JMIR Publications

ABSTRACT

Background:

Background:

Children diagnosed with Cerebral Palsy (CP) often experience various limitations, particularly in gross motor function and activities of daily living (ADLs). Transcranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation technique that has been used to improve movement, gross motor function, and ADLs.

Objective:

This study aims to evaluate the effects of physiotherapy combined with tDCS in children with CP.

Methods:

This is a two-arm randomized controlled trial (RCT) that will compare the effects of tDCS as an adjunctive treatment during rehabilitation sessions to rehabilitation without tDCS. Children with CP classified by the Gross Motor Function Classification System (GMFCS) as levels I and II will be randomly assigned to either the sham + rehabilitation group (RG) or the tDCS + rehabilitation group (TG). The primary outcome will be assessed using the Gross Motor Function Measure (GMFM) domain E scores, and the secondary outcome will be the measurement scores of the children’s quality of life (PEDSQL). The intervention will consist of a ten-day stimulation protocol with tDCS spread over two weeks, with stimulation/sham tDCS administered for 20 minutes at a frequency of 1 Hz, in combination with physiotherapy. Physical therapy exercises will be conducted in a circuit based on each child’s baseline GMFM results. The participants' performance changes will be evaluated in both groups.

Results:

Recruitment and assignment of participants is currently underway. Data collection is expected to be completed by January 2025.

Conclusions:

This is an RCT study in Brazil to investigate the impact of tDCS on motor performance and quality of life in children with Cerebral Palsy using standardized measures and comparing therapeutic strategies. The standardization of measures and well-defined sample and outcomes may help on the stratification of the best therapeutic strategy for homogeneous population. Trial Registration: Study with Registration number - U1111-1293-2771 The Universal Trial Number (UTN).

Objective:

This study was designed to examine the impact of the combination of Transcranial Direct Current Stimulation (tDCS) and conventional rehabilitation exercises on the improvement of gross motor function in children with Cerebral Palsy (CP) classified as level I and II in the Gross Motor Function Classification System (GMFCS). The primary outcome measure will be assessed using the scores of the Gross Motor Function Measure (GMFM) Dimension E and the secondary outcome is children quality of life.

Methods:

This study is a single-blind randomized controlled trial. The participants will be blinded to the treatment allocation during the trial, but the researchers conducting the study will be aware of the treatment allocation. The study will conform to the Consolidated Standards of Reporting Trials (CONSORT) guidelines for nonpharmacological interventions. The study has been approved by the Ethics Committee in Research. Recruitment All patients with Cerebral Palsy who meet the previously described criteria for inclusion will be invited to participate in the study who will be realized in Molecular Medicine Center (CTMM) of the Universidad Federal de Minas Gerais (UFMG) in Brazil. Sample Size The sample size was calculate using G* Power software (Düsseldorf, Germany, version 3.1) [8]. Considering an effect size = 0.05, power = 0.95 probability of type 1 error (α) of 5% and, therefore, the probability of significance (p) being less than 0.05. The total sample size should be n = 176, with two groups of 88 volunteers. For the exact calculation, the two-exposure t-test statistical test was used. Pilot study will include 40 participants who will be randomized into two groups, the control group and the TDCS group. The impact of the intervention will be evaluated in the pilot phase to determine an accurate estimate of the population sample size. Participants and Eligibility Criteria The participants in the study will be recruited through advertisements at clinics and the intervention will take place at the Molecular Medicine Center (CTMM) of the Universidade Federal de Minas Gerais (UFMG) in Brazil. The participants and their guardians will be informed about the research protocols and will be required to sign the Free and Informed Consent Form (ICF) and the Free and Clarified Assent Form (CAF). Participation will only be allowed when both the child and parent have agreed to participate. To be eligible, participants must have a medical diagnosis of cerebral palsy, be classified as GMFCS I or II, be between the ages of 8 and 12 years old, be able to walk independently, and be able to understand commands. Exclusion criteria includes other neurological conditions, recent history of surgery, uncontrolled epilepsy, a cranial metallic implant, and the use of a hearing aid. Waiting list group will have access granted after in case of proof of evidence. Measures Both instruments will be applied to all participants before and after the interventions to assess whether there was a significant improvement in gross motor movement according to the E domain of the GMFM or in quality of life as determined as outcomes. A. Gross Motor Function Classification System (GMFCS) This is a scale used to classify the level of impairments of the gross motor function of the CP population [9]. GMFCS allows to classify functionality about walking, sitting, and standing [8]. It classifies gross motor function into five levels, as follows: Level I; No access; Level II: walks with limitation; Level III: walks using a manual mobility device (such as a Canadian crutch, walker, or cane); Level IV: self-mobility with a limitation (such as using a regular or automatic wheelchair); Level V: patient transported via manual wheelchair by a responsible. Initially, the entire sample will be evaluated using this instrument [10]. B. Gross Motor Function Measure (GMFM) This instrument evaluates quantitatively the change in gross motor function in children with CP. The evaluation has five dimensions: A, bed, and roll; B sitting, C; crawl and kneel; D standing; E, walking, running, and jumping [11]. The scoring system is as follows: a score of zero is assigned if the individual is unable to start the activity, a score of one is assigned if the individual starts the activity, a score of two is assigned if the individual starts the activity but only completes half of it, and a score of three is assigned if the activity is completed. The scores for each dimension should be calculated separately by summing the scores for that dimension and dividing by the total score for that dimension. At the end, the scores for each dimension should be multiplied by 100 to find the percentage that the child achieved in each dimension. Finally, the percentages for all dimensions should be added and divided by 5 (the number of dimensions evaluated), yielding the percentage that the child scored in the GMFM (domain E). This method is based on the study by De Pina and Loureiro (2006). Both scales, the GMFM and the GMFCS, have been validated for use with children with cerebral palsy. The GMFM assesses gross motor function and the GMFCS stratifies the functional level of children with CP. The Gross Motor Ability Estimator (GMAE) program will be used to analyze the GMFM results. C. Pediatric Quality of Life Inventory (PedsQL) The Pediatric Quality of Life Inventory (PedsQL) is a multidimensional tool to measure health-related quality of life in children and adolescents. It is a practical scale on the dimensions of health outlined by the World Health Organization, with questions related to the frequency of problems faced in the last month. The 23 item-PedsQL has 8 items for physical functioning; 5 for social functioning; 5 for emotional functioning; 5 for school functioning, with 15 on patients' psychosocial health. tDCS Intervention The Intervention Group (IG) will receive 10 sessions of transcranial Direct Current Stimulation (tDCS) with a frequency of five daily sessions per week, over a period of two weeks. The stimulation will be administered during rehabilitation sessions. The electrodes will be 35 cm2 sponges moistened with normal saline (0.9% NaCl solution). The stimulation will consist of anodal stimulation in the primary motor cortex (M1) and cathodal stimulation in the supraorbital region on the contra-lateral side, at an intensity of 1 mA and a duration of 20 minutes at a steady-state level, with a ramp-up and ramp-down of 4 seconds. The stimulation will be combined with specific exercises in circuit format to target dimensions D and E of the GMFM [12]. Control Group (CG) will undergo 10 sessions of sham tDCS associated with rehabilitation activities five times per week, for a total of two weeks. Activities, which target dimension E of the GMFM, will be organized as a circuit including running, walking, and jumping. 1.Safety The device used tDCS Soterix Medical, model no.1300-A serial no. 13ITC0619005 is approved by FDA for use as an experimental device and some for clinical purposes. (ANVISA – 80969860041). 3,5 cm2 electrodes will be used. Woods et al., 2016 prove if the purpose is to modulate neurophysiological measures for resting motor cortex stimulation in healthy young humans (1 mA intensity), tDCS for 4 s induces acute excitability alterations. Krishnan et al (2015) demonstrated adequate safety of tDCS in children and adolescents. Well-accepted threshold of tDCS current density is <142.9 A/m2 or 14.29 mA/cm2. Each patient will undergo a thorough health assessment, medications in use will be registered as well as all health conditions. Cardiac frequency, blood pressure, temperature, respiration, clinical assessment of mental and functional status, and physical examination will be measured [13]. 2. Adverse Effects Accordingly, adverse effects will be assessed using the tDCS Adverse Effects Questionnaire [14]. The dropout rate will also be reported, and the dropout reason will be stated [13]. tDCS is generally well tolerated, and with no serious adverse events [15]. Effects reported are rare, mild, and transient; with “redness”, “slight tingling”, “itching”, and “burning sensation” as the most reported events. Intensity of current, density and electrode size will be optimized to modulate the tingling and itch perception during transcranial stimulation. Further on, we will not pass the well-accepted threshold of tDCS current density (<142.9 A/m2 or 14.29 mA/cm2) [15]. Allocation Participants will be randomly assigned to tDCS groups with a 1:1 allocation as per a computer-generated randomization schedule stratified by the patient’s age using five permuted blocks of 6 participants. Implementation All participants will be randomized, and the randomization will be performed by the researcher who will carry out an intervention, the others will not know which group the participant is in. This member will upload the randomization results to the institution's Research Electronic Data Capture (REDCap) database [16]. The researcher who will perform a physiotherapeutic intervention and the researcher who will apply the assessments and questionaries will not have information about group allocation. Blinding Is a double bind study and during the study, the participant will be seen by tree different teams: (1) the research who realized the assessment and questionaries, (2) the neuromodulation team, who applicated the tDCS and (3) the physiotherapist who realized the physiotherapy exercises. There will be no members working simultaneously on both teams. The results of randomization will only be available to the neuromodulation member responsible for the intervention, and the scales' results will only be available to the researcher who realized the assessment and questionaries. The results will be held in a different project in REDCap and will be available only to researcher who make de assessment and questionaries. Emergency unblinding Emergency unblinding will be available under determination of the study staff, in case of safety concerns related with the intervention. Interventions: participants Initially, we will explain to the child how the intervention process will be carried out. The electrodes will be moistened in saline solution and will be placed on the participant's head, which may cause slight discomfort as it will wet the child's head and, to minimize this discomfort, we will frequently dry their face. Associated with this, the child will perform physical therapy exercises. Control groups for tDCS will receive placebo stimulation for 30 seconds, for ten sessions to give the child an initial feeling of stimulation. Associated with the placebo, the child will perform physical therapy exercises, focusing on the demands of the GMFM dimension E. The tDCS intervention will receive a current of 1 mA, for 20 minutes, for ten sessions also associated with physical therapy exercises, focusing on the demands of the GMFM dimension E. The intervention lasts from 25 to 35 minutes with each participant and will have a researcher with exclusive dedication during the intervention period for data collection. There will be five sessions with each participant per week over two consecutive weeks, using weekdays and saving the weekend. All participants prepared a session on the same day of intervention that completed up to ten sessions. The tDCS device contains two electrodes, an anode, and a cathode, in the form of two non-metallic sponges measuring 5x5 cm2, moistened with saline solution. The anode will be positioned on the M1 of the participant's dominant hemisphere, according to the 10-20 System EEG, while the cathode will be placed on the supraorbital region of the region contralateral to the anode. In the case of the experimental group, a current will be applied to M1 for 20 minutes associated with neurorehabilitation. After ten sessions, the GMFM test will be repeated with each patient along with the PedsQL. One researcher will carry out the intervention or the placebo with tDCS and the other researcher will evaluate the results blindly, without knowing which group is the intervention and which is the control. The use of the equipment and the evaluation will be carried out in different rooms to guarantee the researchers' blindness. Only the researcher in charge of using the tDCS will be aware of the allocation of children between experimental and control groups. It is worth noting that the patients in the control groups learned, at the end of the study, the intervention that had the best effect on their motor function, respecting the study's ethical perspective that all children should receive the best treatment.

Results:

This study is a single-blind randomized controlled trial. The participants will be blinded to the treatment allocation during the trial, but the researchers conducting the study will be aware of the treatment allocation. In this protocol, we are only using GMFCS level I and II children, who are functional children who do not require any type of assistive device for mobility.

Conclusions:

According to Lefebvre et al. (2015), the neuromodulation effects of tDCS on cortical excitability optimize motor learning and functional improvements in patients with neurological injuries, such as CP - being promising as a therapeutic technique to improve gait. It has been proven that the use of tDCS has an effect on postural control, especially in reducing the displacement area. Studies in children with CP have shown positive effects compared to the control group in gait training with anodic tDCS on the primary motor cortex (M1) (DUARTE, Natália de Almeida Carvalho et al, 2014). Recent studies show that tDCS seems to have good results in children with CP for balance, gross motor function and gait outcomes. The included population in many studies is always heterogeneous. In this protocol, stimulation is being done on children without assistive support. Variability and heterogeneity of clinical presentation still demanding more studies to built consistent analysis/literature. Further studies still necessary to fully understand the improvement in the outcome of gross motor function with standardized measure in a targeted population. Clinical Trial: Study with Registration number - U1111-1293-2771 The Universal Trial Number (UTN).