The use of transcranial direct current stimulation in individuals with cerebral palsy: a scoping review

| BACKGROUND: Cerebral palsy (CP) is a neurodevelopmental condition that begins in early childhood and persists throughout life, causing limitations in daily activities and social participation. Neuromodulatory interventions using non-invasive brain stimulation, like transcranial direct current stimulation (tDCS), have been increasingly investigated, aiming to influence cortical excitability in neurologic conditions, including CP. OBJECTIVE: To summarize current evidence for the use of tDCS on individuals with CP. METHODS: Using scoping review methodology, the terms "cerebral palsy" and "transcranial direct current stimulation" were screened in PubMed, Cochrane, LILACS, SciELO, PEDro


Introduction
Cerebral palsy (CP) is a well-recognized neurodevelopmental condition that begins in early childhood and persists throughout life 1 , attributed to non-progressive disturbances that affect fetal or infant brain development, with repercussions on movement and posture, causing limitations in daily activities and social participation. 2 CP is the leading cause of childhood disability, with a prevalence of approximately three per 1000 births. 3 CP is most often classified as spastic, dyskinetic, or ataxic. 4,5 Dyskinesia and ataxia usually affect all four limbs, whereas spasticity is categorized topographically as hemiplegia (one side affected), diplegia (lower limbs affected more than upper limbs), and quadriplegia (whole-body involvement). However, some experts recommend abandoning these labels and advocate specific classifications such as unilateral or bilateral, which must be accompanied by a description of other components, including motor abnormalities (nature and typology of the motor disorder, and functional motor abilities), accompanying impairments, anatomical and neuroimaging findings, causation and timing. 2,4 Over the past 25 years, tremendous progress has been made in understanding CP-associated movement disturbances, its early detection, classification, and how to measure change over time with reliable and valid measurements. Scientific, clinical, and social progress is converging to support the empowerment of individuals with CP and their families, changing the focus of rehabilitation from controlling or eliminating disabilities to achieve better results in activities/ participation, thus impacting the quality of life. 6 The understanding of brain function, injury recovery, and neuroplasticity provided a basis for the development of technologies, which have already been well-studied for decades, and whose applicability in the clinical environment is more recent and is becoming part of neurorehabilitation approaches. 7 Neuromodulatory interventions using non-invasive brain stimulation have been increasingly investigated, aiming to influence cortical excitability in neurologic conditions including stroke, epilepsy, and cerebral palsy. 8 In contrast to many other neuromodulatory methods, transcranial direct current stimulation (tDCS) has low cost, safety, feasibility, and simple applicability. 9 Its application involves placing two conductive-rubber electrodes wrapped in saline-soaked sponges on the scalp, held in place by a rubber band. A low-intensity direct current, often 1 to 2 mA, is delivered to cortical areas from the device. This current has the effect of spontaneously modulating neural networks. The primary mechanism of action is an alteration in resting membrane neuronal potential. The application can be performed by anodic or cathodic stimulation, which corresponds to the positive and negative terminals of the battery that operates the device. 10 Individuals with CP may benefit from the neuromodulatory effects of tDCS as it presents an attractive adjunct to physical therapy to improve motor function. 11,12 Studies suggest that tDCS has a potentiating effect on motor training, providing additional targeted stimulation to the motor cortex; thus, specific brain networks would be activated by a task, for example, during rehabilitation training. The tDCS may be combined with basically any other therapeutic intervention, with motor training, cognitive or behavioral interventions in a significant way. 7,[11][12][13][14] Despite the reported promising results, the literature still lacks a scoping review covering the reported methods, outcomes, and potential therapeutic applications in individuals with CP across different age ranges. This review aims to fill this gap, summarizing current evidence by reporting, comparing, and discussing studies that used tDCS in individuals with CP. Moreover, this review provides recommendations for future studies in the field to facilitate their development and comparison.

Method
We systematically performed a scoping review of articles describing the use of tDCS in individuals with CP. The methodology for this review was based on the framework proposed by Arksey and O'Malley 15 and later advanced by others. 16,17 Furthermore, in keeping with the suggestion of Colquhoun et al. 18 for scoping reviews, we followed the relevant aspects of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. 19 PubMed, Cochrane, LILACS, SciELO, PEDro, and Embase databases were searched from inception until February 2021. The following blocks of search terms were used, selected from MeSH (Medical Subject Headings) and DeCS (Health Descriptors). A title search was performed through specific terms combined by "AND" (between term blocks) and "OR" (intra terms), the term blocks and combinations. MeSH [(Cerebral Palsy)] AND MeSH [(transcranial direct current stimulation)] were used for these databases (Table 1).
Titles and abstracts were screened by the authors to identify potentially eligible studies and exclude duplicates. Full texts of the selected studies were retrieved and independently assessed by each author (disagreements were resolved through discussion with a third author).

Eligibility criteria
Studies should meet the following criteria: (1) clinical study with data (on the manuscript or upon request) on CP dysfunctions preintervention and postintervention (and active vs. sham conditions, when applicable); (2) participants should have a clinically established CP diagnosis at baseline; and (3) studies that investigated tDCS as a single treatment or associated with another therapy. No restriction on language or year of publication was stipulated. We excluded studies: (1) non-invasive brain stimulation techniques other than tDCS; (2) case reports, systematic reviews, and protocol studies.

Quality assessment
A quality assessment was conducted for each included study by using the Physiotherapy Evidence Database (PEDro scale), in order to most effectively identify gaps in the existing body of evidence. The PEDro scale includes 11 specific criteria, graded on a ''yes''/''no'' scale in which the first item relates to external validity and the other 10 items assess the internal validity of a clinical trial. The first criterion does not count toward the overall score that the paper receives for the quality of its study design. The PEDro scale is marked out of 10; the higher the PEDro score, the higher the assumed ''quality'' of the trial as assessed by the following cut-points defined by Foley et al.: 9-10, excellent; 6-8, good; 4-5, fair and below 4, poor. 20,21

Results
Following the initially determined search criteria, a total of 1773 articles were found in the databases. Forty-six duplicate articles were removed; 1678 articles had titles that did not address the CP condition and the tDCS intervention; 25 studies were case reports, systematic reviews, or protocol studies; and 10 studies were not completed. The details of the process of searching, screening, and selecting articles are described in detail in Flowchart 1.
In this same context, five studies were conducted on individuals with spastic bilateral CP (n=93). In some studies, we found an experimental group and a control group with a mixed composition, that is, participants with unilateral and bilateral CP. Ataxictype CP was addressed in only one study. 34

Country/location of studies
In the current study, there was no use of filters by language, country, and time.

Outcomes
The effects of tDCS were analyzed on different  Functioning and gross motor function were outcomes evaluated using the Pediatric Evaluation of Disability Inventory (PEDI) 23,24,34 and Gross Motor Function Measure (GMFM) 23,25 . The motor evoked potential (MEP) was used to assess the excitability of a neural network for the movement assessed, in addition to all the structures involved in the execution of this movement. 25 The Pediatric PC Quality of Life Inventory was also used. 27 Spasticity and passive range of motion of upper limb joints (goniometry) were evaluated in only one study. 25,28 Interventions The current intensity applied varied from 0,7 31,33 to 1,5 mA 32 , with most studies using 1mA [22][23][24][25][26][27][28]30,34,35 , and a duration of 20 min, except in one study that used 10 min. 29 Eight studies applied tDCS over repeated sessions ranging from 5 28 to 10 [23][24][25][26][27]30,31 , and three in a single-session. 22

Quality assessment
The studies' quality assessment is shown in Figure  3. The scores obtained for methodological quality ranged from eight to 10 points, ranging from good to excellent methodological quality.

Discussion
The results of this systematic review provide evidence from 14 studies with relatively high methodological quality in support of tDCS when applied to selected individuals with CP, although sample sizes were generally small. Participants presented with uni or bilateral spastic CP, varying in GMFCS level from I to IV and MACS level from I to V. However, the majority of participants had unilateral CP, with GMFCS classification ranging from I to III, and the most severe conditions (level V) were less frequent. 28,31,33 Reflections on the characteristics of this sample should not be limited to the higher frequency of the spastic type (79.2%). 36 Possibly, the characteristics of other associated intervention modalities may also have guided the choice of this population, for example, there may be no safety in performing treadmill gait training in some dyskinetic patients. This argument may also explain the greater inclusion of patients with lower functional levels, despite epidemiological studies indicating a higher frequency of major functional impairments, such as 73.3% classified in GMFCS levels III to V. 36   There is consensus that for motor improvements to be lasting, tDCS must occur in conjunction with training. 37 This may enhance skill acquisition by increasing afferent inputs to the cortex while its intrinsic excitability is being enhanced by tDCS, which has been shown to beneficially enhance the effects on motor outcomes of CIMT 30,31 ; intensive bimanual therapy 30 ; virtual reality mobility training protocols 23,26 ; treadmill gait training 24,25,34 ; goal-directed, peersupported, after-school motor learning camp 27 , functional training of the paretic upper limb 35 ; and physical therapy training. 28 In contrast, Nemanich et al. 33 were unable to show any additional benefit of tDCS combined with CIMT in neurophysiologic outcomes (motor-evoked potential amplitude or cortical silent period duration). Studies that analyzed the combination of tDCS and motor training showed longer-lasting results in some cases (up to one month after the end of stimulation). The variation in the follow-up time of the studies in this review ranged from 20 minutes to three months. It is also important to note that the three studies 22,29,32 without training association were single-session studies and were particularly interested in analyzing safety.
The absence of adverse events was recorded in five 25,26,30,33,35 of the 14 studies; the remaining studies recorded some mild and transient side effects (e.g., redness, headache, tingling, itchiness, and sleepiness) and were relatively the same as those reported in adults with different health conditions. 38 Safety conclusions in non-invasive neuromodulation studies have been based on the absence of serious adverse effects such as seizures, hearing problems, or pain, and experience with tDCS in children has been limited compared to adults. 8,38 However, only 4% of the >16,000 human studies on non-invasive brain stimulation studied children. 38 Our study adds that the type and magnitude of adverse events reported do not differ between children, adolescents, and adults with CP. We emphasize that although adverse effects are minimal in most studies, some trials do not report them clearly or do not bring this important information to the literature, since from it, we can identify a profile of who developed them and if there are similarities. This will only be possible with the methodological improvement of the reports.
The safety concerns of tDCS application in children are also related to current intensity and age. Conventional current intensities range from 0.1 mA (occasionally used as a sham) to 4.0 mA, with most studies applying 1.0 mA and 2.0 mA. 38 Most of the studies analyzed in this review applied 1.0 mA. Only one study investigated the effect of a single session of anodic tDCS with an intensity of 1.5 mA, with no reports of serious effects. 32 Evidence from relevant animal models indicates that brain injury by tDCS occurs at predicted brain current densities that are over an order of magnitude above those produced by conventional tDCS. 38 A more specific issue for the use of tDCS in children concerns the age and its relationship with possible effects on brain development. In the present scoping review, age ranged from five to 27 years.
The largest prospective pediatric cohort to date supports evidence of compatible safety, feasibility, and tolerability in school-aged children. In their study, 612 tDCS sessions were followed, including 92 children, among which one group stands out for being relatively similar to ours, children with perinatal stroke, whose ages ranged from eight to 18 years. 39 However, there is a study that refers to the safety of transcranial electrical stimulation in children from 2.5 years. 8 This study was found in a review article on the application safety in the pediatric population, but was not found in the databases consulted in our study. In this double-blind crossover clinical trial, in particular, seven children received stimulation at home for 16 weeks, twice a day, with 10-minute sessions and with an intensity of 0.5 mA, and no adverse events were reported. 40 Although in other therapeutic modalities early intervention is recommended as crucial for individuals with CP, in relation to tDCS, more caution is necessary.
As the mature brain and the developing brain differ in anatomy and function, data on the effect of tDCS on the mature brain may not reveal possible side effects of stimulating a developing brain. Further, the atypically developing brain may respond differently from the typically developing brain. 41 In the literature available so far, there is no age limit for starting the use of tDCS, only the reaffirmation that the risks for its use in school-age children are minimal. 38 Therefore, some considerations should be made when interfering with the brain development process of children through transcranial stimulation, such as: head circumference, the thickness of the skull bones, the synapses functioning, connections and brain networks, knowledge of the detailed description of existing structural changes, structured monitoring of the therapeutic process and the application of tDCS. Dosage modifications may be necessary to ensure safety and efficacy. 38 The understanding of all these peculiarities can enable the early use of this therapeutic resource in the population with CP, expanding the development opportunities of each child.
The tDCS montage, including electrodes location, current intensity, duration, and session's number, was similar in 11 articles [22][23][24][25][26][27]30,31,33,35 of the 14 included in this review. Although the choice of electrodes placement should be related to the functional complaint and, consequently, the brain region that would generate more effective benefits and changes when activated or inhibited, M1 was the most frequent application target among the studies, even for different outcomes. The most studied outcomes were manual dexterity 27,[30][31][32][33]35 , balance 22,24,26,34 , and gait. 22,25,34 Also, regarding tDCS montage, in most studies, the anode was positioned in M1, and the cathode was in the contralateral supraorbital region. Few studies chose to place the cathode in the right deltoid muscle 28 , but also without any neurophysiological explanation for this. This raises the question of whether the choice of the therapeutic target would be more related to conclusions of safety and effects in studies with adults than to the particularities of individuals with CP, which consequently would direct a safe choice of research groups to stimulate already known targets. M1 represents a key structure to produce lasting polarity-specific effects on corticospinal excitability and motor learning in humans. 42,43 However, CP is a heterogeneous disease affecting a diverse population. The establishment of participant selection criteria based on lesion location and/or integrity of the corticospinal pathway may assist in determining which patients are most likely to benefit from tDCS.
When analyzing the studies, it is clear that most of them were carried out by the same research groups, and it is relevant to consider their importance for the technique foundation in the world scenario; however, it can lead to a possible publication bias, reducing the evidence strength. 44 The tDCS protocols, samples, and outcomes in these studies were quite similar, which stands out for the difficulty of conducting randomized controlled trials with individuals with CP, since there are many differences in the location and extent of the lesion, motor disorders, associated impairments, previous treatment, and family-related issues. 45 New studies that address a greater variability of participants, with different functional conditions, in addition to the variation of interventions and outcomes tested, will be necessary for a better understanding of tDCS effects in individuals with CP. The intrinsic difficulties in scientific research in some scenarios are known, where access to equipment, and access of participants to study sites, are extremely difficult and often lead to abandonment or withdrawal from participation, influencing followup and the methodological quality of the study. Most of the available literature supporting interventions for children and adolescents with CP originates from high-income countries. 46 Some limitations of the current study should be pointed out. First, although the focus of this review has been the use of tDCS in individuals with CP, due to the combination of this resource with other intervention modalities, we were faced with the lack of standardization of the terms of motor therapies, or lack of description of the components of the associated interventions, which can make it difficult to interpret the results of some studies. Second, some search terms may not have been included and reduced the number of articles found.

Conclusion
The main therapeutic effects of anodal tDCS were reported on manual dexterity, balance, and gait. The combined use of tDCS with other motor training techniques, such as CIMT and treadmill locomotor training, showed better results. Emerging evidence reveals that the use of tDCS in individuals with CP is safe, feasible, easy to apply, tolerable, and effective when performed according to the recommendations available to date. The tDCS protocols in the studies were partially homogeneous, and sample sizes were generally small. More large-scale longitudinal studies are needed, particularly in individuals with ataxic and dyskinetic CP.