Physiological basis of obesity treatment by percutaneous vagus nerve stimulation

Wolf V., Kühnel A., Teckentrup V., Koenig J., Kroemer N.B.

Non-invasive brain stimulation techniques, such as transcutaneous auricular vagus nerve stimulation (taVNS), have considerable potential for clinical use. Beneficial effects of taVNS have been demonstrated on symptoms in patients with mental or neurological disorders as well as transdiagnostic dimensions, including mood and motivation. However, since taVNS research is still an emerging field, the underlying neurophysiological processes are not yet fully understood, and the replicability of findings on biomarkers of taVNS effects has been questioned. The objective of this analysis was to synthesize the current evidence concerning the effects of taVNS on vagally mediated heart rate variability (vmHRV), a candidate biomarker that has, so far, received most attention in the field. We performed a living Bayesian random effects meta-analysis. To keep the synthesis of evidence transparent and up to date as new studies are being published, we developed a Shiny web app that regularly incorporates new results and enables users to modify study selection criteria to evaluate the robustness of the inference across potential confounds. Our analysis focuses on 16 single-blind studies comparing taVNS versus sham in healthy participants. The meta-analysis provides strong evidence for the null hypothesis (g = 0.014, CIshortest = [-0.103, 0.132], BF01 = 24.678), indicating that acute taVNS does not alter vmHRV compared to sham. To conclude, there is no support for the hypothesis that vmHRV is a robust biomarker for acute taVNS. By increasing transparency and timeliness, the concept of living meta-analyses can lead to transformational benefits in emerging fields such as non-invasive brain stimulation.

Farmer A.D., Strzelczyk A., Finisguerra A., Gourine A.V., Gharabaghi A., Hasan A., Burger A.M., Jaramillo A.M., Mertens A., Majid A., Verkuil B., Badran B.W., Ventura-Bort C., Gaul C., Beste C., et. al.

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.

Yap J.Y., Keatch C., Lambert E., Woods W., Stoddart P.R., Kameneva T.

Several studies have illustrated that transcutaneous vagus nerve stimulation (tVNS) can elicit therapeutic effects that are similar to those produced by its invasive counterpart, vagus nerve stimulation (VNS). VNS is an FDA-approved therapy for the treatment of both depression and epilepsy, but is limited to the management of more severe, intervention-resistant cases as a second or third-line treatment option, due to perioperative risks involved with device implantation. In contrast, tVNS is a non-invasive technique that involves the application of electrical currents through surface electrodes at select locations, most commonly targeting the auricular branch of the vagus nerve (ABVN) and the cervical branch of the vagus nerve in the neck. Although it has been shown that tVNS elicits hypo- and hyper-activations in various regions of the brain associated with anxiety and mood regulation, the mechanism of action and influence of stimulation parameters on clinical outcomes remains predominantly hypothetical. Suppositions are largely based on correlations between the neurobiology of the vagus nerve and its effects on neural activity. However, tVNS has also been investigated for several other disorders, including tinnitus, migraine and pain, by targeting the vagus nerve at sites in both the ear and the neck. As most of the described methods differ in the parameters and protocols applied, there is currently no firm evidence on the optimal location for tVNS, or the stimulation parameters that provide the greatest therapeutic effects for a specific condition. This review presents the current status of tVNS with a focus on stimulation parameters, stimulation sites and available devices. For tVNS to reach its full potential as a non-invasive clinically-relevant therapy, it is imperative that systematic studies be undertaken to reveal the mechanism of action and optimal stimulation modalities.

Chang E.H., Chavan S.S., Pavlov V.A.

Obesity and obesity-associated disorders have become world-wide epidemics, substantially increasing the risk of debilitating morbidity and mortality. A characteristic feature of these disorders, which include the metabolic syndrome (MetS) and type 2 diabetes, is chronic low-grade inflammation stemming from metabolic and immune dysregulation. Inflammation in the CNS (neuroinflammation) and cognitive impairment have also been associated with obesity-driven disorders. The nervous system has a documented role in the regulation of metabolic homeostasis and immune function, and recent studies have indicated the important role of vagus nerve and brain cholinergic signaling in this context. In this review, we outline relevant aspects of this regulation with a specific focus on obesity-associated conditions. We outline accumulating preclinical evidence for the therapeutic efficacy of cholinergic stimulation in alleviating obesity-associated inflammation, neuroinflammation and metabolic derangements. Recently demonstrated beneficial effects of galantamine, a centrally-acting cholinergic drug and cognitive enhancer, in patients with MetS are also summarized. These studies provide a rationale for further therapeutic developments using pharmacological and bioelectronic cholinergic modulation for therapeutic benefit in obesity-associated disorders.

Johnson R.L., Wilson C.G.

In this review, we provide an overview of the US Food and Drug Administration (FDA)-approved clinical uses of vagus nerve stimulation (VNS) as well as information about the ongoing studies and preclinical research to expand the use of VNS to additional applications. VNS is currently FDA approved for therapeutic use in patients aged >12 years with drug-resistant epilepsy and depression. Recent studies of VNS in in vivo systems have shown that it has anti-inflammatory properties which has led to more preclinical research aimed at expanding VNS treatment across a wider range of inflammatory disorders. Although the signaling pathway and mechanism by which VNS affects inflammation remain unknown, VNS has shown promising results in treating chronic inflammatory disorders such as sepsis, lung injury, rheumatoid arthritis (RA), and diabetes. It is also being used to control pain in fibromyalgia and migraines. This new preclinical research shows that VNS bears the promise of being applied to a wider range of therapeutic applications.

Pavlov V.A., Chavan S.S., Tracey K.J.

The nervous system regulates immunity and inflammation. The molecular detection of pathogen fragments, cytokines, and other immune molecules by sensory neurons generates immunoregulatory responses through efferent autonomic neuron signaling. The functional organization of this neural control is based on principles of reflex regulation. Reflexes involving the vagus nerve and other nerves have been therapeutically explored in models of inflammatory and autoimmune conditions, and recently in clinical settings. The brain integrates neuro-immune communication, and brain function is altered in diseases characterized by peripheral immune dysregulation and inflammation. Here we review the anatomical and molecular basis of the neural interface with immunity, focusing on peripheral neural control of immune functions and the role of the brain in the model of the immunological homunculus. Clinical advances stemming from this knowledge within the framework of bioelectronic medicine are also briefly outlined.

Hoover D.B.

The nervous system and immune system have broad and overlapping distributions in the body, and interactions of these ubiquitous systems are central to the field of neuroimmunology. Over the past two decades, there has been explosive growth in our understanding of neuroanatomical, cellular, and molecular mechanisms that mediate central modulation of immune functions through the autonomic nervous system. A major catalyst for growth in this field was the discovery that vagal nerve stimulation (VNS) caused a prominent attenuation of the systemic inflammatory response evoked by endotoxin in experimental animals. This effect was mediated by acetylcholine (ACh) stimulation of nicotinic receptors on splenic macrophages. Hence, the circuit was dubbed the "cholinergic anti-inflammatory pathway". Subsequent work identified the α7 nicotinic ACh receptor (α7nAChR) as the crucial target for attenuation of pro-inflammatory cytokine release from macrophages and dendritic cells. Further investigation made the important discovery that cholinergic T cells within the spleen and not cholinergic nerve cells were the source of ACh that stimulated α7 receptors on splenic macrophages. Given the important role that inflammation plays in numerous disease processes, cholinergic anti-inflammatory mechanisms are under intensive investigation from a basic science perspective and in translational studies of animal models of diseases such as inflammatory bowel disease and rheumatoid arthritis. This basic work has already fostered several clinical trials examining the efficacy of VNS and cholinergic therapeutics in human inflammatory diseases. This review provides an overview of basic and translational aspects of the cholinergic anti-inflammatory response and relevant pharmacology of drugs acting at the α7nAChR.

Consolim-Colombo F.M., Sangaleti C.T., Costa F.O., Morais T.L., Lopes H.F., Motta J.M., Irigoyen M.C., Bortoloto L.A., Rochitte C.E., Harris Y.T., Satapathy S.K., Olofsson P.S., Akerman M., Chavan S.S., MacKay M., et. al.

Metabolic syndrome (MetS) is an obesity-driven condition of pandemic proportions that increases the risk of type 2 diabetes and cardiovascular disease. Pathophysiological mechanisms are poorly understood, though inflammation has been implicated in MetS pathogenesis. The aim of this study was to assess the effects of galantamine, a centrally acting acetylcholinesterase inhibitor with antiinflammatory properties, on markers of inflammation implicated in insulin resistance and cardiovascular risk, and other metabolic and cardiovascular indices in subjects with MetS.In this randomized, double-blind, placebo-controlled trial, subjects with MetS (30 per group) received oral galantamine 8 mg daily for 4 weeks, followed by 16 mg daily for 8 weeks or placebo. The primary outcome was inflammation assessed through plasma levels of cytokines and adipokines associated with MetS. Secondary endpoints included body weight, fat tissue depots, plasma glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), cholesterol (total, HDL, LDL), triglycerides, BP, heart rate, and heart rate variability (HRV).Galantamine resulted in lower plasma levels of proinflammatory molecules TNF (-2.57 pg/ml [95% CI -4.96 to -0.19]; P = 0.035) and leptin (-12.02 ng/ml [95% CI -17.71 to -6.33]; P < 0.0001), and higher levels of the antiinflammatory molecules adiponectin (2.71 μg/ml [95% CI 1.93 to 3.49]; P < 0.0001) and IL-10 (1.32 pg/ml, [95% CI 0.29 to 2.38]; P = 0.002) as compared with placebo. Galantamine also significantly lowered plasma insulin and HOMA-IR values, and altered HRV.Low-dose galantamine alleviates inflammation and insulin resistance in MetS subjects. These findings support further study of galantamine in MetS therapy.ClinicalTrials.gov, number NCT02283242.Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil, and the NIH.

Chavan S.S., Pavlov V.A., Tracey K.J.

Active research at the frontiers of immunology and neuroscience has identified multiple points of interaction and communication between the immune system and the nervous system. Immune cell activation stimulates neuronal circuits that regulate innate and adaptive immunity. Molecular mechanistic insights into the inflammatory reflex and other neuro-immune interactions have greatly advanced our understanding of immunity and identified new therapeutic possibilities in inflammatory and autoimmune diseases. Recent successful clinical trials using bioelectronic devices that modulate the inflammatory reflex to significantly ameliorate rheumatoid arthritis and inflammatory bowel disease provide a path for using electrons as a therapeutic modality for targeting molecular mechanisms of immunity. Here, we review mechanisms of peripheral sensory neuronal function in response to immune challenges, the neural regulation of immunity and inflammation, and the therapeutic implications of those mechanistic insights.

Malbert C., Picq C., Divoux J., Henry C., Horowitz M.

Acute vagal stimulation modifies glucose and insulin metabolism, but the effect of chronic bilateral vagal stimulation is not known. Our aim was to quantify the changes in whole-body and organ-specific insulin sensitivities 12 weeks after permanent, bilateral, vagal stimulation performed at the abdominal level in adult mini-pigs. In 15 adult mini-pigs, stimulating electrodes were placed around the dorsal and ventral vagi using laparoscopy and connected to a dual-channel stimulator placed subcutaneously. Animals were divided into three groups based on stimulation and body weight (i.e., lean nonstimulated, obese nonstimulated, and obese stimulated). Twelve weeks after surgery, glucose uptake and insulin sensitivity were measured using positron emission tomography during an isoglycemic clamp. Mean whole-body insulin sensitivity was lower by 34% (P &lt; 0.01) and the hepatic glucose uptake rate was lower by 33% (P &lt; 0.01) in obese-nonstimulated mini-pigs but was no different in obese-stimulated compared with lean mini-pigs. An improvement in skeletal glucose uptake rate was also observed in obese-stimulated compared with obese-nonstimulated groups (P &lt; 0.01). Vagal stimulation was associated with increased glucose metabolism in the cingulate and prefrontal brain areas. We conclude that chronic vagal stimulation improves insulin sensitivity substantially in diet-induced obesity by both peripheral and central mechanisms.

Samniang B., Shinlapawittayatorn K., Chunchai T., Pongkan W., Kumfu S., Chattipakorn S.C., KenKnight B.H., Chattipakorn N.

Long-term high-fat diet (HFD) consumption leads to not only obese-insulin resistance, but also impaired left ventricular (LV) function. Vagus nerve stimulation (VNS) has been shown to exert cardioprotection. However, its effects on the heart and metabolic parameters under obese-insulin resistant condition is not known. We determined the effects of VNS on metabolic parameters, heart rate variability (HRV) and LV function in obese-insulin resistant rats. Male Wistar rats were fed with HFD for 12 weeks and were randomly divided into sham and VNS groups. VNS was applied for the next 12 weeks. Echocardiography, blood pressure and HRV were examined. Blood samples were collected for metabolic parameters. At the end, the heart was removed for determination of apoptosis, inflammation, oxidative stress and cardiac mitochondrial function. VNS for 12 weeks significantly decreased plasma insulin, HOMA index, total cholesterol, triglyceride, LDL and visceral fat. Serum adiponectin was significantly increased in the VNS group. VNS also significantly decreased blood pressure, improved HRV and LV function, decreased cardiac MDA, TNF-α and Bax levels and improved cardiac mitochondrial function. VNS improves metabolic and hemodynamic parameters and the LV function via its ability against apoptosis, inflammation and oxidative stress and preserved cardiac mitochondrial function in obese-insulin resistant rats.

Li H., Zhang J., Xu C., Tang Q., Shen W., Zhou J., Chen J., Wang Y.

Obesity is a major public health problem. Regulating food intake and promoting metabolism of fat are two important options for treating obesity. Auricular vagus nerve stimulation (AVNS) is considered as an alternative approach to vagal nerve stimulation. The aim of this study was to investigate the effects of AVNS and its mechanisms on obesity in obese rats.Male Sprague-Dawley rats were fed either a high-fat diet (HFD) or a normal diet for 8 wk. Qualified HFD rats were randomly divided into three groups: the HFD group, the AVNS group, and the sham group for 6 wk treatment. Body weight and daily energy intake were recorded weekly. The rats were sacrificed for measurement of weight of bilateral perirenal, epididymal white adipose tissue (WAT), dorsal brown adipose tissue (BAT), and gastric emptying. Serum cholecystokinin (CCK), peptide YY3 to 36 (PYY3-36) and norepinephrine (NE) were assayed by enzyme-linked immunosorbent assay. Real-time quantitative polymerase chain reaction was used to assess the mRNA expressions of CCK subtype receptor a (CCKa) in the antrum, PYY3-36 receptor in the distal ileum, β3-adrenoceptor, and uncoupling protein gene 1 (UCP1) in the BAT.Compared with HFD group, AVNS significantly reduced body weight and epididymal WAT and increased BAT weight, serum NE, mRNA expressions of β3-adrenoceptors, and UCP1 of the BAT, but had no effect on daily energy intake, perirenal WAT weight, gastric emptying, serum levels of CCK and PYY, or mRNA expressions of CCKa receptor and PYY3-36 receptor in the relevant tissues. The sham group, as a comparison group for AVNS, saw less effect in any of the indexes compared with the HFD group. AVNS had more effect on weight loss, reduction of perirenal WAT, and increase of NE, β3-adrenoceptor, and UCP1 than sham.AVNS was more effective in reducing body weight and causing visceral fat loss. Biochemical tests found more NE released in the serum and more β3-adrenoceptor and UCP1 expression in the BAT. All of these features suggested that energy expenditure might play an important role in obesity management by AVNS.

Pavlov V.A., Tracey K.J.

Research during the last decade has significantly advanced our understanding of the molecular mechanisms at the interface between the nervous system and the immune system. Insight into bidirectional neuro-immune communication has characterized the nervous system as an important partner of the immune system in the regulation of inflammation. Neuronal pathways, including the vagus nerve-based inflammatory reflex, are physiological regulators of immune function and inflammation. In parallel, neuronal function is altered in conditions characterized by immune dysregulation and inflammation. Here, we review these regulatory mechanisms and describe the neural circuitry modulating immunity. Understanding these mechanisms reveals possibilities to use targeted neuromodulation as a therapeutic approach for inflammatory and autoimmune disorders. These findings and current clinical exploration of neuromodulation in the treatment of inflammatory diseases define the emerging field of Bioelectronic Medicine.

Yuan H., Silberstein S.D.

The development of vagus nerve stimulation (VNS) began in the 19th century. Although it did not work well initially, it introduced the idea that led to many VNS-related animal studies for seizure control. In the 1990s, with the success of several early clinical trials, VNS was approved for the treatment of refractory epilepsy, and later for the refractory depression. To date, several novel electrical stimulating devices are being developed. New invasive devices are designed to automate the seizure control and for use in heart failure. Non-invasive transcutaneous devices, which stimulate auricular VN or carotid VN, are also undergoing clinical trials for treatment of epilepsy, pain, headache, and others. Noninvasive VNS (nVNS) exhibits greater safety profiles and seems similarly effective to their invasive counterpart. In this review, we discuss the history and development of VNS, as well as recent progress in invasive and nVNS.

Duca F.A., Zhong L., Covasa M.

Deficits in satiation signaling during obesogenic feeding have been proposed to play a role in hyperphagia and weight gain in animals prone to become obese. However, whether this impaired signaling is due to high fat (HF) feeding or to their obese phenotype is still unknown. Therefore, in the current study, we examined the effects of CCK-8 (0.5, 1.0, 2.0, and 4.0 μg/kg) on suppression of food intake of HF-fed obese prone (OP) and resistant (OR) rats. Additionally, we determined the role of endogenous CCK in lipid-induced satiation by measuring plasma CCK levels following a lipid gavage, and tested the effect of pretreatment with devazepide, a CCK-1R antagonist on intragastric lipid-induced satiation. Finally, we examined CCK-1R mRNA levels in the nodose ganglia. We show that OP rats have reduced feeding responses to the low doses of exogenous CCK-8 compared to OR rats. Furthermore, OP rats exhibit deficits in endogenous CCK signaling, as pretreatment with devazepide failed to abolish the reduction in food intake following lipid gavage. These effects were associated with reduced plasma CCK after intragastric lipid in OP but not OR rats. Furthermore, HF feeding resulted in downregulation of CCK-1Rs in the nodose ganglia of OP rats. Collectively, these results demonstrate that HF feeding leads to impairments in lipid-induced CCK satiation signaling in obese-prone rats, potentially contributing to hyperphagia and weight gain.

Olga N. D., Rogozhkina E.A., Shvartz V.A., Shvartz E.N., Kiselev A.R., Drapkina O.M.

Objective –– to compare heart rate variability (HRV) in patients aged 30-60 years without chronic noncommunicable diseases (CNCDs) with and without obesity. Methods –– The groups of obese (n=43) and nonobese (n=28) patients without CNCDs ranged 30 through 60 years of age. We assessed the conventional HRV indices according to the clinical guidelines, as well as the synchronization index (S) for low-frequency (LF) oscillations evaluated from HRV and photoplethysmogram (PPG). Results –– No statistically significant differences in HRV indices and S index were detected between the study groups. Conclusion –– HRV indices and synchronization of LF oscillations detected from HRV and PPG were not significantly associated with obesity in patients aged 30-60 years without CNCDs.

Shvartz V., Sizhazhev E., Sokolskaya M., Koroleva S., Enginoev S., Kruchinova S., Shvartz E., Golukhova E.

Many previous studies have demonstrated that transcutaneous vagus nerve stimulation (VNS) has the potential to exhibit therapeutic effects similar to its invasive counterpart. An objective assessment of VNS requires a reliable biomarker of successful vagal activation. Although many potential biomarkers have been proposed, most studies have focused on heart rate variability (HRV). Despite the physiological rationale for HRV as a biomarker for assessing vagal stimulation, data on its effects on HRV are equivocal. To further advance this field, future studies investigating VNS should contain adequate methodological specifics that make it possible to compare the results between studies, to replicate studies, and to enhance the safety of study participants. This article describes the design and methodology of a randomized study evaluating the effect of short-term noninvasive stimulation of the auricular branch of the vagus nerve on parameters of HRV. Primary records of rhythmograms of all the subjects, as well as a dataset with clinical, instrumental, and laboratory data of all the current study subjects are in the public domain for possible secondary analysis to all interested researchers. The physiological interpretation of the obtained data is not considered in the article.