Virtual Reality Therapy and Transcranial Direct Current Stimulation in Cerebral Palsy.
Condition: Cerebral Palsy
MeSH terms: Cerebral Palsy
Study type: Interventional

Summary: 
      A double-blinded randomized controlled crossover trial will be conducted, and all
      participants will undertake non-immersive VR tasks and tDCS-active or tDCS-sham. Group 1 will
      start with ten sessions of tDSC-active combined to VR tasks. After one-month washout, this
      group will be reallocated to another 10 sessions with tDCS-sham combined to VR tasks. In
      contrast, Group 2 will do the opposite protocol (participants will start allocated to ten
      sessions of TDCS-sham and VR tasks, and after one-month washout period will be reallocated to
      ten sessions of tDCS-active and VR tasks). All protocol will have the assessment of Autonomic
      Nervous System, through Heart Rate Variability Analysis.
    

Detailed description: 
      Study design A double-blinded randomized controlled crossover trial will be conducted, and
      all participants will undertake non-immersive VR tasks and tDCS-active or tDCS-sham. Group 1
      will start with ten sessions of tDSC-active combined to VR tasks. After one-month washout,
      this group will be reallocated to another 10 sessions with tDCS-sham combined to VR tasks. In
      contrast, Group 2 will do the opposite protocol (participants will start allocated to ten
      sessions of TDCS-sham and VR tasks, and after one-month washout period will be reallocated to
      ten sessions of tDCS-active and VR tasks). The one month washout period has been used in some
      studies and was shown to be enough to reset the effects of the first ten sessions,
      considering that the motor effects of the tDCS are sustained from two hours to three months.

      Participants and sampling Participants will be recruited through referral by the coordinators
      of two clinics in Brazil: Intensiva and Therapies. Those interested in participating will
      undergo a detailed screening against the eligibility criteria for enrollment in the study.

      Inclusion criteria Participants will be included if they have the agreement to participate in
      the research conserve, have a clinical diagnosis of CP done by a neuropediatric clinician
      with non- progressive etiology (with GMFCS levels I and II and MACS I and II), signing the
      informed consent form by the parents or guardians.

      Exclusion criteria Participants will be excluded if they do not understand the tasks. The
      understanding of the task will be evaluated through five attempts of each task in VR, because
      even with low IQ a large part of the adolescents can understand virtual tasks and interact
      with improved performance.

      Dropout criteria Participants will be withdrawn from the study if they are not willing to
      continue their participation, cannot be present on the day of the experiment or miss two
      treatment section, and/or change their form of rehabilitation during the study.

      Randomization Participants will be randomly allocated to either group 1 (TDCS-active and VR
      tasks) or group 2 (TDCS-sham and VR tasks) with a 1:1 allocation defined by a
      computer-generated randomization using the R package (R Foundation for Statistical
      Computing). Randomization will be under the control of a blinded investigator who will be the
      only person allowed to manage the electronic security file of the randomization to assign the
      individuals. The investigator will be blind to the group in which the participant is
      allocated to.

      Blinding The participants, researchers, and outcome assessors will remain blind to group
      allocation during the study. To ensure proper blinding, participants will receive codes and
      will be concealed from the allocation process by one different researcher. The researchers
      responsible for applying the intervention and the outcome assessors will not know the study
      design, allocation, objectives, and expected outcomes. In addition, for the blinding of the
      experimenter (responsible for applying the intervention), one assessor (responsible for
      randomization) will be in charge of giving the active device to the experimenter. The sham
      device has exactly the same shape of the active. Further details are presented in the
      "TDCS-sham" section.

      Allocation concealment Allocation concealment will successfully be reached since no one
      involved in this study (i.e. the participants, researchers, and outcome assessors) will be
      aware of the treatment allocations. Furthermore, investigators will have no control over the
      order of patients randomized. A blinded investigator will encode the individuals and groups
      of intervention. To perform the allocation procedure, the encoded groups will be placed
      inside a closed opaque envelope, which will be labeled with the code for each participant.
      Envelopes will be opened only during the time of active or sham intervention.

      Intervention

      All participants will attend the assigned TDCS and VR intervention as follows: there will be
      twenty sessions over four weeks with TDCS and non-immersive VR tasks, in which ten sessions
      will be TDCS-active and VR tasks and ten will be TDCS-sham and VR tasks, separated by a one
      month washout period. The sessions will be administered consecutively and once a day. The
      researchers will be trained to perform all interventions TDCS-sham, TDCS-active and VR tasks.

      Virtual reality intervention. Moreover, after the application of the TDCS-active or Sham, in
      all sessions will be performed tasks in non-immersive virtual reality environment to
      stimulate and verify improvement of motor performance. Thus, the "Bridge Games" software
      tasks will be used. A software developed by the Research and Technological Applications in
      Rehabilitation (Grupo de Pesquisa e Aplicação Tecnológica em Reabilitação - PATER) group of
      the School of Arts, Sciences, and Humanities of the University of Sao Paulo (EACH-USP).

      Heart Rate Variability HRV analysis will follow the guidelines of the Task Force of the
      European Society of Cardiology and the North American Society of Pacing and Electrophysiology
      (TFESC & NASPE, 1996). The strap (for data collection) will be positioned on the
      participant's chest, and the Polar RS800cx heart rate receiver will be positioned next to it.
      HRV will be recorded after the initial assessments at rest for 10 minutes, and during virtual
      reality combined to tDCS training for 20 minutes. For analysis of HRV data at rest 1000
      consecutive RR intervals will be used and during the tasks 256 consecutive RR intervals will
      be used.

      HR will be recorded beat by beat throughout the protocol by the Polar RS800CX FC Portable
      Monitor (Polar Electro, Finland) and RR intervals recorded by the monitor will be transferred
      to the Polar ProTreiner program (3.0 v., Polar Electro, Finland) , which allows HR
      visualization and cardiac period extraction in the "txt" file format.

      Moderate digital filtering will be performed in the program itself complemented with manual
      filtering performed in Excel software to eliminate premature ectopic beats and artifacts, and
      only series with more than 95% sinus beats will be included in the study (Vanderlei et al.,
      2008).

      HRV analysis will be performed using linear (time and frequency domain) and nonlinear methods
      that will be analyzed using Kubios HRV® software (Kubios HRV v.1.1 for Windows, Biomedical
      Signal Analysis Group, Department of Applied Physics, University of Kuopio, Finland).

      TDCS intervention.

      TDCS-active The TDCS-active will be performed over ten consecutive sessions per weekday (i.e.
      one session daily, no stimulation during the weekend) before the practice of VR games,
      TDCS-active will be performed with a frequency of 2 Hz and xxxxx pulse trains. The
      stimulation intensity will be set at 100%..... The stimulation target will be the area
      associated with the bilateral lower-limb motor area (i.e. vertex, Cz) of the M1.

      TDCS-sham The TDCS-sham will be performed over ten consecutive sessions per weekday (i.e. one
      session daily, no stimulation during the weekend). The TDCS-sham will be used because it
      ensures the attenuation of stimulous while appearing to be the same device, with good. In
      addition, the tactile contact of the foam with the skull is maintained.

      Procedure During the ETCC protocol, participants will be seated comfortably in a common
      chair, with their hands arranged over their legs and feet resting on the floor. The
      demarcation and application of the active TDCS will then be performed in the cortical area
      corresponding to the primary motor cortex contralateral to the side of the lesion according
      to EEG System 10-20 (area M1).

      Therefore, anodic TDCS with electrodes between 25-35 cm2, intensity of 1 mA, density of up to
      0.057 mA / cm2 for a period of 20 minutes will be used. However, for the TDCS-sham (placebo)
      the same active procedure setting will be used, however, the current will be interrupted
      after 20 seconds. This configuration will ensure that the electrical stimulus is interrupted
      before generating considerable stimuli, while the other characteristics of the intervention
      will be maintained. After each session the participant will be questioned about the presence
      of adverse effects. The device used will be the DS-Stimulator, from NeuroConn, which allows
      blindness of the subjects of the research and the experimenters.

      After 20 minutes of stimulation, the individuals will perform the training in VR. The
      training protocol will count on the execution of the following sequence of games: Labyrinth
      (5 minutes of training with labyrinths of the same dimension, but different ways of solving
      the task), Memory (5 minutes of training with progressive increase of difficulty according to
      the number of hits), Fitts (5 minutes) and Interception (5 minutes). The training time will
      be 20 minutes in total.

      Data analysis Considering timing coincident task for the inferential analysis of the initial
      tasks (transversal) and the longitudinal protocol with ETCC and RV, as dependent variables,
      the error measures (Constant, Absolute and Variable errors) will be considered (time in
      milliseconds), if the data meet the assumptions for use of parametric analysis, analysis of
      variance (ANOVA) will be performed to identify intra and inter-group differences.
      Differences, if any, will be detected by the post-hoc Tukey-HSD test. If the normality
      assumptions are not met, non-parametric analyzes will be used to identify and locate the
      differences: Friedman - post-hoc Wilcoxon as a test (within groups) and Kruskal-Wallis and
      Mann-Whitney U as a post-hoc test (between groups). For the between groups analysis of HRV
      indices, it will also be used Multiple Variance Analysis (MANOVA), with repeated measures for
      within groups analyzes (for evaluations and follow-up) or Mann-Whitney for intergroup
      analyzes and Friedman for intragroup analyzes. A significance level of 0.05 (5%) will be
      defined and all intervals constructed throughout the work will be 95% statistical confidence.
      The statistical program will be SPSS (Statistical Package for Social Sciences), version 26.0.
    

Intervention name(s): tDSC-active; tDCS-sham
Intervention type(s): Device; Device
Intervention description(s): 10 sessions of active Transcranial Direct Current Stimulation combined to Virtual Reality therapy followed by a one-month washout and 10 sessions of sham Transcranial Direct Current Stimulation; 10 sessions of sham Transcranial Direct Current Stimulation combined to Virtual Reality therapy followed by a one-month washout and 10 sessions of active Transcranial Direct Current Stimulation
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Group 1 will start with ten sessions of tDSC-active combined to VR tasks. After one-month washout, this group will be reallocated to another 10 sessions with tDCS-sham combined to VR tasks. In contrast, Group 2 will do the opposite protocol (participants will start allocated to ten sessions of TDCS-sham and VR tasks, and after one-month washout period will be reallocated to ten sessions of tDCS-active and VR tasks).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment