Transcranial direct current stimulation for motor recovery of upper limb function after stroke

Accepted Manuscript

Title: Transcranial direct current stimulation for motorrecovery of upper limb function after stroke

Author: Jitka Podubecka Kathrin Bosl Sandra RothhardtGeert Verheyden Dennis Alexander Nowak

PII: S0149-7634(14)00187-0DOI: http://dx.doi.org/doi:10.1016/j.neubiorev.2014.07.022Reference: NBR 1999

To appear in:

Received date: 10-2-2014Revised date: 25-7-2014Accepted date: 28-7-2014

Please cite this article as: Podubecka, J., Bosl, K., Rothhardt, S., Verheyden,G., Nowak, D.A.,Transcranial direct current stimulation for motor recovery ofupper limb function after stroke, Neuroscience and Biobehavioral Reviews (2014),http://dx.doi.org/10.1016/j.neubiorev.2014.07.022

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http://dx.doi.org/doi:10.1016/j.neubiorev.2014.07.022

http://dx.doi.org/10.1016/j.neubiorev.2014.07.022

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Transcranial direct current stimulation for motor recovery of upper

limb function after stroke

1Jitka Podubecká, 1Kathrin Bösl, 1Sandra Rothhardt, 2Geert Verheyden, 1,3Dennis Alexander

Nowak

1Neurologische Fachklinik Kipfenberg, Kipfenberg, Germany

2Department of Rehabilitation Sciences, KU Leuven, Belgium

3Department of Neurology, University Hospital, Philipps-University, Marburg, Germany

Jitka Lüdemann-Podubecká

Klinik Kipfenberg

Neurologische Fachklinik

Kindinger Strasse 13

D-85110 Kipfenberg

Tel.: 0049 (0)8465-175-66131

Fax: 0049 (0)8465-175-184

E-mail: [email protected]

Abstract: Backround: Changes in neural processing after stroke have been postulated to impede recovery from stroke. Transcranial direct current stimulation has the potential to alter cortico‐spinal excitability and thereby might be beneficial in stroke recovery. Methods: We review the pertinent literature prior to 30/09/2013 on transcranial direct current stimulation in promoting motor recovery of the affected upper limb after stroke. Results: We found overall 23 trials (they included 523 participants). All stimulation protocols pride on interhemispheric imbalance model. In a comparative approach, methodology and effectiveness of (a) facilitation of the affected hemisphere, (b) inhibition of the unaffected hemisphere and (c) combined application of transcranial direct current stimulation over the affected and unaffected hemispheres to treat impaired hand function after stroke are presented. Conclusions: Transcranial direct current stimulation is associated with improvement of the affected upper limb after stroke, but current evidence does not support its routine use.

Keywords: transcranial direct current stimulation, stroke, motor recovery, upper limb

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Introduction

Stroke is the leading cause of permanent disability in Europe and the United States

(Kolominsky-Rabas et al., 2001; Taylor et al., 1996). More than 50% of stroke victims retain

severe neurological impairments, most often those affecting motor function. Among these

patients, about 80% will retain some grasping deficits linked to upper limb impairments

(Jørgensen et al., 1995a, 1995b).

The better understanding of the stroke-induced remodelling of neural processing following

stroke have contributed to the development of novel targeted therapies that are thought to

promote neuroplasticity, among those non-invasive methods, such as repetitive transcranial

magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) (Nowak et al.,

2010; Madhavan and Shah, 2012). TDCS and rTMS change cortico-spinal excitability for

several minutes outlasting the stimulation period (Lang and Siebner, 2007; Nitsche and

Paulus, 2007), induce remote changes within the cortical motor system and thereby may

improve motor function of the affected upper limb after stroke.

In the past few years, there has been a rapid increase in the application of non-invasive brain

stimulation to study brain-behaviour relations and to enhance the effectiveness of neuro-

rehabilitation. This paper summarizes the current knowledge of the effectiveness of tDCS to

enhance recovery of motor function of the affected upper limb after stroke.

Neural plasticity following stroke

Focal brain ischemia releases a complex cascade of metabolic and cytotoxic reactions causing

a loss of functional and structural integrity of neural tissue (Schallert et al., 2000) often

accompanied by typical changes in behaviour. Neuroplasticity is the ability of the brain to

adjust its functional capacities to novel situations. Compensation for damage of neural tissue

proceeds in effect by reorganizing and forming new connections between intact neurons

causing alterations of movement-related neural activation within peri-lesional and more

distant brain areas of both the ipsi- and contralesional hemisphere (Loubinoux et al., 2003).

“Positive” plasticity means modulation within the remaining intact motor network to optimize

neural resources for recovery of function. But one important finding is the notion that

plasticity is not always adaptive:

Several studies described a bilateral neural activation within motor areas of both hemispheres

during movements of the affected hand after stroke which cannot be found in healthy subjects

or when patients move the unaffected hand. E.g. one of the first longitudinal studies in

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recovering stroke patients compared fMRI motor activation patterns obtained in the first days

after stroke with those acquired 3 to 6 months post-stroke and described a stronger

bilateralization of neural activity in sensorimotor areas during the acute phase of stroke,

which returned to a more physiological, lateralized activation pattern 3 to 6 months post-

stroke (Marshall et al., 2000).

Neuroimaging analyses (PET, fMRI) of stroke subjects have noted enhanced task-related

neural activation in the contralesional primary motor cortex (M1), contralesional premotor

cortex, ipsilesional cerebellum, bilateral supplementary motor area and parietal cortex for

movements of the affected hand (Grefkes and Ward, 2014; Nowak et al., 2010; Rehme et al.,

2012). Importantly, enhanced recruiting of motor and non-motor areas in the unaffected

hemisphere was often associated with poor motor outcome of the affected hand: Stroke

victims with good functional outcome exhibited more lateralized neural activation within the

ipsilesional hemisphere for movements of the affected hand, while patients whose motor

deficit remained more severe recruited motor areas in both the ipsi- and contralesional

hemispheres (Grefkes and Ward, 2014; Nowak et al., 2010; Rehme et al., 2012).

These observations have helped the formulation of the interhemispheric imbalance model,

which assigns the increased neural activation of the non-lesioned hemisphere unambiguously,

playing a negative role on motor recovery of the affected hand. This model describes the brain

remodelling changes following stroke as “disruption of the balance” between the lesioned and

non-lesioned hemisphere (this phenomen is likely to be related to interhemispheric inhibition

between motor areas exerted via transcallosal connections) with the “shift balance” towards

the non-lesioned hemisphere being detrimental for the lesioned hemisphere (Nowak et al.,

2009, 2010). The increased activity within motor areas in the non-lesioned hemisphere and

the inhibitory influence towards the motor areas of the lesioned hemisphere affect negatively

the recovery of the affected upper limb.

Recent studies have questioned the general validity of the interhemispheric imbalance model.

The key findings from neuroimaging studies suggest, that the role of the contralesional motor

areas for recovery of motor function depends on several various factors such time since

stroke, lesion location or dimension of motor deficit (Grefkes and Ward, 2014; Rehme et al.,

2012): E.g. one fMRI study shows no significant difference of motor-related neural activity

between patients with mild motor impairments and healthy controls. In contrast, patients with

initially severe motor deficits featured a general reduction of motor-related neural activity in

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the first 1 to 3 days after stroke, which in the ensuing 10 days gradually increased in both

hemispheres. Increases in neural activity correlated with better motor recovery (Rehme et al.,

2011). Present data illustrate inter-individual differences in the evolution of neural activity

changes after stroke, which on the severity of the motor deficit and are probably linked to

inter-individual differences in the role of contralesional motor areas for motor recovery. The

increased neural activity within contralesional motor areas may have a supportive role on

motor recovery in patients with a severe deficit of the affected hand (at least during some

period since stroke). This does not apply to patients with a mild motor deficit.

Collectively, all these data described the relationship between localization of neural activity

and a dimension of motor recovery after stroke. Additionally, functional neuroimaging allows

us to compute how activity in one region is releated to activity in another region. These

relations are referred to as “functional” and “effective” connectivity (Grefkes and Ward,

2014; Grefkes and Fink, 2014).

Functional connectivity refers to a correlation of the neural activation between two (or more)

brain regions, without direction or causal interaction and can be probed in absence of a

structured task (resting-state) using fMRI. The recovery from motor deficits is typically

associated with a steady increase of resting-state connectivity, particularly between the

ipsilesional M1 and contralesional areas (Grefkes and Fink, 2014). Numerous studies showed

also reduced functional connectivity between ipsilesional M1 and contralesional M1, which

was correlated with the amount of motor impairment (Carter et al., 2012; Park et al., 2011;

Wang et al., 2010). Moreover, it was found that the contralesional premotor and posterior

parietal cortices have reduced functional connectivity with the ispilesional M1 (Wang et al.,

2010) whereas and that stronger functional connectivity between ipsiläsional M1 and other

brain areas in the early subacute phase post stroke is associated with a better motor recovery 6

months later (Park et al., 2011). These findings certify the association between disruption of

the physiological relationship between both hemispheres and an unfavourable motor outcome

of the affected upper limb, according to task-related neuroimaging studies (Grefkes and Ward,

2014; Nowak et al., 2010; Rehme et al., 2012). Additional, these findings illustrate a key-role

of functional connectivity of ipsilesional M1 with other brain areas (especially with

contralesional M1) for motor recovery after stroke.

The effective connectivity describes the influence that one region exerts onto the activity of

another and can be probed either by using of fMRI (during a voluntary motor task) or by

transcranial magnetic stimulation (TMS) paradigms. Dynamic causal modeling applied to

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fMRI data obtained from healthy individuals suggests that the movements of the hand lead to

an increase of excitatory effects from premotor areas exerted on the contralateral M1 activity,

whereas ipsilateral M1 activity is suppressed (Grefkes et al. 2008). In patients with stroke the

excitatory influence of the lesioned hemisphere is reduced (Grefkes and Fink, 2014).

Importantly, some patients show an additional negative influence exerted from the

contralesional M1 on the ipsilesional M1, which correlates with the degree of motor

impairment (Grefkes et al. 2008). The more impaired a subject is, the more the contralesional

M1 exerts an inhibitory influence on the ipsilesional M1, which further reduces the motor

output of the lesioned hemisphere beyond that which could be due only to the anatomical

damage (Grefkes and Fink, 2014).

Interestingly, the connectivity between motor areas within one hemisphere, as well as the

connectivity between both hemispheres vary during different stages of stroke (Grefkes and

Fink, 2014). A longitudinal study in acute stroke subjects showed reduced positive coupling

of ipsilesional SMA and dPMC with ipsilesional M1. Coupling parameters among these areas

increased with recovery and predicted a better outcome. Likewise, negative influences from

ipsilesional areas to contralesional M1 were attenuated. In subacute stroke, contralesional M1

exerted a positive influence on ipsilesional M1. Negative influences from ipsilesional areas on

contralesional M1 subsequently normalized, but patients with poorer outcome in the chronic

stage now showed enhanced negative coupling from contralesional upon ipsilesional M1

(Rehme et al. 2011). Another study showed a reduced interhemispheric inhibition in severly

impaired chronic stroke patients, which correlated strongly with reduced ipsilesional motor

cortex excitability (Volz et al. 2014).

Pertinent data indicate that the plastic changes in neural processing and their impact on motor

recovery after stroke are more complex than the simple interhemispheric imbalance model

may suggest. In summary, the best part of these studies favours the hypothesis that the poor

motor function and/ or motor recovery is associated with a disruption of the physiological

balance between motor areas of both hemispheres as well as with reduced positive coupling

between motor areas of ipsilesional hemisphere.

Transcranial direct current stimulation and modulation of neural plasticity for motor

recovery after stroke

The increasing interest in the application of tDSC in stroke rehabilitation is based on the fact

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that tDCS modulates cortical excitability thereby and allows direct interaction with potential

maladaptive neural plasticity. TDCS consists of applying a low-intensity current between two

electrodes (anode and cathode) placed on the scalp. Depending on electrode polarity placed

over M1 cortical excitability of M1 will be increased (anodal stimulation) or decreased

(cathodal stimulation). The amount and the duration of the changes in cortical excitability

depend on current density and stimulation duration (Nitsche and Paulus, 2007). To induce

changes in motor cortex excitability that outlast the stimulation period current intensities of at

least 0.6 mA and stimulation durations of at least 3 min. are needed. TDCS stimulation with a

current intensity of 1 mA and a stimulation duration of 5 or 7 minutes induce short-term

changes of cortical excitability that last for 10-15 minutes the stimulation itself. For long-term

changes in motor cortex excitability (one hour or more) a current intensity of 1 mA should be

administered for at least 11 minutes (Nitsche and Paulus, 2000).

A stable long-term effect of tDCS is relevant for its application in rehabilitation. Numerous

studies demonstrated stabilizing of long-term behavioral effect of tDCS. However, any

electrophysiologic effect of these stimulation-protocols they are missing. Therefore, studies to

explore the optimal stimulation-protocol and intersession interval for stabilizing of long-term

electropysiologic effect of tDCS are needed (Nitsche et al., 2008).

The current application of tDCS in rehabilitation of upper limb dysfunction after stroke is

mainly based on the concept of interhemispheric imbalance (Nowak et al., 2009, 2010).

Published studies until today illustrate three ways of neuromodulation within this concept: 1.

increase cortical excitability within the ipsilesional M1 (anodal tDCS to ipsilesional M1), 2.

decrease cortical excitability of contralesional M1 (cathodal tDCS to contralesional M1) or 3.

“bihemispheric stimulation” with the anode placed over ipsilesional M1 and the cathode over

contralesional M1.

In the pertinent literature no relevant side effects of currently used tDCS protocols have been

described. However, knowledge about the safe limits of duration and intensity of tDCS is still

limited (Nitsche et al., 2008). For safety reasons most researchers do not apply tDCS on

humans with implanted brain devices (e.g. deep brain stimulation) that may interfere with the

induced current flow. Also history of epilepsy, or pregnancy are widely held to be a

contraindication for tDCS application.

Methods The PubMed research database was reviewed for relevant articles upon the use of tDCS for

rehabilitation of impaired hand function after stroke up to 30/09/2013. The terms “transcranial

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direct current stimulation” and “stroke” were used. Studies were selected if they met the

following inclusion criteria: 1. study on humans, 2. diagnosis of stroke, 3. tDCS used as an

intervention, 4. motor assessment of the affected upper limb before and after the intervention,

5. Placebo-controlled study-design or study design with at least two experimental groups, 6.

three randomized patients at least.

Results 23 studies were identified that corresponded with the inclusion criteria. These studies included

a total of 523 stroke subjects. The studies showed a large variability of the study population,

the time from stroke when the intervention was performed, the number of the tDCS sessions,

the type of motor assessment performed and the methodological quality.

For sake of simplicity, studies were sub-categorized according to the stimulation protocol: 1.

increase of excitability of motor areas within the ipsilesional hemisphere, 2. decrease of

excitability of motor areas within the contralesional hemisphere, 3. decrease of excitability of

motor areas within the contralesional hemisphere compared to increase excitability motor

areas within the ipsilesional hemisphere, 4. decrease of excitability of motor areas within the

contralesional hemisphere and simultaneous increase of excitability of motor areas within the

ipsilesional hemisphere (bilateral stimulation). Tables 1,2,3, and 4 summarize studies sub-

categorized in each of these categories. The effectiveness of tDCS was calculated as the

percentage change of the outcome measure after the intervention in relation to the baseline

measurement.

Increase of excitability motor areas within the ipsilesional hemisphere

6 placebo-controlled human studies (n=91) investigated the effect of anodal tDCS over

ipsilesional M1 on motor function of the affected upper limb after stroke (Ang et al., 2012;

Hummel et al., 2005, 2006; Kim et al., 2008; Madhavan et al., 2011; Rossi et al., 2013).

Table 1 summarizes these studies.

INSERT TABLE 1 ABOUT HERE

Stimulation-parameters: All studies placed the anode over the ipsilesional M1 and the

cathode over the contralesional supraorbital region (Figure 1). Most of the studies applied

anodal tDCS at an intensity of 1mA tDCS over 20 minutes (Ang et al., 2012; Hummel et al.,

2005, 2006; Kim et al., 2008). Only two studies applied another stimulation protocols: 0,5

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mA over 15 minutes (Madhavan et al., 2011) and 2 mA over 20 minutes (Rossi et al., 2013).

Relevant side effects were not reported.

INSERT FIGURE 1 ABOUT HERE

Study-design: Most of the studies applied an crossover design with 2-3 experimental

treatments (any treatment 1 session) (Hummel et al., 2005, 2006; Kim et al., 2008; Madhavan

et al., 2011). Two studies investigated the effectiveness of tDCS applied over 5 (Rossi et al.,

2013) and 10 (Ang et al., 2012) days within a study-design including two parallel-groups

(experimental- and control-group). Only two studies included a follow-up test after 1 hour

(Kim et al., 2008) and 3 months (Rossi et al., 2013).

Adjunct therapies: One trial instructed participants to perform tracking movements with the

affected hand during the tDCS-session (Madhavan et al., 2011).

Stroke-aetiology: The majority of studies enrolled patients with ischemic stroke (Hummel et

al., 2005, 2006; Madhavan et al., 2011; Rossi et al. 2013). One study (Kim et al., 2008)

included patients with ischemic and haemorrhagic stroke.

Lesion location: Most studies included patients with subcortical and cortical lesion (Kim et

al., 2008; Madhavan et al., 2011; Rossi et al. 2013). Only two studies (Hummel et al., 2005,

2006) included only patients with a subcortical lesion.

Time after stroke: One study included patients with acute stroke (Rossi et al. 2013). The

remaining studies included patients with chronic stroke (Hummel et al., 2005, 2006; Kim et

al., 2008; Madhavan et al., 2011), and one of them also included patients with subacute stroke

(Kim et al., 2008).

Severity of upper limb impairment: All studies tested the efficiency of tDCS in patients

with moderate to mild sensory-motor impairment of the affected upper limb.

Missing data: One article (Ang et al., 2012) did not specify the aetiology of stroke, lesion

location, time from stroke and degree of impairment of the affected upper limb.

Effectiveness: 5 studies (n=41) reported a positive effect of anodal tDCS on motor function

of the affected upper limb after stroke (Ang et al., 2012; Hummel et al., 2005, 2006; Kim et

al., 2008; Madhavan et al., 2011). All results, but one (Ang et al., 2012), were statistically

significant. One study (Kim et al., 2008) showed a significant lasting tDCS-effect over a

follow-up of 60 minutes. All studies reporting a positive effect of anodal tDCS over

ipsilesional M1 tested chronic stroke patients.

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Only one study (n=50) reported a non-significant negative effect of anodal tDCS (Rossi et al.

2013). The Follow up of this study shows no lasting effect over 3 months.

The effect size of functional improvement was highly variable (percentage improvement

ranging between 19%-67%). On average the sensory-motor function of the affected hand

improved by 25% from baseline.

Summary: The best evidence, for the positive effect of the anodal tDCS on motor recovery of

the affected upper limb after stroke, exists currently for patients with a chronic stroke. There

are no data for patients within subacute stroke. For patients with acute stroke exists currently

only evidence for the negative effect of the anodal tDCS on motor recovery of the affected

hand.

Future studies should investigate the effect of anodal tDCS over ipsilesional M1 applied over

several days in combination with motor trainings, and how long the effect lasts after the

intervention. It is still unclear if anodal tDCS over ipsilesional M1 is effective to improve

hand function in subacute stroke. It is still unclear if anodal tDCS over ipsilesional M1 is

effective to improve hand function in haemorrhagic stroke.

Decrease of excitability of motor areas within the contralesional hemisphere

Three placebo-controlled studies (n=116) tested if cathodal tDCS over contralesional M1

improved motor function of the affecter upper limb after stroke (Nair et al., 2011; Wu et al.,

2013; Zimerman et al., 2012). Table 2 summarizes these studies.


Stimulation-parameters: The cathode was placed over the contralesional M1 in all studies

(Figure 2). In two studies the anode was placed over the contralesional supraorbital region

(Nair et al., 2011; Zimerman et al., 2012), in one study (Wu et al., 2013) the anode was placed

over the unaffected shoulder. Two studies tested the effect of 1mA tDCS applied over 20

(Zimerman et al., 2012) and 30 (Nair et al., 2011) minutes. One study tested tDCS at an

intensity of 1.2mA over 20 minutes (Wu et al., 2013). Relevant side effects were not reported.


Study-design: One trial applied a crossover-design with one session of cathodal tDCS and

one session of placebo condition (Zimerman et al., 2012). Two studies probed the

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effectiveness of serial sessions of cathodal tDCS over 5 days (Nair et al., 2011) and 4 weeks

(Wu et al., 2013) on a study-design with two parallel-groups (cathodal tDCS, sham tDCS).

All studies included a follow-up investigation over 1 day to 4 weeks.

Adjunct therapies: Two studies integrated an occupation therapy (Nair et al., 2011) or motor

training (Zimerman et al., 2012) for the affected hand during the tDCS-session.

Stroke-aetiology: Two studies (Nair et al., 2011; Zimerman et al., 2012) enrolled only

patients with an ischemic insult, one study (n=90) included also patients with haemorrhagic

stroke (Wu et al., 2013).

Lesion location: One study selected only patients with a subcortical lesion (Zimerman et al.,

2012), one study included patients with cortical and subcortical lesions (Nair et al., 2011).

Time after stroke: All trials included primarily patients with chronic stroke.

Severity of upper limb impairment: One study investigated patients with a moderate to mild

impairment of the affected upper limb (Zimerman et al., 2012), two studies tested patients

with a moderate to severe upper limb impairment (Nair et al., 2011; Wu et al., 2013).

Missing data: One study did not specify lesion location (Wu et al., 2013).

Effectiveness: Two studies (Wu et al., 2013; Zimerman et al., 2012) reported a significant

positive effect, one study a positive effect without statistical significance (Nair et al., 2011) of

cathodal tDCS over contralesional M1 on upper limb motor recovery after stroke. Follow-up

shows a significant preservation of the tDCS-effect one day to 4 weeks after the intervention.

The effect size varied between 15%-58% percentage improvement of hand function (average

improvement in relation to baseline: 45%). These results inferred a higher efficiency by

cathodal tDCS, than by anodal tDCS.

Summary: Cathodal tDCS over the contralesional M1 is beneficial for motor recovery of the

moderately to severely impaired upper limb in chronic stroke. Future studies should

investigate the effect in acute and subacute stroke.

Comparison of decrease of excitability of motor areas within the contralesional

hemisphere and increase of excitability of motor areas within the ipsilesional

hemisphere

7 trials (n=204) compared the effectiveness of anodal tDCS over ipsilesional M1 with

cathodal tDCS over contralesional M1 to improve motor recovery of the affected hand after

stroke (Boggio et al., 2007; Fregni et al., 2005; Hesse et al., 2011; Khedr et al., 2013; Kim et

al., 2010; Ochi et al., 2013; Stagg et al., 2012). All but one study (Ochi et al., 2013) were

placebo-controlled.

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Table 3 summarizes these studies.

INCLUDE TABLE 3 ABOUT HERE

Stimulation-parameters: All studies placed the active electrode over the M1 (anodal tDCS

over the ipsiläsional M1/ cathodal tDCS over the contralesional M1) and the reference

electrode over the contralateral supraorbital area. Four studies used a stimulation intensity of

1mA over 10-20 minutes (Boggio et al., 2007; Fregni et al., 2005; Ochi et al., 2013; Stagg et

al., 2012), three studies used a stimulation intensity of 2mA over 20-25 minutes (Hesse et al.,

2011; Khedr et al., 2013; Kim et al., 2010). Significant side effects were not described.

Study-design: With the exception of one study (Ochi et al., 2013) with 2 experimental-groups

(anodal tDCS, cathodal tDCS), three experimental-treatments were performed (anodal tDCS,

cathodal tDCS, sham tDCS) (Boggio et al., 2007; Fregni et al., 2005; Hesse et al., 2011;

Khedr et al., 2013; Kim et al., 2010; Stagg et al., 2012). 4 studies investigated the efficiency

of tDSC on a crossover-design with a treatment over one day to 4 weeks (Boggio et al., 2007;

Fregni et al., 2005; Ochi et al., 2013; Stagg et al., 2012), 3 studies used a study-design with 3

parallel-groups (Hesse et al., 2011; Khedr et al., 2013; Kim et al., 2010) and a treatment over

6 days to 6 weeks. 3 studies implemented a follow-up investigation after 3 to 6 months (Hesse

et al., 2011; Khedr et al., 2013; Kim et al., 2010).

Adjunct therapies: Two studies combined the tDCS-stimulation sessions with robot-assisted

training for the affected upper limb (Hesse et al., 2011; Ochi et al., 2013).

Stroke-aetiology: Most of the studies enrolled patients with ischemic stroke (Hesse et al.,

2011; Khedr et al., 2013; Kim et al., 2010; Stagg et al., 2012). One study (Ochi et al., 2013)

included both ischemic and haemorrhagic stroke aetiologies.

Lesion location: All studies included patients with subcortical and cortical lesions.

Time after stroke: 4 trials tested patients with a chronic stroke (Boggio et al., 2007; Fregni et

al., 2005; Ochi et al., 2013; Stagg et al., 2012), 3 trials patients with an acute stroke (Hesse et

al., 2011; Khedr et al., 2013; Kim et al., 2010).

Severity of upper limb impairment: Two studies (Hesse et al., 2011; Ochi et al., 2013)

tested patients with severe and moderate hand dysfunction. Five studies (Boggio et al., 2007;

Fregni et al., 2005; Khedr et al., 2013; Kim et al., 2010; Stagg et al., 2012) tested the

efficiency of tDCS in patients with moderate to mild impairment of one upper limb.

Missing data: Two studies did not specify stroke-aetiology and lesion location (Boggio et al.,

2007; Fregni et al., 2005).

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Effectiveness: One study (n=96) reported a positive effect (no significant) only for cathodal

tDCS (Hesse et al., 2011). All others placebo-controlled trials (n=95) reported a positive

effect for both cathodal tDCS and anodal tDCS (Boggio et al., 2007; Fregni et al., 2005;

Khedr et al., 2013; Kim et al., 2010; Ochi et al., 2013; Stagg et al., 2012). Two trials (n=58)

of them did not report statistical significances for either intervention (Khedr et al., 2013; Kim

et al., 2010). Both these studies included patients with acute stroke as well as the study

without a positive effect by anodal tDCS (Hesse et al., 2011).

Follow-up measures (Hesse et al., 2011; Khedr et al., 2013; Kim et al., 2010) showed a

preservation of the effect of tDCS over three to six months after intervention.

Effect size of tDCS showed a high variability: Anodal tDCS varied between 46%-78% (on

average 15%) improvement of hand function in relation to baseline, cathodal varied between

5-103% (on average 40%) improvement of hand function in relation to baseline, without

apparent differences between different assessments.

Summary: In a comparative approach cathodal tDCS shows a greater efficiency upon

improvement of hand function in comparison to anodal tDCS.

Decrease of excitability of motor areas within the contralesional hemisphere and

simultaneous increase of excitability within motor areas on the ipsilesional hemisphere

(bilateral tDCS stimulation)

7 trials (n=112) investigated the efficiency of bilateral tDCS for motor recovery of the upper

limb after stroke (Bolognini et al., 2011; Fusco et al., 2013; Lefebvre et al., 2012; Lindenberg

et al., 2010; Mahmoudi et al., 2011; O'Shea et al., 2014; Takeuchi et al., 2012). All studies but

one (Takeuchi et al., 2012) were placebo-controlled. Table 4 summarizes these studies.


Stimulation-parameters: With the exception of one study (which combined faciliatory tDCS

and inhibitory rTMS) (Takeuchi et al., 2012)), all studies applied bilateral stimulation with the

anode placed over the ipsilesional M1 and the cathode placed over the contralesional M1

(Figure 3). 5 studies used a stimulation intensity of 1mA (over 20-30 minutes) (Lefebvre et

al., 2012; Lindenberg et al., 2010; Mahmoudi et al., 2011; O'Shea et al., 2014; Takeuchi et al.,

2012). One study used a stimulation intensity of 1.5mA (over 15 minutes) (Fusco et al., 2013)

and one study 2mA (over 40 minutes) (Bolognini et al., 2011). Negative side effects of the

bilateral stimulation were not described.

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Study-design: 3 placebo-controlled trials tested the efficiency of bilateral tDCS within a

study-design with two experimental conditions (bilateral tDCS and sham tDCS) (Bolognini et

al., 2011; Lefebvre et al., 2012; Lindenberg et al., 2010). 3 placebo-controlled trials used a

study-design with 4-5 experimental conditions (anodal tDCS, anodal tDCS, bilateral tDCS,

sham tDCS) (Fusco et al., 2013; Mahmoudi et al., 2011; Takeuchi et al., 2012). One trial

(without placebo-control) compared the efficiency of bilateral tDCS, cathodal tDCS and

anodal tDCS (O'Shea et al., 2014).

4 trials tested the efficiency of bilateral tDCS on a crossover-design with 2-5 experimental

conditions and stimulation sessions over 1-2 days (Fusco et al., 2013; Lefebvre et al., 2012;

Mahmoudi et al., 2011; O'Shea et al., 2014). 3 trials included 2-3 experimental groups with a

treatment over 1-10 days (Bolognini et al., 2011; Lindenberg et al., 2010; Takeuchi et al.,

2012). 4 trials included a follow-up investigation after 1-4 weeks (Bolognini et al., 2011;

Lefebvre et al., 2012; Lindenberg et al., 2010; Takeuchi et al., 2012).

Adjunct therapies: Two studies combined tDCS-stimulation with constrained induced

movement therapy (Bolognini et al., 2011) or motor training for the affected hand (Lefebvre

et al., 2012).

Stroke-aetiology: 2 trials tested only patients with an ischemic insult (Lindenberg et al.,

2010; Mahmoudi et al., 2011), 4 trials included also patients with haemorrhagic stroke

(Bolognini et al., 2011; Fusco et al., 2013; Lefebvre et al., 2012; Takeuchi et al., 2012).

Lesion location: 4 trials included patients with subcortical and those with a cortical lesion

(Bolognini et al., 2011; Fusco et al., 2013; Lefebvre et al., 2012; Takeuchi et al., 2012), 2

trials included only patients with subcortical lesions (Lindenberg et al., 2010; Mahmoudi et

al., 2011).

Time after stroke: Most of the trials included patients with a chronic stroke (Bolognini et al.,

2011; Lefebvre et al., 2012; Lindenberg et al., 2010; Takeuchi et al., 2012), one trial included

patients with subacute and chronic stroke (Mahmoudi et al., 2011) and one trial included

patients with subacute and acute stroke (Fusco et al., 2013).

Severity of upper limb impairment: All trials included patients with a moderate to mild

impairment of one upper limb.

Missing data: One article did not specify stroke-aetiology, lesion location and time after

stroke (O'Shea et al., 2014).

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Effectivness: All placebo-controlled trials (n=102) reported a positive effect of bilateral tDCS

on motor recovery of the affected upper limb after stroke (Bolognini et al., 2011; Fusco et al.,

2013; Lefebvre et al., 2012; Lindenberg et al., 2010; Mahmoudi et al., 2011; O'Shea et al.,

2014), but two of them (n=29) were without statistical significance (Fusco et al., 2013;

Lindenberg et al., 2010).

Follow-up tests (Bolognini et al., 2011; Lefebvre et al., 2012; Lindenberg et al., 2010;

Takeuchi et al., 2012) showed a lasting effect of tDCS over six days to four weeks after the

intervention.

There was no significant difference between bilateral, anodal or cathodal tDCS on motor

recovery of the affected hand after stroke.

The effect size showed a high variability: bilateral tDCS improved hand function between -

7%-47% from baseline (on average 17%), facilitatory tDCS improved hand function between

0%-35% (on average 12%) and inhibitory tDCS improved hand function by 7%-20% (on

average 12%).

Summary: Bilateral tDCS seems to be more efficient than anodal tDCS or cathodal tDCS.

Future studies should prove the efficiency of the bilateral tDCS and compare it to facilitatory

and inhibitory tDCS within bigger study cohorts. Also its long-term effects should be further

evaluated.

Discussion This review included data from 23 articles including 523 stroke patients. In summary, the

pertinent literature suggests a positive effect of tDCS on motor recovery of the affected hand

after stroke.

Table 5 compares the effectiveness of the cathodal tDCS, anodal tDCS and the bilateral tDCS

to improve hand function after stroke in placebo-controlled trials. There was a large

heterogeneity in between studies regarding patient characteristics, intervention parameters,

outcome measures used and study designs.


Differential effectiveness of various tDCS protocols

Based on the current data cathodal tDCS over contralesional M1 is more effective than anodal

tDCS over ipsilesional M1.

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Cathodal tDCS was associated with an improvement in hand function in all patients tested,

but a significant effect was achieved in only 42% of them. Follow-up tests showed a lasting

effectiveness of cathodal tDCS for up to 6 months in all patients (but this effect was

statistically significant in only 43% (Table 5)).

Anodal tDCS was, by contrast, successful in 53% of tested patients. However, the effect

reached statistical significance in only 30% of them. Follow-up tests showed that in only 41%

of patients there was a lasting effect of tDCS over 6 months, which was statistically

significant in only 14% of those (Table 5).

A direct comparison of the amount of motor improvement to be achieved by cathodal tDCS

and anodal tDCS showed similar results: cathodal tDCS caused a 40% improvement of the

affected upper limb, anodal tDCS, by contrast, only a 20% improvement.

On the basis of the pertinent literature bilateral tDCS appears to be a highly effective protocol

to improve upper limb disability after stroke.

Bilateral tDCS improved hand motor function in all patients, but improvement reached the

level of statistical significance in about 75% of these. Follow-up investigation revealed a

lasting effect of bilateral tDCS for up to four weeks in all patients tested, but this effect was

statistically significant in only 62% of them (Table 5). In addition, bilateral tDCS caused

greater effect sizes than facilitatory tDCS and inhibitory tDCS alone.

Two-thirds of studies investigating the effectivity of tDCS on motor recovery of the affected

upper limb after stroke used a stimulation intensity of 1mA. Other stimulation intensities

(2mA, 1,5mA, 1,2mA, 0,5mA) were less widely applied. However current findings indicate a

smaller beneficial effect of 2mA tDCS compared with 1mA tDCS.

Patients characteristic dependent efficiency

Most studies tested patients with an ischemic stroke. Only recently researchers also included

more and more patients with haemorrhagic stroke aetiology. These studies showed a

comparable efficiency of tDCS to improve upper limb function in ischemic and haemorrhagic

stroke. Future studies should test the efficiency of tDCS on the motor recovery in larger study

cohorts of stroke patients with either stroke aetiology.

The majority of studies included patients with subcortical and cortical lesion. Some studies

tested only patients with subcortical lesions. The current data do not show any significant

difference in the efficiency of tDCS on upper limb improvement in patients with subcortical

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and cortical lesions. However, more data on larger study populations are needed before

definitive conclusions upon the differential effectiveness of various stimulation protocols in

subcortical and cortical stroke locations can be drawn.

At present the best positive evidence of the effect of the tDCS on motor recovery after stroke

exists mainly for patients with a chronic stroke. For patients with a subacute stroke, there are

hardly any data. There are some studies which tested the patients with acute stroke. These

studies show (compared with studies on patients with a chronic stroke) a smaller efficiency of

the tDCS on motor recovery. The facilitatory tDCS brought in patients with acute stroke even

further negative effect.

Most trials investigated the efficiency of tDCS in patients with a moderate to mild impairment

of the affected upper limb. Patients with a more severe motor impairment were much less

under investigation. Despite the fact that studies on the efficiency of tDCS in severely

affected stroke survivors are scarce, this should not be interpreted that tDCS is not effective in

this subpopulation. Again, more data on larger study cohorts are needed to underpin this

assumption. For example, a recent study indicated that inhibitory tDCS improved selective

proximal upper limb control for mildly impaired patients and worsened it for moderate to

severely impaired patients (Brandnam et al., 2012).

Conclusion This review implies that tDCS is safe and effective to support motor recovery of the affected

hand after stroke, however, data are to limited upon today to support its routine use.

The best evidence for the positive effect exists presently on patients with a chronic stroke

suffering from moderate to mild impairment of one upper limb. In contrast, current findings

imply small beneficial effect for patients with acute stroke. Moreover, present fMRI and

connectivity studies show that the neural plasticity and their impact on motor recovery after

stroke are much more complex than the interhemispheric imbalance model represent and not

completely understanding. Consequently, novel hypothetical concepts and surrogate markers

should be developed to predict the potential effectiveness of tDCS in an individual stroke

patient depending on lesion location, distribution, time from stroke and severity of motor

disability among other factors.

acute stroke <1 month after symptom onset

subacute stroke 1-6 months after symptom onset

chronic stroke >6 months after symptom onset

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References

Ang, K.K., Guan, C., Phua, K.S., Wang, C., The, I., Chen, C.W., Chew, E., 2012 Transcranial

direct current stimulation and EEG-based motor imagery BCI for upper limb stroke

rehabilitation. Conference proceedings: ....Annual International Conference of the IEEE

Engineering in Medicine and Biology Society. Conference. 2012, 4128-4131.

Bestmann, S., Swayne, O., Blankenburg, F., Ruff, C.C., Teo, J., Weiskopf, N., Driver, J.,

Rothwell, J.C., Ward, N.S., 2010. The role of contralesional dorsal premotor cortex after

stroke as studied with concurrent TMS-fMRI. The Journal of Neuroscience. 30, 11926-11937.

Boggio, P.S., Nunes, A., Rigonatti, S.P., Nitsche, M.A., Pascual-Leone, A., Fregni, F., 2007.

Repeated sessions of noninvasive brain DC stimulation is associated with motor function

improvement in stroke patients. Restorative neurology and neuroscience. 25, 123-129.

Bolognini, N., Vallar, G., Casati, C., Latif, L.A., El-Nazer, R., Williams, J., Banco, E., Macea,

D.D., Tesio, L., Chessa, C., Fregni, F., 2011. Neurophysiological and behavioral effects of

tDCS combined with constraint-induced movement therapy in poststroke patients.

Neurorehabilitation and neural repair. 25, 819-829.

Brandnam, L.V., Stimear, C.M., Barber, P.A, Byblow, W.D., 2012. Contralesional

hemisphere control of the proximal paretic upper limb following stroke. Cerebral Cortex. 22,

2662-2671.

Carter, A.R., Patel, K.R., Astafiev, S.V., Snyder, A.Z., Rengachary, J., Strube, M.J., Pope, A.,

Shimony, J.S., Lang, C.E., Shulman, G.L., Corbetta, M., 2012. Upstream dysfunction of

somatomotor functional connectivity after corticospinal damage in stroke. Neurorehabilitation

and Neural Repair. 26, 7-19.

Fregni, F., Boggio, P.S., Mansur, C.G., Wagner, T., Ferreira, M.J., Lima, M.C., Rigonatti,

S.P., Marcolin, M.A., Freedman, S.D., Nitsche, M.A., Pascual-Leone, A., 2005. Transcranial

direct current stimulation of the unaffected hemisphere in stroke patients. Neuroreport. 16,

1551-1555.

Page 18 of 32

Accep

ted

Man

uscr

ipt

Fusco, A., De Angelis, D., Morone, G., Maglione, L., Paolucci, T., Bragoni, M., Venturiero,

V., 2013. The ABC of tDCS: Effects of Anodal, Bilateral and Cathodal Montages of

Transcranial Direct Current Stimulation in Patients with Stroke-A Pilot Study. Stroke research

and treatment. 2013, 837595.

Grefkes, C., Eickhoff S.B., Nowak, D.A., Dafotakis, M., Fink, G.R., 2008. Dynamic intra-

and interhemispheric interactions during unilateral and bilateral hand movements assessed

with fMRI and DCM. Neuroimage. 41, 1382-1394.

Grefkes, C., Fink G.R., 2014. Connectivity-based approaches in stroke and recovery of

function. The Lacent Neurology. 13, 206-216.

Grefkes, C., Nowak, D.A., Eickhoff, S.B., Dafotakis, M,, Küst, J., Karbe, H., Fink, G.R.,

2008. Cortical connectivity after subcortical stroke assessed with functional magnetic

resonance imaging. Annals of neurology, 63, 236-246

Grefkes, C., Ward, N.S., 2014. Cortical Reorganization After Stroke: How Much and How

Functional? The Neuroscientist. 20, 56-70.

Hesse, S., Waldner, A., Mehrholz, J., Tomelleri, C., Pohl, M., Werner, C., 2011. Combined

transcranial direct current stimulation and robot-assisted arm training in subacute stroke

patients: an exploratory, randomized multicenter trial. Neurorehabilitation and neural repair.

25, 838-846.

Hummel, F., Celnik, P., Giraux, P., Floel, A., Wu, W.H., Gerloff, C., Cohen, L.G., 2005.

Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain.

128, 490-499.

Hummel, F.C., Voller, B., Celnik, P., Floel, A., Giraux, P., Gerloff, C., Cohen, L.G., 2006.

Effects of brain polarization on reaction times and pinch force in chronic stroke. BMC

neuroscience. 7, 73.

Jørgensen, H.S., Nakayama, H., Raaschou, H.O., Vive-Larsen, J., Støier, M., Olsen, T,S.,

1995. Part I: Outcome. The Copenhagen Stroke Study. Archives of Physical Medicine and

Rehabilitation. 76, 399-405.

Page 19 of 32

Accep

ted

Man

uscr

ipt

Jørgensen, H.S., Nakayama, H., Raaschou, H.O., Vive-Larsen, J., Støier, M., Olsen, T,S.,

1995. Outcome and time course of recovery in stroke. Part II: Time course of recovery. The

Copenhagen Stroke Study. Archives of Physical Medicine and Rehabilitation. 76, 406-412.

Khedr, E.M., Shawky, O.A., El-Hammady, D.H., Rothwell, J.C., Darwish, E.S., Mostafa,

O.M., Tohamy, A.M., 2013. Effect of Anodal Versus Cathodal Transcranial Direct Current

Stimulation on Stroke Rehabilitation: A Pilot Randomized Controlled Trial.


Kim, D.Y., Lim, J.Y., Kang, E.K., You, D.S., Oh, M.K., Oh, B.M., Paik, N.J., 2010. Effect of

transcranial direct current stimulation on motor recovery in patients with subacute stroke.

American journal of physical medicine & rehabilitation/ Association of Academis Physiatrits.

89, 879-886.

Kim, D.Y., Ohn, S.H., Yang, E.J., Park, C.I., Jung, K.J., 2009. Enhancing motor performance

by anodal transcranial direct current stimulation in subacute stroke patients. American journal

of physical medicine & rehabilitation/ Association of Academis Physiatrits. 88, 829-836.

Kolominsky-Rabas, P.L., Weber, M., Gefeller, O., Neundoerfer, B., Heuschmann, P.U., 2001.

Epidemiology of ischemic stroke subtypes according to the TOAST criteria: incidence,

recurrence, and long-term survival in ischemic stroke subtypes: a population-based study.

Stroke. 32, 2735-2740.

Lang, N., Siebner, H.R., 2007. Repetitive transkranielle Magnetstimulation, in: Siebner, H.R.,

Ziemann, U. Das rTMS Buch. Heidelberg, pp. 499-513.

Lefebvre, S., Laloux, P., Peeters, A., Desfontaines, P., Jamart, J., Vandermeeren, Y., 2012.

Dual-tDCS Enhances Online Motor Skill Learning and Long-Term Retention in Chronic

Stroke Patients. Frontiers in human neuroscience. 6, 343.

Lindenberg, R., Renga, V., Zhu, L.L., Nair, D., Schlaug, G., 2010. Bihemispheric brain

stimulation facilitates motor recovery in chronic stroke patients. Neurology. 75, 2176-2184.

Loubinoux, I., Carel, C., Pariente, J., Dechaumont, S., Albucher, J.F., Marque, P., Manelfe,

C., Chollet, F., 2003. Correlation between cerebral reorganization and motor recovery after

subcortical infarcts. NeuroImage. 20, 2166-2180.

Page 20 of 32

Accep

ted

Man

uscr

ipt

Madhavan, S., Shah, B., 2012. Enhancing motor skill learning with transcranial direct current

stimulation - a concise review with applications to stroke. Frontiers in psychiatry. 3, 66.

Madhavan, S., Weber, K.A. 2nd, Stinear, J.W., 2011. Non-invasive brain stimulation

enhances fine motor control of the hemiparetic ankle: implications for rehabilitation.

Experimental brain research. 209, 9-17.

Mahmoudi, H., Borhani Haghighi, A., Petramfar, P., Jahanshahi, S., Salehi, Z., Fregni, F.,

2011. Transcranial direct current stimulation: electrode montage in stroke. Disability and

rehabilitation. 33, 1383-1388.

Marshall, R.S., Perera, G.M., Lazar, R.M., Krakauer, J.W., Constantine, R.C., DeLaPaz, R.L.,

2000. Evolution of cortical activation during recovery from corticospinal tract infarction.

Stroke. 31, 656-661.

Nair, D.G., Renga, V., Lindenberg, R., Zhu, L., Schlaug, G., 2011. Optimizing recovery

potential through simultaneous occupational therapy and non-invasive brain-stimulation using

tDCS. Restorative neurology and neuroscience. 29, 411-420.

Nitsche, M.A., Cohen, L.G., Wassermann, E.M., Priori, A., Lang, N., Antal, A., Paulus, W.,

Hummel, F., Boggio, P.S., Fregni, F., Pascual-Leone, A., 2008; Transcranial direct current

stimulation: State of the art 2008. Brain Stimulation. 1, 206-23.

Nitsche, M.A., Paulus, W., 2000. Excitability changes induced in the human motor cortex by

weak transcranial direct current stimulation. The Journal of physiology. 3, 633-639.

Nitsche, M.A., Paulus, W., 2007. Transkranielle Gleichstromstimulation, in: Siebner, H.R.,

Ziemann, U. Das rTMS Buch. Heidelberg, pp. 533-542.

Nowak, D.A., Bösl, K., Podubeckà, J., Carey, J.R., 2010. Noninvasive brain stimulation and

motor recovery after stroke. Restorative Neurology and Neuroscience. 28, 531-544.

Nowak, D.A., Grefkes, C., Ameli, M., Fink, G.R., 2009. Interhemispheric competition after

stroke: brain stimulation to enhance recovery of function of the affected hand.


Page 21 of 32

Accep

ted

Man

uscr

ipt

Ochi, M., Saeki, S., Oda, T., Matsushima, Y., Hachisuka, K., 2013. Effects of anodal and

cathodal transcranial direct current stimulation combined with robotic therapy on severely

affected arms in chronic stroke patients. Journal of rehabilitation medicine. 45, 137-140.

O'Shea, J., Boudrias, M.H., Stagg, C.J., Bachtiar, V., Kischka, U., Blicher, J.U., Johansen-

Berg, H., 2014. Predicting behavioural response to TDCS in chronic motor stroke.

NeuroImage. 85, 924-933.

Park, C.H., Chang, W.H., Ohn, S.H., Kim, S.T., Bang, O.Y., Pascual-Leone, A., Kim, Y.H.,

2011. Longitudinal changes of resting-state functional connectivity during motor recovery

after stroke. Stroke. 42, 1357-1362.

Rehme, A.K., Eickhoff, S.B., Rottschy, C., Fink, G.R., Grefkes, C., 2012. Activation

likelihood estimation meta-analysis of motor-related neural activity after stroke. NeuroImage.

59, 2771-2782.

Rehme, A.K., Eickhoff S.B., Wang L.E., Fink G.R., Grefkes C., 2011. Dynamic causal

modeling of cortical excitability from the acute to the chronic stage after stroke. Neuroimage.

55, 1147-1158.

Rehme, A.K., Fink, G.R., von Cramon, D.Y., Grefkes, C., 2011. The role of the contralesional

motor cortex for motor recovery in the early days after stroke assessed with longitudinal

FMRI. Cerebral Cortex. 21, 756-768.

Rossi, C., Sallustio, F., Di Legge, S., Stanzione, P., Koch, G., 2013. Transcranial direct

current stimulation of the affected hemisphere does not accelerate recovery of acute stroke

patients. European journal of neurology. 20, 202-204.

Schallert, T., Leasure, J.L., Kolb, B., 2000. Experience-associated structural events,

subependymal cellular proliferative activity, and functional recovery after injury to the central

nervous system. Journal of Cerebral Blood Flow & Metabolism. 20, 1513-1528.

Stagg CJ, Bachtiar V, O'Shea J, et al. Cortical activation changes underlying stimulation-

induced behavioural gains in chronic stroke. Brain 2012; 135:276-284.

Takeuchi, N., Tada, T., Matsuo, Y., Ikoma, K., 2012. Low-frequency repetitive TMS plus

anodal transcranial DCS prevents transient decline in bimanual movement induced by

Page 22 of 32

Accep

ted

Man

uscr

ipt

contralesional inhibitory rTMS after stroke. Neurorehabilitation and neural repair. 26, 988-

998.

Taylor, T.N., Davis, P.H., Torner, J.C. Holmes, J., Meyer, J.W., Jacobson, M.F., 1996.

Lifetime cost of stroke in the United States. Stroke. 27, 1459-1466.

Volz, L.J., Sarfeld A.S., Diekhoff S., Rehme A.K., Pool E.M., Eickhoff S.B., Fink G.R.,

Grefkes C., 2014. Motor cortex excitability and connectivity in chronic stroke: a multimodal

model of functional reorganization. Brain structure & function. Epub ahead of print

Wang, L., Yu, C., Chen, H., Qin, W., He, Y., Fan, F., Zhang, Y., Wang, M., Li, K., Zang, Y.,

Woodward, T.S., Zhu, C., 2010. Dynamic functional reorganization of the motor execution

network after stroke. Brain. 133, 1224-1238.

Wu, D., Qian, L., Zorowitz, R.D., Zhang, L., Qu, Y., Yuan, Y., 2013. Effects on decreasing

upper-limb poststroke muscle tone using transcranial direct current stimulation: a randomized

sham-controlled study. Archives of physical medicine and rehabilitation. 94, 1-8.

Zimerman, M., Heise, K.F., Hoppe, J., Cohen, L.G., Gerloff, C., Hummel, F.C., 2012. Modulation of training by single-session transcranial direct current stimulation to the intact motor cortex enhances motor skill acquisition of the paretic hand. Stroke. 43, 2185-219.

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‐ Highlights

‐ We review the literature on tDCS in rehabiliation of the affected hand after stroke.

‐ We found overall 23 placebo‐controlled trials.

‐ All stimulation protocols pride on interhemispheric imbalance model.

‐ TDCS is associated with improvement of the affected upper limb after stroke.

‐ Current evidence does not support its routine use.

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Intensity Duration

20 min 1 JTHF 9% (*) -3% na na 2

1 mA 20 min 1 reaction time 6% (*) -5% - - 2

pinch force 4% -3% - -

1 mA 20 min 1 BBT 21% (*) 3% 18% (*) 3% 2

finger

acceleration

67% (*) 0% 42% (*) -15%

0,5

mA

15 min 1 tDCS

les

tDCS

non-les

tDCS

sham1

tracking

accuracy

18% (**) -1% (*) 7% - -

MEPipsiles 29% 8% 11% - -

MEPcontrales -12% 13% 4% - -

2 mA 20 min 5 FM(UL) 83% 101% 2

5 participants; age: na; time

from stroke: na; lesion

location: na; stroke

epidemiology: na; upper limb

impairment: na

1 mA 20 min 10 randomized;

parallel-

group; sham-

controlled

2 experimental

groups: tDCSreal

+ MP (n=3),

tDCSsham + MP

(n=2)

accuracies of

detecting

motor imagery

2% -20% - - 2

50 participants; age 68,2±13,9

years; 1 day after the stroke;

ischemic corical (n=38) and

subcortical (n=12) stroke;

moderate to mild motor

impairment of upper limb

1 mA double-blind;

crossover;

sham-

controlled;

longitudinal

randomized;

parallel-

group;

double-blind;

sham-

controlled;

longitudinal

tDCS

sham

Patients charakteristics Study

description

Assesment Follow upStimulation

232%

tDCS

real

OG

SC

Study

design

Outcome

2 experimental

groups: tDCSreal,

tDCSsham; 3

months after

stroke follow up

2 experimental

sessions:

tDCSanodal,

tDCSsham; 10

days follow up

2 experimental

sessions:

tDCSanodal,

tDCSsham

Table 1. Facilitatory tDCS in promoting motor recovery of the affected hand after stroke


years; 6,4±3 months after the

stroke; ischemic (n=8) and

hamorrhagic (n=2), subcortical

(n=9) and cortical (n=1) stroke;

moderate to mild impairment of

upper limb

single-blind;

crossower;

sham-

controlled

2 experimental

sessions:

tDCSreal,

tDCSsham; 60

mitutes follow up


years; 3,7±1,1 years after the

stroke; ischemic subcortical

stroke; moderate to mild motor


Number

section

tDCS

real

tDCS

sham

11 participants; age 57±16

years; 41,8±26,4 months after

the stroke; ischemic

subcortical stroke; moderate to

mild motor impairment of

upper limb

pseudo-

randomized;

double-blind;

crossover;

sham-

controlled


years; 10,9±6,7 years after the

stroke; ischemic cortical (n=2)

and subcortical (n=7) stroke;



crossover;

sham-

controlled

3 experimental

sessions:

tDCSreal over

lesioned M1 +

TM, tDCSreal

over non-lesioned

M1 + TM,

tDCSsham + TM

Table(s)

http://ees.elsevier.com/neubiorev/download.aspx?id=75472&guid=4b741725-5f34-4030-86fb-36031f4824cb&scheme=1

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description

Assesment

1 mA 30 min 5 FM(UL) na na 14% (*) 6% 3

ROM 16% 1% 16% (*) 4%

1,2 mA 20 min 20 FM(UL) 83% (**) 25% #### (**) 88% 4

MAS elbow 50% (**) 0% 50% (**) -50%

MAS wrist 50% (**) 0% 50% (**) -50%

1 mA 20 min 1

finger

movement

task

56% (*) 17% na (*) na 5

MEPipsiles -29% (*) na na na

SICIipsiles na (*) na na na

SICIcontrales na (*) na na na

Duration

14 participants; age

58,5±13,5 years; 30,5±24

months after the stroke;

ischemic cortical (n=9) and

subcortical (n=5) stroke;

moderate to severe motor


randomized;

paralle-group;

double-blind;

sham-

controlled;

longitudinal

2 experimental

groups:

tDCSreal+OT;

tDCSsham+OT; 7

days follow up

correlation between FM(UL)-improvement and

decreased activation in the contralesional motor

cortex (FMRI)

Table 2. Inhibitory tDCS in promoting motor recovery of the affected hand after stroke

Stimulation Study design Outcome Follow up

Number

section OG

SC

Intensity

correlation between finger movement task-

improvement and SICIipsiles-change (r2=0,63)

tDCS

sham

2 experimental

sessions:

tDCSreal+MT,

tDCSsham+MT;

90min, 24 hours

and 90 days (5

participants)

follow up

tDCS

real

tDCS

sham

tDCS

real


47,6±11,9 years; 4,9±3,0


lesion location: na; ischemic

(n=53) and hemorrhagic

(n=37) stroke, moderate to

severe motor impairment of

upper limb

cathode over M1

ipsilesional, anode over

the unaffected shoulder

randomized;

parallel-group;

double-blind;

sham-

controlled;

longitudinal

5 block á 3 minutes

with 2 minutes breaks

double-blind;

crossover;

sham-controlled


58,3±13,3 years; 33,4±15,8


subcortical ischemic stroke;



2 experimental

groups:

tDCSreal+PT,

tDCSsham+PT; 4

weeks follow up

24 hours

Table(s)

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6 participants; age 53,7

years; 27,1 months after

the stroke; lesion location:

na; mild to moderate

motor impairment of

upper limb

1 mA 20 min 1 randomized;

crossover;

double-blind;

sham-

controlled

3 experimental

sessions:

tDCScathodal,

tDCSanodal,

tDCSsham

JTHF 6,8% (*) 11,7% (*) 4% - - - 3 Fregni et

al. 2005

9 participants; age

57,4±12,9 years; 40,9


subcortical stroke;

etiology of stroke: na;

mild to moderate motor


1 mA 20 min 20 double-blind;

crossover;

sham-

controlled

3 experimental

treatments:

tDCSanodal,

tDCScathodal,

tDCS sham

JTHF 7,3% (*) 9,5% (*) na - - - 2 Boggio et

al. 2007


57,8±13,0 years;

25,6±16,7 days after the

stroke; ischemic cortical

(n=5), corticosubcortical

(n=4) and subcortical

(n=9) stroke; moderate to

mild motor impairment of

upper limb

2mA 20 min 10 randomized;

parallel-

group;

double-blind;

sham-

controlled;

longitudinal

3 experimental

groups:

tDCSanodal,

tDCScathodal,

tDCSsham; 6

months follow

up

FM(UL) 45% 35% 20% 85% 53% 2% 5 Kim et al.

2010

2mA 20 min 30 FM(UL) 145% 139% 134% 197% 197% 174% 5

BBT na na na na na na

MRC 240% 372% 277% 234% 366% 297%

MAS 106% 250% 150% 125% 250% 171%

1 mA 20 min

10 min

1 response time

task (exp. 1)

5% (*) 0% (*) -7% - - - 1 Stagg et

al. 2012

grip force task na na na - - -

response time

task (exp. 2)

10% (*) -2% -10% - - -

MRI ipsiles 85% 10% - - -

MRI contrales 45% 5% - - -

1 mA 10 min 5 FM(UL) 6% 4% - - - - 2

MAS Elbow 12% 20% - - - -

MAS Wrist 20% 17% - - - -

MAS Finger 17% 28% (*) - - - -

MAL 6% 6% - - - -

hand grip

strenght

120% 79% 50% 193% 132% 125%

shoulder

abduction

88% 113% 10% 147% 175% 75%

rMTcontrales -2% -4% -3%

rMTipsiles "-20% (**) "-14%

(*)

"-6% (*)

aMTcontrales -1% -1% -4%

aMTipsiles "-21% (**) "-14%

(*)

"-8% (*)

3 months 5 Khedr et

al. 2013

correlation between the change in MT and increase in grip

strength

2mA 25 min 6 randomized;

paralell-

group;

double-blind;

sham-

controlled;


years; 4,4 years after the

stroke; ischemic (n=7)

and hemorrhagic (n=11);

subcortical and cortical

stroke; moderate to

severe motor impairment

of upper limb

randomized;

double-blind;

crossover

2 experimental

treatments:

tDCSanodal+R

AAT,

tDCScathodal+

RAAT

Ochi et al.

2013

the patients with right hemispheric lesion improved significantly

larger with DCScathodal then with tDCSanodal

tDCSanodal - a negative correlation between decreases in

response time and increases in task-related cortical activation

in the ipsilesional M1


years; 38 months after


(n=16) and hemorrhagic

(n=1), subcortical (n=10)

and cortical (n=7) stroke;



randomized;

crossover;

sham-

controlled;

crossover

3 experimental

sessions:

tDCSanodal,

tDCScathodal,

tDCSsham


65,0±9,8 years; 3,1±1,6

weeks after the stroke;

ischemic subcortical and

cortical stroke; severe

motor impairment of

upper limb

randomized;

parallel-

group;

double-blind;

sham-

controlled;

multicenter;

longitudinal

3 experimental

groups:

tDCSanodal +

BRT,

tDCScathodal +

BRT,

tDCSsham +

BRT; 3 months

follow up

OG

SCAssesment

Number

section

Intensity Duration


description

tDCScathodal - the patients with a subcortical lesion improved

significantly larger then those patients with a cortical

involvement

Outcome

tDCS

anodal

tDCS

cathodal

tDCS sham

Follow up


58,4±8,9 years; 12,9±4,9

days after the stroke;

subcortical (n=14) and

cortical (n=26) ischemic

stroke; moderate to mild

motor impairment of

upper limb

3 experimental

groups:

tDCSanodal,

tDCScathodal,

tDCSsham; 1, 2,

and 3 months

follow up

Table 3. Facilitatory and inhibitory tDCS in promoting motor recovery of the affected hand after stroke

tDCS

anodal

tDCS

cathodal

tDCS

sham

Refere

nce

Stimulation Study

design

Hesse et

al. 2011

Table(s)

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1 mA 30 min 5 FM(UL) 15.0% 3.0% 16.0% 3.0% 4

WMFT 15.0% 5.0% 16.0% 6.0%

2 mA 40 min 10 3JTHF 33% (*) 3% 29% (*) 9%

Handgrip

Strenght

33% (*) -14% 48% (*) -6%

FM(UE) 25% (*) 7% 31% (*) 4%

MAL 75% 42% 75% 59%

MEP ipsiles 21% (*) -9%

TI ipsiles 34% (*) 14%

TI contrales 0% 1%

1mA 20 min 1 JTHF 15% (*) A: 11% (*) 8% (*) 1% 2

B: 4%

rTMS+ tDCS tDCS rTMS rTMS+

tDCS

tDCS rTMS

pinch force 14% (**) -1% 9% (*) 24% (**) 5% 19% (*)

acceleration 22% 10% 22% 26% 11% 22%

bimanual

coordination

5% 7% 24% (**) 8% 6% 8%

MEPcontrales "-24% (**) -3% "-21% (**) 0% -1% 3%

MEP ipsiles 24% (**) 20% (**) 22% (*) -2% -3% 3%

TCI contrales -14% -9% "-24% 1% 1% 1%

TCI ipiles 16% -2% 2% -1% 2% -1%

TCI ratio "-25% (**) -3% "-26% (**) 5% 1% 5%

correlation between bimanual coordination- and TCI contrales-changes (r=-0,486)

1 NHPT 14% 34% 19% "-1%-11% - - - - 1

grip force -7% 0% 13% 0% - - - -

30 min 1 4

PPT 19% 0% 13% (*) 3%

grip force -1% -4% 0% 5%

learning index na na 44% 4%

correlation between pinch force- and TIC ratio-changes (r=-0,477)

9 participants; age

53,5±20,7 years;

28,3±10,4 days after


(n=8) and

hemorrhagic (n=1),

cortical and

subcortical stroke;

upper limb

impairment: na

1,5mA 15 min single-

blind;

sham-

controlled;

crossover

3 experimental

groups:

tDCSanodal

(n=3),

tDCScathodal

(n=3),

tDCSbilateral

(n=3)

20 min 1 longitudinal

; parallel-

group

3 experimental

groups:

tDCSanodal,

rTMSinhibitory,

DCSanodal+rT

MSinhibitory; 1

session; 30min

and 7days

follow up

07 days

Table 4. Bilateral tDCS in promoting motor recovery of the affected hand after stroke

tDCS anodal tDCS

anodal

tDCS

sham

Stimulation Study

design

Assesment

OG

SC

tDCS

bilateral

tDCS

cathodal

Follow up

tDCSbilateral - correlation between WMFT- and precentral gyrus

activation laterality- changes

tDCSbilateral - stronger activation of intact ipsilesional motor regions

during paced movements of the affected limb then tDCSsham

correlation between TI ipsiles- and JTHF- changes (r=-0,55)

patients with subcortical lesion: the effect after tDCSbilateral was

almost twice as large compared with tDCS cathodal and tDCSanodal

correlation between MEP ipsiles- und FM(UE)- changes (r=0,67)

4 weeks

Outcome

tDCS bilateral tDCS

cathodal

5 experimental

sessions:

tDCSbilateral,

tDCScathodal,

tDCSanodalA

(cathode over

contralateral

supraorbital

area),

tDCSanodalB

(cathode on

contralateral

deltoid muscle),

tDCSsham

tDCS

sham

double-

blind;

parallel-

group;

sham-

controlled;

longitudinal

2 experimental

groups:

tDCSbilateral +

CIMT,

tDCSsham +

CIMT; 2 and 4

weaks follow up

double-

blind;

parallel-

group;

sham-

controlled;

longitudinal

2 experimantal

groups:

tDCSbilateral,

tDCSsham; 3

and 7 days

follow up


61±9 years; 2,6±1,5

years after the stroke;

ischemic (n=16) and

hemorrhagic (n=2),


cortical (n=11) stroke;

moderate to mild

motor impairment of

upper limb

Intensity Duration Number

section


58,8±13,8 years;

35,4±22,4 months

after the stroke;

ischemic subcortical

stroke; moderate to

mild motor impairment

of upper limb


60,8±14,1 years;

8,3±5,5 months after


cortical (n=7),


brainstem (n=1)

stroke; morderate to

mild motor impairment

of upper limb

Patients

charakteristics


46,7±13,6 years;

35,2±25,5 months

after the stroke;

ischemic (n=12) and

hemorrhagic (n=2);

subcortical (=5) and

cortical (n=9) stroke;

moderate to mild

motor impairment of

upper limb


61,5±7,6 years;

67,1±48,4 months

after the stroke;

ischemic and

hemorrhagic

subcortical stroke;

moderate to mild

motor impairment of

upper limb

1 mA

tDCS

1Hz

rTMS

90%

rMT

Study

description

randomized

; double-

blind; sham-

controlled;

crossover;

longitudinal

2 experimental

sessions:

tDCSbilateral+

MT,

tDCSsham+MT;

30min, 60min

and 1 weak

follow up

1 mA 1 Woche

(**)

(**) (**)

double-

blind; sham-

controlled,

randomized

; crossover

Table(s)

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Study

description

1mA 20 min 1 reaction

time

2%(*) 6%(*) 0%(*) -7% - - - - 0

MI-BCI motor imagery Brain-Computer Interface RAAT robot-assisted arm training

JTHF Jebsen Taylor Hand Function Test MAL Motor Activity Log

na not available aMT active motor treshold

PNS peripheral nerve stimulation rMT resting motor treshold

BBT Box and Block Test PT physical therapy

TM Tracking movements WMFT Wolf Motor Function Test

FM(UL) Flugl-Meyer (upper limb) TI Transcallosal inhibition

MP motor practise NHPT Nine-Hole-Peg-Test

OT occupational therapy PPT Purdue Pegboard Test

ROM Range-Of-Motion (*) (**) along a numeral a significant time-effect for this group but not for the control group

MAS Modified Ashworth Scale (*) (**) between two numerals a significant between-groups-difference

MT motor training

SICI Short Interval Intracortical Inhibition

MRC Medical Research Counsil

MAS Modified Ashworth-Summenscore

BRT bilateral robot training

BBT Box and Block Test

Table 4. (continued) bilateral tDCS in promoting motor recovery of the affected hand after stroke

Follow up

OG

SC Refere

ncetDCS

sham

tDCS

bilateral

tDCS

sham

OutcomePatients charakteristics

13 participants; age 66 years;

time after stroke: na; lesion

location: na; etiology of stroke:

na; moderate to mild


sham-

controlled;

crossover

4 experimental

sessions:

tDCSbilateral,

tDCSanodal,

tDCScathodal,

tDCSsham

Number

section

tDCS

cathodal

tDCS

bilateral

tDCS

anodal

tDCS

cathodal

tDCS

anodal

O´Shea et

al. 2013

correlation between the effects of anodal and cathodal tDCS (r= 0,6)

and between cathodal and bilateral tDCS (r=0,65)

Stimulation Study

design

Assesm

entIntensity Duration

Table(s)

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facilitatory tDCS inhibitory tDCS bilateral tDCS

placebocontrolled trials 15 (n=309) 12 (n=304) 6 (n=112)

placebocontrolled trials with a positive

effect

13 (n=163)

9 (n=91)

of this with a statistical

significance

12 (n=304)

7 (n=127)


significance

6 (n=112)

4 (n=83)


significance

placebocontrolled trials without a

positive effect2 (n=146) 0 (n=0) 0 (n=0)

placebocontrolled trials with follow up 5 (n=214) 6 (n=270) 3 (n=53)

placebocontrolled trials with a positive

effect by follow up

3 (n=88)

1 (n=30)


significance

6 (n=270)

3 (n=116)


significance

3 (n=53)

2 (n=33)


significance

placebocontrolled trials without a

positive effect by follow up2 (n=146) 0 (n=0) 0 (n=0)

Tab. 5 The review of the trials, which investigated the efect of the facilitatory tDCS, the inhibitory tDCS and the bilateral

tDCS for motor recovery of the affected upper limb after stroke

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Figure 1: Increase of cortical excitability within the ipsilesional M1 by facilitatory (anodal)

tDCS. The anodal electrode (+) is placed over standard scalp coordinates for ipsilesional M1,

the cathodal electrode (-) over the contralesional supraorbital rige.

Figure

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Figure 2: Decrease of cortical excitability within the contralesional M1 (thereby reducing the

transcallosal inhibition drive towards ipsilesional M1) by means of inhibitory (cathodal)

tDCS. The cathodal electrode (-) is placed over standard scalp coordinates for contralesional

M1, the anodal electrode (+) over the ipsilesional supraorbital rige.

Figure

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Figure 3: Increase of cortical excitability within ipsilesional M1 by stimultaneous bilateral

tDCS. The anodal electrode (+) is placed over standard scalp coordinates for ipsilesional M1,

the cathodal electrode (-) over standard scalp coordinates for contralesional M1.

Figure

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Transcranial direct current stimulation for motor recovery of upper limb function after stroke