Bi-cephalic transcranial direct current stimulation combined with functional electrical stimulation for upper-limb stroke rehabilitation: A double-blind randomized controlled trial

G Model

REHAB 1272 1–8 Annals of Physical and Rehabilitation Medicine xxx (2018) xxx–xxx

Available online at

ScienceDirect www.sciencedirect.com

1 2 3 4 5 6 7 8 9 10 11

12 13 14 15 16 17 18 19

Original article

Bi-cephalic transcranial direct current stimulation combined with functional electrical stimulation for upper-limb stroke rehabilitation: A double-blind randomized controlled trial Paula Salazar a,b, Veronica Cimolin c, Giulia Palermo Schifino a,b, Ka´tia Daniele Rech a,b, Ritchele Redivo Marchese a,b, Aline Souza Pagnussat a,b,*

Q1 Ana

a

Rehabilitation Sciences Graduate Program, Universidade Federal de Cieˆncias da Sau´de de Porto Alegre (UFCSPA), 45, Sarmento Leite Street, 90050-170 Porto Alegre RS, Brazil b Movement Analysis and Rehabilitation Laboratory, Universidade Federal de Cieˆncias da Sau´de de Porto Alegre (UFCSPA), Brazil c Department of Electronics, Information and Bioengineering, Politecnico di Milano, Italy

A R T I C L E I N F O

A B S T R A C T

Article history: Received 31 January 2019 Accepted 1st May 2019

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. Our secondary aim was to verify the effects of the combined 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 UL motor performance (movement cycle time, velocity profile) and movement quality (smoothness, trunk contribution, joint angles), handgrip force and motor impairment were assessed before and after the intervention. Results: For those participants allocated to the tDCS plus FES group, therapy was effective to improve movement cycle time (P = 0.039), mean reaching phase velocity (P = 0.022) and handgrip force (P = 0.034). Both groups showed improved mean returning phase velocity (P = 0.018), trunk contribution (P = 0.022), and movement smoothness (P = 0.001) as well as alleviated UL motor impairment (P = 0.002). Conclusions: Concurrent bi-cephalic tDCS and FES slightly improved reaching motor performance and handgrip force of individuals with moderate and severe UL impairment after stroke. Trial registration: ClinicalTrials.gov (NCT02818608).  C 2019 Elsevier Masson SAS. All rights reserved.

Q2 1. Introduction

Upper-limb (UL) motor impairment is one of the most common, persistent and limiting disabilities in the chronic phase of stroke [1]. Individuals with moderate and severe UL impairment usually have reduced motor control with poor motor performance and movement quality when reaching forward [2]. Kinematic motor performance (cycle time, velocity) and kinematic movement quality * Corresponding author at: Rehabilitation Sciences Graduate Program, Universidade Federal de Cieˆncias da Sau´de de Porto Alegre (UFCSPA), 45, Sarmento Leite Street, 90050-170 Porto Alegre RS, Brazil. E-mail address: [email protected] (A.S. Pagnussat).

measures (movement smoothness, joint angles, trunk movements) are used to quantify movement patterns after stroke [3]. 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 [4,5] as well as control of movement direction and speed [6]. Under regular conditions, both hemispheres have mutual and balanced inhibitory actions [7]. 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 [7]. This excitability imbalance negatively affects the UL functional recovery [8].

https://doi.org/10.1016/j.rehab.2019.05.004 C 2019 Elsevier Masson SAS. All rights reserved. 1877-0657/

Please cite this article in press as: , et al. Bi-cephalic transcranial direct current stimulation combined with functional electrical stimulation for upper-limb stroke rehabilitation: A double-blind randomized controlled trial. Ann Phys Rehabil Med (2019), https:// doi.org/10.1016/j.rehab.2019.05.004

20 21 22 23 24 25 26 27 28 29 30 31

G Model

REHAB 1272 1–8 2

et al. / Annals of Physical and Rehabilitation Medicine xxx (2018) xxx–xxx

32 Combining rehabilitation approaches has been proposed to 33 improve functional recovery after stroke [1,9]. Transcranial direct 34 current stimulation (tDCS) seems a promising therapeutic 35 Q3 modality able to alter cortical excitability and enhance the effects 36 of conventional rehabilitation treatments [10]. tDCS acts by 37 affecting cortical areas when a weak electrical direct current 38 passes through the cortical tissue [11]. This current de- or 39 hyperpolarizes neuronal resting membrane potentials and thereby 40 alters cortical excitability [12]. Bi-cephalic tDCS with anodal tDCS 41 (a-tDCS) applied on the affected M1 and cathodal tDCS (c-tDCS) 42 over the non-affected M1 has been used to normalize excitatory 43 and inhibitory corticospinal networks and rehabilitate the affected 44 UL after stroke [7,13]. 45 Functional electrical stimulation (FES) is widely used in stroke 46 rehabilitation as an adjuvant strategy to improve UL motor 47 function after stroke [14]. FES consists of short-duration electrical 48 pulses applied over muscles, via surface electrodes, to produce 49 muscle contractions during a functional activity [15]. This 50 approach induces important clinical improvements in UL force, 51 motor function and reaching after stroke [9,15,16]. 52 To the best of our knowledge, no study has investigated the 53 effect of concurrent tDCS and FES on UL reaching parameters in 54 chronic post-stroke individuals with moderate and severe UL 55 impairment. Thus, the main goal of this double-blind randomized 56 controlled trial was to investigate the effect of concurrent bi57 cephalic tDCS and FES on UL reach-to-target kinematic motor 58 performance and movement quality. Secondary aims were to 59 verify the effects of this treatment on grip force and UL motor 60 impairment.

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.

90 91 92 93 94 95

2.4. Interventions

96

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 had scapular, shoulder, elbow, wrist and finger passive mobilization for approximately 10 min.

97 98 99 100 101

2.5. Transcranial direct current stimulation

102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117

61

2. Methods

Individuals allocated to the tDCS plus FES group received bicephalic 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 [19]. Anode electrodes were positioned over the ipsilesional M1 and cathodes over the contralesional M1 [10,20,21]. 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 [13]. The applied current was set to deliver 2 mA bi-cephalic tDCS [10,20,21], with a relative current density of 0.08 mA/m2, for 30 min [10]. 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 [20].

62

2.1. Study design

2.6. Functional electrical stimulation

118

63 64 65 66 67 68

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 Cieˆncias da Sau´de de Porto Alegre, Brazil (CAAE: 43503615.7.0000.5345) and conducted according to the principles of the 1964 Declaration of Helsinki.

69

2.2. Participants

70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86

Participants were recruited by convenience via an institutional website and 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, who were male or female, aged 18 to 80 years, with moderate (32-47/66) or severe hemiparesis (9-31/66) according to the Fugl–Meyer score [17]. Participants had to have minimal cognitive ability on the Mini Mental State Examination [> 20/30 points (illiterate) or > 24/30 points (literate) [18] 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, and the same blinded examiners performed all assessments.

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 [22], (2) pulse width = 300 ms [22]; (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.

119 120 121 122 123 124 125 126 127 128 129 130 131 132

2.7. Blinding assessment

133

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 [23]. This assessment was performed at the end of the last evaluation session.

134 135 136 137 138

2.8. Perception of improvement

139

87

2.3. Randomization

88 89

Participants were stratified according to the level of impairment (FMA-UL score) and were randomly divided into

At the end of treatment, a blinded assessor asked all participants if they noticed some improvement or no change or deterioration after the treatment. Those 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.

140 141 142 143 144 145

Please cite this article in press as: , et al. Bi-cephalic transcranial direct current stimulation combined with functional electrical stimulation for upper-limb stroke rehabilitation: A double-blind randomized controlled trial. Ann Phys Rehabil Med (2019), https:// doi.org/10.1016/j.rehab.2019.05.004

G Model

REHAB 1272 1–8 et al. / Annals of Physical and Rehabilitation Medicine xxx (2018) xxx–xxx

146

2.9. Adherence and safety

147 148 149 150 151 152 153 154 155

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 [15,24]. Nevertheless, participants were asked at every stimulation session about effects experienced such as ‘‘tingling’’, ‘‘burning’’, ‘‘headache’’, ‘‘sleepiness’’, ‘‘muscle pain’’ and others.

156

2.10. Outcome measures

157 158 159 160 161

Outcome measures were collected at the Movement Analysis and Neurological Rehabilitation Laboratory (Universidade Federal de Cieˆncias da Sau´de de Porto Alegre), Brazil, at baseline (preintervention; 2 days before the first session) and post-intervention (1 day after the last session).

162

2.11. Primary outcome

163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185

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 [25] was used. 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 [26]. A lowpass second-order Butterworth digital filter at 6 Hz was applied. During the evaluation, individuals remained seated on a heightadjustable chair with elbows flexed at approximately 908 and the palms of hands placed on the table surface. They were asked to start 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

3

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 [26]. This procedure was measured 3 times with a 60-s rest between the trials. The mean score for trials was used for data analysis.

186 187 188 189 190

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 [26] (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 [26]; (2) mean reaching and mean returning phase velocity (cm/s): mean of the hand marker velocity during the reaching and returning phase [26]; (3) peak velocity (cm/s): maximum velocity achieved during the reaching phase [26]. 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 [26] 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 [27]; (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.

191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221

2.12. Secondary outcomes

222

2.12.1. Handgrip force This outcome was measured by using a Jamar1 hydraulic hand dynamometer (JA Preston Corp., USA). During the evaluation, subjects were seated with the shoulder placed at approximately 308 abduction and 08 flexion, with the elbow flexed at 908 and the

223 224 225 226 227

Fig. 1. Positioning of markers.

Please cite this article in press as: , et al. Bi-cephalic transcranial direct current stimulation combined with functional electrical stimulation for upper-limb stroke rehabilitation: A double-blind randomized controlled trial. Ann Phys Rehabil Med (2019), https:// doi.org/10.1016/j.rehab.2019.05.004

G Model

REHAB 1272 1–8 et al. / Annals of Physical and Rehabilitation Medicine xxx (2018) xxx–xxx

4

Fig. 2. Representative graph displaying the velocity profile during the reach-to-target task. Graph is divided in reaching phase, adjusting phase and returning phase.

228 229 230

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 [28].

231 232 233 234 235 236 237 238 239

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 [29]. The 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 [17].

240

3. Statistical analysis

Sample size was calculated based on a previous study [30] by 241 242 using G. Power 3.1. We estimated that we needed 12 participants 243 per group to detect a mean difference of 0.24 s in the reaching 244 movement cycle time [30], considering 90% power and two-sided 245 alpha 0.05. Assuming a possible 20% withdrawal rate, we 246 determined a final sample size of 30 participants. 247 An intent-to-treat analysis was applied to compare the 248 outcomes. Data normality and variance homogeneity were verified 249 by Shapiro–Wilk and Levene tests, respectively. Nonparametric 250 Mann–Whitney and Chi-square tests were used to compare 251 demographic and stroke-related characteristics between groups. 252 Baseline variables were compared by Student t test if data were 253 normally distributed and Mann–Whitney test if not normally 254 distributed. 255 Variables regarding the primary and secondary outcomes were 256 analyzed by using the Generalized Estimation Equation (GEE). 257 Effects of group (tDCS plus FES and ShamtDCS plus FES), time (pre 258 and post), and group  time interactions were verified. Analyses 259 were adjusted, adding ‘‘time since stroke’’ as a covariate. 260 Bonferroni post-hoc testing was used to identify differences 261 between groups and times and the group  time interaction. 262 Statistical analyses involved using IBM SPSS 22 (SPSS Inc, Chicago, 263 IL). The level of significance was set at P < 0.05. Effect sizes (ESs) 264 were estimated for comparing paretic UL between groups with 265 Q4 Cohen’sd, which classifies ES as small (0.2 to 0.5), medium (0.5 to 266 0.8), and large (> 0.8) [31]. Kappa measure of agreement (k) was 267 used to test whether participants successfully judged the 268 stimulation condition. Kappa results were interpreted as  0, no 269 agreement, and 0.01–0.20, none to slight; 0.21–0.40, fair; 0.41– 270 0.60, moderate; 0.61–0.80, substantial; and 0.81–1.00 almost 271 perfect agreement [32].

4. Results

272

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.

273 274 275 276 277 278 279

4.1. Primary outcome (Table 2)

280

4.1.1. Reach-to-target kinematic analysis

281

4.1.1.1. Motor performance. The between-group comparisons showed a time  group interaction for movement cycle time

282 283

Fig. 3. Flow diagram of the study. FMA: Fugl Meyer Assessment–Upper Limb; MMSE: Mini Mental State Examination; FES: functional electrical stimulation; tDCS: transcranial electrical stimulation.

Please cite this article in press as: , et al. Bi-cephalic transcranial direct current stimulation combined with functional electrical stimulation for upper-limb stroke rehabilitation: A double-blind randomized controlled trial. Ann Phys Rehabil Med (2019), https:// doi.org/10.1016/j.rehab.2019.05.004

G Model

REHAB 1272 1–8 et al. / Annals of Physical and Rehabilitation Medicine xxx (2018) xxx–xxx

5

Table 1 Demographic characteristics of participants with stroke who received transcranial direct current stimulation (tDCS) or sham tDCS with functional electrical stimulation (FES) at baseline.

Q7

Sex, n (%)# Male Female Age, years, mean (SD)* Dominant hand, n (%)# Right Left Stroke type, n (%)# Ischemic Hemorrhagic Time since stroke, month, median (range)y Affected side, n (%)# Right Left Motor impairment FMA-UL (0–66), median (range)* Grip strength, kgf, median (range)* Spasticity# MAS, frequency (0/1/1 + /2/3/4) Shoulder flexors Elbow flexors Wrist flexors

tDCS plus FES (n = 15)

Sham tDCS plus FES (n = 15)

P-value

10 (67) 5 (33) 60 (10.34)

10 (67) 5 (33) 56 (16.08)

15 (100) -

12 (80) 3 (20)

14 (93) 1 (7) 21 (6–59)

11 (73) 4 (27) 23 (8–59)

7 (47) 8 (53)

7 (47) 8 (53)

25 (9–46) 6 (0–18)

29 (16–46) 10 (0–20)

0.436 0.134

2/4/3/5/1/1 0/5/4/5/1/0 2/5/6/1/1/0

2/4/3/6/0/0 1/5/5/1/3/0 3/5/4/1/1/1

0.896 0.311 0.901

1.000

0.464 0.224

0.330

0.512 1.000

FMA-UL: Fugl-Meyer Assessment–Upper Limb; MAS: Modified Ashworth Scale. # Chi-square analysis. * t-Student test. y U-Mann–Whitney.

284 285 286 287 288 289 290 291

(P = 0.039) and mean reaching phase velocity (P = 0.022). According to the post-hoc analysis, tDCS plus FES was effective for improving both variables [D of movement cycle time:  0.66 s (95% CI  1.29–  0.06, P = 0.022)]; D of mean reaching phase velocity: 6.3 cm/s (1.49–10.46, P = 0.003). We observed a time effect in mean returning phase velocity (P = 0.018), showing a difference between pre- and post-evaluation in both groups but no group effect for any motor performance variable.

292 293 294 295 296 297 298

4.1.1.2. Movement quality. We found no time  group interaction for any variables but found a time effect for NMU (P = 0.001) and trunk forward inclination (P = 0.022). Thus, both groups showed a significant improvement when comparing pre and post data. We found no group effect for movement quality variables. The covariate ‘‘time since stroke’’ did not influence any of the parameters evaluated.

299

4.2. Secondary outcomes (Table 2)

300 301 302 303 304 305 306 307

We found a time  group interaction for handgrip force (P = 0.034). tDCS plus FES was effective in enhancing this outcome [D in handgrip force: 2.38 (95% CI 0.32–4.48, P = 0.014)]. We found a time effect for this outcome (P = 0.002) (i.e., a significant difference between pre- and post-evaluation) in both groups but no time  group interaction. Group had no effect on any of the secondary outcomes, nor did the covariate ‘‘time since stroke’’ influence any of the parameters evaluated.

308

4.3. Adherence and safety

309 310 311 312 313 314 315 316

All participants received the intervention to which they were initially allocated, without dropouts. Participants in both groups received 10 sessions, for 30 min of stimulation during the 2-week intervention period. No serious adverse effects occurred during the treatment. Five participants in the active tDCS reported moderate tingling that persisted for the first 1 min of stimulation. Also, 4 participants in the sham group reported mild tingling that continued for the first 30 s of stimulation.

4.4. Blinding integrity

317

Overall, 10/15 (67%) participants with tDCS plus FES and 11/15 318 (73.3%) with ShamtDCS plus FES believed they had received the 319 real therapy. Only 14/30 (46.6%) participants judged the stimula- 320 tion condition correctly, which represents no agreement 321 (k = 0). Thus, the blinding integrity was effective. Q5322 4.5. Perception of improvement

323

For all individuals allocated to the active tDCS group (100%), the median perception of improvement was 5 (range 2–7) on the 0–10 rating scale and for 12/15 (80%) participants in the shamtDCS group, the median perception of improvement was 5 (range 0–6). Finally, 3/15 (20%) participants in the shamtDCS group reported no change after the treatment (P = 0.806).

324 325 326 327 328 329

5. Discussion

330

This double-blind randomized controlled trial aimed to verify the effect of concurrent tDCS and FES on UL reaching motor performance and movement quality of chronic post-stroke individuals with moderate and severe impairment. tDCS plus FES slightly improved motor performance during a reach-to-target task by reducing movement cycle time and enhancing movement velocity. The ability to perform functional tasks faster could determine the individual’s choice of using the paretic UL during daily living activities. Regarding the kinematic movement quality variables, both groups showed improvements in UL movement smoothness and trunk contribution after treatment (time effect). This result was expected considering the vast literature about the positive effects of trunk restraint, which was adopted in this study during both interventions [33]. Using strategies to avoid trunk compensatory movements during rehabilitation may increase elbow extension and reduce compensatory movements during functional tasks [33].

331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348

Please cite this article in press as: , et al. Bi-cephalic transcranial direct current stimulation combined with functional electrical stimulation for upper-limb stroke rehabilitation: A double-blind randomized controlled trial. Ann Phys Rehabil Med (2019), https:// doi.org/10.1016/j.rehab.2019.05.004

ShamtDCS plus FES

Q9

3.35 (2.83–3.96) 2.69 (2.28–3.18)y

2.70 (2.28–3.96) 2.69 (2.24–3.23)

Effect size

Wald x2

df

P-value

4.269

1

0.039#

0.75

Power

Time effect

Effect size

Wald x2

df

P-value

0.77

4.343

1

0.037#

0.39

Power

Group effect

Effect Size

Power

Wald x2

df

P-value

0.5

1.127

1

0.354

–

–

24.28 (19.92–29.59) 30.58 (26.52–35.26)y

32.29 (28.45–36.65) 32.72 (28.93–37.0)

5.254

1

0.022#

0.90

0.90

6.628

1

0.010#

0.48

0.71

3.304

1

0.069

–

–

27.71 (24.86–3.88) 31.95 (27.28–37.41)*

33.63 (29.17–38.75) 35.60 (31.00–4.87)*

0.916

1

0.339

–

–

5.573

1

0.018#

0.41

0.58

2.962

1

0.085

–

–

48.50 (4.36–58.28) 54.60 (48.20–61.86)

6.06 (53.59–67.32) 62.84 (55.12–71.63)

0.589

1

0.443

–

–

2.923

1

0.087

–

–

3.885

1

0.059

–

–

4.96 (4.19–5.87) 3.96 (3.15–4.98)*

4.05 (3.28–5.00) 3.71 (2.99–4.59)*

2.705

1

0.100

–

–

1.502

1

0.001#

0.58

0.87

1.275

1

0.259

–

–

54.32 (43.87–67.27) 5.20 (39.90–63.16)*

55.45 (43.43–7.80) 45.86 (34.73–6.55)*

0.895

1

0.344

–

–

5.253

1

0.022#

0.42

0.61

0.045

1

0.832

–

–

14.79 (11.97–18.27) 16.00 (12.82–19.96)

15.65 (11.69–2.95) 17.64 (13.72–22.70)

0.062

1

0.803

–

–

1.427

1

0.232

–

–

0.241

1

0.623

–

–

4.484

1

0.034#

0.79

0.81

1.551

1

0.001#

0.58

0.87

1.485

1

0.223

–

–

6.5 (4.18–1.10) 8.88 (5.92–13.32)y

9.82 (7.64–12.64) 1.49 (8.28–13.29)

25.26 (21.29–29.97) 26.66 (22.23–31.97)*

29.43 (24.50–35.37)* 31.21 (26.58–36.65)*

0.016

1

0.899

–

–

9.815

1

0.002#

0.65

0.93

1.590

1

0.207

–

–

Data are mean and 95% confidence intervals; NMUs: number of movement units; UL: upper limb; FMA-UL: Fugl Meyer Assessment–Upper Limb; tDCS: transcranial direct current stimulation; FES: functional electrical stimulation; RoM: range of motion; Wald x2: Wald chi-square. y P < .05 regarding to pre-evaluation (interaction effect). * P < .05 compared to pre-evaluation (time effect). Q10 # Significant values.

et al. / Annals of Physical and Rehabilitation Medicine xxx (2018) xxx–xxx

Primary outcomes Motor performance measures Movement cycle time, s Pre Post Mean reaching phase velocity, cm/s Pre Post Mean returning phase velocity, cm/s Pre Post Peak velocity, cm/s Pre Post Movement quality measures Smoothness, NMUs, n Pre Post Trunk compensatory movements Trunk forward inclination, % Pre Post Joint angles Elbow RoM Pre Post Secondary outcomes Handgrip strength, kgf Pre Post Motor impairment, FMA-UL, score Pre Post

Time*group interaction

G Model

tDCS plus FES

REHAB 1272 1–8

6

Please cite this article in press as: , et al. Bi-cephalic transcranial direct current stimulation combined with functional electrical stimulation for upper-limb stroke rehabilitation: A double-blind randomized controlled trial. Ann Phys Rehabil Med (2019), https:// doi.org/10.1016/j.rehab.2019.05.004

Table 2

Q8 Kinematic measures..

G Model

REHAB 1272 1–8 et al. / Annals of Physical and Rehabilitation Medicine xxx (2018) xxx–xxx

349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386

In this study, the experimental group showed a slight improvement that may not be considered clinically relevant [34]. For this reason, we believe that the use of bi-cephalic tDCS is not recommended as a primary choice of treatment for individuals in the chronic phase of stroke and with high levels of impairment. One possible explanation for the lack of positive results could be that individuals in the chronic phase after stroke and with worse motor impairment have less surviving brain tissue. Previous studies suggest that having enough surviving brain tissue is essential for achieving a good response to tDCS [35]. Several other factors may also have influenced the results of combining treatment approaches, such as severity of stroke, integrity of cortical connections and time after stroke [36–38]. The time-based window of tDCS delivery and the type of therapy to be combined also affect motor recovery [35]. In the present study, we chose bicephalic tDCS delivering 2 mA for 30 min based on a previous meta-analysis [39]. The authors showed that bi-cephalic tDCS appeared to offer superior recovery as compared with anodal or cathodal montages. They explained this result by the simultaneous downregulation of neural activity on the non-lesioned hemisphere via cathodal stimulation and upregulation of neural activity on the lesioned hemisphere via anodal stimulation [39]. As mentioned before, all participants performed task-specific training with trunk restriction during tDCS plus FES or ShamtDCS plus FES. Training consisted of reaching forward with different levels of difficulty (see Appendix B). Repetitive training alone can restore motor function and promote brain reorganization after stroke [40]. Thus, exercise-induced brain plasticity may explain the improvement found in some variables for both groups (i.e. time effect). Overall, our study suggests that for individuals with moderate to severe UL impairment after stroke, bi-cephalic tDCS combined with FES might help improve reaching motor performance and handgrip force. However, bi-cephalic tDCS does not enhance the effects of FES in improving either movement quality variables or motor impairment. Further trials testing different protocols and times of treatment with adequate follow-up are strongly encouraged.

387

5.1. Limitations

388 389 390 391 392 393 394 395 396 397

We did not use methods to collect data of neural excitability, such as measuring motor-evoked potentials or interhemispheric interactions. Also, this study did not provide any data on the longterm efficacy of interventions. The object affordance may have influenced our results because the target did not have a real-life functional goal [41]. Finally, even though we found no statistical difference in baseline data, some variables presented a huge numeric difference between groups. However, statistical analysis indicated FMA improvement over time for both groups, although this change was very low to be considered clinically relevant [42].

398

6. Conclusions

399 400 401

Concurrent tDCS and FES induced a slight improvement in reaching motor performance and handgrip strength of individuals with chronic hemiparesis and moderate to severe UL impairment.

402

Funding

403 404 405 406

This study received financial support from Conselho Nacional Q6 de Pesquisa (CNPq) (grant universal 461254/2014-0) and in part by

the Coordenac¸a˜o de Aperfeic¸oamento de Pessoal de Nı´vel Superior – Brasil (CAPES, finance code 001).

7

Appendix A. Supplementary data

407

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.rehab.2019.05.004.

408 409

Disclosure of interest

410

The authors declare that they have no competing interest.

411

References

412

[1] Hatem SM, Saussez G, Della Faille M, Prist V, Zhang X, Dispa D, et al. Rehabilitation of Motor Function after Stroke: A Multiple Systematic Review Focused on Techniques to Stimulate Upper Extremity Recovery. Front Hum Neurosci 2016;10:442. [2] McCrea PH, Eng JJ, Hodgson AJ. Biomechanics of reaching: clinical implications for individuals with acquired brain injury. Disabil Rehabil 2002;24:534–41. [3] Subramanian SK, Yamanaka J, Chilingaryan G, Levin MF. Validity of movement pattern kinematics as measures of arm motor impairment poststroke. Stroke 2010;41:2303–8. [4] Harris-Love ML, Morton SM, Perez MA, Cohen LG. Mechanisms of short-term training-induced reaching improvement in severely hemiparetic stroke patients: a TMS study. Neurorehabil Neural Repair 2011;25:398–411. [5] Kawashima R, Roland PE, O’Sullivan BT. Fields in human motor areas involved in preparation for reaching, actual reaching, and visuomotor learning: a positron emission tomography study. J Neurosci 1994;14:3462–74. [6] d’Avella A, Lacquaniti F. Control of reaching movements by muscle synergy combinations. Front Comput Neurosci 2013;7:42. [7] Nowak DA, Grefkes C, Ameli M, Fink GR. Interhemispheric competition after stroke: brain stimulation to enhance recovery of function of the affected hand. Neurorehabil Neural Repair 2009;23:641–56. [8] Adeyemo BO, Simis M, Macea DD, Fregni F. Systematic review of parameters of stimulation, clinical trial design characteristics, and motor outcomes in noninvasive brain stimulation in stroke. Front Psychiatry 2012;3:88. [9] Menezes IS, Cohen LG, Mello EA, Machado AG, Peckham PH, Anjos SM, et al. Combined Brain and Peripheral Nerve Stimulation in Chronic Stroke Patients With Moderate to Severe Motor Impairment. Neuromodulation 2018;21:176–83. [10] Lindenberg R, Renga V, Zhu LL, Nair D, Schlaug G. Bihemispheric brain stimulation facilitates motor recovery in chronic stroke patients. Neurology 2010;75:2176–84. [11] Polania R, Nitsche MA, Ruff CC. Studying and modifying brain function with non-invasive brain stimulation. Nat Neurosci 2018;21:174–87. [12] Nitsche MA, Fricke K, Henschke U, Schlitterlau A, Liebetanz D, Lang N, et al. Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans. J Physiol 2003;553:293–301. [13] Goodwill AM, Teo WP, Morgan P, Daly RM, Kidgell DJ. Bihemispheric-tDCS and upper limb rehabilitation improves retention of motor function in chronic stroke: A pilot study. Front Hum Neurosci 2016;10:258. [14] Eraifej J, Clark W, France B, Desando S, Moore D. Effectiveness of upper limb functional electrical stimulation after stroke for the improvement of activities of daily living and motor function: a systematic review and meta-analysis. Syst Rev 2017;6:40. [15] Nussbaum EL, Houghton P, Anthony J, Rennie S, Shay BL, Hoens AM. Neuromuscular electrical stimulation for treatment of muscle impairment: Critical review and recommendations for clinical practice. Physiother Can 2017;69:1–76. [16] Cuesta-Gomez A, Molina-Rueda F, Carratala-Tejada M, Imatz-Ojanguren E, Torricelli D, Miangolarra-Page JC. The use of functional electrical stimulation on the upper limb and interscapular muscles of patients with stroke for the improvement of reaching movements: A feasibility study. Front Neurol 2017;8:186. [17] Singer B, Garcia-Vega J. The Fugl-Meyer upper extremity scale. J Physiother 2017;63:53. [18] Almeida OP. Mini mental state examination and the diagnosis of dementia in Brazil. Arq Neuropsiquiatr 1998;56:605–12. [19] Homan RW, Herman J, Purdy P. Cerebral location of international 10-20 system electrode placement. Electroencephalogr Clin Neurophysiol 1987;66:376–82. [20] Bolognini N, Vallar G, Casati C, Latif LA, El-Nazer R, Williams J, et al. Neurophysiological and behavioral effects of tDCS combined with constraint-induced movement therapy in poststroke patients. Neurorehabil Neural Repair 2011;25:819–29. [21] Montenegro RA, Midgley A, Massaferri R, Bernardes W, Okano AH, Farinatti P. Bihemispheric motor cortex transcranial direct current stimulation improves force steadiness in post-stroke hemiparetic patients: A randomized crossover controlled trial. Front Hum Neurosci 2016;10:426. [22] Rosewilliam S, Malhotra S, Roffe C, Jones P, Pandyan AD. Can surface neuromuscular electrical stimulation of the wrist and hand combined with routine therapy facilitate recovery of arm function in patients with stroke? Arch Phys Med Rehabil 2012;93:1715–21.

413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482

Please cite this article in press as: , et al. Bi-cephalic transcranial direct current stimulation combined with functional electrical stimulation for upper-limb stroke rehabilitation: A double-blind randomized controlled trial. Ann Phys Rehabil Med (2019), https:// doi.org/10.1016/j.rehab.2019.05.004

G Model

REHAB 1272 1–8 8

483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511

et al. / Annals of Physical and Rehabilitation Medicine xxx (2018) xxx–xxx

[23] Brunoni AR, Schestatsky P, Lotufo PA, Bensenor IM, Fregni F. Comparison of blinding effectiveness between sham tDCS and placebo sertraline in a 6week major depression randomized clinical trial. Clin Neurophysiol 2014;125:298–305. [24] Bikson M, Grossman P, Thomas C, Zannou AL, Jiang J, Adnan T, et al. Safety of transcranial direct current stimulation: Evidence based update 2016. Brain Stimul 2016;9:641–61. [25] Rab G, Petuskey K, Bagley A. A method for determination of upper extremity kinematics. Gait Posture 2002;15:113–9. [26] Menegoni F, Milano E, Trotti C, Galli M, Bigoni M, Baudo S, et al. Quantitative evaluation of functional limitation of upper limb movements in subjects affected by ataxia. Eur J Neurol 2009;16:232–9. [27] Aprile I, Rabuffetti M, Padua L, Di Sipio E, Simbolotti C, Ferrarin M. Kinematic analysis of the upper limb motor strategies in stroke patients as a tool towards advanced neurorehabilitation strategies: a preliminary study. Biomed Res Int 2014;2014:636123. [28] Boissy P, Bourbonnais D, Carlotti MM, Gravel D, Arsenault BA. Maximal grip force in chronic stroke subjects and its relationship to global upper extremity function. Clin Rehabil 1999;13:354–62. [29] Fugl-Meyer AR, Jaasko L, Leyman I, Olsson S, Steglind S. The post-stroke hemiplegic patient. 1. A method for evaluation of physical performance. Scand J Rehabil Med 1975;7:13–31. [30] Caimmi M, Carda S, Giovanzana C, Maini ES, Sabatini AM, Smania N, et al. Using kinematic analysis to evaluate constraint-induced movement therapy in chronic stroke patients. Neurorehabil Neural Repair 2008;22:31–9. [31] Cohen J, editor. Statistical power analysis for the behavioral sciences. 2nd ed., Hillsdale: L. Erlbaum Associates; 1988. [32] McHugh ML. Interrater reliability: the kappa statistic. Biochem Med (Zagreb) 2012;22:276–82.

[33] Pain LM, Baker R, Richardson D, Agur AM. Effect of trunk-restraint training on function and compensatory trunk, shoulder and elbow patterns during poststroke reach: a systematic review. Disabil Rehabil 2015;37:553–62. [34] Wagner JM, Rhodes JA, Patten C. Reproducibility and minimal detectable change of three-dimensional kinematic analysis of reaching tasks in people with hemiparesis after stroke. Phys Ther 2008;88:652–63. [35] Li LM, Uehara K, Hanakawa T. The contribution of interindividual factors to variability of response in transcranial direct current stimulation studies. Front Cell Neurosci 2015;9:181. [36] Marquez J, van Vliet P, McElduff P, Lagopoulos J, Parsons M. Transcranial direct current stimulation (tDCS): does it have merit in stroke rehabilitation? A systematic review. Int J Stroke 2015;10:306–16. [37] Bradnam LV, Stinear CM, Barber PA, Byblow WD. Contralesional hemisphere control of the proximal paretic upper limb following stroke. Cereb Cortex 2012;22:2662–71. [38] O’Shea J, Boudrias MH, Stagg CJ, Bachtiar V, Kischka U, Blicher JU, et al. Predicting behavioural response to TDCS in chronic motor stroke. Neuroimage 2014;85 Pt 3:924–33. [39] Chhatbar PY, Ramakrishnan V, Kautz S, George MS, Adams RJ, Feng W. Transcranial direct current stimulation post-stroke upper extremity motor recovery studies exhibit a dose-response relationship. Brain Stimul 2016;9:16–26. [40] Schaechter JD. Motor rehabilitation brain plasticity after hemiparetic stroke. Prog Neurobiol 2004;73:61–72. [41] Wu CY, Wong MK, Lin KC, Chen HC. Effects of task goal and personal preference on seated reaching kinematics after stroke. Stroke 2001;32:70–6. [42] Page SJ, Fulk GD, Boyne P. Clinically important differences for the upperextremity Fugl-Meyer Scale in people with minimal to moderate impairment due to chronic stroke. Phys Ther 2012;92:791–8.

Please cite this article in press as: , et al. Bi-cephalic transcranial direct current stimulation combined with functional electrical stimulation for upper-limb stroke rehabilitation: A double-blind randomized controlled trial. Ann Phys Rehabil Med (2019), https:// doi.org/10.1016/j.rehab.2019.05.004

512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540