Title: Adjunctive Vagus Nerve Stimulation for Improving Neural control of Gait in Parkinson’s Disease (AdVaNSING-PD)
Funder: Dunhill Medical Trust

Abstract: Prevention of immobility and falls in older people is a public health priority. In ageing and age-associated conditions such as Parkinson’s disease (PD), gait disorders and their consequences – most notably falls - are common manifestations. Progressive and specific degeneration of the cholinergic system is implicated broadly in PD, and may underpin discrete gait impairments which are present even at disease diagnosis. There is recent evidence that augmentation of acetylcholine using cholinesterase inhibitors may improve gait and reduce falls in PD without dementia. However, these drugs are not without side effects. Non-invasive vagus nerve stimulation (nVNS) is used in treatment of epilepsy and migraine and has been shown to activate cholinergic neurons. We have recently shown in a small study (n=30) that single dose nVNS improved a dopa-resistant gait characteristic that is associated with falls risk, and now aim to assess this in a multi-dose randomised placebo-controlled proof of concept and feasibility study. The potential benefits of a non-pharmacological, low-cost, simple-to-use, home-delivered electroceutical approach to boost cholinergic function, improve gait parameters and reduce falls risk in this patient group are immense. We will recruit 40 participants with PD and randomise to receive either active or sham treatment. Participants will undergo baseline assessments of clinical measures (including disease severity), cognition (using computerised cognitive tests), gait (using an instrumented walkway and body worn sensors) and short latency afferent inhibition, an electrophysiological measure of cholinergic function. The active group will receive nVNS using the gammaCore® handheld device. The sham group will receive a device identical to the nVNS but which delivers an electrical stimulus that causes a buzzing sensation to the skin which does not stimulate the vagus nerve. Participants will be shown how to use the device for two minutes on the left side of the neck and asked to repeat this at home twice a day for 12 weeks, at which time the baseline assessments will be repeated. Questionnaires on the suitability of the intervention will be completed and a subset of participants will contribute to a focus group discussion. Data collection including: acceptability of the intervention; recruitment rate; barriers to implementation; feedback from patient and public involvement and sample size calculations will inform development of a scientifically sound clinical trial protocol. We will also aim to establish proof of concept of multi-dose nVNS.

Lay abstract: Parkinson’s is a common condition with currently no cure, although it can be treated with medicine that replaces a chemical called dopamine. Dopamine is lost from certain areas of the brain in people with Parkinson’s (PwP) and results in slowness and stiffness of movements. Recent research has shown that there is a loss of other chemicals in the brain such as acetylcholine. It is thought that acetylcholine has an important role in memory, thinking and walking. This is important, as changes in the way PwP walk can increase risk of falling. We are interested in a new (non-drug) treatment known as non-invasive (applied to the skin) vagus nerve stimulation (nVNS) which uses a small handheld device placed on the neck to stimulate a nerve called the vagus nerve. This treatment is currently licensed as a safe treatment for both epilepsy and migraine. It is thought that by stimulating the vagus nerve we may increase the amount of acetylcholine available in the brain. We have shown in a small study (30 participants) that a single dose nVNS may improve walking in PwP. We are now looking to extend these findings by giving multiple doses of nVNS at home over a 12 week period to see if there are still improvements, and to see if this treatment is acceptable to PwP. Forty PwP (mild-moderately affected) will be asked to attend our research unit on two occasions, each visit lasting around 3-4 hours (we will provide taxis and refreshments). At the first visit, we will ask some questions about general health and mood, in addition to computer based tests of thinking, a walking test, and a measurement of brain wave activity. Participants will be randomly split to receive either the ‘active’ stimulation or the ‘placebo’ treatment. The participant (plus carer) will be shown how to use the device to deliver the stimulation to the neck for two minutes, and be asked to use the device at home twice a day for two minutes for 12 weeks. A researcher will phone to check there are no problems and will be available if there are any questions. At 12 weeks the baseline measurements will be repeated at our research unit, and we will ask some detailed questions about how PwP found using the device. We will ask some participants to take part in a focus group discussion to help plan a further trial.

Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: NEUROLOGICAL;INJURIES AND ACCIDENTS