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Han HJ, Kim H, Kim DJ. Systematic review for VNS vs. pharmaceutical modulations for multifaceted neurological disorder management through cross-case, network meta-analysis. Brain Stimul 2025; 18:909-936. [PMID: 40220956 DOI: 10.1016/j.brs.2025.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 03/19/2025] [Accepted: 04/07/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND As an adjunct or alternative to conventional pharmacotherapy, vagus nerve stimulation (VNS) which is FDA-approved has arisen as a novel means for various neurological disorders. METHOD We searched multiple databases (through 2024) for randomised trials and observational studies of VNS (invasive and transcutaneous) and pharmacological treatments (e.g. cholinergic agents, antiepileptics, antidepressants) across several neurological disorders. Prior to comparing between VNS and pharmacological treatments, subgroup analyses of VNS studies were performed for disorder type, patient demographics, VNS stimulation parameters, and treatment duration to illustrate whether VNS itself can be effective to a satisfactory extent to be compared against the conventional method. Efficacy and adverse effects were evaluated, based on the proportion of patients achieving more than 50 % symptom reduction or equivalent clinical improvement, or all-cause mortality where applicable. Evaluation between VNS and pharmacological treatments was performed through network meta-analysis, followed by assessment of heterogeneity (I2) and meta-regression. Risk of bias was evaluated with Cochrane criteria, and all studies (including those with high risk of bias) were included in the primary analysis (with sensitivity analyses excluding high-bias studies). RESULTS We included 56 VNS-related studies (n = 5773 participants) and 29 pharmacological drug-based studies (n = 14827 participants) from spanning epilepsy, depression, migraine/headache, Alzheimer's disease, inflammatory disorders, and heart failure. A network meta-analysis directly comparing VNS to pharmacological drugs yielded an overall advantage for VNS (summary SMD = 0.27 favouring VNS, 95 % CI 0.19-0.35). However, the high heterogeneity and risk of bias have been assessed, indicating potential issues with the VNS studies. CONCLUSION Overall, VNS was shown to be a viable therapeutic modality across diverse neurological disorders, superior to standard pharmacological treatments with a distinct adverse effect profile. It appears particularly beneficial in conditions where conventional drugs have limited success (e.g. refractory epilepsy, depression), although patient-specific factors influence outcomes. Further high-quality trials are anticipated to optimise stimulation parameters, confirm long-term benefits, and manage patient selection for VNS.
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Affiliation(s)
- Hyun-Jee Han
- Department of Pharmacology, University of Cambridge, UK
| | - Hakseung Kim
- Department of Brain and Cognitive Engineering, Korea University, Seoul, South Korea
| | - Dong-Joo Kim
- Department of Brain and Cognitive Engineering, Korea University, Seoul, South Korea; Department of Neurology, Korea University College of Medicine, Seoul, South Korea.
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Muniyandi M, Chelvanayagam K, Salam SA, Vadamalai S, Rajsekar K, Ramachandran R. Significant reduction of seizure frequency in patients with drug-resistant epilepsy by vagus nerve stimulation: Systematic review and meta-analysis. Epilepsy Res 2025; 210:107510. [PMID: 39809131 DOI: 10.1016/j.eplepsyres.2025.107510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 10/01/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025]
Abstract
BACKGROUND Epilepsy is a major neurological disorder, typically managed with Anti-Seizure Medication (ASM). Nevertheless, a substantial 30 % of patients did not respond satisfactorily to ASMs, classifying their condition as Drug-Resistant Epilepsy (DRE). Vagus Nerve Stimulation (VNS) was recommended as a potential solution. OBJECTIVE To evaluate clinical efficacy of VNS on patients with DRE in reduction of seizures through a systematic review and meta-analysis using a random effects model. METHODS A systematic search was done from PubMed, ScienceDirect, Cochrane Library and Google Scholar databases on observational studies and randomized controlled trials (RCTs) for the clinical effectiveness of VNS among DRE patients. A meta-analysis was performed to obtain the pooled estimate of the clinical effectiveness of VNS in terms of seizure reduction and the odds ratio (OR) for patients achieving > 50 % seizure reduction. Heterogeneity was assessed using visual inspection of forest plots and I2 statistic. RESULTS A total of 1023 articles were retrieved from the electronic search. After removing duplicates, non-relevance and non-availability of efficacy data, 28 articles were included in the final analysis. Of these, 9 are RCTs and 19 are observational studies. The pooled estimate of > 50 % seizure reduction was 0.46 (95 % CI: 0.40-0.51) and the pooled estimate of the OR comparing > 50 % vs ≤ 50 % seizure reduction was 0.76 (95 % CI: 0.44-1.29). CONCLUSION Our meta-analysis showed that 46 % of DRE patients have experienced ≥ 50 % seizure reduction with VNS treatment. It should be considered in patients in whom ASM has failed or who continue to experience seizures after medication.
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Affiliation(s)
| | | | - Sahil Abdul Salam
- ICMR-National Institute for Research in Tuberculosis, Chennai, India
| | | | - Kavitha Rajsekar
- Department of Health Research, Ministry of Health and Family Welfare, New Delhi, India
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Rice LJ, Agu J, Carter CS, Cho YH, Harris J, Heilman K, Nazarloo HP, Naanai H, Porges S, Einfeld SL. The relationship between cardiac activity, behaviour and endogenous oxytocin and vasopressin in Prader-Willi Syndrome: An exploratory study. Int J Psychophysiol 2024; 205:112429. [PMID: 39237036 DOI: 10.1016/j.ijpsycho.2024.112429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 08/26/2024] [Accepted: 09/02/2024] [Indexed: 09/07/2024]
Abstract
This study aimed to increase our understanding of cardiac activity abnormalities in Prader-Willi Syndrome (PWS) and the relationship between cardiac activity, PWS behaviours thought to be associated with cardiac vagal tone and endogenous oxytocin and vasopressin levels. We compared cardiac activity (respiratory sinus arrhythmia (RSA), low-frequency heart rate variability (LF-HRV), heart period) in 30 adolescents and adults with PWS to 30 typically developing age-matched controls. RSA, LF-HRV, and heart period were lower in individuals with PWS than in the control group. In the control group, RSA was higher for females than males. However, for those with PWS, there was no difference between the sexes. Individuals with the mUPD genetic subtype had lower RSA and LF-HRV than participants with the PWS deletion subtype and compared to typically developing controls, no difference was found between the latter two groups. Heart period was also lower for those with mUPD compared to controls. Higher RSA reduced the odds of having temper outbursts and skin-picking. RSA was lower in those with PWS and psychosis compared to those with PWS without psychosis. Finally, we found RSA correlated with vasopressin for those with mUPD but not deletion. There was no relationship between RSA and oxytocin plasma or saliva levels. Our findings suggest autonomic dysfunction in PWS that is more marked in mUPD than deletion and potentially due to greater loss of parasympathetic activity in mUPD.
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Affiliation(s)
- Lauren J Rice
- Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, New South Wales, Australia; Faculty of Medicine and Health, Specialty of Child and Adolescent Health, The University of Sydney Children's Hospital Westmead Clinical School, Westmead, New South Wales, Australia.
| | - Josephine Agu
- Faculty of Medicine and Health, Specialty of Child and Adolescent Health, The University of Sydney Children's Hospital Westmead Clinical School, Westmead, New South Wales, Australia
| | - C Sue Carter
- Department of Psychology, University of Virginia; Kinsey Institute, Indiana University, Bloomington, IN, USA
| | - Yoon Hi Cho
- Faculty of Medicine and Health, Specialty of Child and Adolescent Health, The University of Sydney Children's Hospital Westmead Clinical School, Westmead, New South Wales, Australia; Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
| | - James Harris
- Department of Psychiatry and Behavioural Sciences and Paediatrics, Johns Hopkins University, Baltimore, MD, USA
| | - Keri Heilman
- Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA
| | | | - Habiba Naanai
- Faculty of Medicine and Health, Specialty of Child and Adolescent Health, The University of Sydney Children's Hospital Westmead Clinical School, Westmead, New South Wales, Australia
| | - Stephen Porges
- Kinsey Institute, Indiana University, Bloomington, IN, USA; Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA
| | - Stewart L Einfeld
- Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, New South Wales, Australia
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Xue R, Wu Q, Guo L, Ye D, Cao Q, Zhang M, Xian Y, Chen M, Yan K, Zheng J. Pyridostigmine attenuated high-fat-diet induced liver injury by the reduction of mitochondrial damage and oxidative stress via α7nAChR and M3AChR. J Biochem Mol Toxicol 2024; 38:e23671. [PMID: 38454809 DOI: 10.1002/jbt.23671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 01/18/2024] [Accepted: 02/23/2024] [Indexed: 03/09/2024]
Abstract
Obesity is a major cause of nonalcohol fatty liver disease (NAFLD), which is characterized by hepatic fibrosis, lipotoxicity, inflammation, and apoptosis. Previous studies have shown that an imbalance in the autonomic nervous system is closely related to the pathogenesis of NAFLD. In this study, we investigated the effects of pyridostigmine (PYR), a cholinesterase (AChE) inhibitor, on HFD-induced liver injury and explored the potential mechanisms involving mitochondrial damage and oxidative stress. A murine model of HFD-induced obesity was established using the C57BL/6 mice, and PYR (3 mg/kg/d) or placebo was administered for 20 weeks. PYR reduced the body weight and liver weight of the HFD-fed mice. Additionally, the serum levels of IL-6, TNF-α, cholesterol, and triglyceride were significantly lower in the PYR-treated versus the untreated mice, corresponding to a decrease in hepatic fibrosis, lipid accumulation, and apoptosis in the former. Furthermore, the mitochondrial morphology improved significantly in the PYR-treated group. Consistently, PYR upregulated ATP production and the mRNA level of the mitochondrial dynamic factors OPA1, Drp1 and Fis1, and the mitochondrial unfolded protein response (UPRmt) factors LONP1 and HSP60. Moreover, PYR treatment activated the Keap1/Nrf2 pathway and upregulated HO-1 and NQO-1, which mitigated oxidative injury as indicated by decreased 8-OHDG, MDA and H2 O2 levels, and increased SOD activity. Finally, PYR elevated acetylcholine (ACh) levels by inhibiting AChE, and upregulated the α7nAChR and M3AChR proteins in the HFD-fed mice. PYR alleviated obesity-induced hepatic injury in mice by mitigating mitochondrial damage and oxidative stress via α7nAChR and M3AChR.
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Affiliation(s)
- Runqing Xue
- Department of Pharmacy, The Affiliated Hospital of Northwest University, Xi'an, China
| | - Qing Wu
- Department of Pharmacy, The Affiliated Hospital of Northwest University, Xi'an, China
| | - Lulu Guo
- Department of Pharmacy, The Affiliated Hospital of Northwest University, Xi'an, China
- The College of Life Sciences, Northwest University, Xi'an, China
| | - Dan Ye
- Department of Pharmacy, The Affiliated Hospital of Northwest University, Xi'an, China
| | - Qing Cao
- Department of Pharmacy, The Affiliated Hospital of Northwest University, Xi'an, China
| | - Meng Zhang
- Department of Pharmacy, The Affiliated Hospital of Northwest University, Xi'an, China
| | - Yushan Xian
- Department of Pharmacy, The Affiliated Hospital of Northwest University, Xi'an, China
| | - Minchun Chen
- Department of Pharmacy, The Affiliated Hospital of Northwest University, Xi'an, China
| | - Kangkang Yan
- Department of Pharmacy, The Affiliated Hospital of Northwest University, Xi'an, China
| | - Jie Zheng
- Department of Pharmacy, The Affiliated Hospital of Northwest University, Xi'an, China
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Leinen M, Grandy EF, Gebel LMU, Santana TM, Rodriguez AL, Singh SK, Fernandez MI, Dalugdug JC, Garcia-Colon EM, Lybeshari K, Alexander DR, Maura MI, Gonzalez MDC, De Paula Cunha Almeida C, Anyaso-Samuel S, Datta S, Schiefer MA. Bilateral Subdiaphragmatic Vagal Nerve Stimulation Using a Novel Waveform Decreases Body Weight, Food Consumption, Adiposity, and Activity in Obesity-Prone Rats. Obes Surg 2024; 34:1-14. [PMID: 38040984 PMCID: PMC10781827 DOI: 10.1007/s11695-023-06957-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 11/05/2023] [Accepted: 11/13/2023] [Indexed: 12/03/2023]
Abstract
INTRODUCTION Obesity affects millions of Americans. The vagal nerves convey the degree of stomach fullness to the brain via afferent visceral fibers. Studies have found that vagal nerve stimulation (VNS) promotes reduced food intake, causes weight loss, and reduces cravings and appetite. METHODS Here, we evaluate the efficacy of a novel stimulus waveform applied bilaterally to the subdiaphragmatic vagal nerve stimulation (sVNS) for almost 13 weeks. A stimulating cuff electrode was implanted in obesity-prone Sprague Dawley rats maintained on a high-fat diet. Body weight, food consumption, and daily movement were tracked over time and compared against three control groups: sham rats on a high-fat diet that were implanted with non-operational cuffs, rats on a high-fat diet that were not implanted, and rats on a standard diet that were not implanted. RESULTS Results showed that rats on a high-fat diet that received sVNS attained a similar weight to rats on a standard diet due primarily to a reduction in daily caloric intake. Rats on a high-fat diet that received sVNS had significantly less body fat than other high-fat controls. Rats receiving sVNS also began moving a similar amount to rats on the standard diet. CONCLUSION Results from this study suggest that bilateral subdiaphragmatic vagal nerve stimulation can alter the rate of growth of rats maintained on a high-fat diet through a reduction in daily caloric intake, returning their body weight to that which is similar to rats on a standard diet over approximately 13 weeks.
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Affiliation(s)
- Monique Leinen
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Rd, Gainesville, FL, 32608, USA
| | - Elise F Grandy
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Rd, Gainesville, FL, 32608, USA
| | - Lourdes M Ubeira Gebel
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Rd, Gainesville, FL, 32608, USA
| | - Tahimi Machin Santana
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Rd, Gainesville, FL, 32608, USA
| | - Amanda L Rodriguez
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Rd, Gainesville, FL, 32608, USA
| | - Sundip K Singh
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Rd, Gainesville, FL, 32608, USA
| | - Michael I Fernandez
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Rd, Gainesville, FL, 32608, USA
| | - Justin C Dalugdug
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Rd, Gainesville, FL, 32608, USA
| | - Elaine M Garcia-Colon
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Rd, Gainesville, FL, 32608, USA
| | - Kamela Lybeshari
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Rd, Gainesville, FL, 32608, USA
| | - Daniel R Alexander
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Rd, Gainesville, FL, 32608, USA
| | - Maria I Maura
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Rd, Gainesville, FL, 32608, USA
| | - Maria D Cabrera Gonzalez
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Rd, Gainesville, FL, 32608, USA
| | | | - Samuel Anyaso-Samuel
- Department of Biostatistics, University of Florida, 2004 Mowry Rd, 5Th Fl, Gainesville, FL, 32603, USA
| | - Somnath Datta
- Department of Biostatistics, University of Florida, 2004 Mowry Rd, 5Th Fl, Gainesville, FL, 32603, USA
| | - Matthew A Schiefer
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, 1601 SW Archer Rd, Gainesville, FL, 32608, USA.
- Department of Biomedical Engineering, University of Florida, 1275 Center Dr, Gainesville, FL, 32611, USA.
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Batson S, Shankar R, Conry J, Boggs J, Radtke R, Mitchell S, Barion F, Murphy J, Danielson V. Efficacy and safety of VNS therapy or continued medication management for treatment of adults with drug-resistant epilepsy: systematic review and meta-analysis. J Neurol 2022; 269:2874-2891. [PMID: 35034187 PMCID: PMC9119900 DOI: 10.1007/s00415-022-10967-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/05/2022] [Accepted: 01/06/2022] [Indexed: 11/30/2022]
Abstract
Vagus nerve stimulation (VNS) Therapy® is an adjunctive neurostimulation treatment for people with drug-resistant epilepsy (DRE) who are unwilling to undergo resective surgery, have had unsuccessful surgery or are unsuitable for surgery. A systematic review and meta-analysis were conducted to determine the treatment effects of VNS Therapy as an adjunct to anti-seizure medications (ASMs) for the management of adults with DRE. A literature search was performed in August 2020 of the Medline®, Medline® Epub Ahead of Print, Embase, and the Cochrane library databases. Outcomes examined included reduction in seizure frequency, seizure freedom, ASM load, discontinuations, and serious adverse events (SAEs). Comparators included best medical practice, ASMs, low-stimulation or sham VNS Therapy. Four RCTs and six comparative observational studies were identified for inclusion. Against comparators, individuals treated with VNS had a significantly better odds of experiencing a ≥ 50% reduction in seizure frequency (OR: 2.27 [95% CI 1.47, 3.51]; p = 0.0002), a ≥ 75% reduction in seizure frequency (OR: 3.56 [95% CI 1.59, 7.98]; p = 0.002) and a reduced risk for increased ASM load (risk ratio: 0.36 [95% CI 0.21, 0.62]; p = 0.0002). There was no difference in the odds of discontinuation or the rate of SAEs between VNS versus comparators. This meta-analysis demonstrated the benefits of VNS Therapy in people with DRE, which included improvement in seizure frequency without an increase in the rate of SAEs or discontinuations, thereby supporting the consideration of VNS Therapy for people who are not responding to ASMs and those unsuitable or unwilling to undergo surgery.
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Affiliation(s)
- Sarah Batson
- Sarah Batson, Mtech Access Limited, 30 Murdock Road, Bicester, OX26 4PP, Oxfordshire, England.
| | - Rohit Shankar
- Neuropsychiatry, Peninsula School of Medicine, University of Plymouth, Plymouth, England
| | - Joan Conry
- Children's National, Washington, District of Columbia, USA
| | - Jane Boggs
- Wake Forest Baptist Health, Winston-Salem, NC, USA
| | | | - Stephen Mitchell
- Sarah Batson, Mtech Access Limited, 30 Murdock Road, Bicester, OX26 4PP, Oxfordshire, England
| | - Francesca Barion
- Pricing, Health Economics, Market Access and Reimbursement (PHEMAR), LivaNova, London, England
| | - Joanna Murphy
- Pricing, Health Economics, Market Access and Reimbursement (PHEMAR), LivaNova, London, England
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Mao H, Chen Y, Ge Q, Ye L, Cheng H. Short- and Long-Term Response of Vagus Nerve Stimulation Therapy in Drug-Resistant Epilepsy: A Systematic Review and Meta-Analysis. Neuromodulation 2021; 25:327-342. [PMID: 35396068 DOI: 10.1111/ner.13509] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 06/22/2021] [Accepted: 06/29/2021] [Indexed: 01/24/2023]
Abstract
OBJECTIVES To compare the short- and long-term efficacies as well as tolerability of vagus nerve stimulation (VNS) for the patients with drug-resistant epilepsy (DRE) in comparison with status at baseline. MATERIALS AND METHODS We conducted a specific and systematic search in online data bases for relevant literature published prior to December 2020. The literature retrieved, including randomized clinical trials (RCTs) and observational studies, were then reviewed, and analyzed. A fixed-effect model was used to evaluate the pooled odds ratio (OR) of responder rates and complications associated with RCTs. A random-effect model was used to generate overall responder rates and overall incidences of complication. RESULTS A total of 61 studies, featuring 5223 patients, were included in our study. The pooled ORs of responder rates, hoarseness/voice change, throat pain, coughing, dyspnea, paresthesia, muscle pain, and headache during the short-term phase were 2.195 (p = 0.001), 5.527 (p = 0.0001), 0.935 (p = 0.883), 1.119 (p = 0.655), 2.901 (p = 0.005), 1.775 (p = 0.061), 3.606 (p = 0.123), and 0.928 (p = 0.806), respectively. The overall responder rates in 3, 6, 12, 24, 36, 48, and 60 months postoperatively were 0.421, 0.455, 0.401, 0.451, 0.482, 0.502, and 0.508, respectively. The overall incidences of complication were 0.274 for hoarseness/voice change, 0.099 for throat pain, 0.133 for coughing, 0.099 for dyspnea, 0.102 for paresthesia, 0.062 for muscle pain, 0.101 for headache, 0.015 for dysphagia, 0.013 for neck pain, 0.040 for infection, 0.030 for lead fracture, 0.019 for vocal cord palsy, and 0.020 for device malfunction, respectively. CONCLUSIONS The estimating of efficacy and tolerability, using data from the existing literature, indicated VNS therapy is a safe and effective treatment option for patients with DRE.
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Affiliation(s)
- Hongliang Mao
- Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Yonghao Chen
- First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Qintao Ge
- First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Lei Ye
- Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hongwei Cheng
- Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Marras CE, Colicchio G, De Palma L, De Benedictis A, Di Gennaro G, Cavaliere M, Cesaroni E, Consales A, Asioli S, Caulo M, Villani F, Zamponi N. Health Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant Epilepsy. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:E6150. [PMID: 32847092 PMCID: PMC7504285 DOI: 10.3390/ijerph17176150] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 07/31/2020] [Accepted: 08/13/2020] [Indexed: 01/12/2023]
Abstract
Background: Vagus nerve stimulation (VNS) is a palliative treatment for medical intractable epileptic syndromes not eligible for resective surgery. Health technology assessment (HTA) represents a modern approach to the analysis of technologies used for healthcare. The purpose of this study is to assess the clinical, organizational, financial, and economic impact of VNS therapy in drug-resistant epilepsies and to establish the congruity between costs incurred and health service reimbursement. Methods: The present study used an HTA approach. It is based on an extensive detailed bibliographic search on databases (Medline, Pubmed, Embase and Cochrane, sites of scientific societies and institutional sites). The HTA study includes the following issues: (a) social impact and costs of the disease; (b) VNS eligibility and clinical results; (c) quality of life (QoL) after VNS therapy; (d) economic impact and productivity regained after VNS; and (e) costs of VNS. Results: Literature data indicate VNS as an effective treatment with a potential positive impact on social aspects and on quality of life. The diagnosis-related group (DRG) financing, both on national and regional levels, does not cover the cost of the medical device. There was an evident insufficient coverage of the DRG compared to the full cost of implanting the device. Conclusions: VNS is a palliative treatment for reducing seizure frequency and intensity. Despite its economic cost, VNS should improve patients' quality of life and reduce care needs.
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Affiliation(s)
- Carlo Efisio Marras
- Neurosurgery Unit, Department of Neuroscience, IRCCS Bambino Gesù Children Hospital, 00165 Rome, Italy; (A.D.B.); (M.C.)
| | - Gabriella Colicchio
- Department of Neurosurgery, UCSC Gemelli University Hospital, 00167 Rome, Italy;
| | - Luca De Palma
- Pediatric Neurology Unit, Department of Neuroscience, IRCCS Bambino Gesù Children Hospital, 00165 Rome, Italy;
| | - Alessandro De Benedictis
- Neurosurgery Unit, Department of Neuroscience, IRCCS Bambino Gesù Children Hospital, 00165 Rome, Italy; (A.D.B.); (M.C.)
| | | | - Marilou Cavaliere
- Neurosurgery Unit, Department of Neuroscience, IRCCS Bambino Gesù Children Hospital, 00165 Rome, Italy; (A.D.B.); (M.C.)
- Institute of Neurosurgery, University of Milan Bicocca, 20900 Milan, Italy
| | - Elisabetta Cesaroni
- Pediatric Neurology Unit, Salesi Children Hospital, 60123 Ancona, Italy; (E.C.); (N.Z.)
| | | | - Sofia Asioli
- Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, Bellaria Hospital, University of Bologna, 40139 Bologna, Italy;
| | - Massimo Caulo
- Department of Neuroscience, Imaging and Clinical Sciences, University of Chieti, 66100 Chieti, Italy;
| | - Flavio Villani
- Division of Clinical Neurophysiology and Epilepsy Center, IRCCS, San Martino Hospital, 16132 Genoa, Italy;
| | - Nelia Zamponi
- Pediatric Neurology Unit, Salesi Children Hospital, 60123 Ancona, Italy; (E.C.); (N.Z.)
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Obst MA, Heldmann M, Alicart H, Tittgemeyer M, Münte TF. Effect of Short-Term Transcutaneous Vagus Nerve Stimulation (tVNS) on Brain Processing of Food Cues: An Electrophysiological Study. Front Hum Neurosci 2020; 14:206. [PMID: 32625072 PMCID: PMC7314996 DOI: 10.3389/fnhum.2020.00206] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 05/07/2020] [Indexed: 12/20/2022] Open
Abstract
Background: The vagus nerve plays an important role in the regulation of food intake. Modulating vagal activity via electrical stimulation (VNS) in patients and animal studies caused changes in food intake, energy metabolism, and body weight. However, the moderating impact of cognitive processes on VNS effects on eating behavior has not been investigated so far. Hypothesis: We hypothesized that transcutaneous VNS (tVNS) affects food intake by altering cognitive functions relevant to the processing of food-related information. Methods: Using a repeated-measurement design, we applied tVNS and a sham stimulation for 2 h on two different days in normal-weight subjects. We recorded standard scalp EEG while subjects watched food and object pictures presented in an oddball task. We analyzed the event-related potentials (ERPs) P1, P2, N2, and LPP and also examined the amount of consumed food and eating duration in a free-choice test meal. Results: Significant differences between stimulations were observed for the P1, P2, and N2 amplitudes. However, we found no tVNS-dependent modulation of food intake nor a specific food-related stimulation effect on the ERPs. Further analyses revealed a negative relationship between P2 amplitude and food intake for the sham stimulation. Significant effects are additionally confirmed by Bayesian statistics. Conclusion: Our study demonstrates tVNS’ impact on visual processing. Since the effects were similar between food and object stimuli, a general effect on visual perceptual processing can be assumed. More detailed investigations of these effects and their relationship with food intake and metabolism seem reasonable for future studies.
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Affiliation(s)
- Martina A Obst
- Department of Neurology, University of Lübeck, Lübeck, Germany
| | - Marcus Heldmann
- Department of Neurology, University of Lübeck, Lübeck, Germany.,Institute of Psychology II, University of Lübeck, Lübeck, Germany
| | - Helena Alicart
- Cognition and Brain Plasticity Group, University of Barcelona, Barcelona, Spain
| | - Marc Tittgemeyer
- Max-Planck-Institute for Metabolism Research, Cologne, Germany.,Cluster of Excellence in Cellular Aging and Aging-Associated Diseases (CECAD), Cologne, Germany
| | - Thomas F Münte
- Department of Neurology, University of Lübeck, Lübeck, Germany.,Institute of Psychology II, University of Lübeck, Lübeck, Germany
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10
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Pelot NA, Grill WM. Effects of vagal neuromodulation on feeding behavior. Brain Res 2018; 1693:180-187. [PMID: 29425906 PMCID: PMC6003853 DOI: 10.1016/j.brainres.2018.02.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 01/23/2018] [Accepted: 02/01/2018] [Indexed: 02/06/2023]
Abstract
Implanted vagus nerve stimulation (VNS) for obesity was recently approved by the FDA. However, its efficacy and mechanisms of action remain unclear. Herein, we synthesize clinical and preclinical effects of VNS on feeding behavior and energy balance and discuss engineering considerations for understanding and improving the therapy. Clinical cervical VNS (≤30 Hz) to treat epilepsy or depression has produced mixed effects on weight loss as a side effect, albeit in uncontrolled, retrospective studies. Conversely, preclinical studies (cervical and subdiaphragmatic VNS) mostly report decreased food intake and either decreased weight gain or weight loss. More recent clinical studies report weight loss in response to kilohertz frequency VNS applied to the subdiaphragmatic vagi, albeit with a large placebo effect. Rather than eliciting neural activity, this therapy putatively blocks conduction in the vagus nerves. Overall, stimulation parameters lack systematic exploration, optimization, and justification based on target nerve fibers and therapeutic outcomes. The vagus nerve transduces, transmits, and integrates important neural (efferent and afferent), humoral, energetic, and inflammatory information between the gut and brain. Thus, improved understanding of the biophysics, electrophysiology, and (patho)physiology has the potential to advance VNS as an effective therapy for a wide range of diseases.
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Affiliation(s)
- Nicole A Pelot
- Department of Biomedical Engineering, Duke University, Room 1427, Fitzpatrick CIEMAS, 101 Science Drive, Campus Box 90281, Durham, NC, USA
| | - Warren M Grill
- Department of Biomedical Engineering, Duke University, Room 1427, Fitzpatrick CIEMAS, 101 Science Drive, Campus Box 90281, Durham, NC, USA; Department of Electrical and Computer Engineering, Duke University, Room 130, Hudson Hall, Campus Box 90291, Durham, NC, USA; Department of Neurobiology, Duke University, Room 101B, Bryan Research Building, 311 Research Drive, Campus Box 3209, Durham, NC, USA; Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA.
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11
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Lu Y, Wu Q, Liu LZ, Yu XJ, Liu JJ, Li MX, Zang WJ. Pyridostigmine protects against cardiomyopathy associated with adipose tissue browning and improvement of vagal activity in high-fat diet rats. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1037-1050. [PMID: 29309922 DOI: 10.1016/j.bbadis.2018.01.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 12/22/2017] [Accepted: 01/04/2018] [Indexed: 01/07/2023]
Abstract
Obesity, a major contributor to the development of cardiovascular diseases, is associated with an autonomic imbalance characterized by sympathetic hyperactivity and diminished vagal activity. Vagal activation plays important roles in weight loss and improvement of cardiac function. Pyridostigmine is a reversible acetylcholinesterase inhibitor, but whether it ameliorates cardiac lipid accumulation and cardiac remodeling in rats fed a high-fat diet has not been determined. This study investigated the effects of pyridostigmine on high-fat diet-induced cardiac dysfunction and explored the potential mechanisms. Rats were fed a normal or high-fat diet and treated with pyridostigmine. Vagal discharge was evaluated using the BL-420S system, and cardiac function by echocardiograms. Lipid deposition and cardiac remodeling were determined histologically. Lipid utility was assessed by qPCR. A high-fat diet led to a significant reduction in vagal discharge and lipid utility and a marked increase in lipid accumulation, cardiac remodeling, and cardiac dysfunction. Pyridostigmine improved vagal activity and lipid metabolism disorder and cardiac remodeling, accompanied by an improvement of cardiac function in high-fat diet-fed rats. An increase in the browning of white adipose tissue in pyridostigmine-treated rats was also observed and linked to the expression of UCP-1 and CIDEA. Additionally, pyridostigmine facilitated activation of brown adipose tissue via activation of the SIRT-1/AMPK/PGC-1α pathway. In conclusion, a high-fat diet resulted in cardiac lipid accumulation, cardiac remodeling, and a significant decrease in vagal discharge. Pyridostigmine ameliorated cardiomyopathy, an effect related to reduced cardiac lipid accumulation, and facilitated the browning of white adipose tissue while activating brown adipose tissue.
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Affiliation(s)
- Yi Lu
- Department of Pharmacology, School of Basic Medical Sciences, Xian Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, People's Republic of China
| | - Qing Wu
- Department of Pharmacology, School of Basic Medical Sciences, Xian Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, People's Republic of China
| | - Long-Zhu Liu
- Department of Pharmacology, School of Basic Medical Sciences, Xian Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, People's Republic of China
| | - Xiao-Jiang Yu
- Department of Pharmacology, School of Basic Medical Sciences, Xian Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, People's Republic of China
| | - Jin-Jun Liu
- Department of Pharmacology, School of Basic Medical Sciences, Xian Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, People's Republic of China
| | - Man-Xiang Li
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Medical Collage, Xian Jiaotong University, Xi'an 710061, Shaanxi, People's Republic of China
| | - Wei-Jin Zang
- Department of Pharmacology, School of Basic Medical Sciences, Xian Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, People's Republic of China.
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12
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Khan FA, Poongkunran M, Buratto B. Desensitization of stimulation-induced weight loss: A secondary finding in a patient with vagal nerve stimulator for drug-resistant epilepsy. EPILEPSY & BEHAVIOR CASE REPORTS 2017; 8:51-54. [PMID: 28879091 PMCID: PMC5577401 DOI: 10.1016/j.ebcr.2017.07.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 07/01/2017] [Accepted: 07/13/2017] [Indexed: 02/07/2023]
Affiliation(s)
- Fawad A Khan
- The International Center for Epilepsy at Ochsner, Ochsner Neuroscience Institute, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, United States.,The University of Queensland School of Medicine, Ochsner Clinical School, 1514 Jefferson Highway, New Orleans, LA 70121, United States
| | - Mugilan Poongkunran
- The International Center for Epilepsy at Ochsner, Ochsner Neuroscience Institute, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, United States
| | - Bonnie Buratto
- The International Center for Epilepsy at Ochsner, Ochsner Neuroscience Institute, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, United States
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13
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Liu T, Zhong MW, Liu Y, Huang X, Cheng YG, Wang KX, Liu SZ, Hu SY. Effects of sleeve gastrectomy plus trunk vagotomy compared with sleeve gastrectomy on glucose metabolism in diabetic rats. World J Gastroenterol 2017; 23:3269-3278. [PMID: 28566886 PMCID: PMC5434432 DOI: 10.3748/wjg.v23.i18.3269] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 04/25/2017] [Accepted: 05/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effects of sleeve gastrectomy plus trunk vagotomy (SGTV) compared with sleeve gastrectomy (SG) in a diabetic rat model.
METHODS SGTV, SG, TV and Sham operations were performed on rats with diabetes induced by high-fat diet and streptozotocin. Body weight, food intake, oral glucose tolerance test, homeostasis model assessment of insulin resistance (HOMA-IR), hepatic insulin signaling (IR, IRS1, IRS2, PI3K and AKT), oral glucose stimulated insulin secretion, GLP-1 and ghrelin were compared at various postoperative times.
RESULTS Both SG and SGTV resulted in better glucose tolerance, lower HOMA-IR, up-regulated hepatic insulin signaling, higher levels of oral glucose-stimulated insulin secretion, higher postprandial GLP-1 and lower fasting ghrelin levels than the TV and Sham groups. No significant differences were observed between the SG and SGTV groups. In addition, no significant differences were found between the TV and Sham groups in terms of glucose tolerance, HOMA-IR, hepatic insulin signaling, oral glucose-stimulated insulin secretion, postprandial GLP-1 and fasting ghrelin levels. No differences in body weight and food intake were noted between the four groups.
CONCLUSION SGTV is feasible for diabetes control and is independent of weight loss. However, SGTV did not result in a better improvement in diabetes than SG alone.
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14
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Ekmekçi H, Kaptan H. Vagus Nerve Stimulation. Open Access Maced J Med Sci 2017; 5:391-394. [PMID: 28698761 PMCID: PMC5503741 DOI: 10.3889/oamjms.2017.056] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 03/11/2017] [Accepted: 03/31/2017] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND: The vagus nerve stimulation (VNS) is an approach mainly used in cases of intractable epilepsy despite all the efforts. Also, its benefits have been shown in severe cases of depression resistant to typical treatment. AIM: The aim of this study was to present current knowledge of vagus nerve stimulation. MATERIAL AND METHODS: A new value has emerged just at this stage: VNS aiming the ideal treatment with new hopes. It is based on the placement of a programmable generator on the chest wall. Electric signals from the generator are transmitted to the left vagus nerve through the connection cable. Control on the cerebral bioelectrical activity can be achieved by way of these signal sent from there in an effort for controlling the epileptic discharges. RESULTS: The rate of satisfactory and permanent treatment in epilepsy with monotherapy is around 50%. This rate will increase by one-quarters (25%) with polytherapy. However, there is a patient group roughly constituting one-thirds of this population, and this group remains unresponsive or refractory to all the therapies and combined regimes. The more the number of drugs used, the more chaos and side effects are observed. The anti-epileptic drugs (AEDs) used will have side effects on both the brain and the systemic organs. Cerebral resection surgery can be required in some patients. The most commonly encountered epilepsy type is the partial one, and the possibility of benefiting from invasive procedures is limited in most patients of this type. Selective amygdala-hippocampus surgery is a rising value in complex partial seizures. Therefore, as epilepsy surgery can be performed in very limited numbers and rather developed centres, success can also be achieved in limited numbers of patients. The common ground for all the surgical procedures is the target of preservation of memory, learning, speaking, temper and executive functions as well as obtaining a good control on seizures. However, the action mechanism of VNS is still not exactly known. On the other hand, it appears to be a reliable method that is tolerated well in partial resistant seizures. It has been observed that adverse effects are generally of mild-medium severity, and most of the problems can be eliminated easily through the re-adjustment of the stimulator. CONCLUSION: VNS, which is a treatment modality that will take place it deserves in epilepsy treatment with “the correct patient” and “correct reason”, must be known better and its applications must be developed.
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Affiliation(s)
- Hakan Ekmekçi
- Selcuk University, Faculty of Medicine, Department of Neurology, Konya, Turkey
| | - Hülagu Kaptan
- Dokuz Eylül University, Medical Faculty, Inciralti 35340, Izmir, Turkey
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15
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Abstract
Increasing energy expenditure is an appealing therapeutic target for the prevention and reversal of metabolic conditions such as obesity or type 2 diabetes. However, not enough research has investigated how to exploit pre-existing neural pathways, both in the central nervous system (CNS) and peripheral nervous system (PNS), in order to meet these needs. Here, we review several research areas in this field, including centrally acting pathways known to drive the activation of sympathetic nerves that can increase lipolysis and browning in white adipose tissue (WAT) or increase thermogenesis in brown adipose tissue (BAT), as well as other central and peripheral pathways able to increase energy expenditure of these tissues. In addition, we describe new work investigating the family of transient receptor potential (TRP) channels on metabolically important sensory nerves, as well as the role of the vagus nerve in regulating energy balance.
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Affiliation(s)
- Magdalena Blaszkiewicz
- School of Biology and Ecology and Graduate School of Biomedical Sciences and Engineering, University of Maine, 5735 Hitchner Hall, Rm 301, Orono, ME, 04469, USA
| | - Kristy L Townsend
- School of Biology and Ecology and Graduate School of Biomedical Sciences and Engineering, University of Maine, 5735 Hitchner Hall, Rm 301, Orono, ME, 04469, USA.
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16
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Chapleau MW, Rotella DL, Reho JJ, Rahmouni K, Stauss HM. Chronic vagal nerve stimulation prevents high-salt diet-induced endothelial dysfunction and aortic stiffening in stroke-prone spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 2016; 311:H276-85. [PMID: 27208157 PMCID: PMC4967207 DOI: 10.1152/ajpheart.00043.2016] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 05/16/2016] [Indexed: 01/17/2023]
Abstract
Parasympathetic activity is often reduced in hypertension and can elicit anti-inflammatory mechanisms. Thus we hypothesized that chronic vagal nerve stimulation (VNS) may alleviate cardiovascular end-organ damage in stroke-prone spontaneously hypertensive rats. Vagal nerve stimulators were implanted, a high-salt diet initiated, and the stimulators turned on (VNS, n = 10) or left off (sham, n = 14) for 4 wk. Arterial pressure increased equally in both groups. After 4 wk, endothelial function, assessed by in vivo imaging of the long posterior ciliary artery (LPCA) after stimulation (pilocarpine) and inhibition (N(ω)-nitro-l-arginine methyl ester) of endothelial nitric oxide synthase (eNOS), had significantly declined (-2.3 ± 1.2 μm, P < 0.05) in sham, but was maintained (-0.7 ± 0.8 μm, nonsignificant) in VNS. Furthermore, aortic eNOS activation (phosphorylated to total eNOS protein content ratio) was greater in VNS (0.83 ± 0.07) than in sham (0.47 ± 0.08, P < 0.05). After only 3 wk, ultrasound imaging of the aorta demonstrated decreased aortic strain (-9.7 ± 2.2%, P < 0.05) and distensibility (-2.39 ± 0.49 1,000/mmHg, P < 0.05) and increased pulse-wave velocity (+2.4 ± 0.7 m/s, P < 0.05) in sham but not in VNS (-3.8 ± 3.8%, -0.70 ± 1.4 1,000/mmHg, and +0.1 ± 0.7 m/s, all nonsignificant). Interleukin (IL)-6 serum concentrations tended to be higher in VNS than in sham (34.3 ± 8.3 vs. 16.1 ± 4.6 pg/ml, P = 0.06), and positive correlations were found between NO-dependent relaxation of the LPCA and serum levels of IL-6 (r = +0.70, P < 0.05) and IL-10 (r = +0.56, P < 0.05) and between aortic eNOS activation and IL-10 (r = +0.48, P < 0.05). In conclusion, chronic VNS prevents hypertension-induced endothelial dysfunction and aortic stiffening in an animal model of severe hypertension. We speculate that anti-inflammatory mechanisms may contribute to these effects.
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Affiliation(s)
- Mark W Chapleau
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa; Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa; Veterans Affairs Medical Center, Iowa City, Iowa
| | - Diane L Rotella
- Department of Health and Human Physiology, University of Iowa, Iowa City, Iowa
| | - John J Reho
- Department of Pharmacology, University of Iowa, Iowa City, Iowa; and
| | - Kamal Rahmouni
- Department of Pharmacology, University of Iowa, Iowa City, Iowa; and
| | - Harald M Stauss
- Department of Health and Human Physiology, University of Iowa, Iowa City, Iowa;
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17
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Meng FG, Jia FM, Ren XH, Ge Y, Wang KL, Ma YS, Ge M, Zhang K, Hu WH, Zhang X, Hu W, Zhang JG. Vagus Nerve Stimulation for Pediatric and Adult Patients with Pharmaco-resistant Epilepsy. Chin Med J (Engl) 2016; 128:2599-604. [PMID: 26415797 PMCID: PMC4736866 DOI: 10.4103/0366-6999.166023] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Background: Over past two decades, vagus nerve stimulation (VNS) has been widely used and reported to alleviate seizure frequency worldwide, however, so far, only hundreds of patients with pharmaco-resistant epilepsy (PRE) have been treated with VNS in mainland China. The study aimed to evaluate the effectiveness of VNS for Chinese patients with PRE and compare its relationship with age cohort and gender. Methods: We retrospectively assessed the clinical outcome of 94 patients with PRE, who were treated with VNS at Beijing Fengtai Hospital and Beijing Tiantan Hospital between November 2008 and April 2014 from our database of 106 consecutive patients. The clinical data analysis was retrospectively examined. Results: Seizure frequency significantly decreased with VNS therapy after intermittent stimulation of the vagus nerve. At last follow-up, we found McHugh classifications of Class I in 33 patients (35.1%), Class II in 27 patients (28.7%), Class III in 20 patients (21.3%), Class IV in 3 patients (3.2%), and Class V in 11 patients (11.7%). Notably, 8 (8.5%) patients were seizure-free while ≥50% seizure frequency reduction occurred in as many as 60 patients (63.8%). Furthermore, with regard to the modified Engel classification, 12 patients (12.8%) were classified as Class I, 11 patients (11.7%) were classified as Class II, 37 patients (39.4%) were classified as Class III, 34 patients (36.2%) were classified as Class IV. We also found that the factors of gender or age are not associated with clinical outcome. Conclusions: This comparative study confirmed that VNS is a safe, well-tolerated, and effective treatment for Chinese PRE patients. VNS reduced the seizure frequency regardless of age or gender of studied patients.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Jian-Guo Zhang
- Beijing Key Laboratory of Neuromodulation, Beijing Municipal Science and Technology Commission; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
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18
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Manning KE, McAllister CJ, Ring HA, Finer N, Kelly CL, Sylvester KP, Fletcher PC, Morrell NW, Garnett MR, Manford MRA, Holland AJ. Novel insights into maladaptive behaviours in Prader-Willi syndrome: serendipitous findings from an open trial of vagus nerve stimulation. JOURNAL OF INTELLECTUAL DISABILITY RESEARCH : JIDR 2016; 60:149-55. [PMID: 26018613 PMCID: PMC4950305 DOI: 10.1111/jir.12203] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Revised: 02/03/2015] [Accepted: 04/14/2015] [Indexed: 05/27/2023]
Abstract
BACKGROUND We report striking and unanticipated improvements in maladaptive behaviours in Prader-Willi syndrome (PWS) during a trial of vagus nerve stimulation (VNS) initially designed to investigate effects on the overeating behaviour. PWS is a genetically determined neurodevelopmental disorder associated with mild-moderate intellectual disability (ID) and social and behavioural difficulties, alongside a characteristic and severe hyperphagia. METHODS Three individuals with PWS underwent surgery to implant the VNS device. VNS was switched on 3 months post-implantation, with an initial 0.25 mA output current incrementally increased to a maximum of 1.5 mA as tolerated by each individual. Participants were followed up monthly. RESULTS Vagal nerve stimulation in these individuals with PWS, within the stimulation parameters used here, was safe and acceptable. However, changes in eating behaviour were equivocal. Intriguingly, unanticipated, although consistent, beneficial effects were reported by two participants and their carers in maladaptive behaviour, temperament and social functioning. These improvements and associated effects on food-seeking behaviour, but not weight, indicate that VNS may have potential as a novel treatment for such behaviours. CONCLUSIONS We propose that these changes are mediated through afferent and efferent vagal projections and their effects on specific neural networks and functioning of the autonomic nervous system and provide new insights into the mechanisms that underpin what are serious and common problems affecting people with IDs more generally.
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Affiliation(s)
- K E Manning
- Department of Psychiatry, University of Cambridge, Cambridge, UK
| | - C J McAllister
- Department of Psychiatry, University of Cambridge, Cambridge, UK
| | - H A Ring
- Department of Psychiatry, University of Cambridge, Cambridge, UK
- National Institute for Health Research (NIHR) Collaborations for Leadership in Applied Health Research and Care (CLAHRC) East of England, Cambridge, UK
- Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK
| | - N Finer
- National Centre for Cardiovascular Prevention and Outcomes, UCL Institute of Cardiovascular Sciences, London, UK
- Addenbrooke's Hospital, Cambridge, UK
| | - C L Kelly
- Department of Psychiatry, University of Cambridge, Cambridge, UK
| | | | - P C Fletcher
- Department of Psychiatry, University of Cambridge, Cambridge, UK
- Addenbrooke's Hospital, Cambridge, UK
| | - N W Morrell
- Addenbrooke's Hospital, Cambridge, UK
- Department of Medicine, University of Cambridge, Cambridge, UK
- Papworth Hospital NHS Trust, Cambridge, UK
| | | | - M R A Manford
- Addenbrooke's Hospital, Cambridge, UK
- Bedford Hospital NHS Trust, Bedford, UK
| | - A J Holland
- Department of Psychiatry, University of Cambridge, Cambridge, UK
- National Institute for Health Research (NIHR) Collaborations for Leadership in Applied Health Research and Care (CLAHRC) East of England, Cambridge, UK
- Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK
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19
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Val-Laillet D, Aarts E, Weber B, Ferrari M, Quaresima V, Stoeckel L, Alonso-Alonso M, Audette M, Malbert C, Stice E. Neuroimaging and neuromodulation approaches to study eating behavior and prevent and treat eating disorders and obesity. Neuroimage Clin 2015; 8:1-31. [PMID: 26110109 PMCID: PMC4473270 DOI: 10.1016/j.nicl.2015.03.016] [Citation(s) in RCA: 304] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 03/18/2015] [Accepted: 03/19/2015] [Indexed: 12/11/2022]
Abstract
Functional, molecular and genetic neuroimaging has highlighted the existence of brain anomalies and neural vulnerability factors related to obesity and eating disorders such as binge eating or anorexia nervosa. In particular, decreased basal metabolism in the prefrontal cortex and striatum as well as dopaminergic alterations have been described in obese subjects, in parallel with increased activation of reward brain areas in response to palatable food cues. Elevated reward region responsivity may trigger food craving and predict future weight gain. This opens the way to prevention studies using functional and molecular neuroimaging to perform early diagnostics and to phenotype subjects at risk by exploring different neurobehavioral dimensions of the food choices and motivation processes. In the first part of this review, advantages and limitations of neuroimaging techniques, such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), pharmacogenetic fMRI and functional near-infrared spectroscopy (fNIRS) will be discussed in the context of recent work dealing with eating behavior, with a particular focus on obesity. In the second part of the review, non-invasive strategies to modulate food-related brain processes and functions will be presented. At the leading edge of non-invasive brain-based technologies is real-time fMRI (rtfMRI) neurofeedback, which is a powerful tool to better understand the complexity of human brain-behavior relationships. rtfMRI, alone or when combined with other techniques and tools such as EEG and cognitive therapy, could be used to alter neural plasticity and learned behavior to optimize and/or restore healthy cognition and eating behavior. Other promising non-invasive neuromodulation approaches being explored are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct-current stimulation (tDCS). Converging evidence points at the value of these non-invasive neuromodulation strategies to study basic mechanisms underlying eating behavior and to treat its disorders. Both of these approaches will be compared in light of recent work in this field, while addressing technical and practical questions. The third part of this review will be dedicated to invasive neuromodulation strategies, such as vagus nerve stimulation (VNS) and deep brain stimulation (DBS). In combination with neuroimaging approaches, these techniques are promising experimental tools to unravel the intricate relationships between homeostatic and hedonic brain circuits. Their potential as additional therapeutic tools to combat pharmacorefractory morbid obesity or acute eating disorders will be discussed, in terms of technical challenges, applicability and ethics. In a general discussion, we will put the brain at the core of fundamental research, prevention and therapy in the context of obesity and eating disorders. First, we will discuss the possibility to identify new biological markers of brain functions. Second, we will highlight the potential of neuroimaging and neuromodulation in individualized medicine. Third, we will introduce the ethical questions that are concomitant to the emergence of new neuromodulation therapies.
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Key Words
- 5-HT, serotonin
- ADHD, attention deficit hyperactivity disorder
- AN, anorexia nervosa
- ANT, anterior nucleus of the thalamus
- B N, bulimia nervosa
- BAT, brown adipose tissue
- BED, binge eating disorder
- BMI, body mass index
- BOLD, blood oxygenation level dependent
- BS, bariatric surgery
- Brain
- CBF, cerebral blood flow
- CCK, cholecystokinin
- Cg25, subgenual cingulate cortex
- DA, dopamine
- DAT, dopamine transporter
- DBS, deep brain stimulation
- DBT, deep brain therapy
- DTI, diffusion tensor imaging
- ED, eating disorders
- EEG, electroencephalography
- Eating disorders
- GP, globus pallidus
- HD-tDCS, high-definition transcranial direct current stimulation
- HFD, high-fat diet
- HHb, deoxygenated-hemoglobin
- Human
- LHA, lateral hypothalamus
- MER, microelectrode recording
- MRS, magnetic resonance spectroscopy
- Nac, nucleus accumbens
- Neuroimaging
- Neuromodulation
- O2Hb, oxygenated-hemoglobin
- OCD, obsessive–compulsive disorder
- OFC, orbitofrontal cortex
- Obesity
- PD, Parkinson's disease
- PET, positron emission tomography
- PFC, prefrontal cortex
- PYY, peptide tyrosine tyrosine
- SPECT, single photon emission computed tomography
- STN, subthalamic nucleus
- TMS, transcranial magnetic stimulation
- TRD, treatment-resistant depression
- VBM, voxel-based morphometry
- VN, vagus nerve
- VNS, vagus nerve stimulation
- VS, ventral striatum
- VTA, ventral tegmental area
- aCC, anterior cingulate cortex
- dTMS, deep transcranial magnetic stimulation
- daCC, dorsal anterior cingulate cortex
- dlPFC, dorsolateral prefrontal cortex
- fMRI, functional magnetic resonance imaging
- fNIRS, functional near-infrared spectroscopy
- lPFC, lateral prefrontal cortex
- pCC, posterior cingulate cortex
- rCBF, regional cerebral blood flow
- rTMS, repetitive transcranial magnetic stimulation
- rtfMRI, real-time functional magnetic resonance imaging
- tACS, transcranial alternate current stimulation
- tDCS, transcranial direct current stimulation
- tRNS, transcranial random noise stimulation
- vlPFC, ventrolateral prefrontal cortex
- vmH, ventromedial hypothalamus
- vmPFC, ventromedial prefrontal cortex
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Affiliation(s)
| | - E. Aarts
- Radboud University, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
| | - B. Weber
- Department of Epileptology, University Hospital Bonn, Germany
| | - M. Ferrari
- Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy
| | - V. Quaresima
- Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy
| | - L.E. Stoeckel
- Massachusetts General Hospital, Harvard Medical School, USA
| | - M. Alonso-Alonso
- Beth Israel Deaconess Medical Center, Harvard Medical School, USA
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20
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[Vagus nerve stimulation therapy in epilepsy patients: long-term outcome and adverse effects: a retrospective analysis]. DER NERVENARZT 2014; 84:1473-85. [PMID: 24212419 DOI: 10.1007/s00115-013-3923-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
BACKGROUND Vagus nerve stimulation (VNS) is one of the numerous stimulation procedures used in the treatment of neurological diseases in which there has been growing interest in recent years. Since 1988 it has been frequently used in the therapy of epilepsies but the mechanism of action is still unknown. It is considered to be low in adverse effects. TOPICS Decision-making process on VNS therapy as well as long-term outcome and adverse effects. METHOD Retrospective analysis of all 62 patients treated over a long period by VNS in the Epilepsy Center of the University Hospital of Freiburg (Germany) from 1 August 2002 through 4 January 2011. RESULTS OUTCOME the results show that 2 out of 62 patients became seizure-free under VNS therapy while maintaining the already existing anti-ictal medication and 4 more patients under VNS plus dosage increase of the already existing medication and/or new medication. However, in 34 out of 62 patients VNS therapy did not improve the seizure situation. Adverse effects: VNS is not as low in adverse effects as is generally considered. Only 9 out of 62 patients did not show any adverse effects and on the other hand severe, even life-threatening adverse effects also occurred. CONCLUSION Patients undergoing VNS therapy have to be carefully checked for possible adverse effects, not only at the beginning of VNS therapy but also in the long-term course. These results have to be considered in the cost-benefit analysis of this treatment.
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Sathananthan M, Ikramuddin S, Swain JM, Shah M, Piccinini F, Dalla Man C, Cobelli C, Rizza RA, Camilleri M, Vella A. The effect of vagal nerve blockade using electrical impulses on glucose metabolism in nondiabetic subjects. Diabetes Metab Syndr Obes 2014; 7:305-12. [PMID: 25050073 PMCID: PMC4103924 DOI: 10.2147/dmso.s65733] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
PURPOSE Vagal interruption causes weight loss in humans and decreases endogenous glucose production in animals. However, it is unknown if this is due to a direct effect on glucose metabolism. We sought to determine if vagal blockade using electrical impulses alters glucose metabolism in humans. PATIENTS AND METHODS We utilized a randomized, cross-over study design where participants were studied after 2 weeks of activation or inactivation of vagal nerve blockade (VNB). Seven obese subjects with impaired fasting glucose previously enrolled in a long-term study to examine the effect of VNB on weight took part. We used a standardized triple-tracer mixed meal to enable measurement of the rate of meal appearance, endogenous glucose production, and glucose disappearance. The 550 kcal meal was also labeled with (111)In-diethylene triamine pentaacetic acid (DTPA) to measure gastrointestinal transit. Insulin action and β-cell responsivity indices were estimated using the minimal model. RESULTS Integrated glucose, insulin, and glucagon concentrations did not differ between study days. This was also reflected in a lack of effect on β-cell responsivity and insulin action. Furthermore, fasting and postprandial endogenous glucose production, integrated meal appearance, and glucose disposal did not differ in the presence or absence of VNB. Similarly, gastric emptying and colonic transit were unchanged by VNB. CONCLUSION In this pilot study in nondiabetic humans, electrical vagal blockade had no acute effects on glucose metabolism, insulin secretion and action, or gastric emptying. It remains to be determined if more pronounced effects would be observed in diabetic subjects.
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Affiliation(s)
- Matheni Sathananthan
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Sayeed Ikramuddin
- Division of General Surgery, University of Minnesota, Minneapolis, MN, USA
| | - James M Swain
- Division of General Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA
- Scottsdale Healthcare Bariatric Center, Scottsdale, AZ, USA
| | - Meera Shah
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA
| | | | - Chiara Dalla Man
- Department of Information Engineering, University of Padua, Padua, Italy
| | - Claudio Cobelli
- Department of Information Engineering, University of Padua, Padua, Italy
| | - Robert A Rizza
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Adrian Vella
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA
- Correspondence: Adrian Vella, Endocrine Research Unit, Mayo Clinic College of Medicine, 200 First St SW, 5-194 Joseph Rochester, MN 55905, USA, Tel +1 507 255 6515, Fax +1 507 255 4828, Email
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Vagus nerve stimulation in refractory epilepsy: new indications and outcome assessment. Epilepsy Behav 2013; 28:374-8. [PMID: 23835092 DOI: 10.1016/j.yebeh.2013.05.021] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Revised: 05/05/2013] [Accepted: 05/20/2013] [Indexed: 01/27/2023]
Abstract
Although vagus nerve stimulation (VNS) is an effective alternative option for patients with refractory epilepsy unsuitable for conventional resective surgery, predictors of a better control of seizure frequency and severity are still unavailable. This prospective study reports on 39 patients, including 4 children affected by epilepsia partialis continua (EPC), who underwent VNS for refractory epilepsy. The overall seizure frequency outcome was classified into three groups according to reduction rate: ≥75%, ≥50%, and <50%. Engel and McHugh classifications were also used. The median follow-up period was 36months. A seizure reduction rate ≥50% or EPC improvement was observed in 74% of the patients. Twenty-one out of 35 cases (60%) resulted in Engel classes II and III. Outcome, as defined by the McHugh scale, showed a responder rate of 71%. These results suggest that younger patient age and focal or multifocal epilepsy are related to a better seizure control and cognitive outcome. Vagus nerve stimulation could also be considered as an effective procedure in severe conditions, such as drug-refractory EPC.
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Choi SJ, Hong SC, Seo DW, Joo EY, Cho JR, Hwang KJ, Kim JY, Hong SB. Long-Term Outcome of Vagus Nerve Stimulation for Refractory Epilepsy: A Longitudinal 4 year Follow-up Study in Korea. J Epilepsy Res 2013; 3:16-20. [PMID: 24649466 PMCID: PMC3957311 DOI: 10.14581/jer.13003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Accepted: 05/22/2013] [Indexed: 11/05/2022] Open
Abstract
Background and Purpose: We evaluated the long-term outcome of patients with refractory epilepsy who were treated with vagus nerve stimulation (VNS). Methods: This investigation is designed as an uncontrolled, open-label, retrospective and long-term study. From June 1999 to October 2009, 20 patients were suitable for inclusion criteria: 4-year follow-up and documented seizure frequency before and after implantation. Seizure frequency was collected by clinical recording and interview. Primary outcome measures were the reduction in mean seizure frequency and responder rate (seizure frequency reduction of >50%). Results: In 20 patients (M:F=16:4), mean age at the time of implantation was 22.3 years (range 8–44) and mean disease duration was 13.9 years (range 1–37). Mean maximum stimulation output current was 1.90 mA (range 0.25–3.5). Overall mean seizure frequency reduction rate was 61.8% at 4 year follow-up comparison with baseline (p<0.001). Proposition of responder (> 50% seizure frequency reduction) of yearly follow-up were 40 % at 1 yr, 50% at 2 yrs, 45% at 3 yrs, and 60% at 4 yrs. There was no difference of stimulation parameter between the responders and non-responders. Conclusions: Long-term outcome of VNS suggests that VNS is an effective treatment option that can be alternative to surgery in patients with refractory epilepsy.
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Affiliation(s)
- Su Jung Choi
- Brain-Nerve Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Chyul Hong
- Brain-Nerve Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dae-Won Seo
- Brain-Nerve Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun Yeon Joo
- Brain-Nerve Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jounhong Ryan Cho
- Brain-Nerve Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung Jin Hwang
- Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Young Kim
- Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Bong Hong
- Brain-Nerve Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Banni S, Carta G, Murru E, Cordeddu L, Giordano E, Marrosu F, Puligheddu M, Floris G, Asuni GP, Cappai AL, Deriu S, Follesa P. Vagus nerve stimulation reduces body weight and fat mass in rats. PLoS One 2012; 7:e44813. [PMID: 23028630 PMCID: PMC3460935 DOI: 10.1371/journal.pone.0044813] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2011] [Accepted: 08/14/2012] [Indexed: 01/19/2023] Open
Abstract
Among the manifold effects of vagus nerve stimulation (VNS) delivered as an add-on treatment to patients with drug-resistant epilepsy, a moderate loss of body weight has been observed in some individuals. We have now investigated this effect in rats. Exposure of rats to VNS for 4 weeks reduced feed conversion efficiency as well as body weight gain (by ∼25%) and the amount of mesenteric adipose tissue (by ∼45%) in comparison with those in sham-operated control animals. A pair-fed experiment showed that both lower dietary intake and increase energy expenditure independently contributed to the reduction of body weight and mesenteric adipose tissue. Moreover, VNS increased the level of non-esterified fatty acids in plasma and mesenteric adipose tissue by ∼50 and 80%, respectively, without affecting that in the liver. In addition, VNS reduced the amounts of endocannabinoids and increased N-palmitoylethanolamide, an endogenous ligand of the transcription factor PPARα (peroxisome proliferator–activated receptor α) in mesenteric adipose tissue but not in the hypothalamus. These effects were accompanied by increased expression of the gene for brain-derived neurotrophic factor (BDNF) in the hypothalamus and up-regulation of the abundance of PPARα in the liver. Our results suggest that the reduction in body fat induced by VNS in rats may result from the action of both central and peripheral mediators. The reduced feed conversion efficiency associated with VNS may be mediated by hypothalamic BDNF, down-regulation of endocannabinoid tone in mesenteric adipose tissue and a PPARα-dependent increase in fatty acid oxidation in the liver, which in concerted action may account for the anorexic effect and increased energy expenditure.
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Affiliation(s)
- Sebastiano Banni
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
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Vagal afferent controls of feeding: a possible role for gastrointestinal BDNF. Clin Auton Res 2012; 23:15-31. [PMID: 22717678 DOI: 10.1007/s10286-012-0170-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Accepted: 05/24/2012] [Indexed: 01/08/2023]
Abstract
INTRODUCTION Vagal gastrointestinal (GI) afferents do not appear to contribute to long-term controls of feeding, despite downstream connections that could support such a role. This view is largely attributable to a lack of evidence for long-term effects, especially the failure of vagal afferent lesions to produce hyperphagia or obesity. AIMS Here, the possibility is evaluated that "side effects" of vagal lesion methods resulting largely from complexities of vagal organization would probably suppress long-term effects. Criteria based on knowledge of vagal organization were utilized to critique and compare vagal lesion methods and to interpret their effects on GI function, feeding and body weight. RESULTS AND CONCLUSIONS This analysis suggested that it was premature to eliminate a long-term vagal GI afferent role based on the effects of these lesions and highlighted aspects of vagal organization that must be addressed to reduce the problematic side effects of vagal lesions. The potential of "genetic" lesions that alter vagal sensory development to address these aspects, examination of the feasibility of this approach, and the properties of brain-derived neurotrophic factor (BDNF) that made it an attractive candidate for application of this approach are described. BDNF knockout from GI smooth muscle unexpectedly demonstrated substantial overeating and weight gain associated with increased meal size and frequency. The decay of eating rate during a scheduled meal was also reduced. However, meal-induced c-Fos activation was increased in the dorsal motor nucleus of the vagus, suggesting that the effect on eating rate was due to augmentation of GI reflexes by vagal afferents or other neural systems.
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Fox EA, Biddinger JE. Early postnatal overnutrition: potential roles of gastrointestinal vagal afferents and brain-derived neurotrophic factor. Physiol Behav 2012; 106:400-12. [PMID: 22712064 PMCID: PMC3517218 DOI: 10.1016/j.physbeh.2012.04.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Abnormal perinatal nutrition (APN) results in a predisposition to develop obesity and the metabolic syndrome and thus may contribute to the prevalence of these disorders. Obesity, including that which develops in organisms exposed to APN, has been associated with increased meal size. Vagal afferents of the gastrointestinal (GI) tract contribute to regulation of meal size by transmitting satiation signals from gut-to-brain. Consequently, APN could increase meal size by altering this signaling, possibly through changes in expression of factors that control vagal afferent development or function. Here two studies that addressed these possibilities are reviewed. First, meal patterns, meal microstructure, and the structure and density of vagal afferents that innervate the intestine were examined in mice that experienced early postnatal overnutrition (EPO). These studies provided little evidence for EPO effects on vagal afferents as it did not alter meal size or vagal afferent density or structure. However, these mice exhibited modest hyperphagia due to a satiety deficit. In parallel, the possibility that brain-derived neurotrophic factor (BDNF) could mediate APN effects on vagal afferent development was investigated. Brain-derived neurotrophic factor was a strong candidate because APN alters BDNF levels in some tissues and BDNF knockout disrupts development of vagal sensory innervation of the GI tract. Surprisingly, smooth muscle-specific BDNF knockout resulted in early-onset obesity and hyperphagia due to increases in meal size and frequency. Microstructure analysis revealed decreased decay of intake rate during a meal in knockouts, suggesting that the loss of vagal negative feedback contributed to their increase in meal size. However, meal-induced c-Fos activation within the dorsal vagal complex suggested this effect could be due to augmentation of vago-vagal reflexes. A model is proposed to explain how high-fat diet consumption produces increased obesity in organisms exposed to APN, and may be required to reveal effects of EPO on vagal function.
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Affiliation(s)
- Edward A Fox
- Behavioral Neurogenetics Laboratory & Ingestive Behavior Research Center, Department of Psychological Sciences, Purdue University, West Lafayette, IN 47907, USA.
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Colicchio G, Policicchio D, Barbati G, Cesaroni E, Fuggetta F, Meglio M, Papacci F, Rychlicki F, Scerrati M, Zamponi N. Vagal nerve stimulation for drug-resistant epilepsies in different age, aetiology and duration. Childs Nerv Syst 2010; 26:811-9. [PMID: 20091042 DOI: 10.1007/s00381-009-1069-2] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2009] [Accepted: 12/02/2009] [Indexed: 10/19/2022]
Abstract
PURPOSE The aim of the study was to compare the outcome with respect to age of implant, aetiology and duration of epilepsy. METHODS One hundred thirty-five drug-resistant epileptic patients, excluded from ablative surgery, were submitted to vagal nerve stimulation (1995-2007). Aetiology was cryptogenic in 57 and symptomatic in 78 patients. Ages of implant were 0.5-6 years (18 patients), 7-12 years (32 patients), 13-18 years (31 patients) and more than 18 years (54 patients). Epilepsy types were Lennox-Gastaut (18 patients), severe multifocal epilepsy (33 patients) and partial (84 patients). Duration of epilepsy is 3 months to 57 years. Clinical outcome was determined by comparing the seizure frequency after stimulation at 3-6-12-18-24-36 months with the previous 3 months. 'Responders' were the patients experiencing a seizure frequency reduction of 50% or more during follow-up. In statistical analysis, Wilcoxon and McNemar tests, general linear model for repeated measures, logistic regression and survival analysis were used. RESULTS The seizure frequency reduction was significant in the group as a whole between baseline and the first follow-up (Wilcoxon test). The percentage of responder increases with time (McNemar test p = 0.04). Univariate analysis showed a significant effect of the age of implant on seizure frequency reduction: Adult patient had worst clinical outcome than children (p < 0.001) and adolescents (p = 0.08). Patients with severe multifocal epilepsy had better percentage seizure reduction compared with Lennox-Gastaut and partial (p = 0.03). Lesser duration of epilepsy had positive influence on outcome. Multivariate analysis confirmed age of implant to be the strongest factor influencing prognosis. Furthermore, positive is the association between lesional aetiology and young age. CONCLUSIONS The best responder could be a young lesional epileptic patient; after 3 years of follow-up, the percentage of responders is still in progress.
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Affiliation(s)
- Gabriella Colicchio
- Neurosurgery, Catholic University, Largo Agostino Gemelli 1, 00168, Rome, Italy.
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Wang H, Chen X, Lin Z, Shao Z, Sun B, Shen H, Liu L. Long-term effect of vagus nerve stimulation on interictal epileptiform discharges in refractory epilepsy. J Neurol Sci 2009; 284:96-102. [PMID: 19427651 DOI: 10.1016/j.jns.2009.04.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2008] [Revised: 03/19/2009] [Accepted: 04/08/2009] [Indexed: 10/20/2022]
Abstract
BACKGROUND Vagus nerve stimulation (VNS) therapy has been widely recognized as an effective alternative for the treatment of refractory epilepsy. However, the precise mechanism of VNS is poorly understood. The purpose of this study was to observe the long-term interictal EEG changes induced by VNS, and to investigate the probable mechanism of action of VNS in achieving seizure control. METHODS Eight patients with VNS were selected from two epilepsy centers in China (Harbin and Shanghai) between 2001 and 2004. We studied the clinical efficacy by long-term follow-up, ranging from 37 to 81 months (mean 55.8 months). Moreover, serial EEGs were performed at the different time (preoperative baseline, 3, 6, 12, and 24 months after VNS initiation) and the different states of VNS stimulator ("activation", "deactivation" and "reactivation"). RESULTS A > or = 50% seizure reduction was achieved in 12.5%, 62.5%, 75%, 62.5% and 75% of the total patients (n=8) at 6, 12, 18, 24 and 36 months of post-VNS, respectively. The results revealed a statistically significant progressive decrease in the number of IEDs (interictal epileptiform discharges) on EEG with time (P<0.01). Significant correlation had been highlighted after 6 months of VNS stimulation, between the reduction of seizure frequency and the decreasing of IEDs (P<0.01). Furthermore, statistically significant difference of IEDs was seen when comparing the state of "deactivation" with the states of "activation" and "reactivation", respectively (P<0.01). However, there was no significant difference in IEDs between "activation" and "reactivation" (P>0.05). CONCLUSIONS VNS is an efficient, well-tolerated therapy for refractory epilepsy. It can induce progressive electrophysiological effect on epileptiform activity over time. This may reflect the mechanism of chronic action of VNS with desynchronization of EEG in achieving seizure control.
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Affiliation(s)
- Haiyang Wang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
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Pratap R, Farboud A, Patel H, Montgomery P. Vagal nerve stimulator implantation: the otolaryngologist’s perspective. Eur Arch Otorhinolaryngol 2008; 266:1455-9. [DOI: 10.1007/s00405-008-0887-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2008] [Accepted: 11/27/2008] [Indexed: 10/21/2022]
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