Baker, Mark R.

Hunter, Heather

Morris, Rosie

Rochester, Lynn

Taylor, John-Paul

Yarnall, Alison J.

English

Northumbria Research Link

Northumbria Research LinkCitation:  Morris, Rosie, Yarnall,  Alison J.,  Hunter, Heather,  Taylor,  John-Paul,  Baker,  Mark R. and Rochester, Lynn (2019) Noninvasive vagus nerve stimulation to target gait impairment in Parkinson's disease. Movement Disorders, 34 (6). pp. 918-919. ISSN 0885-3185 Published by: Wiley-BlackwellURL: https://doi.org/10.1002/mds.27664 <https://doi.org/10.1002/mds.27664>This version was downloaded from Northumbria Research Link: http://nrl.northumbria.ac.uk/41818/Northumbria University has developed Northumbria Research Link (NRL) to enable users to access the University’s research output. Copyright © and moral rights for items on NRL are retained by the individual author(s) and/or other copyright owners.  Single copies of full items can be reproduced, displayed or performed, and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided the authors, title and full bibliographic details are given, as well as a hyperlink and/or URL to the original metadata page. The content must not be changed in any way. Full items must not be sold commercially in any  format or medium without formal permission of the copyright holder.  The full policy is available online: http://nrl.northumbria.ac.uk/pol  i cies.html  This  document  may differ  from the  final,  published version of  the research  and has been made available online in accordance with publisher policies. To read and/or cite from the published version of the research, please visit the publisher’s website (a subscription may be required.)                        1  Non-invasive vagus nerve stimulation to target gait impairment in Parkinson’s disease  Rosie Morris, PhD,1, 2*, Alison J. Yarnall, MRCP, PhD1*, Heather Hunter, MSc1, John-Paul Taylor, MD, PhD1, Mark R. Baker, FRCP, PhD1,3, Lynn Rochester, PhD1  1Institute of Neuroscience, Newcastle University, Newcastle-upon-Tyne, United Kingdom 2Oregon Health and Science University, Portland, OR, USA 3Department of Clinical Neurophysiology, Royal Victoria Infirmary, Queen Victoria Rd, Newcastle-upon-Tyne, United Kingdom   *these authors contributed equally  Corresponding Author:  Professor Lynn Rochester Institute of Neuroscience Newcastle University Institute for Ageing Newcastle University Newcastle upon Tyne United Kingdom NE4 5PL Lynn.rochester@ncl.ac.uk  Word count: 499 Running Title: Vagus nerve stimulation for gait in PD Key Words: Gait, Parkinson’s disease, Vagus Nerve Stimulation Financial disclosures: AY has received funding from Parkinson’s UK and the NEWCASTLE NIHR BRC. JPT has received grant support from the National Institute of Health (NIHR), Alzheimer's Research UK, Macular Society, Lewy body Society and Wellcome Trust in the past 12 months - no relation to current work. JPT has received speaker fees from GE Healthcare in the past 12 months and consultancy fees to Heptares Therapeutics - no relation to current work. MB is currently supported by grants from the MRC and the William Leech Charity and has previously received grants/funding from the NIHR, Wellcome Trust, Academy of Medical Sciences, Ataxia UK and Friedreich’s Ataxia Research Association. LR receives grant funding from the NIHR, MRC, EU, Stroke Association, Parkinson’s UK, Alzheimer’s Society, GE Healthcare. She has received consultancy for an Ad Board from Biogen. RM and HH have nothing to declare. Funding source: Medical Research Council, Confidence in Concept funding.   2  Gait impairments in Parkinson’s disease (PD) are often present at diagnosis and respond selectively to treatment1. Novel interventions targeting dopa-resistant gait impairments and their consequences - falls risk - are urgently needed. Recent evidence suggests neuronal cholinergic loss from the basal forebrain (nucleus basalis of Meynert) and brainstem (pedunculopontine nucleus) contribute to a functional decline in gait2. A non-invasive technique that activates the cholinergic circuitry, which has gained recent traction in neurological disorders, is non-invasive vagus nerve stimulation (nVNS)3. The exact underlying mechanism of action of nVNS is poorly understood, but an indirect effect mediated through the cholinergic anti-inflammatory pathway has been postulated, through altered regulation of acetylcholine3. Therefore, our aim was to assess the effect of a single dose of nVNS on dopa-resistant gait characteristics (step time variability and step length variability)4 in a pilot feasibility study in PD.  Thirty participants with idiopathic PD (15 active and 15 sham) were recruited to the study. Participants were included if they were able to walk independently for two-minutes, had stable medication over the previous month and provided written consent. Those with significant cognitive impairment (MoCA ≤21), treated with anticholinergics and with contraindications to nVNS were excluded. Figure 1A displays the study design. Gait was measured within one hour both pre- and post- intervention during a two-minute continuous walk at a comfortable walking pace around a 25m circuit inclusive of a 7 x 0.6m instrumented walkway whilst ON dopaminergic medication. Participants in the active group received a single dose (120 seconds) of nVNS between the pre- and post-assessments with the gammaCore® handheld device which was applied to the left side of the neck. For the sham group, an identical device delivered an electrical stimulus that did not activate the vagus nerve. Absolute and percentage change pre- and post-intervention were compared by treatment groups using Mann-Whitney tests. A significant p value was classified as ≤.05. Thirty-one participants were consented and 29 completed the study. There were no significant differences for baseline demographic (Age, gender, MDS-UPDRS part III, Hoehn and Yahr, 3  years of education and levodopa daily dose) or gait data between groups (Supplementary Table 1). In the active group, step time and step length variability decreased whereas an increase was identified in the sham group with step length variability reaching significance (-5.6 vs. 25.4% change for active vs. control group, p=0.045) (Figure 1B).  This exploratory study provides preliminary data suggesting dopa-resistant gait characteristics may improve with nVNS. The underlying mechanism of these findings may be related to amyloid pathology in PD, with cholinergic loss promoting amyloid-β deposition5 and amyloid-β precipitating cholinergic neuronal loss6. However, our study is limited due to the small and heterogeneous cohort. Larger trials should consider using multiple treatment doses of nVNS and a higher intensity of stimulation as moderate stimulation has demonstrated a significant effect on memory consolidation in Alzheimer’s disease7. This small sham-controlled pilot study provides novel evidence of a potential beneficial effect of nVNS on gait in PD. Confirmation is required in a larger multi-dose trial.    Acknowledgements: We would like to acknowledge the Medical Research Council, Confidence in Concept for funding this research study. We would also like acknowledge Electrocore for supplying the active and sham devices for this study. This study was supported by the Newcastle NIHR Biomedical Research Centre. Author Roles: RM: organisation and execution of research project, design and execution of statistical analysis, writing first draft of manuscript AY: Design and execution of statistical analysis, writing first draft of manuscript HH: Execution of research project, review and critique of manuscript JPT: Conception and organisation of research project, review and critique of statistical analysis and manuscript MB: Conception and organisation of research project, review and critique of statistical analysis and manuscript LR: Conception and organisation of research project, review and critique of statistical analysis and manuscript 4   References:  1. Galna B, Lord S, Burn DJ, Rochester L. Progression of gait dysfunction in incident Parkinson's disease: impact of medication and phenotype. Mov Disord 2015;30(3):359-367. 2. Yarnall A, Rochester L, Burn DJ. The interplay of cholinergic function, attention, and falls in Parkinson's disease. Mov Disord 2011;26(14):2496-2503. 3. Johnson RL, Wilson CG. A review of vagus nerve stimulation as a therapeutic intervention. J Inflamm Res 2018;11:203-213. 4. Rochester L, Galna B, Lord S, et al. Decrease in Aβ42 predicts dopa-resistant gait progression in early Parkinson disease. Neurology 2017;88(16):1501-1511. 5. Pepeu G, Grazia Giovannini M. The fate of the brain cholinergic neurons in neurodegenerative diseases. Brain Research 2017;1670:173-184. 6. Hochstrasser T, Hohsfield LA, Sperner‐Unterweger B, Humpel C. β‐Amyloid induced effects on cholinergic, serotonergic, and dopaminergic neurons is differentially counteracted by anti‐inflammatory drugs. Journal of neuroscience research 2013;91(1):83-94. 7. Jacobs HI, Riphagen JM, Razat CM, Wiese S, Sack AT. Transcutaneous vagus nerve stimulation boosts associative memory in older individuals. Neurobiology of Aging 2015;36(5):1860-1867.  

Noninvasive vagus nerve stimulation to target gait impairment in Parkinson's disease

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Noninvasive vagus nerve stimulation to target gait impairment in Parkinson's disease

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