Chronic Vagus Nerve Stimulation Research Articles

Vagus nerve stimulation modulates distinct acetylcholine receptors on B cells and limits the germinal center response.

Acetylcholine is produced in the spleen in response to vagus nerve activation; however, the effects on antibody production have been largely unexplored. Here, we use a chronic vagus nerve stimulation (VNS) mouse model to study the effect of VNS on T-dependent B cell responses. We observed lower titers of high-affinity IgG and fewer antigen-specific germinal center (GC) B cells. GC B cells from chronic VNS mice exhibited altered mRNA and protein expression suggesting increased apoptosis and impaired plasma cell differentiation. Follicular dendritic cell (FDC) cluster dispersal and altered gene expression suggested poor function. The absence of acetylcholine-producing CD4+ T cells diminished these alterations. In vitro studies revealed that α7 and α9 nicotinic acetylcholine receptors (nAChRs) directly regulated B cell production of TNF, a cytokine crucial to FDC clustering. α4 nAChR inhibited coligation of CD19 to the B cell receptor, presumably decreasing B cell survival. Thus, VNS-induced GC impairment can be attributed to distinct effects of nAChRs on B cells.

Neuron-Microglia Interaction is Involved in Anti-inflammatory Response by Vagus Nerve Stimulation in the Prefrontal Cortex of Rats Injected with Polyinosinic:Polycytidylic Acid.

Injection of polyinosinic:polycytidylic acid (poly(I:C)) into experimental animals induces neuroimmunological responses and thus has been used for the study of neurological disorders such as anxiety, depression, and chronic fatigue. Here, we investigated the effects of vagus nerve stimulation (VNS) on poly(I:C)-induced neuroinflammation and associated behavioral consequences in rats. The microglia in the prefrontal cortex (PFC) displayed the activated form of morphology in poly(I:C)-injected rats and changed to a normal shape after acute VNS (aVNS). Production of phospho-NF-κB, phospho-IκB, IL-1β, and cleaved caspase 3 was elevated by poly(I:C) and downregulated by aVNS. In contrast, phospho-Akt levels were decreased by poly(I:C) and increased by aVNS. Neuronal production of fractalkine (CX3CL1) in the PFC was markedly reduced by poly(I:C), but recovered by aVNS. Fractalkine interaction with its receptor CX3CR1 was highly elevated by VNS. We further demonstrated that the pharmacological blockade of CX3CR1 activity counteracted the production of IL-1β, phospho-Akt, and cleaved form of caspase 3 that was modulated by VNS, suggesting the anti-inflammatory effects of fractalkine-CX3CR1 signaling as a mediator of neuron-microglia interaction. Behavioral assessments of pain and temperature sensations by von Frey and hot/cold plate tests showed significant improvement by chronic VNS (cVNS) and forced swimming and marble burying tests revealed that the depressive-like behaviors caused by poly(I:C) injection were rescued by cVNS. We also found that the recognition memory which was impaired by poly(I:C) administration was improved by cVNS. This study suggests that VNS may play a role in regulating neuroinflammation and somatosensory and cognitive functions in poly(I:C)-injected animals.

Stress-induced vagal activity influences anxiety-relevant prefrontal and amygdala neuronal oscillations in male mice

The vagus nerve crucially affects emotions and psychiatric disorders. However, the detailed neurophysiological dynamics of the vagus nerve in response to emotions and its associated pathological changes remain unclear. In this study, we demonstrated that the spike rates of the cervical vagus nerve change depending on anxiety behavior in an elevated plus maze test, and these changes were eradicated in stress-susceptible male mice. Furthermore, instantaneous spike rates of the vagus nerve were negatively and positively correlated with the power of 2–4 Hz and 20–30 Hz oscillations, respectively, in the prefrontal cortex and amygdala. The oscillations also underwent dynamic changes depending on the behavioral state in the elevated plus maze, and these changes were no longer observed in stress-susceptible and vagotomized mice. Chronic vagus nerve stimulation restored behavior-relevant neuronal oscillations with the recovery of altered behavioral states in stress-susceptible mice. These results suggested that physiological vagal-brain communication underlies anxiety and mood disorders.

Short-term effects of transcutaneous auricular vagus nerve stimulation on T-wave alternans in people with focal epilepsy – An exploratory pilot study

High levels of T-wave alternans (TWA) are linked to an increased risk of sudden cardiac death. People with epilepsy display elevated TWA levels that are decreased by chronic vagus nerve stimulation via implanted devices after 2–4 weeks or later. Our objective was to explore short-term effects of transcutaneous auricular vagus nerve stimulation (tVNS) on TWA. Five patients (3 female) with focal epilepsy undergoing video-EEG monitoring were included. TWA levels were determined using a one-channel modified lead I ECG via an open-source TWA-algorithm on two consecutive days, 1 h before, during and after tVNS via the left auricle. Data are given as mean ± SE. Mean TWA at baseline was 3.8 ± 0.4 µV and 3.0 ± 0.6 µV during stimulation on day 2. Stimulations on the second day were associated with TWA reductions by 22 ± 13 % that exceeded stimulation effects on the first day relative to baseline (p < 0.05). Linear mixed-models revealed effects of both stimulation (p < 0.05) and stimulation number (p < 0.005). Normalized TWA showed reproducible peak reductions at both days within 35 min after the initiation of tVNS (p < 0.05). Our observations suggest that tVNS has short-term effects on TWA, supporting the notion that vagus nerve stimulation has a beneficial impact on electrical cardiac properties.

Identification of metabolic biomarkers of chronic vagus nerve stimulation (VNS) in subjects with drug-resistant epilepsy (DRE).

Neuromodulation by means of vagus nerve stimulation (VNS) therapy, reduces seizure frequency and improves quality of life in subjects with drug-resistant epilepsy (DRE), yet its molecular mechanism remains unclear. This study investigates the impact of chronic VNS on lipid bioactive metabolites and fatty acids (FA) in the plasma and red blood cells of seven subjects with DRE. By measuring expression levels of peroxisome proliferator-activated receptor α (PPARα) and sirtuin1 (SIRT1) genes-key regulators in energy and lipid metabolism-and lipid profiles before and after various stages of VNS, this study identifies potential mechanisms by which VNS may reduce seizure frequency. Blood samples collected before VNS device implantation, after acute VNS stimulus, and following gradual intensity increments up to therapeutic levels revealed that VNS increases SIRT1 and PPARα expression and erythrocyte concentrations of PPARα ligands. Additionally, we observe reduced de novo lipogenesis biomarkers in erythrocytes, indicating that VNS may influence systemic lipid and energy metabolism. Our findings suggest that VNS could enhance neuronal function by modulating energy metabolism, thus potentially reducing seizure frequency in subjects with DRE. Future research targeting SIRT1 and PPARα may provide innovative therapeutic strategies for managing DRE. Plain Language Summary: The exact mechanism of VNS is still unknown. This study investigated the effects of VNS Therapy on energetic metabolism, suggesting possible novel biomarkers for DRE subjects and neuromodulation therapies.

Chronic vagus nerve stimulation in patients with heart failure: challenge or failed translation?

Autonomic imbalance between the sympathetic and parasympathetic nervous systems contributes to the progression of chronic heart failure (HF). Preclinical studies have demonstrated that various neuromodulation strategies may exert beneficial cardioprotective effects in preclinical models of HF. Based on these encouraging experimental data, vagus nerve stimulation (VNS) has been assessed in patients with HF with a reduced ejection fraction. Nevertheless, the main trials conducted thus far have yielded conflicting findings, questioning the clinical efficacy of VNS in this context. This review will therefore focus on the role of the autonomic nervous system in HF pathophysiology and VNS therapy, highlighting the potential reasons behind the discrepancy between preclinical and clinical studies.

Neurostimulation und Schlaf bei Epilepsie – Englische Version

Abstract Background Chronic sleep disturbance may affect seizure frequency and efficacy of treatment in epilepsy patients. Vagus nerve stimulation (VNS) and deep brain stimulation (DBS) can both induce sleep disturbance as a side effect. Aim The goal of this review is to provide information and clinical advice about potential interactions between DBS at the anterior nucleus of the thalamus (ANT) and sleep as well as between VNS and sleep. Materials and methods We provide an up-to-date overview of the currently available literature, giving insights for diagnostics and therapy based on clinical studies, and experience in two epilepsy centers with longitudinal cohorts of patients under chronic neurostimulation. Results In patients with chronic ANT-DBS and VNS, stimulation-correlated, probably dose-dependent sleep disturbances have been reported in several studies. The reason for this is assumed to be an accidental co-stimulation of the ascending reticular arousal system in the case of DBS, and an indirect effect via induction of sleep-related breathing disorders in the case of VNS. Furthermore, VNS might also influence sleep through modulation of noradrenergic and dopaminergic, arousal-inducing systems in the pons and midbrain. Reduction of stimulation amplitudes, changes in stimulation parameters, and localization of the active stimulation zone are discussed as treatment strategies in DBS. In the case of VNS-induced sleep disturbance, a nocturnal reduction of stimulation (bilevel therapy) can be offered. Conclusion As data are currently still sparse, it seems important to optimize treatment regimens for VNS and DBS in order not to antagonize their potential anticonvulsant effects by inducing sleep fragmentation.

Vagal Nerve Stimulation Reduces Ventricular Arrhythmias and Mitigates Adverse Neural Cardiac Remodeling Post–Myocardial Infarction

This study sought to evaluate the impact of chronic vagal nerve stimulation (cVNS) on cardiac and extracardiac neural structure/function after myocardial infarction (MI). Groups were control, MI, and MI+ cVNS; cVNS was started 2days post-MI. Terminal experiments were performed 6weeks post-MI. MI impaired left ventricular mechanical function, evoked anisotropic electrical conduction, increased susceptibility to ventricular tachycardia and fibrillation, and altered neuronal and glial phenotypes in the stellate and dorsal root ganglia, including glial activation. cVNS improved cardiac mechanical function and reduced ventricular tachycardia/ventricular fibrillation post-MI, partly by stabilizing activation/repolarization in the border zone. MI-associated extracardiac neural remodeling, particularly glial activation, was mitigated with cVNS.

PO087 / #896 BDNF VAL66MET POLYMORPHISM AS A POSSIBLE BIOMARKER OF EFFICACY OF VNS THERAPY IN SUBJECTS WITH DRUG-RESISTANT EPILEPSY: E-POSTER VIEWING

Vagal nerve stimulation (VNS) is safe and effective in adults and children with epilepsy according to FDA. Brain-derived Neurotrophic Factor (BDNF) is implicated in many neurophysiological processes and exerts effects on hippocampal serotonergic pathways during both acute and chronic VNS stimulation.1 BDNF gene encodes a precursor peptide (proBDNF) and non-conservative single nucleotide polymorphism (SNP) has been identified in humans producing an amino acid substitution (Val66Met). This SNP affects intracellular processing and secretion of BDNF, leading to impaired hippocampal function in humans.

Effects of chronic vagal nerve stimulation in the treatment of β-amyloid-induced neuropsychiatric symptoms

Alzheimer's Disease (AD) is the leading cause of dementia and, at the time of diagnosis, half of AD patients display at least one neuropsychiatric symptom (NPS). However, there is no effective therapy for NPSs; furthermore, current treatments of NPSs accelerate cognitive decline. Due to the ineffectiveness and negative consequences of current treatments for NPSs, new approaches are strongly needed. Currently, indications for vagal nerve stimulation (VNS) include epilepsy, stroke rehabilitation and major depression but not NPSs or AD. Therefore, we investigated whether chronic VNS can treat NPSs in a rat model of AD. Here, we report the intracerebroventricular injection of amyloid-β (Aβ) results in depression-like behaviors and memory impairment in rats. Chronic VNS (0.8 mA, 500 μs, 30 Hz, 5 min/day) showed strong antidepressant and anxiolytic effects, and improved memory performance. Additionally, the anxiolytic effect of VNS was retained in the non-Aβ-treated rats. VNS also decreased aggressiveness and increased locomotor activity in both Aβ-treated and non-Aβ-treated rats. Recent studies showed VNS alters glutamatergic receptor levels, thus levels of GluA1, GluN2A, and GluN2B were determined. A significant reduction in GluN2B levels was seen in the hippocampus of VNS-treated groups which may relate to the anxiolytic effects and increased locomotor activity of VNS. In conclusion, VNS could be an effective treatment of NPSs, especially depression and anxiety, in AD patients without impairing cognition.

Chronic Vagal Nerve Stimulation Rescues Sympathetic Control of the Heart following Myocardial Infarction

Cardiac injury, such as myocardial infarction (MI), leads to neurohormonal activation and autonomic remodeling, resulting in reflexive sympathoexcitation and parasympathetic dysfunction, which further contribute to progression of disease. The purpose of this study was to determine whether chronic cervical vagal nerve stimulation (VNS) influences MI‐associated changes in cardiac sympathetic function. Yucatan minipigs were divided into control (n=6), chronic MI (n=7), and chronic MI + chronic VNS (n=8) groups. VNS therapy was delivered to the right cervical vagus nerve and systematically titrated to an optimal intensity based on heart rate dynamics (5Hz, 2.1±0.3mA, 250μs, 17.5% duty cycle) using telemetry in the conscious state. Chronic MI was created using percutaneous embolization of the left anterior descending coronary artery with polystyrene beads under fluoroscopy (Figure 1A). VNS therapy was started 2 days following MI, and the animals maintained for 6‐8 weeks. At terminal study, we evaluated hemodynamic responses to graded bilateral sympathetic chain stimulation (BSS). Left ventricular (LV) strips encompassing regions of scar, border zone, and normal myocardium were fixed in 10% formalin, embedded in paraffin, sectioned, and studied using Masson's trichrome stain (Figure 1B‐C). Structural changes at the peri‐infarct area were scored (0‐3) for myocyte morphology and presence of hypertrophy or myocytolysis. Animals with MI alone exhibited spontaneous ventricular arrhythmias, including two that experienced sudden cardiac death (Figure 1D). At terminal study, there were no significant differences in baseline systolic function among groups. Moderate (4Hz) and high (10Hz) intensity BSS increased LV contractility (dp/dtmax) in all groups (Figure 2A‐B); however, evoked changes were significantly reduced in the chronic MI compared to control or MI + VNS groups. While control animals displayed evidence of contractile reserve at 10Hz vs 4Hz (1297±266 mmHg/s, p=0.03), chronic MI animals did not (631.9±264 mmHg/s, p=0.11), which was improved with chronic VNS therapy (1027±160.6 mmHg/s, p&lt;0.01, Figure 2C). Chronic VNS therapy also significantly reduced MI‐associated structural remodeling in the peri‐infarct area, including the degree of myocytolysis and dysmorphic myocytes (structural abnormality index 0.6±0.2 vs 1.8±0.2, p&lt;0.01). Our findings suggest that chronic VNS ameliorates sympathetic functional remodeling following myocardial infarction and improves cardiac mechanical performance in response to simulated stress. Furthermore, chronic VNS reduces pathologic myocardial remodeling at the peri‐infarct zone, potentially stabilizing the resultant ventricular scar.

Ventricular Electrophysiological Effects of Vagal Nerve Stimulation in Humans With and Without Structural Heart Disease

Background and ObjectiveClinical trials investigating the benefits of vagus nerve stimulation (VNS) in heart failure have shown mixed results. This variation maybe due to inconsistent stimulation parameters, which may fail to adequately stimulate cardiomotor fibers required for cardio‐protection. However, overstimulation of the vagus nerve may cause adverse off‐target effects. Thus, the aim of this study was to assess the beneficial effects of moderate frequency VNS in patients with structurally normal hearts (SNH) and those with cardiomyopathy (CM).HypothesisModerate frequency VNS (10 Hz) confers ventricular electrophysiological effects.MethodsPatients with SNH and supraventricular tachycardia (n = 5) and cardiomyopathy patients with ventricular tachycardia (CM, n = 5) undergoing electrophysiology procedures were recruited. A multi‐electrode circular electrophysiology catheter was advanced from the femoral to the right internal jugular vein via a long sheath. Bipolar electrode pairs were serially stimulated and capture/stimulation of the vagus nerve identified by a negative chronotropic response. Threshold current was defined as a 10‐15% decrease in heart rate (HR) at 20 Hz and 1 ms pulse‐width. Stimulation was then performed at threshold current for 10 seconds at 10 and 20 Hz. Endocardial unipolar electrograms were continuously recorded using ventricular multielectrode mapping catheters and used to calculate activation recovery intervals (ARI), a validated surrogate of local action potential duration (APD). Electrodes were designated as overlying scar, border zone, or viable myocardium based on standard bipolar voltage mapping criteria in CM patients. ARIs were corrected for HR by the Framingham method.ResultsThe current of stimulation was 13.2 ± 1.7 mA in SNH and 14.4 ± 3.1 mA in CM (p = ns). VNS at 20 Hz significantly decreased HR (p ≤ 0.01) in both SNH and CM patients (12.6 ± 1.4% in SNH vs 12.9 ± 1.7% in CM, p= ns) while significantly prolonging global ventricular ARIs (2.2 ± 0.4% in SNH vs 4.6 ± 1.0% in CM, p= ns). The chronotropic effects of 10 Hz VNS were similar to 20 Hz in SNH (12.0 ± 1.4% at 10 Hz vs 12.6 ± 1.4% at 20 Hz, p = ns) but blunted in CM patients (12.0 ± 1.4% in SNH vs 4.9 ± 2.4% in CM, p≤ 0.05). Surprisingly, despite reduced chronotropic responses, global ARI prolongation persisted (4.0 ± 0.7% at 10 Hz vs 4.6 ± 1.0% at 20 Hz, p= ns) in CM patients. Importantly, ARI prolongation was observed in scar (326 ± 23 to 340 ± 22 ms, p≤ 0.05) and border zone regions (312 ± 18 ms to 323 ± 17 ms, p≤ 0.05). Moreover, after correcting ARI for heart rate (ARIc), 10 Hz VNS in CM patients caused significantly greater prolongation in ARIc than 20 Hz (1.8 ± 0.6% at 10 Hz vs ‐1.0 ± 0.6% at 20 Hz, p≤ 0.05), suggesting that higher frequency VNS may potentially cause a net shortening of ventricular APD.ConclusionsAcute application of moderate frequency VNS (10 Hz) demonstrated ventricular electrophysiological effects, with ARI prolongation observed in scar and border zone regions in diseased hearts. This human data validates previously reported effects of moderate frequency VNS in large animal infarct models. Stimulation at 20 Hz is unnecessary and may have negative ventricular electrophysiological effects. Further clinical trials assessing electrophysiological effects of chronic VNS in humans are required.

Impact Of An Automated Titration Algorithm On Battery Longevity In An Implantable Neurostimulation System For Treatment Of Chronic Heart Failure

Background Autonomic Regulation Therapy (ART) using chronic vagus nerve stimulation (VNS) is a promising new therapy for patients with heart failure (HF) who remain symptomatic despite standard care. In the ANTHEM-HF Pilot Study, a therapeutic VNS intensity was successfully achieved in patients with HFrEF using manually-programmed VNS up-titration. In the ANTHEM-HF Pilot Study (NCT01823887), the mean stimulation parameters were 2.4 ± 0.6 mA amplitude, 5 Hz frequency, 250 µs pulse width, and 23% duty cycle. A TitrationAssist algorithm has been developed for automatically intensifying VNS in small increments to a programmable target and capable of adjustments using a hand-held programmer or magnet. While this algorithm has the potential of dramatically reducing the number and duration of clinic visits for VNS titration, the impact of implementing TitrationAssist on device longevity has not been determined. Methods Current draw was measured from 32 VITARIA pulse generators (LivaNova USA, Houston, USA) with TitrationAssist activated. Testing was performed with a 3000 Ω load at programmed stimulation settings of 250 µsec pulse width, pulse frequency of 5 or 10 Hz, output current of 2.0 or 3.0 mA, and duty cycle of 23% (nominal), 33%, and 50%. The measured data was used in a standard longevity estimate process to determine the minimum longevity reached by at least 95% of devices with 95% confidence. The design requirement for battery longevity was >5 years at 10 Hz / 2.5 mA / 23%. Results Current draw was successfully measured from all 32 pulse generators and used to calculate device longevity. Device longevity, expressed in years, is shown in the table, and exceeds the system longevity requirement. At the expected stimulation parameters of 2.0-3.0 mA amplitude, 5 Hz frequency, 250 µs pulse width, 23% duty cycle, device longevity is expected to be in the range of 7-9 years. Device longevity was not significantly affected by the activation of the TitrationAssist algorithm. Conclusions At the expected stimulation parameters, VITARIA pulse generator battery longevity was determined to be 7-9 years. This exceeds the design requirement and suggests that ART can be titrated using TitrationAssist and chronically delivered without frequent generator replacement. Autonomic Regulation Therapy (ART) using chronic vagus nerve stimulation (VNS) is a promising new therapy for patients with heart failure (HF) who remain symptomatic despite standard care. In the ANTHEM-HF Pilot Study, a therapeutic VNS intensity was successfully achieved in patients with HFrEF using manually-programmed VNS up-titration. In the ANTHEM-HF Pilot Study (NCT01823887), the mean stimulation parameters were 2.4 ± 0.6 mA amplitude, 5 Hz frequency, 250 µs pulse width, and 23% duty cycle. A TitrationAssist algorithm has been developed for automatically intensifying VNS in small increments to a programmable target and capable of adjustments using a hand-held programmer or magnet. While this algorithm has the potential of dramatically reducing the number and duration of clinic visits for VNS titration, the impact of implementing TitrationAssist on device longevity has not been determined. Current draw was measured from 32 VITARIA pulse generators (LivaNova USA, Houston, USA) with TitrationAssist activated. Testing was performed with a 3000 Ω load at programmed stimulation settings of 250 µsec pulse width, pulse frequency of 5 or 10 Hz, output current of 2.0 or 3.0 mA, and duty cycle of 23% (nominal), 33%, and 50%. The measured data was used in a standard longevity estimate process to determine the minimum longevity reached by at least 95% of devices with 95% confidence. The design requirement for battery longevity was >5 years at 10 Hz / 2.5 mA / 23%. Current draw was successfully measured from all 32 pulse generators and used to calculate device longevity. Device longevity, expressed in years, is shown in the table, and exceeds the system longevity requirement. At the expected stimulation parameters of 2.0-3.0 mA amplitude, 5 Hz frequency, 250 µs pulse width, 23% duty cycle, device longevity is expected to be in the range of 7-9 years. Device longevity was not significantly affected by the activation of the TitrationAssist algorithm. At the expected stimulation parameters, VITARIA pulse generator battery longevity was determined to be 7-9 years. This exceeds the design requirement and suggests that ART can be titrated using TitrationAssist and chronically delivered without frequent generator replacement.

Transcutaneous auricular vagus nerve stimulation augments postprandial inhibition of ghrelin.

Vagus nerve stimulation (VNS) facilitates weight loss in animals and patients treated with VNS for depression or epilepsy. Likewise, chronic transcutaneous auricular VNS (taVNS) reduces weight gain and improves glucose tolerance in Zucker diabetic fatty rats. If these metabolic effects of taVNS observed in rats translate to humans is unknown. Therefore, the hypothesis of this study was that acute application of taVNS affects glucotropic and orexigenic hormones which could potentially facilitate weight loss and improve glucose tolerance if taVNS were applied chronically. In two single‐blinded randomized cross‐over protocols, blood glucose levels, plasma concentrations of insulin, C‐peptide, glucagon, leptin, and ghrelin, together with heart rate variability and baroreceptor‐heart rate reflex sensitivity were determined before and after taVNS (left ear, 10 Hz, 300 µs, 2.0–2.5 mA, 30 min) or sham‐taVNS (electrode attached to ear with the stimulator turned off). In a first protocol, subjects (n = 16) were fasted throughout the protocol and in a second protocol, subjects (n = 10) received a high‐calorie beverage (220 kCal) after the first blood sample, just before initiation of taVNS or sham‐taVNS. No significant effects of taVNS on heart rate variability and baroreceptor‐heart rate reflex sensitivity and only minor effects on glucotropic hormones were observed. However, in the second protocol taVNS significantly lowered postprandial plasma ghrelin levels (taVNS: −115.5 ± 28.3 pg/ml vs. sham‐taVNS: −51.2 ± 30.6 pg/ml, p < 0.05). This finding provides a rationale for follow‐up studies testing the hypothesis that chronic application of taVNS may reduce food intake through inhibition of ghrelin and, therefore, may indirectly improve glucose tolerance through weight loss.

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.

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].

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.

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 activates nucleus of solitary tract neurons via supramedullary pathways.

Vagus nerve stimulation (VNS) treats patients with drug-resistant epilepsy, depression and heart failure, but the mechanisms responsible are uncertain. The mild stimulus intensities used in chronic VNS suggest activation of myelinated primary visceral afferents projecting to the nucleus of the solitary tract (NTS). Here, we monitored the activity of second and higher order NTS neurons in response to peripheral vagal activation using therapeutic VNS criteria. A bipolar stimulating electrode activated the left cervical vagus nerve, and stereotaxically placed single tungsten electrodes recorded unit activity from the left caudomedial NTS of chloralose-anaesthetized rats. High-intensity single electrical stimuli established vagal afferent conduction velocity (myelinated A-type or unmyelinated C-type) as well as synaptic order (second vs. higher order using paired electrical stimuli) for inputs to single NTS neurons. Then, VNS treatment was applied. A mid-collicular knife cut (KC) divided the brainstem from all supramedullary regions to determine their contribution to NTS activity. Our chief findings indicate that the KC reduced basal spontaneous activity of second-order NTS neurons receiving myelinated vagal input by 85%. In these neurons, acute VNS increased activity similarly in Control and KC animals. Interestingly, the KC interrupted VNS activation of higher order NTS neurons and second-order NTS neurons receiving unmyelinated vagal input, indicating that supramedullary descending projections to NTS are needed to amplify the peripheral neuronal signal from VNS. The present study begins to define the pathways activated during VNS and will help to better identify the central nervous system contributions to the therapeutic benefits of VNS therapy. KEY POINTS: Vagus nerve stimulation is routinely used in the clinic to treat epilepsy and depression, despite our uncertainty about how this treatment works. For this study, the connections between the nucleus of the solitary tract (NTS) and the higher brain regions were severed to learn more about their contribution to activity of these neurons during stimulation. Severing these brain connections reduced baseline activity as well as reducing stimulation-induced activation for NTS neurons receiving myelinated vagal input. Higher brain regions play a significant role in maintaining both normal activity in NTS and indirect mechanisms of enhancing NTS neuronal activity during vagus nerve stimulation.

Therapeutic responsiveness to vagus nerve stimulation in patients receiving beta-blockade for heart failure with reduced ejection fraction

BackgroundThe effect of beta-blockade (BB) on response to vagus nerve stimulation (VNS) has not been reported in patients with heart failure and reduced ejection fraction (HFrEF). In the ANTHEM-HF Study, 60 patients received chronic cervical VNS. Background pharmacological therapy remained unchanged during the study, and VNS intensity was stable once up-titrated. Significant improvement from baseline occurred in resting 24-hour heart rate (HR), 24-hour HR variability (SDNN), left ventricular EF (LVEF), 6-minute walk distance (6MWD), and quality of life (MLWHFS) at 6 months post-titration. We evaluated whether response to VNS was related to percentage of target BB dose (PTBBD) at baseline.MethodsPatients were categorized by baseline PTBBD, then analyzed for changes from baseline in symptoms and function at 6 months after VNS titration.ResultsAll patients received BB, either PTBBD ≥ 50 % (16 patients, 27 %; group 1) or PTBBD < 50 % (44 patients, 73 %; group 2). Heart rate, systolic blood pressure, LVEF, use of ACE/ARB, and use of MRA were similar between the two groups at baseline. Six months after up-titration, VNS reduced HR and significantly improved SDNN, LVEF, 6MWD, and MLWHFS equally in both groups.ConclusionsIn the ANTHEM-HF study, VNS responsiveness appeared to be independent of the baseline BB dose administered.