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STUDY PROTOCOL

Effect of Transcranial Direct Current Stimulation of Motor Cortex in Cerebral Palsy: A Study Protocol

de Almeida Carvalho Duarte, Natália PhD; Collange Grecco, Luanda André PhD; Delasta Lazzari, Roberta MS; Pasini Neto, Hugo PhD; Galli, Manuela PhD; Santos Oliveira, Claudia PhD

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doi: 10.1097/PEP.0000000000000467
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INTRODUCTION

Cerebral palsy (CP) is a motor development disorder in children. Children may have compromised functional mobility and rehabilitation.1 As gait is an important goal for children with CP, independence with or without the use of a gait-assistance device is a major goal and contributes toward improving motor development.2 The reductions in postural reactions, muscle weakness, and kinematics account for gait impairment in approximately 90% of children with CP.3 This may result in reduced social engagement and difficulty in participation in activities such as sports. Aerobic exercises offer physiological benefits to children with CP.4,5 Thus, gait and balance training have been used to improve the coordination of movements in the gait cycle and selective motor control in children with CP.3,6

The development of novel therapeutic approaches, such as transcranial direct current stimulation (tDCS), combined with conventional methods associated with rehabilitation training, such as treadmill training, can improve function.7 tDCS has positive results when combined with physical rehabilitation. Function has improved for individuals with brain lesions submitted to short periods of brain stimulation.8,9 tDCS is easy to administer, well-tolerated by adults and children, with minimal adverse effects.8,10 Moreover, when combined with motor training of a specific task, tDCS can potentiate cortical neuroplasticity.7

The primary aim of the proposed project described in this protocol is to compare the effects of bilateral and unilateral tDCS over the primary motor cortex combined with treadmill training on functional mobility, gait, static and functional balance, and muscle activity of the lower limbs in children with unilateral spastic CP between the ages of 5 and 12 years classified levels I and II of the Gross Motor Function Classification System (GMFCS).11 The study is a double-blind, randomized, controlled clinical trial. The stabilometry and analysis of parameters of gait were selected as primary outcomes. Secondary outcomes were the pediatric evaluation of disability inventory, pediatric balance scale, quality-of-life questionnaire, and electromyographic activity of lower limbs.

Treadmill Gait Training

Gait improvement is an important goal for rehabilitation of children with CP. The benefits of treadmill training have been studied with the functional objective of improving balance, standing, and the kinematics of gait.9,12,13 Treadmill training is easy to control and execute, reproducing a specific task with consecutive repetitions of the gait cycle, and can be performed with or without body weight support.2 Mackay-Lyons14 suggests that children with CP experience difficulties activating central pattern generators, which are responsible for the rhythmic, automatic steps of gait. Several studies have shown the benefits of treadmill training in children with spastic cerebral palsy.15–17 The treadmill activates repetitive locomotion due to the rhythm imposed by the speed of the treadmill. Since gait stages are triggered rhythmically and repetitively, body adjustments are required to keep walking on the treadmill.15–21 Thus, some authors suggest that treadmill training may favor the learning of a new walking pattern in children with CP, considering that it offers intervention that is continuous and repetitive.19–22 The main benefits of treadmill training cited in previous studies are improvement in function and kinematic patterns,15–21 with improvement in muscle activation in specific stages of gait.22 When treadmill training was associated with anodic tDCS over the motor cortex, the effects obtained by treadmill training were optimized and prolonged, with the maintenance of these results months after the end of the training.9,23

Transcranial Direct Current Stimulation

tDCS is a noninvasive and low-cost technique that stimulates the cerebral cortex through a low-intensity electrical current (1-2 mA) using sponge surface electrodes. This device allows a simulated (sham) administration in a practical and discreet way that reduces the difficulties in clinical trials in terms of masking the intervention for participants.24 The electrical current is delivered through 2 electrodes: an anode with a positive pole and a cathode with a negative pole. The movement of electrons between the 2 electrodes is responsible for modulating effects on cortical functions. The electron flow from the positive to the negative pole is capable of reaching the brain cortex after passing through the skull. A large portion of the current is dissipated by the skin and cerebral fluid, but enough reaches the brain, causing an alteration in the local membrane potential.25 Studies with nonhuman animals demonstrate that the anodal pole facilitates the depolarization of the local membrane, favoring an increase in cortical excitability, whereas the cathode tends to hyperpolarize the postsynaptic membrane, thereby hindering activity in the region. In humans, the same effects are seen when stimulating the primary motor cortex (M1), as anodal stimulation enhances cortical excitability and cathodal stimulation depresses activity.26

In CP, abnormal motor development stems from a primary cerebral lesion with consequent maladaptive motor cortex plasticity. In cases of hemiparesis secondary to a unilateral hemispheric lesion, this maladaptive process may be further exacerbated with an increase in contralateral activity. One of the objectives of physical therapy is to encourage symmetrical patterns of movement to promote independence.27 However, effects of intervention are related to the lesion area and neurological adaptations secondary to injury, one of which is the reduction of cortical excitability in areas responsible for motor control.28 The anodic tDCS contributes to the effects of the training, as it facilitates cortical excitability by reducing the cortical excitability threshold, with activation of the motor cortical areas. Thus, when anodic tDCS is applied over the primary motor cortex during the training of a motor task, motor gains are optimized. The maladaptive pattern of motor cortical excitability secondary to cerebral lesion is reduced, optimizing the functional gains achieved through physical therapy.9,13,20,23

Given the importance of M1 in adaptation and motor learning and the potential of tDCS to enhance cortical excitability, the hypothesis is that anodal stimulation of M1 enhances the magnitude and duration of motor gains achieved in physical therapy, in this protocol, treadmill training. Cathodal stimulation inhibits the function of a particular cortical area, thereby favoring action of the contralateral cortical hemisphere.28–31

Previous findings have demonstrated that electrode positioning involving anodal stimulation of M1 with the cathode positioned over the supraorbital region on the contralateral side can potentiate the effects of treadmill training for children with CP.13 However, the literature also supports that electrode position with anodal stimulation ipsilateral to the lesion and cathodal stimulation contralateral to the lesion can favor the rehabilitation processes of stroke survivors.

Children with spastic hemiparetic CP have an imbalance in the activation between the cerebral hemispheres, with an increase in activation of the nonlesion hemisphere and significant reduction of the activation of the lesioned hemisphere.28 This a pattern after injury that is similar to that in adults with hemiparesis following stroke. In this study we verify the best electrode position during treadmill training for children with unilateral spastic CP.7,8 tDCS can be administered during different motor therapies, modulating the altered cortical activity, enhancing synaptic efficiency, and favoring motor learning.

The protocol for a prospective, analytical, controlled, randomized, double-blind study has been conducted (Figure). The proposed study is in agreement with the Regulating Norms and Directives for Research Involving Human Subjects formulated by the Brazilian National Health Council, Ministry of Health, established in October 1996 and with the Declaration of Helsinki. The study was approved by the ethics committee and was registered. Parents or guardians signed informed consent. Children assented to participation by pointing to a smiling face to confirm the participation or sad face to not confirm. At any time the children could stop participating.

Fig.
Fig.:
Flowchart based on CONSORT statement. tDCS indicates transcranial direct current stimulation.

METHODS

Participants were selected from physical therapy clinics. Inclusion criteria were between 5 and 12 years of age, unilateral spastic CP, classification of the GMFCS as level I or II,11 and children with independent walking (children who walked with a walking aid were not included). Exclusion criteria were surgery on the lower limbs in the past 12 months, use of botulinum toxin in past 6 months, uncontrolled epilepsy, and children with metallic implants in skull.

Sample

Using the results from Grecco et al,13 the sample size was calculated (STATA 11) using gait velocity, as this is important clinical parameter related to mobility and function. With a power of 90%, a bidirectional α of 0.05 and the average of the experimental group of 0.9 ± 0.1 m/s and the control group of 0.6 ± 0.1 m/s, 8 children in each group were required. The sample was increased by 20%, resulting in 10 children per group for a total of 30 children.

Randomization

Children were randomly allocated, by a block randomization method, to 1 of the 3 groups: group 1, anodal tDCS anode over the primary motor cortex and cathode over the contralateral supraorbital region combined with treadmill training; group 2, sham anodal tDCS over the primary motor cortex and sham cathode over the contralateral supraorbital region combined with treadmill training; group 3, anodal tDCS over the primary motor cortex of the lesioned hemisphere and cathodal stimulation over the contralateral nonlesioned primary motor cortex combined with treadmill training. Based on cards contained in sequentially numbered opaque envelopes, the children were addressed to the groups.

Two examiners, masked to group allocation, performed the evaluations. Participants were also masked for this study. There were 3 evaluations: evaluation 1, the day prior to intervention; evaluation 2, after the last intervention; evaluation 3: 1 month following the last intervention.

Gait Analysis

Gait was recorded and analyzed with 8 infrared cameras (SMART-D 140 system, BTS), which detect reflective markers positioned on specifics points on the body using the Davis model.32,33 A force platform (Kistler, model 9286BA) provided the kinetic data (anteroposterior and mediolateral oscillations; ground reaction forces). The force plate was positioned in the center of a catwalk, where the participants walked during the examination. The video system was used to synchronize the kinematic and kinetic data.

Functional Mobility

Functional mobility was evaluated using the Pediatric Evaluation of Disability Inventory (PEDI).34,35 The parent or guardian answered questions related to their child's ability to perform activities of daily living. The PEDI has 3 categories: self-care (73 items), social function (65 items), and mobility (59 items) with a total score for each category.

Static Balance

A force platform with 4 piezoelectric sensors at the extremities (400/600 mm) was used (Kistler, model 9286BA) with an acquisition frequency of 100 Hz. The stabilometric analysis used the anteroposterior (X) and mediolateral (Y) oscillations of the center of pressure in 2 conditions: eyes closed and eyes open (each 60 seconds). The program SWAY (BTS Engineering) was used to record and interpret the data. To get reliable results, the position of the children was standardized, with instructions to remain standing, barefoot on the force plate, heels aligned, unrestricted foot base, and arms at the sides.36

Functional Balance

The Pediatric Balance Scale37 performed for 20 minutes was used to evaluate functional balance. This scale consists of 14 items similar to activities of daily living, with a maximum score of 56. Items are scored on an ordinal scale of 5 points: 0 if the child requires support and 4 if the child is capable of independently performing the activity.

Quality-of-Life Questionnaire

Quality of life was measured with the Autoquestionnaire Qualité de Vie Enfant Imagé developed by Magnificat and Dazord.38 There are 26 items that include family relations, social relations, activities, body functions, and separation as follows (the items related to):

  1. Function: school activities, meals, lying down and going to the doctor (items 1, 2, 4, 5, and 8);
  2. Recreation: vacations, birthdays and relationships with grandparents (items 11, 21, and 25);
  3. Autonomy: independence, relationships with friends and evaluation (items 15, 17, 19, 33, and 24).

The scale is adequate to the specificity and context of pediatrics, including the subjective dimension, as it addresses the sensation of well-being or the satisfaction of children regarding aspects of life without inferences on performance and productivity.

Electromyographic Evaluation. To analyze how the muscles of the lower limbs are activated at each stage of gait, electromyographic (EMG) activity in the tibialis anterior and lateral gastrocnemius was measured using disposable surface electrodes (Ag/AgCl, Medical Trace) 10 mm in diameter positioned on the belly of each muscle, as determined by SENIAM,39 with readings during the gait and balance evaluations with the child on the force plate. The interelectrode distance was 20 mm center to center, and the attachment points of the muscles were cleaned with cotton soaked in alcohol to diminish the impedance between the skin and electrodes. The frequency at which the data are acquired by the sensors was 1000 Hz. The EMG signals were amplified and transferred (wireless system) to a 4-channel conditioner module (BTS FREEMG 100) with a 20- to 450-Hz band pass filter, amplified with 2000-fold gain and a common rejection mode of more than 100 dB. Data were recorded and processed by an A-D converter with 16 bits of resolution (BTS FREEMG 100) at a sampling frequency of 1 kHz.39

INTERVENTION

Transcranial Direct Current Stimulation

tDCS is a technique that can improve the effects of motor activity and was used simultaneously with the treadmill training. The transcranial stimulation equipment (Soterix Medical Inc) was used to perform the stimulation, with 2 sponge electrodes (5×5 cm) moistened in saline solution. For one of the intervention groups, the anode was positioned over primary motor cortex (C3) in the region of the dominant brain hemisphere, following the recommendations of the 10 to 20 international electroencephalogram systems40 and the cathode placed over the contralateral supraorbital region. Another intervention group received anodal stimulation to the injured primary motor cortex and cathodal stimulation contralateral to the injured hemisphere to inhibit the side contralateral to the injury, thereby favoring the activity of the compromised area. The sham stimulation group performed the entire protocol of positioning the 2 electrodes and then the equipment, which has a button where the physical therapist can adjust the intensity parameter, provided sensation during the initial and final 30 seconds of the stimulation. Thus, the children experienced the sensation of the stimulation, but no current was delivered throughout the remainder of the training session.

Gait Training Protocol

In order for children to become familiar with the intervention and prior to the first intervention session, there were 2 treadmill sessions without tDCS. During the intervention, the sessions of the protocol intervention were performed simultaneously to the tDCS stimulation for 5 days per week, with 20-minute sessions for 2 consecutive weeks totaling 10 sessions. Based on the child's feedback, the velocity of Millenium treadmill (Inbramed, RS, Brazil) was gradually increased. During the sessions, treadmill speed was maintained at the maximum comfortable velocity for each child.

STATISTICAL ANALYSIS

To determine the normalcy of data, the Kolmogorov-Smirnov test was performed. If parametric, the data were expressed as means and standard deviations; and if nonparametric, data were expressed as medians and interquartile ranges. To determine the effect size, we considered the difference between means of pre- and postintervention evaluations with respective 95% confidence interquartile range. For the statistical analysis of the immediate effects of tDCS, we used Friedman's test or repeated-measures analysis of variance for nonparametric and parametric variables, respectively. To analyze the effects of treadmill training associated with different electrode positions of tDCS, we used the Kruskal-Wallis test for nonparametric variables and the mixed model analysis of variance for parametric variables. We used the Statistical Package for the Social Sciences (SPSS v.19.0), considering a P value < .05 as significant.

DISCUSSION

This article offers a description in detail of a, controlled, randomized, double-blind, clinical trial to demonstrate the effects of the different electrode positions of tDCS combined with treadmill training in children with unilateral spastic CP, GMFCS levels I and II. The results will be published and support the understanding of the best area of the primary motor cortex for electrode placement during tDCS. This protocol will contribute to improve function for children with cerebral palsy. The strengths of our study include a rigorous and controlled design, with caregivers and outcome assessors blinded to allocation. Our study has limitations that the optimal duration of tDCS is unclear and a larger sample size may be necessary.

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Keywords:

cerebral palsy; gait training; transcranial stimulation

© 2018 Academy of Pediatric Physical Therapy of the American Physical Therapy Association