Transcutaneous Vagal Nerve Stimulation Modulates Stress-induced Plasma Ghrelin Levels: A Double-blind, Randomized, Sham-controlled Trial

Overview

Journal J Affect Disord

Date 2023 Sep 15

PMID 37714385

Authors

Kasra Moazzami

Bradley D Pearce

Nil Z Gurel

Matthew T Wittbrodt

Oleksiy M Levantsevych

Minxuan Huang

Md Mobashir H Shandhi

Isaias Herring

Nancy Murrah

Emily Driggers

MhmtJamil L Alkhalaf

Majd Soudan

Lucy Shallenberger

Allison N Hankus

Jonathon A Nye

Viola Vaccarino

Amit J Shah

Omer T Inan

J Douglas Bremner

Affiliations

Soon will be listed here.

Abstract

Background: Transcutaneous cervical vagus nerve stimulation (tcVNS) has emerged as a potential treatment strategy for patients with stress-related psychiatric disorders. Ghrelin is a hormone that has been postulated to be a biomarker of stress. While the mechanisms of action of tcVNS are unclear, we hypothesized that tcVNS reduces the levels of ghrelin in response to stress.

Methods: Using a randomized double-blind approach, we studied the effects of tcVNS on ghrelin levels in individuals with a history of exposure to traumatic stress. Participants received either sham (n = 29) or active tcVNS (n = 26) after exposure to acute personalized traumatic script stress and mental stress challenges (public speech, mental arithmetic) over a three day period.

Results: There were no significant differences in the levels of ghrelin between the tcVNS and sham stimulation groups at either baseline or in the absence of trauma scripts. However, tcVNS in conjunction with personalized traumatic scripts resulted in lower ghrelin levels compared to the sham stimulation group (265.2 ± 143.6 pg/ml vs 478.7 ± 349.2 pg/ml, P = 0.01). Additionally, after completing the public speaking and mental arithmetic tests, ghrelin levels were found to be lower in the group receiving tcVNS compared to the sham group (293.3 ± 102.4 pg/ml vs 540.3 ± 203.9 pg/ml, P = 0.009).

Limitations: Timing of ghrelin measurements, and stimulation of only left vagus nerve.

Conclusion: tcVNS decreases ghrelin levels in response to various stressful stimuli. These findings are consistent with a growing literature that tcVNS modulates hormonal and autonomic responses to stress.

Citing Articles

Transcutaneous vagus nerve stimulation: a bibliometric study on current research hotspots and status.

Fan S, Yan L, Zhang J, Sun Y, Qian Y, Wang M Front Neurosci. 2024; 18:1406135.

PMID: 39221007 PMC: 11363710. DOI: 10.3389/fnins.2024.1406135.

References

Aaronson S, Sears P, Ruvuna F, Bunker M, Conway C, Dougherty D . A 5-Year Observational Study of Patients With Treatment-Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual: Comparison of Response, Remission, and Suicidality. Am J Psychiatry. 2017; 174(7):640-648. DOI: 10.1176/appi.ajp.2017.16010034. View

Ozsoy S, Besirli A, Unal D, Abdulrezzak U, Orhan O . The association between depression, weight loss and leptin/ghrelin levels in male patients with head and neck cancer undergoing radiotherapy. Gen Hosp Psychiatry. 2014; 37(1):31-5. DOI: 10.1016/j.genhosppsych.2014.09.002. View

Raspopow K, Abizaid A, Matheson K, Anisman H . Anticipation of a psychosocial stressor differentially influences ghrelin, cortisol and food intake among emotional and non-emotional eaters. Appetite. 2013; 74:35-43. DOI: 10.1016/j.appet.2013.11.018. View

Bouillon-Minois J, Trousselard M, Thivel D, Gordon B, Schmidt J, Moustafa F . Ghrelin as a Biomarker of Stress: A Systematic Review and Meta-Analysis. Nutrients. 2021; 13(3). PMC: 7997253. DOI: 10.3390/nu13030784. View

Juster R, Bizik G, Picard M, Arsenault-Lapierre G, Sindi S, Trepanier L . A transdisciplinary perspective of chronic stress in relation to psychopathology throughout life span development. Dev Psychopathol. 2011; 23(3):725-76. DOI: 10.1017/S0954579411000289. View

Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, Oya H . Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol. 2001; 280(5):R1483-7. DOI: 10.1152/ajpregu.2001.280.5.R1483. View

Yildiz B, Suchard M, Wong M, McCann S, Licinio J . Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity. Proc Natl Acad Sci U S A. 2004; 101(28):10434-9. PMC: 478601. DOI: 10.1073/pnas.0403465101. View

Douglas Bremner J, Gurel N, Jiao Y, Wittbrodt M, Levantsevych O, Huang M . Transcutaneous vagal nerve stimulation blocks stress-induced activation of Interleukin-6 and interferon-γ in posttraumatic stress disorder: A double-blind, randomized, sham-controlled trial. Brain Behav Immun Health. 2021; 9:100138. PMC: 8474180. DOI: 10.1016/j.bbih.2020.100138. View

Cummings D, Weigle D, Frayo R, Breen P, Ma M, Dellinger E . Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002; 346(21):1623-30. DOI: 10.1056/NEJMoa012908. View

10.

Gurel N, Wittbrodt M, Jung H, Shandhi M, Driggers E, Ladd S . Transcutaneous cervical vagal nerve stimulation reduces sympathetic responses to stress in posttraumatic stress disorder: A double-blind, randomized, sham controlled trial. Neurobiol Stress. 2020; 13:100264. PMC: 7739181. DOI: 10.1016/j.ynstr.2020.100264. View

11.

McEwen B . Protective and damaging effects of stress mediators. N Engl J Med. 1998; 338(3):171-9. DOI: 10.1056/NEJM199801153380307. View

12.

Zheng J, Dobner A, Babygirija R, Ludwig K, Takahashi T . Effects of repeated restraint stress on gastric motility in rats. Am J Physiol Regul Integr Comp Physiol. 2009; 296(5):R1358-65. DOI: 10.1152/ajpregu.90928.2008. View

13.

Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky S, Anderson J, Jung S . The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat Neurosci. 2008; 11(7):752-3. PMC: 2765052. DOI: 10.1038/nn.2139. View

14.

Bremner J, Gurel N, Wittbrodt M, Shandhi M, Rapaport M, Nye J . Application of Noninvasive Vagal Nerve Stimulation to Stress-Related Psychiatric Disorders. J Pers Med. 2020; 10(3). PMC: 7563188. DOI: 10.3390/jpm10030119. View

15.

Gurel N, Huang M, Wittbrodt M, Jung H, Ladd S, Shandhi M . Quantifying acute physiological biomarkers of transcutaneous cervical vagal nerve stimulation in the context of psychological stress. Brain Stimul. 2019; 13(1):47-59. PMC: 8252146. DOI: 10.1016/j.brs.2019.08.002. View

16.

Joels M, Baram T . The neuro-symphony of stress. Nat Rev Neurosci. 2009; 10(6):459-66. PMC: 2844123. DOI: 10.1038/nrn2632. View

17.

Gurel N, Gazi A, Scott K, Wittbrodt M, Shah A, Vaccarino V . Timing Considerations for Noninvasive Vagal Nerve Stimulation in Clinical Studies. AMIA Annu Symp Proc. 2020; 2019:1061-1070. PMC: 7153149. View

18.

Ricken R, Bopp S, Schlattmann P, Himmerich H, Bschor T, Richter C . Ghrelin Serum Concentrations Are Associated with Treatment Response During Lithium Augmentation of Antidepressants. Int J Neuropsychopharmacol. 2017; 20(9):692-697. PMC: 5581484. DOI: 10.1093/ijnp/pyw082. View

19.

Gurel N, Wittbrodt M, Jung H, Ladd S, Shah A, Vaccarino V . Automatic Detection of Target Engagement in Transcutaneous Cervical Vagal Nerve Stimulation for Traumatic Stress Triggers. IEEE J Biomed Health Inform. 2020; 24(7):1917-1925. PMC: 7393996. DOI: 10.1109/JBHI.2020.2981116. View

20.

Bali A, Jaggi A . An Integrative Review on Role and Mechanisms of Ghrelin in Stress, Anxiety and Depression. Curr Drug Targets. 2015; 17(5):495-507. DOI: 10.2174/1389450116666150518095650. View