tdcs-enhanced motor and cognitive function in neurological diseases

8/20/2019 TDCS-Enhanced Motor and Cognitive Function in Neurological Diseases

1/43

tDCS-enhanced motor and cognitive function in neurological diseases

Agnes Fl öel

PII: S1053-8119(13)00600-9DOI: doi: 10.1016/j.neuroimage.2013.05.098Reference: YNIMG 10537

To appear in: NeuroImage

Accepted date: 23 May 2013

Please cite this article as: Fl¨ oel, Agnes, tDCS-enhanced motor and cognitive function inneurological diseases, NeuroImage (2013), doi: 10.1016/j.neuroimage.2013.05.098

This is a PDF le 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 nal form. Please note that during the production processerrors may be discovered which could affect the content, and all legal disclaimers thatapply to the journal pertain.

http://dx.doi.org/10.1016/j.neuroimage.2013.05.098http://dx.doi.org/10.1016/j.neuroimage.2013.05.098http://dx.doi.org/10.1016/j.neuroimage.2013.05.098http://dx.doi.org/10.1016/j.neuroimage.2013.05.098


2/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

1

tDCS-enhanced motor and cognitive function in neurological diseases

Agnes Flöel

Department of Neurology, Center for Stroke Research, and NeuroCure Cluster of

Excellence, Charité University Medicine

Running title:

tDCS in neurological disease

Address correspondence to

Agnes Flöel, MDDepartment of Neurology, Charite Universitätsmedizin BerlinCenter for Stroke Research Berlin, andNeurocure Cluster of Excellence BerlinChariteplatz 1,10117 BerlinGermanyFon: +49 30 450 660284Fax: +49 30 450 7560284


3/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

2

AbstractTranscranial direct current stimulation (tDCS) is a noninvasive brain stimulation tool that isnow being widely used in neuroscientific and clinical research in humans. While initial studiesfocussed on modulation of cortical excitability, the technique quickly progressed to studies onmotor and cognitive functions in healthy humans and in patients with neurological diseases.In the present review we will first provide the reader with a brief background on the basicprinciples of tDCS. In the main part, we will outline recent studies with tDCS that aimed atenhancing behavioural outcome or disease-specific symptoms in patients suffering from mildcognitive impairment, Alzheimer’s Disease, movement disorders, and epilepsy, or persistentdeficits after stroke. The review will close with a summary statement on the present use oftDCS in treatment of neurological disorders, and an outlook to further developments in thisrealm. tDCS may be an ideal tool to be administered in parallel to intensive cognitive ormotor training in neurological disease, but efficacy for the areas of activities and participationstill needs to be established in controlled randomized trials. Its use to reduce disease-specificsymptoms like dystonia or epileptic seizures is still unclear.

Keywords: non-invasive brain stimulation, Alzheimer’s disease, Parkinson’s disease,dystonia, epilepsy, aphasia, neglect, motor paresis


4/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

3

1. Introduction

The basis for using non-invasive brain stimulation (NIBS) in human studies in health anddisease is its potential to modulate cortical excitability and plasticity. Transcranial magneticstimulation (TMS) and transcranial direct current stimulation (tDCS) have been mostextensively explored in neuroscientific and clinical research so far. Here, we will focus ontDCS; for TMS, see contribution XY in this issue.tDCS modulates cortical excitability by application of weak electrical currents in the form ofdirect current brain polarization. Depending on direct current (DC) polarity, neuronal firingrates increase or decrease, presumably due to DC-induced changes in resting membranepotentials (Liebetanz et al., 2002; Nitsche et al., 2003b), with anodal tDCS in most settingsincreasing, and cathodal tDCS decreasing motor-cortical excitability (Nitsche and Paulus,2000, 2001). The after-effects of tDCS on cortical excitability are modulated by N-methyl-D-aspartate (NMDA) receptor-dependent processes (Nitsche et al., 2004). Furthermore, animaland human studies indicated that tDCS influences long-term potentiation (LTP)- and long-term depression (LTD)-like mechanisms (Liebetanz et al., 2002; Nitsche et al., 2003a). Bothimmediate and after-effects of tDCS are susceptible to external modulation withdopaminergic and serotonergic agents (Monte-Silva et al., 2010b; Nitsche et al., 2009).

Two main strategies for using tDCS to modulate brain function can be distinguished: The firstis to increase cortical excitability or training-induced LTP-like mechanisms in the area ofinterest. Increasing the excitability of neurons in one brain region may promoteimprovements in performance possibly by facilitating LTP-like processes between activatedneurons (Liebetanz et al., 2002). Practising certain behaviours, such as finger movements inthe motor system, naturally heightens motor-cortical excitability (Garry et al., 2004; Koenekeet al., 2006). Therefore, increasing excitability with brain stimulation, whether directly orindirectly, may provide a means of inducing a physiological state that supports acquiringnovel skills (Floel and Cohen, 2010), or may even facilitate off-line learning (Reis et al.,2009).Second, tDCS may be used to inhibit networks. Thus, the behaviour under study will bedisturbed in most set-ups, thus primarily providing evidence about the functional involvementof the specific area for the task under study. This interesting and widely used approach in

neuroscientific research is not the topic of the present review though (to be discussed incontribution XY of this issue). However, note that even inhibitory stimulation can be used toimprove brain function in certain settings, for example after unihemispheric stroke: Here, anarea would be inhibited that interferes with performance, for example an “over-active” righthemispheric region in aphasic patients. Down-regulation of this area would dampen inhibitoryprojections from this area to left-sided language relevant areas, releasing the injuredlanguage area from (over-)inhibition of the other side, and thereby improving its function.Moreover, hyperactive cortical areas as seen for example in dystonia and epilepsy may beinhibited to reduce disease-specific symptoms. Inhibitory tDCS in these settings will bediscussed.The present review will describe the use of tDCS in patients with mild cognitive impairment,Alzheimer’s Disease, movement disorders, epilepsy, and in post-stroke rehabilitation ofmotor and cognitive deficits. Each section will start with a brief introduction to corresponding

studies in healthy individuals (to be discussed primarily in contribution XY of this issue), andthen proceeds in detail to patient work. We will end with a conclusion section on the use oftDCS in the neurological realm and a roadmap to future developments in this research area.For details on tDCS parameters used in the respective studies, please refer to Table 1.


5/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

4

2. Mild cognitive impairment and Alzheimer’s Disease: Does tDCS enhance learningand formation of novel memories? Memory is the ability to store, maintain, and retrieve information from the mind. Memorydeclines with physiological aging, and memory loss, particularly deficits in the ability to formnovel memories, is characteristic of mild cognitive impairment (MCI) and Alzheimer’s disease(AD) (Sperling et al., 2011). Moreover, reduced specificity within dedicated cortical networks,e. g., the default mode network (Geerligs et al., 2012; Liu et al., 2013; Wang et al., 2013)have been noted in both aging and MCI/AD. Given the paucity of treatment options in theseconditions with regard to pharmacological interventions, strategies for non-pharmacologicalenhancement including cognitive training (Jean et al., 2006), physical activity (Kramer andErickson, 2007), or nutrition supplements (Janssen et al., 2010) as well as noninvasive brainstimulation techniques like tDCS and TMS (Floel and Cohen, 2010) have gained increasingattention over the last years. Here, atDCS with its potential to enhance neural plasticity (Floeland Cohen, 2010; Liebetanz et al., 2002) and within-network connectivity (Antonenko andFloel, in press; Meinzer et al., 2012) offers an exciting novel strategy.In healthy older individuals, several studies have demonstrated the potential of tDCS toenhance cognitive functions or learning processes so far. For example, remembering thelocation of objects, an integral part of everyday life, is known to decline with advancing ageand early in the course of neurodegenerative dementia. In a randomized cross-over studyusing anodal tDCS (atDCS; 1 mA, 20 min) over right temporoparietal cortex, improved recallone week after object-location learning under atDCS, compared to object-location learningunder sham, was demonstrated in 20 healthy elderly individuals (Floel et al., 2011b). In patients that already suffer from AD, two studies so far studied the immediate effects ofatDCS on recognition memory: Ferruci and colleagues examined 10 patients with probableAD, using recognition memory and visual attention tasks (Ferrucci et al., 2008). In arandomized cross-over study, they delivered either atDCS, cathodal (c)tDCS (1.5 mA, 15 mineach), or sham over bilateral temporoparietal areas (two stimulation electrodes) in threedifferent sessions. Tasks were tested at baseline and 30 minutes after tDCS ended. It wasfound that after atDCS, accuracy of the word recognition memory task increased, whereas itdecreased after ctDCS and remained unchanged after sham. Visual attention-reaction timesalso remained unchanged. A subsequent study investigated the impact of atDCS onrecognition memory, working memory (WM), and selective attention in AD (Boggio et al.,

2009). Ten patients received three sessions of tDCS (atDCS over left DLPFC, atDCS overleft temporal cortex, 2 mA, 30 min each; or sham), in a randomized cross-over design. Ateach session, Stroop, Digit Span, and a Visual Recognition Memory task (VRM) wereperformed. A significant improvement of VRM was found after temporal and prefrontal atDCScompared with sham. No significant changes in attention as indexed by Stroop taskperformance were noted. While these two studies demonstrated that atDCS may enhance acomponent of recognition memory, patient numbers were small and effects only short-lasting.A subsequent study then examined the impact of a more sustained protocol in AD patientson VRM (Boggio et al., 2011). Here, five consecutive sessions of atDCS, versus sham, wereadministered in a randomized cross-over design in 15 patients. Cognitive functions wereevaluated before and after atDCS (2 mA, 30 min; two stimulation electrodes bilaterally overtemporoparietal areas) or before and after sham. After atDCS, performance in VRMsignificantly improved, while even a small decline was noted after sham. The atDCS effect

persisted for at least 4 weeks. No effect on general cognitive performance measures or avisual attention measure was found.In sum, these first results are encouraging, but it remains unclear if learning per se, orconsolidation, may actually be enhanced by tDCS. Ongoing studies in our group assess theimpact of atDCS in MCI patients on semantic word generation (ClinicalTrials.gov Identifier:NCT01771211), and results will hopefully be available in 2013/2014. Moreover, the mosteffective stimulation parameters are still unclear: Boggio and colleagues used 30 min of 2mA tDCS, a stimulation regime that might even lead to a saturation or reversal of the tDCSeffects, as neurophysiological results in healthy subjects suggested (Monte-Silva et al.,2012). However, the impact of 30 min, 2 mA tDCS on cortical excitability in patients with AD(different neurotransmitter concentrations and excitability at baseline, see (Nardone et al.,


6/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

5

2011)) is yet unknown and should be further explored. Also, bilateral stimulation overtemporoparietal areas with the deltoid as reference in the studies on AD patients will haveled to a markedly different current flow compared to the majority of previous tDCS studiesthat used a cephalic reference montage (for review see (Nitsche and Paulus, 2011)). Thus,putative mechanisms of the demonstrated cognitive effects with an extracephalic referenceelectrode remain unclear. Finally, none of the previous studies so far assessed the impact oftDCS plus training on activities of daily living, participation, or quality of life, an importantendeavour for future clinical trials.

3. Movement disorders3. 1 Dystonia: Does tDCS reduce dystonic symptoms?Dystonia is associated with a loss of inhibition at multiple levels of the neuraxis includingspinal cord, brainstem and cortex. The excessive and inappropriate muscle activationpatterns seen in patients with focal dystonia reflect disinhibition of cortical-subcortical motorcircuits which may be a consequence of abnormalities of sensorimotor integration andmaladaptive plasticity (Hallett, 2006).Thus, down-regulation of cortical excitability by ctDCSseems to be the treatment of choice.However, ctDCS that suppresses excitability in control subjects (Nitsche and Paulus, 2011)may actually increase excitability in dystonia patients (for review see (Wu et al., 2008)). Infact, a carefully controlled study by Quartarone et al (Quartarone et al., 2005) that testedseveral protocols of rTMS and tDCS suggested a disruption of normal homoestatic regulationof excitability in response to both ctDCS and rTMS, and suggested that neither a singlesession of excitatory nor of inhibitory tDCS may restore normal mechanisms of plasticity inthese patients. Consistent with this notion, a recent controlled cross-over study by Buttkus etal (Buttkus et al., 2011) found that neither atDCS nor ctDCS (2 mA, 20 min) applied overprimary motor cortex (M1) in nine professional pianists suffering from musician’s dystoniaduring retraining (slow, voluntary controlled movements on the piano), improved symptomsof dystonia as compared to sham. Recently, an open-label trial in children with dystonia thatapplied ctDCS (1 mA, 2 x 9 min, separated by 20 min) over M1 contralateral to the handmost affected by dystonia found a significant reduction in muscle overflow during taskperformance in 3 out of 10 children, but a behavioural improvement, indicated by reducedtracking errors, in only one (different) child (Young et al., 2012). A single-case study (not

included in Table 1) of repeated transcranial alternating current stimulation (tACS; 15 Hz, 1.5mA, 20 min; 25 cm 2 sponge electrodes over M1 left and right, that is, at C3 and C4 accordingto the international 10/20 EEG electrode system), were applied on 5 consecutive days. Theauthors found both immediate and cumulative effects greater than 50% on dystonicsymptoms in clinical dystonia rating scales (Angelakis et al., 2013). CtDCS over right M1 on5 consecutive days (1.5 mA, 15 min; compared to sham) on the other hand, did not inducesignificant behavioural changes.In sum, for dystonia, tDCS parameters still need to be fine-tuned in order to achieve abeneficial effect on clinical symptoms. Importantly, simply up-or downregulating corticospinalexcitability may not be sufficient to ameliorate clinical deficits in this group. Rather,stimulation parameters need to modulate disrupted homoestatic regulation of excitability inresponse to training protocols. Here, entrainment of cortical oscillatory brain activity, as forexample used in Pogosyan (Pogosyan et al., 2009) (see below), may be a promising option.

3.2 Parkinson’ s disease: Does tDCS reduce bradykinesia and rigidity, and improvecognitive deficits particularly with regard to executive functions and workingmemory?Idiopathic Parkinson’s syndrome (IPS) is characterized by core symptoms of motor features(resting tremor, rigidity, bradykinesia and postural instability), as well as non-motormanifestations including cognitive dysfunction (Bernal-Pacheco et al., 2012), particularlythose related to the prefrontal cortex (executive, WM).With regard to motor symptoms, previous studies demonstrated altered excitability of M1 inIPS patients, particularly in the un-medicated state (Pascual-Leone et al., 1994), andproposed that the dysfunction of the basal ganglia caused by low concentration of dopamine


7/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

6

may result in an adaptive beneficial increase of cortical excitability to compensate for theunderactive pallido–thalamo– cortical drive ((Lefaucheur et al., 2004; Siebner et al., 1999),see (Fregni et al., 2004)) for review. Thus, enhancing cortical excitability by atDCS mayfurther increase cortical excitability and enhance this compensatory mechanism, therebyimproving motor function. Moreover, stimulation may rebalance distributed neural networkactivity, and induce release of dopamine in patients with IPS (for review see (Wu et al.,2008)). With regard to cognitive symptoms, reduced ability to encode novel memories, aswell as reduced specificity within dedicated cortical networks may likewise offer a target foratDCS, see section 2 on MCI and AD. In line with these theories, tDCS has been used tomodulate motor and cognitive functions in IPS in previous studies.Motor functionsIn a first controlled randomized study, Fregni and colleagues (Fregni et al., 2006a) studiedthe effects of atDCS over M1 (1 mA, 20 min) and DLPFC in patients with IPS in the off-state.They found significantly enhanced motor function, as indicated by simple reaction time andmotor scores of unified Parkinson’s Disease rating scale (UPDRS), compared to sham, afterM1 stimulation only. With regard to mechanisms underlying the effect, the authorsdemonstrated that atDCS led to a parallel increase in corticospinal excitability (MEP size,and area under the curve). A further randomised sham-controlled study assessed theefficacy of atDCS applied alternatingly over motor cortex (electrode centre 10 mm anterior toCz) and prefrontal cortex (forehead above eyebrows) over repeated sessions (eight sessionsover 2.5 weeks; starting with the motor location), in a total of 25 patients. Note thatstimulation was thus relatively weak, being applied only every third or forth day over eachcortical area. Primary outcome measure was speed of gait after 3 months, but secondaryoutcomes also included bradykinesia of upper extremities, the UPDRS, the serial reactiontime task and a depression inventory. It was found that alternating motor/prefrontalstimulation improved gait, as evaluated by speed measures, one day after stimulation, andbradykinesia in both on and off states after 3 months, compared to sham. No changes inUPDRS and reaction time could be ascertained (Benninger et al., 2010). Interestingly,Pogosyan et al (Pogosyan et al., 2009) demonstrated that transcranial alternating-currentstimulation could be used to entrain cortical activity at 20 Hz in healthy subjects, at the sametime slowing movements. This study provides the first direct evidence of causality betweenphysiological oscillatory brain activity and concurrent motor behaviour in healthy humans and

may help explain how the exaggerated beta activity found in IPS could be modulated by non-invasive brain stimulation. Note however that in the Benninger trial, stimulation parametersboth with regard to alternating motor and prefrontal cortex stimulation, as well as placementof reference electrode, were dissimilar from most previous neurophysiological trials, so themechanisms of this specific stimulation mode need to be further explored, and to be directlycompared to stimulation of M1 only.Cognitive functionsBoggio and colleagues examined modulation of WM performance in IPS (Boggio et al.,2006). Eighteen patients performed a three-back WM task during atDCS of the left DLPFC,atDCS of M1, or sham. In addition, patients underwent two different types of stimulation withintensities of 1 and 2 mA, respectively. The authors found a significant improvement in WM,as indexed by task accuracy, after atDCS of the left DLPFC with 2 mA. The other conditionsdid not result in a significant task performance change. Their findings were corroborated by a

recent controlled cross-over study that demonstrated that atDCS (2 mA, 20 min) over DLPFCenhanced performance on a phonemic fluency task, and increased functional connectivity inverbal fluency and deactivation in task-related networks (Pereira et al., 2012).In sum, further trials with larger number of patients that focus on outcome measures like theUPDRS may help move the technique closer to clinical practise for treatment of motorsymptoms in IPS, and should now be initiated.With regard to cognitive functions, first evidence has been provided that atDCS overprefrontal cortex may exert beneficial effects. However, these studies only appliedstimulation once and examined immediate effects. In the future, combined training protocolswith repeated atDCS application and long-term outcome need to be conducted to establishthe clinical efficacy for treatment of cognitive deficits in IPS.


8/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

7

4. Epilepsy: Does tDCS reduce seizures or suppress epileptiform discharges? In epileptic seizures, there is an enhanced probability of neuronal networks to firesynchronously at high frequency, initiated by a paroxysmal depolarisation shift. A commongoal in antiepileptic drug therapies is therefore to reduce the occurrence of epileptic seizuresby reducing neuronal excitability (for review, see (Nitsche and Paulus, 2009)), suggestingctDCS as a potential therapeutic tool in epileptic disorders, particularly in drug-resistantpatients.The potential of weak direct currents to locally suppress epileptiform activity was nicelydemonstrated in rat hippocampal slices, see eg (Lian et al., 2003). Subsequently, Liebetanzand colleagues (Liebetanz et al., 2006) evaluated the effects of ctDCS on the occurrence ofepileptic seizures in animal models in vivo. Here, a modified cortical ramp-stimulation modelfor focal seizures was used in freely moving rats. 60 min of ctDCS at 100 µA resulted in anincrease of threshold for localized seizure activity (TLS) that lasted for at least 2 hours.Application of 200 µA induced a similar TLS elevation after 30 min stimulation only.Following these hopeful observations, several smaller studies in human patients wereconducted, with mixed findings so far: A first positive study was reported by Fregni andcolleagues (Fregni et al., 2006b) in a randomized between-subject approach. Here, 19patients with malformations of cortical development and refractory epilepsy underwent ctDCS(1 mA, 20 min) over the epileptogenic focus, or sham. The authors found a significantreduction in the number of epileptiform discharges in the ctDCS group compared to the shamgroup, and a trend for decrease in seizure frequency in favour of the ctDCS group. No sideeffects were noted. Thus, ctDCS appears to be save, and might have an antiepileptic effectbased on clinical and electrophysiological criteria in patients with medication –refractoryepilepsy. These positive effects were corroborated following a longer stimulation protocol in asingle patient: Yook and colleagues (Yook et al., 2011) reported a case of a patient with focalcortical dysplasia of one hemisphere, with medication –refractory seizures. ctDCS (2 mA, 20min daily) over an area with abnormal waves during sleep EEG, over a total of 10 days, ledto a decrease in seizure occurrence and frequency over the following 2 months. This wasfollowed by a second 10-day course of ctDCS, which reduced the seizure frequency toalmost zero. However, a recent study by Varga et al (Varga et al., 2011) tested the potentialof ctDCS (1 mA, 20 min, before sleep; placed on the epileptic focus) to reduce continuous

epileptiform activity during sleep, and reported that spike index remained unchanged in all 5patients. However, note that stimulation was applied before sleep, and thus beforeepileptiform activity was established.In sum, ctDCS may be an optional tool to reduce seizure activity in this difficult-to-treatpatient group, particularly since the side effect profile seems to be excellent. However, abetter definition of stimulation parameters needs to established, as well as larger clinicaltrials with longer follow-up (for review see (Nitsche and Paulus, 2009)).

5. Post-stroke rehabilitation

The largest body of evidence so far has been collected on treatment of post-stroke deficits.In general, one of two main strategies have been used: Either facilitation of the lesionedhemisphere, using atDCS, inhibition of the contralesional hemisphere using ctDCS (each

with a relatively inactive contralateral reference electrode; achieved by placing this electrodeover supraorbital area in most cases and, in some cases, by enlarging it to a size of 10cm x10cm), or a combination of both approaches, with the anodal electrode over the lesioned andthe cathodal electrode over the contralesional hemisphere, termed “dual tDCS”. While atDCSover the lesioned hemisphere may beneficially influence recovery of lost function by itsexcitability-enhancing properties that possibly facilitate LTP-like processes between activatedneurons (Liebetanz et al., 2002), ctDCS over the non-lesioned hemisphere will down-regulate areas that are “over-active” and hamper restitution of networks in the lesionedhemisphere, see Section 1 above for more details.

5.1 Motor functions: Does tDCS improve function of the paretic limb after stroke?


9/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

8

In healthy individuals, a number of trials have demonstrated improved motor function andlearning (for review see (Reis et al., 2008)). If atDCS plus learning sessions wereadministered repeatedly, retention of the beneficial effects lasted up to several months (Reiset al., 2009).In subacute stroke patients, a first non-controlled pilot study by Hesse et al (Hesse et al.,2007) included 10 patients with severe arm paresis days to weeks after the stroke. atDCS(1,5 mA, 7 min) was applied over M1 during the first minutes of a 20 min robot-assisted armtraining sessions, over a total of 30 sessions. The Fugl-Meyer (FM) score was the primaryoutcome measure in all patients; in 5 patients with concomitant aphasia, also the AachenerAphasia Test (AAT) was assessed (for details on language part, see below, “Language”section). The authors found that in 3 patients (2 with subcortical, 1 with cortical lesion), FMscores increased markedly (from 6 to 28, 10 to 49 and 11 to 4 points, respectively), while inthe remaining 7 patients (all cortical lesions), little functional improvement was achieved. Kimand colleagues (Kim et al., 2009) tested, in a randomized controlled between-subject design,subacute stroke patients after either atDCS (1 mA, 20 min) or sham for Box and Block testand finger acceleration measurement, immediately, 30 min, and 60 min after stimulation, andfound significantly improved performance in the Box and Block test for at least 60 min afterstimulation, in finger acceleration until 30 min after stimulation. These first encouragingresults in small patient cohorts and experimental outcome measures were followed by twolarger studies, one with a positive (same authors), the other with a negative outcome: In onetrial, 18 patients were tested with a 10 day treatment of either atDCS over ipsilesional M1 (2mA, 20 min), ctDCS over contralesional M1 (2 mA, 20 min), or sham, delivered during thebeginning of a 30 min occupational therapy session (Kim et al., 2010), in a randomizedcontrolled between subject study. No significant differences were found between conditions 1day after stimulation, however, 6 months later, patients that had been treated with ctDCSshowed a greater improvement in FM score (but not modified Barthel Index (BI)) than shampatients. Even though the authors pointed out that FM score and modified BI had beencomparable between groups at baseline, small differences in baseline scores in the groups(6 patients only in each) may have influenced the outcome. A subsequent study by Rossi etal (Rossi et al., 2012) evaluated the effect of atDCS (2 mA, 20 min, over ipsilesional M1,delivered daily over 5 subsequent days), compared to sham, on NIHSS score and FM score,in a large group of 50 patients in a randomized controlled between-subject study. Here, no

significant improvement in motor function was demonstrated. However, note that this studydid not apply a specific training in parallel to stimulation, and also did not verify that patientsincluded into the study had an intact M1 (Fregni et al., 2005; Hummel et al., 2005).A further multi-center trial incorporating a specific training in parallel to stimulation, andincluding only patients with intact M1, is still ongoing in Germany (Gerloff et al, Hamburg),assessing the impact of daily atDCS (1 mA, 20 min) over the affected hemisphere onfunctional motor outcome (FM) in patients with subacute stroke (ClinicalTrials.gov Identifier:NCT00909714).

The largest body of studies so far has been conducted in the chronic phase after stroke.In the motor domain, two controlled cross-over studies published in 2005 (Fregni et al., 2005;Hummel et al., 2005) showed for the first time that atDCS (1 mA, 20 min), applied overaffected M1 in chronic stroke patients (6 patients each), improved performance in a task of

skilled hand function (Jebsen Taylor Test of Hand Function, JTT). The effect however wasshort-lasting and no longer discernable after 7 days. With regard to mechanisms underlyingthis improvement, Hummel et al were demonstrated that behavioural improvement correlatedwith an increment in motor cortical excitability within the affected hemisphere, expressed asincreased recruitment curves and reduced short-interval intracortical inhibition. Stagg andcolleagues examined mechanisms underlying performance increases on the network level, ina randomized controlled cross-over study on 13 (behavioural) and 11 (fMRI) study, usingatDCS over lesioned M1, ctDCS over contralesional M1 (1 mA, 20 min each), or sham . Inaddition to the effects of atDCS over the lesioned hemisphere (M1) on motor function (13patients), the authors found that the significant improvements in response times with theaffected hand after atDCS to the ipsilesional M1 were associated with an increase in


10/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

9

movement-related cortical activity in stimulated M1 and functionally interconnected regions,as shown on fMRI (11 patients). ctDCS to contralesional M1 led to a functional improvementonly when compared with sham (Stagg et al., 2012). Zimerman and colleagues (Zimerman etal., 2012b) then demonstrated that ctDCS over contralesional M1 (1 mA, 20 min) facilitatedthe acquisition of a new motor skill compared to sham in 12 chronic stroke patients.Differential tDCS-induced behavioural changes were correlated with a tDCS-inducedchanges in intracortical inhibition. Subsequent studies were able to demonstrate a long-lasting effect of the combined approach of atDCS and training. For example, Boggio et al(Boggio et al., 2007) showed in a randomized controlled cross-over study that consecutivedaily sessions of atDCS over lesioned or ctDCS over contralesional M1 (4 sessions, appliedonce a week over a period of 4 weeks, 1 mA, 20 min each), compared to sham, wereassociated with a significant functional improvement, as assessed with the JTT, that lastedfor 2 weeks after treatment. In 96 patients with cortical infarcts and persistent severe deficits,Hesse and colleagues (Hesse et al., 2011) assessed in a randomized controlled study theeffect a high-repetition bilateral arm movement on a robotic assistive device plus either 6weeks of atDCS (2 mA, 20 min) over lesioned M1, ctDCS (2 mA, 20 min) over contralesionalM1, or sham. All groups improved significantly with training, but no significant differencebetween stimulation conditions could be ascertained. Here, it should be noted that severelyaffected patients (FMS at start of study below 10) were included that may not benefit fromexternal up-regulation of the injured or down-regulation of the healthy hemisphere. Moreover,in parallel to down-regulation of the healthy hemisphere or up-regulation of the injuredhemisphere by brain stimulation, bilateral arm training was applied, which may havecounteracted the effects of brain stimulation (that is, up-regulated the healthy hemisphereand, via transcallosal inhibition, down-regulated the injured hemisphere).A recent trial by Wu and colleagues (Wu et al., 2013) focused on the effects of tDCS onspasticity. Here, the authors in 90 patients ranging from the subacute to the chronic stage,using a between-subject design 90, that patients receiving conventional physical therapy andctDCS over lesioned M1 (1.2 mA, 20 min, 5 days per week over 4 weeks), compared tothose receiving conventional physical therapy and sham, showed significantly moreimprovement in spasticity, as assessed by the modified Ashworth scale, both immediatelyafter stimulation and 4 weeks later. In parallel, measures of motor function and activities ofdaily living (FMS and Barthel Index, respectively), improved significantly more in the tDCS

group. Note that contrary to previous trials, inhibition of the lesioned hemisphere led tosignificant behavioural changes, possibly mediated by the decrease in spasticity. Analternative explanation would be that ctDCS, applied over the lesioned hemisphere in strokepatients, actually led to an increase in excitability, as suggested by a recent studyneurophysiological study of the affected hemisphere in stroke patients by Suzuki andcolleagues (Suzuki et al., 2012). Thus, ctDCS could facilitate recovery of motor functions inpatients via the well-described excitability-enhancing mechanisms previously described foratDCS (see sections above for details). These hypotheses should be systematically exploredby including parallel measures of cortical excitability, spasticity and motor function in trials oftDCS in stroke patients in the future.Turning to the lower extremity, a double-blind within-subject sham-controlled study byTanaka and colleagues (Tanaka et al., 2011) in 8 chronic stroke patients demonstrated thatatDCS over the leg representation of the lesioned hemisphere (1 mA, 20 min) led to an

increase in maximal knee extension-force. Furthermore, Madhavan and colleagues(Madhavan et al., 2011) demonstrated that fine motor control of the hemiparetic ankle in 9chronic stroke patients was significantly larger after training plus atDCS over the respectivecortical area (equivalent of 2 mA, 15 min) compared to training plus sham. However, theeffects of these single-session atDCS applications persisted for less than 30 min (Tanaka etal., 2011), or follow-up sessions were not even included (Madhavan et al., 2011). Followingthese hopeful results of short protocols, a subsequent study that applied atDCS combinedwith training over a longer time period could not ascertain a beneficial effect of thestimulation: Here, Geroin and colleagues (Geroin et al., 2011) examined the effect of atDCSover ipsilesional M1 on walking ability. 30 patients were randomized to receive either robot-assisted gait training combined with atDCS (1.5 mA, 7 min), robot assisted gait training with


11/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

10

sham, or overground walking exercises. No significant differences could be ascertained forwalking (six –minute walking test, 10 m walking test) immediately after treatment and 2weeks later between the robot-assisted groups.

A further area of interest with regard to motor rehabilitation pertains to post-stroke dysphagia.Since sensorimotor control of brain stem swallowing is known to be a function with bilateralcortical innervations (Hamdy et al., 1996), up-regulation of both hemispheres may exertbeneficial effects on swallowing, and in fact, both strategies have been followed in previousstudies. Kumar et al (Kumar et al., 2011) assessed 14 patients with subacute stroke andpersistent dysphagia, using standardized swallowing exercises plus atDCS (2 mA, 30 min)over the sensorimotor swallowing area within the unaffected hemisphere, vs sham, in arandomized controlled between-subject design. They found that patients under atDCSshowed significantly improved swallowing function, as assessed with the DysphagiaOutcome and Severity scale. The opposite strategy, with atDCS over the affectedhemisphere, was employed by Yang et al (Yang et al., 2012) who compared atDCS (1 mA,20 min) vs sham in a randomized controlled between-subject design (16 patients total),applied in parallel to a conventional swallowing training for 10 days. Outcome was assessedon the functional dysphagia scale at baseline, immediately after treatment and 3 monthslater. No differential effect of atDCS vs sham was noted directly following intervention, butthe atDCS group showed significantly better results 3 months later.Given the outcome scales used in these studies, differential effects of stimulation on the oralvs the pharyngeal phase of swallowing, which are controlled to a larger degree by the left orthe right hemisphere, respectively (Teismann et al., 2007), cannot be distinguished.Moreover, left and right hemisphere stimulation as such was not varied systematically inthese studies, so future studies will be necessary to determine if atDCS over left hemisphereis particularly beneficial in patients suffering from deficits in the oral phase, right hemisphereatDCS in patients suffering from deficits in the pharyngeal phase of swallowing.

The idea that inhibitory tDCS over the non-affected hemisphere in chronic stroke may bebeneficial for motor recovery was explored with tDCS for the first time in a randomizedcontrolled cross-over study on 6 patients by Fregni et al. (Fregni et al., 2005). Here, theauthors found that ctDCS (1 mA, 20 min) improved motor performance, as assessed with the

JTT immediately following M1 stimulation, compared to sham. Subsequently, Nair et al (Nairet al., 2011) found in a randomized controlled between subject study in 14 patients thatoccupational therapy plus ctDCS (1.5 mA, 30 min) over unaffected M1, compared tooccupational therapy with sham, led to significantly improved motor functions (FM scoreupper extremity, range-of-motion in multiple joints), with the effects outlasting the stimulationby at least 1 week. Interestingly, improvement in motor outcome scores was correlated withdecrease in functional activation (as assessed with fMRI) in the contralesional motor cortex.Recently, Zimerman et al. (Zimerman et al., 2012a) examined the effect of ctDCS (1 mA, 20min) over contralesional M1 on motor sequence learning not only during but also 1.5 and 24hours after the intervention in a randomized controlled cross-over design against sham in 12patients. ctDCS facilitated the acquisition of a new motor skill compared with sham, leadingto improvement of the early online learning period, which then translated into betterperformance for at least 24 hours. Furthermore, they were able to demonstrate a reduction in

intracortical inhibition, as assessed with TMS, in the lesioned hemisphere in the ctDCSsession that correlated with functional improvement.Combining atDCS of the lesioned and ctDCS of the contralesioned hemisphere in abihemispheric montage (“dual tDCS”), Lindenberg and colleagues (Lindenberg et al., 2010)tested 20 chronic stroke patients, in a randomized controlled design, with either 5consecutive daily sessions of dual tDCS (1.5 mA, 30 min) or sham, simultaneous tophysical/occupational therapy, over M1. They found greater improvement in motor functionafter dual tDCS for upper extremity FM score and Wolf Motor Function Test. Importantly, theeffect outlasted the stimulation session by at least one week. Turning to the neural correlatesof this effect, they demonstrated that dual tDCS induced stronger activation of ipsilesionalmotor regions during paced movements of the affected limb following training plus dual


12/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

11

tDCS, compared to training plus sham. This trial for the first time provides Class I evidencethat in adult patients with chronic stroke, dual tDCS plus training leads to a significantimprovement in motor function compared to training alone.In a further study, 14 patients with chronic stroke were randomized to receive eitherconstraint-induced movement therapy plus dual tDCS (2 mA, 40 min, over M1), orconstrained-induced movement therapy plus sham, over a total of 14 days (Bolognini et al.,2011). The authors found that motor function, as assessed by the JTT, handgrip strength,motor activity log scale, and FM score improved in both groups, but to a greater degree inthe dual tDCS group. Moreover, only the dual tDCS group showed a reduction intranscallosal inhibition (assessed with TMS) from the intact to the affected hemisphere andincreased corticospinal excitability in the affected hemisphere, correlated with the magnitudeof behavioural gains.However, the assumption that dual tDCS simply induces an additive effect of atDCS andctDCS may be an over-simplification. In a recent study by our own group (Lindenberg et al.,2012), we were able to show that active stimulation, compared to sham induced a more focalpattern of activation in the task-specific fMRI with a stronger effect of ‘dual’ than ‘anodal’stimulation; however, the overall pattern of atDCS and dual tDCS was similar. The restingstate analysis demonstrated altered connectivity within a multimodal network includingprimary and non-primary motor cortices as well as parietal and temporal regions. Inconclusion, the previously documented stronger behavioral effects of dual as compared tounihemispheric stimulation (Vines et al., 2008) may not be merely mediated by a “simple”add-on effect of cathodal stimulation, but rather due to complex bihemispheric networkmodulations.In sum, for the subacute stage after stroke, the impact of atDCS of the affected hemisphereon motor rehabilitation is still unclear, awaiting the results from am ongoing large trial fromGermany (ClinicalTrials.gov Identifier: NCT00909714). Stimulation without parallel training,and in patient population in whom an intact M1 of the injured hemisphere has not beenascertained, cannot currently not be recommended (Rossi et al., 2012). No firm conclusionscan be drawn about the use of ctDCS over the intact hemisphere in subacute stroke, butfurther pilot trials and subsequent RCTs are warranted.For the chronic stage after stroke, the impact of atDCS of the affected or ctDCS of theunaffected hemisphere in mild to moderately–affected patients has been demonstrated in

several pilot trial; larger RCTs with longer follow-up are still awaited here. Most promisingand consistent results in this stroke population have been seen with dual stimulation, wheretreatment with tDCS has been advanced to Class I level (see eg (Lindenberg et al., 2010)).However, confirmatory RCTs are still needed to advance this treatment to Level Arecommendation for clinical practice, see section 6 for further discussion. With regard toseverely affected chronic patients, atDCS of the affected or ctDCS of the unaffectedhemisphere cannot be recommended at this stage.For the use of tDCS in rehabilitation of lower extremity motor deficits or swallowing deficits,further pilot and subsequent RCTs are needed, see section above for details.

5. 2 Language functions: Does tDCS improve language functions, particularly namingability, after stroke?In the language domain, a number of studies have now demonstrated improved naming

functions in healthy individuals after atDCS over language-relevant areas (for review, see(Floel, 2012)). Thus, a possibly fruitful area for research emerges with regard to namingabilities in patients with post-stroke aphasia, in whom impaired word-retrieval (anomia) is themost frequent symptom, with little or now spontaneous improvement after the first 6 months(Bhogal et al., 2003). Here, tDCS could be an interesting adjuvant therapeutic device.However, in order to induce long-lasting changes in language performance, tDCS may haveto be administered in conjunction not only with a performance measure (to then improveimmediate performance), but rather concomitant to a learning task. The basic idea behindthis combination is that tDCS would modulate the learning process as such, and the resultinglearning effects could be retained over time. This principle was first applied in the realm oflanguage learning for acquisition of a novel vocabulary (Floel et al., 2008). Here, stimulation


13/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

12

was applied over the posterior part of the left perisylvian area in young right-handedindividuals, while participants had to acquire a miniature lexicon, either under atDCS, ctDCS(1 m, 20 min each), or sham, in a randomized controlled cross-over design. Under atDCS,subjects showed faster and better associative learning as compared to sham, followed bybetter transfer of the vocabulary into subjects’ native language in the atDCS group.In subsequent stroke studies, first promising results were gathered in the subacute stage in anon-controlled study already described above (Hesse et al., 2007). Here, atDCS (1,5 mA,7min) was given during the first minutes of a 20 min robot-assisted arm training sessions,over a total of 30 sessions. In 5 patients with concomitant aphasia, also the AAT wasassessed. Aphasia improved in 4 patients. A randomized controlled study by You et al (Youet al., 2011) examined the effect of conventional speech and language therapy, daily over 2weeks, plus either atDCS (2 mA, 30 min) over left superior temporal gyrus, ctDCS over rightsuperior temporal gyrus, or sham, in 21 patients with subacute stroke and persistent aphasia (comprehension deficits). They found that auditory verbal comprehension improvedsignificantly more in the ctDCS group compared to the two other groups. A further study ontreatment of aphasia (secondary outcome) in the subacute is likewise ongoing (Jöbges et al;ClinicalTrials.gov Identifier: NCT01701713).In the chronic stage, Baker and colleagues (Baker et al., 2010) included 10 patients with mildto moderate chronic aphasia in a controlled randomized cross-over study. They used atDCS(1 mA, 20 min) vs sham, applied during a concomitant computerised anomia treatment, over5 consecutive days, and compared the effects to anomia treatment plus sham. Positioning ofthe stimulation electrode was guided by a priori fMRI results for each individual during anovert naming task to ensure that the active electrode was placed over structurally intactcortex. The authors found significantly improved naming accuracy of treated items afteratDCS compared with sham, persisting for at least one week. Patients who demonstrated themost improvement were those with perilesional areas closest to the stimulation site. In asubsequent controlled randomized cross-over study by the same group, the authorsconcentrated on patients with fluent aphasia, and examined the effect of atDCS (1 mA, 20min) versus sham, on RT during overt picture naming using the same concomitantcomputerized training and method for electrode positioning, in 8 patients. Again, significantimprovements (that is, reduced RTs during naming of treated items) were found immediatelyafter treatment and 3 weeks later (Fridriksson et al., 2011).

In patients with moderate to severe aphasia after chronic stroke, stimulation of viable tissue,as well as improvement of language functions dependent on left-hemispheric networks,proves to be difficult. Here, activation of right-hemispheric homologue areas may be anoption to at least partly improve language function. Floel et al (Floel et al., 2011a) exploredthis possibility in a randomized controlled cross-over trial on 12 patients with persistentmoderate to severe aphasia. They tested atDCS versus ctDCS (1 mA, 20 min; 2 x daily over3 consecutive days) vs sham over right temporo-parietal cortex, applied in parallel to a 2hour daily high-frequency anomia training. atDCS significantly enhanced the overall trainingeffect compared to sham, with lower baseline naming ability being associated with largerresponse to right-hemispheric atDCS. The latter finding may be an indication that particularlypatients with severe naming deficits benefit from an up-regulation of the non-languagedominant hemisphere. A similar principle was followed in a small study including 6 patientswith moderate to severe non-fluent aphasia that were treated with melodic intonation therapy

(MIT) plus atDCS over posterior inferior frontal gyrus of the right hemisphere, compared tosham (Vines et al., 2011), in a randomized controlled cross-over treatment. Each treatmentwas administered over three consecutive days, using 20 min of 1.2 mA stimulation or sham.Here, atDCS plus MIT showed significantly better results with regard to fluency of speech,compared to sham plus MIT.Regarding factors associated with larger or smaller response to tDCS, the studies by Bakeret al and Floel et al, see above, yielded some first indication, albeit with small number ofsubjects. A recent study by Jung and colleagues (Jung et al., 2011) only focused on factorsassociated with tDCS-response, including a total of 37 stroke patients with tDCS but withoutsham condition. Here, a rather heterogeneous group of patients from acute, subacute andchronic stage received speech therapy plus ctDCS over left inferior frontal gyrus (Brodman


14/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

13

area 45; 1 mA, 20 min, 10 sessions over 2-3 weeks). Using logistic regression models, theauthors found that response to ctDCS, as assessed by the Korean version of the Westernaphasia battery, was more likely in patients with less severe, fluent aphasia that were startedon therapy within the first month after stroke.A rather unusual approach was followed by Monti and colleagues (Monti et al., 2008), whoevaluated the effect of atDCS, ctDCS (2 mA, 10 min each), and sham on picture namingaccuracy and response time in patients with chronic non-fluent post stroke aphasia in arandomized controlled cross-over trial. Stimulation was applied over left frontotemporalcortex. The authors found an immediate improvement in accuracy of picture naming afterctDCS but not atDCS or sham. Note that this approach is not in line with the other studiescited so far in the motor or the language domain for ctDCS, which aimed at inhibiting thehealthy, not the injured side. However, ctDCS over the injured hemisphere, may in fact haveresulted in an excitability-enhancing effect, given previous excitability-enhancing results of2mA-stimulation with ctDCS in healthy subjects ((Batsikadze et al., 2013), albeit with a totalduration of 30 min), and 1 mA, 10 min ctDCS over the injured hemisphere in motor stroke(Suzuki et al., 2012). Moreover, since the reference electrode was placed over the shoulderin Monti et al, neurophysiological effects on cortical excitability of the stimulation parametersemployed in their study (2 mA, 10 min) cannot be directly inferred from studies using thecephalic montage, and should be explored in more detail in future studies.One single study so far (Marangolo et al., 2011) assessed the effect of atDCS on apraxia ofspeech after stroke. In 3 patients that showed speech apraxia in addition to aphasia, arepetition task was administered over 5 days in addition to atDCS (1 mA, 20 min) overBroca’s area, compared to sham, in a randomized controlled cross-over design. Whilepatients improved under both conditions, response to atDCS + repetition training wassignificantly greater, and this effect was maintained for at least 2 months.In sum, a number of randomized, controlled clinical studies have demonstrated a beneficialeffect of atDCS in language rehabilitation. However, given the heterogeneity of patientsincluded in the studies so far, and the different stimulation protocols employed, a larger,randomized controlled trial, preferably as a multicenter approach and stratified with regard toaphasia severity, needs to be conducted. Moreover, to be moved into routine clinicalpractice, outcome measures reflecting not only function (like naming) but also activities andparticipation have to be included.

5.3 Attention: Does tDCS improve neglect after stroke?With regard to visuospatial attention, Sparing et al (Sparing et al., 2009) first demonstratedthat atDCS (1 mA, 10 min) over the right or left posterior parietal cortex (PPC) biasedvisuospatial attention towards the contralateral hemispace in a visual detection task in right-handed healthy individuals, while ctDCS (1 mA, 10 min) over the right or left PPC biasedvisuospatial attention towards the ipsilateral hemispace. In the same publication, they thenmoved to stroke-induced neglect in a randomized controlled cross-over study, demonstratingthat atDCS (1 mA, 10 min) over the lesioned PPC or ctDCS (1 mA, 10 min) over theunlesioned homologue area reduced symptoms of visuospatial neglect, as assessed by aline bisection task and the subtest neglect from the an attention test battery. Similarly, in arandomized controlled cross-over study, Ko and colleagues (Ko et al., 2008) found thatatDCS (2 mA, 20 min) over right parietal cortex improved performance in two neglect tests

(figure cancellation and line bisection) in subacute stroke patients, while sham did not.In sum, larger randomized controlled trials, with stimulation applied over several sessionsand outcome measures assessed both immediately after the stimulation and after a time-delay, are now needed to delineate clinical utility of tDCS in neglect treatment.

5.4 General cognition: Does tDCS improve executive function and working memoryafter stroke?Executive function: Kang et al (Kang et al., 2009) assessed the impact of atDCS (2 mA, 20min) vs sham over left dorsolateral prefrontal cortex in patients with post-stroke-relatedcognitive decline (MMSE 25) on performance in the Go/No-Go test, in a randomized


15/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

14

controlled cross-over trial. Here, they found significant improvements after atDCS but notsham in response accuracy 1 and 3 hours post-stimulation.Working memory: In healthy individuals, improvements in WM performance with atDCS overleft prefrontal cortex have been demonstrated in numerous studies (for review see (Floel,2012)). After stroke, Jo et al (Jo et al., 2009) were able to demonstrate that atDCS (2 mA, 30min), but not sham, applied over DLPFC in a randomized cross-over trial, improved accuracyin a two-back working memory task.In sum, first small pilot studies seem promising in the realm of general cognition after stroke,but further piloting is needed before progressing to RCTs.

6. Summary and Conclusions

tDCS as a non-invasive brain stimulation tool now widely being used in neuroscientificresearch. A large body of studies has elucidated the neurophysiological basis of thetechnique, and demonstrated facilitation of cognitive and motor processing as well aslearning in the healthy brain see review by XY in this issue.Thus, tDCS could be a highly promising technique in human neurorehabilitation, where (re-)learning, or at least preservation of motor and cognitive abilities, is of utmost importance.Compared to invasive stimulation, as well as NIBS techniques like TMS, tDCS has severaladvantages that render it attractive for clinical use. The technique is non-aversive and elicitsonly a slight tingling under the electrodes. It can be applied continuously and safely for 20(Gandiga et al., 2006; Iyer et al., 2005; Nitsche et al., 2005) or even 30 min (although thelatter has been less extensively explored (Boggio et al., 2011; Lindenberg et al., 2010)),close to the typical duration of a session of rehabilitative treatment, and be administered insynchrony with training protocols (Baker et al., 2010; Floel et al., 2011a; Lindenberg et al.,2010). The device is also easy to use, small (so can even be attached to the patient in arehabilitation session), and relatively inexpensive. Moreover, for the use in randomized,double-blind trials, real tDCS (at least up to the stimulation intensity of 1 mA) and sham tDCSelicit comparably minimal discomfort and duration of sensations in the absence of differencesin attention or fatigue, and can thus not be distinguished from sham by study participants norinvestigators (Gandiga et al., 2006; Iyer et al., 2005; Nitsche et al., 2005). Importantly, it maynot be possible to adequately blind participants and assessors to 2 mA stimulation

(O'Connell et al., 2012), a caveat to be taken into account particularly in the context ofdouble-blind clinical trials.Thus, it comes as no surprise that the device has been quickly moved into small proof-of-principle trials in neurological patient populations. First studies looked at post-stroke motorrehabilitation, but were soon followed by studies on patients with neurodegenerative disease,movement disorders, epilepsy, and post-stroke language, attentional, or executive deficits.Most promising and consistent results have been seen with post-stroke motor rehabilitation.Here, treatment with tDCS has been advanced to Class I level (see eg (Lindenberg et al.,2010). However, Class I categorization is a measure of the strength of the results, and doesnot necessarily translate into Level A recommendation for clinical practice. Thus, single-center, small studies in highly selected groups of subjects receiving standardizedinterventions in a homogenous environment and followed up for a relatively short period oftime cannot be considered definitive or widely generalizable (Kalra and Rossini, 2010).In

order to be moved into the clinical routine, the findings have to be replicated in largermulticenter trials because of variations in patient characteristics, environment, conventionaltherapy inputs, and delivery of interventions. The clinical relevance of these findings alsoremains to be proven with appropriate outcome measures not only covering the specific“function” under study, but also including measures of activities and participation, andinteraction of behavioural effects with concomitant spasticity in motor stroke should be furtherexplored. Moreover, it has to be acknowledged that exact stimulation parameters andstimulation sites differ considerably between studies, even in the same patient groups. Forexample, stimulation parameters vary with regard to mA used (between 1 and 2 mA), lengthof stimulation (between 7 and 40 min), repetition interval (e. g., 20 min of st imulation followedby another 20 min after 40 min (Floel et al., 2011a); 20 min of stimulation followed by 20 min


16/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

15

stimulation at the following day (Kim et al., 2010)); position of the reference electrode(contralateral orbita; dual montage; extracranial reference); or the size of the stimulationelectrodes. For systematic evaluations of stimulation strength, duration, and repetitioninterval, and a more detailed discussion, please see (Batsikadze et al., 2013; Monte-Silva etal., 2012; Monte-Silva et al., 2010a), and the contribution of Kuo, Paulus and Nitsche in thisSpecial Issue. Placement of the stimulation electrode itself has been generally tailored to thespecific function to be improved (e. g., M1 in motor disorders; IFG or temporal cortex forlanguage stimulation; M1 and prefrontal cortex for IPS; epileptogenic focus in epilepticpatients), but has also not been entirely consistent. Before moving into larger multicenterclinical trials, particularly for diseases where stimulation has shown mixed results so far,these questions should be answered beforehand. Note also that effects in chronic strokesurvivors have been most promising so far, while the largest trial in subacute motor strokedid not find a beneficial effect on motor outcome. Thus, use of tDCS in subacute stroke atthis point remains questionable.With regard to ameliorating disease-specific symptoms in dystonia or epilepsy, results fromprevious studies are heterogeneous with regard to improvements, or rely on open-label trialsand case reports. Here, more convincing pilot and mechanistic trials are needed to justifyfurther clinical trials.A further question that has only been touched upon so far in the motor system is theinteraction of the genetic background of the individual with his or her genetic background, forexample with regard to common genetic polymorphisms, since these polymorphisms mayconsiderably alter the response to a specific stimulation protocol (Cheeran et al., 2010).Previous studies have demonstrated differential responses to both TMS and tDCS in carriersof the BDNF Val66Met polymorphism in the motor system (see for example (Cheeran et al.,2008; Fritsch et al., 2010; Witte et al., 2012). Within the language domain, these questionsare currently being pursued in ongoing studies of our laboratory and others.

In sum, tDCS has a high potential to be routinely administered in parallel to intensivecognitive or motor training in neurological diseases in the future. However, more work needsto be done to define exact stimulation parameters and sites for the respective patientpopulations; and large multicenter randomized-controlled trials are needed that examine notonly function but also activities and participation.

Its use to reduce disease-specific symptoms like dystonia or epileptic seizures is unclear.7. Road-map for research regarding the use of tDCS in the clinical realm

1. Optimization of stimulation protocols for healthy subjects. Here, recent studies by(Batsikadze et al., 2013; Monte-Silva et al., 2012; Monte-Silva et al., 2010a) haveyielded first important information on stimulation intensity, duration, and repetitionintervals. Further information is now needed on the optimal number of stimulationsessions.

2. Establish transfer of stimulation protocol to patient populations usingneurophysiological measures

3. Establish transfer of stimulation protocol to patient populations using behaviouralmeasures in pilot trials

4. Establish clinical relevance of specific tDCS protocols in RCTs in patients, using

appropriate outcome measures not only covering the specific “function” under study,but also including measures of activities and participation


17/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

16

Disclosure statements

All authors declare that they have no conflicts of interest .


18/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

17

Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft (Fl-379-8/1;

Fl-379-10; DFG-Exc-257), the Bundesministerium für Bildung und Forschung

(FKZ0315673A; 01EO0801; 01GY1144), and the Else-Kröner Fresenius Stiftung (2009-141;

2011-119).


19/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

18

References

Angelakis, E., Liouta, E., Andreadis, N., Leonardos, A., Ktonas, P., Stavrinou, L.C., Miranda,P.C., Mekonnen, A., Sakas, D.E., 2013. Transcranial alternating current stimulation reducessymptoms in intractable idiopathic cervical dystonia: A case study. Neurosci Lett 533, 39-43.Antonenko, D., Floel, A., in press. Anodal transcranial direct current stimulation temporarilyreverses age-associated cognitive decline and functional brain activity changes. Gerontologyi.Baker, J.M., Rorden, C., Fridriksson, J., 2010. Using transcranial direct-current stimulation totreat stroke patients with aphasia. Stroke 41, 1229-1236.Batsikadze, G., Moliadze, V., Paulus, W., Kuo, M.F., Nitsche, M.A., 2013. Partially non-linear stimulation intensity-dependent effects of direct current stimulation on motor cortexexcitability in humans. J Physiol 591, 1987-2000.Benninger, D.H., Lomarev, M., Lopez, G., Wassermann, E.M., Li, X., Considine, E., Hallett,M., 2010. Transcranial direct current stimulation for the treatment of Parkinson's disease. J

Neurol Neurosurg Psychiatry 81, 1105-1111.Bernal-Pacheco, O., Limotai, N., Go, C.L., Fernandez, H.H., 2012. Nonmotor manifestationsin Parkinson disease. Neurologist 18, 1-16.Bhogal, S.K., Teasell, R., Speechley, M., 2003. Intensity of aphasia therapy, impact onrecovery. Stroke 34, 987-993.Boggio, P.S., Ferrucci, R., Mameli, F., Martins, D., Martins, O., Vergari, M., Tadini, L.,Scarpini, E., Fregni, F., Priori, A., 2011. Prolonged visual memory enhancement after directcurrent stimulation in Alzheimer's disease. Brain Stimul.Boggio, P.S., Ferrucci, R., Rigonatti, S.P., Covre, P., Nitsche, M., Pascual-Leone, A., Fregni,F., 2006. Effects of transcranial direct current stimulation on working memory in patientswith Parkinson's disease. J Neurol Sci 249, 31-38.Boggio, P.S., Khoury, L.P., Martins, D.C., Martins, O.E., de Macedo, E.C., Fregni, F., 2009.

Temporal cortex direct current stimulation enhances performance on a visual recognitionmemory task in Alzheimer disease. J Neurol Neurosurg Psychiatry 80, 444-447.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 functionimprovement in stroke patients. Restor Neurol Neurosci 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 oftDCS combined with constraint-induced movement therapy in poststroke patients.Neurorehabil Neural Repair 25, 819-829.Buttkus, F., Baur, V., Jabusch, H.C., de la Cruz Gomez-Pellin, M., Paulus, W., Nitsche, M.A.,Altenmuller, E., 2011. Single-session tDCS-supported retraining does not improve fine motorcontrol in musician's dystonia. Restor Neurol Neurosci 29, 85-90.Cheeran, B., Koch, G., Stagg, C.J., Baig, F., Teo, J., 2010. Transcranial magnetic stimulation:from neurophysiology to pharmacology, molecular biology and genomics. Neuroscientist 16,210-221.Cheeran, B., Talelli, P., Mori, F., Koch, G., Suppa, A., Edwards, M., Houlden, H., Bhatia, K.,Greenwood, R., Rothwell, J.C., 2008. A common polymorphism in the brain derivedneurotrophic factor gene (BDNF) modulates human cortical plasticity and the response torTMS. J Physiol.Ferrucci, R., Mameli, F., Guidi, I., Mrakic-Sposta, S., Vergari, M., Marceglia, S.,Cogiamanian, F., Barbieri, S., Scarpini, E., Priori, A., 2008. Transcranial direct currentstimulation improves recognition memory in Alzheimer disease. Neurology 71, 493-498.


20/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

19

Floel, A., 2012. Non-invasive brain stimulation and language processing in the healthy brain.Aphasiology epub 01 August.Floel, A., Cohen, L.G., 2010. Recovery of function in humans: cortical stimulation andpharmacological treatments after stroke. Neurobiol Dis 37, 243-251.Floel, A., Meinzer, M., Kirstein, R., Nijhof, S., Deppe, M., Knecht, S., Breitenstein, C.,2011a. Short-Term Anomia Training and Electrical Brain Stimulation. Stroke.

Floel, A., Rosser, N., Michka, O., Knecht, S., Breitenstein, C., 2008. Noninvasive brainstimulation improves language learning. J Cogn Neurosci 20, 1415-1422.Floel, A., Suttorp, W., Kohl, O., Kurten, J., Lohmann, H., Breitenstein, C., Knecht, S., 2011b.Non-invasive brain stimulation improves object-location learning in the elderly. NeurobiolAging.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. Transcranialdirect current stimulation of the unaffected hemisphere in stroke patients. Neuroreport 16,1551-1555.Fregni, F., Boggio, P.S., Santos, M.C., Lima, M., Vieira, A.L., Rigonatti, S.P., Silva, M.T.,Barbosa, E.R., Nitsche, M.A., Pascual-Leone, A., 2006a. Noninvasive cortical stimulationwith transcranial direct current stimulation in Parkinson's disease. Mov Disord 21, 1693-1702.Fregni, F., Santos, C.M., Myczkowski, M.L., Rigolino, R., Gallucci-Neto, J., Barbosa, E.R.,Valente, K.D., Pascual-Leone, A., Marcolin, M.A., 2004. Repetitive transcranial magneticstimulation is as effective as fluoxetine in the treatment of depression in patients withParkinson's disease. J Neurol Neurosurg Psychiatry 75, 1171-1174.Fregni, F., Thome-Souza, S., Nitsche, M.A., Freedman, S.D., Valente, K.D., Pascual-Leone,A., 2006b. A controlled clinical trial of cathodal DC polarization in patients with refractoryepilepsy. Epilepsia 47, 335-342.Fridriksson, J., Richardson, J.D., Baker, J.M., Rorden, C., 2011. Transcranial direct currentstimulation improves naming reaction time in fluent aphasia: a double-blind, sham-controlledstudy. Stroke 42, 819-821.Fritsch, B., Reis, J., Martinowich, K., Schambra, H.M., Ji, Y., Cohen, L.G., Lu, B., 2010.Direct current stimulation promotes BDNF-dependent synaptic plasticity: potentialimplications for motor learning. Neuron 66, 198-204.Gandiga, P.C., Hummel, F., Cohen, L.G., 2006. Transcranial DC stimulation (tDCS): a toolfor double-blind sham-controlled clinical studies in brain stimulation. Clin Neurophysiol 117,845-850.Garry, M.I., Kamen, G., Nordstrom, M.A., 2004. Hemispheric differences in the relationshipbetween corticomotor excitability changes following a fine-motor task and motor learning. JNeurophysiol 91, 1570-1578.Geerligs, L., Maurits, N.M., Renken, R.J., Lorist, M.M., 2012. Reduced specificity offunctional connectivity in the aging brain during task performance. Hum Brain Mapp.Geroin, C., Picelli, A., Munari, D., Waldner, A., Tomelleri, C., Smania, N., 2011. Combinedtranscranial direct current stimulation and robot-assisted gait training in patients with chronicstroke: a preliminary comparison. Clin Rehabil 25, 537-548.Hallett, M., 2006. Pathophysiology of dystonia. J Neural Transm Suppl, 485-488.Hamdy, S., Aziz, Q., Rothwell, J.C., Singh, K.D., Barlow, J., Hughes, D.G., Tallis, R.C.,Thompson, D.G., 1996. The cortical topography of human swallowing musculature in healthand disease. Nat Med 2, 1217-1224.Hesse, S., Waldner, A., Mehrholz, J., Tomelleri, C., Pohl, M., Werner, C., 2011. Combinedtranscranial direct current stimulation and robot-assisted arm training in subacute strokepatients: an exploratory, randomized multicenter trial. Neurorehabil Neural Repair 25, 838-846.


21/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

20

Hesse, S., Werner, C., Schonhardt, E.M., Bardeleben, A., Jenrich, W., Kirker, S.G., 2007.Combined transcranial direct current stimulation and robot-assisted arm training in subacutestroke patients: A pilot study. Restor Neurol Neurosci 25, 9-15.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. Brain128, 490-499.

Iyer, M.B., Mattu, U., Grafman, J., Lomarev, M., Sato, S., Wassermann, E.M., 2005. Safetyand cognitive effects of frontal DC brain polarization in healthy individuals. Neurology 64,872-875.Janssen, I.M., Sturtz, S., Skipka, G., Zentner, A., Velasco Garrido, M., Busse, R., 2010.Ginkgo biloba in Alzheimer's disease: a systematic review. Wien Med Wochenschr 160, 539-546.Jean, L., Bergeron, M.E., Thivierge, S., Simard, M., 2006. Cognitive intervention programsfor individuals with mild cognitive impairment: systematic review of the literature. Am JGeriatr Psychiatry 18, 281-296.Jo, J.M., Kim, Y.H., Ko, M.H., Ohn, S.H., Joen, B., Lee, K.H., 2009. Enhancing the workingmemory of stroke patients using tDCS. Am J Phys Med Rehabil 88, 404-409.Jung, I.Y., Lim, J.Y., Kang, E.K., Sohn, H.M., Paik, N.J., 2011. The Factors Associated withGood Responses to Speech Therapy Combined with Transcranial Direct Current Stimulationin Post-stroke Aphasic Patients. Ann Rehabil Med 35, 460-469.Kalra, L., Rossini, P.M., 2010. Influencing poststroke plasticity with electromagnetic brainstimulation: myth or reality? Neurology 75, 2146-2147.Kang, E.K., Baek, M.J., Kim, S., Paik, N.J., 2009. Non-invasive cortical stimulation improvespost-stroke attention decline. Restor Neurol Neurosci 27, 645-650.Kim, D.Y., Lim, J.Y., Kang, E.K., You, D.S., Oh, M.K., Oh, B.M., Paik, N.J., 2010. Effect oftranscranial direct current stimulation on motor recovery in patients with subacute stroke. AmJ Phys Med Rehabil 89, 879-886.Kim, D.Y., Ohn, S.H., Yang, E.J., Park, C.I., Jung, K.J., 2009. Enhancing motor performanceby anodal transcranial direct current stimulation in subacute stroke patients. Am J Phys MedRehabil 88, 829-836.Ko, M.H., Han, S.H., Park, S.H., Seo, J.H., Kim, Y.H., 2008. Improvement of visual scanningafter DC brain polarization of parietal cortex in stroke patients with spatial neglect. NeurosciLett 448, 171-174.Koeneke, S., Lutz, K., Herwig, U., Ziemann, U., Jancke, L., 2006. Extensive training ofelementary finger tapping movements changes the pattern of motor cortex excitability. ExpBrain Res 174, 199-209.Kramer, A.F., Erickson, K.I., 2007. Capitalizing on cortical plasticity: influence of physicalactivity on cognition and brain function. Trends Cogn Sci 11, 342-348.Kumar, S., Wagner, C.W., Frayne, C., Zhu, L., Selim, M., Feng, W., Schlaug, G., 2011.Noninvasive brain stimulation may improve stroke-related dysphagia: a pilot study. Stroke 42,1035-1040.Lefaucheur, J.P., Drouot, X., Von Raison, F., Menard-Lefaucheur, I., Cesaro, P., Nguyen,J.P., 2004. Improvement of motor performance and modulation of cortical excitability byrepetitive transcranial magnetic stimulation of the motor cortex in Parkinson's disease. ClinNeurophysiol 115, 2530-2541.Lian, J., Bikson, M., Sciortino, C., Stacey, W.C., Durand, D.M., 2003. Local suppression ofepileptiform activity by electrical stimulation in rat hippocampus in vitro. J Physiol 547, 427-434.Liebetanz, D., Klinker, F., Hering, D., Koch, R., Nitsche, M.A., Potschka, H., Loscher, W.,Paulus, W., Tergau, F., 2006. Anticonvulsant effects of transcranial direct-current stimulation(tDCS) in the rat cortical ramp model of focal epilepsy. Epilepsia 47, 1216-1224.


22/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

21

Liebetanz, D., Nitsche, M.A., Tergau, F., Paulus, W., 2002. Pharmacological approach to themechanisms of transcranial DC-stimulation-induced after-effects of human motor cortexexcitability. Brain 125, 2238-2247.Lindenberg, R., Nachtigall, L., Meinzer, M., Sieg, M.M., Flöel, A., 2012. Modulation ofresting state and task-related activity by bihemispheric motor cortex stimulation in olderadults., Society for Neuroscience Meeting. Society for Neuroscience, New Orleans, LA.

Lindenberg, R., Renga, V., Zhu, L.L., Nair, D., Schlaug, G., 2010. Bihemispheric brainstimulation facilitates motor recovery in chronic stroke patients. Neurology 75, 2176-2184.Liu, Y., Yu, C., Zhang, X., Liu, J., Duan, Y., Alexander-Bloch, A.F., Liu, B., Jiang, T.,Bullmore, E., 2013. Impaired Long Distance Functional Connectivity and Weighted NetworkArchitecture in Alzheimer's Disease. Cereb Cortex.Madhavan, S., Weber, K.A., 2nd, Stinear, J.W., 2011. Non-invasive brain stimulationenhances fine motor control of the hemiparetic ankle: implications for rehabilitation. ExpBrain Res 209, 9-17.Marangolo, P., Marinelli, C.V., Bonifazi, S., Fiori, V., Ceravolo, M.G., Provinciali, L.,Tomaiuolo, F., 2011. Electrical stimulation over the left inferior frontal gyrus (IFG)determines long-term effects in the recovery of speech apraxia in three chronic aphasics.Behav Brain Res 225, 498-504.Meinzer, M., Antonenko, D., Lindenberg, R.U., L., Avirame, K., Flaisch, T., Floel, A., 2012.Electrical brain stimulation improves cognitive performance by modulating functionalconnectivity and task-specific activation. J Neurosci 32, 1859-1866.Monte-Silva, K., Kuo, M.F., Hessenthaler, S., Fresnoza, S., Liebetanz, D., Paulus, W.,Nitsche, M.A., 2012. Induction of late LTP-like plasticity in the human motor cortex byrepeated non-invasive brain stimulation. Brain Stimul.Monte-Silva, K., Kuo, M.F., Liebetanz, D., Paulus, W., Nitsche, M.A., 2010a. Shaping theoptimal repetition interval for cathodal transcranial direct current stimulation (tDCS). JNeurophysiol 103, 1735-1740.Monte-Silva, K., Liebetanz, D., Grundey, J., Paulus, W., Nitsche, M.A., 2010b. Dosage-dependent non-linear effect of L-dopa on human motor cortex plasticity. J Physiol 588, 3415-3424.Monti, A., Cogiamanian, F., Marceglia, S., Ferrucci, R., Mameli, F., Mrakic-Sposta, S.,Vergari, M., Zago, S., Priori, A., 2008. Improved naming after transcranial direct currentstimulation in aphasia. J Neurol Neurosurg Psychiatry 79, 451-453.Nair, D.G., Renga, V., Lindenberg, R., Zhu, L., Schlaug, G., 2011. Optimizing recoverypotential through simultaneous occupational therapy and non-invasive brain-stimulation usingtDCS. Restor Neurol Neurosci 29, 411-420.Nardone, R., Golaszewski, S., Ladurner, G., Tezzon, F., Trinka, E., 2011. A review oftranscranial magnetic stimulation in the in vivo functional evaluation of central cholinergiccircuits in dementia. Dement Geriatr Cogn Disord 32, 18-25.Nitsche, M.A., Fricke, K., Henschke, U., Schlitterlau, A., Liebetanz, D., Lang, N., Henning,S., Tergau, F., Paulus, W., 2003a. Pharmacological modulation of cortical excitability shiftsinduced by transcranial direct current stimulation in humans. J Physiol 553, 293-301.Nitsche, M.A., Jaussi, W., Liebetanz, D., Lang, N., Tergau, F., Paulus, W., 2004.Consolidation of human motor cortical neuroplasticity by d-cycloserine.Neuropsychopharmacology 29, 1573-1578.Nitsche, M.A., Kuo, M.F., Karrasch, R., Wachter, B., Liebetanz, D., Paulus, W., 2009.Serotonin affects transcranial direct current-induced neuroplasticity in humans. BiolPsychiatry 66, 503-508.Nitsche, M.A., Liebetanz, D., Antal, A., Lang, N., Tergau, F., Paulus, W., 2003b. Modulationof cortical excitability by weak direct current stimulation--technical, safety and functionalaspects. Suppl Clin Neurophysiol 56, 255-276.


23/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

22

Nitsche, M.A., Paulus, W., 2000. Excitability changes induced in the human motor cortex byweak transcranial direct current stimulation. J Physiol 527 Pt 3, 633-639.Nitsche, M.A., Paulus, W., 2001. Sustained excitability elevations induced by transcranial DCmotor cortex stimulation in humans. Neurology 57, 1899-1901.Nitsche, M.A., Paulus, W., 2009. Noninvasive brain stimulation protocols in the treatment ofepilepsy: current state and perspectives. Neurotherapeutics 6, 244-250.

Nitsche, M.A., Paulus, W., 2011. Transcranial direct current stimulation - update 2011. RestorNeurol Neurosci.Nitsche, M.A., Seeber, A., Frommann, K., Klein, C.C., Rochford, C., Nitsche, M.S., Fricke,K., Liebetanz, D., Lang, N., Antal, A., Paulus, W., Tergau, F., 2005. Modulating parametersof excitability during and after transcranial direct current stimulation of the human motorcortex. J Physiol 568, 291-303.O'Connell, N.E., Cossar, J., Marston, L., Wand, B.M., Bunce, D., Moseley, G.L., De Souza,L.H., 2012. Rethinking clinical trials of transcranial direct current stimulation: participant andassessor blinding is inadequate at intensities of 2mA. PLOS one 7, e47514.Pascual-Leone, A., Valls-Sole, J., Brasil-Neto, J.P., Cammarota, A., Grafman, J., Hallett, M.,1994. Akinesia in Parkinson's disease. II. Effects of subthreshold repetitive transcranial motorcortex stimulation. Neurology 44, 892-898.Pereira, J.B., Junque, C., Bartres-Faz, D., Marti, M.J., Sala-Llonch, R., Compta, Y., Falcon,C., Vendrell, P., Pascual-Leone, A., Valls-Sole, J., Tolosa, E., 2012. Modulation of verbalfluency networks by transcranial direct current stimulation (tDCS) in Parkinson's disease.Brain Stimul.Pogosyan, A., Gaynor, L.D., Eusebio, A., Brown, P., 2009. Boosting cortical activity at Beta-band frequencies slows movement in humans. Curr Biol 19, 1637-1641.Quartarone, A., Rizzo, V., Bagnato, S., Morgante, F., Sant'Angelo, A., Romano, M., Crupi,D., Girlanda, P., Rothwell, J.C., Siebner, H.R., 2005. Homeostatic-like plasticity of theprimary motor hand area is impaired in focal hand dystonia. Brain 128, 1943-1950.Reis, J., Robertson, E., Krakauer, J.W., Rothwell, J., Marshall, L., Gerloff, C., Wassermann,E., Pascual-Leone, A., Hummel, F., Celnik, P.A., Classen, J., Floel, A., Ziemann, U., Paulus,W., Siebner, H.R., Born, J., Cohen, L.G., 2008. Consensus: "Can tDCS and TMS enhancemotor learning and memory formation?". Brain Stimulat 1, 363-369.Reis, J., Schambra, H.M., Cohen, L.G., Buch, E.R., Fritsch, B., Zarahn, E., Celnik, P.A.,Krakauer, J.W., 2009. Noninvasive cortical stimulation enhances motor skill acquisition overmultiple days through an effect on consolidation. Proc Natl Acad Sci U S A 106, 1590-1595.Rossi, C., Sallustio, F., Di Legge, S., Stanzione, P., Koch, G., 2012. Transcranial directcurrent stimulation of the affected hemisphere does not accelerate recovery of acute strokepatients. Eur J Neurol.Siebner, H.R., Mentschel, C., Auer, C., Conrad, B., 1999. Repetitive transcranial magneticstimulation has a beneficial effect on bradykinesia in Parkinson's disease. Neuroreport 10,589-594.Sparing, R., Thimm, M., Hesse, M.D., Kust, J., Karbe, H., Fink, G.R., 2009. Bidirectionalalterations of interhemispheric parietal balance by non-invasive cortical stimulation. Brain132, 3011-3020.Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett, D.A., Craft, S., Fagan, A.M., Iwatsubo,T., Jack, C.R., Jr., Kaye, J., Montine, T.J., Park, D.C., Reiman, E.M., Rowe, C.C., Siemers,E., Stern, Y., Yaffe, K., Carrillo, M.C., Thies, B., Morrison-Bogorad, M., Wagster, M.V.,Phelps, C.H., 2011. Toward defining the preclinical stages of Alzheimer's disease:recommendations from the National Institute on Aging-Alzheimer's Association workgroupson diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 7, 280-292.


24/43

A C C E P

T E D

M A N U

S C R I P T

ACCEPTED MANUSCRIPT

23

Stagg, C.J., Bachtiar, V., O'Shea, J., Allman, C., Bosnell, R.A., Kischka, U., Matthews, P.M.,Johansen-Berg, H., 2012. Cortical activation changes underlying stimulation-inducedbehavioural gains in chronic stroke. Brain 135, 276-284.Suzuki, K., Fujiwara, T., Tanaka, N., Tsuji, T., Masakado, Y., Hase, K., Kimura, A., Liu, M.,2012. Comparison of the after-effects of transcranial direct current stimulation over the motorcortex in patients with stroke and healthy volunteers. Int J Neurosci 122, 675-681.

Tanaka, S., Takeda, K., Otaka, Y., Kita, K., Osu, R., Honda, M., Sadato, N., Hanakawa, T.,Watanabe, K., 2011. Single session of transcranial direct current stimulation transientlyincreases knee extensor force in patients with hemiparetic stroke. Neurorehabil Neural Repair25, 565-569.Teismann, I.K., Steinstraeter, O., Stoeckigt, K., Suntrup, S., Wollbrink, A., Pantev, C.,Dziewas, R., 2007. Functional oropharyngeal sensory disruption interferes with the corticalcontrol of swallowing. BMC Neurosci 8, 62.Varga, E.T., Terney, D., Atkins, M.D., Nikanorova, M., Jeppesen, D.S., Uldall, P., Hjalgrim,H., Beniczky, S., 2011. Transcranial direct current stimulation in refractory continuous spikesand waves during slow sleep: a controlled study. Epilepsy Res 97, 142-145.Vines, B.W., Cerruti, C., Schlaug, G., 2008. Dual-hemisphere tDCS facilitates greaterimprovements for healthy subjects' non-dominant hand compared to uni-hemispherestimulation. BMC Neurosci 9, 103.Vines, B.W., Norton, A.C., Schlaug, G., 2011. Non-invasive brain stimulation enhances theeffects of melodic intonation therapy. Front Psychol 2, 230.Wang, Y., Risacher, S.L., West, J.D., McDonald, B.C., Magee, T.R., Farlow, M.R., Gao, S.,O'Neill, D.P., Saykin, A.J., 2013. Altered Default Mode Network Connectivity in OlderAdults with Cognitive Complaints and Amnestic Mild Cognitive Impairment. J AlzheimersDis.Witte, A.V., Kuerten, J., Jansen, S., Schirmacher, A., Brand, E., Sommer, J., Floel, A., 2012.Interaction of BDNF and COMT polymorphisms on paired-associative stimulation inducedcortical plasticity. J Neurosci.Wu, A.D., Fregni, F., Simon, D.K., Deblieck, C., Pascual-Leone, A., 2008. Noninvasive brainstimulation for Parkinson's disease and dystonia. Neurotherapeutics 5, 345-361.Wu, D., Qian, L., Zorowitz, R.D., Zhang, L., Qu, Y., Yuan, Y., 2013. Effects on decreasingupper-limb poststroke muscle tone using transcranial direct current stimulation: a randomizedsham-controlled study. Arch Phys Med Rehabil 94, 1-8.Yang, E.J., Baek, S.R., Shin, J

tdcs-enhanced motor and cognitive function in neurological diseases

Documents