Long-term Vagus Nerve Stimulation Research Articles

A predictive model combining connectomics and entropy biomarkers to discriminate long-term vagus nerve stimulation efficacy for pediatric patients with drug-resistant epilepsy.

To predict the vagus nerve stimulation (VNS) efficacy for pediatric drug-resistant epilepsy (DRE) patients, we aim to identify preimplantation biomarkers through clinical features and electroencephalogram (EEG) signals and thus establish a predictive model from a multi-modal feature set with high prediction accuracy. Sixty-five pediatric DRE patients implanted with VNS were included and followed up. We explored the topological network and entropy features of preimplantation EEG signals to identify the biomarkers for VNS efficacy. A Support Vector Machine (SVM) integrated these biomarkers to distinguish the efficacy groups. The proportion of VNS responders was 58.5% (38/65) at the last follow-up. In the analysis of parieto-occipital α band activity, higher synchronization level and nodal efficiency were found in responders. The central-frontal θ band activity showed significantly lower entropy in responders. The prediction model reached an accuracy of 81.5%, a precision of 80.1%, and an AUC (area under the receiver operating characteristic curve) of 0.838. Our results revealed that, compared to nonresponders, VNS responders had a more efficient α band brain network, especially in the parieto-occipital region, and less spectral complexity of θ brain activities in the central-frontal region. We established a predictive model integrating both preimplantation clinical and EEG features and exhibited great potential for discriminating the VNS responders. This study contributed to the understanding of the VNS mechanism and improved the performance of the current predictive model.

Long-term effects of vagus nerve stimulation therapy on cognitive functioning in patients with drug-resistant epilepsy.

Despite the increasing use of vagus nerve stimulation (VNS) for drug-resistant epilepsy, its impact on cognitive functioning remains insufficiently investigated. We aimed to comprehensively assess changes in cognition after long-term VNS therapy in a prospective sample of adults with epilepsy. Between December 2019 and March 2023, patients scheduled for VNS implantation were invited for neuropsychological assessment, including tests of executive functions, working and short-term memory (recall of a verbal logical story and the Rey-Osterrieth complex figure (ROCF)), and social cognition. Participants were re-evaluated after a year of VNS therapy and the pre- and postoperative scores were compared by means of the Student's t or Wilcoxon's signed rank tests for paired samples. Patients available only after a longer follow-up (more than 24 months) were also re-examined and included in a secondary analysis. The study included 28 PWE (16, 57.1% female, average age 33.7 ± 10.0 years). Twenty-two PWE followed-up at 14.5 ± 4.8 months had worse categorical verbal fluency than preoperatively (t = 2.613, p = 0.016). After including patients with long follow-up (n = 28, 21.6 ± 11.4 months), the group scored better on the delayed recall of the ROCF (17.09 ± 8.84 to 20.65 ± 8.32 points, t(22) = - 2.618, p = 0.016) and the Happé strange stories test (5.0 ± 2.6 to 6.1 ± 2.1 points, t(14) = - 3.281, p = 0.005). No significant changes were observed in other cognitive domains (p > 0.05). We suggest improvements in a task of social cognition and short-term visual memory after longer use of VNS therapy. Such findings should be confirmed in larger trials after controlling for changes in ictal or interictal activity.

Immediate Effects of Vagal Nerve Stimulation in Drug-Resistant Epilepsy Revealed by Magnetoencephalographic Recordings.

Objective: Vagus nerve stimulation (VNS) has been a neuromodulatory option for treating drug-resistant epilepsy (DRE), but its mechanism remains unclear. To obtain insight into the mechanism by which VNS reduces epileptic seizures, the immediate effects of VNS in brain networks of DRE patients were investigated when the patients' vagal nerve stimulators were turned on. Methods: The brain network properties of 14 DRE patients with a vagal nerve stimulator and 14 healthy controls were evaluated using magnetoencephalography recordings for 6 main frequency bands. Results: Compared with healthy controls, DRE patients exhibited significant increases in functional connectivity in the theta, alpha, beta, and gamma bands and significant reductions in the small-world measure in the theta and beta bands. During periods when patients' vagal nerve stimulators were turned on, DRE patients showed significant reductions in functional connectivity in the theta and alpha bands and a significant increase in the small-world measure in the theta band when compared with periods when patients' vagal nerve stimulators were turned off. Conclusions: Our results indicate that the brain networks of DRE patients were pathologically hypersynchronous and instantaneous VNS can decrease the synchronization of brain networks of epileptic patients, which might play a key role in the mechanism by which VNS reduces epileptic seizures. In the theta band, instantaneous VNS can increase the network efficiency of DRE patients, and the increment in network efficiency may be helpful for improving brain cognitive function in epileptic patients. Impact statement For the first time, we investigated the immediate effects of vagus nerve stimulation (VNS) in the brain networks of drug-resistant epilepsy patients using magnetoencephalography. Our results show that instantaneous VNS can decrease the hypersynchronization of epileptic networks and increase the network efficiency of epileptic patients. Our results are helpful in understanding the mechanism of action by which VNS reduces epileptic seizures and improves the cognitive function in epileptic patients and the brain network reorganization caused by long-term VNS.

Persistent Autonomic Engagement and Cardiac Control After Four or More Years of Autonomic Regulation Therapy Using Vagus Nerve Stimulation.

IntroductionAlthough heart failure (HF) outcomes have improved dramatically with the use of guideline directed medical therapy and implantable devices, the overall prognosis of patients with HF and reduced ejection fraction (HFrEF) remains poor. Autonomic Regulation Therapy (ART) using chronic vagus nerve stimulation (VNS) has been evaluated in the ANTHEM-HF study, using changes in heart rate (HR) dynamics as a biomarker of autonomic nervous system engagement and cardiac control to guide VNS titration. ART was associated with sustained improvement in cardiac function and HF symptoms in patients with HFrEF and persistent HF symptoms despite guideline-directed medical therapy (GDMT). We sought to determine whether the responsiveness of the autonomic nervous system to ART, as reflected in HR response to vagus stimulation during the VNS duty cycle, is maintained after long-term chronic VNS administration.MethodsFifteen patients with HFrEF and implanted with a VNS systems in the ANTHEM-HF study were evaluated after 4.7 ± 0.3 years (range: 4.0–5.0 years) of chronic ART. ECG electrodes were placed on each patient’s wrists, and ECG rhythm strips were recorded. Instantaneous HR time series was computed at each patient’s chronically programmed VNS intensity and during progressively increasing VNS intensity. HR during active stimulation (on-time) was compared to HR just prior to initiation of each stimulation cycle (off-time).ResultsPersistent autonomic engagement was observed in a majority of patients (11 of 15, 73%) after chronic ART for four or more years. The average magnitude of HR reduction during ART on-time in all patients was 2.4 ± 3.2 bpm at the chronically programmed VNS pulse parameter settings.ConclusionAutonomic responsiveness to VNS persists in patients with HFrEF who received chronic ART for up to 5 years as a supplement to GDMT. This suggests that the effects of ART on autonomic engagement and cardiac control remain durable over time.Clinical Trial Registration[ClinicalTrials.gov], identifier [#NCT01823887, CTRI registration #CTRI/2012/05/002681].

Long-term results of vagus nerve stimulation in children with Dravet syndrome: Time-dependent, delayed antiepileptic effect

ObjectiveThis study aimed to assess the long-term outcomes of vagus nerve stimulation (VNS) in children with pharmaco-resistant Dravet syndrome (DS). MethodsWe enrolled 22 patients with pharmaco-resistant DS who underwent VNS implantation at Severance Children’s Hospital from March 2005 to October 2020. Efficacy and tolerability were assessed at 3, 6, 12, 18, 24, 30, and 36 months after VNS implantation. Efficacy was measured as the percentage reduction in seizure frequency at each follow-up compared with the baseline (pre-implantation) values. ResultsMedian patient age at VNS implantation was 10.0 years (interquartile range 7.7–13.3). The median follow-up period was 4.3 years (interquartile range 3.0–6.5) after VNS implantation. All cases were followed up for ≥2 years after VNS implantation. Three (13.6 %) patients maintained seizure freedom for ≥1 year. Among them, one achieved seizure freedom after 30 months of VNS. More than 50 % reduction in seizure frequency was observed in 36.4 % (8/22), 54.5 % (12/22), and 63.2 % (12/19) of the patients at 12, 24, and 36 months, respectively. The median percent reduction in seizure frequency was 18.8 %, 50.6 %, and 60.0 % at 12, 24, and 36 months, respectively. Compared with the baseline value, the seizure frequency was significantly lower at 24, 30, and 36 months, as well as at the longest follow-up period (p < 0.05, Wilcoxon signed-rank test). The symptom that was mostly associated with adverse events was hoarseness (4/22, 18.2 %); however, they had temporary or minimal effects on activities of daily living. ConclusionsOur findings demonstrate that VNS therapy allows long-term, progressive, and time-dependent improvement in seizure control for pharmaco-resistant DS. Clinicians should be aware of the delayed VNS efficacy over the years and should encourage long-term VNS maintenance by patients.

Short-Term Effects of Vagus Nerve Stimulation on Learning and Evoked Activity in Auditory Cortex

Chronic vagus nerve stimulation (VNS) has been shown to facilitate learning, but effects of acute VNS on neural coding and behavior remain less well understood. Ferrets implanted with cuff electrodes on the vagus nerve were trained by classical conditioning on an auditory tone frequency-reward association. One tone was associated with reward while another tone was not. Tone frequencies and reward associations were changed every 2 d, requiring learning of a new relationship. When tones were paired with VNS, animals consistently learned the new association within 2 d. When VNS occurred randomly between trials, learning within 2 d was unreliable. In passively listening animals, neural activity in primary auditory cortex (A1) and pupil size were recorded before and after acute VNS-tone pairing. After pairing with a neuron’s best-frequency (BF) tone, responses by a subpopulation of neurons were reduced. VNS paired with an off-BF tone or during intertrial intervals had no effect. The BF-specific reduction in neural responses after VNS remained, even after regressing out changes explained by pupil-indexed arousal. VNS induced brief dilation in the pupil, and the size of this change predicted the magnitude of persistent changes in the neural response. This interaction suggests that fluctuations in neuromodulation associated with arousal gate the long-term VNS effects on neural activity.

Development and characterization of a chronic implant mouse model for vagus nerve stimulation.

Vagus nerve stimulation (VNS) suppresses inflammation and autoimmune diseases in preclinical and clinical studies. The underlying molecular, neurological, and anatomical mechanisms have been well characterized using acute electrophysiological stimulation of the vagus. However, there are several unanswered mechanistic questions about the effects of chronic VNS, which require solving numerous technical challenges for a long-term interface with the vagus in mice. Here, we describe a scalable model for long-term VNS in mice developed and validated in four research laboratories. We observed significant heart rate responses for at least 4 weeks in 60-90% of animals. Device implantation did not impair vagus-mediated reflexes. VNS using this implant significantly suppressed TNF levels in endotoxemia. Histological examination of implanted nerves revealed fibrotic encapsulation without axonal pathology. This model may be useful to study the physiology of the vagus and provides a tool to systematically investigate long-term VNS as therapy for chronic diseases modeled in mice.

Effect of Long-Term Treatment with Vagus Nerve Stimulation on Mood and Quality of Life in Korean Patients with Drug-Resistant Epilepsy.

Background and PurposeThis study aimed to determine the long-term effects of vagus nerve stimulation (VNS) treatment on suicidality, mood-related symptoms, and quality of life (QOL) in patients with drug-resistant epilepsy (DRE). We also investigated the relationships among these main effects, clinical characteristics, and VNS parameters.MethodsAmong 35 epilepsy patients who underwent VNS implantation consecutively in our epilepsy center, 25 patients were recruited to this study for assessing the effects of VNS on suicidality, mood-related symptoms, and QOL. The differences in these variables between before and after VNS treatment were analyzed statistically using paired t-tests. Multiple linear regression analyses were also performed to determine how the patients' demographic and clinical characteristics influenced the variables that showed statistically significant changes after long-term VNS treatment.ResultsAfter VNS, our patients showed significant improvements not only in the mean seizure frequency but also in suicidality, depression, and QOL. The reduction in depression was associated with the improvement in QOL and more-severe depression at baseline. The reduction in suicidality was associated with higher suicidality at baseline, smaller changes in depression, and less-severe depression at baseline. Improved QOL was associated with lower suicidality at baseline.ConclusionsThis study found that VNS decreased the mean seizure frequency in patients with DRE, and also improved their depression, suicidality, and QOL. These results provide further evidence for therapeutic effect of VNS on psychological comorbidities of patients with DRE.

Sex Differences in Vagus Nerve Stimulation Effects on Rat Cardiovascular and Immune Systems.

BackgroundInvestigations into the benefits of vagus nerve stimulation (VNS) through pre-clinical and clinical research have led to promising findings for treating several disorders. Despite proven effectiveness of VNS on conditions such as epilepsy and depression, understanding of off-target effects and contributing factors such as sex differences can be beneficial to optimize therapy design.New MethodsIn this article, we assessed longitudinal effects of VNS on cardiovascular and immune systems, and studied potential sex differences using a rat model of long-term VNS. Rats were implanted with cuff electrodes around the left cervical vagus nerve for VNS, and wireless physiological monitoring devices for continuous monitoring of cardiovascular system using electrocardiogram (ECG) signals. ECG morphology and heart rate variability (HRV) features were extracted to assess cardiovascular changes resulting from VNS in short-term and long-term timescales. We also assessed VNS effects on expression of inflammatory cytokines in blood during the course of the experiment. Statistical analysis was performed to compare results between Treatment and Sham groups, and between male and female animals from Treatment and Sham groups.ResultsConsiderable differences between male and female rats in cardiovascular effects of VNS were observed in multiple cardiovascular features. However, the effects seemed to be transient with approximately 1-h recovery after VNS. While short-term cardiovascular effects were mainly observed in male rats, females in general showed more significant long-term effects even after VNS stopped. We did not observe notable changes or sex differences in systemic cytokine levels resulting from VNS.Comparison With Existing MethodsCompared to existing methods, our study design incorporated wireless physiological monitoring and systemic blood cytokine level analysis, along with long-term VNS experiments in unanesthetized rats to study sex differences.ConclusionThe contribution of sex differences for long-term VNS off-target effects on cardiovascular and immune systems was assessed using awake behaving rats. Although VNS did not change the concentration of inflammatory biomarkers in systemic circulation for male and female rats, we observed significant differences in cardiovascular effects of VNS characterized using ECG morphology and HRV analyses.

Efficacy of vagus nerve stimulation for drug-resistant epilepsy in children age six and younger

ObjectivesThe objective of the study were to examine the safety and efficacy of vagus nerve stimulation (VNS) for reducing seizure frequency and antiepileptic drugs (AEDs) in children younger than six years and to examine long-term VNS efficacy for children who receive the device at ages 1–3 and at ages 4–6. MethodsWe conducted a 10-year retrospective analysis of VNS implantations at UPMC Children's Hospital of Pittsburgh. Relevant data were collected within 12 months of VNS implantation and at six months, one, two, and four years after VNS implantation. ResultsThis analysis included 99 patients ages 0–3 (n = 40) and 4–6 (n = 59) at first VNS implantation. Eighty-six patients followed up for ≥4 years. There were no significant differences between age at VNS implant (0–3 vs. 4–6) and seizure etiology or most seizure semiologies. Patients took an average of 3.01 ± 1.29 AEDs prior to VNS and 3.84 ± 1.68 AEDs at their latest follow-up. The overall response to VNS therapy (≥50% seizure reduction) at one year, two years, and four years after VNS implantation was 55%, 60%, and 52%, respectively. At two years, 59% of 0- to 3-year-old patients responded to VNS and 52% of 4- to 6-year-old patients responded to VNS. The overall major complication rate was 5.6%, consistent with VNS use for older age groups. SignificanceThis study demonstrates the safety and efficacy of VNS for children with drug-resistant epilepsy (DRE) younger than six. One, two, and four years after VNS implantation, 55%, 60%, and 52% of these patients, respectively, achieved ≥50% reduction in seizure frequency. The safety of VNS is also comparable with older, better studied, age groups. Based on these data, VNS therapy should be considered for children younger than six.

Vagus Nerve Stimulation Unequally Disturbs Circadian Variation of Cardiac Rhythms in Male and Female Rats.

Vagus nerve stimulation (VNS) is a neurostimulation therapy for epilepsy and severe depression and has been recently shown to be effective for other conditions. Despite its demonstrated safety and efficacy, long-term and off-target effects of VNS remain to be fully determined. One of the complications reported in epilepsy is stimulation-induced sleep abnormalities. As epilepsy itself can impact sleep quality, contribution of VNS alone in such off-target effects remain mainly unknown. In this study, we analyzed data from long-term VNS experiments in rats to characterize effects of VNS on circadian rhythms derived from heart rate and heart rate variability (HRV). We have also explored possible sex differences in long-term effects of VNS on intrinsic biological rhythms. Compared with control animals, significant VNS-induced changes in circadian rhythms were observed particularly in female rats over 24h and 6h light cycles (1PM-7PM). These findings enhance our understanding of VNS contribution and biological sex role on sleep difficulties reported by using VNS therapy.

A Rodent Model for Long-Term Vagus Nerve Stimulation Experiments

Aim: Investigations into the benefits of vagus nerve stimulation (VNS) using rodents have led to promising findings for treating clinical disorders. However, the majority of research has been limited to acute timelines. We developed a rodent model for longitudinal assessment of VNS and validated it with a long-term experiment incorporating continuous physiological monitoring. While the primary aim was not to investigate the effects of VNS on the cardiovascular system, we analyzed cardiovascular parameters to demonstrate the model's capabilities in a long-term stimulation-and-recording setup. Materials &amp; methods: Rats were implanted with a cuff electrode around the cervical vagus nerve and electrocardiogram monitoring devices were implanted in the peritoneal cavity. We also designed a connector mount for seamless access to the cuff electrode for VNS in awake-behaving rats. Results &amp; conclusion: Results signified easy-to-interface VNS system, electrode robustness and discernible physiological signals in a long-term setup. Analysis of the cardiovascular parameters revealed some transient effects during VNS. Our proposed model enables long-term VNS experiments along with physiological monitoring in unanesthetized rats.

Investigating the Effect of Short Term Responsive VNS Therapy on Sleep Quality Using Automatic Sleep Staging.

The goal of this work is to objectively evaluate the effectiveness of responsive (or closed-loop) Vagus nerve stimulation (VNS) therapy in sleep quality in patients with medically refractory epilepsy. Using quantitative features obtained from electroencephalography, we first developed a new automatic sleep-staging framework that consists of a multi-class support vector machine (SVM) classification, based on a decision tree approach. To train and evaluate the performance of the framework, we used polysomnographic data of 23 healthy subjects from the PhysioBank database where the sleep stages have been visually annotated. We then used the trained classifier to label the sleep stages using data from 22 patients with epilepsy, treated with short term responsive VNS therapy during an epilepsy-monitoring unit visit, one month after VNS implantation, and ten VNS-naïve patients with epilepsy. Application of multi-class SVM classifier to classify the three sleep stages of awake, light sleep + rapid eye movement, and deep sleep achieved a classification accuracy of 90%. Results of the application of this methodology to VNS-treated and VNS-naïve patients revealed that the patients treated with short term responsive VNS therapy showed significant increase in sleep efficiency, and significant decrease in seizures plus interictal epileptiform discharges and awakenings. These results indicate that VNS treatment can reduce the epileptiform activities and thus help in achieving better sleep quality for patients with epilepsy. The proposed approach can be used to investigate the effect of long-term VNS therapy on sleep quality.

Comparison of the efficiency of chopped and non-rectangular electrical stimulus waveforms in activating small vagus nerve fibers

BackgroundIn the context of morbid obesity, vagus nerve stimulation could be used to control gastric function targeting the small afferent B-fibers and C-fibers. Compared to large A-fibers, activation thresholds of these small efferent fibers are 10 to 100 times greater, inducing technical constraints and possible nerve damages. Although rectangular waveform is commonly used in nerve stimulation, recent modeling and experimental studies suggest that non-rectangular waveforms could reduced the charge injected by the stimulator. New methodThe objective of the present study is to evaluate the charge injection of complex waveforms such as the ramp, quarter sine and chopped pulses in the context of vagus nerve stimulation. We performed in-vivo study on the porcine abdominal vagus nerves and evaluated charge injection at activation thresholds. A modeling study was performed to further extent the results obtained in-vivo. Comparison with existing methodCompared to the rectangular pulse, the ramp and quarter sine waveforms activated gastric fibers with the lowest charge injection: −23.2% and −30.1% respectively. The efficacy of chopped pulses is questioned through the consideration of the strength-duration curve. ConclusionContinuous ramp and quarter sine waveforms effectively activate small diameter fibers. These pulse shapes may be considered for long-term vagus nerve stimulation. The results predicted by computational models were qualitatively consistent with experiments. This suggested the relevance of using modeling in the context of complex waveforms prior to future in-vivo tests.

Right Vagus Nerve Stimulation With a Novel Self-Sizing Cuff Electrode Improves Left Ventricular Function in Dogs With Heart Failure

Background: Autonomic imbalance namely high sympathetic and low parasympathetic drive, is a maladaptive feature of chronic heart failure (HF) that contributes to progressive left ventricular (LV) dysfunction and remodeling. Electrical right cervical Vagus nerve stimulation (VNS) has been shown to restore autonomic balance and improve LV function in animals with experimentally-induced HF. In this study, we examined the effects of long-term VNS with a novel, self-sizing cuff electrode on LV function and remodeling in dogs with HF. Methods: Studies were performed in 12 dogs with HF (LV ejection fraction, EF !35%) produced by coronary microembolizations. All dogs underwent surgical implantation of the self-sizing cuff electrode around the right Vagus nerve connected to an implantable pulse generator. Delivery of VNS pulses was synchronized to cardiac rhythm assessed from a lead placed in the right ventricle. Dogs were then randomized to no therapy (control, n57) or to active VNS therapy (n55) maintained for 3 months. LV end-diastolic (EDV), end-systolic (ESV) volumes and EF were measured from ventriculograms taken at time of randomization (PRE) and after 3 months of therapy (POST). Results: Results are shown in the table. In controls, heart rate (HR), mean aortic pressure (mAoP), systemic vascular resistance (SVR), EDV, ESV and EF were essentially unchanged between PRE and POST. In VNS-treated dogs, SVR tended to decrease and mAoP and EDV were unchanged. In this group, HR and ESV decreased and EF increased significantly. In 4 dogs, surgical removal of the self-sizing cuff was attempted at the end of 3 months of follow-up and was easily accomplished in every case. Conclusions: Long-term VNS therapy using a novel self-sizing cuff electrode improves LV systolic function in dogs with chronic HF.

Evaluation of heart rate variability in dogs during standard and microburst vagus nerve stimulation: A pilot study

Vagus nerve stimulation (VNS) is an established treatment for epilepsy and depression in human patients, but in both humans and dogs, optimal stimulation parameters remain unknown. Delivering afferent bursts of stimulation may be promising as a means of increasing efficacy, but evaluation of potential effects on the heart due to unavoidable efferent stimulation is required. The present study investigated heart rate variability (HRV) in healthy Beagle dogs treated with 1 h of sham, standard or microburst left-sided VNS in a crossover design. No significant differences were found between the stimulation paradigms for any of the cardiac parameters. Short-term left-sided VNS, including a novel bursting pattern (microburst VNS), had no statistically significant effect on HRV in ambulatory healthy dogs. Studies in a larger number of animals with long-term VNS are recommended.

Long-term vagus nerve stimulation in children with focal epilepsy

The aim of the study was to evaluate the long-term efficacy and hospitalization rates in children with refractory focal epilepsy treated by vagus nerve stimulation. We retrospectively analyzed 15 children with intractable focal epilepsy treated by vagus nerve stimulation (mean age of 14.6 ± 2.5 years at the time of implantation). We analyzed the treatment effectiveness at 1, 2, and 5 year follow-up visits. We counted the average number of urgent hospitalizations and number of days of urgent hospitalization per year for each patient before and after the VNS implantation. The mean seizure reduction was 42.5% at 1 year, 54.9% at 2 years, and 58.3% at 5 years. The number of responders was 7 (46.7%) at 1 year and 9 (60%) at both 2 and 5 years. The mean number of urgent hospitalizations per patient was 1.0 ± 0.6 per year preoperatively and 0.3 ± 0.5 per year post-operatively (P < 0.0001). The mean number of days of urgent hospitalization per patient was 9.3 ± 6.1 per year preoperatively and 1.3 ± 1.8 per year post-operatively ( < 0.0001). Vagus nerve stimulation is an effective method of treating children with refractory focal epilepsy. It leads to a substantial decrease in the number and duration of urgent hospitalizations.

Electrophysiological and neurochemical effects of long-term vagus nerve stimulation on the rat monoaminergic systems

Vagus nerve stimulation (VNS) is an adjunctive treatment for resistant epilepsy and depression. Electrophysiological recordings in the rat brain have already shown that chronic VNS increases norepinephrine (NE) neuronal firing activity and, subsequently, that of serotonin (5-HT) neurons through an activation of their excitatory α1-adrenoceptors. Long-term VNS was shown to increase the tonic activation of post-synaptic 5-HT1A receptors in the hippocampus. This study was aimed at examining the effect of VNS on extracellular 5-HT, NE and dopamine (DA) levels in different brain areas using in vivo microdialysis, on NE transmission in the hippocampus, and DA neuronal firing activity using electrophysiology. Rats were implanted with a VNS device and stimulated for 14 d with standard parameters used in treatment-resistant depression (0.25 mA, 20 Hz, 500 μs, 30 s on-5 min off). The results of the present study revealed that 2-wk VNS significantly increased extracellular NE levels in the prefrontal cortex and the hippocampus and enhanced the tonic activation of post-synaptic α2-adrenoceptors on pyramidal neurons. The electrophysiological experiments revealed a significant decrease in ventral tegmental area DA neuronal firing rate after long-term VNS; extracellular DA levels were nevertheless increased in the prefrontal cortex and nucleus accumbens. Chronic VNS significantly increased extracellular 5-HT levels in the dorsal raphe but not in the hippocampus and prefrontal cortex. In conclusion, the effect of VNS in increasing the transmission of monoaminergic systems targeted in the treatment of resistant depression should be involved, at least in part, in its antidepressant properties observed in patients not responding to many antidepressant strategies.

Effects of long-term Vagus Nerve Stimulation (VNS) on extracellular levels of serotonin and norepinephrine and dopamine in the rat brain

Effects of long-term Vagus Nerve Stimulation (VNS) on extracellular levels of serotonin and norepinephrine and dopamine in the rat brain

Chronic vagus nerve stimulation decreased weight gain, food consumption and sweet craving in adult obese minipigs

Chronic vagus nerve stimulation (VNS) is known to influence food intake and body weight in animals and humans. The aim of our work was to evaluate the effects of long-term VNS in adult obese minipigs. Eight minipigs were fed ad libitum a Western diet to cause obesity, after which half of the animals were implanted with bilateral vagal electrodes connected to constant current stimulators (2mA, 30Hz, 500-μs pulse, ON 30s, OFF 5min). The other animals were implanted with sham devices. Animals were weighed weekly and their daily consumption was measured. Still 14 weeks after surgery, VNS animals (70.3±3.3kg, P>0.10) did not significantly gain weight compared to sham animals (80.6±8.0kg, P<0.05). Furthermore, food consumption decreased in VNS animals (−18%, P<0.02) compared to sham animals (+1%, P>0.10). When subjected to a three-choice meal test (high-fat vs. high-carbohydrates vs. balanced diet), VNS animals decreased their sweet-food consumption compared to sham animals (P<0.05), and increased their balanced diet consumption in comparison to pre-surgery levels. Our results showed that chronic VNS decreased weight gain, food consumption and sweet craving in adult obese minipigs, which indicates that this therapy might be used to decrease appetite in the context of morbid obesity.