Application Of Vagus Nerve Stimulation Research Articles

In vivo tracing of the ascending vagal projections to the brain with manganese enhanced magnetic resonance imaging.

The vagus nerve, the primary neural pathway mediating brain-body interactions, plays an essential role in transmitting bodily signals to the brain. Despite its significance, our understanding of the detailed organization and functionality of vagal afferent projections remains incomplete. In this study, we utilized manganese-enhanced magnetic resonance imaging (MEMRI) as a non-invasive and in vivo method for tracing vagal nerve projections to the brainstem and assessing their functional dependence on cervical vagus nerve stimulation (VNS). Manganese chloride solution was injected into the nodose ganglion of rats, and T1-weighted MRI scans were performed at both 12 and 24 h after the injection. Our findings reveal that vagal afferent neurons can uptake and transport manganese ions, serving as a surrogate for calcium ions, to the nucleus tractus solitarius (NTS) in the brainstem. In the absence of VNS, we observed significant contrast enhancements of around 19-24% in the NTS ipsilateral to the injection side. Application of VNS for 4 h further promoted nerve activity, leading to greater contrast enhancements of 40-43% in the NTS. These results demonstrate the potential of MEMRI for high-resolution, activity-dependent tracing of vagal afferents, providing a valuable tool for the structural and functional assessment of the vagus nerve and its influence on brain activity.

Research Progress of Vagus Nerve Stimulation in Stroke Rehabilitation Treatment

<i>Background: </i>Stroke is the leading cause of adult death in China and the leading cause of death worldwide, characterized by high morbidity, disability, mortality, recurrence and economic burden, often leading to various functional impairments, such as motor impairment, sensory impairment, swallowing impairment, consciousness impairment and cognitive impairment. Therefore, finding effective intervention methods is currently a hot and difficult issue in stroke rehabilitation treatment. Vagus nerve stimulation, as a classical neuromodulation technique, has been widely certified for its safety and effectiveness. In recent years, several studies at home and abroad have reported that VNS can be used as a potential rehabilitation treatment to improve functional impairment after stroke. <i>Objective:</i> In this paper, the clinical application of vagus nerve stimulation in different dysfunctions after stroke is discussed in the context of relevant studies at home and abroad, and the effectiveness, safety and possible mechanisms of action of VNS in stroke treatment are reviewed, aiming to provide new therapeutic ideas for stroke rehabilitation. <i>Conclusion: </i>Vagus nerve stimulation, a classical neuromodulation technique, can help improve various dysfunctions after stroke and improve patients' survivability and quality of life. Vagus nerve stimulation is expected to be a potential new therapy for stroke rehabilitation and play an important role in the rehabilitation of post-stroke dysfunction.

Bibliometric analysis of publication trends and research hotspots in vagus nerve stimulation: A 20-year panorama.

As a promising neuromodulation technique, vagus nerve stimulation (VNS) has been utilized to treat diverse diseases and the number of VNS studies has grown prosperously. Nonetheless, publication trends and research hotspots in this field remain unknown. This study aimed to perform a bibliometric analysis to systematically identify publication trends and research hotspots in VNS research within a 20-year panorama. The Web of Science Core Collection (WoSCC) database was retrieved to screen eligible VNS-related publications from 2002 to 2021. The online analytic tool of the WoSCC database was used to analyze various bibliometric parameters, such as the number of annual publications, the output of countries/regions, journals, total citations, citations per publication, and the Hirsch index. Bibliometrics (http://bibliometric.com/) and CiteSpace (version 5.6.R3) were used to identify research trends and hotspots. A total of 7,283 publications were included for analysis. The annual number of publications increased stably but it increased significantly in recent years. The top five prolific countries were the United States, China, Germany, England, and France. The top five productive institutions were the University of California (Los Angeles), Harvard Medical School, Harvard University, University College London, and the University of Texas at Dallas. Notably, there was a geographical imbalance in countries and institutions. In addition, Epilepsy & Behavior, Epilepsia, and Plos One were the top three journals with the largest number of VNS publications. Michael P Kilgard was the most prolific author. Moreover, evolving research hotspots mainly included the effectiveness and mechanism of VNS on epilepsy, the role of VNS as an anti-inflammatory regulator, the application of VNS for psychiatric disorders, and the neuromodulation effect of VNS in headache management. This study has revealed the overall publication trends and evolving research trends at a global level over a 20-year panorama. The potential collaborators, institutions, hotspots, and future research trends are also identified in this field, which will help guide new research directions of VNS.

Research advances in the application of vagus nerve electrical stimulation in ischemic stroke.

Stroke seriously endangers human well-being and brings a severe burden to family and society. Different post-stroke dysfunctions result in an impaired ability to perform activities of daily living. Standard rehabilitative therapies may not meet the requirements for functional improvement after a stroke; thus, alternative approaches need to be proposed. Currently, vagus nerve stimulation (VNS) is clinically applied for the treatment of epilepsy, depression, cluster headache and migraine, while its treatment of various dysfunctions after an ischemic stroke is still in the clinical research stage. Recent studies have confirmed that VNS has neuroprotective effects in animal models of transient and permanent focal cerebral ischemia, and that its combination with rehabilitative training significantly improves upper limb motor dysfunction and dysphagia. In addition, vagus-related anatomical structures and neurotransmitters are closely implicated in memory-cognition enhancement processes, suggesting that VNS is promising as a potential treatment for cognitive dysfunction after an ischemic stroke. In this review, we outline the current status of the application of VNS (invasive and non-invasive) in diverse functional impairments after an ischemic stroke, followed by an in-depth discussion of the underlying mechanisms of its mediated neuroprotective effects. Finally, we summarize the current clinical implementation challenges and adverse events of VNS and put forward some suggestions for its future research direction. Research on VNS for ischemic stroke has reached a critical stage. Determining how to achieve the clinical transformation of this technology safely and effectively is important, and more animal and clinical studies are needed to clarify its therapeutic mechanism.

The application of vagus nerve stimulation in individuals with misophonia

Stimulating the Vagus nerve helps maintain the autonomic tone, indicating stabilising any hyperactivity in the nervous system. The vagus nerve stimulation is applied in individuals with seizures, depression, sepsis, pain, obesity, cardiovascular disease, lung disease, diabetes, stroke, and traumatic brain injury. Auditory neuroscience has been widely applied in individuals with tinnitus and has been demonstrated as a successful neuromodulation technique. Individuals with peripheral lesions of the hair cells induce a maladaptive change in the plasticity resulting in hyperactivity in the auditory and non-auditory structures. In order to reduce this hyperactivity, neuromodulation techniques such as; transcranial magnetic stimulation, transcranial direct current stimulation, transcranial alternating current stimulation, transcranial random noise stimulation, neurofeedback, epidural and subdural cortical and deep brain stimulation. The vagus nerve stimulation is also one form of neuromodulation technique considered to reduce the symptoms of tinnitus. It is believed that the ramus Auricularis Nervi vagi, an afferent sensory branch of the vagus nerve, innervates the afferent sensory branch of the vagus nerve, the ramus auricularis nervi vagi also innervate the outer ear canal and parts of the auricle. This auricular branch of the vagus nerve also called Arnold's nerve, which gives a projection to the nucleus of the solitary tract. The vagus nerve stimulation in individuals with tinnitus works to activate the auricular branch of the vagus nerve to reduce its symptoms. A similar principle of vagus nerve stimulation can be tried upon in individuals with misophonia. Literatures states that individuals with misophonia have hyperactivity in their non-classical auditory pathway that can be suppressed with the help of vagus nerve stimulation. The article discusses the possible effects of vagus nerve stimulation in individuals with misophonia.

Use of Vagus Nerve Stimulation and Vagal Maneuvers as Adjuvant Therapy for COVID-19 Patients

At present there is no effective specific antiviral drug to treat the ongoing COVID-19 pandemic that has already infected millions of individual and caused hundreds of thousand deaths worldwide. There is strong indication that a cytokine storm is responsible for the severity of COVID-19 patients. Pilot studies using IL-6 receptor inhibitors such as Tolicizumab have shown promising results. However, since the cytokine storm is a complex systemic inflammatory response involving multiple cytokines it can be hypothesized that a “paninhibition” of cytokines and/or cytokine receptors will be more effective. However, at the same time this strategy may cause more adverse effects. In this article, we propose the application of Vagus Nerve Stimulation (NVS) and/or some forms of vagal maneuvers as adjuvant therapies to prevent and/or mitigate the cytokine response in COVID-19 patients. This proposal is based on the ability of NVS and to decrease the production of IL-6 and other cytokines. The potential application of the diving response (one form of vagal maneuver), that has been shown to confer intrinsic resistance to inflammation in the blood of diving mammals, is also discussed as adjuvant therapy for COVID-19 patients. Doi: 10.28991/SciMedJ-2021-03-SI-2 Full Text: PDF

Targeting the Autonomic Nervous System for Risk Stratification, Outcome Prediction and Neuromodulation in Ischemic Stroke.

Ischemic stroke is a worldwide major cause of mortality and disability and has high costs in terms of health-related quality of life and expectancy as well as of social healthcare resources. In recent years, starting from the bidirectional relationship between autonomic nervous system (ANS) dysfunction and acute ischemic stroke (AIS), researchers have identified prognostic factors for risk stratification, prognosis of mid-term outcomes and response to recanalization therapy. In particular, the evaluation of the ANS function through the analysis of heart rate variability (HRV) appears to be a promising non-invasive and reliable tool for the management of patients with AIS. Furthermore, preclinical molecular studies on the pathophysiological mechanisms underlying the onset and progression of stroke damage have shown an extensive overlap with the activity of the vagus nerve. Evidence from the application of vagus nerve stimulation (VNS) on animal models of AIS and on patients with chronic ischemic stroke has highlighted the surprising therapeutic possibilities of neuromodulation. Preclinical molecular studies highlighted that the neuroprotective action of VNS results from anti-inflammatory, antioxidant and antiapoptotic mechanisms mediated by α7 nicotinic acetylcholine receptor. Given the proven safety of non-invasive VNS in the subacute phase, the ease of its use and its possible beneficial effect in hemorrhagic stroke as well, human studies with transcutaneous VNS should be less challenging than protocols that involve invasive VNS and could be the proof of concept that neuromodulation represents the very first therapeutic approach in the ultra-early management of stroke.

Specific vagus nerve stimulation parameters alter serum cytokine levels in the absence of inflammation

BackgroundElectrical stimulation of peripheral nerves is a widely used technique to treat a variety of conditions including chronic pain, motor impairment, headaches, and epilepsy. Nerve stimulation to achieve efficacious symptomatic relief depends on the proper selection of electrical stimulation parameters to recruit the appropriate fibers within a nerve. Recently, electrical stimulation of the vagus nerve has shown promise for controlling inflammation and clinical trials have demonstrated efficacy for the treatment of inflammatory disorders. This application of vagus nerve stimulation activates the inflammatory reflex, reducing levels of inflammatory cytokines during inflammation.MethodsHere, we wanted to test whether altering the parameters of electrical vagus nerve stimulation would change circulating cytokine levels of normal healthy animals in the absence of increased inflammation. To examine this, we systematically tested a set of electrical stimulation parameters and measured serum cytokine levels in healthy mice.ResultsSurprisingly, we found that specific combinations of pulse width, pulse amplitude, and frequency produced significant increases of the pro-inflammatory cytokine tumor necrosis factor (TNF), while other parameters selectively lowered serum TNF levels, as compared to sham-stimulated mice. In addition, serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) were significantly increased by select parameters of electrical stimulation but remained unchanged with others.ConclusionsThese results indicate that electrical stimulation parameter selection is critically important for the modulation of cytokines via the cervical vagus nerve and that specific cytokines can be increased by electrical stimulation in the absence of inflammation. As the next generation of bioelectronic therapies and devices are developed to capitalize on the neural regulation of inflammation, the selection of nerve stimulation parameters will be a critically important variable for achieving cytokine-specific changes.

Vagus Nerve Stimulation and the Cardiovascular System.

The vagus nerve plays an important role in maintaining physiological homeostasis, which includes reflex pathways that regulate cardiac function. The link between vagus nerve activity and the high-frequency component of heart rate variability (HRV) has been well established, correlating with vagal tone. Recently, vagus nerve stimulation (VNS) has been investigated as a therapeutic for a multitude of diseases, such as treatment-resistant epilepsy, rheumatoid arthritis, Crohn's disease, and asthma. Because of the vagus nerve's innervation of the heart, VNS has been identified as a potential therapy for cardiovascular disorders, such as cardiac arrest, acute myocardial infarction, and stroke. Here, we review the current state of preclinical and clinical studies, as well as the potential application of VNS in relation to the cardiovascular system.

Research advances in vagus nerve stimulation for traumatic brain injury

Patients with coma caused by traumatic brain injury (TBI) suffer from poor quality of life and many complications, which brings heavy burden to their families. The exploration of TBI treatment will help patients restore function, reduce disability rate and improve quality of life. At present, the clinical treatment of TBI mainly includes mild hypothermia treatment, hyperbaric oxygen treatment, awakening drugs and median nerve electrical stimulation, which have their own limitations. Currently, a number of studies have focused on the application of vagus nerve stimulation (VNS) in TBI. The possible mechanisms of VNS include anti-inflammatory effect, brain edema reduction and stabilization of intracranial pressure, promoting nerve function recovery, attenuation of blood-brain barrier breakdown, glutamate-mediated excitotoxicity, synaptic plasticity and recruitment of endogenous neural stem cells. VNS can be used as a new method of clinical treatment for patients with TBI, but it also carries risks of complication as an invasive electrical stimulation. The author summarizes the usage, possible mechanism and safety of VNS, so as to provide reference for further understanding the application of VNS in TBI treatment. Key words: Brain injuries; Vagus nerve; Electric stimulation therapy

Vagus nerve stimulation produces a hippocampal formation theta rhythm in anesthetized rats

Vagus nerve stimulation (VNS) has been used for years to treat patients with drug-resistant epilepsy. In the present study, the effect of different stimulation protocols of VNS on the hippocampal formation (HPC) type II theta field potentials were evaluated in anesthetized rats. The following theta parameters were analysed: power, frequency and duration of theta epochs. We documented for the first time the presence of HPC type II theta in response to the application of VNS. A VNS-induced theta rhythm appeared in different experimental protocols and, depending on the current intensity, could occur directly during VNS (brief effect) or after vagal stimulation (delayed effect), using lower intensity stimuli.

Transcutaneous Vagus Nerve Stimulation Modulates Default Mode Network in Major Depressive Disorder

BackgroundDepression is the most common form of mental disorder in community and health care settings and current treatments are far from satisfactory. Vagus nerve stimulation (VNS) is a Food and Drug Administration approved somatic treatment for treatment-resistant depression. However, the involvement of surgery has limited VNS only to patients who have failed to respond to multiple treatment options. Transcutaneous VNS (tVNS) is a relatively new, noninvasive VNS method based on the rationale that there is afferent/efferent vagus nerve distribution on the surface of the ear. The safe and low-cost characteristics of tVNS have the potential to significantly expand the clinical application of VNS. MethodsIn this study, we investigated how tVNS can modulate the default mode network (DMN) functional connectivity (FC) in mild or moderate major depressive disorder (MDD) patients. Forty-nine MDD patients were recruited and received tVNS or sham tVNS (stVNS) treatments. ResultsThirty-four patients completed the study and were included in data analysis. After 1 month of tVNS treatment, the 24-item Hamilton Depression Rating Scale score reduced significantly in the tVNS group as compared with the stVNS group. The FC between the DMN and anterior insula and parahippocampus decreased; the FC between the DMN and precuneus and orbital prefrontal cortex increased compared with stVNS. All these FC increases are also associated with 24-item Hamilton Depression Rating Scale reduction. ConclusionstVNS can significantly modulate the DMN FC of MDD patients; our results provide insights to elucidate the brain mechanism of tVNS treatment for MDD patients.

Low level tragus nerve stimulation is a non-invasive approach for anti-atrial fibrillation via preventing the loss of connexins

Atrial fibrillation (AF) is the most common cardiac arrhythmia, but the mechanism of AF maintenance remains unclear. It has been found that gap junctional remodeling (connexin expression is downregulated and distributed) is closely associated with AF maintenance [ [1] Van der Velden H.M. Ausma J. Rook M.B. Hellemons A.J. van Veen T.A. Allessie M.A. Jongsma H.J. Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat. Cardiovasc. Res. 2000; 46: 476-486 Crossref PubMed Scopus (214) Google Scholar ]. Autonomic nervous system stimulation can exert anti-arrhythmia effects [ 2 Thunsiri K. Shinlapawittayatorn K. Chinda K. Palee S. Surinkaew S. Chattipakorn S.C. KenKnight B.H. Chattipakorn N. Application of vagus nerve stimulation from the onset of ventricular fibrillation to post-shock period improves defibrillation efficacy. Int. J. Cardiol. 2014; 176: 1030-1032 Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar , 3 He B. Lu Z. He W. Huang B. Jiang H. Similar effects of vagus nerve stimulation and atrial ganglionated plexi stimulation on ventricular effective refractory period and action potential duration in canine. Int. J. Cardiol. 2013; 168: 5116-5118 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar ]. Recently, we reported that cervical low level vagal nerve stimulation (LL-VNS) could suppress AF induced high-frequency stimulation [ [4] Yu L. Scherlag B.J. Li S. Sheng X. Lu Z. Nakagawa H. Zhang Y. Jackman W.M. Lazzara R. Jiang H. Po S.S. Low-level vagosympathetic nerve stimulation inhibits atrial fibrillation inducibility: direct evidence by neural recordings from intrinsic cardiac ganglia. J. Cardiovasc. Electrophysiol. 2011; 22: 455-463 Crossref PubMed Scopus (104) Google Scholar ] and then we developed a non-invasive approach, low level tragus nerve stimulation (LL-TS), and found that it had the same effect on suppressing AF [ [5] Yu L. Scherlag B.J. Li S. Fan Y. Dyer J. Male S. Varma V. Sha Y. Stavrakis S. Po S.S. Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve: a noninvasive approach to treat the initial phase of atrial fibrillation. Heart Rhythm. 2013; 10: 428-435 Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar ]. However, whether LL-TS could regulate Cx40 and Cx43 to suppress AF remains unknown. We hypothesized that LL-TS exerted anti-atrial fibrillatory effect via the downregulation of atrial Cx40 and Cx43.

Application of vagus nerve stimulation from the onset of ventricular fibrillation to post-shock period improves defibrillation efficacy

Application of vagus nerve stimulation from the onset of ventricular fibrillation to post-shock period improves defibrillation efficacy

The Potential Role of Regional Anesthesia in Perioperative Anti-Inflammatory Treatments

We as regional anesthesiologists often use peripheral nerve blocks as a modality for intraoperative analgesia, but it is not well understood whether regional anesthesia can play a role beyond simple interruption of peripheral nerve conduction. Several published manuscripts in recent years on the potential non-analgesic applications of regional anesthesia encourage us to expand its role from intraoperative to the perioperative period. However, its clinical advantages are not fully disclosed and even its overall beneficial effect on patient outcome is still controversial (1). The role of inflammation in the development of neuropathic pain has been explained earlier (2), which implies the therapeutic effects of sympathetic block in the treatment of chronic neuropathic pain disorders such as complex regional pain syndrome. The novel finding is the correlation between inflammation and the development of acute pain which has been proposed in a recent animal study (3). Regional anesthesia can play its anti-inflammatory role by anti-sympathetic effects (4) as well as anti-inflammatory properties of administered local anesthetics (5). However, the contribution of anti-inflammatory effects to overall clinical effects of peripheral nerve block is not well understood. This needs to be clarified in more meticulous trials addressing drugs and possibly techniques with more differentiated mechanisms of action. If elucidated, it may turn our views from simple interruption of impulse conduction in peripheral nerves to the possible anti-inflammatory mechanisms. When reviewing the contribution of regional anesthesia to the postoperative pain and inflammation control, we should notice that ‘nerve block’ is just one side of the coin, while the other side, ‘nerve stimulation’ is even more interesting. Studies in recent years explain the role of vagus nerve stimulation (VNS) in the suppression of systemic inflammatory response known as ‘cholinergic anti-inflammatory pathway’ (6). It has been shown in animal studies that VNS reduces systemic levels of pro-inflammatory cytokines and Tumor Necrosis Factor (TNF) (7–9). This novel finding may have implications for postoperative period regarding the fact that uncontrolled inflammation plays an important role in the hyperglycemia, sepsis, shock and their consequent morbidity and mortality of critically ill patients. VNS is currently used for its therapeutic effects in refractory epilepsy (10) and depression (11), and may be used for the treatment of chronic heart failure (12), portal hypertension (13) and eating disorders (14) in the future. Today application of VNS requires implantation of a stimulating electrode surgically (15). This procedure is invasive and has its specific complications (16, 17), which reduces its overall clinical benefit in the perioperative setting. However, favorable anti-inflammatory effects of VNS as well as its new potential perioperative applications such as therapeutic profile in the traumatic brain injury (18, 19) necessitates the development of a more feasible and less invasive approach to the nerve. Regarding the evolution in ultrasound imaging technology, it is expectable to better visualize the branches of vagus nerve and make them available for regional anesthesiologist with minimally invasive approaches. If so, this will expand the field of regional anesthesia from operating room to intensive care units in the near future.

Neuromodulation

&lt;p&gt;This issue of &lt;cite&gt;Psychiatric Annals&lt;/cite&gt; considers the growing field of therapeutic neuromodulation most recently exemplified by vagus nerve stimulation (VNS) and transcranial magnetic stimulation (TMS) for major depression. In this context, Dr. Demitrack considers the role of these device-based therapies in an overall strategy to manage depression. Dr. Richelson explores the neurobiology related to their antidepressant effects. Dr. Sampson and colleagues then describe the clinical role of TMS for major depression, while Drs. Rado and Janicak review the application of VNS to treat more resistant depressive disorders.&lt;/p&gt; &lt;h4&gt;ABOUT THE GUEST EDITORS&lt;/h4&gt; &lt;p&gt;Philip Gregory Janicak, MD, is Professor of Psychiatry and Medical Director, Psychiatric Clinical Research Center, Rush University Medical Center, Chicago, IL.&lt;/p&gt; &lt;p&gt;In addition to his private practice, Dr. Janicak serves as a consultant for the VA Chicago Health Care System, West Side Division, Chicago, IL. He is also an member of the &lt;cite&gt;Psychiatric Annals&lt;/cite&gt; editoral board.&lt;/p&gt; &lt;p&gt;Dr. Janicak received his undergraduate degree from Loyola University of Chicago, and his medical degree from Loyola University of Chicago, Stritch School of Medicine. He completed his residency in Psychiatry at Foster G. McGaw Hospital, Maywood, IL. &lt;/p&gt; &lt;p&gt;Mark A. Demitrack, MD is Vice President and Chief Medical Officer of Neuronetics, in Malvern, PA. Dr. Demitrack has more than 20 years of experience in both academic and industry settings in clinical research of mood disorders and related conditions. &lt;/p&gt; &lt;p&gt;Prior to joining Neuronetics, Dr. Demitrack was Assistant Vice President for Global Medical Affairs in Neuroscience at Wyeth Pharmceuticals. Dr. Demitrack also served as Medical Director of the New Antidepressant Team at Lilly Research Laboratories, where he led the registration clinical development program for the novel antidepressant, duloxetine (Cymbalta). &lt;/p&gt; &lt;p&gt;Prior to his tenure in private industry, Dr. Demitrack was a faculty member of the Department of Psychiatry at the University of Michigan Medical School, where he was Director of the Michigan Eating Disorders Program and received federal grant funding in clinical research activities studying the neuroendocrinology of eating disorders, chronic fatigue syndrome and fibromyalgia. Dr. Demitrack received his undergraduate degree at Columbia University, and his medical degree from the Robert Wood Johnson Medical School in New Jersey. He pursued his residency training at the University of California-San Francisco and completed a research fellowship at the National Institute of Mental Health.&lt;/p&gt;