Transcutaneous Auricular Vagus Nerve Stimulation (tAVNS) Delivered During Upper Limb Interactive Robotic Training Demonstrates Novel Antagonist Control for Reaching Movements Following Stroke

Abstract

Implanted vagus nerve stimulation (VNS) delivered concurrently with upper limb rehabilitation has been shown to improve arm function after stroke. Transcutaneous auricular VNS (taVNS) offers a non-invasive alternative to implanted VNS and may provide similar therapeutic benefit. There is much discussion about the optimal approach for combining VNS and physical therapy, as such we sought to determine whether taVNS administered during robotic training, specifically delivered during the premotor planning stage for arm extension movements, would confer additional motor improvement in patients with chronic stroke. Thirty-six patients with chronic, moderate-severe upper limb hemiparesis (>6 months; mean Upper Extremity Fugl-Meyer score = 25 ± 2, range 13-48), were randomized to receive 9 sessions (1 h in length, 3x/week for 3 weeks) of active (N = 18) or sham (N = 18) taVNS (500 ms bursts, frequency 30 Hz, pulse width 0.3 ms, max intensity 5 mA, ∼250 stimulated movements per session) delivered during robotic training. taVNS was triggered by the onset of a visual cue prior to center-out arm extension movements. Clinical assessments and surface electromyography (sEMG) measures of the biceps and triceps brachii were collected during separate test sessions. Significant motor improvements were measured for both the active and sham taVNS groups, and these improvements were robust at 3 month follow-up. Compared to the sham group, the active taVNS group showed a significant reduction in spasticity of the wrist and hand at discharge (Modified Tardieu Scale; taVNS = -8.94% vs. sham = + 2.97%, p < 0.05). The EMG results also demonstrated significantly increased variance for the bicep peak sEMG amplitude during extension for the active taVNS group compared to the sham group at discharge (active = 26.29% MVC ± 3.89, sham = 10.63% MVC ± 3.10, mean absolute change admission to discharge, p < 0.01), and at 3-month follow-up, the bicep peak sEMG amplitude was significantly reduced in the active taVNS group (P < 0.05). Thus, robot training improved the motor capacity of both groups, and taVNS, decreased spasticity. taVNS administered during premotor planning of movement may play a role in improving coordinated activation of the agonist-antagonist upper arm muscle groups by mitigating spasticity and increasing motor control following stroke. Clinical Trial Registration: www.ClinicalTrials.gov, identifier (NCT03592745).

Keywords: hemiparesis; rehabilitation; robotic therapy; stroke; transcutaneous auricular vagus nerve stimulation (taVNS); vagus nerve stimulation (VNS).

FIGURE 1

Subject receiving taVNS (arrow marks the placement of the stimulator; single 500 ms bursts, 30 Hz, pulse width = 0.3 ms, intensity just below pain threshold between 0.1 and 5.0 mA) during the blinking visual cue for the onset of extension movements on the InMotion ARM^® robot. During each 1 h session patients performed 1,024 active-assist center-out clock movements of the shoulder and elbow, and received stimulation during a total of 256 extensions movements (right = 9 o’clock, 10 o’clock, 12 o’clock, 2 o’clock; left = 10 o’clock, 12 o’clock, 2 o’clock, 3 o’clock).

FIGURE 2

Significant motor improvements and significant changes in sEMG measures of bicep mean frequency were seen in both the active and sham taVNS groups, suggestive of a training benefit from the robot. (A) Upper Extremity Fugl Meyer scores (mean ± SEM) improved for both the sham (N = 15) and active (N = 14) taVNS groups, with a mean improvement of 3 points (Friedman RM-ANOVA, sham P < 0.001, Chi-square = 20.920; active P < 0.001, Chi-square = 16.453). Improvements were significant at discharge and robust through follow-up (Tukey test, sham and active: adm-dc **P < 0.001, adm-fu *P < 0.01). (B) MRC motor power scores (mean ± SEM) were also improved for both the sham (N = 15) and active (N = 14) groups (Friedman RM-ANOVA, sham P < 0.01, Chi-square = 13.0; active P < 0.001, Chi-square = 15.434). These improvements were significant at discharge and robust through follow-up (Tukey test, active and sham: adm-dc *P ≤ 0.01; sham: adm-fu *P < 0.05, active adm-fu *P < 0.001). (C) Directional trends for sEMG are significant for both summed sham and active groups (mean ± SEM; N = 28; blue dashed line). Mean frequency of the biceps during flexion significantly increased across the combined group (One-way RM-ANOVA, P < 0.05, F = 3.274), between admission and follow-up (Tukey test, *P < 0.05). (D) Biceps iEMG (area under the RMS curve) during flexion approached a significant reduction (in% mean voluntary contraction) across the combined group (One-way RM-ANOVA, P = 0.050).

FIGURE 3

taVNS delivered during robotic therapy extension movements significantly reduced spasticity for the active taVNS group (N = 16) compared to sham (N = 17) at discharge (mean raw change score ± SEM), but not follow-up (data not shown). Lower (more negative) scores indicate a greater reduction in spasticity. (A) MTS Wrist/Hand change score at discharge was significantly reduced for the active group (*P < 0.05, Mann-Whitney U-test, U = 77.0; sham = + 0.17 ± 0.26, active = –0.79 ± 0.31). (B) MTS shoulder change score at discharge approached a significant difference for the active taVNS group (P = 0.051, U = 88.50, Mann-Whitney U-test, sham = –0.25 ± 0.24, active = –0.72 ± 0.25).

FIGURE 4

Peak amplitude change score in antagonist (biceps) muscles during extension was notably more dispersed in active taVNS group (N = 17) compared to the sham group (N = 17) at discharge (% mean voluntary contraction change score ± SEM). The change in bicep peak RMS amplitude during extension movements was not significantly different between active and sham groups at discharge or follow-up (Mann-Whitney U-test, discharge: P = 0.796, U = 137.0; follow-up: P = 0.183, U = 69.0), but change score variance was significantly different between groups at discharge (Siegel-Tukey test, *P < 0.01).

FIGURE 5

Bicep Peak amplitude (as represented by% mean voluntary contraction ± SEM) decreased significantly during extension movements in the active taVNS group (N = 14), but not the sham group (N = 14) at follow-up (Friedman RM-ANOVA, sham: P = 0.931; active: P < 0.05, Chi-square = 7.0). Post hoc pairwise comparisons showed a significant reduction in bicep peak RMS amplitude between discharge and follow-up for the active taVNS group (Tukey test, *P < 0.05). There were no significant between-groups differences.