Effects of non-invasive vagus nerve stimulation on clinical symptoms and molecular biomarkers in Parkinson's disease

Abstract

Non-invasive vagus nerve stimulation (nVNS) is an established neurostimulation therapy used in the treatment of epilepsy, migraine and cluster headache. In this randomized, double-blind, sham-controlled trial we explored the role of nVNS in the treatment of gait and other motor symptoms in Parkinson's disease (PD) patients. In a subgroup of patients, we measured selected neurotrophins, inflammatory markers and markers of oxidative stress in serum. Thirty-three PD patients with freezing of gait (FOG) were randomized to either active nVNS or sham nVNS. After baseline assessments, patients were instructed to deliver six 2 min stimulations (12 min/day) of the active nVNS/sham nVNS device for 1 month at home. Patients were then re-assessed. After a one-month washout period, they were allocated to the alternate treatment arm and the same process was followed. Significant improvements in key gait parameters (speed, stance time and step length) were observed with active nVNS. While serum tumor necrosis factor- α decreased, glutathione and brain-derived neurotrophic factor levels increased significantly (p < 0.05) after active nVNS treatment. Here we present the first evidence of the efficacy and safety of nVNS in the treatment of gait in PD patients, and propose that nVNS can be used as an adjunctive therapy in the management of PD patients, especially those suffering from FOG. Clinical trial registration: identifier ISRCTN14797144.

Keywords: Parkinson’s disease; gait; neuroinflammation; oxidative stress; vagus nerve stimulation.

Figure 1

Consort diagram for the randomized cross over controlled trial comparing active non-invasive VNS (nVNS) and sham nVNS. PD, Parkinson’s disease; FOG, freezing of gait; n, number/sample size; VNS, Vagus nerve stimulation; EOT, End of treatment visit.

Figure 2

Comparing levels of serum biomarkers before and after intervention in the active and sham nVNS groups. (A,C,E) The change in serum TNF-α, reduced glutathione and BDNF concentration after active nVNS compared to baseline. (B,D,F) The change in serum TNF-α, reduced glutathione and BDNF concentration after sham nVNS compared to baseline. Statistical differences were assessed using the Wilcoxon Sign Rank Test, where p < 0.05 (*) was considered significant.

Figure 3

Comparing the percentage change in gait parameters between active and sham nVNS groups. Representative gait parameters are presented. (A) Percentage change (from baseline) in gait parameters from the ‘pace’ domain between the active nVNS and sham nVNS groups. (B) Percentage change (from baseline) in gait parameters from the “rhythm” domain for active and sham nVNS groups. (C) Percentage change (from baseline) in gait parameters from the ‘variability’ domain. (D) Percentage change (from baseline) in gait parameters from the ‘asymmetry’ and ‘postural control’ domains. Differences were assessed statistically using the Wilcoxon Sign Rank Test, where p < 0.05 (*) was considered significant.

Figure 4

Comparing the percentage change (from baseline) in clinical characteristics between active and sham nVNS groups. (A) Percentage change (from baseline) in MDS – Unified Parkinson’s disease Rating Scale (UPDRS Part I, II, III) between active and sham nVNS groups. (B) Percentage change (from baseline in time taken for Timed Up and Go Test TUG, Falls Efficacy Scale) (FES score, and Freezing of Gait Questionnaire (FOG-Q) score between active and sham nVNS groups. (C) Percentage change (from baseline) in total Dementia Rating Scale (DRS) score and scores in specific domains (ATT, MEM, I/P, CONS, CONC) and Mini Mental State Examination (MMSE) score between active and sham nVNS groups [AAT, Attention; MEM, Memory; I/P, Initiation and Perseveration; CONS, Construction; CONC, Conceptualisation]. Statistical differences were assessed using the Wilcoxon Sign Rank Test, where p < 0.05 (*) was considered significant.

Figure 5

Putative mechanism of nVNS action at circuit level and cellular level. (A) The pathway of direct stimulation of brain regions. 1&2, Dorsal motor nucleus of the vagus and nucleus tractus solitarius; 3, Locus coeruleus; 4&5, Basal ganglia and thalamus; 6, forebrain cholinergic nucleus (including nucleus basalis of Meynert). (B) Inflammatory reflex through vagus nerve showing the efferent limb. Vagus nerve stimulation leads to secretion of ACh in the splenic ganglion. ACh in turn stimulates the splenic nerve, which provides direct adrenergic innervation to the spleen [Ach, Acetyl Choline; NE, Norepinephrine/Noradrenaline]. (C). The cellular and molecular environment inside the spleen. NE secreted by splenic nerve stimulates T cells (cholinesterase positive to secrete Ach). The secreted neurotransmitter binds with the 7-α subunit of nicotinic ACh receptors on the surface of macrophages and inhibits secretion of TNF-α.