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

Abstract

Gait impairments in Parkinson's disease (PD) are often present at diagnosis and respond selectively to treatment. 1 Novel interventions targeting dopa-resistant gait impairments and their consequences-falls risk-are urgently needed. Recent evidence suggests that neuronal cholinergic loss from the basal forebrain (nucleus basalis of Meynert) and brain stem (pedunculopontine nucleus) contribute to a functional decline in gait. 2 A noninvasive technique that activates the cholinergic circuitry, which has gained recent traction in neurological disorders, is noninvasive 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 the altered regulation of acetylcholine. 3 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.A total of 30 participants with idiopathic PD (15 active and 15 sham) were recruited. The participants were included if they were able to walk independently for 2 minutes, had stable medication during 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. The visits lasted approximately 2 hours. Gait was measured within 1 hour both pre-and post-intervention during a 2-minute continuous walk at a comfortable walking pace around a 25 m circuit inclusive of a 7 × 0.6 m instrumented walkway while ON dopaminergic medication. The participants in the active group received a single dose (120 seconds) of nVNS between the pre-and postassessments with the gammaCore (Basking Ridge, NJ, USA) handheld device 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.

Aerobic Exercise Combined With Transcranial Direct Current Stimulation Over the Prefrontal Cortex in Parkinson Disease: Effects on Cortical Activity, Gait, and Cognition

“…51 Studies assessing the effects of cholinergic augmentation, via pharmacological intervention (i.e., rivastigmine and donepezil) or vagus nerve stimulation, have observed significant reduction of gait variability in people with PD. 52,53 Among various gait domains assessed in the current study, only gait variability (i.e., step time variability) responded to the combined intervention. Thus, it is possible to speculate that the addition of anodal tDCS over the PFC to a session of aerobic exercise may have increased cholinergic activity, leading to reduced gait variability.…”

Differential effects of vagus nerve stimulation paradigms guide clinical development for Parkinson’s disease

“…Another preclinical PD study in rats demonstrated that transcutaneous auricular VNS alleviated neuroinflammation, resulting in reduced SN-DA phenotypic loss and greater motor function, possibly through nicotinic acetylcholine receptor activation [46]. Small human pilot studies in PD showed that a single session of transcutaneous VNS can improve gait [47,48], highlighting the Fig. 3.…”

“…While in rodents these results happened on the order of days to weeks [5,10,66], it is important to note that in epilepsy and depression patients, VNS effects occurred over longer periods on the order of months to years [67e70]. Therefore, while initial pilot studies using external VNS suggested promising motor benefits for PD [47,48], a similar timecourse should be expected for long-term VNS treatment in PD patients due to chronic, ongoing degeneration. While other anti-inflammatory strategies such as nonsteroidal anti-inflammatory drugs have failed to yield convincing clinical results for PD [71], VNS provides greater benefit by altering multiple mechanisms of degeneration.…”

Noninvasive vagus nerve stimulation in Parkinson’s disease: current status and future prospects

“…Due to its clinical properties and widespread effects on Central and Autonomic Nervous Systems (CNS/ANS), VNS may be a suitable therapy in PD as highlighted below in the main body of our manuscript. The effects of nVNS on gait problems in human participants with PD has been demonstrated in three recent publications [24][25][26]. Furthermore, some recent studies have investigated the clinical efficacy of VNS for reducing symptoms that often occur in PD, including fatigue [27] and gastrointestinal symptoms [28,29], neuropsychiatric disorders [30,31], dementia [32,33] and essential tremor [34] providing further theoretical support.…”