Table 1.
Characteristics of the studies included in the systematic review.
| Author (year) | Outcome | Population | Intervention group | Control group | Results |
|---|---|---|---|---|---|
| Dawson et al. (47) (NCT01669161) |
Upper limb motor function | Twenty patients with a history of unilateral supratentorial ischemic stroke that occurred at least 6 months before inclusion. | Nine patients with implanted VNS on the left vagus nerve (0.5 s of charged balanced pulses with 0.8 mA amplitude, 100 μs pulse width, 30-Hz frequency, delivered during each movement repetition) + rehabilitation therapy (6-week course of 2-h therapy sessions, 3x week, and at least 300 to 400 movements per session). | Eleven patients with rehabilitation therapy only (6-week course of 2-h therapy sessions, 3x week, at least 300 to 400 movements per session). This group did not have an implanted device. |
The mean change in the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score in the VNS group was 8.7 (SD 5.8) vs. 3.0 (SD 6.1) in the control group (between group difference = 5.7, 95% CI−0.4; 11.8, p = 0.064) |
| Kimberley et al. (49) (NCT02243020) | Upper limb motor function | Seventeen patients with a history of unilateral supratentorial ischemic stroke that occurred between 4 months to 5 years before randomization | Eight patients with implanted VNS on the left vagus nerve (0.5 s of charged balanced pulses with 0.8 mA amplitude, 100 μs pulse width, 30-Hz frequency, delivered during each movement repetition) + rehabilitation therapy (6-week course of 2-h therapy sessions, 3x week, and 300 to 500 movement repetitions per session). After 6 weeks of in-clinic therapy, participants began daily therapist-prescribed home exercises. For the first 30 days of at-home therapy, participants received 0 maVNS and active VNS thereafter. | Nine patients with sham stimulation (0 mA) + rehabilitation therapy (6-week course of 2-h therapy sessions, 3x week, and 300 to 500 movements per session). After 6 weeks of in-clinic therapy, participants began daily therapist-prescribed home exercises. |
Day 1 after therapy: The mean change in FMA-UE score in the VNS group was 7.6 vs. 5.3 in the sham group (between group difference = 2.3, 95% CI−1.8; 6.4, p = 0.20). Day 90 after therapy: The mean change in FMA-UE score in the VNS group was 9.5 vs 3.8 in the sham group (between group difference = 5.7, 95% CI−1.4; 11.5, p = 0.055). The FMA-UE response rate at day 90 (≥6-point change from baseline) in the VNS group was significantly higher (88.0%) compared with the control group (33.0%) (p = 0.03) |
| Dawson et al. (48) (NCT02243020) |
Upper limb motor function | Seventeen patients with a history of unilateral supratentorial ischemic stroke that occurred between 4 months to 5 years before randomization | Eight patients with implanted VNS initially underwent 6 weeks of in clinic rehabilitation therapy + active VNS followed by home exercises paired with self-administered active VNS. | Nine patients with implanted VNS initially underwent 6 weeks of in clinic rehabilitation therapy + sham VNS followed by home exercises with control VNS through day 90. Subjects in this group then crossed over and received 6-weeks of in-clinic rehabilitation paired with active VNS and continue a home exercise program paired with self-administered active VNS | 1-year follow-up of VNS paired with rehabilitation for all participants: The FMA-UE score increased by 9.2 points (95% CI = 4.7; 13.7; P = 0.001). 73% demonstrated a clinically meaningful improvement (≥6 points) in FMA-UE |
| Dawson (2021) (34) (NCT03131960) |
Upper limb motor function | Hundred and eight patients with history of unilateral supratentorial ischemic stroke that occurred between 9 months and 10 years before enrolment. | Fifty-three with implanted VNS on the left vagus nerve (0.5 s of charged balanced pulses with 0.8 mA amplitude, 100 μs pulse width, 30-Hz frequency, delivered during each movement repetition) + rehabilitation therapy (6-week course of 2-h therapy sessions, 3x week, and > 300 movement repetitions per session). After 6 weeks of in-clinic therapy, participants began daily therapist-prescribed home exercises. For the first 30 days of at-home therapy, participants received 0 maVNS and active VNS thereafter. | Fifty-five patients with sham stimulation (0 mA) + rehabilitation therapy (6-week course of 2-h therapy sessions, 3x week, and >300 movement repetitions per session). After 6 weeks of in-clinic therapy, participants began daily therapist-prescribed home exercises. |
Day 1 after therapy: The FMA-UE score was significantly increased in the VNS group compared with the control group (5.0 [SD 4.4] vs. 2.4 [SD 3.8]); between group difference = 2.6, 95%CI 1.0; 4.2, (p = 0.0014). Day 90 after therapy: The FMA-UE score was significantly increased in the VNS group compared with the control group (5.8 [SD 6.0] vs. 2.8 [SD 5.2]); between group difference = 3.0, 95%CI 0.8; 5.1, (p = 0.0077). The FMA-UE response rate (≥6-point change from baseline) in the VNS group was significantly higher (47.0%) compared with the control group (24.0%) (between group difference 24.0%, 95%CI 6; 41, p = 0.0098). |
| Capone et al. (46) | Upper limb motor function | Fourteen patients with either ischemic or hemorrhagic stroke that occurred at least 1 year before inclusion. | Seven patients with transcutaneous auricular VNS (location = left external acoustic meatus, frequency = 20 Hz, pulse width = 0.3 ms, duration = 20 s, intensity = level between the detection and pain thresholds) repeated every 5 min for 60 min + robot-assisted therapy (three sessions of 320 assisted movements per day) Immediately after the stimulation. The intervention was delivered daily for 10 consecutive working days | Seven patients with sham stimulation (location = left ear lobe, frequency = 20 Hz, pulse duration = 0.3 ms, duration = 20 s, intensity = level between the detection and pain thresholds) repeated every 5 min for 60 min + robot-assisted therapy (three sessions of 320 assisted movements per day) Immediately after the stimulation. The intervention was delivered daily for 10 consecutive working days. |
The FMA-UE score was significantly increased in the VNS group compared with the control group (5.4 vs 2.8; Mann– Whitney U = 5 00, p = 0.048) |
| Redgrave et al. (45) (NCT03170791) | Upper limb motor function | 13 patients with an anterior circulation ischemic stroke at least 3 months before enrolment | 13 patients with transcutaneous auricular VNS (location = left cymba concha, frequency = 25 Hz, pulse width = 0.1 ms, intensity = maximum tolerable level) delivered during each movement repetition + rehabilitation therapy (6-week course of 1-h therapy sessions, 3x week consisting of upper limb repetitive task practice: 30–50 repetitions of 7–10 arm movements) | No control group | The mean (SD) improvement in FMA-UE was 17.1 (SD 7.8). Ten patients (83%) achieved a clinically relevant increase of >10 points with an overall effect size of 0.68 |
| Wu (57) (registration no. ChiCTR1800019635) | Upper limb motor function | Twenty two patients with a history of ischemic stroke that occurred between 0.5 and 3 months before enrollment | Ten patients with transcutaneous auricular VNS (location = left cymba concha, frequency = 20 Hz, pulse width = 0.3 ms, intensity = maximum tolerable level, lasting 30 seconds each time, stimulating once every 5 min) performed for 30 min + rehabilitation therapy (30 min, performed after the end the stimulation) per day for 15 consecutive days | Eleven patients with sham stimulation (electrodes were fixed to the cymba conchae of the left ear without electrical stimulation) performed for 30 min + rehabilitation therapy (30 min, performed after the end the stimulation) per day for 15 consecutive days | Day 1 after therapy: The FMA-UE score was significantly increased in the VNS group compared with the control group (6.9 [SD 1.85] vs 3.18 [SD 1.17]); between group difference = 3.72, 95%CI 2.32; 5.12, p < 0.001). Week 4 after therapy: The FMA-UE score was significantly increased in the VNS group compared with the control group (7.70 [SD 1.49] vs. 3.36 [SD 1.75]); between group, p < 0.001) |
| Chang et al. (44)(NCT03592745) | Upper limb motor function | Thirty-four patients with unilateral supratentorial stroke and chronic (>6 months) upper limb hemiparesis | Seventeen patients with transcutaneous auricular VNS (location = left cymba concha, frequency = 30 Hz, pulse width = 0.3 ms, intensity = maximum tolerable level) ~ 250 stimulated movements per session + shoulder/elbow robotic therapy (total of 1,024 flexion, extension, and rotational movements of the elbow and shoulder joints) 3 days per week for 3 weeks (9 sessions) | Seventeen patients with sham stimulation (location = left cymba concha, intensity = 0 ma) + shoulder/elbow robotic therapy (total of 1,024 flexion, extension, and rotational movements of the elbow and shoulder joints) 3 days per week for 3 weeks (9 sessions) | At discharge: The FMA-UE score was increased in the VNS group compared with the control group (3.10 [SEM 0.57] vs. 2.86 [SEM 0.50]). Follow up (3 months after intervention): The FMA-UE score was increased in the VNS group compared with the control group (2.79 [SEM 0.84] vs. 3.22 [SEM 1.0]) |
SEM, Standard error of the mean.