Control of inflammation using non-invasive neuromodulation: past, present and promise

Aisling Tynan, Michael Brines, Sangeeta S Chavan, Aisling Tynan, Michael Brines, Sangeeta S Chavan

Abstract

The nervous system has been increasingly recognized as a novel and accessible target in the regulation of inflammation. The use of implantable and invasive devices targeting neural circuits has yielded successful results in clinical settings but does have some risk or adverse effects. Recent advances in technology and understanding of mechanistic pathways have opened new avenues of non-invasive neuromodulation. Through this review we discuss the novel research and outcomes of major modalities of non-invasive neuromodulation in the context of inflammation including transcutaneous electrical, magnetic and ultrasound neuromodulation. In addition to highlighting the scientific observations and breakthroughs, we discuss the underlying mechanisms and pathways for neural regulation of inflammation.

Keywords: auricular; inflammatory reflex; ultrasound; vagus.

© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Society for Immunology.

Figures

Fig. 1.
Fig. 1.
Timeline indicating the important developments in neuromodulation therapy (Created with BioRender.com).

References

    1. Brewer, D. J. and Friedman, R. 1990. Fish and Fishing in Ancient Egypt. American University in Cairo Press, Cairo, Egypt.
    1. Heidland, A., Fazeli, G., Klassen, al. . 2013. Neuromuscular electrostimulation techniques: historical aspects and current possibilities in treatment of pain and muscle waisting. Clin. Nephrol. 79(Suppl. 1):S12.
    1. Kane, K. and Taub, A. 1975. A history of local electrical analgesia. Pain 1:125.
    1. Tsoucalas, G. and Sgantzos, M. 2016. Electric current to cure arthritis and cephalaea in ancient Greek medicine. Mediterr. J. Rheumatol. 27:198.
    1. Pavlov, V. A., Chavan, S. S. and Tracey, K. J. 2020. Bioelectronic medicine: from preclinical studies on the inflammatory reflex to new approaches in disease diagnosis and treatment. Cold Spring Harb. Perspect. Med. 10:a034140.
    1. Chavan, S. S., Ma, P. and Chiu, I. M. 2018. Neuro-immune interactions in inflammation and host defense: implications for transplantation. Am. J. Transplant. 18:556.
    1. Serhan, C. N. and Savill, J. 2005. Resolution of inflammation: the beginning programs the end. Nat. Immunol. 6:1191.
    1. Balkwill, F. and Mantovani, A. 2001. Inflammation and cancer: back to Virchow? Lancet 357:539.
    1. Pavlov, V. A. and Tracey, K. J. 2012. The vagus nerve and the inflammatory reflex—linking immunity and metabolism. Nat. Rev. Endocrinol. 8:743.
    1. Chavan, S. S., Pavlov, V. A. and Tracey, K. J. 2017. Mechanisms and therapeutic relevance of neuro-immune communication. Immunity 46:927.
    1. Dinarello, C. A. 2010. Anti-inflammatory agents: present and future. Cell 140:935.
    1. Anonymous. 2020. Anti-Inflammatory Biologics Market Size, Share & Global Report, 2016–2020. Available at: .
    1. Bluestone, J. A. and Anderson, M. 2020. Tolerance in the age of immunotherapy. N. Engl. J. Med. 383:1156.
    1. Bongartz, T., Sutton, A. J., Sweeting, M. al. . 2006. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295:2275.
    1. Wallis, R. S. 2007. Reactivation of latent tuberculosis by TNF blockade: the role of interferon γ. J. Investig. Dermatol. Symp. Proc. 12:16.
    1. Guerra, I., Algaba, A., Pérez-Calle, J. al. . 2012. Induction of psoriasis with anti-TNF agents in patients with inflammatory bowel disease: a report of 21 cases. J. Crohns Colitis 6:518.
    1. Mayberg, H. S., Lozano, A. M., Voon, al. . 2005. Deep brain stimulation for treatment-resistant depression. Neuron 45:651.
    1. Deuschl, G., Schade-Brittinger, C., Krack, al. ; German Parkinson Study Group, Neurostimulation Section. 2006. A randomized trial of deep-brain stimulation for Parkinson’s disease. N. Engl. J. Med. 355:896.
    1. Thaha, M. A., Abukar, A. A., Thin, N. al. . 2015. Sacral nerve stimulation for faecal incontinence and constipation in adults. Cochrane Database Syst. Rev. 24:CD004464.
    1. Pai, R. G., Varadarajan, P. and Pai, S. M. 2018. Pacemakers and defibrillators. Cardiology Board Review, 1st edn, p. 463. John Wiley & Sons, Hoboken, NJ.
    1. Toffa, D. H., Touma, L., El Meskine, al. . 2020. Learnings from 30 years of reported efficacy and safety of vagus nerve stimulation (VNS) for epilepsy treatment: a critical review. Seizure 83:104.
    1. Koopman, F. A., Chavan, S. S., Miljko, al. . 2016. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 113:8284.
    1. Bonaz, B., Sinniger, V., Hoffmann, al. . 2016. Chronic vagus nerve stimulation in Crohn’s disease: a 6-month follow-up pilot study. Neurogastroenterol. Motil. 28:948.
    1. Tracey, K. J. 2002. The inflammatory reflex. Nature 420:853.
    1. Chavan, S. S. and Tracey, K. J. 2017. Essential neuroscience in immunology. J. Immunol. 198:3389.
    1. Pavlov, V. A., Chavan, S. S. and Tracey, K. J. 2018. Molecular and functional neuroscience in immunity. Annu. Rev. Immunol. 36:783.
    1. Kressel, A. M., Tsaava, T., Levine, Y. al. . 2020. Identification of a brainstem locus that inhibits tumor necrosis factor. Proc. Natl Acad. Sci. USA 117:29803.
    1. Rosas-Ballina, M., Olofsson, P. S., Ochani, al. . 2011. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334:98.
    1. Wang, H., Yu, M., Ochani, al. . 2003. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421:384.
    1. Uchida, M., Yamamoto, R., Matsuyama, al. . 2021. Gateway reflexes, neuronal circuits that regulate the autoreactive T cells in organs having blood barriers. Int. Immunol. 2021.
    1. Chavan, S. S. and Tracey, K. J. 2014. Regulating innate immunity with dopamine and electroacupuncture. Nat. Med. 20:239.
    1. Torres-Rosas, R., Yehia, G., Peña, al. . 2014. Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nat. Med. 20:291.
    1. Lim, H. D., Kim, M. H., Lee, C. al. . 2016. Anti-inflammatory effects of acupuncture stimulation via the vagus nerve. PLoS One 11:e0151882.
    1. Roh, E., Song, D. K. and Kim, M. S. 2016. Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism. Exp. Mol. Med. 48:e216.
    1. Gabanyi, I., Muller, P. A., Feighery, al. . 2016. Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell 164:378.
    1. Staats, P., Emala, C., Simon, al. . 2018. Neurostimulation for asthma. In Krames E. S., Hunter Peckham P., and Rezai A. R. eds., Neuromodulation, 2nd edn, p. 1339. Elsevier, Amsterdam, The Netherlands.
    1. Kaczmarczyk, R., Tejera, D., Simon, al. . 2018. Microglia modulation through external vagus nerve stimulation in a murine model of Alzheimer’s disease. J. Neurochem. 146:76.
    1. Masi, E. B., Levy, T., Tsaava, al. . 2019. Identification of hypoglycemia-specific neural signals by decoding murine vagus nerve activity. Bioelectron. Med. 5:9.
    1. Payne, S. C., Furness, J. B., Burns, al. . 2019. Anti-inflammatory effects of abdominal vagus nerve stimulation on experimental intestinal inflammation. Front. Neurosci. 13:418.
    1. Hou, Y., Zhou, Q. and Po, S. S. 2016. Neuromodulation for cardiac arrhythmia. Heart Rhythm 13:584.
    1. Borovikova, L. V., Ivanova, S., Zhang, al. . 2000. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458.
    1. Levine, Y. A., Koopman, F. A., Faltys, al. . 2014. Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis. PLoS One 9:e104530.
    1. de Jonge, W. J., van der Zanden, E. P., The, F. al. . 2005. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat. Immunol. 6:844.
    1. Lange, G., Janal, M. N., Maniker, al. . 2011. Safety and efficacy of vagus nerve stimulation in fibromyalgia: a phase I/II proof of concept trial. Pain Med. 12:1406.
    1. Spuck, S., Tronnier, V., Orosz, al. . 2010. Operative and technical complications of vagus nerve stimulator implantation. Neurosurgery 67(2 Suppl. Operative):489.
    1. Asconapé, J. J., Moore, D. D., Zipes, D. al. . 1999. Bradycardia and asystole with the use of vagus nerve stimulation for the treatment of epilepsy: a rare complication of intraoperative device testing. Epilepsia 40:1452.
    1. Fahy, B. G. 2010. Intraoperative and perioperative complications with a vagus nerve stimulation device. J. Clin. Anesth. 22:213.
    1. Marzec, M., Edwards, J., Sagher, al. . 2003. Effects of vagus nerve stimulation on sleep-related breathing in epilepsy patients. Epilepsia 44:930.
    1. Yakunina, N., Kim, S. S. and Nam, E. C. 2017. Optimization of transcutaneous vagus nerve stimulation using functional MRI. Neuromodulation 20:290.
    1. Kraus, T., Hösl, K., Kiess, al. . 2007. BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation. J. Neural. Transm. 114:1485.
    1. Dietrich, S., Smith, J., Scherzinger, al. . 2008. A novel transcutaneous vagus nerve stimulation leads to brainstem and cerebral activations measured by functional MRI. Biomed. Tech. 53:104.
    1. Kraus, T., Kiess, O., Hösl, al. . 2013. CNS BOLD fMRI effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal—a pilot study. Brain Stimul. 6:798.
    1. Frangos, E. and Komisaruk, B. R. 2017. Access to vagal projections via cutaneous electrical stimulation of the neck: fMRI evidence in healthy humans. Brain Stimul. 10:19.
    1. Ben-Menachem, E., Revesz, D., Simon, B. al. . 2015. Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. Eur. J. Neurol. 22:1260.
    1. Yuan, H. and Silberstein, S. D. 2016. Vagus nerve and vagus nerve stimulation, a comprehensive review: part II. Headache 56:259.
    1. Mertens, A., Raedt, R., Gadeyne, al. . 2018. Recent advances in devices for vagus nerve stimulation. Expert Rev. Med. Devices 15:527.
    1. Lerman, I., Hauger, R., Sorkin, al. . 2016. Noninvasive transcutaneous vagus nerve stimulation decreases whole blood culture-derived cytokines and chemokines: a randomized, blinded, healthy control pilot trial. Neuromodulation 19:283.
    1. Tarn, J., Legg, S., Mitchell, al. . 2019. The effects of noninvasive vagus nerve stimulation on fatigue and immune responses in patients with primary Sjögren’s syndrome. Neuromodulation 22:580.
    1. Nesbitt, A. D., Marin, J., Tomkins, al. . 2031. Non-invasive vagus nerve stimulation for the treatment of cluster headache: a case series. Headache Pain 14(Suppl. 1):P231.
    1. Steyn, E., Mohamed, Z. and Husselman, C. 2013. Non-invasive vagus nerve stimulation for the treatment of acute asthma exacerbations—results from an initial case series. Int. J. Emerg. Med. 6:7.
    1. Staats, P., Giannakopoulos, G., Blake, al. . 2020. The use of non-invasive vagus nerve stimulation to treat respiratory symptoms associated with COVID-19: a theoretical hypothesis and early clinical experience. Neuromodulation 23:784.
    1. Mourdoukoutas, A. P., Truong, D. Q., Adair, D. al. . 2018. High-resolution multi-scale computational model for non-invasive cervical vagus nerve stimulation. Neuromodulation 21:261.
    1. Drewes, A. M., Brock, C., Rasmussen, S. al. . 2021. Short-term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity and pro-inflammatory cytokines in rheumatoid arthritis: results of a pilot study. Scand. J. Rheumatol. 50:20.
    1. Zhao, X. P., Zhao, Y., Qin, X. al. . 2019. Non-invasive vagus nerve stimulation protects against cerebral ischemia/reperfusion injury and promotes microglial M2 polarization via interleukin-17A inhibition. J. Mol. Neurosci. 67:217.
    1. Ay, I., Nasser, R., Simon, al. . 2016. Transcutaneous cervical vagus nerve stimulation ameliorates acute ischemic injury in rats. Brain Stimul. 9:166.
    1. Mercante, B., Ginatempo, F., Manca, al. . 2018. Anatomo-physiologic basis for auricular stimulation. Med. Acupunct. 30:141.
    1. Peuker, E. T. and Filler, T. J. 2002. The nerve supply of the human auricle. Clin. Anat. 15:35.
    1. Kaniusas, E., Kampusch, S., Tittgemeyer, al. . 2019. Current directions in the auricular vagus nerve stimulation I—a physiological perspective. Front. Neurosci. 13:854.
    1. Clancy, J. A., Mary, D. A., Witte, K. al. . 2014. Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimul. 7:871.
    1. Zhao, Y. X., He, W., Jing, X. al. . 2012. Transcutaneous auricular vagus nerve stimulation protects endotoxemic rat from lipopolysaccharide-induced inflammation. Evid. Based Complement. Alternat. Med. 2012:627023.
    1. Hong, G. S., Zillekens, A., Schneiker, al. . 2019. Non-invasive transcutaneous auricular vagus nerve stimulation prevents postoperative ileus and endotoxemia in mice. Neurogastroenterol. Motil. 31:e13501.
    1. Ma, J., Zhang, L., He, al. . 2016. Transcutaneous auricular vagus nerve stimulation regulates expression of growth differentiation factor 11 and activin-like kinase 5 in cerebral ischemia/reperfusion rats. J. Neurol. Sci. 369:27.
    1. Addorisio, M. E., Imperato, G. H., de Vos, A. al. . 2019. Investigational treatment of rheumatoid arthritis with a vibrotactile device applied to the external ear. Bioelectron. Med. 5:4.
    1. Marsal, S., Corominas, H., De Agustin De Oro, J. al. . 2020. Non-invasive vagus nerve stimulation improves signs and symptoms of rheumatoid arthritis: results of a pilot study. ACR Convergence Meeting 2020, Abstract Number 1995. Available at: .
    1. Marsal, S., Corominas, H., De Agustin, J. al. . 2021. AB0264 1-year results of a non-invasive auricular vagus nerve stimulation device in patients with rheumatoid arthritis. Ann. Rheum. Dis. 80(Suppl. 1):1158.
    1. Hong, G. S., Pintea, B., Lingohr, al. . 2019. Effect of transcutaneous vagus nerve stimulation on muscle activity in the gastrointestinal tract (transVaGa): a prospective clinical trial. Int. J. Colorectal Dis. 34:417.
    1. Rong, P., Liu, A., Zhang, al. . 2014. Transcutaneous vagus nerve stimulation for refractory epilepsy: a randomized controlled trial. Clin. Sci. 2014.
    1. Rong, P., Liu, J., Wang, al. . 2016. Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: a nonrandomized controlled pilot study. J. Affect. Disord. 195:172.
    1. Yu, L., Scherlag, B. J., Li, al. . 2013. Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve: a noninvasive approach to treat the initial phase of atrial fibrillation. Heart Rhythm. 10:428.
    1. Stavrakis, S., Humphrey, M. B., Scherlag, B. al. . 2015. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J. Am. Coll. Cardiol. 65:867.
    1. Stavrakis, S., Humphrey, M. B., Scherlag, al. . 2017. Low-level vagus nerve stimulation suppresses post-operative atrial fibrillation and inflammation: a randomized study. JACC Clin. Electrophysiol. 3:929.
    1. Aranow, C., Atish-Fregoso, Y., Lesser, al. . 2021. Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial. Ann. Rheum. Dis. 80:203.
    1. Kaniusas, E., Szeles, J. C., Kampusch, al. . 2020. Non-invasive auricular vagus nerve stimulation as a potential treatment for Covid19-originated acute respiratory distress syndrome. Front. Physiol. 11:890.
    1. Ellrich, J. 2019. Transcutaneous auricular vagus nerve stimulation. J. Clin. Neurophysiol. 36:437.
    1. Lampros, M., Vlachos, N., Zigouris, al. . 2021. Transcutaneous vagus nerve stimulation (t-VNS) and epilepsy: a systematic review of the literature. Seizure 91:40.
    1. Redgrave, J. N., Moore, L., Oyekunle, al. . 2018. Transcutaneous auricular vagus nerve stimulation with concurrent upper limb repetitive task practice for poststroke motor recovery: a pilot study. J. Stroke Cerebrovasc. Dis. 27:1998.
    1. Ramkissoon, C. M., Güemes, A. and Vehi, J. 2021. Overview of therapeutic applications of non-invasive vagus nerve stimulation: a motivation for novel treatments for systemic lupus erythematosus. Bioelectron. Med. 7:8.
    1. Rossini, P. M., Rossini, L. and Ferreri, F. 2010. Transcranial magnetic stimulation: a review. IEEE Eng. Med. Biol. Mag. 29:84.
    1. Treister, R., Lang, M., Klein, M. al. . 2013. Non-invasive transcranial magnetic stimulation (TMS) of the motor cortex for neuropathic pain—at the tipping point? Rambam Maimonides Med. J. 4:4.
    1. Chail, A., Saini, R. K., Bhat, P. al. . 2018. Transcranial magnetic stimulation: a review of its evolution and current applications. Ind. Psychiatry J. 27:172.
    1. Sasso, V., Bisicchia, E., Latini, al. . 2016. Repetitive transcranial magnetic stimulation reduces remote apoptotic cell death and inflammation after focal brain injury. J. Neuroinflammation. 13:150.
    1. Kanjanapanang, N., Munakomi, S. and Chang, K.-V. 2021. Peripheral Magnetic Stimulation. StatPearls Publishing, Treasure Island, FL.
    1. Khedr, E. M., Ahmed, M. A., Alkady, E. al. . 2012. Therapeutic effects of peripheral magnetic stimulation on traumatic brachial plexopathy: clinical and neurophysiological study. Neurophysiol. Clin. 42:111.
    1. Massé-Alarie, H., Flamand, V. H., Moffet, al. . 2013. Peripheral neurostimulation and specific motor training of deep abdominal muscles improve posturomotor control in chronic low back pain. Clin. J. Pain 29:814.
    1. Smania, N., Corato, E., Fiaschi, al. . 2005. Repetitive magnetic stimulation a novel therapeutic approach for myofascial pain syndrome. J. Neurol. 252:307.
    1. Wood, A. K. and Sehgal, C. M. 2015. A review of low-intensity ultrasound for cancer therapy. Ultrasound Med. Biol. 41:905.
    1. McHale, A. P., Callan, J. F., Nomikou, al. . 2016. Sonodynamic therapy: concept, mechanism and application to cancer treatment. Adv. Exp. Med. Biol. 880:429.
    1. Liu, H. L., Hua, M. Y., Chen, P. al. . 2010. Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment. Radiology 255:415.
    1. Yang, H., Yuan, Y., Wang, al. . 2020. Closed-loop transcranial ultrasound stimulation for real-time non-invasive neuromodulation in vivo. Front. Neurosci. 14:445.
    1. Mijajlovic, M. D., Pavlovic, A. M. and Covickovic-Sternic, N. 2013. Is sonothrombolysis an effective stroke treatment? J. Ultrasound Med. 32:1117.
    1. Madersbacher, S., Schatzl, G., Djavan, al. . 2000. Long-term outcome of transrectal high-intensity focused ultrasound therapy for benign prostatic hyperplasia. Eur. Urol. 37:687.
    1. Hurwitz, M. D., Ghanouni, P., Kanaev, S. al. . 2014. Magnetic resonance–guided focused ultrasound for patients with painful bone metastases: phase III trial results. J. Natl Cancer Inst. 106:dju082.
    1. Friedmann, D. P. 2015. A review of the aesthetic treatment of abdominal subcutaneous adipose tissue: background, implications, and therapeutic options. Dermatol. Surg. 41:18.
    1. Padilla, F., Puts, R., Vico, al. . 2014. Stimulation of bone repair with ultrasound: a review of the possible mechanic effects. Ultrasonics 54:1125.
    1. Rutjes, A., Nüesch, E., Sterchi, al. . 2010. Therapeutic ultrasound for osteoarthritis of the knee or hip. Cochrane Database Syst. Rev. 20:CD003132.
    1. Page, M., O’Connor, D., Pitt, al. . 2012. Therapeutic ultrasound for carpal tunnel syndrome. Cochrane Database Syst. Rev. 18:CD009601.
    1. Blackmore, J., Shrivastava, S., Sallet, al. . 2019. Ultrasound neuromodulation: a review of results, mechanisms and safety. Ultrasound Med. Biol. 45:1509.
    1. Ninet, J., Roques, X., Seitelberger, al. . 2005. Surgical ablation of atrial fibrillation with off-pump, epicardial, high-intensity focused ultrasound: results of a multicenter trial. J. Thorac. Cardiovasc. Surg. 130:803.
    1. Tempany, C. M., Stewart, E. A., McDannold, al. . 2003. MR imaging-guided focused ultrasound surgery of uterine leiomyomas: a feasibility study. Radiology 226:897.
    1. Klingler, H. C., Susani, M., Seip, al. . 2008. A novel approach to energy ablative therapy of small renal tumours: laparoscopic high-intensity focused ultrasound. Eur. Urol. 53:810.
    1. Miller, D. L., Smith, N. B., Bailey, M. al. . 2012. Overview of therapeutic ultrasound applications and safety considerations. J. Ultrasound Med. 31:623.
    1. Gigliotti, J. C., Huang, L., Ye, al. . 2013. Ultrasound prevents renal ischemia-reperfusion injury by stimulating the splenic cholinergic anti-inflammatory pathway. J. Am. Soc. Nephrol. 24:1451.
    1. Gigliotti, J. C., Huang, L., Bajwa, al. . 2015. Ultrasound modulates the splenic neuroimmune axis in attenuating AKI. J. Am. Soc. Nephrol. 26:2470.
    1. Cotero, V., Fan, Y., Tsaava, al. . 2019. Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation. Nat. Commun. 10:952.
    1. Anderson, D. W. and Barrett, J. T. 1979. Ultrasound: a new immunosuppressant. Clin. Immunol. Immunopathol. 14:18.
    1. Anderson, D. W. and Barrett, J. T. 1981. Depression of phagocytosis by ultrasound. Ultrasound Med. Biol. 7:267.
    1. Zachs, D. P., Offutt, S. J., Graham, R. al. . 2019. Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis. Nat. Commun. 10:951.
    1. Wang, S., Li, B., Li, al. . 2020. Low-intensity ultrasound modulation may prevent myocardial infarction-induced sympathetic neural activation and ventricular arrhythmia. J. Cardiovasc. Pharmacol. 75:432.
    1. Wasilczuk, K. M., Bayer, K. C., Somann, J. al. . 2019. Modulating the inflammatory reflex in rats using low-intensity focused ultrasound stimulation of the vagus nerve. Ultrasound Med. Biol. 45:481.
    1. Binder, A., Hodge, G., Greenwood, A. al. . 1985. Is therapeutic ultrasound effective in treating soft tissue lesions? Br. Med. J. 290:512.
    1. Nagao, M., Tanabe, N., Manaka, al. . 2017. LIPUS suppressed LPS-induced IL-1α through the inhibition of NF-κB nuclear translocation via AT1-PLCβ pathway in MC3T3-E1 cells. J. Cell. Physiol. 232:3337.
    1. Chung, J. I., Barua, S., Choi, B. al. . 2012. Anti-inflammatory effect of low intensity ultrasound (LIUS) on complete Freund’s adjuvant-induced arthritis synovium. Osteoarthr. Cartil. 20:314.
    1. Eckel, R. H., Grundy, S. M. and Zimmet, P. Z. 2005. The metabolic syndrome. Lancet 365:1415.
    1. Bastard, J. P., Maachi, M., Lagathu, al. . 2006. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur. Cytokine Netw. 17:4.
    1. Hotamisligil, G. S. 2006. Inflammation and metabolic disorders. Nature 444:860.
    1. Esser, N., Paquot, N. and Scheen, A. J. 2015. Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease. Expert Opin. Investig. Drugs. 24:283.
    1. Huerta, T. S., Devarajan, A., Tsaava, al. . 2021. Targeted peripheral focused ultrasound stimulation attenuates obesity-induced metabolic and inflammatory dysfunctions. Sci. Rep. 11:5083.
    1. Chardack, W. M., Gage, A. A. and Greatbatch, W. 1960. A transistorized, self-contained, implantable pacemaker for the long-term correction of complete heart block. Surgery 48:643.
    1. Trummer, M. J., Walter, E. P., Volk, al. . 1962. The use of a self-contained, implantable pacemaker in the long-term management of complete heart block. Mil. Med. 127:647.
    1. Penry, J. K. and Dean, J. C. 1990. Prevention of intractable partial seizures by intermittent vagal stimulation in humans: preliminary results. Epilepsia 31(Suppl. 2):S40.
    1. Barker, A. T., Jalinous, R. and Freeston, I. L. 1985. Non-invasive magnetic stimulation of human motor cortex. Lancet 1:1106.
    1. Napadow, V., Edwards, R. R., Cahalan, C. al. . 2012. Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. Pain Med. 13:777.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe