Effects Of Vagus Nerve Stimulation Research Articles

Multifactorial Benefits of Chronic Vagus Nerve Stimulation on Autonomic Function and Cardiac Electrical Stability in Heart Failure Patients With Reduced Ejection Fraction.

Heart failure with reduced left ventricular ejection fraction is a progressive disease that claims > 352,000 lives annually in the United States alone. Despite the development of an extensive array of pharmacologic and device therapies, prognosis remains poor. Disruption in autonomic balance in the form of heightened sympathetic nerve activity and reduced vagal tone have been established as major causes of heart failure progression. Interest in chronic neuromodulation mediated by vagus nerve stimulation (VNS) has intensified in recent years. This review focuses on four main goals: (1) To review the preclinical evidence that supports the concept of a cardioprotective effect of VNS on autonomic function and cardiac electrical stability along with the underlying putative mechanisms. (2) To present the initial clinical experience with chronic VNS in patients with heart failure and highlight the controversial aspects of the findings. (3) To discuss the latest findings of the multifactorial effects of VNS on autonomic tone, baroreceptor sensitivity, and cardiac electrical stability and the state-of-the-art methods employed to monitor these relationships. (4) To discuss the implications of the current findings and the gaps in knowledge that require attention in future investigations.

Effects of Stable Vagus Nerve Stimulation Efficacy on Autistic Behaviors in Ten Pediatric Patients With Drug Resistant Epilepsy: An Observational Study.

Vagus nerve stimulation (VNS) is a safe and effective therapy for pediatric patients with drug-resistant epilepsy (DRE). However, in children with DRE, the effects of VNS on autistic behaviors remain controversial. We retrospectively collected data from 10 children with DRE who underwent VNS implantation and regular parameter regulation in three pediatric epilepsy centers, and completed the behavioral assessments, including the autistic behavior checklist and the child behavior checklist, at follow-ups 1 (mean 2.16 years) and 2 (mean 2.98 years). The 10 children maintained stable seizure control between the two follow-ups. Their autistic behaviors, especially in language, social and self-help, were reduced at follow-up 2 compared to follow-up 1 (p = 0.01, p = 0.01, respectively). Moreover, these improvements were not associated with their seizure control, whether it was positive or negative. These results suggested that the VNS had a positive effect on autistic behaviors, which provided a preliminary clinical basis that VNS may benefit to younger children with DRE comorbidity autism spectrum disorder (ASD).

Common Cholinergic, Noradrenergic, and Serotonergic Drugs Do Not Block VNS-Mediated Plasticity.

Vagus nerve stimulation (VNS) delivered during motor rehabilitation enhances recovery from a wide array of neurological injuries and was recently approved by the U.S. FDA for chronic stroke. The benefits of VNS result from precisely timed engagement of neuromodulatory networks during rehabilitative training, which promotes synaptic plasticity in networks activated by rehabilitation. Previous studies demonstrate that lesions that deplete these neuromodulatory networks block VNS-mediated plasticity and accompanying enhancement of recovery. There is a great deal of interest in determining whether commonly prescribed pharmacological interventions that influence these neuromodulatory networks would similarly impair VNS effects. Here, we sought to directly test the effects of three common pharmaceuticals at clinically relevant doses that target neuromodulatory pathways on VNS-mediated plasticity in rats. To do so, rats were trained on a behavioral task in which jaw movement during chewing was paired with VNS and received daily injections of either oxybutynin, a cholinergic antagonist, prazosin, an adrenergic antagonist, duloxetine, a serotonin-norepinephrine reuptake inhibitor, or saline. After the final behavioral session, intracortical microstimulation (ICMS) was used to evaluate reorganization of motor cortex representations, with area of cortex eliciting jaw movement as the primary outcome. In animals that received control saline injections, VNS paired with training significantly increased the movement representation of the jaw compared to naïve animals, consistent with previous studies. Similarly, none of the drugs tested blocked this VNS-dependent reorganization of motor cortex. The present results provide direct evidence that these common pharmaceuticals, when used at clinically relevant doses, are unlikely to adversely impact the efficacy of VNS therapy.

Vagus nerve stimulation alleviated cerebral ischemia and reperfusion injury in rats by inhibiting pyroptosis via \u03b17 nicotinic acetylcholine receptor

Cumulative evidence suggests that pyroptosis, a new sort of programmed cell death, is closely related to cerebral ischemia/reperfusion (I/R) injury. Our previous studies have testified that vagus nerve stimulation (VNS) was involved in many different neuroprotective and neuroplasticity pathways via α7 nicotinic acetylcholine receptor (α7nAchR), a vital node of the cholinergic anti-inflammatory pathway during cerebral I/R injury. We aimed to determine the neuroprotective effects of VNS through α7nAchR-mediated inhibition of pyroptosis. Focal cerebral ischemic stroke rat models were obtained by middle cerebral artery occlusion for 120 min. Expression of the NLRP3 inflammasome was evaluated using western blotting and immunofluorescence (IF) staining. The neurological deficit score, infarct volume, TUNEL staining findings, transmission electron microscopy findings, and expression of inflammatory cytokines were assessed 3 days after I/R injury. Our findings suggested that the protein expression levels of NLRP3, GSDMD-N, cleaved caspase-1, and ASC gradually increased until they peaked on day 3 after I/R injury. VNS inhibited the expression of pyroptosis-related molecules and decreased the number of pyroptotic cells and membrane pores. Administration of α7nAchR-antagonist and agonist helped in further assessment of the role of α7nAchR in pyroptosis. α7nAchR-agonist mimicked VNS’s neuroprotective effects on the improvement of neurological deficits, the reduction of infarct volumes, and the inhibition of neuronal pyroptosis after cerebral I/R injury. Conversely, the neuroprotection provided by VNS could be reversed by the administration of α7nAchR-antagonist. In conclusion, VNS-induced neuroprotection via inhibition of neuronal pyroptosis was α7nAchR-dependent, highlighting the pivotal role of α7nAChR in suppressing cellular pyroptosis and neuroinflammation. These findings may allow a better understanding of treatment principles for cerebral I/R injury.

The potential of invasive and non-invasive vagus nerve stimulation to improve verbal memory performance in epilepsy patients

It has been demonstrated that acute vagus nerve stimulation (VNS) improves word recognition memory in epilepsy patients. Transcutaneous auricular vagus nerve stimulation (taVNS) has gained interest as a non-invasive alternative to improve cognition. In this prospective randomized cross-over study, we investigated the effect of both invasive VNS and taVNS on verbal memory performance in 15 patients with drug-resistant epilepsy. All patients conducted a word recognition memory paradigm in 3 conditions: VNS ON, VNS OFF and taVNS (3-period 3-treatment cross-over study design). For each condition, patients memorized 21 highlighted words from text paragraphs. Afterwards, the intervention was delivered for 30 s. Immediate recall and delayed recognition scores were obtained for each condition. This memory paradigm was repeated after 6 weeks of VNS therapy in 2 conditions: VNS ON and VNS OFF (2-period 2-treatment cross-over study design). Acute VNS and taVNS did not improve verbal memory performance. Immediate recall and delayed recognition scores were significantly improved after 6 weeks of VNS treatment irrespective of the acute intervention. We can conclude that the previously described positive effects of invasive VNS on verbal memory performance could not be replicated with invasive VNS and taVNS. An improved verbal memory performance was seen after 6 weeks of VNS treatment, suggesting that longer and more repetitive stimulation of the vagal pathway is required to modulate verbal memory performance.Clinical trial registration number: NCT05031208.

Vagus nerve stimulation modulates hippocampal inflammation caused by continuous stress in rats

BackgroundPrevious studies have shown that vagus nerve stimulation (VNS) can attenuate inflammatory responses in peripheral tissues and also improve some neurological disorders and cognitive function in the brain. However, it is not clear how VNS is involved in neuropathological processes in brain tissues. Here, we investigated the regulatory effects of VNS on the production of proinflammatory cytokines in the hippocampus of an animal model of continuous stress (CS).MethodsCS was induced by placing rats in cages immersed with water, and acute or chronic electrical stimulation was applied to the cervical vagus nerve of CS animals. Protein levels in the gastric and hippocampal tissues were measured by western blotting and protein signals analyzed by immunofluorescence staining. von Frey test and forced swimming test were performed to assess pain sensitivity and depressive-like behavior in rats, respectively.ResultsLevels of TNF-α, IL-1β, and IL-6 in the gastric and hippocampal tissues were significantly increased in CS animals compared to the untreated control and downregulated by acute VNS (aVNS). Iba-1-labeled microglial cells in the hippocampus of CS animals revealed morphological features of activated inflammatory cells and then changed to a normal shape by VNS. VNS elevated hippocampal expression of α7 nicotinic acetylcholine receptors (α7 nAChR) in CS animals, and pharmacological blockade of α7 nAChR increased the production of TNF-α, IL-1β, and IL-6, thus suppressing cholinergic anti-inflammatory activity that was mediated by VNS. Chronic VNS (cVNS) down-regulated the hippocampal production of active form of caspase 3 and 5-HT1A receptors and also decreased levels of TNF-α, IL-1β, and IL-6 in the gastric and hippocampal tissues of CS animals. Pain sensitivity and depressive-like behavior, which were increased by CS, were improved by cVNS.ConclusionsOur data suggest that VNS may be involved in modulating pathophysiological processes caused by CS in the brain.

A Numerical Model of the Acute Cardiac Effects Provoked by Cervical Vagus Nerve Stimulation.

Today, the diverse acute cardiac effects of vagus nerve stimulation (VNS) are still not fully understood. Therefore, we propose a numerical model that can predict the acute cardiac responses to VNS and explain the underlying mechanisms on different levels. We integrated a model of vagal nerve fiber recruitment and acetylcholine (ACh) kinetics at vagal nerve terminals into a cardiovascular system model. A sensitivity analysis was performed to identify the most important parameters of vagal cardiac pathways. These parameters were tuned, and the model was validated based on published data of experiments in anesthetized sheep. The four most important parameters are related to vagus nerve anatomy (electrode-fiber distances, fiber diameters) and ACh kinetics in the vagal neuroeffector junction (rate of ACh release and -hydrolysis) which together explain >53% of the observed variability in acute cardiac responses to VNS. The mean electrode-fiber distance and nerve fiber diameters obtained from tuning are 1.3 ± 0.09 mm, and 4.9 ± 0.25 μm; the ACh release and -hydrolysis rate constants are 0.023 s-1 and 0.77 s-1, respectively. With this parameterization, the model could accurately predict published data on the acute cardiac effects of VNS. The model can explain the cardiac responses to VNS on multiple levels. The results highlight the importance of four parameters tied to ACh dynamics and vagus nerve anatomy for predicting the cardiac effects of VNS. The model represents a substantial improvement in terms of comprehensibility of the underlying mechanisms of the acute cardiac responses to VNS.

Abstract WMP44: Complications Of Implanted Vagal Nerve Stimulation: A Systematic Review And Meta-analysis

Introduction: Vagus nerve stimulation (VNS) is a surgical technique that has been used to modulate disease processes by activating the parasympathetic system and has been used to treat conditions such as epilepsy and depression. More recently, VNS has been a promising tool in ischemic stroke rehabilitation. However, there has been no literature summarizing the adverse effects of this procedure, information that is critical for both patients and providers when obtaining informed consent for this novel treatment. This systematic review and meta-analysis aims to report the adverse effects of VNS. Methods: A systematic review was performed in accordance with PRISMA guidelines in order to identify common complications after VNS therapy. The search was executed in three databases: Cochrane Central Register of Controlled Trials, Embase, and Ovid MEDLINE. All prospective, randomized controlled trials using implanted VNS therapy in adult patients were eligible for inclusion. Case studies and studies lacking complete complication reports were excluded. Extracted data included technology name, location of implantation, follow-up duration, purpose of VNS, and adverse event rates. Results: After title-and-abstract screening of 4933 studies identified by the created search strategy, 21 studies were selected for final inclusion. Included papers studied VNS as a potential therapy for epilepsy (9), depression (8), anxiety (1), ischemic stroke (1), chronic heart failure (1), and fibromyalgia (1). In total, 1474 patients received VNS implantation in the 21 studies. The 5 most common post-implant adverse events were voice alteration/hoarseness (n=671, 45.5%), paresthesia (n = 233, 15.8%), cough (n = 221, 15.0%), dyspnea (n = 211, 14.3%), and pain (n = 170, 11.5%). Conclusions: Complications from VNS are relatively mild and transient, with reduction in severity and number of adverse events with increasing follow-up time. The most common complications included voice changes or hoarseness, increased cough, and pain with swallowing after surgery. In summary, VNS presents a powerful tool for the treatment of many difficult-to-treat conditions. In the future, the use of VNS in recovery after intracerebral hemorrhage should be explored.

Chronic vagus nerve stimulation (VNS) altered IL-6, IL-1β, CXCL-1 and IL-13 levels in the hippocampus of rats with LiCl-pilocarpine-induced epilepsy

An increasing number of observations have indicated that the activation of inflammatory processes is involved in the pathogenesis of epilepsy. As an effective adjunctive therapy for medically intractable seizures, vagus nerve stimulation (VNS) is thought to interact with the inflammatory process to play an antiepileptic role. In this study, we examined the levels of multiple cytokine in focal brain tissue and peripheral blood to determine whether the antiepileptic effect of chronic VNS is related to the expression of cytokines. We observed that the frequency and duration of seizures significantly decreased in epileptic rats after two weeks of chronic VNS treatment. Pathological staining showed that the number of neural cells in the hippocampus was higher in the Epi + VNS group than in the Epi group, indicating that chronic VNS had a significant neuroprotective effect on epileptic rats. After comparing the expression of 9 cytokines, we found that the levels of the proinflammatory cytokines IL-6, IL-1β and CXCL-1 in the hippocampus were significantly increased in the Epi group, while these cytokines were significantly decreased in the Epi + VNS group. Moreover, the level of the anti-inflammatory cytokine IL-13 was found to be reduced in Epi rats, while its levels were increased after VNS treatment. However, these changes in cytokine expression were not found in the hypothalamus or peripheral blood. These results suggest that the antiepileptic mechanism of VNS may work by inhibiting the activation of inflammatory processes in the epileptogenic focus.

Vagus Nerve Stimulation Reduces Indomethacin-Induced Small Bowel Inflammation.

Crohn’s disease is a chronic, idiopathic condition characterized by intestinal inflammation and debilitating gastrointestinal symptomatology. Previous studies of inflammatory bowel disease (IBD), primarily in colitis, have shown reduced inflammation after electrical or pharmacological activation of the vagus nerve, but the scope and kinetics of this effect are incompletely understood. To investigate this, we studied the effect of electrical vagus nerve stimulation (VNS) in a rat model of indomethacin-induced small intestinal inflammation. 1 min of VNS significantly reduced small bowel total inflammatory lesion area [(mean ± SEM) sham: 124 ± 14 mm2, VNS: 62 ± 14 mm2, p = 0.002], intestinal peroxidation and chlorination rates, and intestinal and systemic pro-inflammatory cytokine levels as compared with sham-treated animals after 24 h following indomethacin administration. It was not known whether this observed reduction of inflammation after VNS in intestinal inflammation was mediated by direct innervation of the gut or if the signals are relayed through the spleen. To investigate this, we studied the VNS effect on the small bowel lesions of splenectomized rats and splenic nerve stimulation (SNS) in intact rats. We observed that VNS reduced small bowel inflammation also in splenectomized rats but SNS alone failed to significantly reduce small bowel lesion area. Interestingly, VNS significantly reduced small bowel lesion area for 48 h when indomethacin administration was delayed. Thus, 1 min of electrical activation of the vagus nerve reduced indomethacin-induced intestinal lesion area by a spleen-independent mechanism. The surprisingly long-lasting and spleen-independent effect of VNS on the intestinal response to indomethacin challenge has important implications on our understanding of neural control of intestinal inflammation and its potential translation to improved therapies for IBD.

Effects of Vagus Nerve Stimulation on Sleep-Disordered Breathing, Daytime Sleepiness, and Sleep Quality in Patients With Drug-Resistant Epilepsy.

Background and PurposeThis study aimed to determine the long-term effects of vagus nerve stimulation (VNS) on sleep-disordered breathing (SDB), daytime sleepiness, and sleep quality in patients with drug-resistant epilepsy (DRE). It also investigated the relationships among these main effects, clinical characteristics, and VNS parameters.MethodsTwenty-four patients were recruited. Paired t-tests and multiple linear regression analyses were performed to determine how the demographic and clinical characteristics of the patients influenced the variables that changed significantly after VNS treatment.ResultsAfter VNS, the patients showed significant increases in the apnea-hypopnea index (AHI), respiratory disturbance index (RDI), apnea index, hypopnea index, and oxygen desaturation index (ODI), as well as a significant decrease in the lowest arterial oxygen saturation (SaO2 nadir) (p<0.05). The multiple linear regression analyses demonstrated that the predictor of larger increases in AHI and RDI was being older at baseline, and that the predictor of a larger increase in apnea index was a longer epilepsy duration. The strongest predictor of a larger increase in ODI was a higher frequency of aura episodes at baseline, followed by a longer epilepsy duration. The strongest predictor of a larger decrease in SaO2 nadir was a higher frequency of aura episodes at baseline, followed by a longer epilepsy duration.ConclusionsThis study has confirmed that VNS improves seizure control in patients with DRE, whereas it increases obstructive sleep apnea (OSA). Furthermore, the increase in OSA is affected by age and the duration of epilepsy. Therefore, careful observation and monitoring of SDB is recommended in patients who undergo VNS.

Effectiveness of vagus nerve stimulation therapy in refractory hypoxic-ischemic encephalopathy-induced epilepsy.

Epilepsy is one of the important long-term sequelae of neonatal hypoxic-ischemic encephalopathy (HIE) and is typically characterized by drug resistance and poor surgical outcomes. Vagus nerve stimulation (VNS) is a promising neuromodulation therapy for refractory epilepsy. The present study aimed to first evaluate the effectiveness of VNS in patients with refractory HIE-induced epilepsy and scrutinize potential clinical predictors. We retrospectively collected the outcomes of VNS in all patients with refractory HIE-induced epilepsy and at least 2 years of follow-up. Subgroups were classified as responders and nonresponders according to the effectiveness of VNS (⩾50% or <50% reduction in seizure frequency). Preoperative data were analyzed to screen for potential predictors of VNS effectiveness. A total of 55 patients with refractory HIE-induced epilepsy who underwent VNS therapy were enrolled. Responders represented 56.4% of patients, and 12.7% of patients achieved seizure freedom at the last follow-up. In addition, the responder rate increased over time with rates of 23.6%, 38.2%, 50.9%, and 56.4% at the 3-, 6-, 12- and 24-month follow-ups, respectively. After multivariate analysis, neonatal seizure was identified as a negative predictor (OR: 4.640, 95% CI: 1.129-19.066), and a predominant seizure type of generalized onset was identified as a positive predictor (OR: 0.261, 95% CI: 0.078-0.873) of VNS effectiveness. VNS therapy was effective in patients with refractory HIE-induced epilepsy and was well tolerated over a 2-year follow-up period. VNS therapy demonstrated better effectiveness in patients without neonatal seizures or with a predominant seizure type of generalized onset.

Vagus nerve spiking activity modulates prefrontal–amygdalar circuit related to anxiety

The vagus nerve has critical for brain-body interaction. It conveys internal physiological information from peripheral organs to the brain, causing interoception. Although numerous studies have shown that an alternation in vagal sensory input affects emotional states such as anxiety and depression, the mechanism by which vagus nerve activity is correlated with anxiety-related brain activity remains unknown. We have previously established a vagal spike recording method using a cuff-shaped electrode while simultaneously recording central and peripheral bioelectrical signals in freely moving rodents. In the present study, we investigated correlation between vagus nerve and anxiety-related brain activity on an elevated plus maze. We combined the recording method of vagus nerve with recording of local field potentials (LFPs) of the prefrontal cortex and the amygdala, which are crucial for expression of anxiety. Vagus nerve activity was negatively correlated with anxiety-related 4-7 Hz activity in the prefrontal cortex and the amygdala. The correlation was abolished by left cervical vagotomy. Chronic social defeat stress decorrelated vagus nerve activity with 4-7 Hz LFP oscillations. These results imply neurophysiological mechanisms underlying anxiolytic effects of vagus nerve stimulation and provide insights into neurophysiological underpinnings of the relationship between vagus nerve and emotion-related behavior.

Vagus nerve stimulation outcome prediction: from simple parameters to advanced models.

Since its approval as an adjunct treatment for refractory partial epilepsy, the positive effects of vagus nerve stimulation (VNS) on seizure frequency and severity have been supported by many studies. Seizure reduction of more than 50 % can be expected in at least 50 % of patients. However, a complete post-VNS seizure freedom is rarely achieved and 25 % of patients do not benefit from VNS. Our study provides an overview of the potential predictors of VNS response, from the most simple and basic data to sophisticated EEG processing studies and functional imaging studying brain connectivity. The data support better outcomes in younger patients with early VNS implantation, in patients with posttraumatic epilepsy or tuberous sclerosis, and in patients without bilateral interictal epileptiform discharges. The variability of heart activity has also been studied with some promising results. Because the generally accepted hypothesis of the VNS mechanism is the modulation of synaptic activity in multiple cortical and subcortical regions of the brain, the studies of brain response to external stimulation and/or of brain connectivity were used for models predicting the effect of VNS in individual patients. Although the predictive value of these models is high, the required special equipment and sophisticated mathematical tools limit their routine use (Ref. 58). Keywords: epilepsy, vagus nerve stimulation, response predictor, EEG.

Norwegian population-based study of long-term effects, safety, and predictors of response of vagus nerve stimulation treatment in drug-resistant epilepsy: The NORPulse study.

This study was undertaken to evaluate the efficacy of vagus nerve stimulation (VNS) over time, and to determine which patient groups derive the most benefit. Long-term outcomes are reported in 436 epilepsy patients from a VNS quality registry (52.8% adults, 47.2% children), with a median follow-up of 75months. Patients were stratified according to evolution of response into constant responders, fluctuating responders, and nonresponders. The effect was evaluated at 6, 12, 24, 36, and 60months. Multivariate regression analysis was used to identify predictors of response. The cumulative probability of ≥50% seizure reduction was 60%; however, 15% of patients showed a fluctuating course. Of those becoming responders, 89.5% (230/257) did so within 2years. A steady increase in effect was observed among constant responders, with 48.7% (19/39) of those becoming seizure-free and 29.3% (39/133) with ≥75% seizure reduction achieving these effects within 2-5years. Some effect (25%-<50%) at 6months was a positive predictor of becoming a responder (odds ratio [OR] = 10.18, p<.0001) and having ≥75% reduction at 2years (OR = 3.34, p=.03). Patients without intellectual disability had ORs of 3.34 and 3.11 of having ≥75% reduction at 2 and 5years, respectively, and an OR of 6.22 of being seizure-free at last observation. Patients with unchanged antiseizure medication over the observation period showed better responder rates at 2 (63.0% vs. 43.1%, p=.002) and 5years (63.4% vs. 46.3%, p=.031) than patients whose antiseizure medication was modified. Responder rates were higher for posttraumatic (70.6%, p=.048) and poststroke epilepsies (75.0%, p=.05) than other etiologies (46.5%). Our data indicate that the effect of VNS increases over time and that there are important clinical decision points at 6 and 24months for evaluating and adjusting the treatment. There should be better selection of candidates, as certain patient groups and epilepsy etiologies respond more favorably.

How Is the Norepinephrine System Involved in the Antiepileptic Effects of Vagus Nerve Stimulation?

Vagus Nerve Stimulation (VNS) is an adjunctive treatment for patients suffering from inoperable drug-resistant epilepsy. Although a complete understanding of the mediators involved in the antiepileptic effects of VNS and their complex interactions is lacking, VNS is known to trigger the release of neurotransmitters that have seizure-suppressing effects. In particular, norepinephrine (NE) is a neurotransmitter that has been associated with the clinical effects of VNS by preventing seizure development and by inducing long-term plastic changes that could restore a normal function of the brain circuitry. However, the biological requisites to become responder to VNS are still unknown. In this review, we report evidence of the critical involvement of NE in the antiepileptic effects of VNS in rodents and humans. Moreover, we emphasize the hypothesis that the functional integrity of the noradrenergic system could be a determining factor to obtain clinical benefits from the therapy. Finally, encouraging avenues of research involving NE in VNS treatment are discussed. These could lead to the personalization of the stimulation parameters to maximize the antiepileptic effects and potentially improve the response rate to the therapy.

TVNS in the management of headache and pain.

First clinical observations of the therapeutic effect of vagus nerve stimulation were of patients who were treated for refractory epilepsy with a fully implanted vagus nerve stimulator, who also reported an improvement of their migraine and cluster headache. With the development of non-invasive vagus nerve stimulation, first clinical studies concerning a possible therapeutic effect in migraine and cluster headache were performed. In a controlled study, transcutaneous cervical vagus nerve stimulation (tcVNS) showed a significant but limited effect in acute treatment of a migraine attack. There was no significant prophylactic effect in episodic migraine. Concerning cluster headache, there was a clear beneficial effect in the prophylaxis of chronic cluster headache and in the attack treatment in episodic cluster headache. There are fewer studies in the literature on the effect of transcutaneous auricular vagus nerve stimulation (taVNS), with a partial overlap with studies on electrical ear acupuncture. In a small controlled clinical trial, there was a significant effect of taVNS in the prevention of chronic migraine. In less defined clinical studies, there were some positive signs that the method may be beneficial in chronic back pain and in unspecific gastro-intestinal pain in adolescents. Based on the available evidence, it is probable that vagus nerve stimulation can have a clinically meaningful influence on pain syndromes, but there are still several questions (e.g. frequency of the stimulation; duration of the stimulation; differential effects of auricular vagus stimulation and cervical vagus stimulation) to answer before vagus stimulation can be used widely in the clinic.

P.0217 Effect of vagus nerve stimulation on attention and working memory in epilepsy and mood disorders: a systematic review

P.0217 Effect of vagus nerve stimulation on attention and working memory in epilepsy and mood disorders: a systematic review

Effect of vagus nerve stimulation paired with rehabilitation for upper limb function improvement after stroke: a systematic review and meta-analysis of randomized controlled trials.

Vagus nerve stimulation (VNS) could potentially facilitate arm function recovery after stroke. The aim of this review was to evaluate the effect of VNS paired with rehabilitation on upper limb function recovery after stroke. We considered randomized controlled trials (RCTs) that used VNS paired with rehabilitation for the improvement of upper limb function after stroke and were published in English. Eligible RCTs were identified by searching electronic databases, including MEDLINE, Web of Science, Embase, CENTRAL and PEDro, from their inception until June 2021. Quality of included studies was assessed using PEDro score and Cochrane’s risk of bias assessment. A meta-analysis was performed on the collected data. Five studies with a total of 178 participants met the inclusion criteria. Overall, the present meta-analysis revealed a significant effect of VNS on Fugl–Meyer Assessment for Upper Extremity (FMA-UE, MD = 3.59; 95% CI, 2.55–4.63; P < 0.01) when compared with the control group. However, no significant difference was observed in adverse events associated with device implantation between the invasive VNS and control groups (RR = 1.10; 95% CI, 0.92–1.32; P = 0.29). No adverse events associated with device use were reported in invasive VNS, and one was reported in transcutaneous VNS. This study revealed that VNS paired with rehabilitation can facilitate the recovery of upper limb function in patients with stroke on the basis of FMA-UE scores, but the long-term effects remain to be demonstrated.

Human intracranial recordings reveal distinct cortical activity patterns during invasive and non-invasive vagus nerve stimulation

Vagus nerve stimulation (VNS) is being used increasingly to treat a wide array of diseases and disorders. This growth is driven in part by the putative ability to stimulate the nerve non-invasively. Despite decades of use and a rapidly expanding application space, we lack a complete understanding of the acute effects of VNS on human cortical neurophysiology. Here, we investigated cortical responses to sub-perceptual threshold cervical implanted (iVNS) and transcutaneous auricular (taVNS) vagus nerve stimulation using intracranial neurophysiological recordings in human epilepsy patients. To understand the areas that are modulated by VNS and how they differ depending on invasiveness and stimulation parameters, we compared VNS-evoked neural activity across a range of stimulation modalities, frequencies, and amplitudes. Using comparable stimulation parameters, both iVNS and taVNS caused subtle changes in low-frequency power across broad cortical networks, which were not the same across modalities and were highly variable across participants. However, within at least some individuals, it may be possible to elicit similar responses across modalities using distinct sets of stimulation parameters. These results demonstrate that both invasive and non-invasive VNS cause evoked changes in activity across a set of highly distributed cortical networks that are relevant to a diverse array of clinical, rehabilitative, and enhancement applications.