dysfunction of the gastrointestinal tract. • Restoration of vagal tone is a therapeutic target in some gastrointestinal diseases. Vagus nerve stimulation, either invasive or non-invasive, opens therapeutic avenues.

Abstract appears as a goal in such diseases. Among the The vagus nerve (VN) is a key element of the therapeutic tools, such as drugs targeting the cholin- autonomic nervous system. As a mixed nerve, the ergic system and/or complementary medicine (hypno- VN contributes to the bidirectional interactions sis, meditation...), deep breathing, physical exercise, between the brain and the gut, i.e., the brain-gut axis. VN stimulation (VNS), either invasive or non-invasive, In particular, after integration in the central auto- appears as innovative. There is new evidence in the nomic network of peripheral sensations such as current issue of this Journal supporting the role of VNS inflammation and pain via vagal and spinal afferents, in the modulation of gastrointestinal functions. an efferent response through modulation of pregan- Keywords inflammatory bowel disease, motility, glionic parasympathetic neurons of the dorsal motor pain, vagal tone, vagus nerve stimulation. nucleus of the vagus and/or preganglionic sympathetic neurons of the spinal cord is able to modulate gastrointestinal nociception, motility, and inflammation. A low vagal tone, as assessed by heart rate INTRODUCTION variability, a marker of the sympatho-vagal balance, is In the current issue of this journal, Frokjaer et al.1 observed in functional digestive disorders and inflam- assessed, in healthy volunteers, the effects of transcu- matory bowel diseases. To restore a normal vagal tone taneous vagus nerve stimulation (VNS) and deep slow breathing on validated cardiometrically derived param- Address for Correspondence eters of vagal tone, musculoskeletal pain thresholds, Bruno Bonaz, MD-PhD, Clinique Universitaire d’Hepato- descending pain modulation and gastroduodenal motil- Gastroenterologie, CHU Grenoble, CS-10217, 38043 Grenoble ity in a randomized, sham-controlled, single-blind, Cedex 09, France. Tel: +33476765597; fax: +33476765297; crossover trial. They showed that transcutaneous VNS e-mail: [email protected] increased: (i) vagal tone, (ii) thresholds to bone pain, Received: 2 February 2016 (iii) frequency of antral contractions, and (iv) Accepted for publication: 9 February 2016

gastro-duodenal motility index. These data have poten- tract. Finally, we will review nonpharmacological tial therapeutic implications in the domain of chronic ANS modulation therapies, focusing on VNS, com- pain and gastrointestinal motility disturbances but also menting on novel technologies and strategies on the inflammatory disorders of the gastrointestinal tract as horizon. observed in functional dyspepsia, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and THE AUTONOMIC NERVOUS SYSTEM others. AND THE CENTRAL AUTONOMIC The VN is a key part of the autonomic nervous NETWORK system (ANS), composed of the parasympathetic and sympathetic nervous systems. Information regarding Visceral information conveyed by vagal and spinal the extent of its involvement in the regulation of the afferents are integrated in the CAN containing brain digestive tract homeostasis is rapidly expanding and regions highly interconnected and distributed through- provides new insights from a therapeutic point of view. out the neuraxis involved in the autonomic, endocrine, The VN is the longer nerve in the body; it is a mixed motor, immune, and behavioral responses.9 These nerve containing approximately 80% afferent and 20% regions include: the frontal, insular, and anterior cingu- efferent fibers2 supplying mostly visceral organs. Vagal late cortices; the amygdala (central nucleus); several afferents are activated by gastrointestinal and pancre- areas of the hypothalamus, in particular the paraven- atic hormones, mechanical distortion of the mucosa, tricular nucleus (PVH); the midbrain periaqueductal luminal osmolarity and ingested macronutrients, and gray matter; the parabrachial nucleus in the pons; and, are involved in the regulation of food intake, pancreatic in the medulla, the nucleus tractus solitarius (NTS), the exocrine and endocrine secretion, and cardiac and first relay station for general visceral afferents, ventro- respiratory rhythm generation. lateral reticular formation and raphe nuclei. This brain In normal resting conditions, there is a balance network can be divided roughly into structures such as between the parasympathetic and sympathetic nervous the frontal cortex, which are involved in higher level systems as indexed by heart rate variability (HRV).3 executive functions, and structures such as the hypotha- This balance is modified in acute stress condition lamus and limbic system, which are involved in home- because stress induces a parasympathetic withdrawal ostatic functions. These areas receive converging and stimulates the sympathetic nervous system.4 This visceral and nociceptive inputs and, after integration, balance is restored after acute stress but in chronic generate stimulus-specific patterns of autonomic stress conditions it can be disrupted for long periods. responses via projections to preganglionic sympathetic Stress is involved in the pathophysiology of functional neurons in the spinal cord and parasympathetic neurons and organic diseases of the gastrointestinal tract such of the dorsal motor nucleus of the VN to modulate the as functional dyspepsia, IBS, IBD (Crohn’s disease, ANS and thus the vagal tone. Many of these areas are ulcerative colitis).5,6 An imbalance between the ANS also components of pain modulatory circuits and con- and the hypothalamic pituitary adrenal (HPA) axis has trol nociceptive processing via projections to the spinal been reported in such diseases.7 This imbalance is and trigeminal dorsal horns. The CAN is a complex often the consequence of an imbalance between the system including many positive and negative feedback prefrontal cortex (PFC) and the amygdala which inner- loops governing both sympathetic and parasympathetic vate central autonomic network (CAN) areas.8 Thus, outputs. Because of this complexity, it is difficult to an abnormal vagal tone could be the cause and/or the predict the final results of activity of this system since consequence of such an imbalance. Consequently, prefrontal activation might induce enhancement of restoration of normal vagal tone could be of interest sympathetic activity in one situation but enhancement in the medical management of such diseases either of vagal activity in another. through drugs targeting the cholinergic system, complementary medicine (hypnosis, meditation...), deep VAGAL TONE AND THE CENTRAL breathing, physical exercise, VNS. This might favor- AUTONOMIC NETWORK ably prevent an individual’s risk profile. In this mini-review, we highlight the anatomy of the Vagal tone could be explored via the cardiac vagal tone ANS with a special focus on the VN and the central by means of HRV measurement.3 However, correla- ANS and the control/evaluation of vagal tone in tions between cardiac vagal tone and, for example, normal and pathological conditions through HRV. We gastrointestinal vagal tone require further study, par- will focus on the role of vagal tone on sensitivity, ticularly under pathophysiological conditions. There is motility, and inflammation of the gastrointestinal no a priori reason why vagal output from the nucleus

ambiguus to the heart is regulated in concert with tomy but persists after spinal cord transection.19 It has vagal output from the dorsal motor nucleus of the VN been suggested that nociceptive input through the VN to the stomach. Actually, this method even if not may contribute to the affective-emotional rather than direct, provides the advantage of being non-invasive, to the sensory-discriminative aspect of pain. Thus, the easy to apply and perform comparisons among different VN may indirectly modulate abdominal hyperalgesia. studies. The cardiac vagal tone and HRV have allowed Electrical stimulation of abdominal vagal afferents the construction of the neurovisceral integration inhibits or facilitates somatic nociceptive impulse model that includes the CAN.10 A decreased HRV at transmission in the spinal dorsal horn, and depresses rest reflects a low vagal tone and could be considered as nociceptive behavior, depending on whether unmyeli- a marker of stress.11 Decreased vagal function and HRV nated or myelinated vagal afferents are excited.18 are associated with increased fasting glucose level, Patients with VNS for epilepsy and depression often increased overnight urinary cortisol, and increased pro- report improvement of pain. There is evidence for a inflammatory cytokines and acute-phase proteins.12 relationship between VN activity and pain, based on All of these factors have been associated with increased the fact that the VN inhibits factors that are etiologic allostatic load and poor health. A high level of HRV is to pain such as inflammation, oxidative stress, and associated with good health and well-being and good sympathetic activity, activates brain regions that can resilience in emotional self-regulation.13,14 A high oppose the brain ‘pain matrix’, and finally influences level of HRV with low level of cortisol reflects the the analgesic effects of opioids.20 Administration of inhibitory influence of the PFC on amygdala.12 The cholecystokinin (CCK)-8 enhances memory retention PFC contributes to negative feedback control of the in the mice after aversive training; this effect is HPA axis.15 The hypoactivity of the PFC and the blocked by vagotomy indicating that CCK-8 may enhancement of amygdala activity are strongly influ- produce its effect on memory retention by activating enced by stress. The PFC regulates peripheral immune vagal afferents.21 Thus, in a number of gastrointestinal cells through the autonomic and neuroendocrine disorders, such as IBS, nutrient content may contribute pathways and controls vagal tone by modulating the to painful visceral perception by enhancing visceral VN efferent outflow. Increased inflammatory markers, aversive memory via vagal afferent pathways.22 e.g., C reactive protein and IL-6 are associated with Activation of vagal afferents is part of the mechanism decreased HRV.16 We have described an imbalance that not only gives rise to vago-vagal reflex but also can between the HPA axis and vagal tone in CD and IBS modulate brain cortex neuronal activity and plays a role patients.7 Furthermore, we highlighted the specific in the behavioral control of nociception and memory homeostatic link between a low vagal tone and tumor storage processes.23 It is well known that a hot drink or a necrosis factor (TNF)-a in Crohn’s disease and epi- nourishing meal are relaxing and help to calm anxiety nephrine in IBS in relation with a strong comorbidity of suggesting that enhanced sensory vagal inputs originat- negative mood, anxiety, and visceral pain that has been ing from the gut modulate attitude and behavior.24 Vagus observed in those diseases.7 These data, underline the nerve stimulation suppresses experimentally induced link between brain areas involved in cognition and pain through activation of vagal afferents which termi- mood regulation, visceral perception and conscious- nate in the NTS; NTS neurons then innervate the CAN ness, stress response, and HRV as a marker of vagal and the nucleus raphe magnus and locus coeruleus, to tone in gut diseases. cause subsequent activation of descending inhibitory pain pathways.25 Low-intensity VNS that activates vagal afferent Ad fibers reduces visceral pain suggesting that a VAGAL TONE AND SENSITIVITY group of vagal afferents innervating viscera may have Classically, pain arising from the viscera is mediated functions related to visceral pain inhibition.23 exclusively by spinal afferents and there is evidence that the sympathetic nervous system is involved in VAGAL TONE AND MOTILITY pain generation in chronic pain states.17 There is growing evidence that the VN modulates nociceptive The VN innervates classically the digestive tract from processing in the spinal cord and the brain.18 Studies the esophagus to the splenic flexure while the rest of have shown that vagal afferents respond to nociceptive the digestive tract, i.e., the left colon and rectum, is mechanical and chemical stimulation and this leads to innervated by the sacral parasympathetic nucleus. brainstem representation of nociceptive signals. The However, for some anatomists, the VN innervates all increase in NTS c-fos expression observed in response the digestive tract in human.26 The VN is a major to noxious gastric distention is attenuated by vago- component in the control of upper gastrointestinal

motility, thus a low vagal tone could favor gastroin- inflammatory cytokines, such as IL-1beta, activate testinal motility disturbances. Vagal dysfunction is vagal afferents and then the HPA axis through nora- known to contribute to esophageal hypomotility.27 drenergic projections from the NTS to the PVH.35 More Physiological vagal input to cholinergic enteric neu- recently, an anti-inflammatory role of vagal efferents rons is necessary to maintain a basal gastric tone and has been described by Tracey’s group. Indeed, VNS- vagal cooling induces a decrease in gastric tone.28 A induced acetylcholine release from the peripheral ter- very low tonic vagal activity is apparently necessary minals of vagal efferents dampens the release of TNF-a and sufficient to produce basic antral motility, while by macrophages in a model of endotoxic shock in rats. more sustained vagal activity is necessary for high- This effect is mediated via activation of a7-nicotinic amplitude gastric contractions and significant sus- receptors on macrophages and defined as the inflamma- tained fundic relaxation; the maximal effect of vagal tory reflex, i.e., the cholinergic anti-inflammatory stimulation on amplitude and length of gastric con- pathway.36 The same group has described a vago- traction is already reached at 2–4 Hz, with no further sympathetic link involving a stimulatory effect of the increase at 8 Hz.29 Chewing gum, via activation of VN on the spleen through an interaction with the cephalic stimulation, is an adequate stimulus to splenic sympathetic nerve resulting in the inhibition of induce vagally mediated normalization of meal- TNF-a release by spleen macrophages36 although this induced antral motility in functional dyspepsia, sug- pathway has been recently revisited.37 We have shown gesting that hypomotility is related to inadequate vagal that vagal tone is significantly blunted in IBD in relation stimulation.30 Antral dysmotility is a consistent find- with negative affect,38 and high TNF-a levels.7 Conse- ing in diabetics with delayed gastric emptying and quently, low vagal tone has a pro-inflammatory effect. impaired gastric autonomic innervation probably con- Low vagal tone is a significant predictor of necrotizing tributes to this dysmotility. Patients with Type 1 enterocolitis, an exaggerated inflammatory response diabetes mellitus have impaired meal-induced volume resulting in high levels of pro-inflammatory cytokines, response, possibly as a consequence of reduced vagal in preterm infants39 which opens up avenues for its role tone.31 Gastric dysmotility in diabetes is thus caused, as a predictive biomarker of this disease. Stress is at least in part, by vagal neuropathy and the VN is evoked in the pathophysiology of inflammatory disor- important for gastric meal accommodation in man. ders such as IBD, at least through an inhibition of vagal Stress is well known to delay gastric emptying, alter tone either through activation of projections from the intestinal transit and colonic motility and inhibit vagal hypothalamus to the dorsal motor nucleus of the VN or tone; this effect is mediated, at least in part, by through modifications of the fronto-amygdaloid com- corticotrophin-releasing factor.4 Autonomic dysfunc- plex.5 We have shown that low frequency (5 Hz) VNS tion has been frequently reported in patients with improves colitis in rats40 and may exert an anti- gastrointestinal motility disorders. By stimulating inflammatory effect in Crohn’s disease patients that gastrointestinal motility via activation of vagal path- exhibit an autonomic imbalance.41 We showed that ways,32 gum chewing reduces the duration of postop- VNS induced a clinical, biological, and endoscopic erative ileus in abdominal surgery.33 Nicotine gum remission at 6 months in the majority (5/7) of patients chewing combines the stimulation of the cephalic- with mild to moderate active Crohn’s disease and vagal reflex by gum chewing and the activation of the restored autonomic balance toward the homeostatic cholinergic anti-inflammatory pathway by nicotine values observed in healthy subjects.38 We have also administration; it might be beneficial for the preven- shown, in a case report, that VNS induced significant tion of postoperative ileus.34 Improving vagal tone changes in resting EEG.42 In particular, activation was through gum chewing, deep breathing,1 moderate- observed over the mediofrontal electrodes for both low pressure massage therapy, or other exercises that have and high frequency bands with the most important a strong effect on heart rate and its variability or activation for theta band. Significant correlations were through VNS could have prokinetic effects. Further detected between EEG and high frequency-HRV for investigations are needed to explore the intestinal delta, theta, beta, and gamma frequency bands. component of digestive tract motility under the modulation of vagal tone re-inforcement. THERAPEUTIC IMPLICATIONS: ACTIVATION OF VAGAL AFFERENTS/ VAGALTONEANDINFLAMMATION EFFERENTS The VN exerts a dual anti-inflammatory role through its Vagus nerve stimulation can be used to modu- afferents and efferents. Classically, peripheral pro- late gastrointestinal inflammation, motility, and

ImplantableVNS devices Non-implantable VNS devices

Figure 1 Implantable VNS systems: (top) VNS Therapy system (Cyberonics, Houston, TX, USA); (bottom) CardioFit (BioControl Medical Ltd.). Non-implantable VNS systems: (top) NEMOS (Cerbomed), (bottom) gammaCore (electroCore LLC). nociception, in addition to its current use for drug- efferents alone. In addition, one may speculate that resistant epilepsy and depression and open new activation of both vagal afferents and efferents may be avenues in the therapeutic armamentarium. Implan- of interest in the domain of inflammation, pain, and table VNS is an invasive technique, which poses a risk gastrointestinal motility. The total charge for the for adverse events from infection, although the risk is device plus implantation varies from $12 000 to low since the technique is well described and com- $25 000. By comparison, the cost of a 1 year treatment monly used. To avoid potential bradycardia, VNS of biosimilar infliximab is ~6000 euros for the treat- electrodes are placed on the left cervical VN which is ment alone in IBD. easily accessible at the level of the neck. ~100 000 Newer non-invasive VNS delivery systems do not patients have been implanted with invasive VNS for require surgery and permit patient-administered stim- epilepsy and depression. Depending on the therapeutic ulation on demand. These non-invasive VNS systems purpose, either anti-inflammatory and/or anti-nocicep- improve the safety and tolerance of VNS and are easy tive, or prokinetic, one might suggest activating vagal to use, making it more accessible and facilitating afferents in case of nociception or vagal efferents in further investigations across a wider range of uses. Two case of inflammation and for prokinetic effect. How- non-invasive VNS devices are currently on the market ever, classically while low (5–10 Hz) frequency VNS is (Fig. 1). NEMOS (Cerbomed, Erlangen, Germany) is an supposed to activate vagal efferents and high (20– external device that provides transcutaneous auricular 30 Hz) frequency is supposed to activate vagal affer- VNS (ta-VNS) by using a dedicated intra-auricular ents, in practice things are not so simple. Indeed, we electrode (like an earphone) which stimulates the have shown that even low frequency (5 Hz) VNS is able auricular branch of the VN. No clinically relevant to modulate CNS functions.43 Consequently, it seems adverse events, either cardiovascular or otherwise, unlikely to selectively activate vagal afferents or have been reported with this device. The recom-

mended daily stimulation duration is 4 h and should parasympathetic withdrawal) that is maladaptive in be reached daily. Transcutaneous auricular VNS is able heart failure. Unfortunately, CardioFit is an invasive to increase HRV and reduce sympathetic nerve outflow system. A VNS device coupled to skin conductance in healthy controls.44 GammaCore (electroCore LLC, evaluation, as a marker of sympathetic nervous system Basking Ridge, NJ, USA), is a non-invasive VNS device activity, would be of interest as well. In the same way, that uses two stainless steel round discs as skin a VNS device coupled to circulating TNF-a levels contacts to deliver a programmable number of stimu- would be of interest. Indeed, following intraperitoneal lation cycles through a transcutaneous low voltage administration of TNF-a, the VN senses changes in electrical signal to the cervical VN, each lasting 120 s peripheral inflammatory status within 3 min, and at a frequency of 25 Hz. This device is currently being increases vagal tone in response.50 This defines a tested for headache, epilepsy, and gastrointestinal mechanism of inflammation sensing by the brain. disorders.45 Another point, is the improvement of VNS device Some data is emerging regarding the use of VNS, through a miniaturization of the device and a multi- either invasive on non-invasive, in fibromyalgia, contact electrode that would stimulate ideally all the pelvic pain, and headaches (see for review 46). Lange fibers components of the VN or selectively afferents or et al.47 examined the safety and tolerability of inva- efferents. However, the exact topographic distribution sive VNS in treatment resistant fibromyalgia and of vagal afferents/efferents in the VN needs to be determined preliminary measures of efficacy as a specified. Although non-implantable devices are attrac- secondary endpoint in this small cohort. Together tive, they raise the problem of compliance as observed with what is already known about VNS and its in the medical treatment of chronic diseases with antinociceptive and anti-inflammatory effects, find- drugs and which is avoided by the classical invasive ings from preliminary studies are promising in terms VNS. of addressing the hyperalgesia and central sensitiza- tion associated with chronic pelvic pain and other CONCLUSION chronic pain syndromes.48 Ideally, VNS coupled to the detection of HRV would As a bidirectional link between the brain and the be of interest, particularly in patients with vagal gastrointestinal tract the VN is involved in maintain- dysautonomia, i.e., vagal hypotony as observed in IBD ing the homeostasis of gut functions such as sensitiv- and IBS. The neurostimulator itself, for example, could ity, motility, and immunity both through its sensing also be used to measure HRV.38 For example, CardioFit and modulatory roles. A dysfunction of the vagal tone (BioControl Medical Ltd., Yehud, Israel) is an implan- is observed in functional and inflammatory digestive table VNS device being investigated in heart failure disorders. To restore a normal vagal tone is a thera- that acts through preferential activation of vagal peutic goal in such diseases where VNS appears as an efferents.49 The system consists of a stimulator, a interesting tool. sensor lead and a stimulation lead, which are implanted under the skin of the chest. The sensor lead FUNDING is extended from the stimulator to the right ventricle of the heart, and the stimulation lead is extended from No funding obtained for this mini review. the stimulator to the VN on the right side of the neck. Once activated, the stimulator’s electrical pulses are CONFLICTS OF INTEREST transferred via the stimulation lead to the VN. The stimulation is designed to correct the autonomic No conflicts of interest exist. imbalance (sustained sympathetic overdrive and

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