Developmental Cognitive Neuroscience 6 (2013) 176–194

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Developmental Cognitive Neuroscience

jour nal homepage: http://www.elsevier.com/locate/dcn

Review

Can transcranial electrical stimulation improve learning

difficulties in atypical brain development? A future

possibility for cognitive training

∗

Beatrix Krause , Roi Cohen Kadosh

Department of Experimental Psychology, University of Oxford, Oxford, UK

a r t i c l e i n f o a b s t r a c t

Article history:

Learning difficulties in atypical brain development represent serious obstacles to an individ-

Received 2 July 2012

ual’s future achievements and can have broad societal consequences. Cognitive training can

Received in revised form 7 April 2013

improve learning impairments only to a certain degree. Recent evidence from normal and

Accepted 8 April 2013

clinical adult populations suggests that transcranial electrical stimulation (TES), a portable,

painless, inexpensive, and relatively safe neuroenhancement tool, applied in conjunction

Keywords:

with cognitive training can enhance cognitive intervention outcomes. This includes, for

Cognitive training

instance, numerical processing, language skills and response inhibition deficits commonly

Transcranial electrical stimulation

Neuroplasticity associated with profound learning difficulties and attention-deficit hyperactivity disorder

Learning difficulties (ADHD). The current review introduces the functional principles, current applications and

Dyscalculia promising results, and potential pitfalls of TES. Unfortunately, research in child populations

Dyslexia is limited at present. We suggest that TES has considerable promise as a tool for increas-

ADHD

ing neuroplasticity in atypically developing children and may be an effective adjunct to

cognitive training in clinical settings if it proves safe. The efficacy and both short- and long-

term effects of TES on the developing brain need to be critically assessed before it can be

recommended for clinical settings. © 2013 The Authors. Published by Elsevier Ltd. Open access under CC BY license.

Contents

1. Introduction ...... 177

2. An introduction to TES...... 178

2.1. TES: types and mechanisms ...... 186

3. Improving cognitive training using TES in the adult brain...... 187

4. Targeting learning difficulties in the developing brain ...... 188

5. Potential risks and pitfalls of TES ...... 189

6. Physical side effects...... 190

7. Cognitive side effects ...... 190

8. Guidelines...... 191

∗

Corresponding author at: Department of Experimental Psychology, University of Oxford, 9 South Parks Road, Oxford OX1 3UD, UK.

Tel.: +44 01865 271381.

E-mail address: [email protected] (B. Krause).

1878-9293 © 2013 The Authors. Published by Elsevier Ltd. Open access under CC BY license. http://dx.doi.org/10.1016/j.dcn.2013.04.001

B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194 177

9. Conclusion ...... 191

Conflict of interest statement ...... 191

Acknowledgements ...... 191

References ...... 192

1. Introduction profound difficulties in learning and involves delayed corti-

cal development (Shaw et al., 2012); (2) current TES studies

Learning refers to the “the acquisition of knowledge or in adults have shown the efficacy in improving cognitive

skills through study, experience, or being taught” (“Oxford functions that are assumed to be impaired in ADHD (e.g.,

Dictionaries Online”, 2012). For the majority of individuals, Weiss and Lavidor, 2012), which might also have implica-

this definition might be applicable. However, for a signifi- tions for those who are interested in improving learning in

cant proportion of the population, children and adults alike, ADHD. While according to diagnostic criteria ADHD does

learning does not necessarily follow from studying, expe- not constitute a learning disability, we will here refer to

riencing or being taught. The aim of the current review is learning difficulties associated with atypical brain develop-

to introduce the potential of transcranial electrical stimu- ment to include ADHD and potential other developmental

lation (TES), a non-invasive form of brain stimulation that problems that meet the abovementioned criteria.

might be used to improve learning in those who have learn- The current discussion will focus on DD and dyslexia,

ing difficulties based on atypical brain development, and along with ADHD, as they are the best-known childhood

to evaluate the relevant evidence on TES from research in developmental problems associated with profound diffi-

adult populations. culties in learning and atypical brain development, and

There is currently no generally accepted definition of evidence in healthy adults suggests that TES has favourable

learning disabilities (for a recent discussion see Scanlon, effects on the cognitive functions commonly impaired in

2013). However, based on the Diagnostic and Statistical these learning difficulties.

Manual of Mental Disorders (5th ed.; DSM-5), learning DD refers to severe difficulties in manipulating numeri-

disabilities are defined as: (1) an academic-based disor- cal information and performing arithmetic operations, and

der that originates in the central nervous system, and can some have suggested that the deficit cannot otherwise

manifest itself in reading, writing, and/or mathematics; (2) be explained by low intelligence or by reading or atten-

a discrepancy in aptitude and achievement that can be tion deficits (Butterworth et al., 2011). Dyslexia, on the

identified using psychometric methods (e.g., mathemati- other hand, denotes severe difficulties in reading and text

cal achievement scores below the 5th percentile, despite comprehension, despite an (at least) average IQ (Shaywitz,

average IQ). Further criteria for the diagnosis of learning 2003). In ADHD, several domains of executive functioning

disabilities include stipulations that: (3) learning disabili- can be deficient, including working memory, divided atten-

ties cannot be attributed to a disparate array of difficulties tion and response inhibition (impulsivity) (Pasini et al.,

such as low motivation or self-affect, albeit the individ- 2007).

ual might exhibit some of these difficulties in addition to Learning difficulties have important consequences for

the learning disability; (4) when assessing learning dis- the individual and the society they live in. The rates of

abilities, factors such as age, gender, cultural and language unemployment, reduced income and low socioeconomic

group, socioeconomic factors, and level of education should status throughout adulthood are often high in individ-

be taken into account, as these factors may influence the uals with learning disabilities (Stein et al., 2011; Parsons

symptom evaluation; (5) learning disabilities do not repre- and Bynner, 2005). Further consequences include unem-

sent an “all-or-none” phenomenon, and vary in severity; ployment, loss of tax payments, drug abuse, crime, special

(6) learning disabilities are regarded mainly as a neu- education, and depression treatment (Gross et al., 2009).

rodevelopmental disorder. This might suggest that other In addition, the overall social and health-related conse-

cognitive impairments can be observed to a lesser extent in quences can be especially detrimental, as they are likely

other domains (Karmiloff-Smith, 1998). Furthermore, we to cover the individual’s entire life span (Stein et al., 2011).

would like to note that learning disabilities may appear in For instance, it has been suggested that the lack of success

one (e.g., reading) or more (e.g., reading and mathemat- and achievement in individuals with learning difficulties

ics) cognitive domains. While the aptitude–achievement predicts high rates of psychiatric diagnoses (Raskind et al.,

discrepancy is currently the most established means for 1999). These factors in turn affect the state economy, in the

the identification of learning disabilities, academic per- sense that extreme annual expenses are required to coun-

formance has now been suggested as an identifier in the teract the deleterious societal consequences. These costs

DSM-5 (Scanlon, 2013). are estimated to equal nearly £2.4 billion in the UK alone

In the current review, we discuss the potential role of for numeracy problems (Gross et al., 2009), £1.8 billion in

TES to enhance cognitive training effects in learning disabil- the UK for reading disabilities (Jones et al., 2006), and $42.5

ities such as dyslexia and developmental dyscalculia (DD), billion for ADHD in the US (Matza et al., 2005). This demon-

which fit the aforementioned criteria. We further extend strated burden on both the individual and the society

our discussion to attention-deficit hyperactivity disorder stresses the pressing need to design successful training and

(ADHD). The inclusion of ADHD for the purpose of the intervention methods to counteract these dramatic effects

current review was twofold: (1) ADHD is associated with of learning difficulties at the individual and societal level.

178 B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194

Table 1

Potential known and possible consequences caused by TES in the developing brain. Unknown factors need to receive scientific attention and careful

exploration in order to be able to label the method ‘safe’ in paediatric population.

Population Adults Children

Short-term effects Long-term effects Potential short-term effects Potential long-term effects

Physical tolerability Tingling (70.6%), itching (30.4%), None reported Induction of seizures Neurological impairments

burning sensation (21.6%), pain and/or risk for epilepsy

(15.7%), skin irritation (redness),

headaches (4.9%), fatigue (35.3%)

(Poreisz et al., 2007)

Cognitive effects Task-specific improvements or Persistence of Maladaptation and Irreversible shaping of the

associated with reductions in performance improvements on dysfunctional integration network leading to faulty

stimulated brain (Tables 2 and 3) experimental task (up of neural network under cognitive functioning, or

region to 6 months: Cohen development transfer effects to another

Kadosh et al., 2010) cognitive domain

Cognitive effects Unknown Unknown Remote effects or Unintended cognitive

associated with other secondary plastic changes impairments compromised

brain regions (e.g., by lateral inhibition of by dominant stimulated

the stimulated region) brain region

(Zheng et al., 2011)

This review focuses on the application of TES together more moderate neurological and clinical conditions (Cohen

with cognitive training as a new approach to further Kadosh, 2013; Nitsche et al., 2008), including learning

enhance the outcome of existing cognitive training and difficulties and atypical cortical development in children

intervention approaches to improve learning difficulties. (Cohen Kadosh et al., 2012b).

In the following section, we will discuss different TES TES has currently only few known, minor side effects,

protocols and their underlying mechanisms. This will such as skin irritation and nausea (see Table 1). In healthy

be followed by an overview of the current evidence on adults, no cases of seizures have been reported to date

improvements in cognitive training using TES in both (Poreisz et al., 2007). It is important to stress, however,

healthy and clinical adult populations. Besides a critical that the associated risk of TES should not automatically

discussion on the interpretation of results and associ- be inferred from adult to child samples and evidence from

ated pitfalls and risks of the method, we will also outline paediatric samples is very limited (see Mattai et al., 2011;

the potential benefits for TES as a future intervention Schneider and Hopp, 2011, for a detailed discussion, see

technique in children with learning difficulties and dis- Section 5).

cuss its potential role in ameliorating associated learning The TES current, which is typically delivered at 1–2 mA

deficits. (Tables 2 and 3 ), is applied by a battery-driven current

generator (e.g., a 9 V battery), through electrodes that are

2. An introduction to TES fixed to the scalp surface by straps or a cap. The elec-

trodes are covered by rubber sponges and are usually

Two thousand years ago, physicians applied the electri- soaked in saline solution to enhance conductivity with the

cal current emitted by torpedo fish to alleviate a variety skin (Zaghi et al., 2010). The exact locations of the tar-

of medical symptoms. As known from Islamic and Greco- get stimulation regions are usually determined using the

Roman writings, headaches, epileptic seizures, pain and international 10–20 system for EEG electrode recording

other symptoms were treated by applying the electri- (Auvichayapat and Auvichayapat, 2011). One or more elec-

cal current of the fish to the symptom site (Finger and trodes are placed over the to-be-stimulated site, with a

Piccolino, 2011). Almost two millenia later, in the 18th reference electrode elsewhere on the head or body, and

century, applying electricity to the head was re-pioneered current flows from one to the other. In the majority of

as a cure for mental illnesses such as epilepsy and hys- experiments, behavioural performance during the stimu-

teria (Gilman, 2008). It has since been refined and has lation is contrasted against the performance during the

become a widely applied technique in both scientific corresponding sham (placebo) stimulation (Tables 2 and 3).

and clinical rehabilitation settings. The most frequently In some cases, a control brain region is used (e.g., Bolognini

used forms are deep brain stimulation (DBS) and TES. In et al., 2010; Sparing et al., 2008). The participant, and in

DBS, implanted electrodes stimulate specific cortical and some cases the experimenter, is blind to the respective con-

subcortical regions to treat a variety of neuropsychiatric dition. One of the major advantages of TES is that its sham

conditions, such as Parkinson’s disease (Huys et al., 2012). condition is indistinguishable from the real stimulation

In TES, cortical brain areas are targeted from the out- to the person receiving it (Gandiga et al., 2006), as pre-

side surface of the scalp by using one or more electrodes programmed settings allow an initial stimulation period

(Im et al., 2012; Nitsche and Paulus, 2001). Due to its (e.g., 30 s), which then ramps down and offsets the current.

non-invasiveness and its possibility to induce long-term The participant experiences the skin sensations typical of

synaptic plasticity, TES has considerable potential as a reha- TES during this initial period and thereby remains unaware

bilitation method for enhancing cognitive performance in of the real condition.

B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194 179 the IPL:

SMA: d ) in

1.07

5 .91; .43;

=

.06);

= =

d Language =

d d 2

day

d sham: anodal: cortex;

transcranial

anodal:

<

=

1

(Cohen’s ATDCS provided sham memory;

.57

sham: right sham: =

0.06 0.03 N/A 0.07 0.08 left day < < < vs. vs.

d (sham:

not size

anodal

<

parietal

anodal

5 5 cathodal

1.04 .37; 1.18 .52

= = = =

working

N/A CTDCS day CTDCS Patients: anodal right day anodal Healthy: anodal d Effect d d sham: d

size mA/cm

CTDCS: whenever posterior , cm cmcm 0.03 cm

WM:

2

5 5 5 5

2 × × × ×

cm

PPC: cm

cm cm cm cm RTs

reference electrode 30 Electrode 7 7 N/A 16.3 5

speech

estimated

and lt.-anodal;

mA stimulation; cortex;

verbal

quotients

improved: improved improved improved: been

ACC

1.2

ACC

mA mAmA 7 mA mA Amp

1 2 1 2 have current parietal

ATDCS aphasia spontaneous CTDCS auditory ATDCS ATDCS

• • • Results • speech naming • • comprehension • rt.-cathodal,

PC:

sizes

direct

RCLA: CTDCS, sham 1 sham sham

sham

Effect

cortex; 2

with 5

both

for

ATDCS, ATDCS, ATDCS ATDCS, ATDCS, (WS) sham (WS) (WS) TES TDCS for

transcranial sham

task available.

week days: between training

prefrontal lt.-cathodal;

patients:

a days

and

of in

size. not

anodal

times consec. days days

effect

Training 5 5 3 each/ aphasic repetition ATDCS 6 consec. weeks fluency

retrieval

rt.-anodal,

ATDCS: dorsolateral

‘ large ’ information

a Speech Cognitive function Speech Naming Speech Syntax acquisition Word

RALC:

is

− ) DLPFC:

0.8

accuracy; detailed ≤

d

dropouts

gyrus; (retest

3f,

N/A: ACC:

No − + +

and

stimulation;

m patients:

size

12m 2m 8

time; frontal

m

design;

noise 9f, 1f, 6 2f, 3m N/A Healthy: 7m; Sex

effect

blind

inferior

reaction

random

IFG: (in RT:

6–21

45–70

+ + + ‘ moderate ’ 10.40,

a age ±

4.4, 30–81 left;

7.9,

between-subject

48–82 ± gyrus;

±

lt.:

BS:

53–79 Mean 67, N/A 68.13 56.2, 9.8 years) Healthy: 55 transcranial

represents right;

duration Double

temporal design;

0.5

Rt: 3

≤

d

min min min

superior size ,

Stimulation healthy, 20 20 30

N stroke 21 3 6 10 10 8 STG:

populations. effect within-subject

WS:

CP5), ‘ small ’

cortex; area

(CP5), clinical

a

area)

5

(CP6),

stroke lobe; CP5 with with

as

stroke

(high-frequency/low-frequency) area,

sites

over

area

patients patients patients children

rt.

STG STG

motor

global aphasia aphasia autism

to subjects: lt.

rt. days

frontal

(Broca’s

group: involving TRNS: patients:

parietal

Sub-acute stroke Stroke Population Healthy subjects, Chronic Lt. Minimally verbal stroke aphasia with with with with patients aphasia aphasia patients IFG TDCS

primary considered

ATDCS: Stimulation Lt. Healthy ATDCS/sham TDCS/sham (Wernicke’s occipito-parietal Wernicke’s sham consec. or (O2); CTDCS: is

(hf-/lf-) M1:

superior

0.2 functions

d :

(2011)

SPL: area;

(2011)

(2011) (2011)

Hopp lobe; al.

cognitive al. al.

Cohen’s

stimulation;

motor

et (2011) et et

and on (2011) (2011)

(2011) (2011)

al.

al. al.

al. al.

paper. et parietal

et et current

et et 2

studies

Fiori Fiori Authors Language You Authors You Marangolo Fridriksson Vines Schneider Marangolo original Table TES direct inferior supplemental

180 B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194 d )

1.98 of

week =

sham

1 .11) d weeks later:

2

later: end =

pre- pre-

syntax: 4 baseline

testing:

pre-TDCS: pre-TDCS: > <

( d change .23; .89;

1.07; of > >

(Cohen’s

= =

= week

.02; .05

sham:

d d from d N/A 0.06

= = weeks mean 1 sham:

>

end size vocabulary:

d d

4

.96; 2.78 .35; 0; .28;

= = = = =

Percentage Mean post-CTDCS d d post-TDCS Effect d CTDCS: later: ATDCS: d unchanged later: testing: post-TDCS Post-ATDCS anodal d TDCS: Change size mA/cm

deltoid

, 2 2 at 1

RT cm cm

at

had

weeks Electrode N/A 35 64

RT for

4 (stable

improved reduced

follow-up posttest

at reduced

mA and

task

to

recognition recognition

ACC ACC ACC

improved improved

improved follow-up patients recognition visual

1.5

items fluency improved

acquisition

ACC recognition weeks of

mA

Amp pre-

3 2

naming

weeks ATDCS 75% ATDCS TDCS ATDCS: CTDCS: Sham: ATDCS Sham: Persistent

in • • • syntax from • speech trained stable and 3 • Results performance • visual memory recognition memory unchanged memory • • • • follow-up CTDCS,

sham (WS)

days

71 per per

apart

of anomia

average

days (WS) sham TES TDCS, ATDCS,

of vocabulary

consec.

week on

(10 days

training training

1

(5

and conditions

of of

apart

stimulation

sessions

consec. days days

and

10 3 Syntax condition) testing training training, per condition condition 3 5 apart); days attention

Cognitive function Word recognition memory Visual recognition memory visual

dropouts Training

+ N/A + + +

3m 8m

7f, 7f, Sex vs.

pre

blind No

(in

(only

8.2

+ post) − + + 7.3

age ±

±

Mean 75.2 79.05 years) min minmin +

20 20 30 duration Double

F8)

on

min min to

region Stimulation

30 15 cathode N 10 15

IFG cortex,

cathode (F3),

posterior

cm

lobe rt. posterior posterior DLPFC

forehead supraorbital

areas

muscle and

Rt. Lt. Lt. (2.5 reference rt. rt.

T4),

Stimulation sites Bilateral temporo- parietal Temporal reference P6-T4) (P3-T5 deltoid (T3, Population Alzheimer patients Alzheimer patients

(2011)

(2011) ).

Hopp al.

(2008) (2008)

(2012) (2012)

et (2011)

al. al.

and

al. al.

et et al.

et et

et ( continued

2

Vines Schneider Fridriksson Memory Ferrucci Authors Memory Ferrucci Boggio Boggio Authors Table

B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194 181 the

direct in

size size parietal

rate: d ) d )

cm cm

hf-

Stroop < 3 5

size size 2

× × 2 supplemental

1.09 .85; .55 .7 .28 cm

provided inferior cm cm cm = = = = =

ATDCS d d Learning automaticity: d TRNS: d Effect Electrode 3 3 Electrode 16 7 Effect (Cohen’s (Cohen’s d transcranial

SMA:

IPL:

been

not

on cathodal

cortex;

RCLA

memory; has

DLPFC

Stroop

sham,

it

mA mA

mA to and

learning Amp 1 1 to

mA compared

Stroop

CTDCS: improved 1.5 Amp 2

parietal

working follow-up

RALC RALC numbers rate

rate

performance enhanced automaticity

improved exploration

whenever

ATDCS WM:

improved

compared sham,

ATDCS

decreased month

posterior TRNS Rt.

6 Stroop learning to between

• Results • learning visual to

PPC DLPFC

stimulation;

articificial Cz

PPC at

in

increased decreased to to

PPC:

to for

estimated

RCLA

lt.-anodal;

sham sham,

current

RALC RCLA Sham Stable RCLA RALC (WS)

automaticity rates • automaticity RCLA decreased • numerical Results • • • compared • been cortex;

1

per

lf-TRNS; sham

RCLA,

(DLPFC),

direct

sham

CTDCS,

have apart

rt.-cathodal,

parietal

TES RALC, RALC (PPC), session

days sizes

Training N/A 1 condition, week

TES hf-TRNS, ATDCS, ATDCS PC:

session

RCLA:

min)

transcranial size.

Effect

consec.

6 Single (120 Training cortex;

effect

anodal

lt.-cathodal; available.

‘ large ’

a min min prefrontal

not

ATDCS:

visual

abilities abilities is

22 Stimulation duration 30 function

0.8 function

rt.-anodal, min min

≤

d

20 20 Stimulation duration exploration accuracy;

dorsolateral Cognitive Numerical Numerical RALC: information

and

(P4)

the

Cognitive Orientation discrimination Multi-sensory field

ACC:

size PPS cortex

F4) hf-TRNS

PC DLPFC: sites rt.

above P4),

detailed

time;

for

rt. effect

(F3,

visual

cm

(P3), Cz stimulation; P4) (P3,

N/A: gyrus; and

10m 3.5

PPS PPC DLPFC (P3, sites Lt.

N/A 9f, Sex reaction noise

Stimulation inion), Primary Lt. (V1, ‘ moderate ’

frontal RT:

design;

a

42m 4m

random only left;

inferior 42f, 16f, Sex lt.:

represents month

IFG: (in dropouts Stimulation

6

(dropout right;

0.5

+ + follow-up) No at 20–22 20–31 + No dropouts + age

transcranial

≤

between-subject Rt.:

d

gyrus;

BS:

Mean Range Range years) size ,

(in

2.5,

age Double blind − N/A effect

temporal for

design;

±

blind range

populations.

(not

2 19–30 Mean 21.7 24, 20–26 years) ‘ small ’ 19 N 15

a

superior Double N/A + Hf-TRNS condition)

normal

as

mA/cm 0.1 0.1 STG:

within-subject

2

N 84 20

involving

(high-frequency/low-frequency) WS:

cortex; considered

mA/cm 0.09 0.06 (2013) (2013) is

lobe; TRNS:

0.2

motor

= functions

d

Kadosh Kadosh (2010) (2010)

(hf-/lf)

parietal al. al.

(2011) (2011) (2010) (2010) primary

et et

Cohen Cohen Cohen’s cognitive

al. al. al. al.

M1: abilities abilities et et et et

on

and and superior

Kadosh Kadosh

paper. stimulation;

area; 3

SPL:

studies

Iuculano Iuculano Bolognini Authors Numerical Authors Numerical Vision Fertonani Bolognini Vision Fertonani Cohen Cohen Authors Authors Table TES lobe; original motor current

182 B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194 d )

.39

size

.72; =

cm cm cm cm cm cm

= d

5 5 5 5 5 5

2 d .27; .08 vs. vs.

LHA-RHC: LHC-RHA: .1.79;

× × × × × × LHA-RHC LHC-RHA

= =

= sham(RT): sham(RT):

cm d d (Cohen’s

d vs. vs. < < cm cm cm cm cm cm

items: items:

sham(RT) sham(RT):

sham:

35 Electrode 7 7 7 7 5 7 < 5 7 sham sham < task: task: estimation) sham:

<

size

RT RT sham: .27; .33; .53 .31 .99; .72;

items: mA ======

CTDCS d 3 (rough 2 N/A TDCS TDCS(RT) 1-back d d d LHA-RHC LHC-RHA: LHA-RHC: 2-back Effect TDCS(RT) LHC-RHA versus vs. d d in mA

in

of 2

RT

WM mA mA

sham of

mA mA mA, mA mA

task: tapping

RT

task, 1.5 Amp 1 1 1.5 1 1 1 compared RT

stim.

1-back

abolished and

in

to in reductions and

distracters

current

and enhanced improved

reduced interaction

finger

presence 2-back

consolidation LCRA-TDCS

improvements

but

on sham

the

ATDCS ATDCS No Interaction CTDCS

in ACC • • • Results • • abolished between early strength RCLA-TDCS reductions condition task; compared measured LARC-TDCS to sequences incorrect recognition performance trained RT (WS)

sham

sham min

ATDCS

(WS) (WS)

(50

onset)

condition condition, condition, mA),

days

to sham sham sham CTDCS, hf-TRNS, sham

(1

per per per (BS)

apart

mA),

offset

ATDCS, (2 TES ATDCS, ATDCS Lt.-anodal-rt.-cathodal, sham ATDCS, ATDCS, ATDCS, (WS) separate minutapart

week session session session

Training from 1 N/A 1 Single-session 1 30 1 on in

min min min min min

20 10 10 Stimulation duration 15 13 WM WM Procedural consolidation WM WM Cognitive function Selective attention WM WM

rt.

P4) sites

orbit

(P4), cheek

(F3) DLPFC,

rt. lt. and PC

(C4) lt. electrode

(per

(P3

M1 25m 5m DLPFC

5m 5m 6m 4m

Stimulation Rt. Anode Lt. PPC Active cathode cathode inferior 22f, 6f, 10f, 4f, 7f, Sex 5f, group)

+ No dropouts − − + − (in

9.18

20–30 ± 5.8 3.5

age

5 3 2, ± ±

± ± ±

Mean 29 22 27.23, 22–55 25 25 29.4 26.5 years) blind

(blinding

+ Double N/A + N/A N/A compromised)

12 15 N 14 11 44 27 10 2

0.03, 0.06 0.03 0.04 mA/cm 0.03 0.04

). (2011)

(2010) (2010) (2012) (2012) (2012) (2012)

al.

(2010) (2010)

al. al. al. al. al. al. et

al. al.

(2008)

(2011) (2011) et et et et et et

et et

al.

al. al.

( continued

et 3

et et

Gladwin Teo Berryhill Mulquiney Ohn Teo Sandrini Gladwin Authors Memory Tecchio Sandrini Memory Tecchio Berryhill Authors Table

B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194 183 d ) d )

no

min

size

after

cm cm cm cm, cm sham:

vs.

after after 30

4 5 5 4 5

2 2 post: vs.

× × × × × .22;

.15; .58; .84; =

cm cm (Cohen’s (Cohen’s vs. sham: CTDCS:

= = = 1.77 d cm cm cm cm cm

ATDCS d d d

= passive 7 Electrode 4 7 Active 4 35 35 5

TDCS vs. vs.

d size size

pre-

completion:

.36; .45 .64 3.25; .54 min: min; min:

= = = = =

TDCS ATDCS after d Effect Effect d 10 d TDCS: ATDCS baseline: d d 20 30

mA mA mA

mA mA mA

for 1.5 1 1 2 Amp 1.5 1.5

RT min ACC,

after

30

a

task

larger enhanced

memory IPS/SPL-rt.

control decreased enhanced

towards maintained inhibitory another

IPL

improved

showed

exp.

2-back

even

3 :

(BS)

anodal min; the least

control ATDCS ATDCS exp.

ATDCS CTDCS Lt. at Results • • effect 30 in CTDCS CTDCS no CTDCS, CTDCS,

to

ATDCS,

Results • • inhibitory control reducing • cathodal recognition tendency (BS) (WS)

1 :

sham;

Exp. TES ATDCS, ATDCS, ATDCS, ATDCS, ATDCS, (WS) stimulation sham sham region ATDCS 2 :

week

1

task

WM

session,

Training N/A N/A 1

×

inhibition memory ADHD)

visual 3 3-back apart Training

control planning function

and orienting

mA min

Recognition Behavioural Inhibitory Cognitive Attention Executive Audio- (addressing spatial 10 10 Stimulation duration

min min

20 Stimulation duration 10 6m;

8m 1m 3m;

7m;

lt.- 6f,

control: 7f,

10f, 9f,

15f, + (control,

rt.

sites

1 ; 2 : 5m 10m

stimulation 8m; 5m, 5m 5m superior

M1

cathode

prefrontal area 7f, 6f, Sex ATDCS 20f, 19f, 7f, 7f, exp.3 : (control) no exp. Exp.

sites

vs.

P6)+,

(F3) (F3),

+

Stimulation rt.-IPL-anode Pre-SMA, Rt.-IPL-cathode- lt.-IPS/SPL-anode (P3 IPS/SPL-cathode (P6) (exp.) middle Fz) contralateral

DLPFC DlPFC

supraorbital Lt. Lt. over Stimulation 2 : 4

± 22.1,

4.16

exp.

25 years)

± M1:

6;

control : 18–48 19–32 (in

±

group:

exp.3 : 23.58 24

No dropouts − +

8.7, 0.9 5.9, 18–27

20–26 age

3.16, 5; ± ± ±

1 :

± ± No dropouts − +

24.2 Mean Pre-SMA ATDCS 26.5 24 Exp. 22 21.79, range

blind

Double blind − +

controls 26.7

Double − − 12

+

2

2 N 28 22 30 24 48 12

0.04 mA/cm 0.09 mA/cm 0.03 0.04

(2012)

). (2011)

(2010)

(2012a) (2012a)

(2009) al.

al.

al. al. et

al. (2012)

Lavidor

et (2008) (2011) (2011)

et et

et al.

al. al. al.

and

( continued

et

et et et 3

Jacobson Ditye Weiss Dockery Ohn Jacobson Authors Mulquiney Authors Attention Hsu Bolognini Authors Attention Hsu Table

184 B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194 S3: d )

.38; (S)

S1:

cm

S3:

=

size

.38; d

cm cm cm cm cm cm,

10

control: =

5 5 5 5 5 5

.22; × <

d

× × × × × × ATDCS: ATDCS: S2:.12; S2: =

session 4

d CTDCS:

.27; .43 cm (Cohen’s

S2:

cm cm cm cm cm cm = =

control: ATDCS(Flanker sham(Flanker

(estimated) ref. 10 Electrode 5 7 7 7 7 7 d d day ACC: S2:

< ATDCS

− .23; − .22; − .12; .48; > >

size

.46;

= = = =

3: =

CTDCS:

d d d d

.29; 3.24 .67; .84; − .45

d

= = = = =

CTDCS(Flanker effect) S3: d S3: RT: Day effect): effect): d CTDCS(Flanker effect) ATDCS S1: N/A S1: Effect d d d 1:

mA

by the to

mA mA mA mA mA

Amp 1.5 2 2 1 2 1 task

PPC

if

A-TDCS ATDCS

(RSE) rt.

redundant

later

months and

preceded to performance (retested orienting

by

to inhibition during in

improved if improved improved 12

particularly

processing

improved

sham) effect

modality-specific

and sham crossmodal

CP5 ATDCS

6 sham

(BS)

CTDCS

TDCS CTDCS CTDCS ATDCS CTDCS A-TDCS control:

(WS) (WS)

to

• • • • Results persistent and response compared planning flanker planning acquisition follow-up under at sessions consolidation signal • and preceded improved stimuli, probabilistic audiovisual both •

Cz

CP5,

sham CTDCS, sham sham sham, control : sham to over

5

CP5; CP6, 1 per

per

SST on ATDCS, TES ATDCS, ATDCS, ATDCS ATDCS, ATDCS, ATDCS to to (WS)

days

session of

apart

session sessions min

training Training 1 2 8 Single stimulation condition, condition week consec.

language knowledge

fluency function

and and violation

efficiency naming

min min min min naming

15 15 15 Stimulation duration 15 Cognitive Reading Associative Speech; Semantic Picture Syntactic phonemic detection rule-based learning

(P4); orbit

(O2);

rt. between

PPC V1 cortex deltoid (P4);

forehead lt.

5m sites

rt. rt. F8-Cz),

to

eyebrow) (F3),

5f,

PPC lt.

to to

(P4),

lt. (anode

and rt.

10m 25m;

10m 3m 10m

IFG PPC DLPFC

19f, Sex 15f, 9f, 7f, N/A 5f, control : Stimulation Rt. Rt. Lt. A-TDCS orbitofrontal contralateral cathode supraorbital A-TDCS (above muscle T4-Fz reference sham

years)

No dropouts + − − −

control : 22–32

(in

62–74

2.7, 3.2 3.7 2.1; 2.4

age

20–50

± ± ± ± ±

range

23.7 Mean 26.7, 25.6 69, 23.6 26.9

Double blind − N/A − + 2 controls 22.6

10

+

0.04 0.03 mA/cm 0.06 0.09 N 23 19 10 10 15 44

(2012)

(2011) ).

(2010)

(2011) (2010)

(2009) al. (2011)

(2008)

al.

al. et al.

al. (2012) al.

Lavidor

(2008) al.

et

et et

et et al.

et

al.

and ( continued

et

et

3

Vries

Bolognini Weiss Dockery Authors Authors Ditye Language Turkeltaub Flöel Holland Cattaneo Sparing De Table

B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194 185 d )

1.35; .26

1.16 1.57 = =

latency = =

d d

.44; .47; .34 d d

sham

= = =

< vs. vs. d d

d (Cohen’s

.27 sham: sham:

naming (RT)

sham: sham: = > <

size CP5:

> > d

>

.49

=

CTDCS ATDCS TDCS TDCS (RT): ATDCS Effect ATDCS(RT) picture d ATDCS(RT) sham(RT): sham(RT): CP6 area ACC

in

latency

readers Broca’s

and

detection

sham

in violations

area

Broca’s

to tasks in the was

speed increased increased decreased improved over to

speed reading

signal production

semantic

associative

syntactic

Word ATDCS ATDCS ATDCS ATDCS ATDCS ATDCS

• • Results • • • learning • efficiency • naming BOLD word Wernicke’s below-average improved compared enhanced picture-naming of area phonemic both improved and

at each

per per per

apart

apart h session

condition, 4

sessions session days session session

Training 2 1 Single-session 1 1 Single 7 stim. condition condition, least

min min min min min

min

7 Stimulation duration 20 20 20 20 20 Cp5),

rt. TP7); TP8 (CP5),

and area,

area

ref. region (CP6), (in region temoral area area, perisylvian

sites and and

area pTC

on Cz point

T7 T8 T3-Fz

rt.

area,

Broca’s (PPR) (pTC) (Broca’s

posterior posterior IFG posterior

Stimulation Lt. Lt. Lt. Anode Wernicke’s Broca’s peri-sylvian between contralateral supraorbital between region reference cortex between (Wernicke’s FC5) (crossing F7-Cz) cathode Supraorbital rt. reference

No dropouts + + + + + −

Double blind − + N/A − N/A N/A 2

mA/cm 0.06 0.03 0.06 0.06 0.06 0.03

(2011) ).

(2011) (2010)

al. (2011)

(2008)

al. et al.

al.

(2008) al.

et et

et

et

al.

( continued

et

3

Vries

De Flöel Sparing Holland Cattaneo Authors Language Turkeltaub Table

186 B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194

It is important to make a clear distinction between TES

and a similar, but more familiar, neuroscientific technique,

called transcranial magnetic stimulation (TMS). TMS and

TES both have advantages and disadvantages, depending

on the intended research field and parameters of use (for

a review see Wagner et al., 2007). In TMS, magnetic pulses

are administered to the scalp surface with a magnetic coil,

which induces a magnetic field in the cortical region below

(Walsh and Pascual-Leone, 2003). This magnetic field leads

directly to the depolarization of cortical neurons and thus

leads to action potentials, which can be followed by an

observable, short-term change in the behavioural response

(e.g., finger movement after M1 stimulation) (Schläpfer

and Kayser, 2012). This makes TMS particularly useful to

explore the causal role of a given cortical region in cognition

and functioning. Depending on the preferred parameters,

Fig. 1. Electrode placement for the lateral prefrontal cortex stimulation.

it can induce either immediate activation by triggering

The electrodes are wired with the stimulator (bottom left), which is a 9 V

action potentials in the stimulated region, or temporary battery pack and are held in place using a headband.

Reprinted from Current Biology, 22, Cohen Kadosh, R., Levy, N., O’Shea, J.,

virtual ‘lesions’ by inhibiting activation in the given region

Shea, N., & Savulescu, J. The neuroethics of non-invasive brain stimulation,

(Ruff et al., 2009). The direct change in the behavioural

R108-R111 (2012), with permission from Elsevier.

response reveals whether the targeted region is involved

in the processing of the task at hand.

to administer (Brunoni et al., 2012; Cohen Kadosh et al.,

In contrast to TMS, TES affects the stimulated neurons

2012b). Overall, these factors make TES more suitable for

in a more subtle fashion. Namely, it modulates neu-

experimental and clinical settings than TMS, especially for

ron membrane potentials—and thus concurrent cortical

the purpose of repeated cognitive training and for modu-

excitability—during task execution, and thereby possibly

lating neuroplasticity (Fig. 1).

induces more long-lasting cognitive changes (Zaghi et al.,

2010). These long-term changes might therefore have a

higher rehabilitative value than TMS for individuals with 2.1. TES: types and mechanisms

cognitive dysfunctions (Brunoni et al., 2012). In addition,

the repeated administration of TMS increases the chance Currently, there are three main types of TES: (1) trans-

for epileptic seizures (Wassermann, 1998). Therefore, TES cranial direct current stimulation (TDCS); (2) transcranial

seems to be more favourable in cases where repeated use random noise stimulation (TRNS); and (3) transcranial

is required, such as in multiple cognitive training ses- alternating current stimulation (TACS). TDCS is the most

sions. widely used to date and offers two subtypes of stimulation:

Another advantage of TES is that it is more comfortable (1) anodal stimulation (ATDCS) enhances neuronal firing

for the receiving individual than TMS. TMS generates loud by inducing depolarizations (neuronal excitation); and (2)

clicking noises that are associated with “tapping” sensa- cathodal stimulation (CTDCS) depresses the firing rate and

tions on the skin, with a high potential for eliciting facial hyperpolarizes neuronal firing (inhibition) (Nitsche and

twitches in some areas (Wagner et al., 2007). Moreover, Paulus, 2000). In other words, in ATDCS, the firing thresh-

the discomfort induced by unwanted action potentials in old of neurons is decreased, such that the neurons in the

the muscles under the skin at the stimulation position can stimulated area require less input to fire. In CTDCS, the

also affect the performance on cognitive tasks (Abler et al., firing threshold of neurons is increased, such that the stim-

2005). ulated area becomes inhibited and requires more input.

However, one of the potential advantages of TMS over Depending on the intended goal (facilitation or inhibition),

TES is its higher spatial and temporal resolution (Wagner ATDCS or CTDCS can be selected to either enhance or reduce

et al., 2007). Nevertheless, there is no evidence yet that neuronal excitability and thereby modulate cognitive abil-

these advantages are critical for inducing neuroplasticity ities.

during learning. Since TES training is repeatedly admin- TES studies with healthy adults and patients with brain

istered over an extended period of time, a temporal damage and/or cognitive dysfunctions demonstrate how

resolution of 1 millisecond (vs. 5 min) may not add any neural circuits can be modulated during cognitive train-

benefit in this case. The relatively poor focality of TES ing to improve deficient cognitive functioning; in some

ranges in the order of centimetres, but at the same time instances, long-lasting effects have even been demon-

diminishes the necessity for complex and expensive func- strated (Tables 2 and 3). The modulatory effect of ATDCS

tional MRI- or MRI-based neuronavigation systems, as is reduces regional levels of the inhibitory neurotransmit-

used in TMS (Sack et al., 2009). Compared to the costly ter gamma-Aminobutyric acid (GABA), whereas CTDCS

technical equipment, as well as the required advanced decreases glutamate transmission in the motor cortex in

knowledge and skills in its administration of TMS, TES is conjunction with a simple motor task (Stagg et al., 2009).

relatively inexpensive (simple devices can start at around GABA levels correlate negatively with learning (Floyer-

£500). Furthermore, unlike TMS, TES equipment is com- Lea et al., 2006) and are therefore likely to play a role in

pact and portable and does not require extensive training learning and cognitive enhancement associated with TDCS.

B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194 187

Furthermore, animal studies have shown that ATDCS can serves as either anode or cathode (Zaghi et al., 2010). The

enhance the secretion of brain-derived neurotrophic fac- ideal stimulation frequency for behavioural effects hereby

tor (BDNF), which is a crucial growth factor in synaptic depends on the current cortical oscillation pattern and

learning. This in turn can modulate long-term potentiation therefore may vary with task requirements. For exam-

(LTP) (Castillo et al., 2011; Fritsch et al., 2010), which is ple, when investigated under different lighting conditions,

known to be mediated by NMDA-receptor activity (Nitsche visual cortex excitability, as indicated by the perception

et al., 2003). Whereas most cognitive functions (e.g., read- of phosphenes, is optimally enhanced at beta frequencies

ing, speech, decision making, or arithmetic) are aimed to (14–22 Hz), whereas alpha frequencies (8–14 Hz) induce

be improved using ATDCS by enhancing cortical excitabil- the most effective stimulation when applied in darkness

ity (Cohen Kadosh et al., 2010; Flöel et al., 2008; Hecht et al., (Kanai et al., 2008). Despite these results, the cogni-

2010; Holland et al., 2011), certain frontal functions, such tive effects of TACS have received minimal attention and

as response inhibition, can be improved by suppressing the thus remain poorly understood. The different types of

neural activity in related networks using CTDCS (see e.g., TES allow the administrator to flexibly choose between

Hsu et al., 2011). In this case, the inhibition functions as a applying excitatory and inhibitory stimulation with TDCS,

filter on impulsive responses. inducing random noise in TRNS, or altering brain oscil-

TRNS is a recently introduced version of TES, which lations with TACS, depending on the desired cognitive

applies the current at quickly varying frequency bands outcome.

(Terney et al., 2008). In this method, the stimulation

emanates from both electrodes simultaneously (which are 3. Improving cognitive training using TES in the

the same electrodes used for TDCS) and can excite both adult brain

stimulated brain regions at the same time. There are two

advantages for TRNS over TDCS: (1) due to its lower prob- The goal of cognitive training is to improve a tar-

ability of causing skin sensations compared to TDCS, TRNS geted cognitive function, if possible to the optimal degree.

can provide even superior blinding conditions (Ambrus The outcome may be different from individual to indi-

et al., 2010); (2) it can modulate two brain regions simul- vidual. However, performance needs to be quantifiable

taneously without facing inhibitory cathodal effects under to measure the effect, especially in order to assess the

the second electrode. For example, TRNS would be desir- effect of TES. Most training studies compare reaction time

able in the case of arithmetic training where the bilateral and/or accuracy pre- and post-training to monitor the

dorsolateral prefrontal cortex (DLPFC) is heavily involved success of the intervention. In addition, it is desirable

(Zamarian et al., 2009). Indeed, it has been found that the that follow-up measures should be taken post-training

application of TRNS to the bilateral DLPFC during 5 days of to ascertain long-term effects and to allow flexible re-

arithmetic training increased the learning rate compared to application of the training if necessary. Additional tasks

sham stimulation (Snowball et al., 2013). In both TRNS and using non-practiced material can be applied pre- and

TDCS, even brief stimulation durations (e.g., 10 min) can post-training to examine whether the trained material gen-

lead to excitability increases both during and up to 60 min eralises to broader cognitive performance in the same or

after stimulation, and have been demonstrated to facili- other domains.

tate the effects of learning, compared to sham stimulation Working memory, attention, language, and visual

(Terney et al., 2008). processing are frequently reported as cognitive training

Fertonani and associates (Fertonani et al., 2011) sug- targets in TES studies (Table 3). Many of these studies have

gested that the effects induced by TRNS can be explained achieved significant improvements in performance com-

by a phenomenon called stochastic resonance. According to pared to cognitive training alone under sham conditions.

the stochastic resonance framework, the presence of neu- Some of this research is directly related to clinical condi-

ronal noise can make neurons more sensitive to a given tions, such as language impairments (Table 2). For instance,

range of weak inputs. in various TES studies participants were trained on the

Since the brain is a nonlinear system, it can use the noise memorization of words (Flöel et al., 2008), repeated nam-

to enhance performance (Moss et al., 2004). Another expla- ing of objects presented in a picture (Holland et al., 2011),

nation, which has been offered by Terney et al. (2008), is or reading practice (Turkeltaub et al., 2011). Even short

that by using TRNS, sodium channel activity can be aug- training periods (e.g., 20 min) can significantly improve

mented. According to this explanation, sodium channels cognitive performance (e.g., Berryhill et al., 2010; Cattaneo

would reopen (repolarisation) within a shorter time frame et al., 2011; Flöel et al., 2008; Gladwin et al., 2012; Holland

after depolarisation under TRNS compared to non-TRNS et al., 2011; Sandrini et al., 2012; Teo et al., 2011). Such

and thereby make the neuron ready for repeated excita- an effect might be mediated by changes in the functional

tion. However, as TRNS is a recent version of TES, such architecture of the brain, as those can already be observed

suggestions as to the operating mechanism are currently after only a few minutes of TES (Chaieb et al., 2009; Polanía

only hypotheses and supporting experimental evidence is et al., 2012).

required. At the moment, it is still unclear what relevance the

The third type of TES is TACS. In contrast to the quickly observed improvements will have in a real-life setting

varying random frequencies in TRNS, TACS stimulates at outside the testing laboratory. For example, the average

a fixed frequency (e.g., 10 Hz). The stimulation is applied improvement in reaction times for different types of cog-

at low intensities and the direction of the current is con- nitive processing is often below 70 ms compared to sham

stantly alternating, so that each electrode interchangeably stimulation, which might be meaningless for most real-life

188 B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194

situations (Pascual-Leone et al., 2012). However, many TES findings in adults indeed indicate that various cognitive

studies also report significant improvements in accuracy training effects can be significantly enhanced with TES

(e.g., Ferrucci et al., 2008; Fiori et al., 2011; Flöel et al., 2008; compared to cognitive training alone. TES combined with

Marangolo et al., 2011; Ohn et al., 2008; Turkeltaub et al., cognitive training showed positive results with moderate

2011). to high effect sizes, even within stimulation periods as

According to Pascual-Leone et al. (2012), scientific brief as a single session (Tables 2 and 3; see also Jacobson

issues such as small and biased samples (i.e. often dom- et al., 2012b). This provides support for the potential effi-

inated by university students), behavioural detriments cacy of this technique. However, the true nature of the

induced by the stimulation, and publication biases need to cognitive outcome in real-life situations, especially in cog-

be addressed for a more qualitative evaluation of exper- nitive deficits, still needs to be established. Study designs

imental outcomes (Iuculano and Cohen Kadosh, 2013). need to be improved in the future in order to guaran-

Weak or null effects may never make it into the pool of tee unbiased and satisfactory outcomes leading to clear

scientific literature, despite their importance for the critical interpretations for such studies. Current interpretations of

evaluation of the method’s effects. In the absence of effects, findings therefore look promising but need to be critically

it is uncertain whether the method itself lacks the poten- evaluated.

tial for cognitive enhancement, or whether the task and/or

stimulation site may be irrelevant for the cognitive function 4. Targeting learning difficulties in the developing

in question. It is therefore necessary for researchers to also brain

publish unsuccessful experiments and to carefully moni-

tor previously used stimulation parameters and cognitive Based on the results from TES in the adult brain, we

tasks in relation to the stimulated region in order to ascer- suggest that by targeting brain regions that subserve the

tain unbiased results. These parameters could be changed impaired cognitive skills during cognitive training, the

and adapted in future studies. For example, stimulating the atypical trajectory of neural development in learning diffi-

IPS in a subject with low numerical abilities during numer- culties may be altered in the short term. In the long term,

ical training may not optimize cognitive training because TES may thereby be effective for ameliorating the brain’s

the subject might apply different strategies than other indi- plasticity constraints on learning, and potentially restoring

viduals of the same age; the subject may therefore recruit normal learning processes and a more typical develop-

frontal regions, instead, for the same type of processing mental pathway. We hereby provide a new perspective for

(Rivera et al., 2005). Similarly, it is possible that changes in developmental cognitive neuroscientists, and suggest that

other parameters such as the current intensity (e.g., from TES can have the potential to address both the neural and

1 mA to 1.5 mA) will lead to stronger effects (Teo et al., behavioural level of child learning difficulties.

2011). Even though there is substantial overlap in the symp-

Another important consideration for TES application tom profiles of different learning difficulties (Gilger and

and research is that the effect of ATDCS versus CTDCS Kaplan, 2001), it has also been suggested that learning

can result in opposing directions of behavioural effects in difficulties often exhibit more specialized impairments

different brain regions and for different cognitive tasks (Scanlon, 2013). As an example, we will focus here on

(Tables 2 and 3). For instance, CTDCS has been found to DD, which involves problems in relating magnitudes to

decrease memory performance when applied to temporo- spatial representations along a mental number line (e.g.,

parietal regions (Ferrucci et al., 2008), and similarly 20 is larger than 18 but smaller than 25) (Ashkenazi and

working memory recognition when the inferior posterior Henik, 2010; Von Aster and Shalev, 2007). This lack of

parietal cortex was stimulated (Berryhill et al., 2010). On understanding of numbers might contribute to broader

the contrary, CTDCS to the right posterior parietal cortex issues with mathematical thinking and should be tar-

has improved measures of attention (Weiss and Lavidor, geted by training that attempts to alleviate effects of

2012; for examples in other domains see Antal et al., 2004; DD. Indeed, number line training has been shown to

Dockery et al., 2009; Terhune et al., 2011). The difference improve spatial representations and improved arithmetic

may be explained by the nature of the cognitive func- performance in children with DD (Kucian et al., 2011).

tion subserved by the stimulation region, such that areas A recent study in young adults provided proof of con-

in which higher activation correlates with superior per- cept that TES during artificial number training improved

formance show performance enhancement when ATDCS performance on the number line task after 6 days of

is applied, whereas areas involved in attentional regula- training (Cohen Kadosh et al., 2010). The TES effect

tion might benefit from inhibition. In the latter case CTDCS remained during a follow-up test 6 months after the end

would act to induce an attentional filter (Weiss and Lavidor, of the training. The persistence of the TES training effect

2012). suggests the possibility of TES improving cognitive func-

In summary, the interpretation of results in TES research tioning with long-term effects. Notably, recent studies

is often complex and may be counterintuitive in cer- in the field of numerical cognition have shown simi-

tain cases. This is mainly due to a lack of understanding lar long-term effects after arithmetic training (Snowball

of the exact interaction of effects between the cognitive et al., 2013), fraction training (Looi et al., 2013), as well

function and the region to be stimulated. Such ambigu- as numerosity discrimination training (Cappelletti et al.,

ities might be partly resolved by systematically varying 2013).

stimulation parameters and adding a wider range of test- It is important to mention that we do not intend in

ing materials to study designs using TES. So far, current any way to belittle the effect of cognitive training itself.

B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194 189

Cognitive training alone has been shown to induce a cer- Miniussi et al., 2008). In addition, learning difficulties are

tain amount of change at both performance and neural suitable for TES treatment, as their underlying brain atyp-

levels (e.g., Krafnick et al., 2011; Kucian et al., 2011; icalities involve mainly cortical regions that are accessible

Takeuchi et al., 2011). However, current results indicate to TES (Wagner et al., 2007).

that electrical stimulation can enhance training effects with Recent studies on adults have found that TES modu-

measurable changes in the brain by modulating neuro- lates the stimulated brain region (Holland et al., 2011),

chemicals that are involved in LTP (Fritsch et al., 2010; as well as the network the stimulated region is part of

Stagg et al., 2009) and may therefore prime it for neu- (Keeser et al., 2011; Zheng et al., 2011). Therefore, while

roplasticity. This may subsequently optimize the effect of TES modulates the cortical excitability of the stimulated

the training. This could optimize the cognitive benefits of brain region, the simultaneously administered TES and

training, especially for skills subserved by dysfunctional cognitive training may lead to the strengthening of weak

networks, which otherwise are too weak to unfold the full connections within the deficient network by lowering

learning potential. Since in these cases the brain is subop- the neuronal threshold and repeatedly activating the net-

timally developed at anatomical and/or functional levels work. Since the integration and specialization of neural

(Gilger and Kaplan, 2001), TES could facilitate synaptic circuits throughout development involve the interaction

strengthening in the stimulated neural circuit during and of different brain areas, including their excitatory and

after training, by the mechanisms described earlier (Section inhibitory interconnections (Cohen Kadosh, 2011; Johnson,

2.1). It has been suggested that by facilitating synap- 2011), the potential to modulate the functioning of local,

tic strengthening, the child’s cognitive potential could be as well as global network functioning, is very appealing.

increased (Holt and Mikati, 2011) and may even exceed This means that TES aims to modulate the functioning

the limits that were initially imposed by the learning diffi- of a deficient cortical region but affects the entire cir-

culties. cuit involved in the processing of the task. The selective

Learning difficulties are associated with complex pat- choice of the cognitive training in combination with the

terns of brain atypicality at both functional and structural choice of the cortical region to be stimulated may deter-

levels (e.g., DD: Kucian et al., 2006; Mussolin et al., 2009; mine which cognitive function and which neural circuit

Price et al., 2007; Rykhlevskaia et al., 2009; dyslexia: will be affected.

Stein and Walsh, 1997; Temple et al., 2003; ADHD: Shaw For instance, research in healthy adults and clini-

et al., 2012). Successful cognitive training itself, when cal populations has shown that cognitive training paired

applied during sensitive periods of plasticity, has the poten- with brain-targeted intervention can maximize neuro-

tial to alter or even redirect atypical brain functioning plasticity and thereby significantly improve behavioural

and thereby possibly promote structural reorganization performance (for reviews see Cohen Kadosh, 2013; Holland

(Knudsen, 2004). Unfortunately, extensive training cannot and Crinion, 2012; Jacobson et al., 2012b), including long-

always be provided at the right time. Due to factors such lasting effects (Cohen Kadosh et al., 2010; Reis et al., 2009).

as late identification, training might occur after the end of Longer-lasting effects yet need to be established. Espe-

a sensitive period, yet one would still want to maximize cially for paediatric populations, long-term follow-ups over

the success of cognitive training. Moreover, conventional several years of development will be both necessary and

cognitive training programmes have several limitations. valuable to gain an understanding of long-term TES effects

First, school-based intervention programmes are costly and on the developing brain.

time-consuming (e.g., the annual cost for one-to-one tutor- To summarize, the neuroplasticity induced by TES could

ing in numeracy or literacy is ∼£2500 per child in the UK support and complement the cognitive training effects and

(Gross et al., 2009)). Second, typical training intervention potentially even adapt or redirect the ill-defined develop-

spans several months and adds an additional workload to mental trajectories of underdeveloped brain regions. The

the child’s existing schoolwork, which may increase emo- burden on the individual child, the child’s immediate and

tional and cognitive strains on the child. Third, a lengthy social environment, and the economic burden could all be

intervention programme also adds to the workload of staff mitigated in this way. The potential for enhancing plastic-

involved in the intervention, and may limit the amount ity may also benefit different age groups (e.g., adults) and

of children that receive intervention. The combination of different profiles of cognitive impairments. Currently, this

both financial and training resources is not always avail- is a future perspective and further research needs to estab-

able for each child, and therefore limits the possibilities lish the grounds for such an application in order to make it

for receiving lengthy cognitive training (Rabipour and Raz, safe and effective. Despite the promising potential of TES

2012). to improve cognitive functions, it is also important to con-

These caveats could be circumvented by introducing sider its potential risks and pitfalls in stimulating the child

new ways to directly affect neuroplasticity in the deficient brain.

neural networks, in order to enhance the effect of cognitive

training and lead to similar outcomes in a shorter inter-

5. Potential risks and pitfalls of TES

vention period. Similar motivation has driven the usage

of TES with neurological patients (Holland and Crinion,

Even though there is increasing evidence for the effi-

2012). TES seems sufficiently potent to induce such plastic

cacy of TES in improving cognitive functions, it is important

neural changes and may thereby be likely to improve cogni-

to consider its possible physical and psychological side

tion in the long-term, as it frequently modulates neuronal

effects, especially when applied to children.

excitability in a task-dependent way (Cohen Kadosh, 2013;

190 B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194

6. Physical side effects stimulation in the individual learning difficulties are

unknown and might change with development. Typically

Seizure induction is currently considered the most crit- developing children recruit different brain regions or use

ical and hazardous possible consequence resulting from the same regions but to a different extent and at different

brain stimulation. Researchers must be aware that side time points in development, and apply different cogni-

effects in children might be either qualitatively or quan- tive strategies, than adults (Cohen Kadosh et al., 2012a;

titatively different from those observed in adults, and that Cohen Kadosh, 2011; Jolles and Crone, 2012). During nor-

critical evaluation of pre-existing health conditions in chil- mal development, for instance, arithmetic abilities shift

dren that might impact the effect of TES is essential. It will from recruiting mainly frontal regions at younger ages to

be necessary to ascertain and possibly extend screening relying more on parietal regions later in life (Rivera et al.,

measures and current exclusion criteria used for adults to 2005). The exact time of the shift can hardly be predicted in

exclude participants with a family history of epilepsy or typically developing children and might be even less pre-

other neurological and psychiatric disorders. Even then, dictable in children with atypical development. In addition,

a residual risk of the child unknowingly being prone to the atypically developing brain might respond and adapt

seizure activity will remain. It is also highly important that differently to the stimulation. This complex issue requires

parents and children undergoing TES are well-informed especially careful scientific exploration and attention.

and understand the potential risks and what these might Experimental data is required to assess what time dur-

pose to the child’s health. ing development would benefit the cognitive deficit most

Since the electrical current of TES is kept very low (e.g., and whether certain periods during development should

1–2 mA), the risk of major physical side effects such as tis- even be avoided. In addition, more knowledge on the exact

sue damage is considered unlikely and has not yet been developmental trajectory in learning difficulties is needed,

observed to occur in experimental settings (Brunoni et al., but the current consensus of data can serve as a starting

2012). Some of the few reported minor physical side effects point for TES study designs. In this respect, the synergy

during stimulation involve tingling, itching or a burning between cognitive training, neuroimaging and TES stud-

sensation of the skin under the electrode and in rare cases ies will help acquire knowledge not only about the neural

discomfort, including slight nausea and headaches (Poreisz correlates of cognitive development, but also about the

et al., 2007; Table 1). Most studies, including modelling direct causal relationship between the function of a given

work such as current density magnitude evaluation, have brain area (using TES) and the acquisition of cognitive abil-

thus far included only adults. Since the child central ner- ities. This in turn will have practical implications for both

vous system might respond differently to TES (e.g., due to applied and basic sciences on intervention in atypical brain

smaller distances between the scalp and the brain tissue, development.

or due to differences in the organization of gyri and sulci), Secondly, remote regions may be modulated by the relo-

the potential physical side effects of TES cannot be entirely cation of blood flow and energy supply to the stimulated

anticipated at this point. Currently, there have been only brain area. For instance, haemodynamic changes after TDCS

a limited number of published TES studies involving atyp- were found to be altered in the targeted region (Holland

ically developing children and adolescents (Mattai et al., et al., 2011), but also in more distant brain regions that were

2011; Schneider and Hopp, 2011), which have mostly con- functionally related to the stimulated region (Keeser et al.,

firmed their tolerability for TES. Neither study reported any 2011; Zheng et al., 2011). The stimulation of a particular

significant physical side effects during or after TES treat- brain area (e.g., Broca’s area) along with the associated cog-

ment. nitive enhancement (e.g., language) might thereby reduce

The current gap in paediatric research can most likely the cognitive functions of other domains that are subserved

be explained by the lack of experience and consequen- by proximal brain regions (e.g., cognitive control in the dor-

tial systematic avoidance of non-invasive brain stimulation solateral prefrontal cortex (Brass et al., 2005)). A recent

techniques in children for two reasons: (1) researchers in study has shown that this scenario is possible. In this study,

developmental cognitive neuroscience might be unaware TES to the posterior parietal cortices improved artificial

of TES and of the current findings of improving cognitive number learning but impaired automaticity on the learn-

learning and training in adults using TES; (2) concerns of ing task, whereas TES to the dorsolateral prefrontal cortices

causing irreversible changes in the developing brain might impaired the learning but improved automaticity of artifi-

deter scientists, as the current lack of paediatric research in cial number learning (Iuculano and Cohen Kadosh, 2013).

this domain inflicts a significant amount of responsibility Especially during brain development, the balance between

on the researcher. different brain areas might be more easily disturbed by

changes induced by TES and training.

7. Cognitive side effects Effects of TES on the untrained cognitive functions need

to be examined in addition to the specific target function,

While cognitive side effects of TES have hardly been to ascertain that enhancing one cognitive domain will not

examined at this point, clinicians and researchers should be impair another. Therefore, it is important to assess a larger

aware of potential risks and the relative lack of systematic range of functions (e.g., attention, working memory, execu-

research in this field when applying the method. tive functions, social skills) rather than merely the domain

Firstly, the developing brain represents a ‘flexible of interest. This is not only of interest immediately after

target’ and due to continuous plastic changes in both the training but also for follow-up tests that assess long-

brain structure and function, the ideal brain regions for term cognitive effects. It is therefore highly important for

B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194 191

the scientific community to critically assess and monitor Moreover, one of the misconceptions about TES is that

long-term effects of TES. it improves cognitive performance by itself. In fact, the

We would like to stress that we do not regard TES as a opposite is the case: it is essential to combine TES with

potential panacea that can solve all possible cortical defi- the appropriate cognitive training, and to apply it to the

ciencies by enhancing neuroplasticity in general. Instead correct brain region, in order to use its full potential to

we argue that it is important to examine whether TES improve cognitive performance (Reis and Fritsch, 2011).

can be a successful support for cognitive training in chil- Careful education and communication with the families

dren with atypical cortical functioning. This in turn, will and the child’s general practitioner prior to the treatment

add value to current interventions, even potentially for is essential for research experiments. It is important that

cognitive functions and deficits that have not yet been con- children eligible for TES studies will understand what the

sidered with this method. Even if it proves successful in procedure they are undergoing entails, and what they give

one form of atypical brain development, it might show their assent to.

either negative, positive or no effects in other domains.

The complex interactions of affected brain circuits are too 9. Conclusion

diverse across disabilities to generalize result interpreta-

tions from one to the other. The success of TES in each Research from various laboratories worldwide, using

individual developmental disability or disorder is thereby a range of parameters and involving different cognitive

by no means guaranteed but needs to be empirically estab- domains, has shown that in many cases, TES coupled with

lished. cognitive training can improve cognitive training effects in

While we acknowledge the potential risks of TES, both healthy and clinical adult populations. This suggests

neglecting it as a possible method to improve the cogni- that TES may be a useful aid in promoting cognitive train-

tive learning and subsequently the lives of large numbers of ing effects where there are atypicalities in the brain that

children and adults, might be considered as an ethical fail- are otherwise not optimally addressed by cognitive train-

ure (Cohen Kadosh et al., 2012b). We suggest that the first ing alone. However, the step from this adult research to

stage of research should involve small sample sizes of chil- child populations and atypical development still needs to

dren with learning difficulties that should be monitored for be made. We suggest that with several precautions taken,

behavioural changes and improvements post-treatment, TES can serve as a successful addition to cognitive train-

before conducting studies that will involve larger samples. ing for learning difficulties. Such precautions include the

This in turn will assist in assessing the potential of TES as an careful investigation of both short- and long-term effects of

intervention method in children with learning difficulties TES on the atypically developing brain, as well as the intro-

in clinical settings. duction of guidelines and restrictions for the use of TES in

In order to protect paediatric participants from any paediatrics for researchers and licensed professionals only.

potential harm that could be caused by TES in research, Current findings need to be viewed from a critical per-

minimal risk standards need to be established by review spective and research designs in the future have to be

boards. The risk exposure should be based on weighing adjusted and refined in order to provide consistent and sat-

possible negative consequences against the benefit for the isfactory outcomes with relevance for real-life outcomes.

individual child (Wendler and Varma, 2006). Closing the current gap in developmental cognitive neuro-

science in respect to TES, along with its potential effects and

8. Guidelines possible risks, will allow us to assess whether optimizing

cognitive training of individuals with atypical brain devel-

Cohen Kadosh and colleagues discuss the subject of opment using TES is achievable. This will thereby help to

ethics in child brain stimulation in more detail (Cohen devise new ways to reduce the severe consequences of cog-

Kadosh et al., 2012b) and offer several potential solutions to nitive disability on the individuals’ lives, their families, and

issues arising from bringing TES into clinical settings. For society.

instance, the use of TES machines needs to be restricted

to prevent premature use by unqualified or inadequately Conflict of interest statement

trained individuals, including parents. Overly concerned

or motivated parents might be tempted to purchase a sti- R.C.K. is a Wellcome Trust Career Development Fellow

mulator, which is nowadays publicly available online, in (0883781). R.C.K. filed a patent for an apparatus for improv-

order to train their children at home without the required ing and/or maintaining numerical ability.

knowledge about the necessary cognitive training, or the

parameters and sites for stimulation and thereby cause Acknowledgements

no effects, or even physical and cognitive impairments. In

order to avoid such premature use, we suggest that training We would like to thank the Wellcome Trust and the

needs to be required for practitioners, in order to restrict Economic and Social Research Council (ESRC) for their kind

the use of TES to professionals. This is not yet the case, support, as well as the Deutscher Akademischer Austausch-

such that the current use of TES does not follow any formal dienst (DAAD) and the Studienstiftung des Deutschen

regulations. If TES gains popularity in the general society, Volkes. We also thank Dr Devin Terhune and Jackie Thomp-

it might also be advisable to publicly warn and educate son for their support in correcting the manuscript and

people of the danger of using TES without the required Dr Ann Dowker for her advice on child development and

technical knowledge and awareness of its risks. mathematical difficulties.

192 B. Krause, R. Cohen Kadosh / Developmental Cognitive Neuroscience 6 (2013) 176–194

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