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ta-VNS for acute stroke

Efficacy and safety of transcutaneous auricular vagus nerve stimulation combined with conventional rehabilitation training in acute stroke patients: a randomized controlled trial conducted for 1 year involving 60 patients

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Year of Publication: 2022

Authors: Jia-Ni Li, Chen-Chen Xie, Chang-Qing Li, ..., Ling-Chuan Niu

Journal: Neural Regeneration Research

Citation: Neural Regen Res 17(8):1809-1813.

Link: https://pmc.ncbi.nlm.nih.gov/articles/PM...NRR-17-1809.pdf

PDF: https://pmc.ncbi.nlm.nih.gov/articles/PM...NRR-17-1809.pdf

Clinical Question

To investigate the efficacy and safety of transcutaneous auricular vagus nerve stimulation (ta-VNS) combined with conventional rehabilitation training on the recovery of motor function, sensory function, and emotional responses in patients with acute ischemic or hemorrhagic stroke over a 1-year follow-up period.

Study Overview

Objective

To assess the long-term efficacy and safety of transcutaneous auricular vagus nerve stimulation (ta-VNS) combined with rehabilitation in patients with acute ischemic or hemorrhagic stroke.

Study Summary

Transcutaneous auricular VNS paired with rehabilitation significantly improved motor function, sensory function, and quality of life vs sham at 1 year
Patients received 4 weeks of rehabilitation paired with either active ta-VNS or sham stimulation and were followed for 1 year.
The ta-VNS group showed significantly greater improvements in motor function, sensory function, emotional state, and quality of life compared to the control group.
These benefits were apparent from 2 weeks post-treatment and were sustained for the entire 1-year follow-up. The treatment was safe and well-tolerated.

Intervention

4 weeks of conventional rehabilitation training preceded by either active or sham transcutaneous auricular vagus nerve stimulation (ta-VNS) in patients within 1 month of an ischemic or hemorrhagic stroke. Follow-up was for 1 year.

Bottom Line

In patients with acute ischemic or hemorrhagic stroke, non-invasive transcutaneous auricular vagus nerve stimulation (ta-VNS) combined with conventional rehabilitation training was safe and significantly improved the recovery of motor and sensory functions, as well as emotional responses, compared to sham stimulation with rehabilitation. These benefits were observed starting from 2 weeks and were sustained for up to 1 year.

        Major Points
        This was a double-blind, randomized, sham-controlled trial involving 60 patients with acute stroke (both ischemic and hemorrhagic) within one month of symptom onset.
Patients were randomized 1:1 to receive either active ta-VNS or sham ta-VNS, with both groups also receiving conventional rehabilitation training.
The intervention consisted of 20-minute stimulation sessions five times per week for four weeks, immediately followed by a 30-minute rehabilitation session.
The ta-VNS group showed significantly greater improvements compared to the control group across all functional outcomes (FMA-U, FMA-L, FMA-S, WMFT score, and WMFT time) at all follow-up time points from 2 weeks to 1 year.
Patients in the ta-VNS group also reported significantly less anxiety and depression (HADS) and better quality of life (SIS) compared to controls.
The treatment was safe and well-tolerated, with no major side effects reported and no significant changes in cardiovascular vital signs.

      

Design

Study Type: Two-group, pragmatic, double-blinded, randomized controlled trial

Randomization: 1

Blinding: Double-blind (participants, physical therapists, and researchers)

Enrollment Period: November 2018 to March 2020

Follow-up Duration: 1 year

Centers: 1

Countries: China

Sample Size: 60

Analysis: Per-protocol analysis included 28 participants in each group (n=28 per arm; 4 losses: 1 ta-VNS death from lung infection, 1 ta-VNS withdrawal, 1 control recurrent stroke, 1 control withdrawal). Outcomes (physiological parameters, FMA-U, FMA-L, FMA-S, WMFT score, WMFT time, HADS, and SIS) were analyzed using two-way analysis of variance followed by Šidák's post hoc multiple comparison test.

Inclusion Criteria

Age 18-80 years
History of first-time symptomatic ischemic or hemorrhagic stroke, demonstrated by imaging
Stroke had occurred within the previous month

Exclusion Criteria

Progressive decline in cardiac, pulmonary, liver, or kidney function
Apraxia
Resting heart rate <50 beats/min
Previous operation on the vagus nerve
Alcohol or drug abuse
Participation in other clinical experiments
Other diagnoses that might interfere with rehabilitation or outcome assessments

Baseline Characteristics

Characteristic	Control	Active
Group	Control (n=30)	ta-VNS (n=30)
Age (yr), mean±SD	68.3±12.1	69.2±12.3
Male, n (%)	14 (47)	15 (50)
Type of stroke (ischemic/hemorrhagic), n	28/2	27/3
Days post-stroke, mean±SD	10.4±6.9	10.8±7.7
Stroke hemisphere (right/left), n	10/20	12/18
FMA-U, mean±SD	30.8±5.3	31.4±5.7
FMA-L, mean±SD	17.2±2.9	17.6±3.0
FMA-S, mean±SD	12.9±3.8	13.2±4.0
SIS, mean±SD	129.7±53.2	143.1±57.2
HADS-A, mean±SD	11.3±2.0	10.9±1.9
HADS-D, mean±SD	8.5±1.5	8.3±1.4

Arms

Field	Control	ta-VNS + Rehabilitation
Intervention	A 4-week course of conventional rehabilitation training (30-minute sessions, 5x/week) immediately preceded by a 20-minute session of sham ta-VNS, where electrodes were placed but no electrical current was delivered.	A 4-week course of conventional rehabilitation training (30-minute sessions, 5x/week) immediately preceded by a 20-minute session of active transcutaneous auricular vagus nerve stimulation (0.3-ms square pulses at 20 Hz for 30 seconds, repeated every 5 minutes).
Duration	4 weeks of treatment	4 weeks of treatment

Outcomes

Outcome	Type	Control	Intervention	P-value
Motor and sensory function following treatment, assessed by the Wolf Motor Function Test (WMFT score and WMFT time) and Fugl-Meyer Assessment (FMA-U upper limb, FMA-L lower limb, FMA-S sensory) at baseline and 2 weeks, 1, 3, 6 months, and 1 year from the beginning of treatment (per-protocol analysis n=28 per arm).	Primary	Showed improvement from baseline but was significantly worse than the ta-VNS group on WMFT score, WMFT time, FMA-U, FMA-L, and FMA-S at every follow-up time point.	Showed significantly greater improvement on WMFT score, WMFT time, FMA-U, FMA-L, and FMA-S compared with the control group at every follow-up time point (2 weeks, 1, 3, 6, and 12 months). At 3 months, improvements in the ta-VNS group were approximately FMA-U 52%, FMA-L 62%, and FMA-S 72%.	<0.05 for all comparisons at all follow-up time points
Emotional state — Hospital Anxiety and Depression Scale (HADS-A and HADS-D)	Secondary	Improved from baseline but remained significantly higher (worse) than the ta-VNS group from the 1-month assessment onward (n=28).	Significantly lower HADS-A and HADS-D scores than control from month 1 through 1 year (n=28).	<0.05 from month 1 onward
Quality of life — Stroke Impact Scale (SIS, range 64-420)	Secondary	Improved from baseline but remained significantly lower than the ta-VNS group from the 3-month assessment onward (n=28).	Significantly higher SIS scores than control from month 3 through 1 year (n=28).	<0.05 from month 3 onward
Cardiovascular safety — heart rate, systolic and diastolic blood pressure measured before and after each stimulation session for 20 consecutive days	Secondary	No statistically significant within-group change in HR, SBP, or DBP before vs after treatment.	No statistically significant within-group change in HR, SBP, or DBP before vs after treatment.	>0.05
Skin redness (device-contact)	Adverse	0 participants	2 participants (both in ta-VNS group; resolved after adjusting current)
Death (serious lung infection)	Adverse	0	1 participant (died between the 1- and 3-month assessments; excluded after 1-month assessment)
Recurrent stroke	Adverse	1 participant (occurred between 6 months and 1 year; excluded after 6-month assessment)	0
Vocal cord palsy, nausea, dysphagia, or other major side effects	Adverse	0	0

Criticisms

The study had a small sample size (60 patients randomized; 28 per arm in the per-protocol analysis).
The lack of an active stimulation control group means that placebo effects and non-activation of vagal nerve fibers cannot be entirely ruled out.
The optimal parameters for electrical stimulation (initiation timing, electrode placement, waveform) have not been identified and may have influenced the therapeutic effect.
Single-center trial in China limits generalizability.

Funding

Medical Scientific Research Project of Chongqing Municipal Health Commission of China (Nos. 2018ZDXM022, 2019MSXM017, and 2020MSXM106); and a grant from Chongqing General Hospital of China (No. 2019ZDXM03), all to LCN and JXM.

Based on: ta-VNS for acute stroke (Neural Regeneration Research, 2022)