Effects of Non-invasive Vagus Nerve Stimulation on Behavioral, Physiological, and Neural Responses to Food in Humans: A Traditional Review

Berçem YARa , Sara RAZZAGHI-ASLb,c, Maria Geraldine VELDHUIZENa,b,c,d

aMersin University Faculty of Science and Letters, Department of Psychology, Mersin, Türkiye
bMersin University Faculty of Economics and Administrative Sciences, Department of Business Administration, Mersin, Türkiye
cBilkent University National Magnetic Resonance Research Center (UMRAM), Ankara, Türkiye
dMersin University Faculty of Medicine, Department of Anatomy, Mersin, Türkiye

ABSTRACT
Non-invasive vagus nerve stimulation (nVNS) is an effective treatment alternative to invasive vagus nerve stimulation (iVNS) when treating pharmacologically intractable depression or epilepsy. Pre-clinical work has shown a role for decreased vagus nerve responses in obesity and iVNS has anecdotally been implicated in weight loss. Various recent studies have focused on modulation of behavioral, neural and physiological responses to food stimuli by nVNS. Here we present a narrative review on these modulations. We observed a wide variety of manipulations and observations, some inconsistent. Concerning perception, nVNS was observed to improve perception of food odors (but not of flavors). nVNS also improved hedonic and motivation aspects, like liking and wanting, but only for stimuli that are lower in liking and wanting or only in participants with anhedonia. Concerning physiological parameters, nVNS generally reduced heart rate variability after fasting and sometimes suppressed gastric frequency. Ghrelin reductions and gastrin increases have also been observed. Concerning neural responses, nVNS strengthens gut-brain signal correlations and these are modulated by perceived hunger. Liking of food photographs also modulates the effect of nVNS on neural responses in reward areas. A tentative picture that emerges from this is that nVNS may only boost food reward responses under reward-deficiency conditions such as hunger, less liked stimuli or depression. Future studies should focus on making systematic comparisons of the varying conditions that modulate nVNS effectiveness in food reward. We recommend that such studies focus on internal state manipulations and anticipatory vs consummatory manipulations, as well as populations with known anhedonia or dopamine deficiency.
Keywords: Eating; reward; motivation; perception; neuroimaging

Referanslar

  1. Colzato L, Beste C. A literature review on the neurophysiological underpinnings and cognitive effects of transcutaneous vagus nerve stimulation: challenges and future directions. J Neurophysiol. 2020;123(5):1739-55. [Crossref]  [PubMed]
  2. Neuser MP, Teckentrup V, Kühnel A, Hallschmid M, Walter M, Kroemer NB. Vagus nerve stimulation boosts the drive to work for rewards. Nat Commun. 2020;11(1):3555. [Crossref]  [PubMed]  [PMC]
  3. Obst MA, Heldmann M, Alicart H, Tittgemeyer M, Münte TF. Effect of Short-Term Transcutaneous Vagus Nerve Stimulation (tVNS) on Brain Processing of Food Cues: An Electrophysiological Study. Front Hum Neurosci. 2020;14:206. [Crossref]  [PubMed]  [PMC]
  4. Frangos E, Richards EA, Bushnell MC. Do the psychological effects of vagus nerve stimulation partially mediate vagal pain modulation? Neurobiol Pain. 2017;1:37-45. [Crossref]  [PubMed]  [PMC]
  5. Berthoud H r. Vagal and hormonal gut-brain communication: from satiation to satisfaction. Neurogastroenterol. Motil. 2008;20(s1):64-72. [Crossref]  [PubMed]  [PMC]
  6. de Lartigue G. Role of the vagus nerve in the development and treatment of diet-induced obesity. J Physiol. 2016;594(20):5791-815. [Crossref]  [PubMed]  [PMC]
  7. Yuan H, Silberstein SD. Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part I. Headache. 2016;56(1):71-8. [Crossref]  [PubMed]
  8. Williams EK, Chang RB, Strochlic DE, Umans BD, Lowell BB, Liberles SD. Sensory Neurons that Detect Stretch and Nutrients in the Digestive System. Cell. 2016;166(1):209-21. [Crossref]  [PubMed]  [PMC]
  9. Han W, Tellez LA, Perkins MH, Perez IO, Qu T, Ferreira J, et al. A Neural Circuit for Gut-Induced Reward. Cell. 2018;175(3):665-78.e23. Erratum in: Cell. 2018;175(3):887-88. [Crossref]  [PubMed]  [PMC]
  10. Tan HE, Sisti AC, Jin H, Vignovich M, Villavicencio M, Tsang KS, et al. The gut-brain axis mediates sugar preference. Nature. 2020;580(7804):511-6. [Crossref]  [PubMed]  [PMC]
  11. Burneo JG, Faught E, Knowlton R, Morawetz R, Kuzniecky R. Weight loss associated with vagus nerve stimulation. Neurology. 2002;59(3):463-4. [Crossref]  [PubMed]
  12. Ogbonnaya S, Kaliaperumal C. Vagal nerve stimulator: Evolving trends. J Nat Sci Biol Med. 2013;4(1):8-13. [Crossref]  [PubMed]  [PMC]
  13. Bodenlos JS, Kose S, Borckardt JJ, Nahas Z, Shaw D, O'Neil PM, et al. Vagus nerve stimulation acutely alters food craving in adults with depression. Appetite. 2007;48(2):145-53. [Crossref]  [PubMed]
  14. de Araujo IE. Multiple Reward Layers in Food Reinforcement. Neurobiology of Sensation and Reward. CRC Press/Taylor & Francis, Boca Raton (FL); 2011. p.263-86.
  15. Small DM. Food reward. In: Food and addiction: A comprehensive handbook. New York, NY, US: Oxford University Press; 2012. p.178-84. [Crossref]
  16. Alicart H, Heldmann M, Göttlich M, Obst MA, Tittgemeyer M, Münte TF. Modulation of visual processing of food by transcutaneous vagus nerve stimulation (tVNS). Brain Imaging Behav. 2021;15(4):1886-97. [Crossref]  [PubMed]  [PMC]
  17. Maharjan A, Wang E, Peng M, Cakmak YO. Improvement of Olfactory Function With High Frequency Non-invasive Auricular Electrostimulation in Healthy Humans. Front Neurosci. 2018;12:225. [Crossref]  [PubMed]  [PMC]
  18. Maharjan A, Peng M, Cakmak YO. Non-invasive High Frequency Median Nerve Stimulation Effectively Suppresses Olfactory Intensity Perception in Healthy Males. Front Hum Neurosci. 2019;12:533. [Crossref]  [PubMed]  [PMC]
  19. Xu H, Jin T, Zhang R, Xie H, Zhuang C, Zhang Y, et al. Cerebral cortex and hippocampus neural interaction during vagus nerve stimulation under in vivo large-scale imaging. Front Neurosci. 2023;17:1131063. [Crossref]  [PubMed]  [PMC]
  20. Takahashi T. Mechanism of acupuncture on neuromodulation in the gut--a review. Neuromodulation. 2011;14(1):8-12; discussion 12. [Crossref]  [PubMed]
  21. Öztürk L, Büning PE, Frangos E, de Lartigue G, Veldhuizen MG. tVNS Increases Liking of Orally Sampled Low-Fat Foods: A Pilot Study. Front Hum Neurosci. 2020;14:600995. [Crossref]  [PubMed]  [PMC]
  22. Altınkaya Z, Öztürk L, Büyükgüdük İ, Yanık H, Yılmaz DD, Yar B, et al. Non-invasive vagus nerve stimulation in a hungry state decreases heart rate variability. Physiol Behav. 2023;258:114016. [Crossref]  [PubMed]
  23. Müller FK, Teckentrup V, Kühnel A, Ferstl M, Kroemer NB. Acute vagus nerve stimulation does not affect liking or wanting ratings of food in healthy participants. Appetite. 2022;169:105813. [Crossref]  [PubMed]
  24. Koepp V, Klaus J, Ferstl M, Müller FK, Kühnel A, Kroemer NB. Non-invasive vagus nerve stimulation normalizes food liking and improves liking ratings in depression. PsyArXiv. 2021 preprint. [Crossref]
  25. Lucchi F, Lloyd B, Nieuwenhuis S. Non-invasive vagus nerve stimulation and the motivation to work for rewards: a replication. bioRxiv. 2023 preprint. [Crossref]
  26. Ferstl M, Kühnel A, Klaus J, Lin WM, Kroemer NB. Non-invasive vagus nerve stimulation conditions increased invigoration and wanting in depression. medRxiv. 2023 preprint. [Crossref]
  27. Ferstl M, Teckentrup V, Lin WM, Kräutlein F, Kühnel A, Klaus J, et al. Non-invasive vagus nerve stimulation boosts mood recovery after effort exertion. Psychol Med. 2022;52(14):3029-39. [Crossref]  [PubMed]  [PMC]
  28. Svaldi J, Tuschen-Caffier B, Peyk P, Blechert J. Information processing of food pictures in binge eating disorder. Appetite. 2010;55(3):685-94. [Crossref]  [PubMed]
  29. Li JN, Xie CC, Li CQ, Zhang GF, Tang H, Jin CN, et al. Efficacy and safety of transcutaneous auricular vagus nerve stimulation combined with conventional rehabilitation training in acute stroke patients: a randomized controlled trial conducted for 1 year involving 60 patients. Neural Regen Res. 2022;17(8):1809-13. [Crossref]  [PubMed]  [PMC]
  30. Wu D, Ma J, Zhang L, Wang S, Tan B, Jia G. Effect and Safety of Transcutaneous Auricular Vagus Nerve Stimulation on Recovery of Upper Limb Motor Function in Subacute Ischemic Stroke Patients: A Randomized Pilot Study. Neural Plast. 2020;2020:8841752. [Crossref]  [PubMed]  [PMC]
  31. Badran BW, Jenkins DD, Cook D, Thompson S, Dancy M, DeVries WH, et al. Transcutaneous Auricular Vagus Nerve Stimulation-Paired Rehabilitation for Oromotor Feeding Problems in Newborns: An Open-Label Pilot Study. Front Hum Neurosci. 2020;14:77. [Crossref]  [PubMed]  [PMC]
  32. Jenkins DD, Moss HG, Adams LE, Hunt S, Dancy M, Huffman SM, et al. Higher Dose Noninvasive Transcutaneous Auricular Vagus Nerve Stimulation Increases Feeding Volumes and White Matter Microstructural Complexity in Open-Label Study of Infants Slated for Gastrostomy Tube. J Pediatr. 2023;262:113563. [Crossref]  [PubMed]  [PMC]
  33. Aljuhani T, Haskin H, Davis S, Reiner A, Moss HG, Badran BW, et al. Transcutaneous auricular vagus nerve stimulation (taVNS) given for poor feeding in at-risk infants also improves their motor abilities. J Pediatr Rehabil Med. 2022;15(3):447-57. [Crossref]  [PubMed]  [PMC]
  34. Wang Y, He Y, Jiang L, Chen X, Zou F, Yin Y, et al. Effect of transcutaneous auricular vagus nerve stimulation on post-stroke dysphagia. J Neurol. 2023;270(2):995-1003. [Crossref]  [PubMed]
  35. Gouveia FV, Silk E, Davidson B, Pople CB, Abrahao A, Hamilton J, et al. A systematic review on neuromodulation therapies for reducing body weight in patients with obesity. Obes Rev. 2021;22(10):e13309. [Crossref]  [PubMed]
  36. Robinson E, Haynes A, Hardman CA, Kemps E, Higgs S, Jones A. The bogus taste test: Validity as a measure of laboratory food intake. Appetite. 2017;116:223-31. [Crossref]  [PubMed]  [PMC]
  37. Grollman A. Physiological variations in the cardiac output of man. Am J Physiol. 1929;89(2):366-70. [Crossref]
  38. Rominger C, Weber B, Aldrian A, Berger L, Schwerdtfeger AR. Short-term fasting induced changes in HRV are associated with interoceptive accuracy: Evidence from two independent within-subjects studies. Physiol Behav. 2021;241:113558. [Crossref]  [PubMed]
  39. Compher C, Frankenfield D, Keim N, Roth-Yousey L; Evidence Analysis Working Group. Best practice methods to apply to measurement of resting metabolic rate in adults: a systematic review. J Am Diet Assoc. 2006;106(6):881-903. [Crossref]  [PubMed]
  40. de Graaf C, Blom WA, Smeets PA, Stafleu A, Hendriks HF. Biomarkers of satiation and satiety. Am J Clin Nutr. 2004;79(6):946-61. [Crossref]  [PubMed]
  41. Koch KL, Stern RM. Handbook of electrogastrography. Oxford University Press; 2003. [Crossref]
  42. Hong GS, Pintea B, Lingohr P, Coch C, Randau T, Schaefer N, et al. Effect of transcutaneous vagus nerve stimulation on muscle activity in the gastrointestinal tract (transVaGa): a prospective clinical trial. Int J Colorectal Dis. 2019;34(3):417-22. [Crossref]  [PubMed]
  43. Teckentrup V, Neubert S, Santiago JCP, Hallschmid M, Walter M, Kroemer NB. Non-invasive stimulation of vagal afferents reduces gastric frequency. Brain Stimul. 2020;13(2):470-3. [Crossref]  [PubMed]
  44. Teckentrup V, Krylova M, Jamalabadi H, Neubert S, Neuser MP, Hartig R, et al. Brain signaling dynamics after vagus nerve stimulation. NeuroImage. 2021;245:118679. [Crossref]
  45. Gancheva S, Bierwagen A, Markgraf DF, Bönhof GJ, Murphy KG, Hatziagelaki E, et al. Constant hepatic ATP concentrations during prolonged fasting and absence of effects of Cerbomed Nemos® on parasympathetic tone and hepatic energy metabolism. Mol Metab. 2018;7:71-9. [Crossref]  [PubMed]  [PMC]
  46. Kaduk K, Petrella A, Müller SJ, Koenig J, Kroemer NB. Non-invasive vagus nerve stimulation decreases vagally mediated heart rate variability. bioRxiv. 2023 preprint. [Crossref]
  47. Vosseler A, Zhao D, Fritsche L, Lehmann R, Kantartzis K, Small DM, et al. No modulation of postprandial metabolism by transcutaneous auricular vagus nerve stimulation: a cross-over study in 15 healthy men. Sci Rep. 2020;10(1):20466. [Crossref]  [PubMed]  [PMC]
  48. Kozorosky EM, Lee CH, Lee JG, Nunez Martinez V, Padayachee LE, Stauss HM. Transcutaneous auricular vagus nerve stimulation augments postprandial inhibition of ghrelin. Physiol Rep. 2022;10(8):e15253. [Crossref]  [PubMed]  [PMC]
  49. Goldstein N, McKnight AD, Carty JRE, Arnold M, Betley JN, Alhadeff AL. Hypothalamic detection of macronutrients via multiple gut-brain pathways. Cell Metab. 2021;33(3):676-87.e5. [Crossref]  [PubMed]  [PMC]
  50. van der Laan LN, de Ridder DT, Viergever MA, Smeets PA. The first taste is always with the eyes: a meta-analysis on the neural correlates of processing visual food cues. Neuroimage. 2011;55(1):296-303. [Crossref]  [PubMed]
  51. Chen EY, Zeffiro TA. Hunger and BMI modulate neural responses to sweet stimuli: fMRI meta-analysis. Int J Obes (Lond). 2020;44(8):1636-52. [Crossref]  [PubMed]  [PMC]
  52. Tang DW, Fellows LK, Small DM, Dagher A. Food and drug cues activate similar brain regions: a meta-analysis of functional MRI studies. Physiol Behav. 2012;106(3):317-24. [Crossref]  [PubMed]
  53. Huerta CI, Sarkar PR, Duong TQ, Laird AR, Fox PT. Neural bases of food perception: coordinate-based meta-analyses of neuroimaging studies in multiple modalities. Obesity (Silver Spring). 2014;22(6):1439-46. [Crossref]  [PubMed]  [PMC]
  54. Rajiah R, Takahashi K, Aziz Q, Ruffle JK. Brain effect of transcutaneous vagal nerve stimulation: A meta-analysis of neuroimaging evidence. Neurogastroenterol Motil. 2022;e14484. [Crossref]  [PubMed]
  55. Carbine KA, Rodeback R, Modersitzki E, Miner M, LeCheminant JD, Larson MJ. The utility of event-related potentials (ERPs) in understanding food-related cognition: A systematic review and recommendations. Appetite. 2018;128:58-78. [Crossref]  [PubMed]
  56. Müller SJ, Teckentrup V, Rebollo I, Hallschmid M, Kroemer NB. Vagus nerve stimulation increases stomach-brain coupling via a vagal afferent pathway. Brain Stimul. 2022;15(5):1279-89. [Crossref]  [PubMed]
  57. Teckentrup V, Kroemer NB. Mechanisms for survival: vagal control of goal-directed behavior. Trends Cogn Sci. 2024;28(3):237-51. [Crossref]  [PubMed]