Vagus nerve stimulation in Crohn's disease: long-term outcomes, mechanistic insights, and the promise of non-invasive approaches.

Su1381 Vagus Nerve Stimulation in Active Crohn's Disease

Accumulating evidence suggests that the respiratory control system exhibits an impressive degree of plasticity, as do many other neural networks in the central nervous system (Eldridge & Millhorn, 1986; McCrimmon et al. 1995; Ling et al. 1997a; Powell et al. 1998; Mitchell et al. 2001). For example, episodic hypoxia induces a persistent augmentation of respiratory activity (Cao et al. 1992; Bach & Mitchell, 1996; Turner & Mitchell, 1997; Olson et al. 2001; McGuire et al. 2002), known as long-term facilitation (LTF). Episodic carotid sinus nerve (CNS) stimulation (CSNS) also elicits phrenic LTF in anaesthetized animals (Millhorn et al. 1980a; Hayashi et al. 1993; Ling et al. 1997b), which is not abolished by decerebration or spinal transection at the C7-T1 level (Eldridge & Millhorn, 1986). These results suggest that LTF is elicited by central mechanisms located in the brainstem and/or cervical spinal cord, and that the carotid body, respiratory mechanics, systemic hypoxia, forebrain and the lower spinal cord are not necessary for its expression (Eldridge & Millhorn, 1986). Both hypoxia- and CSNS-induced LTF are serotonin-dependent (Millhorn et al. 1980b; Bach & Mitchell, 1996). Recent evidence further suggests that spinal serotonin receptors (Baker-Herman & Mitchell, 2002) and the synapses transmitting bulbospinal, inspiratory drive to the phrenic motoneurons (Fuller et al. 2002) play key roles in phrenic LTF. In these experiments, respiratory LTF is always preceded by repeated inspiratory augmentation. This fact suggests that induction of respiratory LTF is somehow related to inspiratory augmentation, and more specifically, that phrenic LTF relies heavily on an activity-dependent Hebbian mechanism (coincident pre- and post-synaptic activity strengthens synapses) in the synapses on the phrenic motoneurons. However, as all LTF to date has been induced by episodic inspiratory-excitatory stimulation, it has been difficult to directly test these hypotheses by separating the LTF from inspiratory augmentation. In contrast, vagus nerve (VN) stimulation (VNS) suppresses inspiration during stimulation, and induces a reduction (< 1 min duration) in phrenic amplitude and frequency after stimulation (0.5 min duration; Eldridge & Millhorn, 1986). We speculate that a relatively longer post-stimulation inhibitory memory is possible if using episodic and longer VNS. VNS has also been used as a tool in brain research (e.g. evoked potentials recorded from the cerebral cortex, hippocampus, thalamus and cerebellum; Rutecki, 1990) and neurophysiological studies of several reflexes (e.g. cough, swallow and Hering-Breuer reflex or inspiratory off-switch mechanisms) because vagal afferents provide an easily accessible, peripheral route by which to modulate the central nervous system function. However, these investigators all used brief VNS and focused mainly on immediate or short-term (< several min) effects, during and/or after VNS. For many years, episodic VNS has been used clinically as a common treatment for patients with medically intractable epilepsy (Schachter, 2002). However, the precise underlying mechanisms and the consequence of long-term VNS remain unclear. The aims of the present study were to (1) examine the long-term effects of episodic phrenic-inhibitory VNS on phrenic nerve activity and compare them with those elicited by phrenic-excitatory CSNS and (2) explore the possibility of using VNS as a tool to suppress phrenic motor neurons during LTF elicitation. We hypothesized that episodic VNS would induce phrenic long-term depression, but that phrenic activity would eventually return to baseline in less than 60 min.

A SENSORY CORTICAL REPRESENTATION OF THE VAGUS NERVE: WITH A NOTE ON THE EFFECTS OF LOW BLOOD PRESSURE ON THE CORTICAL ELECTROGRAM

Transcutaneous auricular vagus nerve stimulation for managing pain: A scoping review

To the Editor: We enjoyed the recent article entitled “Right-sided vagus nerve stimulation as a treatment for refractory epilepsy in humans” by McGregor et al. (1). We agree that right vagus nerve stimulation may be used in humans with epilepsy, as prior reports of cardiac effects after right-sided vagus nerve stimulation were based on experiments in dogs (2). Although complications with vagus nerve stimulation are low, as found in our report of 74 children undergoing this procedure (3), as surgeons, the option of left versus right side for vagus nerve stimulation is appealing, especially in cases of concomitant left-sided ventriculoperitoneal shunts, so that additional hardware (i.e., vagus nerve stimulator) is moved farther away from the shunt system, thus decreasing the risk of infection of the shunt. Our experience also has shown that another cardiovascular nerve (the carotid sinus nerve) can be stimulated on both left and right sides in a dog model with equal effect on causing cessation of cortically induced seizures (4). Furthermore, we found no significant cardiovascular effects when this nerve (carotid sinus nerve) was stimulated with parameters comparable to those used for vagus nerve stimulation in humans (4). Interestingly, both of these nerves synapse proximally in the cardiorespiratory part of the nucleus tractus solitarius. After right-sided vagus nerve stimulation, we have been unable to alter the cardiorespiratory system in a porcine model (5). These data imply, whether with vagus or carotid sinus nerve stimulation, that nerve stimulation responses (e.g., right-sided cardiorespiratory responses) may be species specific. We also agree with the authors' statement that the right vagus nerve may be desired for stimulation when a left-sided vagus nerve has been used and removed after infection. Indeed, we have shown in a single case that a left-sided vagus nerve that was often stimulated and removed at autopsy had severe demyelination (6).

Emerging non-invasive therapeutic approaches targeting hypocholinergic neural systems in Parkinson's disease.

Imbalanced autonomic function has been reported in gastrointestinal (GI) disorders. The vagus nerve is a major component in the regulation of upper GI motility. Vagal nerve stimulation (VNS) has been shown to improve symptoms of various GI disorders by enhancing parasympathetic activity. This review aims to summarize the clinical efficacy of transcutaneous VNS for GI disorders, focusing on abdominal pain, other GI symptoms, and GI motility, and to discuss the mechanisms of action of transcutaneous VNS. Randomized clinical trials investigating transcutaneous VNS in several major GI disorders, including functional dyspepsia, gastroparesis, constipation, irritable bowel syndrome, and inflammatory bowel disease, were reviewed and discussed. The forms of transcutaneous VNS covered in this review include transcutaneous auricular VNS, transcutaneous cervical VNS, and percutaneous electrical nerve field stimulation. Transcutaneous VNS has been shown to relieve abdominal pain, improve GI symptoms, and accelerate GI motility by enhancing vagal activity in patients with various GI disorders. Transcutaneous VNS is an innovative, effective, and safe therapy for patients with GI disorders; however, large-scale clinical trials are necessary to establish optimal treatment modalities and efficacy.

Rapid Remission of Conditioned Fear Expression with Extinction Training Paired with Vagus Nerve Stimulation

Video Podcast: https://www.youtube.com/watch?v=YvSVHZ3tqh8&amp;feature=youtu.be

Cardiac Autonomic Nerve Stimulation in the Treatment of Heart Failure

Vagal nerve stimulation for treatment of children with epilepsy

The vagus nerve has anti-inflammatory properties. We aimed to investigate vagus nerve stimulation (VNS) as a new therapeutic strategy targeting an intrinsic anti-inflammatory pathway in a pilot study in Crohn's disease patients. The main objectives addressed the questions of long-term safety, tolerability, and anti-inflammatory effects of this therapy. This study is the continuation of previous reported findings at 6months. Nine patients with moderate active disease underwent VNS. An electrode wrapped around the left cervical vagus nerve was continuously stimulated over 1year. Clinical, biological, endoscopic parameters, cytokines (plasma, gut), and mucosal metabolites were followed-up. After 1year of VNS, five patients were in clinical remission and six in endoscopic remission. C-reactive protein (CRP) and fecal calprotectin decreased in six and five patients, respectively. Seven patients restored their vagal tone and decreased their digestive pain score. The patients' cytokinergic profile evolved toward a more "healthy profile": Interleukins 6, 23, 12, tumor necrosis factor α, and transforming growth factorβ1 were the most impacted cytokines. Correlations were observed between CRP and tumor necrosis factor α, and some gut mucosa metabolites as taurine, lactate, alanine, and beta-hydroxybutyrate. VNS was well tolerated. Vagus nerve stimulation appears as an innovative and well-tolerated treatment in moderate Crohn's disease. After 12months, VNS has restored a homeostatic vagal tone and reduced the inflammatory state of the patients. VNS has probably a global modulatory effect on the immune system along with gut metabolic regulations. This pilot study needs replication in a larger randomized double-blinded control study.

Objective: Electrical vagus nerve stimulation inhibits proinflammatory cytokine production and prevents shock during lethal systemic inflammation through an [alpha]7 nicotinic acetylcholine receptor ([alpha]7nAChR)-dependent pathway to the spleen, termed the cholinergic anti-inflammatory pathway. Pharmacologic [alpha]7nAChR agonists inhibit production of the critical proinflammatory mediator high mobility group box 1 (HMGB1) and rescue mice from lethal polymicrobial sepsis. Here we developed a method of transcutaneous mechanical vagus nerve stimulation and then investigated whether this therapy can protect mice against sepsis lethality. Design: Prospective, randomized study. Setting: Institute-based research laboratory. Subjects: Male BALB/c mice. Interventions: Mice received lipopolysaccharide to induce lethal endotoxemia or underwent cecal ligation and puncture to induce polymicrobial sepsis. Mice were then randomized to receive electrical, transcutaneous, or sham vagus nerve stimulation and were followed for survival or euthanized at predetermined time points for cytokine analysis. Measurements and Main Results: Transcutaneous vagus nerve stimulation dose-dependently reduced systemic tumor necrosis factor levels during lethal endotoxemia. Treatment with transcutaneous vagus nerve stimulation inhibited HMGB1 levels and improved survival in mice with polymicrobial sepsis, even when administered 24 hrs after the onset of disease. Conclusions: Transcutaneous vagus nerve stimulation is an efficacious treatment for mice with lethal endotoxemia or polymicrobial sepsis.

Transcutaneous vagus nerve stimulation (tVNS) protocol for the treatment of major depressive disorder: A case study assessing the auricular branch of the vagus nerve.

Distribution of local repolarization changes produced by efferent vagal stimulation in the canine ventricles