Highlights
- •
Bi-cephalic transcranial direct current stimulation (tDCS) plus functional electrical stimulation (FES) slightly improves reaching motor performance after stroke.
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Bi-cephalic tDCS plus FES does not enhance reaching movement quality after stroke.
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Bi-cephalic tDCS plus FES improves handgrip strength after stroke.
Abstract
Background
Stroke survivors often present poor upper-limb (UL) motor performance and reduced movement quality during reaching tasks. Transcranial direct current stimulation (tDCS) and functional electrical stimulation (FES) are widely used strategies for stroke rehabilitation. However, the effects of combining these two therapies to rehabilitate individuals with moderate and severe impairment after stroke are still unknown.
Objective
Our primary aim was to evaluate the effects of concurrent bi-cephalic tDCS and FES on UL kinematic motor performance and movement quality of chronic post-stroke subjects with moderate and severe compromise. Our secondary aim was to verify the effects of combining these therapies on handgrip force and UL motor impairment.
Methods
We randomized 30 individuals with moderate and severe chronic hemiparesis after stroke into tDCS plus FES ( n = 15) and sham tDCS plus FES ( n = 15) groups. Participants were treated 5 times a week for 2 weeks. Kinematic motor performance (movement cycle time, velocity profile) and movement quality (smoothness, trunk contribution, joint angles) were assessed during an UL reach-to-target task.Handgrip force and motor impairment were also recorded before and after the intervention.
Results
Participants allocated to the tDCS plus FES group improved movement cycle time ( P = 0.039), mean reaching velocity ( P = 0.022) and handgrip force ( P = 0.034). Both groups improved the mean returning phase velocity ( P = 0.018), trunk contribution ( P = 0.022), movement smoothness ( P = 0.001) and UL motor impairment ( P = 0.002).
Conclusions
Concurrent bi-cephalic tDCS and FES slightly improved reaching motor performance and handgrip force of chronic post-stroke individuals with moderate and severe UL impairment.
Trial registration
ClinicalTrials.gov ( NCT02818608 ).
1
Introduction
Upper-limb (UL) motor impairment is one of the most common, persistent and limiting disabilities in the chronic phase of stroke . Individuals with moderate and severe UL impairment usually have reduced motor control with poor motor performance and movement quality when reaching forward . Kinematic motor performance (cycle time, velocity) and kinematic movement quality measures (movement smoothness, joint angles, trunk movements) are used to quantify movement patterns after stroke .
The primary motor cortex (M1) has an important role in the planning and execution of reaching movements, including the efferent control of peripheral muscle contraction, the preparatory activity for reaching as well as control of movement direction and speed . Under regular conditions, both hemispheres have mutual and balanced inhibitory actions . After a stroke, the ipsilesional M1 shows reduced excitability and the contralesional M1 presents higher activity, which reduces even more the activity in the affected M1 . This excitability imbalance negatively affects the UL functional recovery .
Combining rehabilitation approaches has been proposed to improve functional recovery after stroke . Transcranial direct current stimulation (tDCS) is a promising therapeutic modality which enables the alteration of cortical excitability and enhances the effects of conventional rehabilitation treatments . tDCS acts by affecting cortical areas when a weak electrical direct current passes through the cortical tissue . This current de- or hyperpolarizes neuronal resting membrane potentials and thereby alters cortical excitability . Bi-cephalic tDCS with anodal tDCS (a-tDCS) applied on the affected M1 and cathodal tDCS (c-tDCS) over the non-affected M1 has been used to normalize excitatory and inhibitory corticospinal networks and rehabilitate the affected UL after stroke .
Functional electrical stimulation (FES) is widely used in stroke rehabilitation as an adjuvant strategy to improve UL motor function after stroke . FES consists of short-duration electrical pulses applied over muscles, via surface electrodes, to produce muscle contractions during a functional activity . This approach induces important clinical improvements in UL force, motor function and reaching after stroke .
To the best of our knowledge, no study has investigated the effect of concurrent tDCS and FES on UL reaching parameters of chronic post-stroke individuals with moderate and severe UL impairment. Thus, the main goal of this double-blind randomized controlled trial was to investigate the effect of concurrent bi-cephalic tDCS and FES on UL reach-to-target kinematic motor performance and movement quality. Secondary aims were to verify the effects of this treatment on grip force and UL motor impairment.
2
Methods
2.1
Study design
This double-blind randomized controlled trial was registered at ClinicalTrials.gov ( NCT02818608 ), approved by the Institutional Research Ethical Review Board of the Universidade Federal de Ciências da Saúde de Porto Alegre, Brazil (CAAE: 43503615.7.0000.5345) and conducted according to the principles of the 1964 Declaration of Helsinki.
2.2
Participants
Participants were recruited by convenience via social networks and selected according to eligibility criteria. We included individuals with ischemic or hemorrhagic chronic stroke confirmed by head CT or MRI at least 6 months before recruitment, aged between 18 and 80 years, with moderate (32-47/66) or severe hemiparesis (9-31/66) according to the Fugl–Meyer score . Participants had to have minimal cognitive ability on the Mini Mental State Examination [> 20/30 points (illiterate) or > 24/30 points (literate) and no history of seizures. Furthermore, participants had to be able to reach forward with both ULs. Individuals who presented shoulder pain, adhesive capsulitis or glenohumeral luxation and any contraindications for electrical stimulation were excluded.
We instructed participants to maintain their regular activities during the 2 weeks of treatment. A trained physiotherapist delivered the treatment to both groups.The same blinded examiners performed all assessments.
2.3
Randomization
Participants were stratified according to the level of impairment (FMA-UL score) and were randomly divided into 2 groups — tDCS plus FES or ShamtDCS plus FES — by using a computer-generated random number of sequences ( http://www.random.com ). Concealed randomization was performed in blocks of 4 to 6 individuals. An investigator who was not involved in the assessment, treatment or statistical analysis conducted the randomization.
2.4
Interventions
Both groups underwent 10 sessions of concurrent tDCS and FES or placebo tDCS (ShamtDCS) and FES during 30 min, 5 times a week for 2 weeks (excluding weekends). Before each stimulation session, participants underwentscapular, shoulder, elbow, wrist and finger passive mobilization for approximately 10 min.
2.5
Transcranial direct current stimulation
Individuals allocated to the tDCS plus FES group received bi-cephalic tDCS and FES at the same time. tDCS electrodes were placed on the participant’s head at the M1 area (C3 and C4) according to the electroencephalogram 10–20 system . Anode electrodes were positioned over the ipsilesional M1 and cathodes over the contralesional M1 . tDCS was delivered by a TCT neurostimulator (Research Version) developed by TransCranial Research Ltd. (Hong Kong, China) via a pair of 5 × 5 cm saline-soaked sponge surface electrodes . The applied current was set to deliver 2 mA bi-cephalic tDCS , with a relative current density of 0.08 mA/m 2 , for 30 min . The ShamtDCS modality involved the same electrode montage used for active tDCS. The stimulation stopped after a ramp-up and ramp-down period of 30 s each to provide an equivalent scalp sensation .
2.6
Functional electrical stimulation
FES (Dualpex-071 Quark Medical, Brazil) was applied during task-specific training for 30 min via surface electrodes positioned on the anterior deltoid, serratus anterior, triceps brachii and wrist extensor muscles of the paretic arm. The placement of electrodes depended on the muscle area in which the best muscle contraction occurred. Muscles were activated at the same time. Stimulation parameters were set as follows: (1) frequency = 40 Hz , (2) pulse width = 300 μs ; (3) ON time (contraction) = 6 or 8 s; (4) OFF time = 2 × ON time. A ramp-up time of 2 s and ramp-down time of 2 s were included to allow for smooth movements. The intensity of electrical stimulation was adjusted to the maximum tolerated by each participant.
The activities used for task-specific training are detailed in Appendix B .
2.7
Blinding assessment
To assess the effective blinding of participants, they were asked to answer whether they were aware of receiving real or sham tDCS. Participants were allowed to answer only YES or NO . This assessment was performed at the end of the last evaluation session.
2.8
Perception of improvement
At the end of treatment, a blinded assessor asked all participants if they noticed some improvement,no change or deterioration after the treatment. Those subjects who answered that they noticed some improvement were asked an additional question to quantify the improvement on a Likert scale from 0, any improvement, to 10, full improvement.
2.9
Adherence and safety
Adherence to treatment was determined as the proportion of participants who finished the 2-week treatment course and completed all assessments. tDCS and FES are safe and widely used techniques in stroke rehabilitation. The tDCS and FES parameters used in this study did not previously result in any serious adverse effects in post-stroke individuals . Nevertheless, participants were asked at every stimulation session about effects experienced such as “tingling”, “burning”, “headache”, “sleepiness”, “muscle pain” and others.
2.10
Outcome measures
Outcome measures were collected at the Movement Analysis and Neurological Rehabilitation Laboratory (Universidade Federal de Ciências da Saúde de Porto Alegre), Brazil, at baseline (pre-intervention – 2 days before the first session) and post-intervention (1 day after the last session).
2.11
Primary outcome
2.11.1
Reach-to-target kinematic analysis
A synchronized optoelectronic system with 6 infrared cameras (acquisition frequency of 100 Hz; BTS SMART DX 400 System, Italy) and 2 digital video cameras (BTS eVIXTA, Italy) was used to evaluate reach-to-target kinematic motor performance and movement quality. For this purpose, a modified version of the Rab protocol was applied. Fourteen reflective markers were placed on the participant’s body: 3 on the head (nasion, right and left zygomatic protuberance), 3 on the trunk (midsternum, right and left acromions), 3 on each forearm (right and left olecranon, right and left radial styloid process, and right and left ulna styloid process), and 1 on each hand (right and left third metacarpal head) ( Fig. 1 ). The software Smart Analyzer (BTS Bioengineering Corp. NY, USA) was used to filter the raw data, define the reaching phases and determine the motor performance and movement quality variables. Kinematic data were sampled at 100 Hz, and the cutoff frequency of the low-pass filter was chosen after a residual analysis . A low-pass second-order Butterworth digital filter at 6 Hz was applied.
During the evaluation, individuals remained seated on a height-adjustable chair with elbows flexed at approximately 90° and the palms of hands placed on the table surface. They were asked to start the task with the non-paretic UL after hearing a “GO signal” (beep sound), move one limb at a time as quickly and precisely as they could, try to touch the target with the index finger and return to the initial position. An additional marker was used as a target and placed in the mid-sagittal plane at 80% of the individual’s arm length . This procedure was measured 3 times with a 60-s rest between the trials. The mean score for trials was used for data analysis.
2.11.2
Phases of movement definitions
The reach-to-target task was analyzed considering different phases of movement: (1) reaching phase (ballistic/transport phase to reach the target), (2) adjusting phase (precisely locating and touching the target), and (3) returning phase (ballistic/transport phase to return to the initial position). These parameters were calculated according to the hand marker velocity. The onset and offset of reaching, adjusting and returning phases were defined as the moment at which the hand velocity exceeded (reaching and returning phases) or was lower than (adjusting phase) a threshold of 5 cm/s ( Fig. 2 ). Then, the following variables were extracted only from the paretic UL:
Motor performance measures: (1) total movement duration (s): the total time required to complete the reach-to-target task ; (2) mean reaching and mean returning phase velocity (cm/s): mean of the hand marker velocity during the reaching and returning phase ; (3) peak velocity (cm/s): maximum velocity achieved during the reaching phase . Higher movement duration and lower velocities correspond to worse motor performance.
Movement quality measures: (1) movement smoothness [number of movement units’ NMUs)]: the number of online corrections during the ongoing phase and calculated as the number of velocity peaks > 10% peak velocity; (2) trunk forward inclination (%): relative trunk contribution to reaching forward and calculated as the percentage ratio between the sternum forward displacement and hand forward displacement ; (3) elbow range of motion (degree): measured by using the markers on wrist, elbow, and shoulder during all reaching movements. Higher NMU and percentage of trunk contribution and lower degree of elbow extension indicated worse movement quality.
2.12
Secondary outcomes
2.12.1
Handgrip force
This outcome was measured by using a Jamar® hydraulic hand dynamometer (JA Preston Corp., USA). During the evaluation, subjects were seated with the shoulder placed at approximately 30° abduction and 0° flexion, with the elbow flexed at 90° and the wrist in neutral position. Maximal voluntary grip forces were established as the highest values recorded during 3 maximal voluntary exertions separated by a 2-min rest .
2.12.2
Upper-limb impairment
The Fugl Meyer Assessment for the UL (FMA-UL) was used to classify participants according to the level of motor impairment. This evaluation consists of 9 domains that measure reflex activity, flexor and extensor synergy, movement combining synergies and movement out of synergy . Total score ranges from 0 to 66. The following cut-off scores were used to distinguish severe (9 to 31 points) from moderate (32 to 47 points) UL motor impairment .
3
Statistical analysis
Sample size was calculated based on a previous study by using G. Power 3.1. We estimated that we needed 12 participants per group to detect a mean difference of 0.24 s in the reaching movement cycle time , considering 90% power and two-sided alpha 0.05. Assuming a possible 20% withdrawal rate, we determined a final sample size of 30 participants.
An intent-to-treat analysis was applied to compare the outcomes. Data normality and variance homogeneity were verified by Shapiro–Wilk and Levene tests, respectively. Nonparametric Mann–Whitney and Chi-square tests were used to compare demographic and stroke-related characteristics between groups. Baseline variables were compared by Student t test if data were normally distributed and Mann–Whitney test if not normally distributed.
Primary and secondary outcomes were analyzed by using the Generalized Estimation Equation (GEE). Effects of group (tDCS plus FES and ShamtDCS plus FES), time (pre and post), and group × time interactions were verified. Analyses were adjusted, adding “time since stroke” as a covariate. Bonferroni post-hoc testing was used to identify differences between groups and times and the group × time interaction. Statistical analyses were performed using IBM SPSS 22 (SPSS Inc, Chicago, IL). Level of significance was set at P < 0.05. Effect sizes (ESs) were estimated for comparing paretic UL between groups with Cohen’s d, which classifies ES as small (d=0.2 to 0.5), medium (d=0.5 to 0.8), and large (d> 0.8) . Kappa measure of agreement (κ) was used to test whether participants successfully judged the stimulation condition. Kappa results were interpreted as ≤ 0, no agreement, and 0.01–0.20, none to slight; 0.21–0.40, fair; 0.41–0.60, moderate; 0.61–0.80, substantial; and 0.81–1.00 almost perfect agreement .
4
Results
Participants were recruited from March 2016 to June 2018; the final measurement occurred in July 2018. A total of 102 stroke survivors were contacted ( Fig. 3 ) and we finally included 30 individuals. Baseline demographic and clinical characteristics of participants are in Table 1 . Table 2 presents the effects of group, time and group × time interactions for primary and secondary outcomes.
| tDCS plus FES ( n = 15) | Sham tDCS plus FES ( n = 15) | P -value | |
|---|---|---|---|
| Sex, n (%) # | 1.000 | ||
| Male | 10 (67) | 10 (67) | |
| Female | 5 (33) | 5 (33) | |
| Age, years, mean (SD) * | 60 (10.34) | 56 (16.08) | 0.464 |
| Dominant hand, n (%) # | 0.224 | ||
| Right | 15 (100) | 12 (80) | |
| Left | – | 3 (20) | |
| Stroke type, n (%) # | 0.330 | ||
| Ischemic | 14 (93) | 11 (73) | |
| Hemorrhagic | 1 (7) | 4 (27) | |
| Time since stroke, month, median (range) † | 21 (6–59) | 23 (8–59) | 0.512 |
| Affected side, n (%) # | 1.000 | ||
| Right | 7 (47) | 7 (47) | |
| Left | 8 (53) | 8 (53) | |
| Motor impairment | |||
| FMA-UL (0–66), median (range) * | 25 (9–46) | 29 (16–46) | 0.436 |
| Grip strength, kgf, median (range) * | 6 (0–18) | 10 (0–20) | 0.134 |
| Spasticity # | |||
| MAS, frequency (0/1/1 + /2/3/4) | |||
| Shoulder flexors | 2/4/3/5/1/1 | 2/4/3/6/0/0 | 0.896 |
| Elbow flexors | 0/5/4/5/1/0 | 1/5/5/1/3/0 | 0.311 |
| Wrist flexors | 2/5/6/1/1/0 | 3/5/4/1/1/1 | 0.901 |
| tDCS plus FES | ShamtDCS plus FES | Time * group interaction | Effect size | Power | Time effect | Effect size | Power | Group effect | Effect Size | Power | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Wald χ 2 | df | P -value | Wald χ 2 | df | P -value | Wald χ 2 | df | P -value | |||||||||
| Primary outcomes | |||||||||||||||||
| Motor performance measures | |||||||||||||||||
| Movement cycle time, s | |||||||||||||||||
| Pre | 3.35 (2.83–3.96) | 2.70 (2.28–3.96) | 4.269 | 1 | 0.039 # | 0.75 | 0.77 | 4.343 | 1 | 0.037 # | 0.39 | 0.5 | 1.127 | 1 | 0.354 | – | – |
| Post | 2.69 (2.28–3.18) † | 2.69 (2.24–3.23) | |||||||||||||||
| Mean reaching phase velocity, cm/s | |||||||||||||||||
| Pre | 24.28 (19.92–29.59) | 32.29 (28.45–36.65) | 5.254 | 1 | 0.022 # | 0.90 | 0.90 | 6.628 | 1 | 0.010 # | 0.48 | 0.71 | 3.304 | 1 | 0.069 | – | – |
| Post | 30.58 (26.52–35.26) † | 32.72 (28.93–37.0) | |||||||||||||||
| Mean returning phase velocity, cm/s | |||||||||||||||||
| Pre | 27.71 (24.86–3.88) | 33.63 (29.17–38.75) | 0.916 | 1 | 0.339 | – | – | 5.573 | 1 | 0.018 # | 0.41 | 0.58 | 2.962 | 1 | 0.085 | – | – |
| Post | 31.95 (27.28–37.41) * | 35.60 (31.00–4.87) * | |||||||||||||||
| Peak velocity, cm/s | |||||||||||||||||
| Pre | 48.50 (4.36–58.28) | 6.06 (53.59–67.32) | 0.589 | 1 | 0.443 | – | – | 2.923 | 1 | 0.087 | – | – | 3.885 | 1 | 0.059 | – | – |
| Post | 54.60 (48.20–61.86) | 62.84 (55.12–71.63) | |||||||||||||||
| Movement quality measures | |||||||||||||||||
| Smoothness, NMUs, n | |||||||||||||||||
| Pre | 4.96 (4.19–5.87) | 4.05 (3.28–5.00) | 2.705 | 1 | 0.100 | – | – | 1.502 | 1 | 0.001 # | 0.58 | 0.87 | 1.275 | 1 | 0.259 | – | – |
| Post | 3.96 (3.15–4.98) * | 3.71 (2.99–4.59) * | |||||||||||||||
| Trunk compensatory movements | |||||||||||||||||
| Trunk forward inclination, % | |||||||||||||||||
| Pre | 54.32 (43.87–67.27) | 55.45 (43.43–7.80) | 0.895 | 1 | 0.344 | – | – | 5.253 | 1 | 0.022 # | 0.42 | 0.61 | 0.045 | 1 | 0.832 | – | – |
| Post | 5.20 (39.90–63.16) * | 45.86 (34.73–6.55) * | |||||||||||||||
| Joint angles | |||||||||||||||||
| Elbow RoM | |||||||||||||||||
| Pre | 14.79 (11.97–18.27) | 15.65 (11.69–2.95) | 0.062 | 1 | 0.803 | – | – | 1.427 | 1 | 0.232 | – | – | 0.241 | 1 | 0.623 | – | – |
| Post | 16.00 (12.82–19.96) | 17.64 (13.72–22.70) | |||||||||||||||
| Secondary outcomes | |||||||||||||||||
| Handgrip strength, kgf | 4.484 | 1 | 0.034 # | 0.79 | 0.81 | 1.551 | 1 | 0.001 # | 0.58 | 0.87 | 1.485 | 1 | 0.223 | – | – | ||
| Pre | 6.5 (4.18–1.10) | 9.82 (7.64–12.64) | |||||||||||||||
| Post | 8.88 (5.92–13.32) † | 1.49 (8.28–13.29) | |||||||||||||||
| Motor impairment, FMA-UL, score | |||||||||||||||||
| Pre | 25.26 (21.29–29.97) | 29.43 (24.50–35.37) * | 0.016 | 1 | 0.899 | – | – | 9.815 | 1 | 0.002 # | 0.65 | 0.93 | 1.590 | 1 | 0.207 | – | – |
| Post | 26.66 (22.23–31.97) * | 31.21 (26.58–36.65) * | |||||||||||||||
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