Top

BMC Neurology

Published in:

Open Access 01-12-2023 | Mild Neurocognitive Disorder | Study Protocol

Safety and feasibility of transcutaneous vagus nerve stimulation in mild cognitive impairment: VINCI-AD study protocol

Authors: Helena Dolphin, Adam H. Dyer, Tim Dukelow, Ciaran Finucane, Sean Commins, Sean P Kennelly

Published in: BMC Neurology | Issue 1/2023

Abstract

Background

Over 55 million adults are living with dementia globally, which is projected to reach 157 million by 2050. Mild cognitive impairment (MCI), a syndrome of memory impairment with intact activities of daily living, may precede dementia by several years. Around 5–15% of individuals with MCI convert to dementia annually. Novel treatments which delay progression of MCI to dementia are urgently needed. Transcutaneous vagal nerve stimulation (tVNS) is a non-invasive neuromodulation technique that targets the vagus nerve. Importantly, tVNS has been shown to improve cognition in healthy volunteers, but has not been extensively examined as a potential therapeutic approach in MCI. VINCI-AD will examine the safety and feasibility of tVNS in older adults with MCI.

Design

VINCI-AD is an investigator-led, single-site, single-blind, sham-controlled crossover pilot study which aims to assess the safety and feasibility of tVNS in 40 participants with amnestic MCI. All participants will attend for three consecutive study visits during which they will be randomised to receive no stimulation (baseline), active tVNS stimulation (stimulation at cymba conchae of left ear) or sham tVNS stimulation (at earlobe). Safety will be primarily assessed by ascertainment of adverse events. Further safety assessment will examine the impact of acute tVNS on subjective (orthostatic symptoms), peripheral (finometry-based blood pressure) and central (assessed via Near Infrared Spectroscopy [NIRS]) haemodynamic responses to active stand. Feasibility will be determined using a custom-designed occupational assessment of device usability. Exploratory secondary analysis in VINCI-AD will examine the potential impact of acute tVNS on associative memory, spatial memory and inhibitory control to inform sample size estimates for future trials of tVNS in older adults with MCI.

Discussion

VINCI-AD will report on the safety (adverse events/haemodynamic responses to active stand) and feasibility of tVNS as a potential therapeutic option in MCI. Detailed reporting of study eligibility and completion rates will be reported. Exploratory analysis will examine the potential cognitive benefits of acute tVNS on cognitive function in MCI to report potential effect sizes that may inform future clinical trials in this cohort.

Trial registration

https://clinicaltrials.gov/ct2/show/NCT05514756. Trial Registration Number NCT05514756 (24th August 2022 for this protocol, version 1.0.)

Available only for authorised users

Petersen R. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256:183–94.CrossRefPubMed

Petersen RC. Mild cognitive impairment: current research and clinical implications. Semin Neurol. 2007;27(1):22–31.

Xu Y, Qiu Z, Zhu J, Liu J, Wu J, Tao J et al. The modulation effect of non-invasive brain stimulation on cognitive function in patients with mild cognitive impairment: A systematic review and meta-analysis of randomized controlled trials. BMC Neurosci [Internet]. 2019;20(1):1–11. Available from: https://bmcneurosci.biomedcentral.com/articles/https://doi.org/10.1186/s12868-018-0484-2.

Mercante B, Ginatempo F, Manca A, Melis F, Enrico P, Deriu F. Anatomo-Physiologic Basis for Auricular Stimulation. Med Acupunct [Internet]. 2018;30(3):141. Available from: /pmc/articles/PMC6011382/.

Frangos E, Komisaruk BR. Access to Vagal Projections via Cutaneous Electrical Stimulation of the Neck: fMRI Evidence in Healthy Humans. Brain Stimul. 2017;10(1):19–27.

Yakunina N, Kim SS, Nam EC. Optimization of Transcutaneous Vagus Nerve Stimulation Using Functional MRI. Neuromodulation [Internet]. 2017;20(3):290–300. Available from: https://pubmed.ncbi.nlm.nih.gov/27898202/.

Kraus T, Kiess O, Hösl K, Terekhin P, Kornhuber J, Forster C. CNS BOLD fMRI effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal - A pilot study. Brain Stimul. 2013;6(5):798–804.

Ellrich J. Transcutaneous vagus nerve stimulation. Eur Neurol Rev. 2011;6(4):254–6.CrossRef

Ben-Menachem E. Vagus-nerve stimulation for the treatment of epilepsy. Lancet Neurol. 2002;1(8):477–82.

10.

O’Reardon JP, Cristancho P, Peshek AD. Vagus Nerve Stimulation (VNS) and Treatment of Depression: To the Brainstem and Beyond. Psychiatry (Edgmont) [Internet]. 2006;3(5):54. Available from: /pmc/articles/PMC2990624/.

11.

Clark KB, Naritoku DK, Smith DC, Browning RA, Jensen RA. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nat Neurosci. 1999;2(1):94–8.

12.

Ghacibeh GA, Shenker JI, Shenal B, Uthman BM, Heilman KM. The influence of vagus nerve stimulation on memory. Cogn Behav Neurol [Internet]. 2006;19(3):119–22. Available from: https://pubmed.ncbi.nlm.nih.gov/16957488/.

13.

McGlone J, Valdivia I, Penner M, Williams J, Sadler RM, Clarke DB. Quality of life and memory after vagus nerve stimulator implantation for epilepsy. Can J Neurol Sci [Internet]. 2008;35(3):287–96. Available from: https://pubmed.ncbi.nlm.nih.gov/18714795/.

14.

Schevernels H, van Bochove ME, de Taeye L, Bombeke K, Vonck K, van Roost D et al. The effect of vagus nerve stimulation on response inhibition. Epilepsy & Behavior [Internet]. 2016;64:171–9. Available from: http://www.epilepsybehavior.com/article/S1525505016304553/fulltext.

15.

Sun L, Peräkylä J, Holm K, Haapasalo J, Lehtimäki K, Ogawa KH et al. Vagus nerve stimulation improves working memory performance. J Clin Exp Neuropsychol [Internet]. 2017;39(10):954–64. Available from: https://pubmed.ncbi.nlm.nih.gov/28492363/.

16.

van Bochove ME, de Taeye L, Raedt R, Vonck K, Meurs A, Boon P et al. Reduced distractor interference during vagus nerve stimulation. Int J Psychophysiol [Internet]. 2018;128:93–9. Available from: https://pubmed.ncbi.nlm.nih.gov/29574234/.

17.

Sjögren MJC, Hellström PTO, Jonsson MAG, Runnerstam M, Silander HC, son, Ben-Menachem E. Cognition-enhancing effect of vagus nerve stimulation in patients with Alzheimer’s disease: a pilot study. J Clin Psychiatry. 2002;63(11):972–80.CrossRefPubMed

18.

Merrill CA, Jonsson MAG, Minthon L, Ejnell H, Silander HCS, Blennow K, et al. Vagus nerve stimulation in patients with Alzheimer’s disease: additional follow-up results of a pilot study through 1 year. J Clin Psychiatry. 2006;67(8):1171–8.CrossRefPubMed

19.

Steenbergen L, Sellaro R, Stock AK, Verkuil B, Beste C, Colzato LS. Transcutaneous vagus nerve stimulation (tVNS) enhances response selection during action cascading processes. Eur Neuropsychopharmacol [Internet]. 2015;25(6):773–8. Available from: https://pubmed.ncbi.nlm.nih.gov/25869158/.

20.

Sellaro R, van Leusden JWR, Tona KD, Verkuil B, Nieuwenhuis S, Colzato LS. Transcutaneous Vagus Nerve Stimulation Enhances Post-error Slowing. J Cogn Neurosci. 2015;27(11):2126–32.

21.

Beste C, Steenbergen L, Sellaro R, Grigoriadou S, Zhang R, Chmielewski W et al. Effects of Concomitant Stimulation of the GABAergic and Norepinephrine System on Inhibitory Control – A Study Using Transcutaneous Vagus Nerve Stimulation. Brain Stimul. 2016;9(6):811–8.

22.

Colzato LS, Ritter SM, Steenbergen L. Transcutaneous vagus nerve stimulation (tVNS) enhances divergent thinking. Neuropsychologia. 2018;1:111:72–6.

23.

Jongkees BJ, Immink MA, Finisguerra A, Colzato LS. Transcutaneous vagus nerve stimulation (tVNS) enhances response selection during sequential action. Front Psychol. 2018;9.

24.

Keute M, Barth D, Liebrand M, Heinze HJ, Kraemer U, Zaehle T. Effects of Transcutaneous Vagus nerve stimulation (tVNS) on conflict-related behavioral performance and Frontal Midline Theta Activity. J Cogn Enhancement. 2020;4(2):121–30.

25.

Sun JB, Cheng C, Tian QQ, Yuan H, Yang XJ, Deng H et al. Transcutaneous Auricular Vagus Nerve Stimulation Improves Spatial Working Memory in Healthy Young Adults. Front Neurosci [Internet]. 2021;0:1694. Available from: https://www.frontiersin.org/articles/https://doi.org/10.3389/fnins.2021.790793/full.

26.

Kaan E, de Aguiar I, Clarke C, Lamb DG, Williamson JB, Porges EC. A transcutaneous vagus nerve stimulation study on verbal order memory. J Neurolinguistics. 2021;59.

27.

Ridgewell C, Heaton KJ, Hildebrandt A, Couse J, Leeder T, Neumeier WH. The effects of transcutaneous auricular vagal nerve stimulation on cognition in healthy individuals: A meta-analysis. Neuropsychology [Internet]. 2021;35(4):352–65. Available from: https://pubmed.ncbi.nlm.nih.gov/34043386/.

28.

Ballard C, Shaw F, McKeith L, Kenny R. High prevalence of neurovascular instability in neurodegenerative dementias. Neurology [Internet]. 1998;51(6):1760–2. Available from: https://pubmed.ncbi.nlm.nih.gov/9855544/.

29.

Isik AT, Erken N, Yavuz I, Kaya D, Ontan MS, Ates Bulut E et al. Orthostatic hypotension in patients with Alzheimer’s disease: a meta-analysis of prospective studies. Neurol Sci [Internet]. 2022;43(2):999–1006. Available from: https://pubmed.ncbi.nlm.nih.gov/34255194/.

30.

Hayakawa T, McGarrigle CA, Coen RF, Soraghan CJ, Foran T, Lawlor BA et al. Orthostatic Blood Pressure Behavior in People with Mild Cognitive Impairment Predicts Conversion to Dementia. J Am Geriatr Soc [Internet]. 2015;63(9):1868–73. Available from: https://pubmed.ncbi.nlm.nih.gov/26313614/.

31.

de Heus RAA, de Jong DLK, Rijpma A, Lawlor BA, Olde Rikkert MGM, Claassen JAHR. Orthostatic Blood Pressure Recovery Is Associated With the Rate of Cognitive Decline and Mortality in Clinical Alzheimer’s Disease. J Gerontol A Biol Sci Med Sci [Internet]. 2020;75(11):2169–76. Available from: https://pubmed.ncbi.nlm.nih.gov/32449919/.

32.

Sierra-Marcos A. Regional Cerebral Blood Flow in Mild Cognitive Impairment and Alzheimer’s Disease Measured with Arterial Spin Labeling Magnetic Resonance Imaging. Int J Alzheimers Dis [Internet]. 2017;2017. Available from: /pmc/articles/PMC5442339/.

33.

Gatti PJ, Johnson TA, Massari VJ. Can neurons in the nucleus ambiguus selectively regulate cardiac rate and atrio-ventricular conduction? J Auton Nerv Syst 1996;57(1–2):123–7.

34.

Massari VJ, Johnson TA, Gatti PJ. Cardiotopic organization of the nucleus ambiguus? An anatomical and physiological analysis of neurons regulating atrioventricular conduction. Brain Res 1995;679(2):227–40.

35.

Ferrari M, Quaresima V. A brief review on the history of human functional near-infrared spectroscopy (fNIRS) development and fields of application. Neuroimage 2012;63(2):921–35.

36.

Pérez-Denia L, Claffey P, Byrne L, Rice C, Kenny RA, Finucane C. Increased multimorbidity is associated with impaired cerebral and peripheral hemodynamic stabilization during active standing. J Am Geriatr Soc [Internet]. 2022;70(7):1973–86. Available from: https://onlinelibrary.wiley.com/doi/full/https://doi.org/10.1111/jgs.17810.

37.

Höper S, Kaess M, Koenig J. Prefrontal cortex oxygenation and autonomic nervous system activity under transcutaneous auricular vagus nerve stimulation in adolescents. 2022; Available from: https://doi.org/10.1016/j.autneu.2022.103008.

38.

Yeung MK, Chan AS. A Systematic Review of the Application of Functional Near-Infrared Spectroscopy to the Study of Cerebral Hemodynamics in Healthy Aging. Neuropsychol Rev [Internet]. 2021;31(1):139–66. Available from: https://pubmed.ncbi.nlm.nih.gov/32959167/.

39.

Yeung MK, Chan AS. Functional near-infrared spectroscopy reveals decreased resting oxygenation levels and task-related oxygenation changes in mild cognitive impairment and dementia: A systematic review. J Psychiatr Res [Internet]. 2020;124:58–76. Available from: https://pubmed.ncbi.nlm.nih.gov/32120065/.

40.

Beishon L, Haunton VJ, Panerai RB, Robinson TG. Cerebral hemodynamics in mild cognitive impairment: a systematic review. J Alzheimer’s Disease 2017;59(1):369–85.

41.

Butcher NJ, Monsour A, Mew EJ, Chan AW, Moher D, Mayo-Wilson E, et al. Guidelines for reporting outcomes in Trial Protocols: the SPIRIT-Outcomes 2022 extension. JAMA. 2022;20(23):2345–56.

42.

Redgrave J, Day D, Leung H, Laud PJ, Ali A, Lindert R et al. Safety and tolerability of Transcutaneous Vagus Nerve stimulation in humans; a systematic review. Brain Stimul [Internet]. 2018;11(6):1225–38. Available from: http://www.brainstimjrnl.com/article/S1935861X18302936/fulltext.

43.

Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res [Internet]. 2011;21(2):69–72. Available from: https://pubmed.ncbi.nlm.nih.gov/21431947/.

44.

Hartman-Maeir A, Harel H, Katz N. Kettle test-a brief measure of cognitive functional performance: reliability and validity in stroke rehabilitation. American Journal of Occupational Therapy [Internet]. 2009;63(5):592–9. Available from: https://www.researchgate.net/publication/26852216_Kettle_Test--A_Brief_Measure_of_Cognitive_Functional_Performance_Reliability_and_Validity_in_Stroke_Rehabilitation.

45.

Amariglio RE, Frishe K, Olson LE, Wadsworth LP, Lorius N, Sperling RA et al. Validation of the Face Name Associative Memory Exam in cognitively normal older individuals. J Clin Exp Neuropsychol [Internet]. 2012;34(6):580–7. Available from: https://pubmed.ncbi.nlm.nih.gov/22765048/.

46.

Rentz DM, Amariglio RE, Becker JA, Frey M, Olson LE, Frishe K et al. Face-name Associative Memory Performance is Related To Amyloid Burden in Normal Elderly. Neuropsychologia [Internet]. 2011;49(9):2776. Available from: /pmc/articles/PMC3137730/.

47.

Jacobs HIL, Riphagen JM, Razat CM, Wiese S, Sack AT. Transcutaneous vagus nerve stimulation boosts associative memory in older individuals. Neurobiol Aging. 2015;36(5):1860–7.CrossRefPubMed

48.

Manly T, Robertson IH. The sustained attention to response test (SART). Neurobiology of attention. Jan. 2005;1:337–8.

49.

Spiers HJ, Coutrot A, Hornberger M. Explaining World-Wide Variation in Navigation Ability from Millions of People: Citizen Science Project Sea Hero Quest. Top Cogn Sci [Internet]. 2021;0:1–19. Available from: https://onlinelibrary-wiley-com.elib.tcd.ie/doi/full/https://doi.org/10.1111/tops.12590.

50.

Coughlan G, Puthusseryppady V, Lowry E, Gillings R, Spiers H, Minihane AM et al. Test-retest reliability of spatial navigation in adults at-risk of Alzheimer’s disease. PLoS One [Internet]. 2020;15(9):e0239077. Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239077.

51.

Giraudier M, Ventura-Bort C, Weymar M. Transcutaneous Vagus nerve stimulation (tVNS) improves high-confidence recognition memory but not emotional Word Processing. Front Psychol. 2020;9:11:1276.

52.

Liu KY, Elliott T, Knowles M, Howard R. Heart rate variability in relation to cognition and behavior in neurodegenerative diseases: A systematic review and meta-analysis. Ageing Res Rev [Internet]. 2022;73:101539. Available from: http://creativecommons.org/licenses/by/4.0/.

53.

Dyer AH, McKenna L, Batten I, Jones K, Widdowson M, Dunne J et al. Peripheral Inflammation and Cognitive Performance in Middle-Aged Adults With and Without Type 2 Diabetes: Results From the ENBIND Study. Front Aging Neurosci [Internet]. 2020;12. Available from: https://pubmed.ncbi.nlm.nih.gov/33424582/.

54.

Contreras JA, Aslanyan V, Albrecht DS, Pa J. Higher inflammation levels in cognitively normal older adults are associated with conversion to mild cognitive impairment and Alzheimer’s disease. Alzheimer’s & Dementia [Internet]. 2021;17:e054590. Available from: https://onlinelibrary.wiley.com/doi/full/https://doi.org/10.1002/alz.054590.

55.

Rufener KS, Geyer U, Janitzky K, Heinze HJ, Zaehle T. Modulating auditory selective attention by non-invasive brain stimulation: Differential effects of transcutaneous vagal nerve stimulation and transcranial random noise stimulation. European Journal of Neuroscience [Internet]. 2018;48(6):2301–9. Available from: https://onlinelibrary.wiley.com/doi/full/https://doi.org/10.1111/ejn.14128.

56.

Sutoko S, Sato H, Maki A, Kiguchi M, Hirabayashi Y, Atsumori H et al. Tutorial on platform for optical topography analysis tools. Neurophotonics [Internet]. 2016;3(1):010801. Available from: https://pubmed.ncbi.nlm.nih.gov/26788547/.

57.

Luu S, Chau T. Decoding subjective preference from single-trial near-infrared spectroscopy signals. J Neural Eng [Internet]. 2009;6(1). Available from: https://pubmed.ncbi.nlm.nih.gov/19104138/.

58.

Wang L, Zhang J, Guo C, He J, Zhang S, Wang Y et al. The efficacy and safety of transcutaneous auricular vagus nerve stimulation in patients with mild cognitive impairment: A double blinded randomized clinical trial. Brain Stimul [Internet]. 2022;15(6):1405–14. Available from: http://www.brainstimjrnl.com/article/S1935861X22002078/fulltext.

59.

Herrera AP, Snipes SA, King DW, Torres-Vigil I, Goldberg DS, Wenberg AD. Disparate Inclusion of Older Adults in Clinical Trials: Priorities and Opportunities for Policy and Practice Change. Am J Public Health [Internet]. 2010;100(Suppl 1):S105. Available from: /pmc/articles/PMC2837461/.

60.

Doyle J, Sillevis Smitt M, Smith S, McAleer P, van Leeuwen C, Jacobs A et al. Older adults’ Experiences of using Digital Health Technology for Multimorbidity Self-Management: findings from a longitudinal study. ICCHP-AAATE 2022 Open Access Compendium “Assistive Technology, accessibility and Inclusion” Part II. 2022;236–44.

Title: Safety and feasibility of transcutaneous vagus nerve stimulation in mild cognitive impairment: VINCI-AD study protocol
Authors: Helena Dolphin
Adam H. Dyer
Tim Dukelow
Ciaran Finucane
Sean Commins
Sean P Kennelly
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Mild Neurocognitive Disorder
Vagus Nerve Stimulation
Nerve Stimulation
Published in: BMC Neurology / Issue 1/2023
Electronic ISSN: 1471-2377
DOI: https://doi.org/10.1186/s12883-023-03320-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Safety and feasibility of transcutaneous vagus nerve stimulation in mild cognitive impairment: VINCI-AD study protocol

Abstract

Background

Design

Discussion

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Design

Discussion

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2023

Evaluating the impact of patient-reported outcome measures on depression and anxiety levels in people with multiple sclerosis: a study protocol for a randomized controlled trial

Intravenous thrombolysis for acute ischemic stroke during two COVID-19 outbreaks in China: Wuhan pandemic and Beijing pandemic

Different words for stroke: the same concept? an analysis of associated symptoms and intended reaction in Brazil

A novel case of two siblings harbouring homozygous variant in the NEUROG1 gene with autism as an additional phenotype: a case report

Acceptability of a digital health application to empower persons with multiple sclerosis with moderate to severe disability: single-arm prospective pilot study

Stroke epidemiology and outcomes of stroke patients in Nepal: a systematic review and meta-analysis