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John S, Bhowmick K, Park A, Huang H, Yang X, Mishra L. Recent advances in targeting obesity, with a focus on TGF-β signaling and vagus nerve innervation. Bioelectron Med 2025; 11:10. [PMID: 40301996 PMCID: PMC12042417 DOI: 10.1186/s42234-025-00172-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 03/31/2025] [Indexed: 05/01/2025] Open
Abstract
Over a third of the global population is affected by obesity, fatty liver disease (Metabolic Dysfunction-Associated Steatotic Liver Disease, MASLD), and its severe form, MASH (Metabolic Dysfunction-Associated Steatohepatitis), which can ultimately progress to hepatocellular carcinoma (HCC). Recent advancements include therapeutics such as glucagon-like peptide 1 (GLP-1) agonists and neural/vagal modulation strategies for these disorders. Among the many pathways regulating these conditions, emerging insights into transforming growth factor-β (TGF-β) signaling highlight potential future targets through its role in pathophysiological processes such as adipogenesis, inflammation, and fibrosis. Vagus nerve innervation in the gastrointestinal tract is involved in satiety regulation and energy homeostasis, and vagus nerve stimulation has been applied in weight loss and diabetes. This review explores clinical trials in obesity, novel therapeutic targets, and the role of TGF-β signaling and vagus nerve modulation in obesity-related liver diseases and HCC.
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Affiliation(s)
- Sahara John
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Krishanu Bhowmick
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA
| | - Andrew Park
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Hai Huang
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Xiaochun Yang
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
| | - Lopa Mishra
- Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
- Department of Surgery, George Washington University, Washington, DC, 20037, USA.
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Lin J, Shen Y, Xia Y, Li Y, Jiang T, Shen X, Fu Y, Zhang D, Yang L, Xu H, Xu Z, Wang L. Vagotomy suppresses food intake by increasing GLP-1 secretion via the M3 AChR-AMPKα pathway in mice. Mol Cell Endocrinol 2025; 599:112464. [PMID: 39848433 DOI: 10.1016/j.mce.2025.112464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 01/25/2025]
Abstract
OBJECTIVE The gut-brain axis (GBA) is involved in the modulation of multiple physiological activities, and the vagus nerve plays an important role in this process. However, the association between vagus nerve function and nutritional regulation remains unclear. Here, we explored changes in the nutritional status of mice after vagotomy and investigated the underlying mechanisms responsible for these changes. METHODS We performed vagotomies in mice and verified nerve resection using immunofluorescence staining. We then observed the food intake and body weight of the mice and tested nutritional and inflammation-related markers using enzyme-linked immunosorbent assay (ELISA) kits. The role of glucagon-like peptide 1 (GLP-1) in the GBA was determined using qRT-PCR and ELISA kits. Western blot and ELISA kits were used to explore the underlying mechanisms. RESULTS After vagotomy, the mice experienced a deterioration in their nutritional status, which manifested as a significant reduction in body weight and food intake. The expression of the proglucagon gene (GCG), which encodes GLP-1, significantly increased after vagotomy. Mechanistically, acetylcholine (ACh) reversed the HG (high glucose) -induced elevation of GLP-1 secretion. ACh upregulated AMPKα phosphorylation, thereby reducing GLP-1 secretion. Moreover, the level of AMPKα phosphorylation was enhanced by ACh via M3AChR. CONCLUSIONS ACh released by the vagus nerve counteracts the anorectic effects of GLP-1 under normal physiological conditions. Vagotomy blocks this feedback, resulting in a loss of food intake and body weight in mice.
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Affiliation(s)
- Jie Lin
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yikai Shen
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yiwen Xia
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Ying Li
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Tianlu Jiang
- Department of General Surgery, Wuxi Medical Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Peolple's Hospital, Wuxi, Jiangsu Province, China
| | - Xusheng Shen
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yiwang Fu
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Diancai Zhang
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Li Yang
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Hao Xu
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Zekuan Xu
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
| | - Linjun Wang
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
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Knutson JS, Chepla KJ, Wilson RD, Fu MJ, Imka EC, Bender SA, Chae J, Kilgore KL, Bhadra N. First-in-Human Demonstration of High-Frequency Electrical Motor Nerve Block: Case Report. Am J Phys Med Rehabil 2025; 104:e37-e40. [PMID: 38958190 DOI: 10.1097/phm.0000000000002577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/04/2024]
Abstract
ABSTRACT This feasibility study tested the capability of high-frequency stimulation to block muscle contractions elicited by electrical stimulation of the same nerve proximally. During a tendon lengthening surgery in the forearm, the anterior interosseous nerve was exposed. A specialized nerve cuff electrode was placed around the nerve, and a stimulating probe held on the nerve 1 cm proximal to the cuff electrode delivered pulses of current causing the pronator quadratus muscle to contract. Through the cuff electrode, 20-kHz high-frequency stimulation was delivered to the nerve for 10 secs during proximal stimulation. High-frequency stimulation amplitudes between 5 and 10 mA peak-to-peak were tested to determine which produced complete and partial block of the electrically induced contractions. The minimum high-frequency stimulation amplitude that produced complete block was 8 mA, with lower amplitudes producing partial block. In all trials, muscle contractions resumed immediately after high-frequency stimulation was turned off. This demonstration of high-frequency electrical nerve block is a milestone in the road to clinical implementation of high-frequency stimulation mediated motor block for spasticity.
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Affiliation(s)
- Jayme S Knutson
- From the Department of Physical Medicine and Rehabilitation, The MetroHealth System, Cleveland, Ohio (JSK, RDW, MJF, JC, KLK, NB); Department of Orthopedic Surgery, The MetroHealth System, Cleveland, Ohio (KLK); Division of Plastic Surgery, The MetroHealth System, Cleveland, Ohio (KJC); Department of Physical Medicine and Rehabilitation, Case Western Reserve University, Cleveland, Ohio (JSK, RDW, MJF, JC, KLK, NB); Department of Orthopedic Surgery, Case Western Reserve University, Cleveland, Ohio (KLK), Department of Electrical, Computer, and Systems Engineering, Case Western Reserve University, Cleveland, Ohio (MJF); Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio (MJF, SAB, JC, NB); Department of Surgery, Case Western Reserve University, Cleveland, Ohio (KJC); and Research Service, Cleveland Functional Electrical Stimulation Center, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, Ohio (JSK, KJC, RDW, MJF, ECI, JC, KLK)
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Austelle CW, Cox SS, Wills KE, Badran BW. Vagus nerve stimulation (VNS): recent advances and future directions. Clin Auton Res 2024; 34:529-547. [PMID: 39363044 PMCID: PMC11543756 DOI: 10.1007/s10286-024-01065-w] [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: 01/24/2024] [Accepted: 09/09/2024] [Indexed: 10/05/2024]
Abstract
PURPOSE Vagus nerve stimulation (VNS) is emerging as a unique and potent intervention, particularly within neurology and psychiatry. The clinical value of VNS continues to grow, while the development of noninvasive options promises to change a landscape that is already quickly evolving. In this review, we highlight recent progress in the field and offer readers a glimpse of the future for this bright and promising modality. METHODS We compiled a narrative review of VNS literature using PubMed and organized the discussion by disease states with approved indications (epilepsy, depression, obesity, post-stroke motor rehabilitation, headache), followed by a section highlighting novel, exploratory areas of VNS research. In each section, we summarized the current role, recent advancements, and future directions of VNS in the treatment of each disease. RESULTS The field continues to gain appreciation for the clinical potential of this modality. VNS was initially developed for treatment-resistant epilepsy, with the first depression studies following shortly thereafter. Overall, VNS has gained approval or clearance in the treatment of medication-refractory epilepsy, treatment-resistant depression, obesity, migraine/cluster headache, and post-stroke motor rehabilitation. CONCLUSION Noninvasive VNS represents an opportunity to bridge the translational gap between preclinical and clinical paradigms and may offer the same therapeutic potential as invasive VNS. Further investigation into how VNS parameters modulate behavior and biology, as well as how to translate noninvasive options into the clinical arena, are crucial next steps for researchers and clinicians studying VNS.
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Affiliation(s)
- Christopher W Austelle
- Department of Psychiatry and Behavioral Sciences, Stanford University, 401 Quarry Road, Palo Alto, CA, 94305, USA.
- Veterans Affairs Palo Alto Healthcare System, and the Sierra Pacific Mental Illness, Research, Education, and Clinical Center (MIRECC), Palo Alto, CA, USA.
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.
| | - Stewart S Cox
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Kristin E Wills
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Bashar W Badran
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA
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Zou N, Zhou Q, Zhang Y, Xin C, Wang Y, Claire-Marie R, Rong P, Gao G, Li S. Transcutaneous auricular vagus nerve stimulation as a novel therapy connecting the central and peripheral systems: a review. Int J Surg 2024; 110:4993-5006. [PMID: 38729100 PMCID: PMC11326027 DOI: 10.1097/js9.0000000000001592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 04/26/2024] [Indexed: 05/12/2024]
Abstract
Currently, clinical practice and scientific research mostly revolve around a single disease or system, but the single disease-oriented diagnostic and therapeutic paradigm needs to be revised. This review describes how transcutaneous auricular vagus nerve stimulation (taVNS), a novel non-invasive neuromodulation approach, connects the central and peripheral systems of the body. Through stimulation of the widely distributed vagus nerve from the head to the abdominal cavity, this therapy can improve and treat central system disorders, peripheral system disorders, and central-peripheral comorbidities caused by autonomic dysfunction. In the past, research on taVNS has focused on the treatment of central system disorders by modulating this brain nerve. As the vagus nerve innervates the heart, lungs, liver, pancreas, gastrointestinal tract, spleen and other peripheral organs, taVNS could have an overall modulatory effect on the region of the body where the vagus nerve is widespread. Based on this physiological basis, the authors summarize the existing evidence of the taVNS ability to regulate cardiac function, adiposity, glucose levels, gastrointestinal function, and immune function, among others, to treat peripheral system diseases, and complex diseases with central and peripheral comorbidities. This review shows the successful examples and research progress of taVNS using peripheral neuromodulation mechanisms from more perspectives, demonstrating the expanded scope and value of taVNS to provide new ideas and approaches for holistic therapy from both central and peripheral perspectives.
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Affiliation(s)
- Ningyi Zou
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences
| | - Qing Zhou
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences
| | - Yuzhengheng Zhang
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences
| | - Chen Xin
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences
| | - Yifei Wang
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences
| | | | - Peijing Rong
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences
| | - Guojian Gao
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Shaoyuan Li
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences
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Waataja JJ, Honda CN, Asp AJ, Nihilani RK, Farajidavar A. The Duration and Intensity of High Frequency Alternating Current Influences the Degree and Recovery of Nerve Conduction Block. IEEE Trans Biomed Eng 2024; 71:2170-2179. [PMID: 38335073 DOI: 10.1109/tbme.2024.3364350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2024]
Abstract
OBJECTIVE The purpose of this paper is to investigate the persistence of nerve blockade beyond the duration of applying high frequency alternating current (HFAC) to thinly myelinated and non-myelinated fibers, also termed a "carry-over effect". METHODS In this study, we used electrically-evoked compound action potentials from isolated rat vagus nerves to assess the influence of 5 kHz HFAC amplitude and duration on the degree of the carry-over effect. Current amplitudes from 1-10 mA and 5 kHz durations from 10-120 seconds were tested. RESULTS By testing 20 different combinations of 5 kHz amplitude and duration, we found a significant interaction between 5 kHz amplitude and duration on influencing the carry-over effect. CONCLUSION The degree of carry-over effect was dependent on 5 kHz amplitude, as well as duration. SIGNIFICANCE Utilizing the carry-over effect may be useful in designing energy efficient nerve blocking algorithms for the treatment of diseases influenced by nerve activity.
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Berthon A, Wernisch L, Stoukidi M, Thornton M, Tessier-Lariviere O, Fortier-Poisson P, Mamen J, Pinkney M, Lee S, Sarkans E, Annecchino L, Appleton B, Garsed P, Patterson B, Gonshaw S, Jakopec M, Shunmugam S, Edwards T, Tukiainen A, Jennings J, Lajoie G, Hewage E, Armitage O. Using neural biomarkers to personalize dosing of vagus nerve stimulation. Bioelectron Med 2024; 10:15. [PMID: 38880906 PMCID: PMC11181600 DOI: 10.1186/s42234-024-00147-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 05/17/2024] [Indexed: 06/18/2024] Open
Abstract
BACKGROUND Vagus nerve stimulation (VNS) is an established therapy for treating a variety of chronic diseases, such as epilepsy, depression, obesity, and for stroke rehabilitation. However, lack of precision and side-effects have hindered its efficacy and extension to new conditions. Achieving a better understanding of the relationship between VNS parameters and neural and physiological responses is therefore necessary to enable the design of personalized dosing procedures and improve precision and efficacy of VNS therapies. METHODS We used biomarkers from recorded evoked fiber activity and short-term physiological responses (throat muscle, cardiac and respiratory activity) to understand the response to a wide range of VNS parameters in anaesthetised pigs. Using signal processing, Gaussian processes (GP) and parametric regression models we analyse the relationship between VNS parameters and neural and physiological responses. RESULTS Firstly, we illustrate how considering multiple stimulation parameters in VNS dosing can improve the efficacy and precision of VNS therapies. Secondly, we describe the relationship between different VNS parameters and the evoked fiber activity and show how spatially selective electrodes can be used to improve fiber recruitment. Thirdly, we provide a detailed exploration of the relationship between the activations of neural fiber types and different physiological effects. Finally, based on these results, we discuss how recordings of evoked fiber activity can help design VNS dosing procedures that optimize short-term physiological effects safely and efficiently. CONCLUSION Understanding of evoked fiber activity during VNS provide powerful biomarkers that could improve the precision, safety and efficacy of VNS therapies.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Guillaume Lajoie
- Université de Montréal and Mila-Quebec AI Institute, Montréal, Canada
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Lim J, Zoss PA, Powley TL, Lee H, Ward MP. A flexible, thin-film microchannel electrode array device for selective subdiaphragmatic vagus nerve recording. MICROSYSTEMS & NANOENGINEERING 2024; 10:16. [PMID: 38264708 PMCID: PMC10803373 DOI: 10.1038/s41378-023-00637-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 10/18/2023] [Accepted: 11/17/2023] [Indexed: 01/25/2024]
Abstract
The vagus nerve (VN) plays an important role in regulating physiological conditions in the gastrointestinal (GI) tract by communicating via the parasympathetic pathway to the enteric nervous system (ENS). However, the lack of knowledge in the neurophysiology of the VN and GI tract limits the development of advanced treatments for autonomic dysfunctions related to the VN. To better understand the complicated underlying mechanisms of the VN-GI tract neurophysiology, it is necessary to use an advanced device enabled by microfabrication technologies. Among several candidates including intraneural probe array and extraneural cuff electrodes, microchannel electrode array devices can be used to interface with smaller numbers of nerve fibers by securing them in the separate channel structures. Previous microchannel electrode array devices to interface teased nerve structures are relatively bulky with thickness around 200 µm. The thick design can potentially harm the delicate tissue structures, including the nerve itself. In this paper, we present a flexible thin film based microchannel electrode array device (thickness: 11.5 µm) that can interface with one of the subdiaphragmatic nerve branches of the VN in a rat. We demonstrated recording evoked compound action potentials (ECAP) from a transected nerve ending that has multiple nerve fibers. Moreover, our analysis confirmed that the signals are from C-fibers that are critical in regulating autonomic neurophysiology in the GI tract.
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Affiliation(s)
- Jongcheon Lim
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN USA
- Birck Nanotechnology Center, Purdue University, West Lafayette, IN USA
- Center for Implantable Devices, Purdue University, West Lafayette, IN USA
| | - Peter A. Zoss
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN USA
| | - Terry L. Powley
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN USA
- Department of Psychological Sciences, Purdue University, West Lafayette, IN USA
- Purdue Institute of Integrative Neuroscience, Purdue University, West Lafayette, IN USA
| | - Hyowon Lee
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN USA
- Birck Nanotechnology Center, Purdue University, West Lafayette, IN USA
- Center for Implantable Devices, Purdue University, West Lafayette, IN USA
| | - Matthew P. Ward
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN USA
- Indiana University School of Medicine, Indianapolis, IN USA
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Sun Y, Zhang Y, Liu X, Liu Y, Wu F, Liu X. Association between body mass index and respiratory symptoms in US adults: a national cross-sectional study. Sci Rep 2024; 14:940. [PMID: 38195711 PMCID: PMC10776771 DOI: 10.1038/s41598-024-51637-z] [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: 07/04/2023] [Accepted: 01/08/2024] [Indexed: 01/11/2024] Open
Abstract
The correlation between body mass index (BMI) and the development of cough, shortness of breath, and dyspnea is unclear. Therefore, this study aimed to investigate the association between these parameters. Data from individuals who participated in the National Health and Nutrition Examination Survey between 2003 and 2012 were analyzed. Weighted logistic regression analysis and smoothed curve fitting were used to examine the correlation between BMI and respiratory symptoms. In addition, the relationship between BMI, chronic obstructive pulmonary disease (COPD), and bronchial asthma was examined. Stratified analysis was used to discover inflection points and specific groups. Weighted logistic regression and smoothed curve fitting revealed a U-shaped relationship between BMI and respiratory symptoms. The U-shaped relationship in BMI was also observed in patients with bronchial asthma and COPD. Stratified analysis showed that the correlation between BMI and wheezing and dyspnea was influenced by race. In addition, non-Hispanic black individuals had a higher risk of developing cough than individuals of the other three races [OR 1.040 (1.021, 1.060), p < 0.0001], and they also exhibited an inverted U-shaped relationship between BMI and bronchial asthma. However, the association of BMI with cough, wheezing, dyspnea, COPD, and asthma was not affected by sex. High or low BMI was associated with cough, shortness of breath, and dyspnea, and has been linked to bronchial asthma and COPD. These findings provide new insights into the management of respiratory symptoms and respiratory diseases.
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Affiliation(s)
- Yuefeng Sun
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yueyang Zhang
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiangyang Liu
- School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yingying Liu
- Department of Pulmonary and Critical Care Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Fan Wu
- School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xue Liu
- Department of Pulmonary and Critical Care Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
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Zhuo J, Weidrick CE, Liu Y, Moffitt MA, Jansen ED, Chiel HJ, Jenkins MW. Selective Infrared Neural Inhibition Can Be Reproduced by Resistive Heating. Neuromodulation 2023; 26:1757-1771. [PMID: 36707292 PMCID: PMC10366334 DOI: 10.1016/j.neurom.2022.12.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/22/2022] [Accepted: 12/06/2022] [Indexed: 01/26/2023]
Abstract
OBJECTIVES Small-diameter afferent axons carry various sensory signals that are critical for vital physiological conditions but sometimes contribute to pathologies. Infrared (IR) neural inhibition (INI) can induce selective heat block of small-diameter axons, which holds potential for translational applications such as pain management. Previous research suggested that IR-heating-induced acceleration of voltage-gated potassium channel kinetics is the mechanism for INI. Therefore, we hypothesized that other heating methods, such as resistive heating (RH) in a cuff, could reproduce the selective inhibition observed in INI. MATERIALS AND METHODS We conducted ex vivo nerve-heating experiments on pleural-abdominal connective nerves of Aplysia californica using both IR and RH. We fabricated a transparent silicone nerve cuff for simultaneous IR heating, RH, and temperature measurements. Temperature elevations (ΔT) on the nerve surface were recorded for both heating modalities, which were tested over a range of power levels that cover a similar ΔT range. We recorded electrically evoked compound action potentials (CAPs) and segmented them into fast and slow subcomponents on the basis of conduction velocity differences between the large and small-diameter axonal subpopulations. We calculated the normalized inhibition strength and inhibition selectivity index on the basis of the rectified area under the curve of each subpopulation. RESULTS INI and RH showed a similar selective inhibition effect on CAP subcomponents for slow-conducting axons, confirmed by the inhibition probability vs ΔT dose-response curve based on approximately 2000 CAP measurements. The inhibition selectivity indexes of the two heating modalities were similar across six nerves. RH only required half the total electrical power required by INI to achieve a similar ΔT. SIGNIFICANCE We show that selective INI can be reproduced by other heating modalities such as RH. RH, because of its high energy efficiency and simple design, can be a good candidate for future implantable neural interface designs.
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Affiliation(s)
- Junqi Zhuo
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Chloe E Weidrick
- Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA
| | - Yehe Liu
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Michael A Moffitt
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - E Duco Jansen
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA; Biophotonics Center, Vanderbilt University, Nashville, TN, USA; Department of Neurological Surgery, Vanderbilt University, Nashville, TN, USA
| | - Hillel J Chiel
- Department of Biology, Case Western Reserve University, Cleveland OH, USA; Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA; Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Michael W Jenkins
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA; Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
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Hritani R, Al Rifai M, Mehta A, German C. Obesity management for cardiovascular disease prevention. OBESITY PILLARS 2023; 7:100069. [PMID: 37990683 PMCID: PMC10662048 DOI: 10.1016/j.obpill.2023.100069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/29/2023] [Accepted: 04/29/2023] [Indexed: 11/23/2023]
Abstract
Background Obesity is a complex disease that leads to higher morbidity and mortality and its rate in the United States is rapidly rising. Targeting obesity management is one of the cornerstones of preventive medicine. Early intervention can significantly reduce the risk of developing cardiovascular disease. While it is well known that lifestyle interventions such as healthful nutrition and routine physical activity are the first and most important step in management, some do not achieve the desired results and require further therapies. Methods A literature review was conducted, that included clinical documents, public scientific citations and peer review articles to evaluate anti-obesity medications, endoscopic procedures and bariatric surgeries in the management of obesity. We also included effects of these interventions on weight loss, cardiovascular disease risk reduction and side effects. Results This clinical review summarizes recent evidence for the different approaches in obesity management including medications, common endoscopic procedures and bariatric surgeries. For more detailed review on the different management options discussed, we recommend reviewing Obesity Medicine Association Clinical Practice Statement [1]. Conclusion Management of obesity reduces cardiovascular risk, improves metabolic parameters and other important health outcomes. Different management approaches are available, hence, a high level of awareness of the growing epidemic of obesity is needed to ensure timely referrals to obesity medicine specialists.
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Affiliation(s)
- Rama Hritani
- Division of Cardiology, Department of Internal Medicine, Medical College of Georgia/Augusta University, Augusta, GA, United States
| | - Mahmoud Al Rifai
- Division of Cardiology, Department of Internal Medicine, Houston Methodist DeBakey Heart & Vascular Center, Houston, TX, United States
| | - Anurag Mehta
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University/VCU Health Pauley Heart Center, Richmond, VA, United States
| | - Charles German
- Division of Cardiology, Department of Internal Medicine, University of Chicago, Chicago, IL, United States
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Frick LD, Hankir MK, Borner T, Malagola E, File B, Gero D. Novel Insights into the Physiology of Nutrient Sensing and Gut-Brain Communication in Surgical and Experimental Obesity Therapy. Obes Surg 2023; 33:2906-2916. [PMID: 37474864 PMCID: PMC10435392 DOI: 10.1007/s11695-023-06739-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/05/2023] [Accepted: 07/14/2023] [Indexed: 07/22/2023]
Abstract
Despite standardized surgical technique and peri-operative care, metabolic outcomes of bariatric surgery are not uniform. Adaptive changes in brain function may play a crucial role in achieving optimal postbariatric weight loss. This review follows the anatomic-physiologic structure of the postbariatric nutrient-gut-brain communication chain through its key stations and provides a concise summary of recent findings in bariatric physiology, with a special focus on the composition of the intestinal milieu, intestinal nutrient sensing, vagal nerve-mediated gastrointestinal satiation signals, circulating hormones and nutrients, as well as descending neural signals from the forebrain. The results of interventional studies using brain or vagal nerve stimulation to induce weight loss are also summarized. Ultimately, suggestions are made for future diagnostic and therapeutic research for the treatment of obesity.
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Affiliation(s)
- Lukas D Frick
- Institute of Neuropathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Mohammed K Hankir
- Department of Experimental Surgery, University Hospital Würzburg, Würzburg, Germany
| | - Tito Borner
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Ermanno Malagola
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY, 10032, USA
| | - Bálint File
- Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary, Institute of Cognitive Neuroscience and Psychology, Research Centre for Natural Sciences, Budapest, Hungary
- Wigner Research Centre for Physics, Budapest, Hungary
| | - Daniel Gero
- Department of Surgery and Transplantation, University Hospital Zurich, University of Zurich, Rämistrasse 100, 8091, Zürich, Switzerland.
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13
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Fadel MG, Fehervari M, Das B, Soleimani-Nouri P, Ashrafian H. Vagal Nerve Therapy in the Management of Obesity: A Systematic Review and Meta-Analysis. Eur Surg Res 2023; 64:365-375. [PMID: 37544303 DOI: 10.1159/000533358] [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: 04/24/2023] [Accepted: 07/28/2023] [Indexed: 08/08/2023]
Abstract
INTRODUCTION The vagus nerve has an important role in satiety, metabolism, and autonomic control in upper gastrointestinal function. However, the role and effects of vagal nerve therapy on weight loss remain controversial. This systematic review and meta-analysis assessed the effects of vagal nerve therapy on weight loss, body mass index (BMI), and obesity-related conditions. METHODS MEDLINE, EMBASE, and CINAHL databases were searched for studies up to April 2022 that reported on percentage excess weight loss (%EWL) or BMI at 12 months or remission of obesity-related conditions following vagal nerve therapy from January 2000 to April 2022. Weighted mean difference (WMD) was calculated, meta-analysis was performed using random-effects models, and between-study heterogeneity was assessed. RESULTS Fifteen studies, of which nine were randomised controlled trials, of 1,447 patients were included. Vagal nerve therapy led to some improvement in %EWL (WMD 17.19%; 95% confidence interval [CI]: 10.94-23.44; p < 0.001) and BMI (WMD -2.24 kg/m2; 95% CI: -4.07 to -0.42; p = 0.016). There was a general improvement found in HbA1c following vagal nerve therapy when compared to no treatment given. No major complications were reported. CONCLUSIONS Vagal nerve therapy can safely result in a mild-to-moderate improvement in weight loss. However, further clinical trials are required to confirm these results and investigate the possibility of the long-term benefit of vagal nerve therapy as a dual therapy combined with standard surgical bariatric interventions.
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Affiliation(s)
- Michael G Fadel
- Department of Bariatric and Metabolic Surgery, Chelsea and Westminster Hospital, London, UK
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Matyas Fehervari
- Department of Bariatric and Metabolic Surgery, Chelsea and Westminster Hospital, London, UK
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Bibek Das
- Department of Surgery and Cancer, Imperial College London, London, UK
| | | | - Hutan Ashrafian
- Department of Surgery and Cancer, Imperial College London, London, UK
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14
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Hachul DT. Auricular Vagus Nerve Stimulation in Heart Failure: Critical Analysis and Future Perspectives. Arq Bras Cardiol 2023; 120:e20230298. [PMID: 37341251 PMCID: PMC12092030 DOI: 10.36660/abc.20230298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/22/2023] Open
Affiliation(s)
- Denise Tessariol Hachul
- Hospital das ClínicasFaculdade de MedicinaUniversidade de São PauloSão PauloSPBrasil Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo , São Paulo , SP – Brasil
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15
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Washington TB, Johnson VR, Kendrick K, Ibrahim AA, Tu L, Sun K, Stanford FC. Disparities in Access and Quality of Obesity Care. Gastroenterol Clin North Am 2023; 52:429-441. [PMID: 37197884 DOI: 10.1016/j.gtc.2023.02.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
Obesity is a chronic disease and a significant public health threat predicated on complex genetic, psychological, and environmental factors. Individuals with higher body mass index are more likely to avoid health care due to weight stigma. Disparities in obesity care disproportionately impact racial and ethnic minorities. In addition to this unequal disease burden, access to obesity treatment varies significantly. Even if treatment options are theoretically productive, they may be more difficult for low-income families, and racial and ethnic minorities to implement in practice secondary to socioeconomic factors. Lastly, the outcomes of undertreatment are significant. Disparities in obesity foreshadow integral inequality in health outcomes, including disability, and premature mortality.
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Affiliation(s)
| | - Veronica R Johnson
- Department of Medicine, Division of General Internal Medicine and Geriatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Karla Kendrick
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
| | - Awab Ali Ibrahim
- Pediatric Gastroenterology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA
| | - Lucy Tu
- Department of Sociology, Harvard College, 33 Kirkland Street, Cambridge, MA 02138, USA; Department of Molecular and Cellular Biology, Harvard College, 33 Kirkland Street, Cambridge, MA 02138, USA
| | - Kristen Sun
- Boston University School of Medicine, Boston, MA 02215, USA
| | - Fatima Cody Stanford
- Department of Medicine- Neuroendocrine Unit, Pediatric Endocrinology, MGH Weight Center, Nutrition Obesity Research Center at Harvard, Massachusetts General Hospital, Harvard Medical School, 50 Staniford Street, Suite 430, Boston, MA 02114, USA
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16
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Nainu F, Frediansyah A, Mamada SS, Permana AD, Salampe M, Chandran D, Emran TB, Simal-Gandara J. Natural products targeting inflammation-related metabolic disorders: A comprehensive review. Heliyon 2023; 9:e16919. [PMID: 37346355 PMCID: PMC10279840 DOI: 10.1016/j.heliyon.2023.e16919] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 05/31/2023] [Accepted: 06/01/2023] [Indexed: 06/23/2023] Open
Abstract
Currently, the incidence of metabolic disorders is increasing, setting a challenge to global health. With major advancement in the diagnostic tools and clinical procedures, much has been known in the etiology of metabolic disorders and their corresponding pathophysiologies. In addition, the use of in vitro and in vivo experimental models prior to clinical studies has promoted numerous biomedical breakthroughs, including in the discovery and development of drug candidates to treat metabolic disorders. Indeed, chemicals isolated from natural products have been extensively studied as prospective drug candidates to manage diabetes, obesity, heart-related diseases, and cancer, partly due to their antioxidant and anti-inflammatory properties. Continuous efforts have been made in parallel to improve their bioactivity and bioavailability using selected drug delivery approaches. Here, we provide insights on recent progress in the role of inflammatory-mediated responses on the initiation of metabolic disorders, with particular reference to diabetes mellitus, obesity, heart-related diseases, and cancer. In addition, we discussed the prospective role of natural products in the management of diabetes, obesity, heart-related diseases, and cancers and provide lists of potential biological targets for high throughput screening in drug discovery and development. Lastly, we discussed findings observed in the preclinical and clinical studies prior to identifying suitable approaches on the phytochemical drug delivery systems that are potential to be used in the treatment of metabolic disorders.
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Affiliation(s)
- Firzan Nainu
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Tamalanrea, Makassar 90245, Indonesia
| | - Andri Frediansyah
- Research Center for Food Technology and Processing (PRTPP), National Research and Innovation Agency (BRIN), Yogyakarta 55861, Indonesia
| | - Sukamto S. Mamada
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Tamalanrea, Makassar 90245, Indonesia
| | - Andi Dian Permana
- Department of Pharmaceutical Science and Technology, Faculty of Pharmacy, Hasanuddin University, Tamalanrea, Makassar 90245, Indonesia
| | | | - Deepak Chandran
- Department of Veterinary Sciences and Animal Husbandry, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University, Coimbatore 642109, India
| | - Talha Bin Emran
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School & Legorreta Cancer Center, Brown University, Providence, RI 02912, USA
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
| | - Jesus Simal-Gandara
- Universidade de Vigo, Nutrition and Bromatology Group, Analytical Chemistry and Food Science Department, Faculty of Science, E32004 Ourense, Spain
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17
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Magouliotis DE, Bareka M, Rad AA, Christodoulidis G, Athanasiou T. Demystifying the Value of Minimal Clinically Important Difference in the Cardiothoracic Surgery Context. Life (Basel) 2023; 13:716. [PMID: 36983869 PMCID: PMC10056462 DOI: 10.3390/life13030716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/08/2023] [Accepted: 03/01/2023] [Indexed: 03/09/2023] Open
Abstract
The aim of this review is to describe the different statistical methods used in estimating the minimal clinically important difference (MCID) for the assessment of quality of life (QOL)-related and clinical improvement interventions, along with their implementation in cardiothoracic surgery. A thorough literature search was performed in three databases (PubMed/Medline, Scopus, Google Scholar) for relevant articles from 1980 to 2022. We included articles that implemented and assessed statistical methods used to estimate the concept of MCID in cardiothoracic surgery. MCID has been successfully implemented in several medical specialties. Anchor-based and distribution-based methods are the most common approaches when evaluating the MCID. Nonetheless, we found only five studies investigating the MCID in the context of cardiothoracic surgery. Four of them used anchor-based approaches, and one used both anchor-based and distribution-based methods. MCID values were very variable depending on the methods applied, as was the clinical context of the study. The variables of interest were certain QOL measuring questionnaires, used as anchors. Multiple anchors and methods were applied, leading to different estimations of MCID. Since cardiothoracic surgery is related to important perioperative morbidity, MCID might represent an important and efficient adjunct tool to interpret clinical outcomes. The need for MCID methodology implementation is even higher in patients with heart failure undergoing cardiac surgery. More studies are needed to validate different MCID methods in this context.
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Affiliation(s)
- Dimitrios E. Magouliotis
- Unit of Quality Improvement, Department of Cardiothoracic Surgery, University of Thessaly, Biopolis, 41110 Larissa, Greece
| | - Metaxia Bareka
- Department of Anesthesiology, University of Thessaly, Biopolis, 41110 Larissa, Greece
| | - Arian Arjomandi Rad
- Department of Surgery and Cancer, Imperial College London, St Mary’s Hospital, London W2 1NY, UK
| | | | - Thanos Athanasiou
- Department of Surgery and Cancer, Imperial College London, St Mary’s Hospital, London W2 1NY, UK
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18
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Electroceuticals for Neurogastroenterology and Motility Disorders. Curr Gastroenterol Rep 2023; 25:91-97. [PMID: 36867326 PMCID: PMC10102147 DOI: 10.1007/s11894-023-00866-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/29/2022] [Indexed: 03/04/2023]
Abstract
PURPOSE OF REVIEW To provide an updated overview on use of electrostimulation in gastrointestinal motility disorders and obesity, with a focus on gastric electrical stimulation, vagal nerve stimulation and sacral nerve stimulation. RECENT FINDINGS Recent studies on gastric electrical stimulation for chronic vomiting showed a decrease in frequency of vomiting, but without significant improvement in quality of life. Percutaneous vagal nerve stimulation shows some promise for both symptoms of gastroparesis and IBS. Sacral nerve stimulation does not appear effective for constipation. Studies of electroceuticals for treatment of obesity have quite varied results with less clinical penetrance of the technology. Results of studies on the efficacy of electroceuticals have been variable depending on pathology but this area remains promising. Improved mechanistic understanding, technology and more controlled trials will be helpful to establish a clearer role for electrostimulation in treatment of various GI disorders.
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19
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Transcutaneous vagus nerve stimulation - A brief introduction and overview. Auton Neurosci 2022; 243:103038. [DOI: 10.1016/j.autneu.2022.103038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 09/25/2022] [Accepted: 09/25/2022] [Indexed: 12/28/2022]
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20
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Payne SC, Romas E, Hyakumura T, Muntz F, Fallon JB. Abdominal vagus nerve stimulation alleviates collagen-induced arthritis in rats. Front Neurosci 2022; 16:1012133. [PMID: 36478876 PMCID: PMC9721112 DOI: 10.3389/fnins.2022.1012133] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/31/2022] [Indexed: 09/10/2024] Open
Abstract
Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory disease. Despite therapeutic advances, a significant proportion of RA patients are resistant to pharmacological treatment. Stimulation of the cervical vagus nerve is a promising alternative bioelectric neuromodulation therapeutic approach. However, recent clinical trials show cervical vagus nerve stimulation (VNS) was not effective in a significant proportion of drug resistant RA patients. Here we aim to assess if abdominal vagus nerve stimulation reduces disease severity in a collagen-induced arthritis (CIA) rat model. The abdominal vagus nerve of female Dark Agouti rats was implanted and CIA induced using collagen type II injection. VNS (1.6 mA, 200 μs pulse width, 50 μs interphase gap, 27 Hz frequency) was applied to awake freely moving rats for 3 h/day (days 11-17). At 17 days following the collagen injection, unstimulated CIA rats (n = 8) had significantly worse disease activity index, tumor necrosis factor-alpha (TNF-α) and receptor activator of NFκB ligand (RANKL) levels, synovitis and cartilage damage than normal rats (n = 8, Kruskal-Wallis: P < 0.05). However, stimulated CIA rats (n = 5-6) had significantly decreased inflammatory scores and ankle swelling (Kruskal-Wallis: P < 0.05) compared to unstimulated CIA rats (n = 8). Levels of tumor necrosis factor-alpha (TNF-α) remained at undetectable levels in stimulated CIA rats while levels of receptor activator of NFκB ligand (RANKL) were significantly less in stimulated CIA rats compared to unstimulated CIA rats (P < 0.05). Histopathological score of inflammation and cartilage loss in stimulated CIA rats were no different from that of normal (P > 0.05). In conclusion, abdominal VNS alleviates CIA and could be a promising therapy for patients with RA.
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Affiliation(s)
- Sophie C. Payne
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Parkville, VIC, Australia
| | - Evange Romas
- Bionics Institute, East Melbourne, VIC, Australia
- Department of Rheumatology, St. Vincent’s Hospital Melbourne, Fitzroy, VIC, Australia
| | - Tomoko Hyakumura
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Parkville, VIC, Australia
| | - Fenella Muntz
- Experimental Sciences Medical Unit, St. Vincent’s Hospital Melbourne, Fitzroy, VIC, Australia
| | - James B. Fallon
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Parkville, VIC, Australia
- Department of Otolaryngology, University of Melbourne, Parkville, VIC, Australia
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21
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Alhawwash A, Muzquiz MI, Richardson L, Vetter C, Smolik M, Goodwill A, Yoshida K. In vivo peripheral nerve activation using sinusoidal low-frequency alternating currents. Artif Organs 2022; 46:2055-2065. [PMID: 35730955 PMCID: PMC9795871 DOI: 10.1111/aor.14347] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/19/2022] [Accepted: 06/09/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND The sinusoidal low-frequency alternating current (LFAC) waveform was explored recently as a novel means to evoke nerve conduction block. In the present work, we explored whether increasing the amplitude of the LFAC waveform results in nerve fiber activation in autonomic nerves. In-silico methods and preliminary work in somatic nerves indicated a potential frequency dependency on the threshold of activation. The Hering-Breuer (HB) reflex was used as a biomarker to detect cervical vagus nerve activation. METHODS Experiments were conducted in isoflurane-anesthetized swine (n = 5). Two stimulating bipolar cuff electrodes and a tripolar recording cuff electrode were implanted on the left vagus nerve. To ensure the electrical stimulation affects only the afferent pathways, the nerve was crushed caudal to the electrodes to eliminate cardiac effects. (1) Standard pulse stimulation (Vstim) using a monophasic train of pulses was applied through the caudal electrode to elicit HB reflex and to identify the activated nerve fiber type. (2) Continuous sinusoidal LFAC waveform with a frequency ranging from 5 through 20 Hz was applied to the rostral electrode without Vstim to explore the activation thresholds at each LFAC frequency. In both cases, the activation of nerve fibers was detected by a HB reflex-induced reduction in the breathing rate. RESULTS LFAC was found to be capable of eliciting an HB response. The LFAC activation thresholds were found to be frequency-dependent. The HB threshold was 1.02 ± 0.3 mAp at 5 Hz, 0.66 ± 0.3 mAp at 10 Hz, and 0.44 ± 0.2 mAp at 20 Hz. In comparison, it was 0.7 ± 0.47 mA for a 100 μs pulse. The LFAC amplitude was within the linear limits of the electrode interface. Damage to the cuff electrodes or the nerve tissues was not observed. Analysis of Vstim-based compound nerve action potentials (CNAP) indicated that the decrease in breathing rate was found to be correlated with the activation of slower components of the CNAP suggesting that LFAC reached and elicited responses from these slower fibers associated with afferents projecting to the HB response. CONCLUSIONS These results suggest the feasibility of the LFAC waveform at 5, 10, and 20 Hz to activate autonomic nerve fibers and potentially provide a new modality to the neurorehabilitation field.
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Affiliation(s)
- Awadh Alhawwash
- Weldon School of Biomedical EngineeringPurdue UniversityWest LafayetteIndianaUSA,Biomedical Technology DepartmentKing Saud UniversityRiyadhSaudi Arabia
| | - M. Ivette Muzquiz
- Department of Biomedical EngineeringIndiana University ‐ Purdue University IndianapolisIndianapolisIndianaUSA
| | - Lindsay Richardson
- Department of Biomedical EngineeringIndiana University ‐ Purdue University IndianapolisIndianapolisIndianaUSA
| | - Christian Vetter
- Department of Biomedical EngineeringIndiana University ‐ Purdue University IndianapolisIndianapolisIndianaUSA
| | - Macallister Smolik
- Department of BiologyIndiana University ‐ Purdue University IndianapolisIndianapolisIndianaUSA
| | - Adam Goodwill
- Department of Integrative Medical SciencesNortheast Ohio Medical UniversityRootstownOhioUSA
| | - Ken Yoshida
- Department of Biomedical EngineeringIndiana University ‐ Purdue University IndianapolisIndianapolisIndianaUSA
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22
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Kapralou AN, Chrousos GP. Metabolic effects of truncal vagotomy when combined with bariatric-metabolic surgery. Metabolism 2022; 135:155263. [PMID: 35835160 DOI: 10.1016/j.metabol.2022.155263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 06/30/2022] [Accepted: 07/04/2022] [Indexed: 11/25/2022]
Abstract
Bariatric-metabolic surgery (BMS) in patients with obesity frequently leads to remission of concurrent type 2 diabetes mellitus (T2DM), even before body weight loss takes place. This is probably based on the correction of a dysmetabolic cycle in the gastrointestinal physiology of T2DM that includes increased vagus-dependent exocrine pancreatic secretion (EPS) and, hence, amplified digestion and nutrient absorption. The resultant chronic exposure of tissues to high plasma levels of glucose, fatty acids and amino acids causes tissue resistance to the actions of insulin and, at a later stage, β-cell dysfunction and reduction of insulin release. We hypothesize that the addition of a surgical truncal vagotomy (TV) may improve and solidify the beneficial results of BMS on T2DM by stably decreasing EPS, - hence reducing the digestion and absorption of nutrients -, and increasing incretin secretion as a result of increased delivery of unabsorbed nutrients to the distal intestine. This hypothesis is supported by surgical data from gastrointestinal malignancies and peptic ulcer operations that include TV, as well as by vagal blockade studies. We suggest that TV may result in a stable reduction of EPS, and that its combination with the appropriate type of BΜS, may enhance and sustain the salutary effects of the latter on T2DM.
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Affiliation(s)
| | - George P Chrousos
- University Research Institute of Maternal and Child Health and Precision Medicine, UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens Medical School, Athens, Greece
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23
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Williams K, Nadler EP. The Role of Devices in the Management of Pediatric Obesity. Curr Obes Rep 2022; 11:55-60. [PMID: 35737260 DOI: 10.1007/s13679-022-00476-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/18/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE OF REVIEW Approximately 20% of children and adolescents in the USA suffer from obesity with significant long-term effects well into adulthood. Metabolic and bariatric surgery, although well adopted in the adult population, has been underutilized in children. RECENT FINDINGS There are four categories of weight loss devices regulated by the Food and Drug Administration for use in adults - gastric bands, gastric balloon systems, electrical stimulation systems, and gastric emptying systems. In this commentary we discuss the role these devices may play in increasing the adoption of procedural intervention for severe obesity in children and adolescents.
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Affiliation(s)
- Kibileri Williams
- Division of Pediatric Surgery, Children's National Hospital, 111 Michigan Ave. NW, Washington, DC, 20010, USA.
| | - Evan P Nadler
- Division of Pediatric Surgery, Children's National Hospital, 111 Michigan Ave. NW, Washington, DC, 20010, USA.
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24
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Chi ZC. Metabolic associated fatty liver disease is a disease related to sympathetic nervous system activation. Shijie Huaren Xiaohua Zazhi 2022; 30:465-476. [DOI: 10.11569/wcjd.v30.i11.465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Strong evidence from animal and human studies shows that sympathetic nervous system (SNS) activation is a key factor in the development of metabolic associated fatty liver disease (MAFLD). Activation of the sympathetic nervous system plays an important role in the pathogenesis of obesity, metabolic syndrome, diabetes, hypertension, and MAFLD. When genetically susceptible subjects are exposed to a variety of epigenetic changes, their liver damage may develop into MAFLD. Thus, the pathogenesis of MAFLD is complex, involving the complex interaction of insulin resistance, abnormal hormone secretion, obesity, diet, genetic factors, immune activation, gut microbiota, and other factors. In these processes, the role of sympathetic nerves cannot be underestimated. Notably, SNS has been proposed as a therapeutic target for MAFLD by inhibiting sympathetic nerves. It is worthy of further discussion and research.
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Affiliation(s)
- Zhao-Chun Chi
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
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25
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Ahmed U, Chang YC, Zafeiropoulos S, Nassrallah Z, Miller L, Zanos S. Strategies for precision vagus neuromodulation. Bioelectron Med 2022; 8:9. [PMID: 35637543 PMCID: PMC9150383 DOI: 10.1186/s42234-022-00091-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/05/2022] [Indexed: 12/21/2022] Open
Abstract
The vagus nerve is involved in the autonomic regulation of physiological homeostasis, through vast innervation of cervical, thoracic and abdominal visceral organs. Stimulation of the vagus with bioelectronic devices represents a therapeutic opportunity for several disorders implicating the autonomic nervous system and affecting different organs. During clinical translation, vagus stimulation therapies may benefit from a precision medicine approach, in which stimulation accommodates individual variability due to nerve anatomy, nerve-electrode interface or disease state and aims at eliciting therapeutic effects in targeted organs, while minimally affecting non-targeted organs. In this review, we discuss the anatomical and physiological basis for precision neuromodulation of the vagus at the level of nerve fibers, fascicles, branches and innervated organs. We then discuss different strategies for precision vagus neuromodulation, including fascicle- or fiber-selective cervical vagus nerve stimulation, stimulation of vagal branches near the end-organs, and ultrasound stimulation of vagus terminals at the end-organs themselves. Finally, we summarize targets for vagus neuromodulation in neurological, cardiovascular and gastrointestinal disorders and suggest potential precision neuromodulation strategies that could form the basis for effective and safe therapies.
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Affiliation(s)
- Umair Ahmed
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Yao-Chuan Chang
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Stefanos Zafeiropoulos
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Zeinab Nassrallah
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - Larry Miller
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Stavros Zanos
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA.
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA.
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26
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Goggins E, Mitani S, Tanaka S. Clinical perspectives on vagus nerve stimulation: present and future. Clin Sci (Lond) 2022; 136:695-709. [PMID: 35536161 PMCID: PMC9093220 DOI: 10.1042/cs20210507] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 04/15/2022] [Accepted: 04/22/2022] [Indexed: 12/30/2022]
Abstract
The vagus nerve, the great wanderer, is involved in numerous processes throughout the body and vagus nerve stimulation (VNS) has the potential to modulate many of these functions. This wide-reaching capability has generated much interest across a range of disciplines resulting in several clinical trials and studies into the mechanistic basis of VNS. This review discusses current preclinical and clinical evidence supporting the efficacy of VNS in different diseases and highlights recent advancements. Studies that provide insights into the mechanism of VNS are considered.
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Affiliation(s)
- Eibhlin Goggins
- Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA, U.S.A
| | - Shuhei Mitani
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Shinji Tanaka
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
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27
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Acute vagus nerve stimulation does not affect liking or wanting ratings of food in healthy participants. Appetite 2021; 169:105813. [PMID: 34798227 DOI: 10.1016/j.appet.2021.105813] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 11/12/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023]
Abstract
The vagus nerve plays a vital role in the regulation of food intake and vagal afferent signals may help regulate food cue reactivity by providing negative homeostatic feedback. Despite strong evidence from preclinical studies on vagal afferent "satiety" signals in guiding food intake, evidence from human studies is largely inconclusive to date. Here, we investigated the acute effects of left or right transcutaneous auricular vagus nerve stimulation (taVNS) on subjective ratings of wanting and liking of various food and non-food items in 82 healthy participants (46 women, MBMI = 23.1 kg/m2). In contrast to previous reports in patients with depression, we found moderate to anecdotal evidence supporting the absence of taVNS-induced changes in food ratings. To test whether the absence of taVNS effects on food ratings is due to heterogeneity in the sample, we conducted post hoc subgroup analyses by splitting the data according to stimulation side and sex (between-subject factors) as well as caloric density, perceived healthiness, and flavor (sweet vs. savory) of the food (within-subject factors). This multiverse analysis largely supported the absence of taVNS-induced changes since the strongest subgroup effects provided only anecdotal evidence in favor of taVNS-induced changes. We conclude that acute taVNS only has a marginal effect on subjective ratings of food, suggesting that it is an unlikely mechanism for the reported long-term effects of VNS on body weight. In light of an absence of acute taVNS effects on conscious food liking and wanting, our results call for future research on the correspondence between acute and chronic effects of vagal afferent stimulation.
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Gouveia FV, Silk E, Davidson B, Pople CB, Abrahao A, Hamilton J, Ibrahim GM, Müller DJ, Giacobbe P, Lipsman N, Hamani C. A systematic review on neuromodulation therapies for reducing body weight in patients with obesity. Obes Rev 2021; 22:e13309. [PMID: 34337843 DOI: 10.1111/obr.13309] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 06/01/2021] [Accepted: 06/02/2021] [Indexed: 12/11/2022]
Abstract
The global prevalence of obesity increases yearly along with a rising demand for efficacious, safe, and accessible treatments. Neuromodulation interventions (i.e., deep brain stimulation [DBS], transcranial magnetic stimulation [TMS], transcranial direct current stimulation [tDCS], percutaneous neurostimulation [PENS], vagus nerve stimulation [VNS], and gastric electrical stimulation [GES]) have been proposed as novel therapies. This systematic review sought to examine the safety and efficacy of neuromodulation therapies in reducing body weight in patients with obesity. Using PRISMA guidelines, we performed a systematic review for studies on neuromodulation for the treatment of obesity, resulting in 60 trials included (7 DBS, 5 TMS, 7 tDCS, 17 PENS and VNS, and 24 GES; a total of 3,042 participants). While promising results have been reported in open label studies, double-blinded randomized clinical trials often did not reach their primary endpoints, with no technique inducing a striking reduction in body weight. Bearing in mind the complexity and multifactorial nature of obesity, it is possible that a single treatment may not be enough for patients to lose or maintain the weight lost at long term.
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Affiliation(s)
| | - Esther Silk
- Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Benjamin Davidson
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.,Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | - Christopher B Pople
- Sunnybrook Research Institute, Toronto, Ontario, Canada.,Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Agessandro Abrahao
- Sunnybrook Research Institute, Toronto, Ontario, Canada.,Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.,Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | - Jill Hamilton
- Division of Endocrinology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - George M Ibrahim
- Division of Neurosurgery, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Daniel J Müller
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Peter Giacobbe
- Sunnybrook Research Institute, Toronto, Ontario, Canada.,Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.,Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | - Nir Lipsman
- Sunnybrook Research Institute, Toronto, Ontario, Canada.,Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.,Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | - Clement Hamani
- Sunnybrook Research Institute, Toronto, Ontario, Canada.,Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.,Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
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29
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Antoniak K, Hansdorfer-Korzon R, Mrugacz M, Zorena K. Adipose Tissue and Biological Factors. Possible Link between Lymphatic System Dysfunction and Obesity. Metabolites 2021; 11:metabo11090617. [PMID: 34564433 PMCID: PMC8464765 DOI: 10.3390/metabo11090617] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 12/27/2022] Open
Abstract
The World Health Organization (WHO) has recognised obesity as one of the top ten threats to human health. Obesity is not only a state of abnormally increased adipose tissue in the body, but also of an increased release of biologically active metabolites. Moreover, obesity predisposes the development of metabolic syndrome and increases the incidence of type 2 diabetes (T2DM), increases the risk of developing insulin resistance, atherosclerosis, ischemic heart disease, polycystic ovary syndrome, hypertension and cancer. The lymphatic system is a one-directional network of thin-walled capillaries and larger vessels covered by a continuous layer of endothelial cells that provides a unidirectional conduit to return filtered arterial and tissue metabolites towards the venous circulation. Recent studies have shown that obesity can markedly impair lymphatic function. Conversely, dysfunction in the lymphatic system may also be involved in the pathogenesis of obesity. This review highlights the important findings regarding obesity related to lymphatic system dysfunction, including clinical implications and experimental studies. Moreover, we present the role of biological factors in the pathophysiology of the lymphatic system and we propose the possibility of a therapy supporting the function of the lymphatic system in the course of obesity.
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Affiliation(s)
- Klaudia Antoniak
- Department of Immunobiology and Environment Microbiology, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland;
| | - Rita Hansdorfer-Korzon
- Department of Physical Therapy, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland;
| | - Małgorzata Mrugacz
- Department of Ophthalmology and Eye Rehabilitation, Medical University of Bialystok, Kilinskiego 1, 15-089 Białystok, Poland;
| | - Katarzyna Zorena
- Department of Immunobiology and Environment Microbiology, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland;
- Correspondence: ; Tel./Fax: +48-583491765
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30
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Beard DJ, Campbell MK, Blazeby JM, Carr AJ, Weijer C, Cuthbertson BH, Buchbinder R, Pinkney T, Bishop FL, Pugh J, Cousins S, Harris I, Lohmander LS, Blencowe N, Gillies K, Probst P, Brennan C, Cook A, Farrar-Hockley D, Savulescu J, Huxtable R, Rangan A, Tracey I, Brocklehurst P, Ferreira ML, Nicholl J, Reeves BC, Hamdy F, Rowley SC, Lee N, Cook JA. Placebo comparator group selection and use in surgical trials: the ASPIRE project including expert workshop. Health Technol Assess 2021; 25:1-52. [PMID: 34505829 PMCID: PMC8450778 DOI: 10.3310/hta25530] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. OBJECTIVES To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials. DESIGN To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout. SETTING A workshop to discuss and summarise the existing knowledge and to develop the new guidelines. RESULTS To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect. CONCLUSIONS The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial. LIMITATIONS Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS. FUTURE WORK Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space. FUNDING Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council-National Institute for Health Research Methodology Research programme.
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Affiliation(s)
- David J Beard
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | | | - Jane M Blazeby
- Centre for Surgical Research, NIHR Bristol and Weston Biomedical Research Centre, Population Health Sciences, University of Bristol, Bristol, UK
| | - Andrew J Carr
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Charles Weijer
- Departments of Medicine, Epidemiology and Biostatistics, and Philosophy, Western University, London, ON, Canada
| | - Brian H Cuthbertson
- Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
| | - Rachelle Buchbinder
- Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Thomas Pinkney
- Academic Department of Surgery, University of Birmingham, Queen Elizabeth Hospital Birmingham, Birmingham, UK
| | - Felicity L Bishop
- Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK
| | - Jonathan Pugh
- The Oxford Uehiro Centre for Practical Ethics, University of Oxford, Oxford, UK
| | - Sian Cousins
- Centre for Surgical Research, NIHR Bristol and Weston Biomedical Research Centre, Population Health Sciences, University of Bristol, Bristol, UK
| | - Ian Harris
- Faculty of Medicine, South Western Sydney Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - L Stefan Lohmander
- Department of Clinical Sciences Lund, Orthopedics, Clinical Epidemiology Unit, Lund University, Lund, Sweden
| | - Natalie Blencowe
- Centre for Surgical Research, NIHR Bristol and Weston Biomedical Research Centre, Population Health Sciences, University of Bristol, Bristol, UK
| | - Katie Gillies
- Health Services Research Unit, University of Aberdeen, Aberdeen, UK
| | - Pascal Probst
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | | | - Andrew Cook
- Wessex Institute, University of Southampton, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | | | - Julian Savulescu
- The Oxford Uehiro Centre for Practical Ethics, University of Oxford, Oxford, UK
| | - Richard Huxtable
- Centre for Surgical Research, NIHR Bristol and Weston Biomedical Research Centre, Population Health Sciences, University of Bristol, Bristol, UK
| | - Amar Rangan
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
- Department of Health Sciences, University of York, York, UK
| | - Irene Tracey
- Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Peter Brocklehurst
- Birmingham Clinical Trials Unit, Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Manuela L Ferreira
- Faculty of Medicine and Health, Institute of Bone and Joint Research, Northern Clinical School, The University of Sydney, Sydney, NSW, Australia
| | - Jon Nicholl
- School of Health and Related Research, University of Sheffield, Sheffield, UK
| | - Barnaby C Reeves
- Clinical Trials Evaluation Unit Bristol Medical School, University of Bristol, Bristol Royal Infirmary, Bristol, UK
| | - Freddie Hamdy
- Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | | | - Naomi Lee
- Editorial Department, The Lancet, London, UK
| | - Jonathan A Cook
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
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31
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Kuchler JC, Siqueira BS, Ceglarek VM, Chasko FV, Moura IC, Sczepanhak BF, Vettorazzi JF, Balbo SL, Grassiolli S. The Vagus Nerve and Spleen: Influence on White Adipose Mass and Histology of Obese and Non-obese Rats. Front Physiol 2021; 12:672027. [PMID: 34248663 PMCID: PMC8269450 DOI: 10.3389/fphys.2021.672027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/30/2021] [Indexed: 11/30/2022] Open
Abstract
The vagus nerve (VN) and spleen represent a complex interface between neural and immunological functions, affecting both energy metabolism and white adipose tissue (WAT) content. Here, we evaluated whether vagal and splenic axis participates in WAT mass regulation in obese and non-obese male Wistar rats. High doses of monosodium glutamate (M; 4 g/Kg) were administered during the neonatal period to induce hypothalamic lesion and obesity (M-Obese rats). Non-obese or Control (CTL) rats received equimolar saline. At 60 days of life, M-Obese and CTL rats were randomly distributed into experimental subgroups according to the following surgical procedures: sham, subdiaphragmatic vagotomy (SV), splenectomy (SPL), and SV + SPL (n = 11 rats/group). At 150 days of life and after 12 h of fasting, rats were euthanized, blood was collected, and the plasma levels of glucose, triglycerides, cholesterol, insulin, and interleukin 10 (IL10) were analyzed. The visceral and subcutaneous WAT depots were excised, weighed, and histologically evaluated for number and size of adipocytes as well as IL10 protein expression. M-Obese rats showed higher adiposity, hyperinsulinemia, hypertriglyceridemia, and insulin resistance when compared with CTL groups (p < 0.05). In CTL and M-Obese rats, SV reduced body weight gain and triglycerides levels, diminishing adipocyte size without changes in IL10 expression in WAT (p< 0.05). The SV procedure resulted in high IL10 plasma levels in CTL rats, but not in the M-Obese group. The splenectomy prevented the SV anti-adiposity effects, as well as blocked the elevation of IL10 levels in plasma of CTL rats. In contrast, neither SV nor SPL surgeries modified the plasma levels of IL10 and IL10 protein expression in WAT from M-Obese rats. In conclusion, vagotomy promotes body weight and adiposity reduction, elevating IL10 plasma levels in non-obese animals, in a spleen-dependent manner. Under hypothalamic obesity conditions, VN ablation also reduces body weight gain and adiposity, improving insulin sensitivity without changes in IL10 protein expression in WAT or IL10 plasma levels, in a spleen-independent manner. Our findings indicate that the vagal-spleen axis influence the WAT mass in a health state, while this mechanism seems to be disturbed in hypothalamic obese animals.
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Affiliation(s)
- Joice Cristina Kuchler
- Postgraduate Program in Applied Health Sciences, Western Paraná State University, Francisco Beltrão, Brazil
- Laboratory of Endocrine and Metabolic Physiology, Postgraduate Program in Biosciences and Health, Western Paraná State University, Cascavel, Brazil
| | - Bruna Schumaker Siqueira
- Laboratory of Endocrine and Metabolic Physiology, Postgraduate Program in Biosciences and Health, Western Paraná State University, Cascavel, Brazil
| | - Vanessa Marieli Ceglarek
- Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
- Postgraduate Program in Biological Sciences, Physiology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Fernanda Vigilato Chasko
- Laboratory of Endocrine and Metabolic Physiology, Postgraduate Program in Biosciences and Health, Western Paraná State University, Cascavel, Brazil
| | - Isllany Carvalho Moura
- Laboratory of Endocrine and Metabolic Physiology, Postgraduate Program in Biosciences and Health, Western Paraná State University, Cascavel, Brazil
| | - Bruna Fatima Sczepanhak
- Laboratory of Endocrine and Metabolic Physiology, Postgraduate Program in Biosciences and Health, Western Paraná State University, Cascavel, Brazil
| | | | - Sandra Lucinei Balbo
- Laboratory of Endocrine and Metabolic Physiology, Postgraduate Program in Biosciences and Health, Western Paraná State University, Cascavel, Brazil
| | - Sabrina Grassiolli
- Postgraduate Program in Applied Health Sciences, Western Paraná State University, Francisco Beltrão, Brazil
- Laboratory of Endocrine and Metabolic Physiology, Postgraduate Program in Biosciences and Health, Western Paraná State University, Cascavel, Brazil
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32
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Loper H, Leinen M, Bassoff L, Sample J, Romero-Ortega M, Gustafson KJ, Taylor DM, Schiefer MA. Both high fat and high carbohydrate diets impair vagus nerve signaling of satiety. Sci Rep 2021; 11:10394. [PMID: 34001925 PMCID: PMC8128917 DOI: 10.1038/s41598-021-89465-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 04/26/2021] [Indexed: 11/23/2022] Open
Abstract
Obesity remains prevalent in the US. One potential treatment is vagus nerve stimulation (VNS), which activates the sensory afferents innervating the stomach that convey stomach volume and establish satiety. However, current VNS approaches and stimulus optimization could benefit from additional understanding of the underlying neural response to stomach distension. In this study, obesity-prone Sprague Dawley rats consumed a standard, high-carbohydrate, or high-fat diet for several months, leading to diet-induced obesity in the latter two groups. Under anesthesia, the neural activity in the vagus nerve was recorded with a penetrating microelectrode array while the stomach was distended with an implanted balloon. Vagal tone during distension was compared to baseline tone prior to distension. Responses were strongly correlated with stomach distension, but the sensitivity to distension was significantly lower in animals that had been fed the nonstandard diets. The results indicate that both high fat and high carbohydrate diets impair vagus activity.
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Affiliation(s)
- Hailley Loper
- Malcom Randall VA Medical Center, Gainesville, FL, USA.,Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA
| | - Monique Leinen
- Malcom Randall VA Medical Center, Gainesville, FL, USA.,Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA
| | - Logan Bassoff
- Malcom Randall VA Medical Center, Gainesville, FL, USA.,Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA
| | - Jack Sample
- Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA.,College of Medicine & Life Sciences, University of Toledo, Toledo, OH, USA
| | - Mario Romero-Ortega
- Departments of Biomedical Engineering and Biomedical Sciences, University of Houston, Houston, TX, USA
| | - Kenneth J Gustafson
- Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA.,Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Dawn M Taylor
- Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA.,Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.,Department of Neurosciences, The Cleveland Clinic, Cleveland, OH, USA
| | - Matthew A Schiefer
- Malcom Randall VA Medical Center, Gainesville, FL, USA. .,Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA. .,Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.
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33
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Farmer AD, Strzelczyk A, Finisguerra A, Gourine AV, Gharabaghi A, Hasan A, Burger AM, Jaramillo AM, Mertens A, Majid A, Verkuil B, Badran BW, Ventura-Bort C, Gaul C, Beste C, Warren CM, Quintana DS, Hämmerer D, Freri E, Frangos E, Tobaldini E, Kaniusas E, Rosenow F, Capone F, Panetsos F, Ackland GL, Kaithwas G, O'Leary GH, Genheimer H, Jacobs HIL, Van Diest I, Schoenen J, Redgrave J, Fang J, Deuchars J, Széles JC, Thayer JF, More K, Vonck K, Steenbergen L, Vianna LC, McTeague LM, Ludwig M, Veldhuizen MG, De Couck M, Casazza M, Keute M, Bikson M, Andreatta M, D'Agostini M, Weymar M, Betts M, Prigge M, Kaess M, Roden M, Thai M, Schuster NM, Montano N, Hansen N, Kroemer NB, Rong P, Fischer R, Howland RH, Sclocco R, Sellaro R, Garcia RG, Bauer S, Gancheva S, Stavrakis S, Kampusch S, Deuchars SA, Wehner S, Laborde S, Usichenko T, Polak T, Zaehle T, Borges U, Teckentrup V, Jandackova VK, Napadow V, Koenig J. International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020). Front Hum Neurosci 2021; 14:568051. [PMID: 33854421 PMCID: PMC8040977 DOI: 10.3389/fnhum.2020.568051] [Citation(s) in RCA: 175] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 09/01/2020] [Indexed: 12/18/2022] Open
Abstract
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.
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Affiliation(s)
- Adam D. Farmer
- Department of Gastroenterology, University Hospitals of North Midlands NHS Trust, Stoke on Trent, United Kingdom
| | - Adam Strzelczyk
- Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe-University Frankfurt, Frankfurt am Main, Germany
| | | | - Alexander V. Gourine
- Department of Neuroscience, Physiology and Pharmacology, Centre for Cardiovascular and Metabolic Neuroscience, University College London, London, United Kingdom
| | - Alireza Gharabaghi
- Institute for Neuromodulation and Neurotechnology, University Hospital and University of Tuebingen, Tuebingen, Germany
| | - Alkomiet Hasan
- Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, University of Augsburg, Augsburg, Germany
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
| | - Andreas M. Burger
- Laboratory for Biological Psychology, Faculty of Psychology and Educational Sciences, University of Leuven, Leuven, Belgium
| | | | - Ann Mertens
- Department of Neurology, Institute for Neuroscience, 4Brain, Ghent University Hospital, Gent, Belgium
| | - Arshad Majid
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom
| | - Bart Verkuil
- Clinical Psychology and the Leiden Institute of Brain and Cognition, Leiden University, Leiden, Netherlands
| | - Bashar W. Badran
- Department of Psychiatry, Medical University of South Carolina, Charleston, SC, United States
| | - Carlos Ventura-Bort
- Department of Biological Psychology and Affective Science, Faculty of Human Sciences, University of Potsdam, Potsdam, Germany
| | - Charly Gaul
- Migraine and Headache Clinic Koenigstein, Königstein im Taunus, Germany
| | - Christian Beste
- Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany
| | | | - Daniel S. Quintana
- NORMENT, Division of Mental Health and Addiction, University of Oslo and Oslo University Hospital, Oslo, Norway
- Department of Psychology, University of Oslo, Oslo, Norway
- KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway
| | - Dorothea Hämmerer
- Medical Faculty, Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University, Magdeburg, Germany
- Institute of Cognitive Neuroscience, University College London, London, United Kingdom
- Center for Behavioral Brain Sciences Magdeburg (CBBS), Otto-von-Guericke University, Magdeburg, Germany
| | - Elena Freri
- Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Eleni Frangos
- Pain and Integrative Neuroscience Branch, National Center for Complementary and Integrative Health, NIH, Bethesda, MD, United States
| | - Eleonora Tobaldini
- Department of Internal Medicine, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Eugenijus Kaniusas
- Institute of Electrodynamics, Microwave and Circuit Engineering, TU Wien, Vienna, Austria
- SzeleSTIM GmbH, Vienna, Austria
| | - Felix Rosenow
- Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe-University Frankfurt, Frankfurt am Main, Germany
| | - Fioravante Capone
- Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Fivos Panetsos
- Faculty of Biology and Faculty of Optics, Complutense University of Madrid and Institute for Health Research, San Carlos Clinical Hospital (IdISSC), Madrid, Spain
| | - Gareth L. Ackland
- Translational Medicine and Therapeutics, Barts and The London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Gaurav Kaithwas
- Department of Pharmaceutical Sciences, School of Biosciences and Biotechnology, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow, India
| | - Georgia H. O'Leary
- Department of Psychiatry, Medical University of South Carolina, Charleston, SC, United States
| | - Hannah Genheimer
- Department of Biological Psychology, Clinical Psychology and Psychotherapy, University of Würzburg, Würzburg, Germany
| | - Heidi I. L. Jacobs
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Maastricht, Netherlands
| | - Ilse Van Diest
- Research Group Health Psychology, Faculty of Psychology and Educational Sciences, University of Leuven, Leuven, Belgium
| | - Jean Schoenen
- Headache Research Unit, Department of Neurology-Citadelle Hospital, University of Liège, Liège, Belgium
| | - Jessica Redgrave
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom
| | - Jiliang Fang
- Functional Imaging Lab, Department of Radiology, Guang An Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jim Deuchars
- School of Biomedical Science, Faculty of Biological Science, University of Leeds, Leeds, United Kingdom
| | - Jozsef C. Széles
- Division for Vascular Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Julian F. Thayer
- Department of Psychological Science, University of California, Irvine, Irvine, CA, United States
| | - Kaushik More
- Institute for Cognitive Neurology and Dementia Research, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
- Neuromodulatory Networks, Leibniz Institute for Neurobiology, Magdeburg, Germany
| | - Kristl Vonck
- Department of Neurology, Institute for Neuroscience, 4Brain, Ghent University Hospital, Gent, Belgium
| | - Laura Steenbergen
- Clinical and Cognitive Psychology and the Leiden Institute of Brain and Cognition, Leiden University, Leiden, Netherlands
| | - Lauro C. Vianna
- NeuroV̇ASQ̇ - Integrative Physiology Laboratory, Faculty of Physical Education, University of Brasilia, Brasilia, Brazil
| | - Lisa M. McTeague
- Department of Psychiatry, Medical University of South Carolina, Charleston, SC, United States
| | - Mareike Ludwig
- Department of Anatomy, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Maria G. Veldhuizen
- Mental Health and Wellbeing Research Group, Vrije Universiteit Brussel, Brussels, Belgium
| | - Marijke De Couck
- Faculty of Health Care, University College Odisee, Aalst, Belgium
- Division of Epileptology, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
| | - Marina Casazza
- Department of Neurosurgery, University of Tübingen, Tübingen, Germany
| | - Marius Keute
- Institute for Neuromodulation and Neurotechnology, University Hospital and University of Tuebingen, Tuebingen, Germany
| | - Marom Bikson
- Department of Biomedical Engineering, City College of New York, New York, NY, United States
| | - Marta Andreatta
- Department of Biological Psychology, Clinical Psychology and Psychotherapy, University of Würzburg, Würzburg, Germany
- Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, Netherlands
| | - Martina D'Agostini
- Research Group Health Psychology, Faculty of Psychology and Educational Sciences, University of Leuven, Leuven, Belgium
| | - Mathias Weymar
- Department of Biological Psychology and Affective Science, Faculty of Human Sciences, University of Potsdam, Potsdam, Germany
- Faculty of Health Sciences Brandenburg, University of Potsdam, Potsdam, Germany
| | - Matthew Betts
- Department of Anatomy, Faculty of Medicine, Mersin University, Mersin, Turkey
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Magdeburg, Germany
- Center for Behavioral Brain Sciences, Otto-von-Guericke University, Magdeburg, Germany
| | - Matthias Prigge
- Neuromodulatory Networks, Leibniz Institute for Neurobiology, Magdeburg, Germany
| | - Michael Kaess
- University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland
- Section for Translational Psychobiology in Child and Adolescent Psychiatry, Department of Child and Adolescent Psychiatry, Centre for Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany
| | - Michael Roden
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research, Munich, Germany
| | - Michelle Thai
- Department of Psychology, College of Liberal Arts, University of Minnesota, Minneapolis, MN, United States
| | - Nathaniel M. Schuster
- Department of Anesthesiology, Center for Pain Medicine, University of California, San Diego Health System, La Jolla, CA, United States
| | - Nicola Montano
- Department of Internal Medicine, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Niels Hansen
- Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany
- Laboratory of Systems Neuroscience and Imaging in Psychiatry (SNIPLab), University of Göttingen, Göttingen, Germany
| | - Nils B. Kroemer
- Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
| | - Peijing Rong
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - Rico Fischer
- Department of Psychology, University of Greifswald, Greifswald, Germany
| | - Robert H. Howland
- Department of Psychiatry, University of Pittsburgh School of Medicine, UPMC Western Psychiatric Hospital, Pittsburgh, PA, United States
| | - Roberta Sclocco
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States
- Department of Radiology, Logan University, Chesterfield, MO, United States
| | - Roberta Sellaro
- Cognitive Psychology Unit, Institute of Psychology, Leiden University, Leiden, Netherlands
- Leiden Institute for Brain and Cognition, Leiden, Netherlands
- Department of Developmental Psychology and Socialisation, University of Padova, Padova, Italy
| | - Ronald G. Garcia
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
- Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Sebastian Bauer
- Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe-University Frankfurt, Frankfurt am Main, Germany
| | - Sofiya Gancheva
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Stavros Stavrakis
- Faculty of Biological Science, School of Biomedical Science, University of Leeds, Leeds, United Kingdom
| | - Stefan Kampusch
- Institute of Electrodynamics, Microwave and Circuit Engineering, TU Wien, Vienna, Austria
- SzeleSTIM GmbH, Vienna, Austria
| | - Susan A. Deuchars
- School of Biomedical Science, Faculty of Biological Science, University of Leeds, Leeds, United Kingdom
| | - Sven Wehner
- Department of Surgery, University Hospital Bonn, Bonn, Germany
| | - Sylvain Laborde
- Department of Performance Psychology, Institute of Psychology, Deutsche Sporthochschule, Köln, Germany
| | - Taras Usichenko
- Department of Anesthesiology, University Medicine Greifswald, Greifswald, Germany
- Department of Anesthesia, McMaster University, Hamilton, ON, Canada
| | - Thomas Polak
- Laboratory of Functional Neurovascular Diagnostics, AG Early Diagnosis of Dementia, Department of Psychiatry, Psychosomatics and Psychotherapy, University Clinic Würzburg, Würzburg, Germany
| | - Tino Zaehle
- Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany
| | - Uirassu Borges
- Department of Performance Psychology, Institute of Psychology, Deutsche Sporthochschule, Köln, Germany
- Department of Social and Health Psychology, Institute of Psychology, Deutsche Sporthochschule, Köln, Germany
| | - Vanessa Teckentrup
- Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
| | - Vera K. Jandackova
- Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, Ostrava, Czechia
- Department of Human Movement Studies, Faculty of Education, University of Ostrava, Ostrava, Czechia
| | - Vitaly Napadow
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States
- Department of Radiology, Logan University, Chesterfield, MO, United States
| | - Julian Koenig
- University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland
- Section for Experimental Child and Adolescent Psychiatry, Department of Child and Adolescent Psychiatry, Centre for Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany
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Cracchiolo M, Ottaviani MM, Panarese A, Strauss I, Vallone F, Mazzoni A, Micera S. Bioelectronic medicine for the autonomic nervous system: clinical applications and perspectives. J Neural Eng 2021; 18. [PMID: 33592597 DOI: 10.1088/1741-2552/abe6b9] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 02/16/2021] [Indexed: 12/11/2022]
Abstract
Bioelectronic medicine (BM) is an emerging new approach for developing novel neuromodulation therapies for pathologies that have been previously treated with pharmacological approaches. In this review, we will focus on the neuromodulation of autonomic nervous system (ANS) activity with implantable devices, a field of BM that has already demonstrated the ability to treat a variety of conditions, from inflammation to metabolic and cognitive disorders. Recent discoveries about immune responses to ANS stimulation are the laying foundation for a new field holding great potential for medical advancement and therapies and involving an increasing number of research groups around the world, with funding from international public agencies and private investors. Here, we summarize the current achievements and future perspectives for clinical applications of neural decoding and stimulation of the ANS. First, we present the main clinical results achieved so far by different BM approaches and discuss the challenges encountered in fully exploiting the potential of neuromodulatory strategies. Then, we present current preclinical studies aimed at overcoming the present limitations by looking for optimal anatomical targets, developing novel neural interface technology, and conceiving more efficient signal processing strategies. Finally, we explore the prospects for translating these advancements into clinical practice.
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Affiliation(s)
- Marina Cracchiolo
- The BioRobotics Institute and Department of Excellence in Robotics & AI, The BioRobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Matteo Maria Ottaviani
- The BioRobotics Institute and Department of Excellence in Robotics & AI, The BioRobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Alessandro Panarese
- The BioRobotics Institute and Department of Excellence in Robotics & AI, The BioRobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Ivo Strauss
- The BioRobotics Institute and Department of Excellence in Robotics & AI, The BioRobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Fabio Vallone
- The BioRobotics Institute and Department of Excellence in Robotics & AI, The BioRobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Alberto Mazzoni
- The BioRobotics Institute and Department of Excellence in Robotics & AI, The BioRobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Silvestro Micera
- The BioRobotics Institute and Department of Excellence in Robotics & AI, The BioRobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy.,Bertarelli Foundation Chair in Translational NeuroEngineering, Centre for Neuroprosthetics and Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
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Zhuo J, Ou Z, Zhang Y, Jackson EM, Shankar SS, McPheeters MT, Ford JB, Jansen ED, Chiel HJ, Jenkins MW. Isotonic ion replacement can lower the threshold for selective infrared neural inhibition. NEUROPHOTONICS 2021; 8:015005. [PMID: 33628860 PMCID: PMC7893321 DOI: 10.1117/1.nph.8.1.015005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 01/21/2021] [Indexed: 06/12/2023]
Abstract
Significance: Infrared (IR) inhibition can selectively block peripheral sensory nerve fibers, a potential treatment for autonomic-dysfunction-related diseases (e.g., neuropathic pain and interstitial cystitis). Lowering the IR inhibition threshold can increase its translational potentials. Aim: Infrared induces inhibition by enhancing potassium channel activation. We hypothesized that the IR dose threshold could be reduced by combining it with isotonic ion replacement. Approach: We tested the IR inhibition threshold on the pleural-abdominal connective of Aplysia californica. Using a customized chamber system, the IR inhibition was applied either in normal saline or in isotonic ion-replaced saline, which could be high glucose saline, high choline saline, or high glucose/high choline saline. Each modified saline was at a subthreshold concentration for inhibiting neural conduction. Results: We showed that isotonically replacing ions in saline with glucose and/or choline can reduce the IR threshold and temperature threshold of neural inhibition. Furthermore, the size selectivity of IR inhibition was preserved when combined with high glucose/high choline saline. Conclusions: The present work of IR inhibition combined with isotonic ion replacement will guide further development of a more effective size-selective IR inhibition modality for future research and translational applications.
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Affiliation(s)
- Junqi Zhuo
- Case Western Reserve University, Department of Biomedical Engineering, Cleveland, Ohio, United States
| | - Zihui Ou
- Case Western Reserve University, Department of Biology, Cleveland, Ohio, United States
| | - Yuhan Zhang
- Case Western Reserve University, Department of Biology, Cleveland, Ohio, United States
| | - Elizabeth M. Jackson
- Case Western Reserve University, Department of Biology, Cleveland, Ohio, United States
| | - Sachin S. Shankar
- Case Western Reserve University, Department of Biomedical Engineering, Cleveland, Ohio, United States
| | - Matthew T. McPheeters
- Case Western Reserve University, Department of Biomedical Engineering, Cleveland, Ohio, United States
| | - Jeremy B. Ford
- Vanderbilt University, Department of Biomedical Engineering, Nashville, Tennessee, United States
- Vanderbilt University, Biophotonics Center, Nashville, Tennessee, United States
| | - E. Duco Jansen
- Vanderbilt University, Department of Biomedical Engineering, Nashville, Tennessee, United States
- Vanderbilt University, Biophotonics Center, Nashville, Tennessee, United States
- Vanderbilt University, Department of Neurological Surgery, Nashville, Tennessee, United States
| | - Hillel J. Chiel
- Case Western Reserve University, Department of Biomedical Engineering, Cleveland, Ohio, United States
- Case Western Reserve University, Department of Biology, Cleveland, Ohio, United States
- Case Western Reserve University, Department of Neurosciences, Cleveland, Ohio, United States
| | - Michael W. Jenkins
- Case Western Reserve University, Department of Biomedical Engineering, Cleveland, Ohio, United States
- Case Western Reserve University, Department of Pediatrics, Cleveland, Ohio, United States
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Baheeg M, Tag El-Din M, Labib MF, Elgohary SA, Hasan A. Long-term durability of weight loss after bariatric surgery; a retrospective study. INTERNATIONAL JOURNAL OF SURGERY OPEN 2021. [DOI: 10.1016/j.ijso.2020.12.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Conde SV, Sacramento JF, Martins FO. Immunity and the carotid body: implications for metabolic diseases. Bioelectron Med 2020; 6:24. [PMID: 33353562 PMCID: PMC7756955 DOI: 10.1186/s42234-020-00061-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/24/2020] [Indexed: 12/14/2022] Open
Abstract
Neuro-immune communication has gained enormous interest in recent years due to increasing knowledge of the way in which the brain coordinates functional alterations in inflammatory and autoimmune responses, and the mechanisms of neuron-immune cell interactions in the context of metabolic diseases such as obesity and type 2 diabetes. In this review, we will explain how this relationship between the nervous and immune system impacts the pro- and anti-inflammatory pathways with specific reference to the hypothalamus-pituitary-adrenal gland axis and the vagal reflex and will explore the possible involvement of the carotid body (CB) in the neural control of inflammation. We will also highlight the mechanisms of vagal anti-inflammatory reflex control of immunity and metabolism, and the consequences of functional disarrangement of this reflex in settlement and development of metabolic diseases, with special attention to obesity and type 2 diabetes. Additionally, the role of CB in the interplay between metabolism and immune responses will be discussed, with specific reference to the different stimuli that promote CB activation and the balance between sympathetic and parasympathetic in this context. In doing so, we clarify the multivarious neuronal reflexes that coordinate tissue-specific responses (gut, pancreas, adipose tissue and liver) critical to metabolic control, and metabolic disease settlement and development. In the final section, we will summarize how electrical modulation of the carotid sinus nerve may be utilized to adjust these reflex responses and thus control inflammation and metabolic diseases, envisioning new therapeutics horizons.
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Affiliation(s)
- Silvia V Conde
- iNOVA4Health, CEDOC, NOVA Medical School, NMS, Universidade Nova de Lisboa, Rua Câmara Pestana, n°6, Edifício 2, piso 3, 1150-274, Lisbon, Portugal.
| | - Joana F Sacramento
- iNOVA4Health, CEDOC, NOVA Medical School, NMS, Universidade Nova de Lisboa, Rua Câmara Pestana, n°6, Edifício 2, piso 3, 1150-274, Lisbon, Portugal
| | - Fatima O Martins
- iNOVA4Health, CEDOC, NOVA Medical School, NMS, Universidade Nova de Lisboa, Rua Câmara Pestana, n°6, Edifício 2, piso 3, 1150-274, Lisbon, Portugal
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Xie H, Yepuri N, Meng Q, Dhawan R, Leech CA, Chepurny OG, Holz GG, Cooney RN. Therapeutic potential of α7 nicotinic acetylcholine receptor agonists to combat obesity, diabetes, and inflammation. Rev Endocr Metab Disord 2020; 21:431-447. [PMID: 32851581 PMCID: PMC7572644 DOI: 10.1007/s11154-020-09584-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/21/2020] [Indexed: 12/12/2022]
Abstract
The cholinergic anti-inflammatory reflex (CAIR) represents an important homeostatic regulatory mechanism for sensing and controlling the body's response to inflammatory stimuli. Vagovagal reflexes are an integral component of CAIR whose anti-inflammatory effects are mediated by acetylcholine (ACh) acting at α7 nicotinic acetylcholine receptors (α7nAChR) located on cells of the immune system. Recently, it is appreciated that CAIR and α7nAChR also participate in the control of metabolic homeostasis. This has led to the understanding that defective vagovagal reflex circuitry underlying CAIR might explain the coexistence of obesity, diabetes, and inflammation in the metabolic syndrome. Thus, there is renewed interest in the α7nAChR that mediates CAIR, particularly from the standpoint of therapeutics. Of special note is the recent finding that α7nAChR agonist GTS-21 acts at L-cells of the distal intestine to stimulate the release of two glucoregulatory and anorexigenic hormones: glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Furthermore, α7nAChR agonist PNU 282987 exerts trophic factor-like actions to support pancreatic β-cell survival under conditions of stress resembling diabetes. This review provides an overview of α7nAChR function as it pertains to CAIR, vagovagal reflexes, and metabolic homeostasis. We also consider the possible usefulness of α7nAChR agonists for treatment of obesity, diabetes, and inflammation.
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Affiliation(s)
- Han Xie
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Natesh Yepuri
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Qinghe Meng
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Ravi Dhawan
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Colin A Leech
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Oleg G Chepurny
- Departments of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, USA
| | - George G Holz
- Departments of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, USA
| | - Robert N Cooney
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA.
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Pelot NA, Goldhagen GB, Cariello JE, Musselman ED, Clissold KA, Ezzell JA, Grill WM. Quantified Morphology of the Cervical and Subdiaphragmatic Vagus Nerves of Human, Pig, and Rat. Front Neurosci 2020; 14:601479. [PMID: 33250710 PMCID: PMC7672126 DOI: 10.3389/fnins.2020.601479] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 10/13/2020] [Indexed: 12/27/2022] Open
Abstract
It is necessary to understand the morphology of the vagus nerve (VN) to design and deliver effective and selective vagus nerve stimulation (VNS) because nerve morphology influences fiber responses to electrical stimulation. Specifically, nerve diameter (and thus, electrode-fiber distance), fascicle diameter, fascicular organization, and perineurium thickness all significantly affect the responses of nerve fibers to electrical signals delivered through a cuff electrode. We quantified the morphology of cervical and subdiaphragmatic VNs in humans, pigs, and rats: effective nerve diameter, number of fascicles, effective fascicle diameters, proportions of endoneurial, perineurial, and epineurial tissues, and perineurium thickness. The human and pig VNs were comparable sizes (∼2 mm cervically; ∼1.6 mm subdiaphragmatically), while the rat nerves were ten times smaller. The pig nerves had ten times more fascicles-and the fascicles were smaller-than in human nerves (47 vs. 7 fascicles cervically; 38 vs. 5 fascicles subdiaphragmatically). Comparing the cervical to the subdiaphragmatic VNs, the nerves and fascicles were larger at the cervical level for all species and there were more fascicles for pigs. Human morphology generally exhibited greater variability across samples than pigs and rats. A prior study of human somatic nerves indicated that the ratio of perineurium thickness to fascicle diameter was approximately constant across fascicle diameters. However, our data found thicker human and pig VN perineurium than those prior data: the VNs had thicker perineurium for larger fascicles and thicker perineurium normalized by fascicle diameter for smaller fascicles. Understanding these differences in VN morphology between preclinical models and the clinical target, as well as the variability across individuals of a species, is essential for designing suitable cuff electrodes and stimulation parameters and for informing translation of preclinical results to clinical application to advance the therapeutic efficacy of VNS.
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Affiliation(s)
- Nicole A. Pelot
- Department of Biomedical Engineering, Duke University, Durham, NC, United States
| | - Gabriel B. Goldhagen
- Department of Biomedical Engineering, Duke University, Durham, NC, United States
| | - Jake E. Cariello
- Department of Biomedical Engineering, Duke University, Durham, NC, United States
| | - Eric D. Musselman
- Department of Biomedical Engineering, Duke University, Durham, NC, United States
| | - Kara A. Clissold
- Histology Research Core, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - J. Ashley Ezzell
- Histology Research Core, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Warren M. Grill
- Department of Biomedical Engineering, Duke University, Durham, NC, United States
- Department of Electrical and Computer Engineering, Duke University, Durham, NC, United States
- Department of Neurobiology, Duke University, Durham, NC, United States
- Department of Neurosurgery, School of Medicine, Duke University, Durham, NC, United States
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40
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Huang KP, Goodson ML, Vang W, Li H, Page AJ, Raybould HE. Leptin signaling in vagal afferent neurons supports the absorption and storage of nutrients from high-fat diet. Int J Obes (Lond) 2020; 45:348-357. [PMID: 32917985 PMCID: PMC7854885 DOI: 10.1038/s41366-020-00678-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 07/30/2020] [Accepted: 09/03/2020] [Indexed: 12/18/2022]
Abstract
Objective: Activation of vagal afferent neurons (VAN) by postprandial gastrointestinal signals terminates feeding and facilitates nutrient digestion and absorption. Leptin modulates responsiveness of VAN to meal-related gastrointestinal signals. Rodents with high-fat diet (HF) feeding develop leptin resistance that impairs responsiveness of VAN. We hypothesized that lack of leptin signaling in VAN reduces responses to meal-related signals, which in turn decreases absorption of nutrients and energy storage from high-fat, calorically dense food. Methods: Mice with conditional deletion of the leptin receptor from VAN (Nav1.8-Cre/LepRfl/fl; KO) were used in this study. Six-week-old male mice were fed a 45% HF for 4 weeks; metabolic phenotype, food intake, and energy expenditure were measured. Absorption and storage of nutrients were investigated in the refed state. Results: After 4 weeks of HF feeding, KO mice gained less body weight and fat mass that WT controls, but this was not due to differences in food intake or energy expenditure. KO mice had reduced expression of carbohydrate transporters and absorption of carbohydrate in the jejunum. KO mice had fewer hepatic lipid droplets and decreased expression of de novo lipogenesis-associated enzymes and lipoproteins for endogenous lipoprotein pathway in liver, suggesting decreased long-term storage of carbohydrate in KO mice. Conclusions: Impairment of leptin signaling in VAN reduces responsiveness to gastrointestinal signals, which reduces intestinal absorption of carbohydrates and de novo lipogenesis resulting in reduced long-term energy storage. This study reveals a novel role of vagal afferents to support digestion and energy storage that may contribute to the effectiveness of vagal blockade to induce weight loss.
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Affiliation(s)
- Kuei-Pin Huang
- School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Michael L Goodson
- School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Wendie Vang
- School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Hui Li
- Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.,South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Amanda J Page
- Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.,South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Helen E Raybould
- School of Veterinary Medicine, University of California Davis, Davis, CA, USA.
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41
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Holland J, Sorrell J, Yates E, Smith K, Arbabi S, Arnold M, Rivir M, Morano R, Chen J, Zhang X, Dimarchi R, Woods SC, Sanchez-Gurmaches J, Wohleb E, Perez-Tilve D. A Brain-Melanocortin-Vagus Axis Mediates Adipose Tissue Expansion Independently of Energy Intake. Cell Rep 2020; 27:2399-2410.e6. [PMID: 31116984 PMCID: PMC6550338 DOI: 10.1016/j.celrep.2019.04.089] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 03/18/2019] [Accepted: 04/18/2019] [Indexed: 02/07/2023] Open
Abstract
The melanocortin system is a brain circuit that influences energy balance by regulating energy intake and expenditure. In addition, the brain-melanocortin system controls adipose tissue metabolism to optimize fuel mobilization and storage. Specifically, increased brain-melanocortin signaling or negative energy balance promotes lipid mobilization by increasing sympathetic nervous system input to adipose tissue. In contrast, calorie-independent mechanisms favoring energy storage are less understood. Here, we demonstrate that reduction of brain-melanocortin signaling actively promotes fat mass gain by activating the lipogenic program and adipocyte and endothelial cell proliferation in white fat depots independently of caloric intake via efferent nerve fibers conveyed by the common hepatic branch of the vagus nerve. Those vagally regulated obesogenic signals also contribute to the fat mass gain following chronic high-fat diet feeding. These data reveal a physiological mechanism whereby the brain controls energy stores that may contribute to increased susceptibility to obesity. Brain-melanocortin signaling controls fat mass indirectly by regulating energy balance and by direct control of lipid mobilization from adipose tissue via sympathetic nervous system activity. Holland et al. show that reduced brain-melanocortin signaling promotes white adipose tissue expansion via signals conveyed by efferent innervation of the vagus nerve.
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Affiliation(s)
- Jenna Holland
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Joyce Sorrell
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Emily Yates
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Kathleen Smith
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Shahriar Arbabi
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Myrtha Arnold
- Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland
| | - Marita Rivir
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Rachel Morano
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jenny Chen
- Genomics, Epigenomics and Sequencing Core, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Xiang Zhang
- Genomics, Epigenomics and Sequencing Core, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Richard Dimarchi
- Novo Nordisk Research Center Indianapolis, IN, USA; Department of Chemistry, Indiana University, Bloomington, IN, USA
| | - Stephen C Woods
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Joan Sanchez-Gurmaches
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Endocrinology and Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA
| | - Eric Wohleb
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Diego Perez-Tilve
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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Di Lorenzo N, Antoniou SA, Batterham RL, Busetto L, Godoroja D, Iossa A, Carrano FM, Agresta F, Alarçon I, Azran C, Bouvy N, Balaguè Ponz C, Buza M, Copaescu C, De Luca M, Dicker D, Di Vincenzo A, Felsenreich DM, Francis NK, Fried M, Gonzalo Prats B, Goitein D, Halford JCG, Herlesova J, Kalogridaki M, Ket H, Morales-Conde S, Piatto G, Prager G, Pruijssers S, Pucci A, Rayman S, Romano E, Sanchez-Cordero S, Vilallonga R, Silecchia G. Clinical practice guidelines of the European Association for Endoscopic Surgery (EAES) on bariatric surgery: update 2020 endorsed by IFSO-EC, EASO and ESPCOP. Surg Endosc 2020; 34:2332-2358. [PMID: 32328827 PMCID: PMC7214495 DOI: 10.1007/s00464-020-07555-y] [Citation(s) in RCA: 285] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 04/07/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Surgery for obesity and metabolic diseases has been evolved in the light of new scientific evidence, long-term outcomes and accumulated experience. EAES has sponsored an update of previous guidelines on bariatric surgery. METHODS A multidisciplinary group of bariatric surgeons, obesity physicians, nutritional experts, psychologists, anesthetists and a patient representative comprised the guideline development panel. Development and reporting conformed to GRADE guidelines and AGREE II standards. RESULTS Systematic review of databases, record selection, data extraction and synthesis, evidence appraisal and evidence-to-decision frameworks were developed for 42 key questions in the domains Indication; Preoperative work-up; Perioperative management; Non-bypass, bypass and one-anastomosis procedures; Revisional surgery; Postoperative care; and Investigational procedures. A total of 36 recommendations and position statements were formed through a modified Delphi procedure. CONCLUSION This document summarizes the latest evidence on bariatric surgery through state-of-the art guideline development, aiming to facilitate evidence-based clinical decisions.
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Affiliation(s)
- Nicola Di Lorenzo
- Department of Surgical Sciences, University of Rome "Tor Vergata", Rome, Italy
| | - Stavros A Antoniou
- Department of Surgery, European University of Cyprus, Nicosia, Cyprus
- Department of Surgery, Mediterranean Hospital of Cyprus, Limassol, Cyprus
| | - Rachel L Batterham
- Centre for Obesity Research, University College London, London, UK
- Biomedical Research Centre, National Institute of Health Research, London, UK
| | - Luca Busetto
- Internal Medicine 3, Department of Medicine, DIMED, Center for the Study and the Integrated Treatment of Obesity, University Hospital of Padua, Padua, Italy
| | - Daniela Godoroja
- Department of Anesthesiology, Ponderas Academic Hospital Regina Maria, Bucharest, Romania
| | - Angelo Iossa
- Department of Medical-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, "La Sapienza" University of Rome-Polo Pontino, Bariatric Centre of Excellence IFSO-EC, Via F. Faggiana 1668, 04100, Latina, Italy
| | - Francesco M Carrano
- Department of Endocrine and Metabolic Surgery, University of Insubria, Ospedale di Circolo and Fondazione Macchi, ASST Sette Laghi, Varese, Italy
| | | | - Isaias Alarçon
- Unit of Innovation in Minimally Invasive Surgery, Department of General and Digestive Surgery, University Hospital "Virgen del Rocío", 41010, Sevilla, Spain
| | | | - Nicole Bouvy
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
| | | | - Maura Buza
- Department of General Surgery, Ponderas Academic Hospital Regina Maria, Bucharest, Romania
| | - Catalin Copaescu
- Department of General Surgery, Ponderas Academic Hospital Regina Maria, Bucharest, Romania
| | - Maurizio De Luca
- Division of General Surgery, Castelfranco and Montebelluna Hospitals, Treviso, Italy
| | - Dror Dicker
- Department of Internal Medicine D, Hasharon Hospital, Rabin Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Angelo Di Vincenzo
- Internal Medicine 3, Department of Medicine, DIMED, Center for the Study and the Integrated Treatment of Obesity, University Hospital of Padua, Padua, Italy
| | - Daniel M Felsenreich
- Division of General Surgery, Department of Surgery, Vienna Medical University, Vienna, Austria
| | - Nader K Francis
- Department of General Surgery, Yeovil District Hospital NHS Foundation Trust, Yeovil, UK
| | - Martin Fried
- Center for Treatment of Obesity and Metabolic Disorders, OB Klinika, Prague, Czech Republic
| | | | - David Goitein
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Surgery C, Chaim Sheba Medical Center, Ramat Gan, Israel
| | - Jason C G Halford
- Department of Psychological Sciences, Institute of Psychology, Health and Society, University of Liverpool, Liverpool, UK
| | - Jitka Herlesova
- Center for Treatment of Obesity and Metabolic Disorders, OB Klinika, Prague, Czech Republic
| | | | - Hans Ket
- VU Amsterdam, Amsterdam, Netherlands
| | - Salvador Morales-Conde
- Unit of Innovation in Minimally Invasive Surgery, Department of General and Digestive Surgery, University Hospital "Virgen del Rocío", 41010, Sevilla, Spain
| | - Giacomo Piatto
- Division of General Surgery, Castelfranco and Montebelluna Hospitals, Treviso, Italy
| | - Gerhard Prager
- Division of General Surgery, Department of Surgery, Vienna Medical University, Vienna, Austria
| | - Suzanne Pruijssers
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Andrea Pucci
- Centre for Obesity Research, University College London, London, UK
- Biomedical Research Centre, National Institute of Health Research, London, UK
| | - Shlomi Rayman
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Surgery C, Chaim Sheba Medical Center, Ramat Gan, Israel
| | - Eugenia Romano
- Department of Psychological Sciences, Institute of Psychology, Health and Society, University of Liverpool, Liverpool, UK
| | | | - Ramon Vilallonga
- Endocrine, Metabolic and Bariatric Unit, General Surgery Department, Vall D'Hebron University Hospital, Center of Excellence for the EAC-BC, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Gianfranco Silecchia
- Department of Medical-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, "La Sapienza" University of Rome-Polo Pontino, Bariatric Centre of Excellence IFSO-EC, Via F. Faggiana 1668, 04100, Latina, Italy.
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Cardel MI, Atkinson MA, Taveras EM, Holm JC, Kelly AS. Obesity Treatment Among Adolescents: A Review of Current Evidence and Future Directions. JAMA Pediatr 2020; 174:609-617. [PMID: 32202626 PMCID: PMC7483247 DOI: 10.1001/jamapediatrics.2020.0085] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Importance Obesity in adolescence has reached epidemic proportions around the world, with the prevalence of severe obesity increasing at least 4-fold over the last 35 years. Most youths with obesity carry their excess adiposity into adulthood, which places them at increased risk for developing obesity-driven complications, such as type 2 diabetes and cardiovascular disease, and negatively affects social and emotional health. Given that adolescence is a unique transition period marked by significant physiologic and developmental changes, obesity-related complications can also negatively affect adolescent growth and developmental trajectories. Observations Provision of evidence-based treatment options that are tailored and appropriate for the adolescent population is paramount, yet complex. The multifactorial etiology of obesity along with the significant changes that occur during the adolescent period increasingly complicate the treatment approach for adolescent obesity. Treatment practices discussed in this review include an overview of evidence supporting currently available behavioral, pharmacologic, surgical, and device interventions for obesity. However, it is important to note that these practices have not been effective at reducing adolescent obesity at the population level. Conclusions and Relevance Because adolescent obesity requires lifelong treatment, effectively addressing this disease will require significant resources, scientific rigor, and the provision of access to quality care similar to other chronic health conditions. Effective and less invasive therapies, effective adjuncts, and comprehensive centers that offer specialized treatment are critical. This considerable need for increased attention to obesity care calls for dedicated resources in both education and research for treatment of obesity in youths.
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Affiliation(s)
- Michelle I Cardel
- Department of Health Outcomes and Biomedical Informatics and Pediatrics, University of Florida College of Medicine, Gainesville
| | - Mark A Atkinson
- Diabetes Institute, Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville
| | - Elsie M Taveras
- Massachusetts General Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
| | - Jens-Christian Holm
- The Children's Obesity Clinic, Holbaek Hospital, University of Copenhagen, Copenhagen, the Netherlands
| | - Aaron S Kelly
- Center for Pediatric Obesity Medicine, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota
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Payne SC, Ward G, MacIsaac RJ, Hyakumura T, Fallon JB, Villalobos J. Differential effects of vagus nerve stimulation strategies on glycemia and pancreatic secretions. Physiol Rep 2020; 8:e14479. [PMID: 32512650 PMCID: PMC7280012 DOI: 10.14814/phy2.14479] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/15/2020] [Accepted: 05/15/2020] [Indexed: 12/14/2022] Open
Abstract
Despite advancements in pharmacotherapies, glycemia is poorly controlled in type 2 diabetic patients. As the vagus nerve regulates energy metabolism, here we evaluated the effect various electrical vagus nerve stimulation strategies have on glycemia and glucose-regulating hormones, as a first step to developing a novel therapy of type 2 diabetes. Sprague-Dawley rats were anesthetized, the abdominal (anterior) vagus nerve implanted, and various stimulation strategies applied to the nerve: (a) 15 Hz; (b) 4 kHz, or 40 kHz and; (c) a combination of 15 Hz and 40 kHz to directionally activate afferent or efferent vagal fibers. Following a glucose bolus (500 mg/kg, I.V.), stimulation strategies were applied (60 min) and serial blood samples taken. No stimulation was used as a crossover control sequence. Applying 15 Hz stimulation significantly increased glucose (+2.9 ± 0.2 mM·hr, p = .015) and glucagon (+17.1 ± 8.0 pg·hr/ml, p = .022), compared to no stimulation. Application of 4 kHz stimulation also significantly increased glucose levels (+1.5 ± 0.5 mM·hr, p = .049), while 40 kHz frequency stimulation resulted in no changes to glucose levels but did significantly lower glucagon (-12.3 ± 1.1 pg·hr/ml, p = .0009). Directional afferent stimulation increased glucose (+2.4 ± 1.5 mM·hr) and glucagon levels (+39.5 ± 15.0 pg·hr/ml). Despite hyperglycemia resulting when VNS, aVNS, and 4 kHz stimulation strategies were applied, the changes in insulin levels were not significant (p ≥ .05). In summary, vagus nerve stimulation modulates glycemia by effecting glucagon and insulin secretions, and high-frequency 40 kHz stimulation may have potential application for the treatment of type 2 diabetes.
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Affiliation(s)
- Sophie C. Payne
- Bionics InstituteEast MelbourneVic.Australia
- Medical Bionics DepartmentThe University of MelbourneParkvilleVic.Australia
| | - Glenn Ward
- Bionics InstituteEast MelbourneVic.Australia
- Department of Endocrinology and DiabetesSt Vincent’s HospitalFitzroyVic.Australia
- Department of MedicineThe University of MelbourneParkvilleVic.Australia
| | - Richard J. MacIsaac
- Bionics InstituteEast MelbourneVic.Australia
- Department of Endocrinology and DiabetesSt Vincent’s HospitalFitzroyVic.Australia
- Department of MedicineThe University of MelbourneParkvilleVic.Australia
| | - Tomoko Hyakumura
- Bionics InstituteEast MelbourneVic.Australia
- Medical Bionics DepartmentThe University of MelbourneParkvilleVic.Australia
| | - James B. Fallon
- Bionics InstituteEast MelbourneVic.Australia
- Medical Bionics DepartmentThe University of MelbourneParkvilleVic.Australia
| | - Joel Villalobos
- Bionics InstituteEast MelbourneVic.Australia
- Medical Bionics DepartmentThe University of MelbourneParkvilleVic.Australia
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Liu H, Zhan P, Meng F, Wang W. Chronic vagus nerve stimulation for drug-resistant epilepsy may influence fasting blood glucose concentration. Biomed Eng Online 2020; 19:40. [PMID: 32471438 PMCID: PMC7257242 DOI: 10.1186/s12938-020-00784-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 05/19/2020] [Indexed: 12/30/2022] Open
Abstract
Background Cervical vagus nerve stimulation (VNS) has been widely accepted as adjunctive therapy for drug-resistant epilepsy and major depression. Its effects on glycemic control in humans were however poorly understood. The aim of our study was to investigate the potential effects of VNS on fasting blood glucose (FBG) in patients with drug-resistant epilepsy. Methods Patients with drug-resistant epilepsy who had received VNS implants at the same hospital were retrospectively studied. Effects on FBG, weight, body mass index and blood pressure were evaluated at 4, 8 and 12 months of follow-up. Results 32 subjects (11 females/21 males, 19 ± 9 years, body mass index 22.2 ± 4.0 kg/m2) completed 12-month follow-up. At the 4 months, there were no significant changes in FBG concentrations from baseline to follow-up in both Sham-VNS (4.89 ± 0.54 vs. 4.56 ± 0.54 mmol/L, N = 13, p = 0.101) and VNS (4.80 ± 0.54 vs. 4.50 ± 0.56 mmol/L, N = 19, p = 0.117) groups. However, after 8 (4.90 ± 0.42 mmol/L, N = 32, p = 0.001) and 12 (4.86 ± 0.40 mmol/L, N = 32, p = 0.002) months of VNS, FBG levels significantly increased compared to baseline values (4.52 ± 0.54 mmol/L, N = 32). Changes in FBG concentrations at both 8 (R2 = 0.502, N = 32, p < 0.001) and 12 (R2 = 0.572, N = 32, p < 0.001) months were negatively correlated with baseline FBG levels. Conclusions Our study suggests that chronic cervical VNS elevates FBG levels with commonly used stimulation parameters in patients with epilepsy. Trial registration VNSRE, NCT02378792. Registered 4 March 2015—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02378792
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Affiliation(s)
- Hongyun Liu
- Research Center for Biomedical Engineering, Medical Innovation & Research Division, Chinese PLA General Hospital, Beijing, 100853, China.,Center of Medical Device R & D and Clinical Evaluation, Chinese PLA General Hospital, Beijing, 100853, China
| | - Ping Zhan
- Center of Medical Device R & D and Clinical Evaluation, Chinese PLA General Hospital, Beijing, 100853, China
| | - Fangang Meng
- Beijing Neurosurgical Institute, Beijing, 100050, China. .,Neurosurgery, Beijing Tian Tan Hospital Capital Medical University, Beijing, 100050, China.
| | - Weidong Wang
- Research Center for Biomedical Engineering, Medical Innovation & Research Division, Chinese PLA General Hospital, Beijing, 100853, China. .,Center of Medical Device R & D and Clinical Evaluation, Chinese PLA General Hospital, Beijing, 100853, China.
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Mechanick JI, Apovian C, Brethauer S, Timothy Garvey W, Joffe AM, Kim J, Kushner RF, Lindquist R, Pessah-Pollack R, Seger J, Urman RD, Adams S, Cleek JB, Correa R, Figaro MK, Flanders K, Grams J, Hurley DL, Kothari S, Seger MV, Still CD. Clinical Practice Guidelines for the Perioperative Nutrition, Metabolic, and Nonsurgical Support of Patients Undergoing Bariatric Procedures - 2019 Update: Cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society for Metabolic and Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Obesity (Silver Spring) 2020; 28:O1-O58. [PMID: 32202076 DOI: 10.1002/oby.22719] [Citation(s) in RCA: 177] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Accepted: 10/09/2019] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The development of these updated clinical practice guidelines (CPGs) was commissioned by the American Association of Clinical Endocrinologists (AACE), The Obesity Society (TOS), American Society for Metabolic and Bariatric Surgery (ASMBS), Obesity Medicine Association (OMA), and American Society of Anesthesiologists (ASA) Boards of Directors in adherence with the AACE 2017 protocol for standardized production of CPGs, algorithms, and checklists. METHODS Each recommendation was evaluated and updated based on new evidence from 2013 to the present and subjective factors provided by experts. RESULTS New or updated topics in this CPG include: contextualization in an adiposity-based chronic disease complications-centric model, nuance-based and algorithm/checklist-assisted clinical decision-making about procedure selection, novel bariatric procedures, enhanced recovery after bariatric surgery protocols, and logistical concerns (including cost factors) in the current health care arena. There are 85 numbered recommendations that have updated supporting evidence, of which 61 are revised and 12 are new. Noting that there can be multiple recommendation statements within a single numbered recommendation, there are 31 (13%) Grade A, 42 (17%) Grade B, 72 (29%) Grade C, and 101 (41%) Grade D recommendations. There are 858 citations, of which 81 (9.4%) are evidence level (EL) 1 (highest), 562 (65.5%) are EL 2, 72 (8.4%) are EL 3, and 143 (16.7%) are EL 4 (lowest). CONCLUSIONS Bariatric procedures remain a safe and effective intervention for higher-risk patients with obesity. Clinical decision-making should be evidence based within the context of a chronic disease. A team approach to perioperative care is mandatory, with special attention to nutritional and metabolic issues.
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Affiliation(s)
- Jeffrey I Mechanick
- Guideline Task Force Chair (AACE); Professor of Medicine, Medical Director, Marie-Josée and Henry R. Kravis Center for Clinical Cardiovascular Health at Mount Sinai Heart; Director, Metabolic Support Divisions of Cardiology and Endocrinology, Diabetes, and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York; Past President, AACE and ACE
| | - Caroline Apovian
- Guideline Task Force Co-Chair (TOS); Professor of Medicine and Director, Nutrition and Weight Management, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts
| | - Stacy Brethauer
- Guideline Task Force Co-Chair (ASMBS); Professor of Surgery, Vice Chair of Surgery, Quality and Patient Safety; Medical Director, Supply Chain Management, Ohio State University, Columbus, Ohio
| | - W Timothy Garvey
- Guideline Task Force Co-Chair (AACE); Butterworth Professor, Department of Nutrition Sciences, GRECC Investigator and Staff Physician, Birmingham VAMC; Director, UAB Diabetes Research Center, University of Alabama at Birmingham, Birmingham, Alabama
| | - Aaron M Joffe
- Guideline Task Force Co-Chair (ASA); Professor of Anesthesiology, Service Chief, Otolaryngology, Oral, Maxillofacial, and Urologic Surgeries, Associate Medical Director, Respiratory Care, University of Washington, Harborview Medical Center, Seattle, Washington
| | - Julie Kim
- Guideline Task Force Co-Chair (ASMBS); Harvard Medical School, Mount Auburn Hospital, Cambridge, Massachusetts
| | - Robert F Kushner
- Guideline Task Force Co-Chair (TOS); Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Richard Lindquist
- Guideline Task Force Co-Chair (OMA); Director, Medical Weight Management, Swedish Medical Center; Director, Medical Weight Management, Providence Health Services; Obesity Medicine Consultant, Seattle, Washington
| | - Rachel Pessah-Pollack
- Guideline Task Force Co-Chair (AACE); Clinical Associate Professor of Medicine, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, New York
| | - Jennifer Seger
- Guideline Task Force Co-Chair (OMA); Adjunct Assistant Professor, Department of Family and Community Medicine, Long School of Medicine, UT Health Science Center, San Antonio, Texas
| | - Richard D Urman
- Guideline Task Force Co-Chair (ASA); Associate Professor of Anesthesia, Brigham and Women's Hospital, Boston, Massachusetts
| | - Stephanie Adams
- Writer (AACE); AACE Director of Clinical Practice Guidelines Development, Jacksonville, Florida
| | - John B Cleek
- Writer (TOS); Associate Professor, Department of Nutrition Sciences, University of Alabama, Birmingham, Alabama
| | - Riccardo Correa
- Technical Analysis (AACE); Assistant Professor of Medicine and Endocrinology, Diabetes and Metabolism Fellowship Director, University of Arizona College of Medicine, Phoenix, Arizona
| | - M Kathleen Figaro
- Technical Analysis (AACE); Board-certified Endocrinologist, Heartland Endocrine Group, Davenport, Iowa
| | - Karen Flanders
- Writer (ASMBS); Massachusetts General Hospital Weight Center, Boston, Massachusetts
| | - Jayleen Grams
- Writer (AACE); Associate Professor, Department of Surgery, University of Alabama at Birmingham; Staff Surgeon, Birmingham VA Medical Center, Birmingham, Alabama
| | - Daniel L Hurley
- Writer (AACE); Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota
| | - Shanu Kothari
- Writer (ASMBS); Fellowship Director of MIS/Bariatric Surgery, Gundersen Health System, La Crosse, Wisconsin
| | - Michael V Seger
- Writer (OMA); Bariatric Medical Institute of Texas, San Antonio, Texas, Clinical Assistant Professor, University of Texas Health Science Center, Houston, Texas
| | - Christopher D Still
- Writer (TOS); Medical Director, Center for Nutrition and Weight Management Director, Geisinger Obesity Institute; Medical Director, Employee Wellness, Geisinger Health System, Danville, Pennsylvania
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Pelot NA, Grill WM. In vivo quantification of excitation and kilohertz frequency block of the rat vagus nerve. J Neural Eng 2020; 17:026005. [PMID: 31945746 DOI: 10.1088/1741-2552/ab6cb6] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
OBJECTIVE There is growing interest in treating diseases by electrical stimulation and block of peripheral autonomic nerves, but a paucity of studies on the excitation and block of small-diameter autonomic axons. We conducted in vivo quantification of the strength-duration properties, activity-dependent slowing (ADS), and responses to kilohertz frequency (KHF) signals for the rat vagus nerve (VN). APPROACH We conducted acute in vivo experiments in urethane-anaesthetized rats. We placed two cuff electrodes on the left cervical VN and one cuff electrode on the anterior subdiaphragmatic VN. The rostral cervical cuff was used to deliver pulses to quantify recruitment and ADS. The caudal cervical cuff was used to deliver KHF signals. The subdiaphragmatic cuff was used to record compound action potentials (CAPs). MAIN RESULTS We quantified the input-output recruitment and strength-duration curves. Fits to the data using standard strength-duration equations were qualitatively similar, but the resulting chronaxie and rheobase estimates varied substantially. We measured larger thresholds for the slowest fibres (0.5-1 m s-1), especially at shorter pulse widths. Using a novel cross-correlation CAP-based analysis, we measured ADS of ~2.3% after 3 min of 2 Hz stimulation, which is comparable to the ADS reported for sympathetic efferents in somatic nerves, but much smaller than the ADS in cutaneous nociceptors. We found greater ADS with higher stimulation frequency and non-monotonic changes in CV in select cases. We found monotonically increasing block thresholds across frequencies from 10 to 80 kHz for both fast and slow fibres. Further, following 25 s of KHF signal, neural conduction could require tens of seconds to recover. SIGNIFICANCE The quantification of mammalian autonomic nerve responses to conventional and KHF signals provides essential information for the development of peripheral nerve stimulation therapies and for understanding their mechanisms of action.
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Affiliation(s)
- N A Pelot
- Department of Biomedical Engineering, Duke University, Room 1427, Fitzpatrick CIEMAS, 101 Science Drive, Campus Box 90281, Durham, NC 27708, United States of America
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Cousins S, Blencowe NS, Tsang C, Lorenc A, Chalmers K, Carr AJ, Campbell MK, Cook JA, Beard DJ, Blazeby JM. Reporting of key methodological issues in placebo-controlled trials of surgery needs improvement: a systematic review. J Clin Epidemiol 2020; 119:109-116. [PMID: 31786153 PMCID: PMC7066579 DOI: 10.1016/j.jclinepi.2019.11.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 11/12/2019] [Accepted: 11/24/2019] [Indexed: 01/09/2023]
Abstract
OBJECTIVES To examine key methodological considerations for using a placebo intervention in randomized controlled trials (RCTs) evaluating invasive procedures, including surgery. STUDY DESIGN AND SETTING RCTs comparing an invasive procedure with a placebo were included in this systematic review. Articles published from database inception to December 31, 2017, were retrieved from Ovid MEDLINE, Ovid EMBASE and CENTRAL electronic databases, by handsearching references and expert knowledge. Data on trial characteristics (clinical area, nature of invasive procedure, number of patients and centers) and key methodological (rationale for using placebos, minimization of risk, information provision, offering the treatment intervention to patients randomized to placebo, delivery of cointerventions, and intervention standardization and fidelity) were extracted and summarized descriptively. RESULTS One hundred thirteen articles reporting 96 RCTs were identified. Most were conducted in gastrointestinal surgery (n = 40, 42%) and evaluated minimally invasive procedures (n = 44, 46%). Over two-thirds randomized fewer than 100 patients (n = 65, 68%) and a third were single center (n = 31, 32%). A third (n = 33, 34%) did not report a rationale for using a placebo. Most common strategies to minimize patient risk were operator skill (n = 22, 23%) and independent data monitoring (n = 28, 29%). Provision of patient information regarding placebo use was infrequently reported (n = 11, 11%). Treatment interventions were offered to patients randomized to placebo in 43 trials (45%). Cointerventions were inconsistently reported, but 64 trials (67%) stated that anesthesia was matched between groups. Attempts to standardize interventions and monitor their delivery were reported in n = 7, (7%) and n = 4, (4%) trials, respectively. CONCLUSION Most placebo-controlled trials in surgery evaluate minor surgical procedures and currently there is inconsistent reporting of key trial methods. There is a need for guidance to optimize the transparency of trial reporting in this area.
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Affiliation(s)
- Sian Cousins
- National Institute of Health Research (NIHR), Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Surgical Innovation theme and the Medical Research Council ConDuCT-II Hub for Trials Methodology Research, Bristol Centre for Surgical Research, Population Health Sciences, Bristol Medical School, Bristol, UK.
| | - Natalie S Blencowe
- National Institute of Health Research (NIHR), Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Surgical Innovation theme and the Medical Research Council ConDuCT-II Hub for Trials Methodology Research, Bristol Centre for Surgical Research, Population Health Sciences, Bristol Medical School, Bristol, UK; Division of Surgery, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Carmen Tsang
- National Institute of Health Research (NIHR), Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Surgical Innovation theme and the Medical Research Council ConDuCT-II Hub for Trials Methodology Research, Bristol Centre for Surgical Research, Population Health Sciences, Bristol Medical School, Bristol, UK
| | - Ava Lorenc
- National Institute of Health Research (NIHR), Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Surgical Innovation theme and the Medical Research Council ConDuCT-II Hub for Trials Methodology Research, Bristol Centre for Surgical Research, Population Health Sciences, Bristol Medical School, Bristol, UK
| | - Katy Chalmers
- National Institute of Health Research (NIHR), Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Surgical Innovation theme and the Medical Research Council ConDuCT-II Hub for Trials Methodology Research, Bristol Centre for Surgical Research, Population Health Sciences, Bristol Medical School, Bristol, UK
| | - Andrew J Carr
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Headington, Oxford, UK; National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Royal College of Surgeons (England) Surgical Interventional Trials Unit (SITU), Botnar Research Centre, University of Oxford, Headington, Oxford, UK
| | | | - Jonathan A Cook
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Headington, Oxford, UK; National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Royal College of Surgeons (England) Surgical Interventional Trials Unit (SITU), Botnar Research Centre, University of Oxford, Headington, Oxford, UK
| | - David J Beard
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Headington, Oxford, UK; National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Royal College of Surgeons (England) Surgical Interventional Trials Unit (SITU), Botnar Research Centre, University of Oxford, Headington, Oxford, UK
| | - Jane M Blazeby
- National Institute of Health Research (NIHR), Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Surgical Innovation theme and the Medical Research Council ConDuCT-II Hub for Trials Methodology Research, Bristol Centre for Surgical Research, Population Health Sciences, Bristol Medical School, Bristol, UK; Division of Surgery, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
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Lee SJ, Krieger JP, Vergara M, Quinn D, McDougle M, de Araujo A, Darling R, Zollinger B, Anderson S, Pan A, Simonnet EJ, Pignalosa A, Arnold M, Singh A, Langhans W, Raybould HE, de Lartigue G. Blunted Vagal Cocaine- and Amphetamine-Regulated Transcript Promotes Hyperphagia and Weight Gain. Cell Rep 2020; 30:2028-2039.e4. [PMID: 32049029 PMCID: PMC7063787 DOI: 10.1016/j.celrep.2020.01.045] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 12/06/2019] [Accepted: 01/15/2020] [Indexed: 12/31/2022] Open
Abstract
The vagus nerve conveys gastrointestinal cues to the brain to control eating behavior. In obesity, vagally mediated gut-brain signaling is disrupted. Here, we show that the cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide synthesized proportional to the food consumed in vagal afferent neurons (VANs) of chow-fed rats. CART injection into the nucleus tractus solitarii (NTS), the site of vagal afferent central termination, reduces food intake. Conversely, blocking endogenous CART action in the NTS increases food intake in chow-fed rats, and this requires intact VANs. Viral-mediated Cartpt knockdown in VANs increases weight gain and daily food intake via larger meals and faster ingestion rate. In obese rats fed a high-fat, high-sugar diet, meal-induced CART synthesis in VANs is blunted and CART antibody fails to increase food intake. However, CART injection into the NTS retains its anorexigenic effect in obese rats. Restoring disrupted VAN CART signaling in obesity could be a promising therapeutic approach.
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Affiliation(s)
- Shin J Lee
- Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland
| | - Jean-Philippe Krieger
- Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland; Department of Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Macarena Vergara
- Department of Pharmacodynamics, Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, USA
| | | | - Molly McDougle
- Department of Pharmacodynamics, Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, USA; The John B. Pierce Laboratory, New Haven, CT, USA
| | - Alan de Araujo
- Department of Pharmacodynamics, Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, USA; The John B. Pierce Laboratory, New Haven, CT, USA; Yale University, New Haven, CT, USA
| | - Rebecca Darling
- Anatomy, Physiology and Cell Biology Department School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Benjamin Zollinger
- The John B. Pierce Laboratory, New Haven, CT, USA; Yale University, New Haven, CT, USA
| | - Seth Anderson
- The John B. Pierce Laboratory, New Haven, CT, USA; Yale University, New Haven, CT, USA
| | - Annabeth Pan
- The John B. Pierce Laboratory, New Haven, CT, USA; Yale University, New Haven, CT, USA
| | - Emilie J Simonnet
- Anatomy, Physiology and Cell Biology Department School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Angelica Pignalosa
- Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland
| | - Myrtha Arnold
- Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland
| | - Arashdeep Singh
- Department of Pharmacodynamics, Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, USA
| | - Wolfgang Langhans
- Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland
| | - Helen E Raybould
- Anatomy, Physiology and Cell Biology Department School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Guillaume de Lartigue
- Department of Pharmacodynamics, Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, USA; The John B. Pierce Laboratory, New Haven, CT, USA; Yale University, New Haven, CT, USA.
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