Transcranial Direct Current Stimulation in Child and Adolescent Psychiatry

Abstract

Objectives:

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that consists of applying a weak electric current over the scalp to modulate cortical excitability. tDCS has been extensively investigated in adults with psychiatric disorders. The aim of this study was to review the current literature regarding the use of tDCS in children and adolescents with psychiatric disorders.

Methods:

We searched MEDLINE and EMBASE databases for studies evaluating the safety and efficacy of tDCS in children and adolescents from age 0 to 18 years with psychiatric disorders.

Results:

We found six studies that evaluated patients with different psychiatric disorders, with diverse study designs and stimulation parameters, including three small randomized clinical trials (RCTs), one evaluating childhood-onset schizophrenia, one RCT with patients with autism spectrum disorders (ASD), and one study in attention-deficit/hyperactivity disorder (ADHD); three open-label studies, two evaluating patients with ASD, and one study of feasibility of the technique in children and adolescents with language disorders and diverse psychiatric disorders, including ASD, intellectual disability, and ADHD. We also found three studies of dosage considerations in the general pediatric population. The technique was well tolerated, with no reports of serious side effects.

Conclusion:

Preliminary research suggests that tDCS may be well tolerated and safe for children and adolescents with psychiatric and neurodevelopmental disorders. Nevertheless, because the literature regarding tDCS in child and adolescent psychiatry is scarce and there exist limited numbers of randomized controlled trials, it is not possible to draw definite conclusions. Future studies should investigate the technique with regard to specific psychiatric conditions in comparison with standard treatments. In addition, long-term efficacy and safety should be monitored.

Introduction

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation (NIBS) technique that consists of applying a weak current over the scalp to modulate cortical excitability by facilitating or inhibiting ongoing neuronal processes. Anodal tDCS during task execution is considered to induce facilitation, while cathodal tDCS induces inhibition (Miniussi et al. 2013). The clinical effects of tDCS are most likely related to modulation of gamma-aminobutyric acid (GABA) and glutamate neurochemistry, which are important for synaptic mechanisms of neuroplasticity (Kadosh et al. 2012). Glutamate and GABA have key roles in long-term potentiation and long-term depression, respectively. Hence, tDCS may confer long-lasting effects through changes in neuroplasticity (Stagg and Nitsche 2011).

The first onset of a variety of mental disorders diagnosed in adults occurs in childhood or adolescence (Kessler et al. 2007). A recent meta-analysis estimated that the prevalence of psychiatric disorders in children and adolescents is 13.4%, (Polanczyk et al. 2015). Further evidence suggests that psychiatric disorders generally identified in school-age children have a high prevalence in preschool children (Merikangas et al. 2009). Early onset of psychiatric conditions is associated with poor clinical outcomes and functional impairment, disrupted peer relationships, high-risk behaviors, life-long psychiatric disorders, and a substantial disease burden (Gleason et al. 2007; Patel et al. 2007; McGorry et al. 2011).

tDCS studies of neuropsychiatric disorders in adults demonstrate a low rate of adverse effects (Kuo et al. 2014). In comparison with other NIBS techniques such as transcranial magnetic stimulation (TMS), tDCS is more portable, economical, and tolerable, has a safer profile, and the potential to reach a broader population (Brunoni et al. 2012). tDCS protocols may impact neuroplasticity and other neuronal functions, thereby presenting a unique opportunity to study neurodevelopment (Brunoni et al. 2011). It could also play a role in the treatment of severe psychiatric disorders with currently restricted treatment options during childhood and adolescence. Furthermore, tDCS can also be combined with other therapeutic tools such as psychotherapy, physical therapy, cognitive rehabilitation, and pharmacotherapy, with the possibility of enhancing their clinical effects (Brunoni et al. 2012; Rubio-Morell et al. 2011; Kadosh et al. 2012).

There are a number of important developmental aspects to consider when using tDCS in children and adolescents. In comparison with adults, children have a smaller head circumference, higher conductivity of the skull tissue, variations in gray and white matter distribution, differences in cerebrospinal fluid content, and evolving neurotransmitter systems (Kessler et al. 2013). These aspects could alter baseline cortical excitability and hence children and adolescents may have very different clinical and neurophysiological responses to tDCS compared with adults (Kessler et al. 2013). Clearly, further safety studies with a neurodevelopmental context are imperative before integrating tDCS into clinical practice of child and adolescent psychiatry. However, the safety profile of tDCS may be favorable when compared with common approaches as with polypharmacy, which despite widespread use in practice, still lack evidence of safety and effectiveness in children and adolescents (Spencer et al. 2013; Feinstein et al. 2015).

Our aim was to review the current literature regarding the use of tDCS in children and adolescents with psychiatric disorders, considering that studies with tDCS in child and adolescent psychiatry are still quite limited and that there are currently no specific guidelines for optimum stimulation parameters.

Methods

The electronic search was performed in MEDLINE and EMBASE databases from their first date available to May 2015. The search was performed using the terms “transcranial direct current stimulation” or “tDCS,” along with “pediatric brain,” “children,” “adolescents,” “pediatric population,” “childhood,” combined with “safety,” and/or “psychiatric disorders,” and also with specific conditions already investigated for TMS (“autism,” “depression,” “attention deficit hyperactive disorder” or “ADHD,” “tic disorder,” “Tourette syndrome,” “psychosis,” “schizophrenia”).

We selected studies that evaluated safety and efficacy of tDCS in children and adolescents from age 0 to 18 years with psychiatric conditions and also computational modeling studies of dosage considerations for children and adolescents. We excluded studies of tDCS safety and efficacy only in adults and trials that evaluated tDCS to nonpsychiatric conditions in children and adolescents.

Quality assessment was performed for each trial individually. We looked for selection bias (i.e., whether the study was adequately randomized and whether allocation was concealed; in studies that used controls, we checked whether matching was adequate; finally, we checked whether the diagnostic assessment was appropriately performed in studies that enrolled psychiatric samples); performance bias (whether patients and raters were blinded); and attrition bias (evidence of intention-to-treat analysis; if number of dropouts was reported and descriptions of how researchers handle missing data). Studies that presented low risk of selection, performance, and attrition bias were classified as having low risk of bias; studies that presented a high risk of bias for any category were classified as having high risk of bias; finally, studies that presented only low and unclear risk of bias in the assessed categories were classified as having unclear risk of bias.

Results

We found six clinical trials (Mattai et al. 2011; Schneider and Hopp 2011; Amatachaya et al. 2014; Andrade et al. 2014; Prehn-Kristensen et al. 2014; D'Urso et al. 2015) that evaluated tDCS in children and adolescents with psychiatric disorders, and three safety studies in the general pediatric population (Minhas et al. 2012; Kessler et al. 2013; Moliadze et al. 2015), two of which employed computational modeling of the pediatric brain (Minhas et al. 2012; Kessler et al. 2013) and one study with a sample of healthy youths, which evaluated the aftereffects of tDCS on motor cortex excitability (Moliadze et al. 2015).

The clinical studies had different designs: three were randomized clinical trials (RCT) (Mattai et al. 2011; Amatachaya et al. 2014; Prehn-Kristensen et al. 2014), two of the RCTs implemented a double-blinded crossover design (Amatachaya et al. 2014; Prehn-Kristensen et al. 2014), and three studies were open label (Schneider and Hopp 2011; Andrade et al. 2014; D'Urso et al. 2015). The following psychiatric disorders were included: schizophrenia (Mattai et al. 2011), attention-deficit/hyperactivity disorder (ADHD) (Andrade et al. 2014; Prehn-Kristensen et al. 2014), autism spectrum disorder (ASD) (Schneider and Hopp 2011; Amatachaya et al. 2014; Andrade et al. 2014), and mild cognitive disability (Andrade et al. 2014). The sample size of each study was small. Amatachaya and colleagues reported on the largest sample size (n = 20) in a study enrolling youth with ASD. Study designs, stimulus delivery, dosing, and sample characteristics diverged considerably among the studies. The methodological characteristics of the clinical studies are described in Table 1.

Table 1.

Characteristics of the Clinical Studies Using Transcranial Direct Current Stimulation for Psychiatric Disorders in Children and Adolescents

		Design				Stimulation protocols
Study	Condition	Randomization	Sham	Blinding	No. of patients (age range in years)	Polarity/location/current/duration	No. of sessions	Outcome	Side effects	Risk of Bias
Mattai et al. (2011)	Schizophrenia	Yes	Yes	Possibility of open treatment	10 (10–17)	Bilateral anodal DLPFC (n = 8) or bilateral cathodal STG (n = 5) 2 mA for 20 min	10 in 2 weeks	Tolerability	Tingling and itching in sham and active	Unclear
Schneider and Hopp (2011)	Autism	No	No	Only statistician	12 (6–21)	Anodal left DLPFC 0.08 mA for 30 min	1 single session	Vocabulary score improvement	None	High
Amatachaya et al. (2014)^a	Autism	Yes crossover	Yes	Yes	20 (5–8)	Anodal left DLPFC 1 mA for 20 min	5 of active and 5 of sham	Decrease in CARS score (p < 0.001). decrease in ATEC (p < 0.001). increase in CGAS (p = 0.042).	None	Low
Amatachaya et al. (2015)^a	Autism	Yes crossover	Yes	Yes	20 (5–8)	Anodal left DLPFC 1 mA for 20 min	1 single session	Increase in PAF in EEG correlated with clinical improvement	None	Low
D'Urso et al. (2015)	Autism	No open-label	No	No	5 with 18 years	Cathodal left DLPFC 1.5 mA for 20 min	10 consecutive	Improvement in ABC	None	High
Andrade et al. (2014)	LD and comorbidities (ADHD [n = 1]/ID [n = 4]/ASD [n = 5])	No open-label	No	No	14 (5–12)	Anodal mid-left IFG (n = 13) or anodal mid-right IFG (n = 1) 2 mA for 30 min	10 in 2 weeks	Feasibility	Acute mood changes; irritability; tingling; itching	High
Prehn-Kristensen et al. (2014)	ADHD	Yes crossover	Yes	Yes	12 healthy (9–14) 12 ADHD (10–14)	Anodal bilateral FL from 0 to 0.25 mA for 5 × 5 min with 1-min interval	1 single session of sham and active	Enhanced slow oscillation power and boosted memory performance in ADHD	None	Low

Stimulation targets are described according to the international 10–20 system.

Same study sample.

ABC, Aberrant Behavior Checklist; ADHD, attention-deficit/hyperactive disorder; ASD, autism spectrum disorder; ATEC, Autism Treatment Evaluation Checklist; CARS, Childhood Autism Rating Scale; DLPFC, dorsolateral prefrontal cortex; EEG, electroencephalogram; FL, frontolateral; ID, intellectual disability; IFG, inferior frontal gyrus; LD, language disorders; min, minute; PAF, peak alpha frequency; STG, superior temporal gyrus.

Schizophrenia

Schizophrenia is a severe disabling disorder of unknown etiology and its pathophysiology remains poorly understood (Rapoport et al. 2012). Patients with schizophrenia display positive, negative, and neurocognitive symptoms, which contribute to considerable functional impairment (Swartz et al. 2003). The neurodevelopment model of schizophrenia implies that alterations in brain circuits occur long before the onset of psychosis (Rapoport et al. 2012). Schizophrenia can appear during childhood with psychiatric symptom profiles and neurobiological abnormalities similar to those found in adults. The differential diagnosis with neurodevelopmental disorders—particularly ASD—can be difficult during childhood (Karp et al. 2001).

Mattai et al. (2011) performed a double-blind sham-controlled trial with 12 youths with childhood-onset schizophrenia to evaluate the tolerability of tDCS. The sample included patients 10 to 17 years old who were randomized to bilateral anodal, cathodal (both active with 2 mA current), or sham stimulation for 20 minutes per day during a period of 10 days. All participants continued pharmacological treatment for the duration of the tDCS trial. Overall, tDCS treatment was well tolerated, with 20% of participants reporting tingling and 40% reporting itching at the electrode sites. In terms of tolerability, there were no differences between active and sham tDCS.

The study had important limitations, such as the concurrent use of medication with possible important side effects, which may have interfered with self-report and differentiation of side effects related to tDCS. In addition, although the authors intended to perform an efficacy evaluation, power analysis revealed that the study did not have sufficient power due to the limited sample size.

Attention-deficit/hyperactivity disorder

ADHD is a childhood-onset disorder characterized by developmentally inappropriate levels of inattention and/or hyperactivity and impulsivity (Spencer et al. 2007). It is the most prevalent neurodevelopmental disorder among children and is associated with lower rates of school graduation and poor peer relationships, leading to high economic and social burdens (Feldman and Reiff 2014).

tDCS may be a promising tool in ADHD. Studies with adults have reported that anodal stimulation on the dorsolateral prefrontal cortex (DLPFC) might increase the synchrony between the default system and the frontoparietal network (Castellanos and Proal 2012). These areas are known to be impaired in some cases of ADHD; however, there are currently no published clinical trials investigating tDCS for core symptoms of ADHD during childhood.

The only published RCT with children with ADHD (Prehn-Kristensen et al. 2014) investigated the effects of transcranial oscillatory direct current stimulation in declarative memory, which might be impaired in ADHD due to reduced frontal brain functions. Prehn-Kristensen and colleagues (2014) conducted an RCT with a crossover design, using bilateral anodal stimulation in frontal regions (F3 and F4 according to electroencephalogram [EEG] 10:20 system), during sleep in 12 children with ADHD (10 to 14 years) compared with 12 healthy controls (9 to 14 years).

Before the stimulation, children with ADHD displayed worse sleep-dependent memory consolidation compared with healthy controls. After active stimulation, controls and patients presented with similar memory performance, indicating improvement of declarative memory in ADHD. On the other hand, sham stimulation did not change the performance of either group.

Autism spectrum disorders

Beginning in early childhood, ASD is defined as a neurodevelopmental disorder characterized by impairment in social communication and in behavioral domains, including repetitive behaviors and specific interests (Lauritsen 2013). Abnormalities in language and communication are core features of autism and many children with ASD do not develop functional language abilities during their schooling (Wodka, et al. 2013).

An open study (Schneider and Hopp 2011) included 10 patients aged 6 to 21 years and evaluated vocabulary and syntax before and after a 30-minute session of anodal tDCS with a 0.08 mA current over the Broca's area and the DLPFC. There was a statistically significant improvement in mean vocabulary and syntax scores with large effect sizes (0.96 and 2.27, respectively) after the stimulation. The study focused on language skills and did not evaluate other aspects of ASD. The stimulation was well tolerated with no reported side effects.

A randomized, double-blinded controlled trial (Amatachaya et al. 2014) evaluated the efficacy of tDCS in a sample of 20 male children (aged between 5 and 8 years) diagnosed with having autism with mild-to-moderate autistic symptoms. The primary outcome was change in the Childhood Autism Rating Scale (CARS) and Autism Treatment Evaluation Checklist (ATEC) subscales. Patients were randomly assigned, in a crossover design, to receive five consecutive sessions of 20 minutes of active or sham tDCS stimulation (1 mA) over the left DLPFC. The study verified that 7 days after the end of the active, but not the sham, stimulation, the patients had improvements in CARS and in three of the four (sociability, sensory and cognitive awareness, and health/physical/behavior problems) subscales of the ATEC questionnaire. In contrast with the Schneider and Hopp's (2011) study, the subscale that evaluates speech/language/communication showed no statistically significant improvement. The authors suggested that this difference occurred because the language evaluation performed reflected comprehensive abilities and not syntax.

The same research group published another study with the same sample (Amatachaya et al. 2015). This study consisted of a single session of anodal tDCS in the DLFPC, comparing sham with active stimulation in a crossover design. Changes in cortical activity were evaluated with EEG, autistic symptoms were evaluated with CARS, and clinical improvements with the ATEC questionnaire. The active stimulation, compared with sham, was associated with greater increase in peak alpha frequency (PAF) on the EEG. PAF is a parameter related to increased cortical activity in the frontal regions. This increase was correlated with clinical improvements in the ATEC social, health, and behavioral problems subscale questionnaire.

A naturalistic study (Andrade et al. 2014) evaluated the feasibility of tDCS in 14 children between 5 and 12 years of age with learning disabilities and different comorbidities, among them ASD (five subjects; one with concurrent ADHD and four with mild cognitive disability). Anodal tDCS was applied over Broca's area using a 2 mA current for 30 minutes for 10 sessions during five consecutive days. Adverse effects were evaluated with a standard questionnaire. Of note, the main adverse effects reported were acute mood changes and irritability. The study team concluded that mood changes and irritability could not be explained by tDCS for 66% and 40% of participants, respectively.

One trial with 12 patients (D'Urso et al. 2015) included five 18-year-olds and 7 adult patients with autism and intellectual deficiency. It used cathodal tDCS over the DLPFC with an aim to improving autistic behaviors by restoring inhibition in this region. The primary outcome was change in the Aberrant Behavior Checklist (ABC) autism scale, which measures core autistic symptoms. The results varied according to diverse symptom spectrums in the scale. Due to the limited sample size of adolescents in this study, it is not possible to draw conclusions about the efficacy of this type of stimulation for this population. The technique was well tolerated with no reports of serious side effects.

Safety and dosage considerations

A study conducted in 2012 (Minhas et al. 2012) using realistic brain models compared a 12-year-old pediatric brain model with a 35-year-old adult model, using both conventional and high-definition tDCS (HD-tDCS). It was found that for the same current intensity, regardless of the type of stimulation (i.e., either conventional or HD-tDCS), the peak electric field was ∼1.5 times higher in the pediatric brain than in the adult model.

A computational modeling study conducted by Kessler et al. (2013) compared individualized, high-resolution, MRI-derived head models from three adults (two females), with different head sizes, to models from two typically developing male children (8 and 12 years). They evaluated both conventional and high-definition anodal and cathodal tDCS in different montages and current intensities (1 and 2 mA for conventional tDCS and 1.5, 1, and 0.5 mA in HD-tDCS). The study found that high current intensities (2 mA) with a fixed electrode montage in the pediatric brain produced higher peak electrical fields when compared with the large adult model. However, when compared with adults with smaller head sizes (the two females), the peak electrical field was similar to that observed in the pediatric brain, with a large overlap between them. In addition, the study showed that with the same montage, lower current intensities (1 mA) applied to the pediatric brain models are comparable with 2 mA density current applied to the large adult model.

One trial, including 19 healthy youths aged between 11 and 16 years (Moliadze et al. 2015), investigated the aftereffects of 10 minutes of 1 mA anodal, cathodal, and sham stimulation on motor cortex excitability by measuring the motor-evoked potential (MEP) with TMS at baseline immediately after tDCS and every 10 minutes until 60 minutes had been reached. An additional control group with 10 participants received 0.5 mA anodal and cathodal stimulation to evaluate the effect of current intensity.

They found that both 1 mA anodal and cathodal stimulation were associated with increased MEP amplitude compared with baseline and sham. In addition, they determined that 0.5 mA cathodal tDCS was associated with a decrease in the corticospinal excitability, but anodal tDCS did not induce MEP changes. Although not statistically significant during all measurements, changes in MEP amplitude with 1 mA anodal stimulation remained until the final measurement 1 hour after tDCS. Despite the limited generalizability, the authors raised the possibility of therapeutic use of tDCS in this population due to long-lasting tDCS effects, similar to what has been observed in adults. There were no reports of serious side effects.

Discussion

Main findings

We evaluated studies with a total number of 77 subjects [13 with ADHD (Andrade et al. 2014; Prehn-Kristensen et al. 2014), 42 with autism (Schneider and Hopp 2011; Amatachaya et al. 2014; Andrade et al. 2014; D'Urso et al. 2015), 10 with schizophrenia (Mattai et al. 2011), and 12 healthy individuals (Prehn-Kristensen et al. 2014)]. Across the studies, there were no reports of severe side effects for all conditions. Thus, tDCS may prove to be a tolerable and safe technique in children and adolescents.

With regard to efficacy of tDCS for psychiatric disorders in childhood, the scientific evidence remains fairly limited. The most robust sample of this review was from patients with ASD. One open-label study with patients with ASD (Schneider and Hopp 2011) found a significant language improvement after one session of anodal tDCS, and the only RCT that evaluated patients with ASD (Amatachaya et al. 2014) resulted in clinical improvement evaluated by gold standard instruments (CARS and ATEC questionnaires), raising the possibility of the use of tDCS as a therapeutic tool for core autistic symptoms. Further studies are needed to replicate these findings.

The main goal of the study that investigated tDCS in childhood-onset schizophrenia was to investigate tolerability, and although the authors performed an efficacy evaluation, the study had no power to draw conclusions due to limited sample size.

In contrast, the literature regarding the use of TMS is far more robust. In a recent study that evaluated the therapeutic use of NIBS for neurological and psychiatric disorders in children and adolescents, the authors gathered information from 11 trials that used TMS, whereas only two trials utilized tDCS (Vicario and Nitsche 2013). Although there are several studies investigating TMS in children and adolescents with ADHD, the majority have evaluated cortical excitability. As such, the literature regarding TMS as a therapeutic tool in this population is also very limited (Bunse et al. 2014).

Cosmo et al. (2015) published the protocol of an RCT that evaluates the effect of tDCS in adults with ADHD. The protocol describes evaluations before and after one single session of 20 minutes of anodal stimulation of DLPFC with 1 mA current to investigate the effect of tDCS in the modulation of inhibitory control, measured using a go-no-go task. Evaluation of brain networks with EEG is the secondary outcome. This is the first study to investigate the applicability of tDCS in individuals with ADHD; results of the primary and secondary outcomes are not available as yet.

Although data from several clinical trials in adults showed significant clinical improvement with active tDCS compared with sham in adults with major depression (Shiozawa et al. 2014), to date no study of tDCS for child and adolescent depression has been conducted.

In these reviewed studies, the most common side effects were tingling, itching, mood changes, and irritability. There were no serious side effects or adverse events. This is reassuring and suggests that tDCS was well tolerated in the existing study samples. A previous study (Krishnan et al. 2015) evaluating the safety of NIBS (tDCS and TMS) in children and adolescents with neurological and psychiatric conditions also reported great tolerability of these techniques. However, the authors also observed that the included studies presented substantial variability in study design, psychiatric conditions, and age range of patients. Furthermore, no standardized questionnaires for tDCS side effects were used, potentially contributing to the low rate of observed adverse effects (Krishnan et al. 2015).

Importantly, in the Moliadze et al. study (2015), 0.5 mA cathodal stimulation reduced cortical excitability, whereas 1 mA cathodal tDCS increased corticospinal excitability, contrary to what would be expected according to adult studies (Nitsche and Paulus 2000). This might be partially explained by differences in brain anatomy and function in children and adolescents. In fact, computational modeling studies (Minhas et al. 2012; Kessler et al. 2013) suggested that children receiving tDCS are exposed to higher peak electrical fields under the same current intensity when compared with adults, although the peak current is likely to be similar to adults with smaller head sizes. In adults, a 2 mA cathodal current intensity (vs. 1 mA) increased, as opposed to decreased cortical excitability (Batsikadze et al. 2013).

Studies with tDCS in adults have shown that current intensities between 0.5 and 2 mA for up to 20 minutes are safe and tolerable (Kessler et al. 2013). However, due to differences in brain structure and function in children and adolescents, these findings may not be extrapolated to this population. Pediatric brain models likely have great utility to compare and evaluate the effect of different montages and current intensities in each brain region and optimize the development of tDCS protocols in this population. Further studies with larger sample sizes, using both anodal and cathodal tDCS, with different current intensities, and neurophysiological measurements should be performed in children and adolescents to clarify optimum stimulation protocols for specific conditions.

Future directions

Clinical trials using tDCS in children and adolescents have the potential to raise ethical concerns. Studies with healthy (nonclinical) youths could be particularly controversial. In some circumstances, such as studies of prevention or vaccine trials, the enrollment of healthy children might be justified as they would possibly benefit from the study results. In tDCS studies, however, healthy children and adolescents may not directly benefit from the procedure and might even be exposed to risks, such as the possibility of maladaptive plasticity (Kadosh et al. 2012).

Despite the demonstrated safety of tDCS and minimal side effects across all trials evaluated in this review, thus far there are no studies evaluating its therapeutic and adverse effects in the long-term, hindering the evaluation of the risk–benefit ratio in healthy children and adolescents. On the other hand, the effects of a single session of tDCS last only a few hours. Thus, studies using repeated sessions of tDCS (such as clinical trials) should only be performed after single-session studies demonstrate that the tested montage is not associated with adverse effects.

In this context, informed consent by parents and assent by children or adolescents is a key concern. Parental permission should be voluntary and informed and is required for research involving children. The purpose is to protect a child from assuming unreasonable and unjustified risks (Roth-Cline and Nelson 2013). However, children and adolescents must also assent to take part in a trial; the researcher is obligated to ensure that the language and explanations are appropriate to the subjects' age and cognitive capacity. Similar to adults, the child's or adolescent's decision must always be respected, with the possibility of freely withdrawing from the trial at any moment (Ecoffey and Dalens 2003; Parsapoor et al. 2014). Some studies evaluating comprehension of the study by children and adolescents showed that children from 9 years of age are already able to understand the benefits and risks of research (Ecoffey and Dalens 2003; Sammons et al. 2009).

Assent might be challenging when dealing with younger children or even youths with psychiatric conditions that impair cognition. In addition, children may not comprehend important concepts of the studies, for instance, reasonably foreseeable risks (Roth-Cline and Nelson 2013), the use of placebo (Kölch et al. 2010; Weimer et al. 2013), and the potential for boosting the performance of higher cognitive functions such as mathematics or language. However, this does not establish that children are incapable of assent. Researchers and internal review boards should consider creative approaches, such as visual aids and developmentally appropriate comprehension assessments, to accurately explain the trial procedures and objectives to this population.

Another critical ethical aspect is the nonmedical use of tDCS. Currently, it is possible to buy a tDCS device online on videogame supply websites targeting individuals who want to improve cognitive skills during gaming. As the use of videogames is frequent during childhood, there is a possibility that youths are being exposed to this procedure. This raises ethical and safety concerns and also highlights the importance of greater involvement of the scientific community and researchers with expertise in the field to provide information to the general population about the risks of noncontrolled use of this tool. This is possible through well-designed and safely conducted clinical research not only in pathological conditions but also in healthy populations.

The use of proper sham methods is another aspect that should be developed in future studies. Although the RCTs included in this study showed no difference between side effects observed in the sham and active groups, the success of blinding was not systematically investigated. Sham stimulation is carried out by increasing the current over a few seconds to the target strength and then tapering off over a few seconds. Even though this method is considered reliable, the frequency of adverse effects might be increased in the active group; particularly at higher current intensities (Kessler et al. 2012), children may be more susceptible and sensitive to sensory perceptions, with a theoretically higher possibility of unblinding. Therefore, we recommend that RCTs with tDCS in children and adolescents systematically evaluate side effects, comparing active and sham and also evaluating the impact of age in blinding success.

Although sham-controlled trials potentially raise ethical issues and are vulnerable to blinding, their use improves the reliability of results and decreases possible biases. For instance, results of psychopharmacology trials with children and adolescents have shown that placebo responses tend to be higher (Weimer et al. 2013) when compared with adults. The mechanisms are not fully understood, but are probably related to higher susceptibility to environmental factors and increased sensitivity to parents' and researcher's views.

Another issue is the current dose that should be used in RCTs involving this population. Although RCTs with adults commonly use 2 mA, we recommend that the dose in children and adolescents should be lower (0.5–1 mA) for three reasons: (1) a computational model study showed that children are exposed to higher peak electrical fields for a given applied current intensity than adults (Kessler et al. 2013); (2) in children, 1 mA of either anodal or cathodal stimulation over the motor cortex induced an increase of MEPs, whereas 0.5 mA of cathodal tDCS decreased MEPs and 0.5 mA of anodal tDCS resulted in no effect (Moliadze 2015)—in contrast, 1 mA anodal increases and cathodal decreases cortical excitability in adults (Nitsche and Paulus 2000); and (3) children might be more vulnerable to breaking blinding than adults, as previously mentioned. In this context, it would be interesting to use computational modeling studies (Minhas et al. 2012; Kessler et al. 2013) in tDCS trials to evaluate the magnitude and distribution of different electric current intensities in diverse pediatric head sizes.

Due to its neuromodulatory properties and advantages such as portability, low cost, and ease of access, tDCS is an interesting tool to be used in combination with other therapeutic treatments, as shown in adult studies utilizing medications (Brunoni et al. 2013) and behavioral strategies (Andrews et al. 2011; Ditye et al. 2012). As such strategies are also frequently used in children and adolescents with psychiatric conditions, future trials should test their combination with tDCS to increase clinical improvements.

The implementation of practical clinical guidelines in children and adolescents might still be premature, considering the need for evidence-based data and valid and reliable information. However, a greater interaction between researchers and clinicians with expertise in neuromodulation, with experts in neurodevelopment, would be of great value to establish optimum safety parameters and standardized questionnaires investigating tDCS side effects to guide future trials in the pediatric population.

Future studies in the pediatric population should invest in combining tDCS with safe neuroimaging and neurophysiological methods such as magnetic resonance imaging, EEG, near-infrared spectroscopy, and TMS, monitoring for possible short and long-term neurochemical, anatomical, and functional changes. This could increase safety, improve the design of tDCS protocols, and shed light on the neurophysiological, structural, and functional involvement associated with specific neuropsychiatric symptoms during sensitive periods of neurodevelopment (Kadosh 2012; Kessler et al. 2013; Vicario and Nitsche 2013).

Study limitations

This review had limitations related to the paucity of published articles regarding tDCS in psychiatric disorders in childhood. One limitation is the small sample size of the included studies. Moreover, the studies used varying designs, with few studies randomly assigning individuals to tDCS with control interventions. In addition, several stimulation parameters were investigated, limiting direct comparisons between studies.

Conclusion

TDCS is promising tool in the field of psychiatry, neurology, and child rehabilitation (Rubio-Morell et al. 2011) and can be combined with pharmacological and nonpharmacological treatments—such as behavioral therapy and neurorehabilitation—to increase their efficiency (Brunoni et al. 2012; Kadosh et al. 2012). During childhood and adolescence, the developing brain can be more sensitive to interventions, which might lead not only to better results compared with adults but also to an increased risk of side effects, likely related to negative or maladaptive plasticity (Vicario and Nitsche 2013).

Nevertheless, the literature regarding tDCS in child and adolescent psychiatry remains fairly limited to small RCTs and pilot studies, and although tDCS has been shown to be well tolerated and safe for children and adolescents with different neurological and neurodevelopmental disorders, it is not possible to draw conclusions about the efficacy of the technique for specific psychiatric conditions. In addition, long-term efficacy and safety should be monitored. Further studies are therefore warranted.

Clinical Significance

There is an urgent need to develop novel treatments for psychiatric disorders in children and adolescents, as current treatments for several conditions are either lacking or limited. This article reviewed the use of tDCS in child and adolescent psychiatry, providing preliminary evidence on the clinical effects, feasibility, and safety profile of this promising tool. We also discussed important ethical issues regarding tDCS use in this population.

Footnotes

Disclosures

A.R.B. is supported by the following grants: 2013 NARSAD Young Investigator from the Brain & Behavior Research Foundation (Grant Number 20493), 2013 FAPESP Young Researcher from the São Paulo State Foundation (Grant Number 20911-5), and National Council for Scientific and Technological Development (CNPq, Grant Number 470904). G.V.P. receives research support from CNPq, FAPESP, Grand Challenges Canada, Fundação Maria Cecilia Souto Vidigal, Bill & Melinda Gates Foundation, and the University of São Paulo. He has served as a consultant for Shire and Johnson & Johnson and he has served on the speakers' bureau of Shire. He has received royalties from Editora Manole. D.M. has nothing to disclose. T.G.C.D. has nothing to disclose.

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