Action Of Vagus Nerve Stimulation Research Articles

Brainstem Associated Somatosensory Evoked Potentials and Response to Vagus Nerve Stimulation: An Investigation of the Vagus Afferent Network.

Despite decades of clinical usage, selection of patients with drug resistant epilepsy who are most likely to benefit from vagus nerve stimulation (VNS) remains a challenge. The mechanism of action of VNS is dependent upon afferent brainstem circuitry, which comprises a critical component of the Vagus Afferent Network (VagAN). To evaluate the association between brainstem afferent circuitry and seizure response, we retrospectively collected intraoperative data from sub-cortical recordings of somatosensory evoked potentials (SSEP) in 7 children with focal drug resistant epilepsy who had failed epilepsy surgery and subsequently underwent VNS. Using multivariate linear regression, we demonstrate a robust negative association between SSEP amplitude (p < 0.01), and seizure reduction. There was no association between SSEP latency and seizure outcomes. Our findings provide novel insights into the mechanism of VNS and inform our understanding of the importance of brainstem afferent circuitry within the VagAN for seizure responsiveness following VNS.

Transcutaneous auricular vagus nerve stimulation cannot modulate the P3b event-related potential in healthy volunteers

ObjectiveThe release of cortical norepinephrine is one of the possible mechanisms of action of vagus nerve stimulation (VNS), a neuromodulatory treatment currently under investigation for cognitive impairment. Transcutaneous auricular VNS (taVNS) may be able to activate vagal nerve branches ending in the brainstem’s locus coeruleus (LC) non-invasively. The aim was to investigate if acute taVNS can modulate the P3b, a cognitive event-related potential (ERP) reflecting noradrenergic brain activation under control of the LC. MethodsThirty-nine healthy volunteers performed an auditory oddball task during no stimulation, sham stimulation and taVNS in a randomized order. P3b amplitude, latency and behavioral outcome parameters were compared between conditions using linear mixed models. ResultsP3b amplitude and latency during taVNS did not differ significantly from sham or control. Reaction time shortened and P3b latency prolonged with repetition of the oddball task. ConclusionsWe were unable to modulate cognitive ERPs by means of acute taVNS in a large group of healthy volunteers. SignificanceTargeting vagal nerve fibres via a transcutaneous approach did not alter the P3b in healthy participants. The stimulation parameters used and transient delivery of taVNS might be insufficient to adequately modulate the LC. Also, a disbalanced locus coeruleus - norepinephrine system in patients may be more prone for improvement.

Translational research to unravel the mechanism of action of vagus nerve stimulation

Abstract Vagus nerve stimulation (VNS) is a neurophysiological treatment for patients with drug resistant epilepsy. To date the precise mechanism of action remains to be elucidated. Better insight in the mechanism of action may identify seizure types or syndromes that respond better to VNS, may guide the search for optimal stimulation parameters and finally improve clinical efficacy. In the field of the search for mechanisms of action animal experiments can provide essential clues such as crucial neuranatomical structures that are involved in the seizure-suppressing effect of VNS. The nucleus of the solitary tract as well as the locus coeruleus have been identified to play such a role. With the development of animal models that mimic human refractory epilepsy more reliably such as the kindling model, the status epilepeticus model and genetic models more valuable and usable information for human applicability may become available. In the past ten years some progress has been made through neurophysiological, neuroanatomical, neurochemical and cerebral blood flow studies in patients and animals undergoing VNS. Interesting results have been found in VNS-treated patients that underwent evoked potential measurements, cerebrospinal fluid investigation, neuropsychological testing and PET, SPECT and fMRI testing. Desynchronisation of abnormal synchronous epileptic activity is one of the hypotheses on the mode of action that might primarily be responsible for an anti-seizure effect. There is however increasing evidence from research and clinical observation that VNS might establish a true and long-term anti-epileptic effect. It has been shown that VNS influences neurotransmission in the brain and provokes long-term changes in cerebral blood flow in areas crucial for epileptogenesis such as the thalamus and medial temporal lobe structures. Further elucidation of the mechanism of action may increase the clinical efficacy of VNS and provide inspiration for the development of new therapeutic modalities in the field of neurostimulation and epilepsy. Keywords: vagus nerve stimulation, mechanism of action, epilepsy

The mechanisms of action of vagus nerve stimulation in difficult-to-treat depression: An update

The mechanisms of action of vagus nerve stimulation in difficult-to-treat depression: An update

Transcutaneous Vagus Nerve Stimulation (tVNS) and the Dynamics of Visual Bistable Perception

Transcutaneous vagus nerve stimulation (tVNS) is widely used for clinical applications, but its mechanism of action is poorly understood. One candidate pathway that might mediate the effects of tVNS is an increase in GABAergic neurotransmission. In this study, we investigated the effect of tVNS on visual bistable perception, which is highly coupled to GABA. Participants were 34 healthy young subjects. We used a static (Necker cube) and a dynamic (structure from motion) bistable perception task. Each subject underwent tVNS as well as sham (placebo) stimulation for ∼45 min. We analyze effects of tVNS on percept durations by means of Bayesian multilevel regression. We find no evidence for a modulation of bistable perception dynamics through tVNS in either task, but the analyses do not ultimately confirm the null hypothesis either. We discuss different possible implications of our finding and propose that GABAergic effects of tVNS should be further investigated using more direct measures of GABA concentration, and, more generally, that a better understanding of the mechanisms of action of vagus nerve stimulation is needed. Finally, we discuss limitations of our study design, data analysis, and conclusions.

Vagus Nerve Stimulation as a Treatment for Catatonia: A Hypothesis.

Background: Catatonia is a syndrome comprising psychomotor, behavioral, and autonomous symptoms which may occur in the context of severe schizophrenic, affective, and other mental disorders or medical conditions. Treatment options include high dose benzodiazepines (lorazepam) and electroconvulsive therapy (ECT) with some evidence for the effectiveness of glutamate antagonists. However, due to a lack of randomized controlled studies in this severely ill population, evidence base is weak.Methods: On occasion of the case of a patient with treatment resistant catatonia in schizoaffective disorder, we developed the hypothesis of vagus nerve stimulation (VNS) being a potential therapy for treatment resistant catatonia.Results: Based on a selective literature search, we found a remarkable overlap of the pathophysiology of catatonia on the one hand and the putative mechanisms of action of VNS on the other hand in several domains: functional brain imaging, involved neurotransmitter systems, clinical, and theoretical. We thus decided to use VNS as a single subject clinical trial. During the 1-year-follow-up, we observed a fluctuating, but ultimately marked improvement of both catatonic symptoms and general psychopathology.Conclusions: We assume there is a sufficient hypothetical corroboration for the potential effectiveness of VNS as a long-term treatment in predominantly catatonic syndromes. This hypothesis could be tested in proof-of-concept clinical trials.

EEG Derived Brain Activity Reflects Treatment Response from Vagus Nerve Stimulation in Patients with Epilepsy.

The mechanism of action of vagus nerve stimulation (VNS) is yet to be elucidated. To that end, the effects of VNS on the brain of epileptic patients were studied. Both when VNS was switched "On" and "Off", the brain activity of responders (R, seizure frequency reduction of over 50%) was compared to the brain activity of nonresponders (NR, seizure frequency reduction of less than 50%). Using EEG recordings, a significant increase in P300 amplitude for R and a significant decrease in P300 amplitude for NR were found. We found biomarkers for checking the efficacy of VNS with accuracy up to 94%. The results show that P300 features recorded in nonmidline electrodes are better P300 biomarkers for VNS efficacy than P300 features recorded in midline electrodes. Using source localization and connectivity analyses, the activity of the limbic system, insula and orbitofrontal cortex was found to be dependent on VNS switched "On" versus "Off" or patient group (R versus NR). The results suggest an important role for these areas in the mechanism of action of VNS, although a larger patient study should be done to confirm the findings.

Update on the elucidation of the mechanism of action of vagus nerve stimulation

Update on the elucidation of the mechanism of action of vagus nerve stimulation

Novel insights in the mechanism of action of vagus nerve stimulation

Novel insights in the mechanism of action of vagus nerve stimulation

The effects of vagus nerve stimulation on tryptophan metabolites in children with intractable epilepsy

BackgroundThe mechanism of action of vagus nerve stimulation (VNS) in intractable epilepsy is not entirely clarified. It is believed that VNS causes alterations in cytokines, which can lead to rebalancing the release of neurotoxic and neuroprotective tryptophan metabolites. We aimed to evaluate VNS effects on tryptophan metabolites and on epileptic seizures and investigated whether the antiepileptic effectiveness correlated with changes in tryptophan metabolism. MethodsForty-one children with intractable epilepsy were included in a randomized, active-controlled, double-blind study. After a baseline period of 12weeks, all children underwent implantation of a vagus nerve stimulator and entered a blinded active-controlled phase of 20weeks. Half of the children received high-output (therapeutic) stimulation (n=21), while the other half received low-output (active control) stimulation (n=20). Subsequently, all children received high-output stimulation for another 19weeks (add-on phase). Tryptophan metabolites were assessed in plasma and cerebrospinal fluid (CSF) by use of liquid chromatography–tandem mass spectrometry (LC–MS/MS) and compared between high- and low-output groups and between the end of both study phases and baseline. Seizure frequency was recorded using seizure diaries. Mood was assessed using Profile of Mood States (POMS) questionnaires. ResultsRegarding tryptophan metabolites, anthranilic acid (AA) levels were significantly higher at the end of the add-on phase compared with baseline (p=0.002) and correlated significantly with improvement of mood (τ=−0.39, p=0.037) and seizure frequency reduction (τ=−0.33, p<0.01). No significant changes were found between high- and low-output groups regarding seizure frequency. ConclusionVagus nerve stimulation induces a consistent increase in AA, a neuroprotective and anticonvulsant tryptophan metabolite. Moreover, increased AA levels are associated with improvement in mood and reduction of seizure frequency.

The P3 event-related potential is a biomarker for the efficacy of vagus nerve stimulation in patients with epilepsy.

Currently, the mechanism of action of vagus nerve stimulation (VNS) is not fully understood, and it is unclear which factors determine a patient's response to treatment. Recent preclinical experiments indicate that activation of the locus coeruleus noradrenergic system is critical for the antiepileptic effect of VNS. This study aims to evaluate the effect of VNS on noradrenergic signaling in the human brain through a noninvasive marker of locus coeruleus noradrenergic activity: the P3 component of the event-related potential. We investigated whether VNS differentially modulates the P3 component in VNS responders versus VNS nonresponders. For this purpose, we recruited 20 patients with refractory epilepsy who had been treated with VNS for at least 18 months. Patients were divided into 2 groups with regard to their reduction in mean monthly seizure frequency: 10 responders (>50 %) and 10 nonresponders (≤50 %). Two stimulation conditions were compared: VNS OFF and VNS ON. In each condition, the P3 component was measured during an auditory oddball paradigm. VNS induced a significant increase of the P3 amplitude at the parietal midline electrode, in VNS responders only. In addition, logistic regression analysis showed that the increase of P3 amplitude can be used as a noninvasive indicator for VNS responders. These results support the hypothesis that activation of the locus coeruleus noradrenergic system is associated with the antiepileptic effect of VNS. Modulation of the P3 amplitude should be further investigated as a noninvasive biomarker for the therapeutic efficacy of VNS in patients with refractory epilepsy.

ELECTROPHYSIOLOGICAL RESPONSES FROM VAGUS NERVE STIMULATION IN RATS

The mechanism of action of vagus nerve stimulation (VNS) for pharmacoresistant epilepsy is unknown and the therapeutic outcome is highly variable. We investigated stimulation-induced vagus nerve electrophysiological responses in rats using various stimulation parameters. Conduction velocity, I(50), rheobase and chronaxie were calculated. We identified an early and late component corresponding to an afferent compound action potential (CAP) and a remote laryngeal motor-evoked potential (LMEP), respectively. The conduction velocity (CAP: 26.2 ± 1.4 m/s; LMEP: 32.4 ± 2.4 m/s) and I(50) (CAP: 2.4 ± 0.3 mA; LMEP: 1.8±0.2 mA) were significantly different for both components, the rheobase (CAP: 140±30 μA; LMEP: 110±26 μA) and chronaxie (CAP: 66±7 μs; LMEP: 73±9 μs) were not. Using a pulse of 10 μs, the CAP saturated between 4-5 mA. Our method can be used to record VNS-induced electrophysiological responses in rats and provides an objective biomarker for electrical stimulation with various parameters in an experimental set-up. Our findings are potentially useful for clinical purposes in the sense that combination of VNS and recording of vagal nerve CAPs may help clinicians to determine the individual optimal intensity required to fully activate fast-conducting afferent fibers.

Cessation of seizure-like oscillations by periodic stimulation in a neuron model with dynamic ion concentrations

Here we describe the effect of adding periodic forcing to a simple model of a generic neuron with slow Na+ and K+ concentration dynamics [1]. With no stimulation, the model exhibits bursting due to the gradual modulation of ion concentrations, this limit cycle is shown in panel (a) of Figure ​Figure1.1. We have identified a range of parameter values where periodic stimulation can stop seizure-like bursting by freezing the slow ionic dynamics. Instead of following the large “bursting” limit cycle in the Na+/K+ phase plane, the stimulation forces the model into much smaller loops in the ion concentration space. These small trajectories are shown in panels (a) and (b) of Figure ​Figure11 for excitatory and inhibitory stimulation respectively. Figure 1 Under stimulation, the model trajectory approaches small loops at locations indicated in (a) by closed(excitatory) or open(inhibitory) symbols for various values of stimulation frequency. Frequency increases upwards (downwards) for excitatory (inhibitory) ... In the case of excitatory stimulation, the model continues to exhibit spikes in voltage, but only at the stimulation frequency—which can be made much lower than the rate of spontaneous spiking seen in bursting. For other parameter values, the addition of stimulation can reduce the amplitude of the bursts, or in some cases, induce bursts. These results may give insight into previous studies which showed that stimulation via electrodes can stop seizures in slice preparations [2], could help explain the mechanism of action of vagus nerve stimulation as treatment for epilepsy [3], and may provide novel avenues for treatment of epilepsy.

Vagus nerve stimulation has antidepressant potential in the kainic acid model for temporal lobe epilepsy

Aim : Depression represents one of the most common and disabling comorbidities in epilepsy patients. There is a growing consensus that both disorders have a common neurobiological cause. Vagus nerve stimulation (VNS) is an add-on treatment for patients with refractory epilepsy or depression. Both the mechanism of this comorbidity and the mechanism of action of VNS are poorly understood. In this study, we investigated the antidepressant potential of VNS in the kainic acid (KA) model for temporal lobe epilepsy (TLE). Methods : Male Sprague Dawley rats (n=29) were implanted with a cuff-electrode around the left vagus nerve. One week after surgery, half of the animals were subjected to a kainic acid KA-induced status epilepticus (SE). The other half of the animals were injected with saline (Sal). Both groups were subdivided in a VNS-treated group and a SHAM-treated group, yielding 4 experimental groups: Sal-SHAM (n=8), Sal-VNS (n=7), KA-SHAM (n=7), KA-VNS (n=7). Five weeks post-SE, the behavioral equivalent of anhedonia (i.e. inability to experience pleasure), was assessed using the saccharin preference test (SPT). To control for loss of taste due to KA-induced SE and subsequent neuronal loss, a quinine preference (of aversion) test (QPT) was performed. Both VNS groups (Sal-VNS and KA-VNS) received 2 weeks of therapeutic VNS, both SHAM groups received SHAM treatment. After this period, SPT and QPT were performed again in the same animals. Results : KA rats showed a significant reduction of taste preference towards saccharin compared to Sal rats (25% vs. 95 %, p < 0.001). No difference in aversion towards quinine was found. Two weeks of VNS significantly increased saccharin preference (SP) in the KA-VNS group (14% to 60% p < 0.001), while no difference could be demonstrated in SHAM-treated animals of the KA group. VNS had no influence on the QPT. There were no significant changes of SP in Sal-VNS and Sal-SHAM group. Conclusion : KA-injected epileptic rats display signs of anhedonia based on the SPT compared to non-epileptic control rats. Two weeks of VNS significantly reduced this anhedonia, suggesting an antidepressant effect of VNS in this rodent model for TLE.

Efficacy of vagus nerve stimulation in the treatment of depression

Major depressive disorder is a disease with prominent individual, medical and economic impacts. A relevant proportion of depressive patients suffering from a therapy-resistant course are increasingly being treated with antidepressant brain stimulation techniques. One of these interventions is the vagus nerve stimulation that has recently been tested in a number of clinical trials. To date, the acute and long-term efficacy of vagus nerve stimulation are still under debate. Thus further studies are required, especially since the exact mode of action of vagus nerve stimulation is still not well understood. In this paper we will review the results of existing clinical trials as well as the neurobiological effects measured with neuroimaging, biochemical and electrophysiology approaches.

Modulation of seizure threshold by vagus nerve stimulation in an animal model for motor seizures

The precise mechanism of action of vagus nerve stimulation (VNS) in suppressing epileptic seizures remains to be elucidated. This study investigates whether VNS modulates cortical excitability by determining the threshold for provoking focal motor seizures by cortical electrical stimulation before and after VNS. Male Wistar rats (n = 8) were implanted with a cuff-electrode around the left vagus nerve and with stimulation electrodes placed bilaterally on the rat motor cortex. Motor seizure threshold (MST) was assessed for each rat before and immediately after 1 h of VNS with standard stimulation parameters, during two to three sessions on different days. An overall significant increase of the MST was observed following 1 h of VNS compared to the baseline value (1420 microA and 1072 microA, respectively; P < 0.01). The effect was reproducible over time with an increase in MST in each experimental session. VNS significantly increases the MST in a cortical stimulation model for motor seizures. These data indicate that VNS is capable of modulating cortical excitability.

Thalamic and limbic involvement in the mechanism of action of vagus nerve stimulation, a SPECT study

To unravel the mechanism of action of neurostimulation as a treatment for seizures, functional neuroimaging tools allow minimally invasive research in humans. We performed single-photon emission computed tomography (SPECT) in patients with epilepsy, treated with vagus nerve stimulation (VNS). Changes in regional cerebral blood flow (rCBF) at the time of initial stimulation as well as after chronic treatment were correlated with long-term clinical efficacy. In this pilot study, 27 patients (14 female and 13 male) who were treated with VNS at Ghent University Hospital for refractory epilepsy underwent a (99m)Tc-ECD (ethyl cystein dimer) SPECT activation study at the time the first stimulation train was administered. 12 patients underwent an additional (99m)Tc-ECD SPECT activation study 6 months later. Image acquisition was performed on a high-resolution triple-headed gamma camera. Significant rCBF changes were correlated with prospectively assessed clinical efficacy data. Significant rCBF changes were found in the thalamus, the hippocampus and the parahippocampal gyrus. Acute limbic hyper-perfusion and chronic thalamic hypo-perfusion correlate with positive clinical efficacy. Acute and chronic electrical stimulation of the vagus nerve induces rCBF changes that can be measured by SPECT on a group-basis. The thalamus and the limbic system are thought to play a key role in the mechanism of action of VNS.

P.1.g.006 New findings on the purported mechanism of action of vagus nerve stimulation in treatment-resistant depression

P.1.g.006 New findings on the purported mechanism of action of vagus nerve stimulation in treatment-resistant depression

Mechanisms of action of vagus nerve stimulation (VNS)

In 1992, Dr Jake Zabara discovered in a canine model that repeated stimulation of the vagus nerve in the neck could stop seizures. Since that time, repeated stimulation of the vagus nerve has been FDA approved as an anticonvulsant. Zabara's work is built on a 50-year-old theme in the literature where scientists had sought to exploit the fact that the vagus nerve is composed of 80% afferent fibers. Thus vagus stimulation might potentially provide a ‘window’ into the brain. This manuscript reviews the basic science and brain imaging work done to date with VNS, attempting to understand how VNS affects the brain. This research is crucial to perfecting VNS as an anticonvulsant, and for determining other neuropsychiatric conditions that might be helped by VNS.

Chronic vagus nerve stimulation improves alertness and reduces rapid eye movement sleep in patients affected by refractory epilepsy.

Our study aimed to evaluate the existence and entity of changes in sleep structure following vagus nerve stimulation in patients with refractory epilepsy. A polysomnographic study was performed on the nocturnal sleep of 10 subjects with refractory epilepsy. Subjects were recorded both in baseline conditions and after chronic vagus nerve stimulation. Sleep parameters of the entire night were evaluated. Mean power value of slow-wave activity was computed in the first non-rapid eye movement sleep cycle. A sleep-wake diary evaluated quantity of both nocturnal and daytime sleep, while visual-analog scales assessed quality of sleep and wake. The differences between the 2 conditions underwent parametric and nonparametric statistical evaluation. Vagus nerve stimulation produced a significant reduction in REM sleep (in all subjects with vagus nerve stimulus intensity greater than 1.5 milliampere, but not in the only patient with a stimulus intensity less than 1.5 milliampere), along with an increase in the number of awakenings, percentage of wake after sleep onset, and stage 1 sleep. Data from a sleep-wake questionnaire show a decrease in both nocturnal sleep and daytime naps and an increased daytime alertness, while the quality of wakefulness is globally improved. Spectral analysis shows an enhancement of delta power during non-rapid eye movement sleep. Our data demonstrate major effects of vagus nerve stimulation on both daytime alertness (which is improved) and nocturnal rapid eye movement sleep (which is reduced). These effects could be interpreted as the result of a destabilizing action of vagus nerve stimulation on neural structures regulating sleep-wake and rapid eye movement/non-rapid eye movement sleep cycles. Lower intensity vagus nerve stimulation seems only to improve alertness; higher intensity vagus nerve stimulation seems able to exert an adjunctive rapid eye movement sleep-attenuating effect.