Eugenijus Kaniusas
Marat Fudim2,3
Christopher J. Czura
Fivos Panetsos- 1Instutute of Biomedical Electronics, Faculty of Electrical Engineering and Information Technology, Vienna University of Technology (TU Wien), Vienna, Austria
- 2Division of Cardiology, Duke University Medical Center, Durham, NC, United States
- 3Duke Clinical Research Institute, Duke University, Durham, NC, United States
- 4Convergent Medical Technologies, Inc, New York, NY, United States
- 5Neurocomputing and Neurorobotics Research Group, Universidad Complutense de Madrid, Madrid, Spain
- 6Institute for Health Research (IdISSC), San Carlos Clinical Hospital, Madrid, Spain
- 7Silk Biomed SL, Madrid, Spain
Editorial on the Research Topic
Neuromodulation in COVID-19: from basic research to clinical applications
Neuromodulation with electrical nerve stimulation has come progressively into focus as a treatment option for various chronic diseases to change end-organ function through systemic effects on the human body (Chen et al., 2020; Cirillo et al., 2022; Kaniusas et al., 2019a). Stimulation affects multiple immunological, physiological, psychometric, and biochemical functions (Tracey, 2007; Krzyzaniak et al., 2011; Mercante et al., 2018). The brain chemistry, nociceptive processing, inflammation, and autonomic function are modulated by neurostimulation for different therapeutic purposes (Li et al., 2015; Babygirija et al., 2017; Kaniusas et al., 2019a). Even though neuromodulation therapy is generally considered safe with only mild and transient adverse effects (Redgrave et al., 2018; Kim et al., 2022), the mechanistic understanding of neuromodulation is still incomplete (Yap et al., 2020). While methodological standardization of the therapy is in progress (Farmer et al., 2021), personalization of neuromodulation is still insufficient (Yu et al., 2022; Kaniusas et al., 2019b) for a successful translation of neuromodulation into mainstream clinical practice (Goggins et al., 2022).
The COVID-19 pandemic may lead to severe respiratory distress, systemic inflammation, cardiovascular damage, and imbalance of the autonomic function, involving acute and chronic damages (Huang et al., 2020; Zheng et al., 2020; Tay et al., 2020). The COVID-19 infection affects several organ systems with different timelines, which suggests the use of electrical neuromodulatory approaches—with their aforementioned systemic regulatory effects—as a very promising and prospective treatment option, during and even before and after COVID-19 (Bonaz et al., 2020; Guo et al., 2021; Badran et al., 2022; Rangon and Niezgoda, 2022; Baptista et al., 2020; Fudim et al., 2020; Kaniusas et al., 2020).
The present Research Topic entitled “Neuromodulation in COVID-19: from basic research to clinical applications” sets out to shed light on a better understanding of the use of neuromodulatory approaches as potential treatment options for Covid-19-related diseases which continue to challenge our society.
For this proposed transdisciplinary exchange from basic science to engineering Research Topic and to clinical applications, we received a number of manuscript proposals, six of which were ultimately accepted for publication. While mechanistic Research Topic on the cellular level are covered by contributions Petrone et al. and Jankauskaite et al., clinical research in COVID-19 patients is reported by Tornero et al. and Seitz et al., all complemented by two review papers by Czura et al. and Linnhoff et al. for clinical settings.
Petrone et al. investigated in her research paper antibody and cellular responses to the ancestral strain and the Delta variant of Corona virus in vaccinated patients with an autoimmune disorder, namely, multiple sclerosis (MS). While cellular responses remained largely intact in MS patients, the magnitude of the antibody responses was reduced in patients treated with specific MS drugs (ocrelizumab or fingolimod) in comparison with subjects without MS. Authors substantiated the mechanistic action of the specific drugs on the vaccine-induced immune response to Corona viral variants in the real-life scenario of MS, and, in the broader sense, of other autoimmune disorders.
Jankauskaite et al. presented a hypothesis paper on the potential use of the vagus nerve stimulation (VNS) in Covid-induced lung injuries, addressing a highly susceptible pediatric population. This population is unfortunately underrepresented in the scientific literature, even though under risk and with distinct immunity and anatomy. The authors discussed the potential benefit of stimulation through inhibition of the damage-associated high-mobility group box protein (HMGB1). This protein is a predictive and initiating factor for inflammatory respiratory-system related diseases in COVID-19. The paper covered not only the cellular biophysics of VNS but also methodological issues and even potential risks of VNS in great depth, as applicable to the early development stage of pediatric population.
Tornero et al. conducted a prospective clinical study on the efficacy and safety of the non-invasive cervical VNS for the treatment of respiratory symptoms and over-inflammation in COVID-19. Patients were hospitalized for COVID-19 without the need for mechanical ventilation. While anti-inflammatory effects [e.g., on C-reactive protein (CRP)] of VNS were proven within 1 week, as well as safety of the VNS procedure, significant effects on the respiratory outcomes (e.g., oxygen saturation) were not observed. Authors argued that since the reduced pro-inflammatory markers are indicative of diminished risks of poor outcomes in COVID-19 (e.g., respiratory failure) as well as of cardiovascular complications (e.g., stroke), further studies of the cervical VNS are warranted.
Seitz et al. investigated the efficacy and safety of the minimally-invasive auricular VNS for the treatment of over-inflammation in COVID-19 within a prospective clinical study. In an instructive contrast to Tornero et al., only severe COVID-19 patients with the need for mechanical ventilation were included. Within 1 week, the auricular VNS reduced not only pro-inflammatory markers (e.g., CRP) but also increased favorably anti-inflammatory markers [e.g., interleukin 10 (IL-10)]; without any stimulation-related adverse events. Authors suggested the auricular VNS as a promising option for additional treatment in severe COVID-19 patients.
Czura et al. conducted a review on neuromodulation strategies to reduce over-inflammation and avoid respiratory complications in COVID-19 patients. The role of the nervous system (incl. vagus and sacral nerves) was systemically discussed for inflammation and respiration, followed by (pre)clinical rationale in using transcutaneous cervical and auricular VNS, electromagnetic transcranial, and focused ultrasound stimulations in Covid-19-related disorders. These neuromodulatory approaches could potentially be used also in systemic disorders triggered by other pathogens. The authors formed the International Consortium on Neuromodulation for COVID-19, which developed recommendations in neuromodulation studies in COVID-19.
Linnhoff et al. reviewed the potential of non-invasive brain stimulation technologies for the treatment of (cognitive) fatigue, the most common and debilitating symptom of Long-Covid. Neuromodulation methods such as transcranial direct and alternating current stimulation, as well as transcutaneous VNS were revised in view of their ability to modulate fatigue-related maladaptive neuronal circuitry; namely, dysregulated immune system, frontoparietal hypometabolism, and reduced cerebral blood flow.
Selected publications show that neuromodulation with its systemic effects on the human body has balancing modulatory effects on the systemically-derailed state in COVID-19 patients. Given the low risk profile of neuromodulation in view of severe complications in COVID-19, we conclude that neuromodulation can act as a promising and prospective treatment option in COVID-19.
Finally, we would like to thank the reviewers for their valuable comments and suggestions. Without their help, the publication of this Research Topic would not have been possible. We hope that the readers will find this collection of papers useful.
Author contributions
EK, MF, CC, and FP contributed to conception and implementation of the Research Topic. EK wrote the first draft of the editorial, MF, CC, and FP wrote sections of the editorial. All authors contributed to revision, read, and approved the submitted version.
Conflict of interest
Author CC holds equity in the company Convergent Medical Technologies, Inc., and has received financial support from Spark Biomedical, Inc., and electroCore, Inc. Author MF received financial support from the American Heart Association (20IPA35310955), Mario Family Award, Duke Chair’s Award, Translating Duke Health Award, Bayer, Bodyport, BTG Specialty Pharmaceuticals, AxonTherapies, Bodyport, Boston Scientific, CVRx, Daxor, Edwards LifeSciences, Fire1, Inovise, NXT Biomedical, Viscardia and Zoll. Author FP is shareholder of the company Silk Biomed SL.
The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Babygirija, R., Sood, M., Kannampalli, P., Sengupta, J. N., and Miranda, A. (2017). Percutaneous electrical nerve field stimulation modulates central pain pathways and attenuates post-inflammatory visceral and somatic hyperalgesia in rats. Neuroscience 356, 11–21. doi:10.1016/j.neuroscience.2017.05.012
Badran, B. W., Huffman, S. M., Dancy, M., Austelle, C. W., Bikson, M., Kautz, S. A., et al. (2022). A pilot randomized controlled trial of supervised, at-home, self-administered transcutaneous auricular vagus nerve stimulation (taVNS) to manage long COVID symptoms. Bioelectron. Med. 8 (1), 13. doi:10.1186/s42234-022-00094-y
Baptista, A. F., Baltar, A., Okano, A. H., Moreira, A., Campos, A. C. P., Fernandes, A. M., et al. (2020). Applications of non-invasive neuromodulation for the management of disorders related to COVID-19. Front. neurology 11, 573718. doi:10.3389/fneur.2020.573718
Bonaz, B., Sinniger, V., and Pellissier, S. (2020). Targeting the cholinergic anti-inflammatory pathway with vagus nerve stimulation in patients with Covid-19? Bioelectron. Med. 6, 15. doi:10.1186/s42234-020-00051-7
Chen, M., Wang, S., Li, X., Yu, L., Yang, H., Liu, Q., et al. (2020). Non-invasive autonomic neuromodulation is opening new landscapes for cardiovascular diseases. Front. physiology 11, 550578. doi:10.3389/fphys.2020.550578
Cirillo, G., Negrete-Diaz, F., Yucuma, D., Virtuoso, A., Korai, S. A., De Luca, C., et al. (2022). Vagus nerve stimulation: A personalized therapeutic approach for crohn's and other inflammatory bowel diseases. Cells 11 (24), 4103. doi:10.3390/cells11244103
Farmer, A. D., Strzelczyk, A., Finisguerra, A., Gourine, A. V., Gharabaghi, A., Hasan, A., et al. (2021). International consensus based review and recommendations for minimum reporting standards in research on transcutaneous vagus nerve stimulation (version 2020). Front. Hum. Neurosci. 14, 568051. doi:10.3389/fnhum.2020.568051
Fudim, M., Qadri, Y. J., Ghadimi, K., MacLeod, D. B., Molinger, J., Piccini, J. P., et al. (2020). Implications for neuromodulation therapy to control inflammation and related organ dysfunction in COVID-19. J. Cardiovasc. Transl. Res. 13 (6), 894–899. doi:10.1007/s12265-020-10031-6
Goggins, E., Mitani, S., and Tanaka, S. (2022). Clinical perspectives on vagus nerve stimulation: Present and future. Clin. Sci. Lond. Engl. 136 (9), 695–709. doi:10.1042/CS20210507
Guo, Z. P., Sörös, P., Zhang, Z. Q., Yang, M. H., Liao, D., and Liu, C. H. (2021). Use of transcutaneous auricular vagus nerve stimulation as an adjuvant therapy for the depressive symptoms of COVID-19: A literature review. Front. psychiatry 12, 765106. doi:10.3389/fpsyt.2021.765106
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., et al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, Engl. 395 (10223), 497–506. doi:10.1016/S0140-6736(20)30183-5
Kaniusas, E., Kampusch, S., Tittgemeyer, M., Panetsos, F., Gines, R. F., Papa, M., et al. (2019a). Current directions in the auricular vagus nerve stimulation I - a physiological perspective. Front. Neurosci. 13, 854. doi:10.3389/fnins.2019.00854
Kaniusas, E., Kampusch, S., Tittgemeyer, M., Panetsos, F., Gines, R. F., Papa, M., et al. (2019b). Current directions in the auricular vagus nerve stimulation II - an engineering perspective. Front. Neurosci. 13, 772. doi:10.3389/fnins.2019.00772
Kaniusas, E., Szeles, J. C., Kampusch, S., Alfageme-Lopez, N., Yucuma-Conde, D., Li, X., et al. (2020). Non-invasive auricular vagus nerve stimulation as a potential treatment for covid19-originated acute respiratory distress syndrome. Front. physiology 11, 890. doi:10.3389/fphys.2020.00890
Kim, A. Y., Marduy, A., de Melo, P. S., Gianlorenco, A. C., Kim, C. K., Choi, H., et al. (2022). Safety of transcutaneous auricular vagus nerve stimulation (taVNS): A systematic review and meta-analysis. Sci. Rep. 12 (1), 22055. doi:10.1038/s41598-022-25864-1
Krzyzaniak, M. J., Peterson, C. Y., Cheadle, G., Loomis, W., Wolf, P., Kennedy, V., et al. (2011). Efferent vagal nerve stimulation attenuates acute lung injury following burn: The importance of the gut-lung axis. Surgery 150 (3), 379–389. doi:10.1016/j.surg.2011.06.008
Li, H., Zhang, J. B., Xu, C., Tang, Q. Q., Shen, W. X., Zhou, J. Z., et al. (2015). Effects and mechanisms of auricular vagus nerve stimulation on high-fat-diet-induced obese rats. Nutr. (Burbank, Los Angel. Cty. Calif.) 31 (11-12), 1416–1422. doi:10.1016/j.nut.2015.05.007
Mercante, B., Ginatempo, F., Manca, A., Melis, F., Enrico, P., and Deriu, F. (2018). Anatomo-physiologic basis for auricular stimulation. Med. Acupunct. 30 (3), 141–150. doi:10.1089/acu.2017.1254
Rangon, C. M., and Niezgoda, A. (2022). Understanding the pivotal role of the vagus nerve in Health from pandemics. Bioeng. (Basel, Switz. 9 (8), 352. doi:10.3390/bioengineering9080352
Redgrave, J., Day, D., Leung, H., Laud, P. J., Ali, A., Lindert, R., et al. (2018). Safety and tolerability of Transcutaneous Vagus Nerve stimulation in humans; a systematic review. Brain Stimul. 11 (6), 1225–1238. doi:10.1016/j.brs.2018.08.010
Tay, M. Z., Poh, C. M., Rénia, L., MacAry, P. A., and Ng, L. F. P. (2020). The trinity of COVID-19: Immunity, inflammation and intervention. Nat. Rev. Immunol. 20 (6), 363–374. doi:10.1038/s41577-020-0311-8
Tracey, K. J. (2007). Physiology and immunology of the cholinergic antiinflammatory pathway. J. Clin. investigation 117 (2), 289–296. doi:10.1172/JCI30555
Yap, J. Y. Y., Keatch, C., Lambert, E., Woods, W., Stoddart, P. R., and Kameneva, T. (2020). Critical review of transcutaneous vagus nerve stimulation: Challenges for translation to clinical practice. Front. Neurosci. 14, 284. doi:10.3389/fnins.2020.00284
Yu, Y., Ling, J., Yu, L., Liu, P., and Jiang, M. (2022). Closed-loop transcutaneous auricular vagal nerve stimulation: Current situation and future possibilities. Front. Hum. Neurosci. 15, 785620. doi:10.3389/fnhum.2021.785620
Keywords: neuromodulation, COVID-19, vagus nerve, inflammation, autonomic function, dysautonomia
Citation: Kaniusas E, Fudim M, Czura CJ and Panetsos F (2023) Editorial: Neuromodulation in COVID-19: From basic research to clinical applications. Front. Physiol. 14:1148819. doi: 10.3389/fphys.2023.1148819
Received: 20 January 2023; Accepted: 08 February 2023;
Published: 16 February 2023.
Edited and reviewed by:
Joel C. Bornstein, The University of Melbourne, AustraliaCopyright © 2023 Kaniusas, Fudim, Czura and Panetsos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Eugenijus Kaniusas, kaniusas@tuwien.ac.at