Vagus nerve stimulation in depression

How the parasympathetic and sympathetic nervous system influence the rate of pacemaker generation and conduction within the sinus node is a subject that has fascinated electrophysiologists for many years. Our early studies in the dog using brief vagal and brief sympathetic nerve stimulation demonstrated that there was a considerable difference in the time course between the effects of the parasympathetic and sympathetic nervous system (Spear and Moore, 1973). The acceleration of sinus node rate caused by brief stellate stimulation was observed to be a gradual acceleration followed by a gradual slowing. The effects of vagal stimulation on sinus rhythm were more brief and more complex. Brief vagal stimulation resulted in an initial slowing of sinus rhythm followed by a transient period of acceleration in which the spontaneous rate sometimes actually exceeded the control sinus rate followed by a second period of sinus slowing. This phenomena of anomalous acceleration following brief vagal stimulation was shown first by Brown and Eccles in 1934 in studies on the cat sinus node. Since Brown and Eccles’ early studies it has been shown that this acceleratory component is not due to a simultaneous stimulation of sympathetic fibers since beta adrenergic blockade does not eliminate the anomalous acceleratory component observed following brief vagal stimulation (Levy et al., 1970; Spear and Moore, 1973).KeywordsVagal StimulationSinus NodeSympathetic StimulationSinus RateBipolar ElectrogramThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

ObjectiveThe long‐term effects of epilepsy surgery (ES) or vagus nerve stimulation (VNS) on antiseizure medication (ASM) usage and status epilepticus (SE) diagnosis in real‐world pediatric drug‐resistant epilepsy (DRE) populations remain unclear. This study aimed to provide a more comprehensive understanding of how VNS and ES affect ASM usage and SE manifestations in pediatric DRE.MethodsWe conducted a nationwide, retrospective cohort study using the Korean Health Insurance Review and Assessment Service database from January 1, 2007, to December 31, 2022. Pediatric patients (<18 years) diagnosed with DRE were categorized into ASM‐only, VNS, and ES groups. Changes in ASM usage and SE diagnostic rates were assessed.ResultsA total of 6075 pediatric patients with DRE were included (ASM‐only, n = 5407; VNS, n = 217; ES, n = 451). Although the VNS and ES groups had more severe epilepsy at baseline, both interventions significantly reduced ASM usage, albeit with distinct trajectories. ES led to a sharp reduction in ASM usage immediately postoperatively, followed by stabilization, with approximately one‐third of the patients discontinuing ASM by the end of follow‐up. VNS stabilized ASM usage rather than reducing it, with fewer than 10% of patients discontinuing ASM. Both interventions were associated with significant decreases in SE diagnostic rates after the intervention (p = 0.007 and 0.02, respectively), but no statistically significant difference was found in the overall SE rates among the three groups (p = 0.18).SignificanceThese findings demonstrate that VNS and CES positively impact ASM usage, reduce the incidence of SE, and underscore the need for timely intervention to optimize outcomes.Plain Language SummaryWe studied children with drug‐resistant epilepsy who were treated with either vagus nerve stimulation (VNS) or brain surgery for epilepsy. We found that brain surgery often led to a large and lasting reduction in seizure medication, whereas VNS helped stabilize medication use. Both treatments were linked to fewer cases of status epilepticus, a severe type of seizure emergency. These findings suggest that VNS and surgery may help reduce medication burden and protect against serious seizures in children with hard‐to‐treat epilepsy.

Pulmonary inflammation contributes to ventilator-induced lung injury. Sepsis-induced pulmonary inflammation (first hit) may be potentiated by mechanical ventilation (MV, second hit). Electrical stimulation of the vagus nerve has been shown to attenuate inflammation in various animal models through the cholinergic anti-inflammatory pathway. We determined the effects of vagotomy (VGX) and vagus nerve stimulation (VNS) on systemic and pulmonary inflammation in a two-hit model. Male Sprague-Dawley rats were i.v. administered lipopolysaccharide (LPS) and subsequently underwent VGX, VNS or a sham operation. 1 hour following LPS, MV with low (8 mL/kg) or moderate (15 mL/kg) tidal volumes was initiated, or animals were left breathing spontaneously (SP). After 4 hours of MV or SP, rats were sacrificed. Cytokine and blood gas analysis was performed. MV with 15, but not 8 mL/kg, potentiated the LPS-induced pulmonary pro-inflammatory cytokine response (TNF-α, IL-6, KC: p<0.05 compared to LPS-SP), but did not affect systemic inflammation or impair oxygenation. VGX enhanced the LPS-induced pulmonary, but not systemic pro-inflammatory cytokine response in spontaneously breathing, but not in MV animals (TNF-α, IL-6, KC: p<0.05 compared to SHAM), and resulted in decreased pO2 (p<0.05 compared to sham-operated animals). VNS did not affect any of the studied parameters in both SP and MV animals. In conclusion, MV with moderate tidal volumes potentiates the pulmonary inflammatory response elicited by systemic LPS administration. No beneficial effects of vagus nerve stimulation performed following LPS administration were found. These results questions the clinical applicability of stimulation of the cholinergic anti-inflammatory pathway in systemically inflamed patients admitted to the ICU where MV is initiated.

Long-Term Vagus Nerve Stimulation for Severe Refractory Depression: A Case Study With a Six-Year Follow-Up

The purpose of this study was to determine the effects and mechanisms of vagal nerve stimulation (VNS) and additive effects of electroacupuncture (EA) on colonic inflammation in a rodent model of IBD. Chronic inflammation in rats was induced by intrarectal TNBS (2,4,6-trinitrobenzenesulfonic acid). The rats were then treated with sham ES (electrical stimulation), VNS, or VNS + EA for 3 wk. Inflammatory responses were assessed by disease activity index (DAI), macroscopic scores and histological scores of colonic tissues, plasma levels of TNFα, IL-1β, and IL-6, and myeloperoxidase (MPO) activity of colonic tissues. The autonomic function was assessed by the spectral analysis of heart rate variability (HRV) derived from the electrocardiogram. It was found that 1) the area under curve (AUC) of DAI was substantially decreased with VNS + EA and VNS, with VNS + EA being more effective than VNS (P < 0.001); 2) the macroscopic score was 6.43 ± 0.61 in the sham ES group and reduced to 1.86 ± 0.26 with VNS (P < 0.001) and 1.29 ± 0.18 with VNS + EA (P < 0.001); 3) the histological score was 4.05 ± 0.58 in the sham ES group and reduced to 1.93 ± 0.37 with VNS (P < 0.001) and 1.36 ± 0.20 with VNS + EA (P < 0.001); 4) the plasma levels of TNFα, IL-1β, IL-6, and MPO were all significantly decreased with VNS and VNS + EA compared with the sham ES group; and 5) autonomically, both VNS + EA and VNS substantially increased vagal activity and decreased sympathetic activity compared with sham EA (P < 0.001, P < 0.001, respectively). In conclusion, chronic VNS improves inflammation in TNBS-treated rats by inhibiting proinflammatory cytokines via the autonomic mechanism. Addition of noninvasive EA to VNS may enhance the anti-inflammatory effect of VNS.NEW & NOTEWORTHY This is the first study to address and compare the effects of vagal nerve stimulation (VNS), electrical acupuncture (EA) and VNS + EA on TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced colitis in rats. The proposed chronic VNS + EA, VNS, and EA were shown to decrease DAI and ameliorate macroscopic and microscopic damages in rats with TNBS-induced colitis via the autonomic pathway. The addition of EA to VNS provided a significant effect on the behavioral assessment of inflammation (DAI, CMDI, and histological score) but not on cytokines or mechanistic measurements, suggesting an overall systemic effect of EA.View this article's corresponding video summary at https://youtu.be/-rEz6HMkErM.

To the Editor

Objective To explore the influence of vagus nerve stimulation (VNS) on inflammatory factors in serum and nucleus of the solitary tract, and hippocampal apoptosis in rats with depression induced by chronic unpredictable stress(CUS). Methods Totally 32 male Sprague Dawley (SD) rats aged 8-9 weeks were selected.Eight rats were chosen as control group, and the other 24 rats were treated as the depression model with CUS. The rats were randomly divided into CUS, fluoxetine and VNS group, with 8 rats in each group after successful modeling. The control group and CUS group were induced by normal saline. Fluoxetine group and VNS group were implanted with VNS stimulation electrode. The VNS stimulation lasted for 28 d. On the time points of before experiment, after modeling and after treatment, the sucrose consumption test and open-field test (OFT) were performed to observe the behavioral changes of rats. Elisa was used to detect the levels of TNF-α, IL-6 and IL-1β in serum and nucleus of the solitary tract. Cell apoptosis was observed with TUNEL staining in hippocampal CA1 region. Results (1) Sucrose consumption experiment and OFT showed that, compared with the CUS group, the consumption of sucrose, percentage of sucrose consumption, scores of vertical and horizontal movement increased significantly in the VNS group (consumption of sucrose: (11.78±2.67) ml, (8.06±2.85) ml; percentage of sucrose consumption: (72.31±9.98)%, (63.67±8.95)%; score of vertical movement: (16.61±3.98), (10.31±3.86); score of horizontal movement: (44.25±9.59), (36.21±7.21)) (t=4.87, 7.98, 5.87, 9.12, all P 0.05). (2) Compared with the CUS group, levels of TNF-α, IL-6 and IL-1β in serum decreased in the VNS group (serum TNF-α: (46.72±11.63) pg/ml, (125.47±15.18) pg/ml; serum IL-6: (243.65±38.90) pg/ml, (441.39±83.31) pg/ml; serum IL-1β: (209.31±32.45) pg/ml, (339.21±76.37) pg/ml) (t=-70.38, -196.25, -131.13, all P 0.05). Conclusion VNS can improve the depression behavior in rats with depression induced by CUS and the mechanism maybe related to inhibiting the expression of TNF-α, IL-6 and IL-1β in serum and nucleus of the solitary tract and cell apoptosis in hippocampal CA1 region. Key words: Chronic unpredictable stress; Vagus nerve stimulation; Nucleus of the solitary Tract; Inflammatory factors; Apoptosis; Rats

Vagus nerve stimulation (VNS) exerts neuroprotective effects against cerebral ischemia/reperfusion (I/R) injury and modulates redox status, potentially through the activity of miR-210, an important microRNA that is regulated by hypoxia-inducible factor and Akt-dependent pathways. The aim of this study was to determine the mechanisms of VNS- and miR-210-mediated hypoxic tolerance. Male Sprague-Dawley rats were preconditioned with a miR-210 antagomir (A) or with an antagomir control (AC), followed by middle cerebral artery occlusion and VNS treatment. The animals were divided into eight groups: sham I/R, I/R, I/R+AC, I/R+A, sham I/R+VNS, I/R+VNS, I/R+VNS+AC, and I/R+VNS+A. Activation of the endogenous cholinergic a7 nicotinic acetylcholine receptor (a7nAchR) pathway was identified using double immunofluorescence staining. miR-210 expression was measured by PCR. Behavioral outcomes, infarct volume, and neuronal apoptosis were observed at 24h following reperfusion. Markers of oxidative stress were detected using ELISA. Rats treated with VNS showed increased miR-210 expression as well as decreased apoptosis and antioxidant stress responses compared with the I/R group; these rats also showed increased p-Akt protein expression and significantly decreased levels of cleaved caspase 3 in the ischemic penumbra, as measured by western blot and immunofluorescence analyses, respectively. Strikingly, the beneficial effects of VNS were attenuated following miR-210 knockdown. In conclusion, our results indicate that miR-210 is a potential mediator of VNS-induced neuroprotection against I/R injury. Our study highlights the neuroprotective potential of VNS, which, to date, has been largely unexplored. Since approved by the FDA in 1997, vagus nerve stimulation (VNS) has proven to be a safe and effective treatment for refractory epilepsy and resistant depression. Recent studies have found that VNS also provided neuroprotective effects against ischemic injury in a rat stroke model. We showed that miR-210 played an important role in the antioxidant stress and anti-apoptosis responses induced by VNS. This is the first report showing the effects of VNS at the mRNA level. Therefore, VNS represents a promising candidate treatment for ischemic stroke patients. Schematic view of the role of miR210 mediated in the protective effects of the VNS on the acute cerebral ischemia. VNS acts to activate neuronal and astrocytes a7nAchR , inhibits the apoptosis and oxidant stress responses possibly associated with increased Akt phosphorylation and miR210 expression.

&lt;h4&gt;EXCERPT &lt;/h4&gt; &lt;p&gt;In July 2005, vagus nerve stimulation (VNS) therapy was approved by the U.S. Food and Drug Administration for the adjunctive long-term treatment of chronic or recurrent depression for patients age 18 and older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments. In this article, I describe the clinical studies of VNS for treatment-resistant depression (TRD), as well as preliminary studies investigating its use for other neuropsychiatric disorders. &lt;/p&gt;

Hypertension (HTN) affects over 1 billion people worldwide, with a significant number who are unable to control their blood pressure (BP) with conventional therapies. Recently, novel device-based therapies targeting the autonomic nervous system have been evaluated for treating HTN, including vagus nerve stimulation (VNS). Numerous studies have indicated the beneficial effects of chronic VNS in various models of HTN, however the acute effects of VNS on physiological responses have not been widely investigated. To better understand the acute effects of VNS, this study evaluates cardiovascular and hemodynamic responses from conscious hypertensive rats implanted with VNS stimulators and physiological telemeters for simultaneous monitoring of BP and heart rate (HR) as therapy is applied. We demonstrated that there are no acute changes in mean BP, HR and contractility measures as a result of VNS stimulation. However, there were significant increases in both HR variability and BP variability during VNS, which returned to baseline levels immediately at the cessation of therapy. The small acute changes observed during intermittent VNS could be additive, leading to beneficial chronic changes in BP and HR control, and may help in furthering the understanding of beneficial effects demonstrated in chronic use of VNS therapy.

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

Editorial| April 2023 Modulating the Cardiac Autonomic Nervous System: Stay Close to My Heart or Keep Your Distance? This article has an Audio Podcast Karsten Bartels, M.D., Ph.D., M.B.A.; Karsten Bartels, M.D., Ph.D., M.B.A. 1Department of Anesthesiology, University of Nebraska Medical Center, Omaha, Nebraska; Outcomes Research Consortium, Cleveland, Ohio. https://orcid.org/0000-0003-2028-4664 Search for other works by this author on: This Site PubMed Google Scholar Amanda A. Fox, M.D., M.P.H. Amanda A. Fox, M.D., M.P.H. 2Department of Anesthesiology and Pain Management, and McDermott Center for Human Growth and Development/Center for Human Genetics, University of Texas Southwestern Medical Center, Dallas, Texas. Search for other works by this author on: This Site PubMed Google Scholar Author and Article Information This editorial accompanies the article on p. 372. Accepted for publication February 1, 2023. Address correspondence to Dr. Bartels: karbartels@unmc.edu Anesthesiology April 2023, Vol. 138, 348–350. https://doi.org/10.1097/ALN.0000000000004529 Connected Content Article: GABAergic Signaling during Spinal Cord Stimulation Reduces Cardiac Arrhythmias in a Porcine Model Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Search Site Citation Karsten Bartels, Amanda A. Fox; Modulating the Cardiac Autonomic Nervous System: Stay Close to My Heart or Keep Your Distance?. Anesthesiology 2023; 138:348–350 doi: https://doi.org/10.1097/ALN.0000000000004529 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll PublicationsAnesthesiology Search Advanced Search Topics: autonomic nervous system, heart Perioperative cardiac protection research is needed to determine how to prevent and mitigate cardiac injury that can lead to cardiovascular morbidity and mortality. In this month’s issue of Anesthesiology, Howard-Quijano et al.1 report effects of high thoracic spinal cord stimulation on decreasing sympathetic stimulation of the heart and corresponding ventricular arrhythmias. What is particularly meaningful about this paper is that the authors do experiments on Yorkshire pigs in order to define the biology underlying the favorable cardiac effects of high thoracic spinal cord stimulation. In their manuscript, the authors report findings from an elegant sequence of experiments demonstrating specifically that (1) spinal cord stimulation therapy during cardiac ischemia resulted in fewer ventricular arrhythmias, (2) intrathecal γ-aminobutyric acid type A (GABAA) and γ-aminobutyric acid type B (GABAB) receptor blockade eliminated the protective effects of spinal cord stimulation, (3) intrathecal administration of γ-aminobutyric acid (GABA) transaminase... You do not currently have access to this content.

The vagus nerve is a major component of the autonomic nervous system, has an important role in the regulation of metabolic homeostasis, and plays a key role in the neuro-endocrine-immune axis. Vagus nerve stimulation (VNS) refers to any technique that stimulates the vagus nerve. Left cervical VNS is an approved therapy for refractory epilepsy and treatment-resistant depression. Right cervical VNS has proven effective for treating heart failure in preclinical studies and a Phase II clinical trial. The effectiveness of noninvasive transcutaneous VNS for epilepsy, depression, and other conditions has not been investigated beyond small pilot studies. The relationship between depression, inflammation, and cardiovascular, cerebrovascular, and metabolic syndromes might be mediated by the vagus nerve. Transcutaneous VNS deserves further study as an antidepressant therapy and for its potential effect on physiological biomarkers associated with depression morbidity and mortality.

Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats

Vagus nerve stimulation is associated with mood improvements in epilepsy patients