Contemporary Clinical Trials 105 (2021) 106396

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Contemporary Clinical Trials

journal homepage: www.elsevier.com/locate/conclintrial

Effects of transcranial direct current stimulation on balance after ischemic

stroke (SANDE trial): Study protocol for a multicentric randomized
controlled trial
Tatiane de Jesus Chagas a, Igor Sandoval dos Santos Cravo a, Rodrigo Bazan b,
Luciane Aparecida Pascucci Sande de Souza a, Gustavo José Luvizutto a, *
a
Physical Therapy Department, Federal University of Triângulo Mineiro (UFTM), Uberaba, Minas Gerais, Brazil
b
Department of Neurology, Psychology and Psychiatry, Botucatu Medical School (UNESP), Botucatu, São Paulo, Brazil

A R T I C L E I N F O A B S T R A C T

Victor Volovici Background: Among the tools used for motor rehabilitation after stroke, transcranial direct current electrical
stimulation (tDCS) aims to modify cortical excitability and improve motor function. Despite promising results,
Keywords: the effects of tDCS on balance after stroke have not yet been assessed using specific protocols. Therefore, this
Stroke study will aim to evaluate the effects of tDCS and rehabilitation on balance after stroke.
Transcranial direct current stimulation
Methods: Eighty-two ischemic stroke patients across two inpatient rehabilitation sites in Brazil will be random­
Balance
ized into one of two treatment programs (anodic tDCS and sham tDCS), both associated with balance training,
Rehabilitation
Physiotherapy each 2 days/week, for six weeks and monitored for exertion, repetition and quality of movements. The primary
outcome measure is the balance. Secondary outcomes will include clinical and functional measures. Outcome
data will be assessed at two time points.
Discussion: This trial will contribute to clarify if anodal tDCS is effective when associated with balance training to
stroke recovery.

Trial Registration can include techniques for non-invasive neuromodulation through brain
stimulation, such as transcranial magnetic stimulation (rTMS) and
Brazilian Registry of Clinical Trials (ReBEC), http://www.ensaiosc transcranial direct current stimulation (tDCS), which create low-
linicos.gov.br/rg/RBR-24shfp/. Register Number:RBR-24shfp. intensity electrical currents in the brain to change the excitability of
cortical regions [8].
1. Background tDCS reversibly polarizes regions of the brain via the topical appli­
cation of low-intensity direct currents to change the potential and
Stroke is the third leading cause of mortality in industrialized modulation of transneuronal membrane excitability levels and firing
countries and the main cause of chronic disability in adults, resulting in rates [9]. The tDCS-induced polarization effect in the brain varies
a major socioeconomic impact and reduced quality of life for these in­ depending on electrode polarity, wherein anodal stimulation (positive
dividuals [1,2]. It is estimated that approximately 70% to 80% of stroke electrode) increases cortical excitability, while cathodal stimulation
patients have impaired cognitive, sensory, and motor functions, which (negative electrode) decreases excitability [10–12].
lead to impaired balance, affecting postural control, and interfering with New studies have shown that non-invasive brain stimulation tech­
social participation and quality of life [3–5]. niques can be used as adjuvant tools to promote the recovery of motor
Advances in rehabilitation approaches have been explored to facili­ function, balance, and locomotion after stroke [13,14]. Case reports
tate the recovery of motor function after stroke [6,7]. Among them, we have shown that a single tDCS session combined with treadmill training

Abbreviations: RT, reaction time; tDCS, transcranial direct current stimulation; CONSORT, Consolidated Standards of Reporting Trials; HAD, Hospital Anxiety and
Depression Scale; EMG, electromyography; SENIAM, Surface Electromyography for the Non-invasive Assessment of Muscles..
* Corresponding author at.: Federal University of Triângulo Mineiro (UFTM), Rua Vigário Carlos, 100, Sala 410 - 4◦ andar - Bairro Abadia, CEP: 38025-350 -
Uberaba-MG, Uberaba, Minas Gerais, Brazil.
E-mail address: [email protected] (G.J. Luvizutto).

https://doi.org/10.1016/j.cct.2021.106396
Received 17 February 2021; Received in revised form 25 March 2021; Accepted 2 April 2021
Available online 5 April 2021
1551-7144/© 2021 Elsevier Inc. All rights reserved.
T.J. Chagas et al. Contemporary Clinical Trials 105 (2021) 106396

improved balance in a patient with chronic stroke [15] and that 15 2. Methods
consecutive sessions of tDCS combined with functional electrical stim­
ulation improved speed during locomotion and physical mobility [16]. 2.1. Study design
Randomized clinical studies have found that within tDCS in chronic
patients after stroke, there has been an improvement in functional This multisite, national clinical trial will use a randomized,
performance, balance, and locomotion [17–19]. The results of these controlled, open-label, parallel, double-blind, two-arm design conduct­
studies suggest that tDCS can be a useful adjunctive treatment to ed according to the standards of cynical trials (CONSORT) [23]. Fig. 1
improve motor function in patients after stroke. However, the method­ provides an overview of the study procedures.
ologies are highly variable and do not use specific protocols to improve
balance. Because tDCS is a cost-effective non-invasive procedure for 2.2. Ethical aspects and location
brain stimulation compared to, for example, magnetic stimulation, we
propose the present research to establish whether it could lead to quality The research project was submitted to and approved by the Ethics
of life improvements [20,21]. Therefore, tDCS is a cost-effective method Committee of the Federal University of Triângulo Mineiro (UFTM -
of non-invasive brain stimulation procedures, and evaluating the effect CAAE: 92804318.7.1001.5154). The study will be conducted in Uber­
of this tool on the balance of patients after a stroke can help healthcare aba, Minas Gerais, at the Biomechanics and Motor Control Laboratory of
professionals and provide new alternatives to the balance rehabilitation the Federal University of Triângulo Mineiro (UFTM) and in the Clinical
treatment of these patients [22]. Research Unit of the Botucatu Medical School of the Universidade
Therefore, the aim of this trial was to evaluate the effectiveness of Estadual Paulista (UNESP).
anodic tDCS associated with balance training physiotherapy, on balance The UFTM (center coordinator) is located in Uberaba city and serves
after stroke. In addition, the effects of tDCS on locomotion, functional 27 municipalities that make up the Southern Triangle macro-region of
performance, muscle activation, and the autonomy and quality of life of the State of Minas Gerais as the only hospital that offers highly complex
these patients will be verified. The hypothesis of this study is that the care, 100% through the Unified Health System (UHS). As for the struc­
anodic tDCS associated with a balance training protocol induces changes ture, the hospital has 302 active beds and 14 operating rooms. The
in balance, and that they are beneficial in improving locomotion, muscle emergency room has 32 beds. The HC-UFTM has five annexes: Ambu­
function, functional independence, and quality of life after stroke. latory Maria da Glória, Ambulatory of Specialties, Ambulatory of Pedi­
atrics, Rehabilitation Center, and Chemotherapy Center, totaling 180
specialized offices to monitor the individuals in the study [24].
HCFMB, the auxiliary center of the study (Center 2), is located in the

Fig. 1. Flowchart of the study.

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T.J. Chagas et al. Contemporary Clinical Trials 105 (2021) 106396

city of Botucatu, in the interior of the state of São Paulo, 235 km from the modified Rankin scale (mRS), which has a total score ranging from 0 to 6
state capital, with an estimated population of 144,820 inhabitants in points, where 0 represents an absence of incapacity and 5 represents
August 2018. HCFMB is the largest public institution linked to the UHS maximum incapacity [26].
in the region, serving 68 municipalities and an estimated population d) Hospital anxiety and depression (HAD) scale: HAD was originally
coverage of 2 million people. This hospital has 490 inpatient beds, a developed by Zigmond and Snaith (1983) [27] and is used to determine
stroke unit with 10 beds, and a clinical research unit and specialized the levels of anxiety and depression that a patient is experiencing,
medical outpatient clinics to monitor the participants [25]. consisting of 14 items. Seven of the items refer to anxiety, and seven
refer to depression. Each questionnaire item is rated from 0 to 3, which
2.3. Patients population means that a person can score between 0 and 21 for anxiety or depres­
sion, and above 8, the patient has a considerable degree of anxiety and
Consecutive patient admissions to one of seven inpatient rehabili­ depression.
tation study sites, with a diagnosis of stroke, will be screened for study e) Mini Mental State Examination (MMSE) [28]: This instrument is
eligibility. Inclusion criteria are patients with unilateral ischemic stroke used for global cognitive evaluation. Scores of 25–30 out of 30 are
diagnosis confirmed using computed tomography (CT) or magnetic considered normal. The National Institute of Health and Care Excellence
resonance imaging (MRI) between 3 weeks and 1 year after ictus, of both (NICE) classifies 21–24 as mild impairment, 10–20 as moderate
sexes, aged over 18 years, modified Rankin scale (mRS) 0 to 2, and with impairment, and < 10 as severe impairment. The MMSE will be used in
the ability to walk without assistance for 10 m without interruption this study for data characterization.
[26]. Individuals will be excluded from the study if they have, any f) 10-m walk test (10WT): For the 10mWT, the time in seconds to
metal-in-cranium injuries near the electrode placement area, intrace­ walk the middle 10-m section of a 14-m walkway was used to compute
rebral vascular clips or any other electrically sensitive support system, comfortable walking speed. Timing started when the participant’s first
clinical instability, epilepsy, bilateral lesions, Broca’s, Wernicke’s and foot crossed the 2-m mark and stopped when the first foot crossed the
global aphasia, previous visual disturbances, depression with scores >8 12-m mark, though the participant continued to walk to the 14-m mark.
in the Hospital Anxiety and Depression (HAD) Scale [27], severe No encouragement was given during the test [29].
cognitive impairment on the Mini Mental State Examination (MMSE)
scale [28], pregnancy, or other neurological diseases. Individuals will be 2.7. Evaluation after screening
discontinuity of the study if they have more than 3 consecutive absences,
do not adapt to training, or have any adverse events during stimulation After randomization and before the first treatment session, the initial
will be excluded. assessment will be applied, which consists of the following items:
a) MiniBest Test: The Mini-BESTest is a 14-item balance scale that
2.4. Procedures measures dynamic balance specifically anticipatory transitions, postural
responses, sensory orientation while standing on a compliant or inclined
Individuals diagnosed with stroke after discharge from the hospital base of support, and dynamic stability during gait. Each task is rated on a
will be sent to the Biomechanics and Motor Control Laboratory of the 2-point ordinal scale from 0 to 2; a score of 0 indicating that a person is
UFTM and to the Clinical Research Unit of the UNESP. All individuals unable to perform the task, score of 2 indicates normal performance. The
with ischemic stroke, as confirmed by a CT or MRI scan, will be invited maximum score for this scale is 28 [30,31].
to participate. The patient, a family member, or a guardian must sign a b) Fugl-Meyer Assessment (FMA) Scale: FMA is a cumulative nu­
free and informed consent form. After signing the consent form, the merical scoring system that assesses six aspects of the patient: range of
individuals will be evaluated to confirm inclusion criteria using the 10- motion, pain, sensitivity, motor function of the upper and lower ex­
m walk test (10WT) and HAD. After confirming the inclusion (walk tremities and balance, in addition to coordination and speed, totaling to
without assistance for 10 m without interruption, mRS between 0 and 2, 226 points. This scale has a total of 100 points for normal motor func­
and scores <8 in the HAD), the patients will be screened for clinical and tion, where the maximum score for the upper extremity is 66 and that for
functional conditions, and the exclusion criteria will be checked for tDCS the lower is 34. The motor evaluation includes measurement of move­
application. ment, coordination, and reflex activity of the shoulder, elbow, wrist,
hand, hip, knee, and ankle [32].
2.5. Randomization and blinding c) Surface electromyography (EMG): The electromyograph used for
the study will be the wireless Delsys Trigno™. The EMG Trigno™ sen­
The concealed randomization schedule will be established using a sors employ four silver bar contacts to detect the EMG signal on the
computer-generated random number sequence, and maintained by an surface of the skin. The silver bars will be directed perpendicularly to the
offsite investigator who is neither involved with the enrollment nor with muscle fibers, the sensor will be fixed to the skin using an adhesive
the assessment of study participants. A second research assistant will interface, and placed in the center of the muscle belly, away from the
consecutively open consecutively numbered, randomly ordered, opaque tendons and the muscle margin. The muscles evaluated by EMG will
envelopes containing the group allocation (in a 1:1 ratio) after the include the rectus femoris, anterior tibialis, gastrocnemius medial fiber
baseline assessment. tDCS will be applied for 12 sessions, twice a week, (GM), and lumbar paravertebral. Skin preparation will follow the Sur­
for 6 weeks. All participants will receive stroke rehabilitation, with 40 face Electromyography for the Non-invasive Assessment of Muscles
min of balance training immediately after all tDCS sessions, regardless of (SENIAM) protocol and the electrode placement protocol will be ac­
the allocated group. cording to the Anatomical Guide for the Electromyographer [33]. The
collection of electromyographic activity will be carried out in a room
2.6. Evaluation during screening with minimal external influences (noise, lamps, and electromagnetic
waves) and positioned in a sitting posture, with the arms and torso
a) Identification of personal, demographic, and clinical data: Data supported in a chair comfortably. Only the ipsilesional side will be
will be collected through an interview with the participant/person in evaluated, where the patient will be submitted to the push test first;
charge and/or analysis of medical records. later, the patient will be instructed to remain in an orthostatic position
b) Structured neurological assessment: Data will be collected for 10 s while standing and then will be asked to sit in a chair and stand
through structured interviews with the participant/guardian and anal­ up.
ysis of medical records. d) Time up and Go (TUG) test: is a simple and quick functional
c) Modified Rankin scale (mRS): Disability was evaluated by the mobility test that assesses walking speed and dynamic balance.

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T.J. Chagas et al. Contemporary Clinical Trials 105 (2021) 106396

Individuals were required to stand up from a chair with armrests, walk 3 2.9. Balance training
m, turn around, return to the chair, and sit down. The time taken to
complete this task was measured in seconds with a stopwatch. The TUG The physiotherapy protocol was based on the description model for
test has excellent reliability (ICC > 0.95) in individuals with chronic replication of interventions (TIDieR) and will be performed immediately
stroke [34]. after performing transcranial electrical stimulation, lasting 40 min
f) Barthel Index: Autonomy was evaluated by the Barthel Index, (SUPPLEMENTAL FILE 1). It will consist of dynamic and static balance
which consists of 10 questions on aspects of day-to-day independence training exercises, including orthostatic, trunk control, gait, and body
and activities of the patient; the higher the score is, the greater the au­ alignment, in addition to strengthening the lower limbs and dissociation
tonomy of the patient [27]. of waists. It is divided into four major modules, from 1 to 4, where each
g) Quality of life questionnaire (Euroquol-5D scale): The European represents a difficulty in balance, associated with strengthening and
(5D) Quality of Life Scale (EuroQol) was used to assess the impact of improving gait. The proposed protocol was based on the movement
stroke on an participants’ quality of life according to five domains: strategies used for posture control, according to the exercises proposed
mobility, personal care, usual activities, pain/discomfort, and anxiety/ by Shumway-Cook and Horak (1992) [40] and Shumway-Cook &
depression. The scores ranged from 0 to 10. The higher the score was, McCollum (1990) [41].
the worse the patient’s perception of quality of life. At the end of the test,
the patient reported their health on an ordinal scale of 0 to 100; the 2.10. Outcomes
closer to 0 the score was, the worse their condition, and the closer to 100
the score was, the better their condition [35,36]. Outcome assessment will also be carried out on the first and last day
At the end of the six-week intervention, the evaluation will be of care.
redone, included screening tests, followed by a 90-day follow-up reas­ a) Primary: Change in the degree of static and dynamic balance
sessment. The study schedule and assessments are shown in Table 1. evaluated by the MiniBest Test.
b) Secondary: Change in gait speed using the 10WT; sensory-motor
function assessed by the Fugl-Meyer scale; muscle activity of the
2.8. Intervention rectus femoris, tibialis anterior, medial gastrocnemius, and lumbar
paravertebral muscles using surface electromyography; functional
a) Group 1, anodic tDCS: tDCS will be applied by means of a battery- mobility by TUG; and degree of functional independence and autonomy
powered current stimulator (model Neurostim V.S. 1.0, Medsuplly®), evaluated by mRS and Barthel index and quality of life by Euroquol-5D
using a pair of sponge surface electrodes (5 cm × 5 cm) soaked in saline scale.
solution. The patient will be placed in a room with minimal external
influences (noise, light bulbs, and electromagnetic waves) in a sitting 2.11. Safety and adverse event monitoring
posture, with the arms and trunk supported on a chair. For stimulation,
the electrodes will be placed on the motor cortex (CZ region—lower Participant safety, during the study, will be of the utmost concern.
limb—of the International Electroencephalography System 10/20) [37]. The questionnaire on the adverse effects of the application of the tDCS
The reference electrodes (cathode) will be placed in the supra-central will be applied [42]. All sites will report minor and serious adverse
orbital region (Násion). It has been shown that this is the optimal po­ events that occur from the baseline evaluation through to the 12-month
sition of the reference electrode to increase motor cortex excitability follow-up evaluation. A Data Safety Monitoring Board will receive re­
[10,38]. A constant current of 2 mA of intensity and resistance of less ports outlining adverse events and study enrollment three times a year.
than 10 kΩ will be applied for 20 min, on the basis of safety guidelines
[39]. The total current density will not exceed 0.08 mA/cm2 during 2.12. Sample size
applications.
b) Group 2 - Sham tDCS: For the control group, the electrodes will be Based on the assumption that participants in the experimental groups
placed in the same position as group 1, with the same programming of will cover at least 4.25 points more in the MiniBest Test based on min­
the device for 20 min, and the current will be delivered for the first 15 s imal detectable change for primary outcome [43], compared to the
and then turned off for 19 min and 45 s. control group at the postevaluation, we calculated that a total sample of
80 participants is required (40/group) to detect a clinically relevant
Table 1 effect size of 80%, with 90% power, at 0.05 alpha, and adjusted for an
Development, schedule and assessments. attrition rate of 15%. The sample size calculation was performed using
Study period G*Power 3.1.3 (Franz Faul, University of Kiel, Kiel, Germany).
Timepoint D0 D1 D2 – D12 Follow- Close-
D11 up out 2.13. Statistical analysis
Enrollment X
Eligibility X To detect changes in continuous outcomes, a comparison between
Inclusion/Exclusion X the anodal tDCS and sham stimulation, will be performed using a linear
Randomization and X regression model with a normal response. This analysis will be adjusted
Allocation
for potential confounders, such as age, mRS score, HAD and MMSE score
Assessments* (G1/G2) X X
at baseline. This analysis approach does not test the validity of the
Interventions model’s theoretical assumptions with a normal response. However, if a
Anodal tDCS - G1 X
fault is identified then the comparison will be performed by adjusting
Sham tDCS - G2 X
Balance training X the regression model with an asymmetric response. In the latter case, the
Statistical analysis X X comparison will be made using the nonparametric Mann-Whitney test.
Data will be analyzed using SPSS version 22 (SPSS Inc., Chicago, IL
D0: Initial study development; D1: Initial assessment within groups; D2-D11: is
equivalent to the stimulation time, being 2× per week, for 6 weeks; D12: Final 60606, USA), and will be considered statistically significant at a p value
assessment within groups; Pre and post intervention assessment items*: 10-min <0.05.
walk test, Modified Rankin scale, Mini Mental State Examination scale, HAD, The clinical relevance of the results will be confirmed by calculating
MiniBest Test, Fugl-Meyer scale, surface electromyography, Timed up and Go, the effect size (Cohen’s d) of the significant differences. The following
Barthel index, and EuroQol quality of life questionnaire. effects will be considered: 0.00–0.49, small; 0.50–0.79, medium; and

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T.J. Chagas et al. Contemporary Clinical Trials 105 (2021) 106396

above 0.80, large (Cohen, 1988). An intention-to-treat analysis will be Appendix A. Supplementary data
conducted.
Supplementary data to this article can be found online at https://doi.
3. Discussion org/10.1016/j.cct.2021.106396.

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