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

Accepted Manuscript Title: Transcranial direct current stimulation for motor recovery of upper limb function after stroke Author: Jitka Podubeck´a Kathrin B¨osl Sandra Rothhardt Geert Verheyden Dennis Alexander Nowak PII: DOI: Reference:

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

To appear in: Received date: Revised date: Accepted date:

10-2-2014 25-7-2014 28-7-2014

Please cite this article as: Podubeck´a, J., B¨osl, K., Rothhardt, S., Verheyden, G., Nowak, D.A.,Transcranial direct current stimulation for motor recovery of upper limb function after stroke, Neuroscience and Biobehavioral Reviews (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.07.022 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Transcranial direct current stimulation for motor recovery of upper limb function after stroke 1

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

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Nowak

Neurologische Fachklinik Kipfenberg, Kipfenberg, Germany

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Department of Rehabilitation Sciences, KU Leuven, Belgium

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

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Jitka Lüdemann-Podubecká

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Klinik Kipfenberg Neurologische Fachklinik

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D-85110 Kipfenberg

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Kindinger Strasse 13

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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

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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

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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

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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

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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.

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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-

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

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

Neural plasticity following stroke

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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-

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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

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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.,

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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

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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

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

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

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

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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

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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

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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

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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

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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

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relations are referred to as “functional” and “effective” connectivity (Grefkes and Ward, 2014; Grefkes and Fink, 2014).

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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

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

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ipsilesional M1 and contralesional areas (Grefkes and Fink, 2014). Numerous studies showed also reduced functional connectivity between ipsilesional M1 and contralesional M1, which

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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).

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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

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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

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damage (Grefkes and Fink, 2014).

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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

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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

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

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contralesional M1 subsequently normalized, but patients with poorer outcome in the chronic stage now showed enhanced negative coupling from contralesional upon ipsilesional M1

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(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

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(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

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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

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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

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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

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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).

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

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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.

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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.

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three randomized patients at least.

Results

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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,

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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.

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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

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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

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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-

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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

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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.

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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.

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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

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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

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

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

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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

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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

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

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2006) included only patients with a subcortical lesion. Time after stroke: One study included patients with acute stroke (Rossi et al. 2013). The

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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

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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

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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

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hand.

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

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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

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effective to improve hand function in haemorrhagic stroke.

Decrease of excitability of motor areas within the contralesional hemisphere

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

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

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

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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.

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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

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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

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stroke (Wu et al., 2013).

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

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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.

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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).

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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

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

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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

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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.

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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

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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.,

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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

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(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

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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

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

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et al., 2011; Khedr et al., 2013; Kim et al., 2010). Adjunct therapies: Two studies combined the tDCS-stimulation sessions with robot-assisted

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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)

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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).

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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.

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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

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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

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improvement of hand function in comparison to anodal tDCS.

Decrease of excitability of motor areas within the contralesional hemisphere and

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(bilateral tDCS stimulation)

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simultaneous increase of excitability within motor areas on the ipsilesional hemisphere

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

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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.

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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

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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,

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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

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

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

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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.,

M

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

te

et al., 2012).

d

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

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

Ac ce p

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).

Page 13 of 32

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;

ip t

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

cr

intervention.

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

us

recovery of the affected hand after stroke.

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

an

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%).

M

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

Discussion

te

evaluated.

d

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

Ac ce p

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.

INSERT TABLE 5 ABOUT HERE

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.

Page 14 of 32

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)).

ip t

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

cr

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

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

us

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

an

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.

M

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

d

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

te

greater effect sizes than facilitatory tDCS and inhibitory tDCS alone.

Ac ce p

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

Page 15 of 32

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

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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

cr

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

us

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

an

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

M

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

te

Conclusion

d

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

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

Ac ce p

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

Page 16 of 32

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te

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Page 22 of 32

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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an

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‐ 

Page 23 of 32

Table(s)

Stimulation Intensity

Number section

Study design

Study description

Assesment

Outcome tDCS real

Follow up tDCS sham

tDCS real

tDCS sham

1

double-blind; crossover; shamcontrolled; longitudinal

2 experimental sessions: tDCSanodal, tDCSsham; 10 days follow up

JTHF

9%

(*)

-3%

na

na

2

11 participants; age 57±16 1 mA 20 min years; 41,8±26,4 months after the stroke; ischemic subcortical stroke; moderate to mild motor impairment of upper limb

1

pseudorandomized; double-blind; crossover; shamcontrolled

2 experimental sessions: tDCSanodal, tDCSsham

reaction time

6%

(*)

-5%

-

-

2

pinch force

4%

-3%

-

-

10 participants; age 62,8±12,5 1 mA 20 min 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

1

single-blind; crossower; shamcontrolled

2 experimental sessions: tDCSreal, tDCSsham; 60 mitutes follow up

BBT

21%

(*)

finger acceleration

67%

(*)

9 participants; age 65,4±13,2 years; 10,9±6,7 years after the stroke; ischemic cortical (n=2) and subcortical (n=7) stroke; moderate to mild motor impairment of upper limb

0,5 mA

1

crossover; shamcontrolled

3 experimental sessions: tDCSreal over lesioned M1 + TM, tDCSreal over non-lesioned M1 + TM, tDCSsham + TM

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

2 mA

20 min

5

randomized; parallelgroup; double-blind; shamcontrolled; longitudinal

2 experimental FM(UL) groups: tDCSreal, tDCSsham; 3 months after stroke follow up

83%

101%

232%

5 participants; age: na; time from stroke: na; lesion location: na; stroke epidemiology: na; upper limb impairment: na

1 mA 20 min

10

randomized; parallelgroup; shamcontrolled

2 experimental accuracies of groups: tDCSreal detecting + MP (n=3), motor imagery tDCSsham + MP (n=2)

2%

-20%

-

ip

18% (*)

0%

42% (*) -15%

3%

2

us

cr

3%

tDCS les

tracking accuracy

tDCS non-les

tDCS sham

1

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

7%

-

-

29%

8%

11%

-

-

MEPcontrales -12%

13%

4%

-

-

2

M

an

MEPipsiles

-

2

ed

15 min

t

1 mA 20 min

Ac ce

pt

6 participants; age 62,2±7,56 years; 3,7±1,1 years after the stroke; ischemic subcortical stroke; moderate to mild motor impairment of upper limb

Duration

OGSC

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

Page 24 of 32

Table(s)

30 min

5

90 participants; age 47,6±11,9 years; 4,9±3,0 months after the stroke; lesion location: na; ischemic (n=53) and hemorrhagic (n=37) stroke, moderate to severe motor impairment of upper limb

1,2 mA 20 min

12 participants; age 58,3±13,3 years; 33,4±15,8 months after the stroke; subcortical ischemic stroke; moderate to mild motor impairment of upper limb

1 mA 20 min 1 5 block á 3 minutes with 2 minutes breaks

randomized; paralle-group; double-blind; shamcontrolled; longitudinal

20 randomized; parallel-group; cathode over M1 ipsilesional, anode over double-blind; the unaffected shoulder shamcontrolled; longitudinal

Assesment

2 experimental FM(UL) groups: ROM tDCSreal+OT; tDCSsham+OT; 7 days follow up

na

Follow up tDCS sham

tDCS real

na

14%

tDCS sham

6%

(*)

3

4% 16% 1% 16% (*) correlation between FM(UL)-improvement and decreased activation in the contralesional motor cortex (FMRI)

2 experimental FM(UL) groups: MAS elbow tDCSreal+PT, MAS wrist tDCSsham+PT; 4 weeks follow up

double-blind; 2 experimental crossover; sessions: sham-controlled tDCSreal+MT, tDCSsham+MT; 90min, 24 hours and 90 days (5 participants) follow up

Outcome tDCS real

83%

(**)

25%

####

(**)

88%

50%

(**)

0%

50%

(**)

-50%

50%

(**)

0%

50%

(**)

-50%

finger movement task

56%

(*)

17%

na

MEPipsiles

-29% (*)

na

na

na

na

na

na

na

na

4

t

1 mA

Study description

ip

Number section

24 hours

SICIipsiles SICIcontrales

na na

cr

Study design

Duration

us

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 impairment of upper limb

Stimulation Intensity

OGSC

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

(*) (*)

na

(*)

na

5

correlation between finger movement task-

Ac ce

pt

ed

M

an

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

Page 25 of 32

Table(s)

tDCS anodal

tDCS cathodal

tDCS sham

tDCS anodal

tDCS cathodal

tDCS sham

Refere nce

JTHF

6,8% (*)

11,7% (*)

4%

-

-

-

3

Fregni et al. 2005

3 experimental treatments: tDCSanodal, tDCScathodal, tDCS sham

JTHF

7,3% (*)

9,5% (*)

na

-

-

-

2

Boggio et al. 2007

randomized; parallelgroup; double-blind; shamcontrolled; longitudinal

3 experimental groups: tDCSanodal, tDCScathodal, tDCSsham; 6 months follow up

FM(UL)

45%

35%

20%

randomized; parallelgroup; double-blind; shamcontrolled; multicenter; longitudinal

3 experimental groups: tDCSanodal + BRT, tDCScathodal + BRT, tDCSsham + BRT; 3 months follow up

FM(UL)

145%

139%

134%

na

na

na

randomized; crossover; shamcontrolled; crossover

3 experimental sessions: tDCSanodal, tDCScathodal, tDCSsham

response time task (exp. 1)

5% (*)

0% (*)

-7%

-

-

-

grip force task

na

na

na

-

-

-

response time task (exp. 2)

10% (*)

-2%

-10%

-

-

-

10%

-

-

-

5%

-

-

-

Study description

Assesment

1

randomized; crossover; double-blind; shamcontrolled

3 experimental sessions: tDCScathodal, tDCSanodal, tDCSsham

20 min

20

double-blind; crossover; shamcontrolled

18 participants; age 2mA 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

20 min

10

96 participants; age 65,0±9,8 years; 3,1±1,6 weeks after the stroke; ischemic subcortical and cortical stroke; severe motor impairment of upper limb

2mA

20 min

30

17 participants; age 63,5 years; 38 months after the stroke; ischemic (n=16) and hemorrhagic (n=1), subcortical (n=10) and cortical (n=7) stroke; moderate to mild motor impairment of upper limb

1 mA

9 participants; age 57,4±12,9 years; 40,9 months after the stroke; subcortical stroke; etiology of stroke: na; mild to moderate motor impairment of upper limb

1 mA

1

pt

ed

20 min 10 min

1 mA 10 min

40 participants; age 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

2mA

5

randomized; 2 experimental double-blind; treatments: crossover tDCSanodal+R AAT, tDCScathodal+ RAAT

Ac ce

18 participants; age 61,1 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

25 min

6

randomized; paralellgroup; double-blind; shamcontrolled;

ip

20 min

Follow up

53%

2%

5

Kim et al. 2010

197%

197%

174%

5

na

na

na

Hesse et al. 2011

1

Stagg et al. 2012

2

Ochi et al. 2013

5

Khedr et al. 2013

85%

cr

6 participants; age 53,7 1 mA years; 27,1 months after the stroke; lesion location: na; mild to moderate motor impairment of upper limb

Outcome

BBT

us

Number section

an

Duration

t

Study design

Intensity

MRC

240%

372%

277%

234%

366%

297%

MAS

106%

250%

150%

125%

250%

171%

tDCScathodal - the patients with a subcortical lesion improved significantly larger then those patients with a cortical involvement

M

Stimulation

OGSC

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

MRI ipsiles

85%

MRI contrales

45%

tDCSanodal - a negative correlation between decreases in response time and increases in task-related cortical activation in the ipsilesional M1 FM(UL)

6%

4%

-

-

-

-

MAS Elbow

12%

20%

-

-

-

-

MAS Wrist

20%

17%

-

-

-

-

MAS Finger

17%

28% (*)

-

-

-

-

MAL

6%

6%

-

-

-

-

the patients with right hemispheric lesion improved significantly larger with DCScathodal then with tDCSanodal 3 experimental groups: tDCSanodal, tDCScathodal, tDCSsham; 1, 2, and 3 months follow up

3 months

hand grip strenght shoulder

120%

79%

50%

193%

132%

125%

88%

113%

10%

147%

175%

75%

abduction rMTcontrales rMTipsiles aMTcontrales aMTipsiles

-2%

-4%

-3%

"-20% (**)

"-14% (*) -1%

"-6% (*)

-1%

-4%

"-21% (**)

"-14% "-8% (*) (*) correlation between the change in MT and increase in grip strength

Page 26 of 32

Table(s)

20 participants; age 1 mA 30 min 58,8±13,8 years; 35,4±22,4 months after the stroke; ischemic subcortical stroke; moderate to mild motor impairment of upper limb

5

14 participants; age 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

10

2 mA

40 min

Study design

Study description

Assesment

doubleblind; parallelgroup; shamcontrolled; longitudinal

2 experimantal groups: tDCSbilateral, tDCSsham; 3 and 7 days follow up

FM(UL) WMFT

doubleblind; parallelgroup; shamcontrolled; longitudinal

2 experimental groups: tDCSbilateral + CIMT, tDCSsham + CIMT; 2 and 4 weaks follow up

Outcome tDCS bilateral tDCS anodal

Follow up

tDCS cathodal

tDCS sham

tDCS bilateral

tDCS tDCS anodal cathodal

tDCS sham

15.0%

3.0%

16.0%

3.0%

15.0%

5.0%

16.0%

6.0%

4

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

4 weeks

3

JTHF

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

t

Number section

ip

Duration

cr

Stimulation Intensity

OGSC

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

0%

1%

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

1

9 participants; age 53,5±20,7 years; 28,3±10,4 days after the stroke; ischemic (n=8) and hemorrhagic (n=1), cortical and subcortical stroke; upper limb impairment: na

15% (*) A: 11% (*) 8% (*)

longitudinal 3 experimental ; parallelgroups: group tDCSanodal, rTMSinhibitory, DCSanodal+rT MSinhibitory; 1 session; 30min and 7days follow up

pt

19 participants; age 1 mA 61±9 years; 2,6±1,5 years after the stroke; ischemic (n=16) and hemorrhagic (n=2), subcortical (n=7) and cortical (n=11) stroke; moderate to mild motor impairment of upper limb

30 min

1

1

singleblind; shamcontrolled; crossover

2

patients with subcortical lesion: the effect after tDCSbilateral was almost twice as large compared with tDCS cathodal and tDCSanodal

7 days

rTMS+ tDCS

tDCS

rTMS

rTMS+ tDCS

tDCS

0

rTMS

pinch force

14% (**)

-1%

9% (*)

acceleration

22%

10%

22%

26%

11% 22%

bimanual coordination

5%

7%

24% (**)

8%

6%

8%

"-24% (**)

-3%

"-21% (**)

MEPcontrales MEP ipsiles

1,5mA 15 min

1%

B: 4%

an

double5 experimental JTHF blind; sham- sessions: controlled, tDCSbilateral, randomized tDCScathodal, ; crossover tDCSanodalA (cathode over contralateral supraorbital area), tDCSanodalB (cathode on contralateral deltoid muscle), tDCSsham

M

1 mA 20 min tDCS 1Hz rTMS 90% rMT

1

ed

20 min

Ac ce

27 participants; age 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

1mA

us

correlation between TI ipsiles- and JTHF- changes (r=-0,55) 10 participants; age 60,8±14,1 years; 8,3±5,5 months after the stroke; ischemic cortical (n=7), subcortical (n=2) and brainstem (n=1) stroke; morderate to mild motor impairment of upper limb

24% (**) 5% 19% (*)

24% (**) 20% (**) 22% (*)

0%

-1%

3%

-2%

-3%

3%

TCI contrales

-14%

-9%

"-24%

1%

1%

1%

TCI ipiles

16%

-2%

2%

-1%

2%

-1%

"-25% (**)

-3%

"-26% (**)

5%

1%

5%

TCI ratio

correlation between pinch force- and TIC ratio-changes (r=-0,477) correlation between bimanual coordination- and TCI contrales-changes (r=-0,486)

3 experimental groups: tDCSanodal (n=3), tDCScathodal (n=3), tDCSbilateral (n=3)

NHPT

14%

34%

19%

"-1%-11%

-

-

-

-

grip force

-7%

0%

13%

0%

-

-

-

-

0%

13% (*)

randomized 2 experimental ; doublesessions: PPT blind; sham- tDCSbilateral+ grip force controlled; MT, learning index crossover; tDCSsham+MT; longitudinal 30min, 60min and 1 weak follow up

1 Woche

19%

(**)

-1% na

(**)

-4%

0%

na

44%

1

4 3% 5%

(**)

4%

Page 27 of 32

Table(s)

Stimulation Intensity

13 participants; age 66 years; 1mA time after stroke: na; lesion location: na; etiology of stroke: na; moderate to mild impairment of upper limb

Duration Number section

20 min

1

Study design

Study description

Assesm ent

shamcontrolled; crossover

4 experimental sessions: tDCSbilateral, tDCSanodal, tDCScathodal, tDCSsham

reaction time

Outcome tDCS bilateral

tDCS anodal

Follow up

tDCS cathodal

tDCS sham

tDCS bilateral

2%(*) 6%(*) 0%(*)

-7%

-

tDCS tDCS anodal cathodal

-

tDCS sham

-

-

OGSC

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

Refere nce

0

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)

motor imagery Brain-Computer Interface

RAAT

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

ip

cr

Box and Block Test

us

bilateral robot training

BBT

Ac ce

pt

ed

M

an

BRT

robot-assisted arm training

t

MI-BCI

Page 28 of 32

Table(s)

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 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) of this with a statistical significance

6 (n=112) 4 (n=83) of this with a statistical significance

placebocontrolled trials without a positive effect

2 (n=146)

0 (n=0)

0 (n=0)

placebocontrolled trials with follow up

5 (n=214)

6 (n=270)

placebocontrolled trials with a positive effect by follow up

3 (n=88) 1 (n=30) of this with a statistical significance

6 (n=270) 3 (n=116) of this with a statistical significance

3 (n=53) 2 (n=33) of this with a statistical significance

placebocontrolled trials without a positive effect by follow up

2 (n=146)

0 (n=0)

0 (n=0)

ip

t

facilitatory tDCS

Ac ce

pt

ed

M

an

us

cr

3 (n=53)

Page 29 of 32

Figure

Ac

ce pt

ed

M

an

us

cr

ip t

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.

Page 30 of 32

Figure

Ac

ce pt

ed

M

an

us

cr

ip t

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.

Page 31 of 32

Figure

Ac

ce pt

ed

M

an

us

cr

ip t

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.

Page 32 of 32