Neuroplasticity and Non-Invasive Brain Stimulation in The Developing Brain

CHAPTER
Neuroplasticity and non-

invasive brain stimulation
in the developing brain
Igor D. Bandeiraa,b,*, Daniel H. Lins-Silvaa,c, Judah L. Barouha,c, Daniela Faria-
3
Guimarãesa,c, Ingrid Dorea-Bandeiraa, Lucca S. Souzaa,c, Gustavo S. Alvesa,c,
Andr
e R. Brunonid, Michael Nitschee,f, Felipe Fregnig, and Rita Lucenah
a
Laboratory of Neuropsychopharmacology, Serviço de Psiquiatria do Hospital Universitário
Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil
b
Programa de Pós-Graduação em Medicina e Saúde, Faculdade de Medicina da Bahia,
Universidade Federal da Bahia, Salvador, Brazil
c
Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, Brazil
d
Service of Interdisciplinary Neuromodulation, Instituto de Psiquiatria, Hospital das Clı´nicas da
Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
e
Department of Psychology and Neurosciences, Leibniz Research Center for Working Environment
and Human Factors, Dortmund, Germany
f
Department of Neurology, University Medical Hospital Bergmannsheil, Bochum, Germany
g
Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation
Hospital and Massachusetts General Hospital, Harvard University, Charlestown,
MA, United States
h
Department of Neuroscience and Mental Health, Faculdade de Medicina da Bahia, Universidade
Federal da Bahia, Salvador, Brazil
*Corresponding author: Tel.: +55-71-3283-8850, e-mail address: igordbandeira@gmail.com
Abstract
The brain is a dynamic organ whose growth and organization varies according to each
subject’s life experiences. Through adaptations in gene expression and the release of neuro-
trophins and neurotransmitters, these experiences induce a process of cellular realignment and
neural network reorganization, which consolidate what is called neuroplasticity. However, de-
spite the brain’s resilience and dynamism, neuroplasticity is maximized during the first years
of life, when the developing brain is more sensitive to structural reorganization and the repair
of damaged neurons. This review presents an overview of non-invasive brain stimulation
(NIBS) techniques that have increasingly been a focus for experimental research and the de-
velopment of therapeutic methods involving neuroplasticity, especially Transcranial Magnetic
Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS). Due to its safety risk
profile and extensive tolerability, several trials have demonstrated the benefits of NIBS as a
feasible experimental alternative for the treatment of brain and mind disorders in children and
Progress in Brain Research, Volume 264, ISSN 0079-6123, https://doi.org/10.1016/bs.pbr.2021.04.003

Copyright © 2021 Elsevier B.V. All rights reserved.
57
58 CHAPTER 3 Neuroplasticity and non-invasive brain stimulation
adolescents. However, little is known about the late impact of neuroplasticity-inducing tools
on the developing brain, and there are concerns about aberrant plasticity. There are also ethical
considerations when performing interventions in the pediatric population. This article will
therefore review these aspects and also obstacles related to the premature application of NIBS,
given the limited evidence available concerning the extent to which these methods interfere
with the developing brain.
Keywords
Neuroplasticity, NIBS, Children, Adolescents, Transcranial direct current stimulation, Tran-
scranial magnetic stimulation
1 Neuroplasticity in the developing brain

The brain of a child requires considerable metabolic activity to provide sufficient
energy to deal with the extent of changes to which it is subjected: from learning
how to process the vast amount of external sensory stimuli to the processing of emo-
tions, in this way it determines how to navigate an external world with its many
challenges. Atypical emotional development, observed in children as they are
experiencing brain development leaps, is connected to adversities, such as stress,
which increase the chance of future developmental dysregulations (Bick and
Nelson, 2016). It follows, therefore, that experience can reshape brain circuitry. Act-
ing independently, stress can even alter brain regions, such as the hippocampus,
tonsils, and prefrontal cortex (Kolb et al., 2017; McEwen and Morrison, 2013).
Different definitions of neuronal plasticity have been developed, all based on the
brain’s ability to change. Neuroplasticity can be defined as the brain’s capacity to
rearrange itself structurally and functionally according to experience and use
(Chang, 2014; Feldman, 2009; McClung and Nestler, 2008). Thus, neuroplasticity
can also be comprehended as an obligatory adaptation in response to each neurobi-
ological process (Pascual-Leone et al., 2005; Smith, 2013). This would suggest that,
through neuronal plasticity, any neurobiological stimulus is able to reshape the
brain’s structure and function and, consequently, induce behavioral changes.
When experiences induce a neurobiological response, subsequent adaptations
occur in the function and structure of the brain. In this way, neuroplasticity can
be classified as functional when it refers to synaptic changes through the strength-
ening or weakening of the postsynaptic neuronal response, thus inducing adap-
tations to neuronal functional properties. Structural neuroplasticity is related to
the sprouting and pruning of axonal and dendritic branches, or even whole neurons.
Neuroplasticity-related functional and structural adaptations, however, are not iso-
lated events, since both occur continually and simultaneously. There is a significant
amount of evidence to suggest that structural and functional plasticity is an impor-
tant physiological foundation for learning and memory formation (Debowska et al.,
2016; Keller and Just, 2016).
2 Neurophysiological basis of non-invasive brain stimulation (NIBS) 59
The main polymorphisms involved in neuroplasticity are related to genes that en-
code the brain-derived neurotrophic factor (BDNF) and apolipoprotein-E (apoE).
BDNF has been found to be crucial in synaptic regulation (Lu et al., 2015), and
different apoE polymorphisms have been found to induce and subsequently decrease
neuronal sprouting (Teter et al., 2002). However, functional changes in a specific
gene do not necessarily involve modifications of the DNA sequence. Physiological
and structural adaptations related to epigenetic processes, such as changes relating to
learning and development, may occur due to modifications in gene expression
(Bronfman et al., 2014).
2 Neurophysiological basis of non-invasive brain

stimulation (NIBS)
The strengthening of synaptic transmission, as a result of a particular neuroactivity
pattern, is termed long-term potentiation (LTP), whereas the weakening of synaptic
efficacy is designated as long-term depression (LTD) (L€uscher and Malenka, 2012).
Although the exact mechanisms of NIBS plasticity on the brain are not fully under-
stood, NIBS techniques can induce LTP-like and LTD-like plasticity in the form of
long-lasting alterations to cerebral excitability, and activity. The glutamatergic sys-
tem is a driver for cortical LTP, since LTP requires alterations in glutamate receptor
activity (Monte-Silva et al., 2013).
The mechanisms underlying the LTP process occur when there is intense activity
at the synapse. In these cases, neuronal mechanisms, such as LTP, become possible.
These are then activated, which enables a co-activation of the AMPA and NMDA
receptor by glutamate (Medeiros et al., 2012). This happens because a magnesium
ion blocks the NMDA receptor, but when Na + manages to enter in sufficient quan-
tity, via the AMPA channel, in response to large glutamate stimuli on the synaptic
fend, this leads to the depolarization of the neuron and the removal of the voltage-
dependent magnesium on the NMDA receptor (Medeiros et al., 2012). Since the
NMDA receptor also binds to glutamate, it allows the calcium on the synaptic fend
to pass through the NMDA receptors. As a result, a cascade is activated, thereby
triggering intracellular factors and contributing to early and late-stage LTP:
• Early stage causes the fusion and greater expression of AMPA receptors in the
synapse and these changes last 30–60 min;
• Late stage results from a constant calcium infusion, that is, constant activation of
the NMDA receptor, which generates greater transcription and consequent
expression of growth factors, and AMPA expression in the synaptic membrane;
thereby facilitating the action potential in that synapse.
These LTP mechanisms are shown in Fig. 1.
The LTD can be seen as the “weakening” of the synaptic connection. The process
occurs when there is a low intensity of depolarization, insufficient to cause the ex-
tensive removal of the Mg ++ ion on the NMDA receptor, but capable of permitting
FIG. 1
A—Glutamate; B—NMDA receptor; Ca ++—calcium ions; C—AMPA receptor; D—vesicles with glutamate. Explaining the LTP mechanism. At 1,
we can see the AMPA receptor opening Na + channels in response to glutamate. This repetitive response and depolarization leads to 2; which we
can no longer see the Mg + blocking the NMDA receptor, that now is open and let the Ca ++ penetrate the cell and induces synaptic changes, that
we can see in 3. The more expression of AMP receptors and a consequent strengthening in the synaptic connection.
some Ca ++ ions to enter the cell; this leads to a cascade that downregulates the
expression of AMPA receptors, making it more difficult to establish a connection
between the two neurons since the postsynaptic neuron becomes less excitable
due to the low levels of AMPA receptors (Bliss and Collingridge, 2013). Glutamate
and NMDA receptors are also involved in several other pathophysiological and treat-
ment mechanisms for mind and brain disorders (Correia-Melo et al., 2018, 2020;
Delfino et al., 2020; Leal et al., 2020; Lewerenz and Maher, 2015; Pittenger
et al., 2008; Vieira et al., 2020).
2.1 Transcranial direct current stimulation

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation
technique that involves attaching electrodes with different polarities to the scalp
and applying a low-intensity direct current generated by a respective stimulator
(Utz et al., 2010). The stimulation is too weak to induce neuronal activity indepen-
dent of afferent input to a given neuron, but sufficient to alter the excitability and
spontaneous activity of neurons, resulting in both acute and long-term effects
depending on stimulation duration and current intensity (Nitsche and Paulus,
2000). Stimulation intensity and duration determine the induction of neuroplastic
changes. These effects are similar to LTP and LTD effects. The use of anodal stim-
ulation on the cortex increases excitability at a macroscopic level (Nitsche and
Paulus, 2001), and is believed to induce LTP effects in neurons. Cathodal stimula-
tion, however, diminishes cortical excitability (Nitsche and Paulus, 2001), and the
effects are related to LTD. This anodal cathodal dichotomy, however, is present
mainly in motor studies. When examining cognitive functions, some studies
show only an anodal excitation significant effect, others demonstrate the reverse
effect, and a few studies report the cathodal inhibitory effect (Antal et al., 2007;
Jacobson et al., 2012). Early phase and late phase LTP differ according to the
duration of excitability alterations and the consequent changes explained above.
In tDCS, late-phase plasticity is achieved through periodical stimulation and is
dependent on a specific time window (Monte-Silva et al., 2013).
Glutamatergic synapses are drivers of tDCS-induced plasticity. Blocking the
N-methyl-D-aspartate receptor (NMDAR) prevents the induction of plasticity by
anodal or cathodal tDCS, whereas, an NMDAR agonist enhances the LTP-like effect
of anodal tDCS (Nitsche et al., 2003). GABA activity is also linked to plasticity
induced by tDCS. Studies of Magnetic Resonance Spectroscopy (MRS) have
reported a reduction in GABA availability after tDCS (Stagg et al., 2009) and it
has been suggested that GABA has a gating effect on the glutamatergic plasticity
of tDCS (Stagg et al., 2018). Therefore, the excitatory effects provoked by anodal
tDCS may involve not only NMDAR alterations, but also GABA reduction, whereas
the inhibitory effect of cathodal tDCS may be a result of glutamatergic and GABA
reduction (Dayan et al., 2013; Stagg et al., 2018).
BDNF also appears to have a role in tDCS-induced plasticity and the modulation
of NMDAR-dependent LTP and LTD. BDNF secretion and Tropomyosin receptor
kinase B (TrkB) activation are increased after anodal tDCS with repetitive low-
frequency synaptic response, which suggests a role for BDNF in the long-term
effects of tDCS (Fritsch et al., 2010). Furthermore, human subjects with BDNF
Val66Met polymorphism with the Met allele, which is associated with lower BDNF
secretion levels, showed less motor skill improvement than subjects without this
polymorphism when exposed to motor training. These results are consistent with
experiments on mice and suggest that BDNF secretion is relevant when acquiring
motor skills. However, after anodal tDCS, the increase in learning between these
groups was similar, suggesting that anodal tDCS could elevate BDNF-dependent
motor skill learning in both genotypes (Fritsch et al., 2010).
The principle mechanism regarding neuroplasticity induced by tDCS follows the
general mechanisms of LTP/LTD induction. The intracellular calcium concentration
will determine whether excitability-enhancing LTP or LTD will occur. When the
concentration is low, LTD occurs, whereas when the concentration is high, LTP
takes place. These occurrences are induced by cathodal and anodal tDCS, respec-
tively, and the amount of calcium that produces these effects is specific. If the
amount of calcium is higher than that required for LTP to occur, or is in between
the concentration required for LTD and LTP, a quantity denominated “no man’s
land,” no induced plasticity occurs (Stagg et al., 2018).
In addition, neurotransmitters and neuromodulators, such as dopamine, adeno-
sine, serotonin, and acetylcholine, depending on dosage and respective receptors,
appear to modulate plasticity (Nitsche et al., 2012). The dopaminergic system has
arguably received the most attention in investigations about neuromodulators effects
on NIBS-induced plasticity (Dayan et al., 2013) and in one particular study, the
blockade of D2 receptors with sulpiride was found to almost completely prevent an-
odal and cathodal tDCS after-effects (Nitsche et al., 2006).
It is important to note that, even though the majority of studies focus on M1, tDCS
has also been studied in the visual, somatosensory, auditory, and multisensory
regions. Changes to tDCS-induced excitability in these regions are directionally sim-
ilar to those seen in M1. However, it is important to consider multiple factors that
determine effects, such as the physiological state of neurons before and throughout
the stimulation protocol; the use of cathodal or anodal current, as well as current
amperage and other factors (Stagg et al., 2018).
2.2 Transcranial magnetic stimulation

TMS is a NIBS technique first introduced in human subjects by Barker et al. (1985).
According to Faraday’s (1831) principles of electromagnetic induction, a magnetic
coil is placed tangentially on the subject’s head, creating a brief, high-current pulse.
A magnetic field, perpendicular to the coil plane, is then generated, passing through
the skin, scalp, and skull until it penetrates the brain. When the magnetic field
reaches the brain, a perpendicular electric current is produced, capable of modifying
the excitability of cortical areas below the coil (Burke et al., 2019; Hallett, 2007).
TMS can be used to study brain physiology in addition to clinical applications for
diagnosing and treating disorders, with good safety and tolerability, and few side-
effects (Burke et al., 2019).
TMS can be applied with single pulses, paired pulses, or repetitive pulses. In the
motor cortex, single pulses can produce muscle contractions, measured as motor-
evoked potentials, which are useful for functional map representations of this region.
Also, single-pulse TMS induces phosphenes (bright spots of light) and transient
scotomas when applied to the visual system. These responses are valuable in ascertain-
ing whether or not the appropriate stimulation parameters were selected according to
the region of the brain studied (Dayan et al., 2013). TMS is assumed to activate neurons
that are oriented perpendicular to the coil and generate a response that can be recorded,
for example, by surface electrodes in the muscle (in the case of motor cortex stimu-
lation). These responses are usually recorded as motor evoked potential (MEP) and
motor thresholds (MT); MT can be defined as the minimum TMS intensity required
to elicit peak-to-peak amplitude of at least 50 microvolts in 50% of the trials. Both of
these parameters are useful in gauging the excitability of the corticospinal tract.
Pharmacological studies have revealed that MT is affected by agents blocking
voltage-gated sodium channels, which are crucial for regulating axon excitability,
as well as by agents acting on ionotropic non-NMDA glutamate receptors, and is
therefore responsible for fast excitatory synaptic transmission in the cortex
(Douglas et al., 2004; Hodgkin and Huxley, 1990; Klomjai et al., 2015). However,
drugs that have effects on other systems, such as GABA, dopamine, serotonin, nor-
epinephrine, and acetylcholine, apparently do not have any effect on MT (Douglas
et al., 2004; Hodgkin and Huxley, 1990; Klomjai et al., 2015).
MEP single pulses are also affected by agents that block sodium channels. How-
ever, unlike MT, MEP is also affected by GABA modulators, norepinephrine, and
dopamine agonists (Klomjai et al., 2015). In paired-pulse TMS, a conditioning stim-
ulus and a test stimulus are applied at different intervals and different intensities. The
two main phenomena involved are the intracortical inhibitory and facilitatory mech-
anisms. The principal measure of interest is usually the modulation of the test stim-
ulus by the conditioning stimulus. These double pulse stimulation techniques allow
us to better comprehend the study transmitter systems. For example, GABA, via
Short Cortical Inhibition (SICI), or NMDA, via Intracortical Facilitation (ICF),
can also be used for brain physiology measurements and to study interactions
between different brain regions (Burke et al., 2019; Dayan et al., 2013).
However, in addition to monitoring cortical excitability, TMS is also suited to
inducing neuroplastic alteration of excitability via repetitive stimulation (rTMS).
rTMS uses at least three pulses at a given intensity with a minimal frequency of
0.5 pulses/s (Burke et al., 2019). With respect to cortical excitability changes,
high-frequency rTMS (5 Hz) usually increases cortical excitability, whereas
low-frequency rTMS (1 Hz) usually reduces excitability (He et al., 2020). The
effects of rTMS outlast the stimulation period for several minutes, providing insight
into the plasticity and behavior of the stimulated area (Dayan et al., 2013; Tsuji and
Rothwell, 2002).
Based on the duration of effect, rTMS (and tDCS) can be divided into online and
offline effects. Online effects are typically disruptive with respect to psychological
and behavioral processes and occur in the stimulation period, while offline effects
have neuromodulatory effects (Burke et al., 2019). This neuromodulatory mecha-
nism is related to the LTP and LTD processes (Burke et al., 2019). While LTP
and LTD mechanisms have already been explained, it is important to state that
late-phase plasticity is related to spaced protocols, i.e., a repetition of stimulation
within a relatively short timeframe (minutes). LTD can be seen as a “weakening”
of the synaptic connection and is usually caused by prolonged low-intensity stimu-
lation; this can be seen in low-frequency stimulation TMS protocols, such as those
carried out at 5 Hz or lower (Allen et al., 2007).
A more recently developed rTMS protocol is theta-burst stimulation (TBS),
which delivers a burst of three 50-Hz trains repeated at 5 Hz. Continuous TBS is typ-
ically inhibitory, while intermittent TBS is usually excitatory. TBS is capable of
inducing neuroplasticity changes rapidly and efficiently (He et al., 2020).
Another possible way for TMS to influence neuroplasticity is through genetic
expression. Certain studies have demonstrated that a single TMS session can increase
mRNA expressions, such as expression of c-fos (Chervyakov et al., 2015), and sev-
eral other studies have demonstrated the ability to induce gene expression and
enzymes (Simis et al., 2013). These findings could be connected to the fact that
TMS has long-lasting effects.
As mentioned above, BDNF is critically involved in plasticity generation. Inter-
estingly, some studies report that an electric field can cause BNDF levels to rise
(Chervyakov et al., 2015; Yukimasa et al., 2006; Zanardini et al., 2006), whereas
others (Gedge et al., 2012) have found no effect. The reason for this heterogeneity
remains unclear but could be due to the different pathologies explored in these stud-
ies, giving rise to the theory that, depending on brain state, different effects might be
accomplished by similar stimulation protocols.
Currently, rTMS exists in different protocols. A multitude of cortical areas can be
tackled by rTMS, and specific stimulation protocols have been developed and tar-
geted to reduce disease-specific pathological alterations of activity and excitability.
The timeframe of the application can vary considerably, from single applications to
longer protocols of several weeks’ duration, depending on expected results (Fregni
et al., 2020).
3 Potential indications for NIBS in children and adolescents

Initially, adult patients were the focus for exploring indications for therapeutic NIBS,
since the knowledge base is concentrated in this group. Information concerning the
efficacy and safety of NIBS applications on children and adolescents is compara-
tively recent yet it is important to consider idiosyncrasies relevant to this population
when transposing protocols normally applied to adults (Kadosh et al., 2012; Krause
and Cohen Kadosh, 2013; Rajapakse and Kirton, 2013; Krishnan et al., 2015).
3 Potential indications for NIBS in children and adolescents 65
In summary, the central nervous system of children and adolescents differs from the
physiological, biochemical, and behavioral development process, with the added
complication of differences within the age group itself, especially in respect of cra-
nial anatomy (Krause and Cohen Kadosh, 2013; Rajapakse and Kirton, 2013). In re-
cent years, this discussion has evolved to create a theoretical basis that has helped to
establish the applicability and validity of NIBS in pediatrics, with encouraging data
that suggests protocols applied to adults could be considered and subsequently
validated for use in young people (Zewdie et al., 2018).
Despite these concerns, many studies have indicated that applying NIBS proto-
cols to the pediatric population produces minimal risks, enjoys good tolerance, and
has indicated potential benefits, in line with the adult population (Andrade et al.,
2014; Antal et al., 2017; Krishnan et al., 2015; Zewdie et al., 2018). In particular,
tDCS may be advantageous in the treatment of cerebral palsy, dystonia, refractory
epilepsy, autism, and attention-deficit/hyperactivity disorder (ADHD) (Palm
et al., 2016). In the context of childhood and adolescence, as well as the induction
of cognitive-behavioral changes through NIBS, neuroplasticity generation has the
potential to produce beneficial effects in multiple brain and mind disorders. These
include traumatic injuries, neuromotor and sensorineural disorders, epilepsy, apha-
sia, dystonia (Krishnan et al., 2015), as well as mental health concerns, such as
autism spectrum disorder, ADHD, dyslexia, mathematical learning disabilities,
Tourette’s syndrome, and mood disorders (Bandeira et al., 2016; Barretto et al.,
2019; Finisguerra et al., 2019; Krishnan et al., 2015; Looi et al., 2017; Rios et al.,
2018). It is worth noting that, in addition to being used for diagnosis, monitoring,
and the treatment of specific disorders, different NIBS techniques have also been
examined to explore their neuroenhancement potential for functional improvement
in healthy children and adolescents (Maslen et al., 2014).
3.1 Neurorehabilitation
Many disorders involving the motor system are associated with the connectivity
change between the primary and secondary motor areas and the extent to which they
interface with the thalamus-cerebellar system, as is seen in epilepsy, aphasia, dysto-
nia, and neuromotor disorders in general. Potentially, these can be treated with NIBS.
Neurotrauma and perinatal stroke can cause hemiparetic cerebral palsy in children.
Following a stroke in a newborn child, ischemia causes loss of viable neurons and
interruption of motor neural chain connectivity, which affects the function of
lesioned areas and their intrahemispheric and interhemispheric synapses (Kirton,
2013). All of these areas and their connections have been studied as therapeutic tar-
gets, and the applicability of NIBS to perinatal stroke has been investigated through
protocols using rTMS and tDCS to increase activity in the lesioned areas, via stim-
ulation of the affected motor cortex (Grecco et al., 2013; Kirton et al., 2015; Kuo
et al., 2018). Increases in connectivity in the motor areas that facilitate cortical
commands associated with motricity are related to better outcomes in motor function
using NIBS (Rajapakse and Kirton, 2013).
A recent systematic review (Mirkowski et al., 2019) studied 18 articles concern-

ing nonpharmacological treatment for motor and cognitive dysfunctions in child and
adolescent stroke victims. The studies involved randomized controlled trials (RCTs),
prospective controlled trials (PCTs), secondary analyses in RCT follow-up, and
pre-post studies. The methodological quality of each RCT was judged using the
physiotherapy evidence database (PEDro) tool and the evidence level was evaluated
using the modified Sackett scale. In terms of upper limb function enhancement,
it concluded that there was level 1b evidence in three situations: superiority of rTMS
over sham rTMS; superiority of rTMS in association with motor learning therapy over
sham rTMS associated with motor learning therapy; and superiority of rTMS plus
constraint-induced movement therapy (CIMT) over sham rTMS associated
with CIMT.
One of the trials evaluated by Mirkowski et al. (2019), in the systematic review
cited above, was a blinded randomized controlled trial by Kirton et al. (2016), who
studied 45 children (aged 6–9) with hemiparesis following perinatal stroke. For
2 weeks, participants were randomly submitted to daily rTMS, CIMT, both rTMS
and CIMT, or neither, and each intervention was associated with daily motor learning
therapy. For brain stimulation, an MRI mapping of the contralesional primary motor
cortex was carried out in patients previously randomly selected for rTMS interven-
tion and it was then possible to identify a target. Results indicated that when motor
learning therapy is associated with rTMS, CIMT, or both, there are significant upper
extremity motor function gains. The authors of the trial noted certain limitations,
such as the sample size and the fact that the study was a single-center trial. Similar
results were found in a randomized controlled trial in the context of congenital hemi-
paresis (Gillick et al., 2014).
In other studies, tDCS has not produced the same outcomes (Kirton et al., 2017;
Mirkowski et al., 2019; Nemanich et al., 2019). A randomized, controlled, double-
blind clinical trial by Kirton et al. (2017), studied the extent to which tDCS is
therapeutic for hemiparesis after perinatal stroke. Twenty-four children (aged
6–18) with hemiparesis due to perinatal stroke were randomized 1:1 for tDCS or
sham tDCS interventions, both in association with motor learning therapy and every
day for 2 weeks. To define the brain stimulation’s target, the contralesional motor
cortex area was MRI-mapped. Results indicated that motor function outcome mea-
sures did not increase significantly under tDCS or sham tDCS, although the authors
suggest therapy underdosing as a possible cause for lack of statistically significant
outcomes.
3.2 Developmental disorders

3.2.1 Dyslexia
Dyslexia is characterized by a difficulty in reading, writing, and speaking, even
though there may be a cognitive ability to achieve a higher level of learning and
to take advantage of educational and socio-cultural opportunities consistent with a
child’s normal development (Lyon et al., 2003). Brain connectivity analysis of
patients with dyslexia has shown deregulation of the neural systems responsible for
reading. Finn et al. (2014), studied the brain’s functionality of patients with dyslexia
and observed a reduction in the connectivity of the primary visual pathways, the as-
sociative visual areas, and their connections with the prefrontal cortex, especially in
respect of regions linked to concentration and attention (D’mello and Gabrieli,
2018). Skeide et al. (2017) observed that literacy training in adults results in the
reorganization of cerebral cortex pathways, cited by D’mello and Gabrieli (2018)
by inducing neuroplasticity, not only in the cortex areas cited, but also by increasing
connectivity between the occipital lobe and the subcortical regions in the thalamus
and the midbrain. These findings support the theory that the classic neural pathways
of the reading mechanism might be therapeutic targets for dyslexia. Moreover, they
also highlight the importance of secondary neural pathways in the physiopathology
of dyslexia and the possibility of their use as future therapeutic targets.
NIBS has proved useful in the treatment of dyslexia, through its modulation of
activity in the dysfunctional cortical areas, such as that observed in the educational,
therapeutic modalities cited above. Stimulation of these regions, by non-invasive
brain methods, increases the connectivity of classic neural pathways in the reading
mechanism, thus enhancing functional performance in dyslexia patients (D’mello
and Gabrieli, 2018). It has been shown that significant changes to physiology and
behavior can be achieved in children, adolescents, and adults, but these changes were
more prominent in children and adolescents (D’mello and Gabrieli, 2018). In a sys-
tematic review, Cancer and Antonietti (2018) investigated nine studies using tDCS
as a protocol aiming at improving reading abilities in individuals diagnosed with
Dyslexia and those with no diagnosis. Improvement in reading abilities, such as word
decoding, was observed in the majority of the trials analyzed; most of them focused
on the left temporo-parietal cortex as a NIBS’s target, because it is an area classically
related to reading tasks. To the best of our knowledge, no meta-analysis regarding
NIBS and dyslexia in children and adolescents was made before 2020.
Costanzo et al. (2016) investigated the effect of tDCS on the neuromodulation of
parietotemporal regions in 19 children and adolescents with dyslexia. At baseline,
the sample was initially submitted for distinct reading and reading-related activities
and assessed by a blinded examiner. These tasks were repeated 20 min after each
tDCS session. Three different tDCS protocols were applied to all participants, at least
24 h after the previous session: left parietotemporal anodal/right parietotemporal
cathodal tDCS to enhance left lateralization of the parietotemporal area; right par-
ietotemporal anodal/left parietotemporal cathodal tDCS to enhance left lateralization
of the parietotemporal area and sham tDCS. After the left anodal/right cathodal tDCS
protocol, there was a notable reduction in text reading errors. An opposite outcome
was observed after the left cathodal/right anodal tDCS protocol. The data were rep-
licated and extended by Rios et al. (2018) and Costanzo et al. (2019), who reported
that multiple tDCS sessions were associated with better reading efficiency rates in
children and adolescents. This reduction in reading problems after neuromodulation
of the parietotemporal region, an association area related to the vision, is consistent
with the pathophysiology described by Finn et al. (2014).
3.2.2 Attention deficit hyperactivity disorder (ADHD)

ADHD is characterized by maladaptive levels of inattention, associated with degrees
of impulsivity and hyperactivity—symptoms that usually manifest during childhood
and which remain throughout adulthood (Thapar and Cooper, 2016). Substantial data
from multiple meta-analyses indicate that, among other factors, ADHD is character-
ized by deficient interaction between different neural systems responsible for exec-
utive functions (EFs), such as motor inhibition pathways, attention, or working
memory (Cortese et al., 2012; Hart et al., 2012, 2013; Lei et al., 2015; McCarthy
et al., 2014; Norman et al., 2016; Rubia, 2018). Changes in the connectivity of these
networks include reduced activation of the prefrontal cortex, especially the left
dorsolateral region, one of the brain areas responsible for mediating EFs, via
connections with fronto-striato-parietal and fronto-cerebellar networks (Norman
et al., 2016; Rubia, 2018). NIBS can modulate these areas, increasing the neuronal
connectivity of the dorsolateral prefrontal cortex in the motor cortex and associated
neural networks, resulting in restoration or generation of neuronal activity in these
previously hyperactivated areas (Rubia, 2018; Sotnikova et al., 2017; Guimarães
et al., 2021).
It should be noted that there are inconsistencies in the information relating to the
use of rTMS in ADHD. A systematic review undertaken by Rubia, in 2018, reminds
us that while there were positive results from the first sham-controlled pilot study,
this represented one single session of rTMS in ADHD adults, and later, larger studies
did not indicate improved effects of rTMS over sham rTMS on ADHD symptoms or
cognitive functions (Rubia, 2018). Cao et al. (2018) performed a 6-week trial with
64 patients (aged 6–13) diagnosed with ADHD and randomly selected to receive
three different interventions. One group received rTMS sessions, with the coil tan-
gentially positioned over DLPFC. The study involved one session per day, and there
were five sessions per week. A second group received atomoxetine hydrochloride
orally, with a dose of 0.5 mg/kg/day for the first 3 days, rising to 1.2 mg/kg/day. Both
associated interventions were administrated to a third group, under the same condi-
tions. There were significant improvements using the ADHD assessments as out-
come measures for all three groups. However, the third group, which received
rTMS associated with atomoxetine, presented better outcomes for all measures.
However, Cao et al. (2018) highlighted certain limitations of this study, including
the small sample size, substantial time protocol, placebo effects, and absence of long
term follow-up.
Studies using tDCS protocols, compared to rTMS state of the art protocols, have
shown more potential outcomes in the ADHD stimulation therapeutic field (Rubia,
2018). In a pilot study by Bandeira et al. (2016), 9 children and adolescents (aged
6–16), diagnosed with ADHD and with no pharmacology therapeutics for at least
1 week prior to initiating the study were each treated in five daily tDCS sessions,
each lasting 30 min. In that protocol, the anode was positioned on the left dorsolateral
prefrontal cortex and the cathode on the right supraorbital. At study completion,
there was an improvement in selective attention and a reduction in the number of
errors and the time required to execute clinical evaluative tests, as well as decreased
symptoms related to ADHD after the intervention, as documented in a family report.

Similar results have been reported in randomized clinical trials with similar protocols
(Rubio et al., 2016; Soff et al., 2017), although more studies are required, with larger
samples and double-blind, randomized, sham-controlled trials.
There are other NIBS methods with therapeutic potential for ADHD, such as Tri-
geminal Nerve Stimulation (TNS) and Transcranial Random Noise Stimulation
(tRNS). In TNS, an adhesive electrode is placed on the face, around one of the
branches of the trigeminal nerve (TN), in order to emit a low-grade electrical current
directed to the nerve. It is suggested, in an animal model, that TNS is transmitted
through sensory pathways to regions of the central nervous system and this method
has already been used in pilot studies for the treatment of major depression and ep-
ilepsy (Cook et al., 2015; Mercante et al., 2017; Schrader et al., 2011). In a double-
blind, sham-controlled, pilot study (McGough et al., 2019), 62 children (aged 8–12)
with ADHD were randomly selected into two groups: every night for 4 weeks one
group received active TNS treatment, while the other group received TNS sham
treatment. At the end of the 4 weeks, the active TNS group showed improvement
in the clinical assessment measures for ADHD, the ADHD Rating Scale—ADHD-
RS. However, the response did not show a long-lasting effect vs the sham TNS and it
is still necessary to establish whether there is a significant improvement on conven-
tional treatments.
tRNS is a transcranial electrical stimulation method that utilizes the same equip-
ment as tDCS, although it uses a different mechanism of induced neuroplasticity
(Chaieb et al., 2015). It has been shown that tRNS can enhance the cognitive ability
of healthy adults, including sustained attention, although the method has not been
widely explored in ADHD (Harty and Cohen Kadosh, 2019). In a randomized
double-blind active-controlled crossover study, 19 children (aged 7–12) with ADHD
and without ongoing treatment were randomly selected to receive active tRNS treat-
ment or tDCS for five consecutive days (Berger et al., 2019). In respect of the study
and the tDCS group, the tRNS group achieved a clinical improvement on the ADHD
measurement scale, ADHD-RS. However, it is important to conduct future studies to
compare tRNS with a sham group in order to provide evidence as to whether both
neuroplasticity and clinical improvement, induced by tRNS, can be sustained over
the long term.
3.2.3 Autism spectrum disorder (ASD)

ASD is manifested in the first years of life as a wide range of quantitative and qual-
itative deficits in a child’s communication skills, in addition to different repetitive
motor behaviors (Lord et al., 2018). Impaired development in ASD individuals
has been associated with early cessation of neuronal plasticity (Berger et al.,
2012). Among the pathogenic mechanisms related to ASD, the most apparent are
atypical brain growth patterns studied through volumetric analysis (Levman et al.,
2018). Morphological changes with accelerated growth were identified mainly in
the frontal cortex, amygdala, and hippocampus (Barnea-Goraly et al., 2014). The
increase in the volume of white and gray matter suggests that cortical neurons
represent the main unit of dysfunction. The role of glial cells in the processes of pro-
liferation and synaptic elimination is also widely acknowledged (Cowan and Petri,
2018). Attempts have been made to associate the dysfunction of certain circuits with
specific phenotypes, on the assumption that neurophysiological signatures are re-
lated to different clinical profiles. Current studies have also focused on understand-
ing autism as a sub-connectivity disorder involving several circuits, such as the
mirror neuron system, the default mode network, the executive control network,
and the salience network (Abbott et al., 2016; Chen et al., 2017). The absence of
a specific anatomical or neuropathological substrate is a challenge for the develop-
ment of NIBS protocols.
The number of studies investigating the role of tDCS in the evolution of autistic
manifestations has been minimal. The majority used small samples and the outcome
was assessed using subjective instruments implying significant methodological lim-
itations (Amatachaya et al., 2014; D’Urso et al., 2014). Most tested anodal tDCS over
the left DLPFC. In one study the Bilingual Aphasia Test (BAT) was applied and
demonstrated an increase in verbal accuracy (Schneider and Hopp, 2011). This study
applied a current of 2 mA for approximately 30 min in a single session, but lacked a
control group to strengthen the veracity of this evidence. In an RCT, anodal tDCS
was used in a single session and a significant improvement in the domains of the
Autism Treatment Evaluation Checklist and an increase in alpha frequency, in elec-
troencephalography evaluation, was observed in tDCS group compared to sham. This
increase persisted and was also prevalent in the second assessment, carried out the
following day (Amatachaya et al., 2015). Reduced alpha frequencies, in EEG eval-
uation of patients with autism, has been founded in some studies (Cantor et al.,
1986; Murias et al., 2007) and Amatachaya et al. (2015) suggested that tDCS could
increase synaptic connectivity, which would be seen as an increase in alpha frequen-
cies, and then would be associated with reduction in autism domain symptoms.
A more recent study applied 10 sessions of tDCS on alternate days. EEG recordings
and data analysis found that the maximum entropy ratio (MER) value significantly in-
creased after tDCS. The results therefore help support the theory that tDCS, applied
over the left DLPFC, positively affects the brain’s complexity, which can be measured
by the alteration of entropy. This change in EEG complexity is specific to the stimu-
lation site and could be used to target activity as a measure of outcome in clinical trials
(Kang et al., 2018). This data is consistent with the increase in cortical excitability and
balances the excitation and inhibition of neurons induced by electrical stimulation.
However, it does not necessarily imply a functional increase and should be interpreted
with caution.
3.3 Mood and other psychiatric disorders

Therapeutic strategies for the treatment of mood disorders in children and adoles-
cents are limited, and these symptoms often persist throughout adulthood. In a
meta-analysis, the case-control research of Zhang et al. (2015) investigated prefron-
tal activation during cognitive tasks, using near-infrared spectroscopy, in patients
diagnosed with major depressive disorder (MDD). In these patients, a bilateral pre-
frontal activation in the cortex was observed that was lower than that of the control
participants. In another meta-analysis, Zhou et al. (2017) carried out studies using
MRI on MDD patients taking/not taking antidepressants, as a technique to analyze
intrinsic brain activity. Their results suggest that the intrinsic activity of the cerebel-
lum is notable in MDD patients who are not taking antidepressant medication. Radhu
et al. (2013) evaluated studies that measured motor cortical inhibition and excitation,
using TMS, on patients with psychiatric disorders and found significant inhibitory
deficits in patients diagnosed with MDD.
Given that some studies have identified changes in cortical excitability and
activity in depressed patients, it has been assumed that early NIBS, especially in pe-
diatric patients, can interfere or interrupt the development of pathological neuronal
circuits, such as those associated with depression or anxiety disorders, thus reducing
the morbidity and chronicity of these disorders (Croarkin et al., 2011, 2012). Im-
provements in depressive disorder may therefore be associated with the restoration
of cortical inhibitory circuits (Doruk Camsari et al., 2019), potentially through the
application of TMS, which is able to modulate and restore brain GABAergic and
Glutamatergic balance (Croarkin and MacMaster, 2019). In fact, NIBS studies for
the treatment of depression in children and adolescents are rare. Most of these are
case series and focus on TMS use, with no consistent data on the use of tDCS in de-
pressed patients (Hameed et al., 2017).
Zhang et al. (2019) conducted an rTMS study on depressed patients to measure its
effectiveness on 171 adolescents and adults aged 10–80 and permitted a maximum of
one type of antidepressant drug during application of the protocol. The TMS coil was
positioned on the left prefrontal cortex in 10 sessions over 2 weeks. The data showed
better outcomes for depressive symptoms in adolescent patients, compared to adult
patients, although there were many limitations to the case series study design. Other
case series have been published in recent years, the majority involving samples of
adolescents, and indicating a significant improvement in depressive symptoms, with
data suggesting increased levels of glutamatergic neurotransmission in the DLPFC.
However, it is important to investigate these findings using randomized controlled
trials (Croarkin et al., 2012, 2016; Yang et al., 2014). In conclusion, rTMS is signif-
icantly more effective than treatment with antidepressant drugs in preventing a recur-
rence of major depressive disorder in young adults as well as adults, although there are
no current studies in children or preadolescents (Wang et al., 2017).
Some rTMS protocols have been applied to depressed adolescents with suicidal
ideation. Croarkin et al. (2018), in an exploratory study, analyzed data from three
previous TMS protocols as a therapy for adolescents with treatment-resistant depres-
sion. All of the sample (n ¼ 19) were taking antidepressant medication throughout
the study, with a minimum effective dose, and, even though some individuals were
receiving psychotherapy, appointment frequency remained consistent. TMS was de-
livered to the left DLPFC, for a total of 30 sessions over 6–8 weeks. At the end of the
study, suicidal ideation, as predicted by objective suicidal ideation measures, signif-
icantly decreased and the authors recommended that this data guide future
randomized controlled trials. Similar outcomes were found in case series with anal-
ogous TMS protocols (Pan et al., 2018).
Data concerning NIBS outcomes in other psychiatric disorders in children and
adolescents is currently limited. However, with an increase in knowledge about
the pathophysiology of certain disorders, hypotheses concerning the potential for
NIBS application as a therapeutic intervention have been developed for syndromes
with pathologically altered cerebral activity, connectivity, and plasticity, suggesting
a broader application of such therapies in children and adolescents with psychiatric
disorders. For example, deficiencies in neuroperceptive systems, such as hearing, in
patients with schizophrenia may be related to dysfunction in cortical activity, sug-
gesting that treatment with neuromodulation using rTMS and tDCS could be bene-
ficial (Bandeira et al., 2020; Voss et al., 2019). Investing in new and emerging
treatments for mental disorders, such as NIBS, could increase evidence-based med-
icine for mental health care and help to reduce the overall burden of mental illness
(Bandeira and Mendoza, 2018; Barreto et al., 2020; Kessler et al., 2009; Silva-
Moraes et al., 2020). Characteristics of the clinical studies, presented in
Section 3, assessing the effects of tDCS or TMS in children and adolescents are dis-
played in Table 1.
4 Ethical concerns, adverse effects, and safety from a

neuroplasticity perspective
Aside from the general ethical and safety concerns of NIBS within adult populations,
applying this treatment to children raises further questions, some of which remain
unanswered. The fact that several studies have suggested that current levels presently
used in NIBS do not have the potential to cause neuron damage, even in the devel-
oping brain, leads us to conclude that the safety of tDCS in children has not been
adequately addressed.
A child’s brain is not analogous to that of a small adult. It is a unique physio-
logical entity with its own neurophysiological characteristics and the potential for
exuberant and unpredictable adaptive and neuroplastic changes (Davis, 2014).
Children have greater excitatory neuronal activity, less glutamate clearance, and
less GABA inhibitory activity, making them particularly susceptible to epileptic
seizures and behavioral symptoms (Hameed et al., 2017; Rakhade and Jensen,
2009). In addition, they may show accelerated neural plasticity compared to adults
after brain stimulation (Brunoni et al., 2012).
Greater cortical excitability is essential for the nervous system’s maturation in the
intrauterine period and childhood. The neuronal circuits in these phases are therefore
hyperexcitable and more prone to injury. In addition, immaturity may be greater in
specific pathological conditions (Rakhade and Jensen, 2009), which may require
greater care.
Primarily, it is worth reiterating that developing human brains undergo a series of
significant anatomical changes until adulthood is reached. For instance, as the brain
Table 1 Characteristics of clinical studies assessing the effects of tDCS or TMS in children and adolescents.
tDCS stimulation protocol TMS stimulation protocol
Current Outcomes/
Montage/ intensity Number Number measures
NIBS’s brain (density)/ tDCS of Frequency/ of (application
Study Population Age range Interventions targets duration design sessions Intensity duration sessions time)
Neurorehabilitation (Section 3.1)

Grecco et al. 40 children with 4–10 years Group 1: Anode: primary 1 mA Offline Group 1: X X X Cortex
(2013) cerebral palsy sham motor cortex of 20 min 10 sham excitability
+ treadmill the dominant Group 2: Functional
training brain 10 active balance
Group 2: hemisphere Group 3: Functional
tDCS Cathode: 10 sham mobility
+ treadmill contralateral Group 4: Functional
training supraorbital 10 active performance
Group 3: region Gross motor
sham + virtual function
reality training Static balance
Group 4: Three-
tDCS + virtual dimensional
reality training gait analysis
(baseline,
1 week,
1 month,
3 months after
end of trial)
Kuo et al. 45 children with 6–19 years Group 1: none Contralesional X X X 90% rMT 1 Hz Group 1: AHA
(2018), perinatal stroke Group 2: CIMT primary motor 20 min 10 sham COPM
Kirton et al. hemiparesis only cortex Group 2: (baseline, end
(2016) Group 3: rTMS 10 sham of trial, 1 week,
only Group 3: 2 months,
Group 4: 10 active 6 months after
CIMT + rTMS Group 4: end of trial)
10 active
Gillick et al. 19 children with 8–17 years Group 1: Contralesional X X X 90% rMT 6Hz Group 1: 5 AHA
(2014) congenital CIMT + rTMS primary motor 10 min active COPM
hemiparesis Group 2: cortex Group 2: 5 Stereognosis
CIMT + sham sham (baseline,
2 days after end
of trial)
Continued
Table 1 Characteristics of clinical studies assessing the effects of tDCS or TMS in children and adolescents.—cont’d
Current Outcomes/
Kirton et al. 24 children with 6–18 years Group 1: tDCS Anode: over 1 mA Offline Group 1: X X X AHA
(2017) perinatal stroke Group 2: contralateral (0.04 mA/cm2) 10 active COPM
hemiparesis sham tDCS forehead 20 min Group 2: (baseline,
Cathode: over 10 sham 1 week,
contralesional 2 months after
primary motor end of trial)
cortex
Nemanich 20 children with 7–21 years Group 1: Anode: 0.7 mA Offline Group 1: X X X AHA
et al. (2019) unilateral CIMT + tDCS contralateral 20 min 10 active Single-pulse
cerebral palsy Group 2: forehead Group 2: TMS
CIMT + sham Cathode: over 10 sham (corticospinal
the TMS- excitability)
derived motor (baseline,
hotspot of the 5 days,
contralesional 5 months after
hemisphere end of trial)
Developmental disorders (Section 3.2)
Dyslexia (Section 3.2.1)
Costanzo 19 children and 10.1–17.8 years tDCS (anodal) Condition 1: 1 mA Offline 2 active X X X Lexical
et al. (2016) adolescents tDCS Anode: left 20 min 1 sham decision
with dyslexia (cathodal) parietotemporal Phoneme
Sham tDCS region blending
Cathode: over Rapid
the contralateral automatized
region naming
Condition 2: Verbal n-back
Anode: right Word,
parietotemporal nonword, and
region text reading
Cathode: over (baseline,
the contralateral 20 min after
region each session)
Rios et al. 12 children and 8–17 years tDCS Anode: between 2 mA Offline 5 active X X X Letter
(2018) adolescents the middle 30 min identification
with dyslexia temporal and left task
posterior Nonword task
temporal areas Syllable task
Cathode: right Text task
supraorbital Word task
region (before, after
each session)
Costanzo 26 children and 10.9–17.1 years Group 1: tDCS Anode: over the 1 mA Offline Group 1: X X X Reading tasks
et al. (2019) adolescents Group 2: left 20 min 18 active (baseline,
with dyslexia Sham tDCS parietotemporal Group 2: immediately
regions 18 sham after each
Cathode: right session,
side of the 1 month,
parietotemporal 2 months after
regions the end of the
trial)
ADHD (Section 3.2.2)
Sotnikova 16 adolescents 12–16 years tDCS Anode: 1 mA Online 1 active X X X Behavioral
et al. (2017) with ADHD Sham tDCS dorsolateral 20 min 1 sham changes fMRI
prefrontal cortex (during, 20 min
Cathode: vertex after session)
Cao et al. 64 patients with 6–13 years Group 1: rTMS Dorsolateral X X X 100% 10 Hz Group 1: CPT
(2018) ADHD Group 2: ATX prefrontal cortex rMT 25 min 30 active IGT
Group 3: Group 3: SNAP-IV scale
rTMS + ATX 30 active WISC
(baseline,
6 weeks after
treatment)
Bandeira 9 children and 6–16 years tDCS Anode: left 1–2 mA Online 5 active X X X Corsi cubes
et al. (2016) adolescents dorsolateral 30 min Digit span (of
with ADHD prefrontal cortex the WISC-III)
Cathode: right IC (of the
supraorbital NEPSY-II)
area TAVIS-3
(baseline, after
the last session)
Soff et al. 15 adolescents 12–16 years tDCS Anode: left 1 mA Online 5 active X X X FBB-ADHD
(2017) with ADHD Sham tDCS dorsolateral 20 min 5 sham (baseline, study
prefrontal cortex day 5, 12)
Cathode: vertex QbTest
(baseline, study
day 2, 3, 4,
5, 12)
Continued
Table 1 Characteristics of clinical studies assessing the effects of tDCS or TMS in children and adolescents.—cont’d
Current Outcomes/
Berger et al. 19 children with 7–12 years Group 1: tRNS Anode: left 0.75 mA Online 5 active X X X ADHD-RS
(2019) ADHD Group 2: tDCS dorsolateral 20 min CGI-S
prefrontal cortex Digit span (of
Cathode: right the WISC-III)
supraorbital MOXO-CPT
area (baseline,
immediately
after each
session,
1 week later)
ASD (Section 3.2.3)
Amatachaya 20 children with 5–8 years tDCS Anode: over the 1 mA Offline 5 active X X X ATEC
et al. (2014) autism Sham tDCS left dorsolateral 20 min 5 sham CARS
prefrontal cortex CGAS
Cathode: right CGI-I (baseline,
shoulder 7 days after
treatment)
Schneider 10 children with 6–21 years tDCS Anode: 2 mA Offline 1 active X X X Syntax test
and Hopp autism dorsolateral (0.08 mA/cm2) Vocabulary test
(2011) prefrontal cortex 30 min (before, after
Cathode: right each session)
supraorbital
area
Kang et al. 26 children with X Group 1: tDCS Anode: 1 mA Offline 10 active X X X MER (baseline,
(2018) ASD Group 2: none dorsolateral 20 min end of trial)
prefrontal cortex
Cathode: right
supraorbital
area
Mood disorders (Section 3.3)
Zhang et al. 42 adolescents 10–80 years rTMS Left prefrontal X X X 120% 10 Hz 10–20 HAMA
(2019) and 75 adults cortex rMT active HAMD
with mood or (baseline, after
anxiety 10 session, end
disorders of protocol)
Croarkin 8 adolescents 14–17 years rTMS Left prefrontal X X X 120% 10 Hz 30 active CDRS-R
et al. (2012) with TRD cortex rMT Motor
threshold
(baseline,
weeks 2, 4, 5)
Croarkin 10 adolescents 13–17 years rTMS Left dorsolateral X X X 120% 10 Hz 30 active Glutamatergic
et al. (2016) with TRD prefrontal cortex rMT alterations
(baseline, end
of treatment)
Yang et al. 6 adolescents 15–21 years rTMS Left dorsolateral X X X 120% 10 Hz 15 active BDI
(2014) with TRD prefrontal cortex rMT Glutamatergic
alterations
HAMA
HAMD
(baseline, end
of each week,
end of
treatment)
Croarkin 19 adolescents 13–19 years rTMS Left dorsolateral X X X 120% 10 Hz 30 active CDRS-R
et al. (2018) with TRD prefrontal cortex rMT C-SSRS
(baseline, after
10, 20,
30 sessions)
Pan et al. 3 depressed 15–17 years rTMS Left dorsolateral X X X 100% 10 Hz 7 active BSI-CV
(2018) adolescents prefrontal cortex rMT MADRS
with suicidal (baseline, days
ideation 3, 7)
Abbreviations: ADHD, attention deficit hyperactivity disorder; ADHD-RS, ADHD rating scale; AHA, assisting hand assessment; ADP, antidepressant; ASD, autism spectrum disorder; ATEC, autism treatment evaluation checklist;
ATX, atomoxetine; BDI, beck depression inventory; BSI-CV, beck scale for suicide ideation-Chinese version; CARS, childhood autism rating scale; CDRS-R, children’s depression rating scale-revised; CGAS, children’s global
assessment scale; CGI-I, clinical global impression-improvement; CGI-S, clinical global impression-severity; CIMT, constraint-induced movement therapy; COPM, Canadian occupational performance measure; CPT, continuous
performance test; C-SSRS, Columbia-suicide severity rating scale; FBB-ADHD, German ADHD rating scale; fMRI, functional magnetic resonance imaging; HAMA, Hamilton rating scale for anxiety; HAMD, Hamilton rating scale for
depression; IC, inhibitory control; IGT, Iowa gambling task; MADRS, Montgomery–Asberg depression rating; Scale MER, maximum entropy ratio; NEPSY, developmental neuropsychological assessment; NIBS, non-invasive brain
stimulation; QbTest, quantified behavioral test; rMT, resting motor threshold; SNAP, Swanson, Nolan, And Pelham; TAVIS, visual attention test; tDCS, transcranial direct-current stimulation; TMS, transcranial magnetic stimulation;
WISC, Wechsler intelligence scale for children.
undergoes typical neurodevelopment, areas related to its developmental milestones

will increase in myelination (Barnea-Goraly et al., 2005). This generates a different
white matter density when a developing brain is compared to that of an adult, and this
has already been shown to influence current distribution in the brain in respect of
NIBS (Shahid et al., 2014; Suh et al., 2012). Even in adults, stimulation of the brain
over a regional target can cause widespread stimulation of the cortex (Romero Lauro
et al., 2014). Given the difference in myelination, it might prove even more difficult
to restrict stimulation to the desired area of a child’s cortex. Unifocal stimulation
could lead to a reinforcement of maladaptive, or dysfunctional, behavior and cogni-
tion (Davis, 2014). However, these anatomical differences can be partially resolved
by individual computational modeling, which provides guidance on electrode con-
figuration and dosing, although children are generally submitted to higher levels than
adults (Kessler et al., 2013).
It is also important to note that many of our synapses are culled during neurode-
velopment in a process called synaptic pruning, which selects only those synapses
with the strongest signal transmission (Neniskyte and Gross, 2017). Theoretically,
with the application of external inputs to this system, and the successive strengthen-
ing of synapses, there is a possibility of modulating typical synaptic pruning. This
process is also influenced, at least in respect of mice, by the microglia (Paolicelli
et al., 2011), which, in turn, is responsive to direct current stimulation (Monai
and Hirase, 2018). In spite of its contribution to neuroplasticity, the effect of tDCS
on the glia has been sparsely researched, and advanced functional imaging tech-
niques could be helpful in bridging this gap (Gellner et al., 2016).
Furthermore, one of the main characteristics of the developing brain is the
presence of critical periods for neuroplasticity triggered by the balance between ex-
citatory and inhibitory stimuli in neuronal circuits (Cohen Kadosh et al., 2015;
Hensch, 2005) and terminated by structural changes and the release of molecular
“brakes” (Bavelier et al., 2010). These periods are windows of opportunity for
experience-dependent circuit refinement for diverse capacities, such as visual devel-
opment (Hensch, 2005), but also periods when the brain is most susceptible to
environmental harm, which can lead to several disorders later in life, such as schizo-
phrenia, ADHD and depression (Andersen and Teicher, 2008; Fatemi and Folsom,
2009; Heyer and Meredith, 2017; Marco et al., 2011; Mill and Petronis, 2008).
In respect of other neurodevelopmental disorders, monogenic animal models
have suggested that impairments that are characteristic of intellectual disability
and ASD may arise from restrictions in critical periods. Also, altered neuronal ac-
tivity due to intrinsic or extrinsic sources in these intervals might have a major
influence on the developmental trajectory of the brain (Meredith, 2015; Meredith
et al., 2012). It might therefore be prudent to further investigate critical periods
and to take the results of these investigations into account when using NIBS in
children. This is important given that interventions in these periods can either be ma-
lign, acting as a risk factor for psychopathology, or benign, acting as compensations
for impairments already established, factors which could be important for the appli-
cation of NIBS in the future (Marco et al., 2011).
4 Ethical concerns, adverse effects, and safety 79
In respect of side effects, recent systematic reviews on the pediatric population

found that the vast majority were minor, such as tingling, twitching, discomfort, red-
ness, and headaches, both for rTMS and tES (tDCS and tACS) (Krishnan et al., 2015;
Saleem et al., 2019). However, there have been occasional reports of severe events
with rTMS, such as seizures, hypomania, and neurocardiogenic syncope in patients
with risk factors, where stimulation was conducted according to adult safety guide-
lines (Krishnan et al., 2015). Concerning seizures, although these patients did not
have any history of previous episodes, cerebral injury, or other relevant conditions,
there was evidence of either epileptogenic medication use or consumption of high
levels of alcohol prior to the procedure, despite the fact that they were minors,
highlighting the importance of screening for these situations (Krishnan et al.,
2015). No severe adverse events were observed with tES (Bikson et al., 2016;
Krishnan et al., 2015; Saleem et al., 2019).
Although the acute side-effect profile in children is very similar to that observed in
adults, it is important to account for long-term effects, which are crucial in evaluating
this population’s safety. Observation of neurodevelopment in the years following inter-
vention should, therefore, be taken into consideration (Kadosh et al., 2012). In one study
on long-term outcomes in children subjected to NIBS, eight adolescents who were trea-
ted with rTMS for refractory depression were re-evaluated after 3 years, and showed no
decline in cognitive functioning (Mayer et al., 2012). However, we could not find any
additional studies that presented a substantive follow-up of children subjected to NIBS
protocols (Krishnan et al., 2015; Mayer et al., 2012; Saleem et al., 2019).
Moreover, there remains a need for more translational studies, involving both an-
imals and research into pediatric and adult populations. For a recent example of this
specific issue, refer to Sánchez-León et al. (2020). As previously discussed, study
models of response prediction in children are also needed, since there is evidence
of different outcomes when using the same levels of current applied to adults
(Kessler et al., 2013; Mall et al., 2004). This would allow us to create more adequate
safety guidelines for the developing brain (Kadosh et al., 2012).
Another issue worth mentioning is the growing availability of affordable home
tDCS devices in the market. Due to the growth of internet-based do-it-yourself com-
munities (Davis and van Koningsbruggen, 2013), and the side-effect profile dis-
cussed earlier, an increasing number of people are applying tDCS in their own
homes, principally for the purpose of neuroenhancement (Fitz and Reiner, 2015),
However, there is a danger that vulnerable groups, for instance parents of children
with severe developmental disorders, such as autism or schizophrenia, might be more
likely to experiment with the procedure (Kadosh et al., 2012).
Thus, it is important to take into consideration the general public’s expectations
of, and reactions to, the field of NIBS, as well as the approach taken by researchers
when publishing their findings. In fact, some authors argue that the term “non-
invasive brain stimulation” might be misleading, suggesting that it is an innocuous
procedure (Davis and van Koningsbruggen, 2013). Therefore, researchers and the
media need to be mindful of the way they present NIBS, focus on taking a realistic
approach, and discuss its positive and negative aspects, while also stressing that there
remains much to be learned. Excessively positive reports may further encourage

its use outside of academia and controlled clinical settings (Fitz and Reiner,
2015), and, as discussed earlier, it might be children who are harmed the most
(Kadosh et al., 2012).
Acknowledgement
This review was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nı́vel
Superior—Brasil (CAPES)—Finance Code 001.
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Neuroplasticity and Non-Invasive Brain Stimulation in The Developing Brain

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CHAPTER

Neuroplasticity and non-

Progress in Brain Research, Volume 264, ISSN 0079-6123, https://doi.org/10.1016/bs.pbr.2021.04.003

1 Neuroplasticity in the developing brain

2 Neurophysiological basis of non-invasive brain

2.1 Transcranial direct current stimulation

2.2 Transcranial magnetic stimulation

3 Potential indications for NIBS in children and adolescents

A recent systematic review (Mirkowski et al., 2019) studied 18 articles concern-

3.2 Developmental disorders

3.2.2 Attention deficit hyperactivity disorder (ADHD)

symptoms related to ADHD after the intervention, as documented in a family report.

3.2.3 Autism spectrum disorder (ASD)

3.3 Mood and other psychiatric disorders

4 Ethical concerns, adverse effects, and safety from a

Neurorehabilitation (Section 3.1)

undergoes typical neurodevelopment, areas related to its developmental milestones

In respect of side effects, recent systematic reviews on the pediatric population

remains much to be learned. Excessively positive reports may further encourage

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