Noninvasive Brain Stimulations for Unilateral Spatial ...downloads.hindawi.com/journals/np/2018/1638763.pdf · Background. Unilateral spatial neglect (USN) is the most frequent perceptual

Review ArticleNoninvasive Brain Stimulations for Unilateral SpatialNeglect after Stroke: A Systematic Review and Meta-Analysis ofRandomized and Nonrandomized Controlled Trials

Flávio Taira Kashiwagi,1 Regina El Dib,2 Huda Gomaa,3 Nermeen Gawish,3

Erica Aranha Suzumura,4 Taís Regina da Silva,1 Fernanda Cristina Winckler,1

Juli Thomaz de Souza,2 Adriana Bastos Conforto ,5 Gustavo José Luvizutto ,6

and Rodrigo Bazan1

1Neurology Department, Botucatu Medical School, Universidade Estadual Paulista (UNESP), Botucatu, SP, Brazil2Science and Technology Institute, Universidade Estadual Paulista (UNESP), São José dos Campos, SP, Brazil3Department of Pharmacy, Tanta Chest Hospital, Tanta, Egypt4Research Institute, Hospital do Coração (HCor), São Paulo, SP, Brazil5Neurostimulation Laboratory, University of São Paulo (USP), São Paulo, SP, Brazil6Department of Applied Physical Therapy, Federal University of Triângulo Mineiro (UFTM), Uberaba, MG, Brazil

Correspondence should be addressed to Gustavo José Luvizutto; [email protected]

Received 7 September 2017; Accepted 15 April 2018; Published 28 June 2018

Academic Editor: Michele Fornaro

Copyright © 2018 Flávio Taira Kashiwagi et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Background. Unilateral spatial neglect (USN) is the most frequent perceptual disorder after stroke. Noninvasive brain stimulation(NIBS) is a tool that has been used in the rehabilitation process to modify cortical excitability and improve perception andfunctional capacity. Objective. To assess the impact of NIBS on USN after stroke. Methods. An extensive search was conductedup to July 2016. Studies were selected if they were controlled and noncontrolled trials examining transcranial direct currentstimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and theta burst stimulation (TBS) in USN after stroke,with outcomes measured by standardized USN and functional tests. Results. Twelve RCTs (273 participants) and 4 non-RCTs(94 participants) proved eligible. We observed a benefit in overall USN measured by the line bisection test with NIBS incomparison to sham (SMD −2.35, 95% CI −3.72, −0.98; p = 0 0001); the rTMS yielded results that were consistent with theoverall meta-analysis (SMD −2.82, 95% CI −3.66, −1.98; p = 0 09). The rTMS compared with sham also suggested a benefit inoverall USN measured by Motor-Free Visual Perception Test at both 1Hz (SMD 1.46, 95% CI 0.73, 2.20; p < 0 0001) and 10Hz(SMD 1.19, 95% CI 0.48, 1.89; p = 0 54). There was also a benefit in overall USN measured by Albert’s test and the line crossingtest with 1Hz rTMS compared to sham (SMD 2.04, 95% CI 1.14, 2.95; p < 0 0001). Conclusions. The results suggest a benefit ofNIBS on overall USN, and we conclude that rTMS is more efficacious compared to sham for USN after stroke.

1. Background

Stroke is the second leading cause of death worldwide and theprimary cause of chronic disability in adults [1]. In theUnited States, it is the fourth leading cause of death overall[2]. Among people who survive a stroke, unilateral spatial

neglect (USN) is the most frequent disorder for right hemi-sphere lesions [3].

The incidence of USN varies widely from 10% to 82%[4, 5]. USN is characterized by the inability to report orrespond to people or objects presented on the side contralat-eral to the lesioned side of the brain and has been associated

HindawiNeural PlasticityVolume 2018, Article ID 1638763, 25 pageshttps://doi.org/10.1155/2018/1638763

http://orcid.org/0000-0001-7869-3490http://orcid.org/0000-0002-6914-7225https://doi.org/10.1155/2018/1638763

with poor functional outcomes and long stays in hospitalsand rehabilitation centers [6].

Pharmacological interventions such as dopamine andnoradrenergic agonists or procholinergic treatment havebeen used in people affected by USN after stroke, butthe evidence derived from a Cochrane systematic reviewthat included only two available RCTs was very low andinconclusive [7].

Other nonpharmacological rehabilitation techniqueshave been explored for USN with the aim to facilitate therecovery of perception and behavior, which include righthalf-field eye-patching [8], mirror therapy [9], prism adapta-tion [10], left-hand somatosensory stimulation with visualscanning training [11], contralateral transcutaneous electri-cal nerve stimulation and optokinetic stimulation [12], trunkrotation [13], repetitive transcranial magnetic stimulation[14], galvanic vestibular stimulation [15], and dressing prac-tice [16]. However, their results do not support the use ofthese techniques in isolation for improvement of secondaryoutcomes such as performance and sensorimotor functions,activities of daily living (ADLs), or quality of life [9, 14, 17].

Noninvasive brain stimulations (transcranial direct cur-rent stimulation (tDCS) and repetitive transcranial magneticstimulation (rTMS)) have already shown their ability tomodify cortical excitability [18]. tDCS is a noninvasivemethod used to modulate cortical excitability by applying adirect current to the brain that is less expensive than repeti-tive transcranial magnetic stimulation (rTMS). The latter isan electric current that creates magnetic fields that penetratethe brain and can modulate cortical excitability by decreasingor increasing it and potentially improve perceptual and cog-nitive abilities [19, 20].

A previous Cochrane systematic review summarizedresults about the effects of tDCS versus control (sham/anyother intervention) on activities of daily living (ADLs)among stroke survivors. The authors included 32 random-ized controlled trials (RCTs) and concluded that tDCS mightenhance ADLs, but upper and lower limb function, musclestrength, and cognitive abilities should be further explored[21]. Another Cochrane systematic review assessed the effi-cacy of repetitive transcranial magnetic stimulation (rTMS)compared to sham therapy or no therapy for improving func-tion in people with stroke. The 19 included trials showed thatrTMS was not associated with a significant increase in ADLsor in motor function; therefore, the authors do not supportthe use of rTMS for the treatment of stroke, and they planto complete further trials to confirm their findings [22].

Previous reviews were, however, limited in that they didnot include non-RCT studies nor did they evaluate the new-est noninvasive brain stimulation—theta burst. We thereforeconducted a systematic review of RCT and non-RCT studiesthat assessed the impact of tDCS, rTMS, and TBS for unilat-eral spatial neglect after stroke.

2. Methods

We adhered to methods described in the Cochrane Hand-book for Intervention Reviews [23]. Our reporting alsoadheres to the Preferred Reporting Items for Systematic

Reviews and Meta-Analyses (PRISMA) [24] and Meta-Analysis of Observational Studies in Epidemiology (MOOSE)statements [25].

2.1. Eligibility Criteria. The eligibility criteria are as follows:

(1) Study designs: RCTs, quasi-RCTs, and non-RCTs

(2) Participants: adults over 18 years of age, regardless ofgender and the duration of illness or severity of theinitial impairment, with USN after any type of strokediagnosis (ischemic or intracranial hemorrhage)measured by clinical examination or radiographicallyby computed tomography (CT) or magnetic reso-nance imaging (MRI), regardless ofwhether theywereincluded after evaluation by standardized USN tests.

(3) Interventions: any noninvasive brain stimulationssuch as tDCS, rTMS, and including theta burst (con-tinuous TBS (cTBS) or intermittent theta burst(iTBS)) (we considered evaluating both the differenttypes of stimulations (i.e., cathodal tDCS versusanodal tDCS versus dual tDCS) and types of fre-quency (i.e., high-frequency versus low frequency))

(4) Comparators: interventions were to be comparedagainst sham stimulation or any conventional strokerehabilitation (e.g., pharmacological therapy or non-pharmacological therapy such as right half-field eye-patching, mirror therapy, prism adaptation, left-handsomatosensory stimulation, andvisual scanning train-ing or other conventional treatment)

We also considered noninvasive brain stimulations as anadjunct to any type of conventional stroke rehabilitation.

(5) Outcomes:

(i) Overall USN measured by any paper-and-pencil tests, such as the line cancellation task[26], the line bisection test [27], or the starcancellation test [28], and by any validatedspecific instrument, such as the CatherineBergego Scale [29], and the Behavioral Inatten-tion Test [30]

(ii) Disability in neurological and functional abili-ties as measured by any validated specificinstrument, such as the National Institutes ofHealth Stroke Scale and the Modified RankinScale [31], the box and block test [32], or theFugl-Meyer Assessment [33] after treatmentand over the long term

(iii) Daily life functions as measured by any vali-dated measurement scale, such as the Barthelindex [31]

(iv) Number of reported falls as measured by dia-ries of falls, by the Morse Fall Scale [34], or bythe Hendrich II Fall Risk Model [35] after treat-ment and over the long term

2 Neural Plasticity

(v) Balance as measured by the Berg Balance Scale,the balance subscale of the Fugl-Meyer test, andthe Postural Assessment Scale for StrokePatients [36] after treatment and over thelong term

(vi) Depression or anxiety as measured by the BeckDepression Inventory, the Hospital Anxietyand Depression Scale, Symptom Checklist-90(SCL-90), and the Hamilton Depression RatingScale [37] after treatment and over the longterm

(vii) Evaluation of poststroke fatigue by the FatigueSeverity Scale [38] after treatment and overthe long term

(viii) Quality of life (however defined by the studyauthors) after treatment and over the long term

(ix) Adverse events (e.g., euphoria, hallucinations,orthostatic hypotension, nausea, insomnia, diz-ziness, and syncope) after treatment and overthe long term

(x) Death

2.2. Data Source and Searches. We searched MEDLINE(OvidSP) (1966 to July 2016), EMBASE (OvidSP) (1980 toJuly 2017), the Cochrane Central Register of Controlled Tri-als (CENTRAL) (The Cochrane Library, 2017, issue 7),CINAHL (1961 to July 2017), and Latin-American andCaribbean Center on Health Sciences Information (LILACS)(from 1982 to July 2017) without language restrictions. Thedate of the most recent search was 26 July 2017. All searcheswere conducted with the assistance of a trained medicallibrarian. We also searched the reference lists of relevant arti-cles and conference proceedings and contacted the authors ofincluded trials.

The search strategy was: (tDCS OR TDCS OR CathodalStimulation Transcranial Direct Current Stimulation ORCathodal Stimulation tDCSs OR Cathodal Stimulation tDCSOR Transcranial Random Noise Stimulation OR Transcra-nial Alternating Current Stimulation OR Transcranial Elec-trical Stimulation OR dual transcranial direct currentstimulation OR Transcranial Electrical Stimulations ORAnodal Stimulation Transcranial Direct Current StimulationOR Anodal Stimulation Tdcs OR Anodal Tdcs OR AnodalStimulation TDCSs OR Repetitive Transcranial ElectricalStimulation OR repetitive transcranial magnetic stimulationOR RTMS OR rTMS OR High-frequency rTMS OR Trasn-cranial Magnetic Stimulation OR Transcranial MagneticStimulations OR Low-frequency transcranial magnetic stim-ulation OR Stimulation Transcranial Magnetic OR Stimula-tions Transcranial Magnetic OR Single Pulse TranscranialMagnetic Stimulation OR Paired Pulse Transcranial Mag-netic Stimulation OR Repetitive Transcranial MagneticStimulation OR theta burst OR theta burst stimulationOR theta-burst OR theta-burst stimulation OR burst stimu-lation OR continuous theta burst stimulation OR continuous

TBS OR TBS) AND (cerebrovascular disorders OR basalganglia cerebrovascular disease OR hemispatial neglect ORhemispatial neglect OR spatial attentional asymmetries ORbrain ischemia OR carotid artery diseases OR intracranialarterial diseases OR intracranial embolism and thrombosisOR intracranial hemorrhages OR stroke OR brain infarctionOR vertebral artery dissection OR post-stroke OR poststrokeOR hemineglect OR hemi-neglect OR unilateral visuospatialneglect OR visuospatial neglect OR visual spatial neglect ORspatial neglect OR unilateral neglect of acute stroke patientsOR unilateral spatial neglect OR patients with stroke ORstroke patients with spatial neglect OR right hemispherestrokes OR rehabilitation after stroke OR chronic spatialneglect after stroke OR unilateral neglect OR spatial neglectOR hemispatial neglect OR visual neglect OR inattentionOR hemi-inattention OR space perception OR visual percep-tion OR perceptual disorders OR perceptual disorder ORextinction OR functional laterality).

2.3. Selection of Studies. Two pairs of reviewers indepen-dently screened all titles and abstracts identified by the liter-ature search, obtained full-text articles of all potentiallyeligible studies, and evaluated them for eligibility. Reviewersresolved disagreement by discussion or, if necessary, withthird party adjudication. We also considered studies reportedonly as conference abstracts.

2.4. Data Extraction. Reviewers underwent calibrationexercises and worked in pairs to independently extractdata from included studies. They resolved disagreementby discussion or, if necessary, with third party adjudication.They abstracted the following data using a pretested dataextraction form: study design, participants, interventions,comparators, outcome assessed, and relevant statistical data.

2.5. Risk of Bias Assessment. Reviewers, working in pairs,independently assessed the risk of bias of included RCTsusing a modified version of the Cochrane Collaboration’sinstrument (http:/distillercer.com/resources/) [39]. That ver-sion includes nine domains: adequacy of sequence gener-ation, allocation sequence concealment, blinding of participantsand caregivers, blinding of data collectors, blinding foroutcome assessment, blinding of data analysts, incom-plete outcome data, selective outcome reporting, and thepresence of other potential sources of bias not accountedfor in the previously cited domains [40]. For incompleteoutcome data in individual studies, we stipulated as lowrisk of bias for loss to follow-up as less than 10% and adifference of less than 5% in missing data between inter-vention/exposure and control groups.

When information regarding risk of bias or other aspectsof methods or results was unavailable, we attempted to con-tact study authors for additional information.

2.6. Certainty of Evidence. We summarized the evidence andassessed its certainty separately for bodies of evidence fromRCT and non-RCT studies. We used the Grading of Recom-mendations Assessment, Development and Evaluation(GRADE) methodology to rate certainty of the evidence for

3Neural Plasticity

http://distillercer.com/resources

each outcome as high, moderate, low, or very low [41]. In theGRADE approach, RCTs begin as high certainty and non-RCT studies begin as moderate certainty. Detailed GRADEguidance was used to assess overall risk of bias [42], impreci-sion [43], inconsistency [44], indirectness [45], and publica-tion bias [46] and to summarize the results in an evidenceprofile (Table 1).

We planned to assess publication bias through visualinspection of funnel plots for each outcome in which weidentified 10 or more eligible studies; however, we were notable to do so because there were an insufficient number ofstudies to allow for this assessment.

2.7. Data Synthesis and Statistical Analysis. We calculatedpooled inverse variance standardized mean difference(SMD) and associated 95% CIs using random-effects models.We addressed variability in results across studies by using I2

statistic and the P value obtained from the Cochran chisquare test. Our primary analyses were based on eligiblepatients who had reported outcomes for each study (com-plete case analysis). We used Review Manager (RevMan)(version 5.3; Nordic Cochrane Centre, Cochrane) for all anal-yses [47].

2.8. Subgroup and Sensitivity Analyses. We planned possiblesubgroup analyses according to the following characteristics:

(i) Participants (stroke type: ischemic stroke versusintracranial hemorrhage)

(ii) Interventions (type of stimulation: cathodal versusanodal and position of electrodes; type of frequency:high frequency versus low frequency)

(iii) Comparator (type of control intervention: phar-macological therapy versus nonpharmacologicaltherapy)

(iv) Different tests for overall USN (star cancellation testversus line bisection test)

We planned to conduct subgroup analyses only when fiveor more studies were available, with at least two in each sub-group. We planned to synthesize the evidence separately forbodies of evidence from RCT and non-RCT studies by a sen-sitivity analysis.

3. Results

3.1. Study Selection. We identified a total of 4129 citationsthrough database searches and a further four studies fromthe reference lists of the Cochrane reviews [22, 48, 49](see Figure 1 for search results). After screening by title andthen by abstract, we obtained full-paper copies for 30 cita-tions that were potentially eligible for inclusion in the review.We excluded 15 studies for the following reasons: case report,case series, self-controlled study, review, and off-topic. Theremaining 12 RCTs [14, 50–60] with a total of 273 partic-ipants and four non-RCTs [61–64] with a total of 94 par-ticipants met the minimum requirements, and we includedthem in this review.

3.2. Study Characteristics. Table 2 describes study charac-teristics related to design of study, setting, number of par-ticipants, mean age, gender, inclusion and exclusioncriteria, and follow-up. Eight studies [14, 54, 56, 59, 61–64]were conducted largely in Europe and eight in Asia [50–53,55, 57, 58, 60]. Randomized trials’ sample sizes rangedfrom 10 [56] to 38 [55], and non-RCT studies rangedfrom 12 [63] to 36 [62]. Typical participants were malesin their 40s, 50s, and 60s. Studies followed participantsimmediately after treatment [50, 57, 58, 62] to one month[51, 52, 54–56].

Table 3 describes study characteristics related to inter-vention and comparators and assessed outcomes. Of the 16included studies, nine trials [14, 50, 52, 54, 55, 59–62] evalu-ated TBS:

(1) Eight trials compared cTBS versus

(i) sham cTBS (both groups received conventionalrehabilitation training [52, 60]);

(ii) 1Hz rTMS, 10Hz rTMS, and sham rTMS (allgroups with addition of routine rehabilitation[55]);

(iii) sham TBS [14];

(iv) sham cTBS [54, 59, 61, 62].

(2) One trial compared iTBS with 80% resting motorthreshold (RMT) versus iTBS 40% RMT [50].

Of the remaining seven studies, four trials [56–58, 64]evaluated tDCS:

(1) Two trials compared tDCS over the left (cathodal)and right (anodal) posterior parietal cortex, one ver-sus placebo at an intensity of 2mA [56] and the otherversus sham tDCS [64].

(2) One trial [57] compared tDCS dual versus eithertDCS single or tDCS sham.

(3) One trial [58] compared tDCS versus sham tDCS.

Three further trials [51, 53, 63] evaluated rTMS:

(1) One trial [51] compared rTMS with sham rTMS,both plus conventional rehabilitation therapy (neu-rodevelopmental facilitation techniques).

(2) Two trials compared 1Hz rTMS, one versus 10HzrTMS and sham rTMS [53] (both groups receivedconventional rehabilitation), and the other trial com-pared 1Hz rTMS versus sham rTMS [63].

None of the included studies evaluated noninvasive brainstimulations as an adjunct to any type of conventionalstroke rehabilitation.

3.3. Risk of Bias. Figure 2 describes the risk of bias assessmentfor the RCTs and non-RCTs, respectively. The major issue

4 Neural Plasticity

Table1:GRADEevidence

profi

leforRCTs:no

ninvasivebrainstim

ulations

forun

ilateralspatialneglectafterstroke.

Qualityassessment

Illustrative

comparative

risks(95%

CI)

Certainty

inestimates

orqu

alityof

evidence

Assum

edrisk

Correspon

ding

risk

Num

berof

participants

(studies)

Range

follow-up

Tim

ein

weeks

Riskof

bias

Inconsistency

Indirectness

Imprecision

Pub

licationbias

Sham

Non

invasive

brain

stim

ulations

OverallUSN

measuredby

star

cancellation

test

116(6)

Immediately

postintervention

4weeks

Seriou

slim

itation1

Seriou

slim

itation2

Noseriou

slim

itation3

Seriou

slim

itation4

Und

etectable

The

meanin

change

inUSN

measuredby

star

cancellation

testwas

45.29(SD

5.94)∗

The

std.

meanin

changes

inUSN

measuredby

star

cancellation

testin

the

intervention

grou

pwas

onaverage0.51

fewer

(1.89fewer

to0.88

more)

Verylow

OverallUSN

measuredby

linebisectiontest

107(5)

Immediately

postintervention

1mon

th

Seriou

slim

itation1

Seriou

slim

itation2

Noseriou

slim

itation3

Noseriou

slim

itation

Und

etectable

The

meanin

change

inUSN

measuredby

line

bisectiontestwas

35.79(SD

18.65)

∗

The

std.

meanin

changes

inUSN

measuredby

line

bisectiontestin

the

intervention

grou

pwas

onaverage2.33

fewer

(3.54fewer

to1.12

fewer)

Low

OverallUSN

measuredby

Motor-FreeVisualP

erceptionTest

38(2)2–4weeks

Seriou

slim

itation1

Noseriou

slim

itation

Noseriou

slim

itation

Noseriou

slim

itation

Und

etectable

The

meanin

change

inUSN

measuredby

Motor-FreeVisual

PerceptionTestwas

16.9(SD2.1)

∗∗

The

std.

meanin

changes

inUSN

measuredby

Motor-FreeVisual

PerceptionTestin

the

intervention

grou

pwas

onaverage1.46

more

(0.73moreto

2.20

more)

Mod

erate

OverallUSN

measuredby

Alberttestandlin

ecrossing

test

50(2)4weeks

Seriou

slim

itation1

Seriou

slim

itation2

Noseriou

slim

itation

Noseriou

slim

itation

Und

etectable

The

meanin

change

inUSN

measuredby

Alberttestandlin

ecrossing

testwas

27.33(SD4.55)∗

∗

The

std.

meanin

changes

inUSN

measuredby

Alberttestandlin

ecrossing

testin

the

intervention

grou

pwas

onaverage1.01

more

(1fewer

to3.02

more)

Low

SD=standard

error;std.=standardized.∗Baselinerisk

estimates

foroverallU

SNcomefrom

controlarm

ofFu

etal.’s

[52]

stud

y(low

estriskof

bias

trialinthemeta-analysis).

∗∗Baselinerisk

estimates

foroverall

USN

comefrom

controlarm

ofCha

etal.’s[51]

stud

y(new

esttrialinthemeta-analysis).

1 The

majorityofthestud

ieswererank

edas

high

risk

ofbiasforboth

allocation

sequ

ence

andallocation

concealm

ent.2 There

was

asubstantialh

eterogeneity

(I2 >

70%).

3 There

was

nosubstantiald

ifference

relatedto

themeanageandeligibility

criteriathrougho

utthesixinclud

edstud

ies.

4 95%

CIforabsoluteeffectsinclud

esclinically

impo

rtantbenefitandno

benefit.

5Neural Plasticity

regarding riskofbias in theRCTsandnon-RCTswasproblemsof random sequence generation [14, 50, 51, 54–59, 61–64] andconcealment of randomization [14, 50, 53–59, 61–64]. Anadditional problem was blinding of the statistician in allincluded studies.

3.4. Outcomes

3.4.1. Synthesized Results from Randomized Controlled Trials

(1) Overall USN Measured by the Star Cancellation Test. Theresults from six RCTs [51–55, 57] comparing noninvasivebrain stimulations with sham failed to show a benefit in over-all USN measured by the star cancellation test (SMD −0.51,95% CI −1.87, 0.85; p = 0 46; I2 = 90%) (Figure 3). Theresults were consistent regardless of the type of noninvasivebrain stimulations (TBS in three RCTs [52, 54, 55] (SMD−1.61, 95% CI −4.28, 1.06; p = 0 24; I2 = 93%); dual-tDCSin one RCT [57] (SMD −0.12, 95% CI −0.99, 0.76; p = 0 79 ;I2 =not applicable); and 1Hz rTMS in two RCTs [51, 53](SMD 0.57, 95% CI −2.95, 4.10; p = 0 75; I2 = 95%))(Figure 3). Certainty in evidence was rated as very lowbecause of imprecision, inconsistency, and risk of bias due tothe studies that were ranked as high risk of bias for bothallocation sequence and allocation concealment (Figure 2).

A sensitivity analysis from the same RCTs using TBS[52, 54, 55], single-tDCS [57], and 10Hz rTMS [51, 53]yielded results that were also consistent with the primaryanalysis and failed to show a difference in the effects ofnoninvasive brain stimulations compared to sham (SMD−0.62, 95% CI −1.89, 0.65; p = 0 34; I2 = 88%) (Figure 4).

(2) Overall USN Measured by the Line Bisection Test. Resultsfrom five RCTs [51–53, 55, 57] comparing noninvasivebrain stimulations with sham suggested a benefit in overallUSN measured by the line bisection test (SMD −2.33, 95%CI −3.54, −1.12; p = 0 0002; I2 = 81%) (Figure 5). The resultswere inconsistent when the data were analyzed by type ofnoninvasive brain stimulations: TBS in two RCTs [52, 55](SMD −3.08, 95% CI −6.54, 0.38; p = 0 08; I2 = 90%) anddual-tDCS in one RCT [57] (SMD −0.66, 95% CI −1.56,0.25; p = 0 15; I2 = not applicable) except by 1Hz rTMSin two RCTs [51, 53] that yielded results that were con-sistent with the overall meta-analysis (SMD −2.33, 95%CI −3.54, −1.12; p < 0 0002; I2 = 81%) (Figure 5). Certaintyin evidence was rated as low because of inconsistency andrisk of bias due to the studies that were ranked as high riskof bias for both allocation sequence and allocation conceal-ment (Figure 2).

A sensitivity analysis from the same RCTs using TBS[52, 55], tDCS [57], and 10Hz rTMS [53] yielded resultsthat were also consistent with the primary analysis and sug-gested a difference in the effects of noninvasive brain stimula-tions compared to sham (SMD −2.35, 95% CI −3.72, −0.98;p = 0 002; I2 = 85%) (Figure 6).

(3) Overall USN Measured by Motor-Free Visual PerceptionTest. The results from two RCTs [51, 53] comparing nonin-vasive brain stimulations with sham suggested a benefit

Number of recordsidentifiedthroughdatabase

searching: 4129

Number of additionalrecords

identifiedthrough other

sources: 4

Reference listfrom Cochrane

reviews: 4

Number of records after duplicatesremoved: 3327

Number of recordsscreened: 3327

Number of recordsexcluded: 3297

Number of full-textarticles

excluded, withreasons: 15

Number of full-textarticles assessedfor eligibility: 30

Number of studiesincluded inqualitative

synthesis: 16

Number of studiesincluded inquantitative

sybthesis(meta-analysis): 6

Case series: 11

Case report: 1

Self-controlled: 1

Review: 1

Off-topic 1

RCTs: 12

Non-RCTs: 4

RCTs: 6

Non-RCTs: 0

MEDLINE: 1903EMBASE: 1377CENTRAL: 830

CINAHL: 13LILACS: 6

Figure 1: Flow diagram of the systematic review.

6 Neural Plasticity

Table2:Stud

ycharacteristicsrelatedto

design

ofstud

y,setting,nu

mberof

participants,m

eanage,gend

er,and

inclusionandexclusioncriteria.

Autho

r,year

Designof

stud

yStatus

ofpu

blication

Location

No.

∗of

participants

Meanage

No.of

males

(%)

Inclusioncriteria

Exclusion

criteria

Rando

mized

controlledtrials

Cao

etal.,

2016

[50]

Parallel

RCT

Fulltext

Asia

I:7

C:6

I:55.0

C:62.0

I:85.7

C:83.3

Right-handedpatientswho

had

afirst-ever

stroke

intheright

hemisph

ereandvisuospatial

neglectwithno

rmalor

corrected-to-normalvision

NR

Cha

andKim

,2016

[51]

Parallel

RCT

Fulltext

Asia

I:15

C:15

I:64.07

C:63.33

I:64

C:60.0

Had

afirstrighthemisph

ere

stroke

(cerebralinfarction

orhemorrhage)

morethan

2weeks

before

thestud

y,which

hadbeen

confi

rmed

bycompu

tedtomograph

yor

magneticresonance

imaging(M

RI);h

adVSN

determ

ined

bylin

ebisection

tests(rightwardbias>12%)

orstar

cancelationtest

(omission

ofanynu

mber

ofstars);h

adaGlasgow

comascalescore<15;

18–80yearsold;

right-hand

ed;

norm

alvision

orno

rmal

correctedvision

;and

had

theability

toun

derstand

thestud

yandsigned

aninform

edconsentform

Allpatientsdidno

thave

brain

tumorsor

otherbrainpathology.

Excludedwerepatientswith

hemiano

pia;subarachno

idhemorrhage,veno

ussinu

sthrombosis,transientischem

icattack,reversibleischem

ia,or

acond

itionexacerbatedby

anewinfarction

orhemorrhage

site;a

medicalhistoryor

family

historyof

seizure;or

with

metaldevicesor

claustroph

obia

preventing

MRI

Fuetal.,

2015

[52]

Parallel

RCT

Fulltext

Asia

I:11

C:11

I:55.1β

C:59.5β

I:80.0

C:80.0

Right-handedpatients

withrighthemisph

ere

stroke

(hem

orrhagicor

ischem

iclesion

)confi

rmed

bycompu

tedtomograph

yor

magneticresonance

imaging>2weeks

before

thebeginn

ingof

thestud

yanddiagno

sisof

visuospatial

neglectbasedon

clinician

judgem

entandon

deficits

inat

leaston

eou

tof

two

paper-penciltests

Age

<30

yearsor

>80

years,

historyof

epilepsy,previous

head

trauma,drug

andalcoho

labuseandpsychiatricdisorders,

recurrentstroke,obvious

aphasiaandcommun

ication

obstacles,family

historyof

seizures,everuseof

tricyclic

antidepressantsor

antipsycho

tic

drugs,diam

agneticmetal

implantssuch

ascardiac

pacemakers,andvisual

fielddefects

7Neural Plasticity

Table2:Con

tinu

ed.

Autho

r,year

Designof

stud

yStatus

ofpu

blication

Location

No.

∗of

participants

Meanage

No.of

males

(%)

Inclusioncriteria

Exclusion

criteria

Fuetal.,

2017

[60]

Parallel

RCT

Fulltext

Asia

I:6

C:6

I:60.17

C:62

I:75

C:75

Had

afirstrighthemisph

ere

stroke

(cerebralinfarction

orhemorrhage)

morethan

2weeks

before

thestud

y,which

hadbeen

confi

rmed

bycompu

tedtomograph

yor

magneticresonance

imaging(M

RI);h

adVSN

determ

ined

bylin

ebisection

tests(rightwardbias>12%)

orstar

cancelationtest

(omission

ofanynu

mber

ofstars);h

adaGlasgow

comascalescore<15;

18–80yearsold;

right-hand

ed;

norm

alvision

orno

rmal

correctedvision

;and

hadthe

ability

toun

derstand

thestud

yandsign

aninform

edconsent

form

;allpatientsdidno

thave

braintumorsor

otherbrain

pathology

Patientswithhemiano

pia;

subarachno

idhemorrhage,

veno

ussinu

sthrombosis,

transientischem

icattack,

reversibleischem

ia,ora

cond

itionexacerbatedby

anewinfarction

orhemorrhagesite;a

medical

historyor

family

history

ofseizure;or

withmetal

devicesor

claustroph

obia

preventing

MRI

Smitetal.,

2015

[56]

RCT

cross-over

stud

yFu

lltext

Europ

eI:5€

C:5

€I:64.8€

C:64.8€

I:60.0€

C:60.0€

Patientswithlefthemispatial

neglectafterright-hemisph

eric

lesion

,right-handed,

olderthan

theageof

18,m

orethan

four

mon

thsafterstroke

Patientswithsevere

language

andcommun

icationdisorders,

bilateralcorticald

amage,

psychiatricdisorders,alcoho

land/or

drug

addiction,

epilepsy,

eczemaor

damages

onthescalp,

metalor

otherforeignparts

inthehead

Yangetal.,

2015

[55]

Parallel

RCT

Fulltext

Asia

I:9

I2:10

I3:9

C:10

I:46.7

I2:48.0

I3:49.4

C:47.7

I:66.6

I2:40.0

I3:55.6

C:30.0

Age

between18

and80;

firststroke

patients(cerebral

infarction

orhemorrhage)

andin

recovery

timewithin

60–180

days;U

SNconfi

rmed

bylin

ebisectiontest,star

cancellation

test,orclinical

exam

ination;

nometallic

implantof

diam

agnetic

substance;signed

the

inform

edconsent

Subarachno

idhemorrhage,

veno

ussinu

sthrombosis,and

reversibleor

transientischem

icattacks;worsening

cond

ition

andnew-onsetinfarction

orhemorrhage;GCSscore<15;

obviou

saphasiaandsevere

cognitive-commun

ication

disorders;family

historyof

epilepsy;im

paired

organ

function

orfailu

rein

the

heart,lung,liver,kidney,or

8 Neural Plasticity

Table2:Con

tinu

ed.

Autho

r,year

Designof

stud

yStatus

ofpu

blication

Location

No.

∗of

participants

Meanage

No.of

males

(%)

Inclusioncriteria

Exclusion

criteria

othervitalo

rgansandlife

expectancy

<6mon

ths;history

ofclaustroph

obiaand

uncoop

erativedu

ring

exam

ination;

andhemiano

psia

Kim

etal.[53]

Parallel

RCT

Fulltext

Asia

I:9

I2:9

C:9

I:68.6

I2:64.1

C:68.3

I:55.6

I2:44.4

C:66.7

Patientswithrightcerebral

ischem

icor

hemorrhagic

withvisuospatialneglect

(con

firm

edusingthelin

ebisectiontest);allp

atients

wereright-hand

ed

Severe

cognitiveim

pairment

makingthem

unableto

understand

theinstructions;

contraindication

sforTMS,

such

asahistoryof

epileptic

seizure,major

head

trauma,

andpresence

ofmetalin

the

skullo

rpacemaker;orun

stable

medicalor

neurologic

cond

itions

Sunw

ooetal.,

2013

[57]

RCT

cross-over

stud

yFu

lltext

Asia

I:10

I2:10

C:10

62.6¢

40.0β

Stroke

patientswithlesion

intherighthemisph

ereinvolving

theparietalcortex,and

left

USN

diagno

sedby

clinical

observationandconfi

rmed

byalin

ebisectiontest;allpatients

werepreviouslyright-hand

ed

Patientswho

hadmetallic

implantsin

thecranial

cavity,a

skulld

efect,history

ofseizure,un

controlled

medicalproblems,and

severe

cognitiveim

pairment

Cazzolietal.,

2012

[14]

Parallel

RCT

Fulltext

Europ

e24

£58.0¢

70.8¢

Ischem

icor

hemorrhagiclesion

totherighthemisph

ereand

left-sided

spatialn

eglect

determ

ined

onthebasisof

deficitsin

atleasttwoou

tof

threeclassesof

paper-

penciltestsandon

clinical

judgem

ent;allp

atientshad

tohave

norm

alor

corrected-to-

norm

alvisualacuity

History

ofepilepsy,prior

head

trauma,drug

and

alcoho

labu

se,and

major

psychiatricdisorders

Koetal.,

2008

[58]

RCT

cross-over

stud

yFu

lltext

Asia

I:15

€

C:15€

I:62.1€

C:62.1€

I:66.6€

C:66.6€

Patientswithsubacutestroke

withneglect

Patientswho

hadmetalin

thecranialcavityor

calvarium,skinlesion

sin

thearea

ofelectrod

e,un

controlledmedical

cond

itions,and

severe

cognitiveim

pairments

9Neural Plasticity

Table2:Con

tinu

ed.

Autho

r,year

Designof

stud

yStatus

ofpu

blication

Location

No.

∗of

participants

Meanage

No.of

males

(%)

Inclusioncriteria

Exclusion

criteria

Kochetal.,

2012

[54]

Parallel

RCT

Fulltext

Europ

eI:10

C:10

I:61.4#

C:71.9#

I:55.5#

C:55.5#

Right-handedpatients,w

ith

righthemisph

eresubacute

ischem

icstroke

affectedby

hemispatialneglect,confi

rmed

byradiologic(CTor

MRI)and

clinicalexam

ination

NR

Bon

nìetal.,

2011

[59]

Parallel

RCT

Con

ference

abstract

Europ

eNR

NR

NR

Subacutestroke

patients

withneglect

NR

Non

-RCTs

Cazzolietal.,

2015

[61]

Non

-RCT

cross-over

stud

y§Fu

lltext

Europ

eI:8¥

C:8

¥I:52.6and54.2α

C:53.0

NR

Patientswithleft-sided,

hemispatialneglectafter

asubacuteright-hemisph

eric

stroke;allpatientshadno

rmal

orcorrected-to-normal

visualacuity

Not

clearlyrepo

rted,

however,autho

rshave

assessed

patientsby

means

ofinternationally

accepted

safety

guidelines

forthe

applicationof

TMS,which

includ

edscreeningfora

historyof

epilepsy,prior

head

trauma,drug

and

alcoho

labu

se,and

major

psychiatricdisorders

Hop

fner

etal.,

2015

[62]

Non

-RCT

cross-over

Fulltext

Europ

eI:18

€

C:18€

I:64.5€

C:64.5€

I:50.0€

C:50.0€

Left-sided

neglect,basedon

clinicaljudgem

entand

neurop

sychologicaltesting,

aftersubacuteright-

hemisph

ericstroke;allsubjects

hadno

rmalor

corrected-to-

norm

alvisualacuity

NR

Làdavasetal.,

2015

[64]

Quasi-

RCT

Fulltext

Europ

eI:8

I2:11

C:11

I:72.0

I2:66.0

C:67.0

I:50.0

I2:54.5

C:54.5

Patientswithrighthemisph

ere

stroke

withhemispatial

neglectandperformance

ontheBehavioralInattention

Testbatterywithscores≤129

Presenceof

widespread

mentald

eterioration

(Mini-

MentalStateExamination

score<20),psychiatric

disorders,ahistoryof

prior

stroke

orhemorrhage,any

severe

internalmedicaldisease,

epilepsy,andaddition

alfactors

influencingtherisk

ofepilepsy

10 Neural Plasticity

Table2:Con

tinu

ed.

Autho

r,year

Designof

stud

yStatus

ofpu

blication

Location

No.

∗of

participants

Meanage

No.of

males

(%)

Inclusioncriteria

Exclusion

criteria

Agostaetal.,

2014

[63]

Non

-RCT

cross-over

stud

yFu

lltext

Europ

eI:6€

C:6

€I:67.83€

C:67.83

€I:66.6€

C:66.6€

Patientswithright

hemisph

ereun

ilaterallesions

dueto

acerebrovascular

stroke,con

firm

edby

radiologicalexam

ination

(CTor

MR),in

theirchronic

stageafterthestroke

(atleastsixmon

thspo

ston

set);

besides,participantswere

right-hand

ed,n

ativeItalian

speakers,and

hadno

rmalor

corrected-to-normalvisualacuity

History

orevidence

ofdegenerative

diseaseor

psychiatricdisorder

C:con

trolgrou

p;CT:com

putedtomograph

y;GCS:Glasgow

comascale;I:intervention

;MR:m

agneticresonanceim

aging;No.:num

ber;RCT:rando

mized

controlledtrial;TMS:transcranialmagneticstim

ulation;

USN

:unilateralspatialneglect.€ Participantsoftheexperimentalgroup

also

served

ascontrols.¥Five

patientswererand

omized

inparalleldesign,andthreefurtherpatientsinclud

edinboth

grou

ps.£The

authorsdid

notspecify

thesamplesize

perstud

iedgrou

p.αDatacomprises

threepatientsthat

received

both

experimentalandcontrolintervention

s.βDatawas

calculated

from

10patients(one

patientwas

exclud

edafter

rand

omization).¢ D

ataarefrom

thewho

lesample,as

theauthorsdidno

tspecify

itperstud

iedgrou

p.# D

ataarefrom

9patients

ineach

grou

p.§ The

stud

ywas

across-over

foron

lythreepatients,forthe

remaining

tenpatientsthestud

ywas

aRCT.

11Neural Plasticity

Table3:Stud

ycharacteristicsrelatedto

intervention

andcontrolgroup

s,assessed

outcom

es,and

follow-up.

Autho

r,year

Description

ofintervention

sDescription

ofcontrolgroup

sMeasuredou

tcom

esFo

llow-up

Rando

mized

controlledtrials

Cao

etal.,

2016

[50]

iTBS80%

RMTin

therTMSgrou

p:stim

ulationwas

appliedusingan

87mm

butterflycoilconn

ectedto

aMagstim

Rapid2(M

agstim

Co.,W

hitland

,UK),

withpeak

intensityof

2.0Tandamaxim

umpu

lselength

of250μs.Pulses(theta

bursttype)

weredelivered

totheleftdo

rsallateralp

refron

tal

cortex,the

F5labelo

fthelefthemisph

ere,which

isbetweentheF3

andF7,at80%

ofrestingmotor

threshold.

Twosessions

wereappliedwitha

15min

intervalon

each

day.Eachsessioninclud

ed20

stim

ulationtrains

consisting

ofthreepu

lses

delivered

atafrequencyof

50Hzin

every200msfor

2s(total10

bursts,30pu

lses)withan

intervalof

8s.

Sameas

intervention

grou

p;ho

wever,p

ulseswere

delivered

at40%

ofRMT

Line

bisectionand

star

cancellation

tests

After

intervention

Cha

andKim

,2016

[51]

RepetitiverT

MS+convention

alrehabilitation

therapy(neurodevelopm

entalfacilitation

techniqu

es)

foratotalo

f40

minutes

(rTMS:10

min;rehabilitation

:30

min)perday,witha10-m

inuterestperiod

halfw

aythroughthesession,

for4weeks,5

days

perweek:

stim

ulationwas

delivered

usingfigure-of-eightcoil

withadiam

eter

of80

mm

conn

ectedto

Magstim

Rapid2(M

agstim

Co.Ltd.,W

ales,U

K).Stim

ulation

was

appliedin

therightpo

steriorparietal(P3andP4

areas)basedon

theelectroencephalogram

10/20

system

atafrequencyof

1Hzfor5minutes

with

90%

ofthemotor

thresholddu

ring

rest.

Sham

rTMSandconvention

alrehabilitationtherapyusing

thesameprotocol

than

the

experimentalgroup

Motor-FreeVisual

PerceptionTest;lin

ebisectiontest;A

lberttest;

star

cancellation

test

4weeks

Fuetal.,

2015

[52]

Leftpo

steriorparietalcortex

cTBS+convention

alrehabilitationtraining:cTBSwas

setover

P5,three-

pulsebu

rstwas

delivered

at30

Hzandrepeated

every

200msfor40

swithintensitywas

80%

oftheresting

motor

threshold.

cTBSwas

delivered

usingaSuper

Rapid

2magneticstim

ulator

(Magstim

,Whitland

,UK)

with2.0-Teslamaxim

umfieldstrength,con

nected

with

afigure-of-eightcoil(diameter

ofou

tsideloop

,87

mm).Patientsreceived

4trains

daily,w

ithan

intervalof

15min,for

14consecutivedays.

Sham

cTBS+convention

alrehabilitationtraining

Star

cancellation

test;

linebisectiontest

4weeks


Table3:Con

tinu

ed.

Autho

r,year

Description

ofintervention

sDescription

ofcontrolgroup

sMeasuredou

tcom

esFo

llow-up

Fuetal.,

2017

[60]

The

cTBSgrou

preceived

continuo

usTBSwiththecoil

placed

tangentiallyto

thescalpat

P3over

theleft

posteriorparietalcortex

(according

tothe10–20

electrod

epo

sition

system

oftheAmerican

Electroenceph

alograph

icAssociation

28).The

magnitude

ofthepu

lses

was

maintainedat

80%

restingmotor

threshold.

Oneach

dayfor10

consecutivedays,4

sessions

ofstim

ulation

weredelivered,w

ithan

intervalof

15min

between

every2sessions.E

achsessionlasted

40sandcontained

600pu

lses

delivered

in200bu

rstsat

5Hz(theta

rhythm

).Eachbu

rstinclud

ed3pu

lses

delivered

at30

Hz.

The

active

controlgroup

received

stim

ulations

with

thesamefeatures

atthe

samepo

sition

asthe

cTBSgrou

p,bu

twith

thecoilplaced

perpendicular

tothescalpsurfaceandthe

amplitud

eof

thestim

ulation

pulses

redu

cedto

40%

restingmotor

threshold

Star

cancellation

test;

linebisectiontest

10days

Smitetal.,

2015

[56]

tDCSwas

appliedfor20

minutes

over

theleft(catho

dal)

andright(ano

dal)po


onfive

consecutivedays

withabattery-driven

directcurrent

stim

ulator

(NeuroCon

nDC-Stimulator;serialnum

ber

0096).Stim

ulationparametersweresetat

acurrentof

2000

mA,and

aresistance

of

Table3:Con

tinu

ed.

Autho

r,year

Description

ofintervention

sDescription

ofcontrolgroup

sMeasuredou

tcom

esFo

llow-up

Group

I3:cTBStwotimes

adayfor2

weeks

+routinerehabilitation:

stim

ulationwas

administeredusingarapidmagneticstim

ulator

(Magstim

Com

pany)withafigure-of-eightcoil,

peak

intensityof

stim

ulationat

2T,and

pulsedu

ration

of250s,at

thecontralateral

hemisph

ere(P3),intensity

80%

ofRMT,

801pu

lses,inbu

rstsof

3pu

lses

at30

Hz,repeated

every100ms.

Kim

etal.,

2013

[53]

Group

A:10sessions

oflow-frequ

ency

(1Hz)

rTMS

over

theno

nlesionedleftpo


(P3)

ata90%

motor

thresholdin

4trains

of5-minute

duration

,eachseparatedby

1minute(resulting

ina

totalstimulationperiod

of20

minutes).rTMSwas

delivered

usingaMagstim

SuperRapid

Magnetic

Stim

ulator

witha70-m

illim

eter,air-cooled8-shaped

coil.rTMSwas

performed

5times

perweekfor2weeks.

Patientsalso

received

convention

alrehabilitation

treatm

ent(including

physical,occup

ational,and

cognitivetherapies).

Group

B:10sessions

ofhigh-frequ

ency

(10Hz)

rTMS

over

thelesion

edrightpo


(P4)

ata

90%

motor

thresholdin

4trains

of5-minutedu

ration

,each

separatedby

55second

s(resulting

inatotal

stim

ulationperiod

of20

minutes).The

remaining

oftheprotocol

followed

thesameinstructions

asgrou

pA.

Sham

rTMS+

convention

alrehabilitation

Motor-FreeVisual

PerceptionTest;

linebisectiontest;

cancellation

test;

Catherine

Bergego

scale;

Korean-mod

ified

Barthelindex

2weeks

Sunw

ooetal.,

2013

[57]

Group

A:d

ual-mod

e(tDCSdu

al)directcurrentwas

delivered

bytwosetsof

battery-po

wered

devices

(Pho

resorIIAutoMod

-elPM850,IO

MED,U

SA)

usingtwopairsof

surfacesalin

e-soaked

spon

geelectrod

es(5cm

×5cm

).Ano

daltDCSof

thefirstcircuit

over

therightPPC(P4)

was

accompanied

bycathod

altD

CSof

thesecond

circuitover

theleftPPC

(P3).T

herefore,inthefirsttD

CScircuit,theanod

ewas

placed

over

P4andthecathod

ewas

placed

over

theleft

supraorbitalarea.Inthesecond

tDCScircuit,the

anod

ewas

placed

over

therightsupraorbitalarea

and

thecathod

ewas

placed

over

theP3.Aconstant

current

of1mAwas

delivered

for20

min.

Sham

mod

e(tDCSsham

)in

thefirstandsecond

tDCS

circuits.T

hestim

ulator

was

turned

onandthecurrent

intensitywas

gradually

increasedfor5s,andwas

then

taperedoff

over

5s

Line

bisectiontest;

star

cancelationtest

Immediately

aftertreatm

ent


Table3:Con

tinu

ed.

Autho

r,year

Description

ofintervention

sDescription

ofcontrolgroup

sMeasuredou

tcom

esFo

llow-up

Group

B:Single-mod

e(tDCSsingle)

directcurrentwas

delivered

bytwosetsof

battery-po

wered

devices

(Pho

resorIIAutoMod

-elPM850,IO

MED,U

SA)using

twopairsof

surfacesalin

e-soaked

spon

geelectrod

es(5cm

×5cm

).The

anod

ewas

placed

over

P4andthe

cathod

eover

theleftsupraorbitalarea

(the

firsttD

CS

circuit),and

realstim

ulationwas

provided,w

hereas

the

second

tDCScircuitreceived

sham

stim

ulation.

Forthe

realstim

ulation,

aconstant

currentof

1mAwas

delivered

for20

min.F

orthesham

stim

ulation,

the

stim

ulator

was

turned

onandthecurrentintensitywas

gradually

increasedfor5s,andwas

then

taperedoff

over

5s.

Cazzolietal.,

2012

[14]

cTBSfor2days

onweek1andsham

TBSfor2days

onweek2.cT

BSwas

appliedby

means

ofaMagPro

X100stim

ulator

(Medtron

icFu

nction

alDiagnostics)

conn

ectedto

aroun

dcoilwith60

mm

outer

radius

(MagneticCoilT

ransdu

cerMC-125).cT

BS

protocol

comprised

801pu

lses,d

elivered

ina

continuo

ustrainandconsisting

of267bu

rsts,

each

onecontainedthreepu

lses

at30

Hz,repeated

at6Hz(totaldu

ration

ofon

esingle,cTBStrainwas

44s),

andeightcT

BStrains

wereappliedover

2days.cTBS

was

appliedover

P3.Besides,p

atientsreceived

neurorehabilitation

therapyinclud

ing1h

neurop

sychologicaltraining,1

hof

occupation

altherapy,and1hof

physiotherapyperday.

Con

trol

A:sham

TBSfor2

days

onweek1andcT

BSfor2

days

onweek2.cT

BSprotocol

was

thesamedescribedfor

intervention

A.B

esides,p

atients

received

neurorehabilitation

therapyinclud

ing1h

neurop

sychologicaltraining,1

hof

occupation

altherapy,and1h

ofph

ysiotherapyperday

Con

trol

B:sham

TBSfor2days

onweek1andsham

TBSfor2

days

onweek2.Besides,

patientsreceived

neurorehabilitation

therapy

includ

ing1h

neurop

sychologicaltraining,

1hof

occupation

altherapy,and

1hof

physiotherapyperday

Catherine

Bergego

scale;Vienn

aTest

System

;rando

mshapecancelation

test

2weeks

Koetal.,

2008

[58]

tDCSto

therightpo


for20

min

(2mAanod

alDCbrainpo

larization

)deliveryby

abattery-po

wered

device

(Pho

resorIIAutomod

elPM850,IO

MED,U

SA),usingapairof

salin

e-soaked

surfacespon

geelectrod

es(5cm

×5cm

).The

anod

ewas

placed

over

P4,andcathod

ewas

placed

over

left

supraorbitalarea.

Sham

tDCS(current

was

delivered

for10

sandthen

turned

off)

Line

bisectiontest;

shape-un

structured

cancellation

test;

letter-structured

cancellation

test

Immediatelypo

stintervention

15Neural Plasticity

Table3:Con

tinu

ed.

Autho

r,year

Description

ofintervention

sDescription

ofcontrolgroup

sMeasuredou

tcom

esFo

llow-up

Kochetal.,

2012

[54]

cTBSwas

delivered

usingaMagStim

SuperRapid

magneticstim

ulator

(Magstim

Com

pany,W

hitland

,Wales,U

K),conn

ectedwithafigure-of-eightcoilwitha

diam

eter

of70

mm.Ineach

session,

3-pu

lsebu

rstsat

50Hzrepeated

every200msfor40

sweredelivered

at80%

oftheactive

motor

thresholdover

theleftPPC(600

pulses).Every

day,2sessions

ofleftPPCcT

BSwere

appliedwithan

intervalof

15minutes

andlasted

for

10days

(5days

perweek,Mon

dayto

Friday).Patients

also

received

rehabilitationprogram

consistedof

20sessions

of45

minutes

each,h

eld5days

perweek(based

oncompu

terizedvisuospatialscanning

training)and

motor

rehabilitationwhennecessary.

Sham

cTBSwas

delivered

withthecoilangled

at90

° ,withon

lytheedge

ofthecoil

restingon

thescalp

Stim

ulus

intensity,expressed

asapercentage

ofthemaxim

umstim

ulator

output,w

assetat

80%

oftheactive

motor

thresholdindu

cing

thesame

acou

sticsensationas

forrealTBS

Patientsalso

received

rehabilitationprogram

Line

crossing

test;

letter

cancellation

test;

star

cancellation

test;

figure

andshape

copyingtest;

representative

draw

ingtest

1mon

th

Bon

nìetal.,

2011

[59]

cTBSover

theleftPPC,for

twoweeks.

Sham

cTBS

Standardized

behaviou

ral

inattentiontest;

excitabilityof

the

parieto-fron

tal

function

alconn

ection

s

NR

Non

-RCTs

Cazzolietal.,

2015

[61]

cTBSover

theleft,con

tralesionalP

PC(P3),w

asapplied

usingaMagPro

X100stim

ulator,con

nected

toeither

aroun

dcoil(M

C-125

Medtron

icFu

nction

alDiagnostics).

The

cTBSprotocol

consistedof

801pu

lses

delivered

inacontinuo

ustrain.

The

trainwas

comprised

of267bu

rsts,w

here

each

containedthreesinglepu

lses

at30

Hz,repeated

at6Hz,andhadatotald

urationof

44s.

App

licationconsistedon

twotrains

separatedby

a15

min

interval.

Sham

cTBSover

theleft,

contralesion

alPPC,w

asappliedusingasham

coil

(MC-P-B70

Medtron

icFu

nction

alDiagnostics)

Com

puterised

balloon

testwith

eyemovem

ent

recording;paper-pencil

cancellation

tasks

8ho

urs

Hop

fner

etal.,

2015

[62]

cTBScomprised

801pu

lses,d

elivered

inacontinuo

ustrainof

267bu

rsts(eachinclud

ing3pu

lses

at30

Hz,

repeated

at6Hz).T

hetotald

urationof

asingle

cTBStrainwas

44s.TwocT

BStrains

wereapplied

overP3,withan

intertrain

intervalof

15min.A

MagPro

X100stim

ulator

(Medtron

icFu

nction

alDiagnostics,F

arum

,Denmark),con

nected

toarou

ndcoil(M

agneticCoilT

ransdu

cerMC-125)was

used

todeliver

biph

asic,repetitivemagneticpu

lses.B

esides,12

(from

18)patientsalso

received

smooth

pursuiteye

movem

enttraining.

Sham

cTBSconn

ectedto

aplacebocoil(M

agneticCoil

Transdu

cerMC-P-B70)

Besides,12(from

18)

patientsalso

received

Smooth

pursuiteye

movem

enttraining

Centerof

cancellation

score;x-po

sition

ofleftmostcancelled

target;n

umberof

cancelledtargets

Right

after

treatm

ent


Table3:Con

tinu

ed.

Autho

r,year

Description

ofintervention

sDescription

ofcontrolgroup

sMeasuredou

tcom

esFo

llow-up

Làdavasetal.,

2015

[64]

Group

A:2-w

eekrehabilitationprogram

consistedof

10sessions

ofcathod

altD

CSlasting30

minutes

each

and

held

5days

perweek.tD

CSwas

appliedusingabattery-

driven

Eldith(neuroCon

nGmbH

,Ilm

enau,G

ermany)

Program

mableDirectCurrent

Stim

ulator

withapair

ofsurfacesalin

e-soaked

spon

geelectrod

es.Ineach

session,

aconstant

currentof

2mAintensity(current

density:0.57

mA/cm2)

was

delivered

lasting20

minutes

ofcathod

altD

CSof

theleft,intactPPC(overP5).

Group

B:2-w

eekrehabilitationprogram

consistedof

10sessions

ofan

odaltD

CSlasting30

minutes

each

and

held

5days

perweek.The

anod

altD

CSwas

placed

over

thePPCof

thedamaged

hemisph

ere(P6).T

heremaining

protocol

was

thesameused

ingrou

pA.

Sham

tDCS(m

ontage

used

inthesham

grou

pmim

ickedthat

used

inthetwoactive

grou

ps)

BehavioralInattention

Test

Finalfollow-up

withinthefirstweek

afterthelastsession

Agostaetal.,

2014

[63]

A10-m

inutetrainof

repetitive

low-frequ

ency

(1Hz)

rTMSover

theleftparietallobe

(P3site)identified

using

the10/20EEGmeasurementsystem

.The

stim

ulus

was

delivered

usinga70

mm

figure-of-eightcoil

conn

ectedto

aMagstim

Rapid2(M

agstim

Co.,U

K).

Stim

ulationstrength

was

setto

90%

ofthethresholdto

evokemotor

respon

sesat

rest.

Sham

rTMSover

the

intactleftparietalcortex

Visualtrackingtask;

unilateraland

bilateral

tasks

30minutes

C:con

trol

grou

p;cT

BS:continuo

usthetabu

rststim

ulation;

I:intervention

;iTBS:interm

ittent

thetabu

rst;PPC:p

osterior

parietalcortex;R

MT:resting

motor

threshold;

rTMS:repetitive

transcranialmagnetic

stim

ulation;

tDCS:transcranialdirectcurrentstim

ulation;

TBS:thetabu

rststim

ulation;

USN

:unilateralspatialneglect.

17Neural Plasticity

in overallUSNmeasured by theMotor-FreeVisual PerceptionTest at 1Hz (SMD1.46, 95%CI0.73, 2.20;p < 0 0001; I2= 0%),and the difference was not observed using 10Hz (SMD 0.97,95% CI −0.02, 1.96; p = 0 06; I2 =not applicable) (Figure 7).

Certainty in evidence was rated as moderate because ofrisk of bias due to the studies that were ranked as highrisk of bias for both allocation sequence and allocationconcealment (Figure 2).

Agosta 2014

Bonní 2011

Cao 2016

Cazzoli 2012

Cazzoli 2015

Cha 2016

Fu 2015

Fu 2017

Hopfner 2015

Kim 2013

Ko 2008

Koch 2012

Làdavas 2015

Smit 2015

Sunwoo 2013

Yang 2015

Rand

om se

quen

ce g

ener

atio

n (s

elec

tion

bias

)

Allo

catio

n co

ncea

lmen

t (se

lect

ion

bias

)

Blin

ding

of p

atie

nts

Blin

ding

of c

areg

iver

s

Blin

ding

of d

ata c

olle

ctor

s

Blin

ding

of s

tatis

ticia

n

Blin

ding

of o

utco

me a

sses

sors

Inco

mpl

ete o

utco

me d

ata (

attr

ition

bia

s)

Sele

ctiv

e rep

ortin

g (r

epor

ting

bias

)

Oth

er b

ias

− − + + + +

+ + + +

+ +

+ +

+

+

++ + + +

+

+

+

+ + + +

+

+

+

++ +

+

++

+

+

+

+

+

+

+

+

+

+

++

+ +

+

+ +

+ + +

+ + +

+ +

+

+

+ + +

+

+

+

+

+ + ++

− −

− − −

− −

− −

−

−

−

−

−

−

−

−

− −

− −

− − − −

− −

−

− − −

−

−

−

− − − − −

− −

− −

−

−−−

− −

−

−

−

−

−

−

−

−

−

−

−

−

−

−

−

−

−

−

−

−

−

− − − −

− − − −

−

−

−

−

− − −

Figure 2: Risk of bias assessment for RCTs and non-RCTs.


(4) Overall USN Measured by Albert’s Test and the LineCrossing Test. The results from two RCTs [51, 54] com-paring noninvasive brain stimulations with sham failedto show a benefit in overall USN measured by Albert’s testand the line crossing test (SMD 1.01, 95% CI −1.0, 3.02;p = 0 32; I2 = 90.2%) (Figure 8). However, in the subgroupanalysis with the use of 1Hz rTMS, we found a statisti-cally significant difference compared to sham (SMD 2.04,95% CI 1.14, 2.95; p < 0 00001; I2 =not applicable). Regard-ing the use of TBS, there was no benefit compared to sham(SMD −0.01, 95% CI −0.89, 0.87; p = 0 98; I2 =not applica-ble). Certainty in evidence was rated as low because of incon-sistency and risk of bias due to the studies that were ranked ashigh risk of bias for both allocation sequence and allocationconcealment (Figure 2).

(5) Other Outcomes: Daily Life Functions and AdverseEvents. Only Kim et al. [53] reported on daily life func-tions with a higher mean in the 10Hz rTMS group thanin the sham and 1Hz rMTS groups; however, there wasonly a statistically significant difference favoring the10Hz rTMS group compared to the sham group (SMD1.83, 95% CI 0.68, 2.97; p = 0 002; I2 = not applicable).Làdavas et al.’s study [64] was the only study that reportedon adverse events; no significant adverse effect of tDCS wasreported, except only a few cases of minimal irritation ofthe skin beneath the electrodes.

None of the included studies reported on the followingoutcomes: neurological and functional disabilities, loss ofbalance, depression or anxiety and evaluation of poststrokefatigue, quality of life, and death.

Noninvasive brain stimulations Sham Std. mean differenceIV, random, 95% CI

Std. mean differenceIV, random, 95% CIStudy or subgroup Mean SD Total Mean SD Total Weight

1.4.1 TBS

Subtotal (95% CI)

Fu 2015Koch 2012Yang 2015

6.2546.8918.46

5.947.964.91

45.2948

14.79

5.945.724.59

12.2%17.8%17.6%47.6%

−6.29 (−8.64, −3.95)−0.15 (−1.03, 0.72)0.74 (−0.23, 1.70)

−1.61 (−4.28, 1.06)

10109

29

10109

29

Subtotal (95% CI)

Subtotal (95% CI)

16.316.4

5.35.4

159

24

159

24

18.1%16.4%34.5%

−1.19 (−1.97, −0.40)2.41 (1.13, 3.69)

0.57 (−2.95, 4.10)

23.43.6

6.34.7

Total (95% CI)

1.4.2 tDCSSunwoo 2013 16.61 36.31 21.37 41.52 17.8%

17.8%−0.12 (−0.98, 0.76)−0.12 (−0.99, 0.76)

1010

1010

Heterogeneity: Tau2 = 5.01; Chi2 = 29.54, df = 2 (P = 0.00001); I2 = 93%



Heterogeneity: not applicableTest for overall effect: Z = 0.26 (P = 0.79)

Test for overall effect: Z = 0.32 (P = 0.75)


1.1.3 rTMSCha 2016Kim 2013

6363 100.0% −0.51 (−1.87, 0.85)

Test for subgroup differences: Chi2 = 1.29, df = 2 (P = 0.52), I2 = 0%


0 10−10 −5 5Favours noninvasive brain stimulations Favours sham

Figure 3: Meta-analysis of overall USN measured by the star cancellation test.


Std. mean differenceIV, random, 95% CI

Favours noninvasive brain stimulations−10 −5 0 5 10

Study or subgroup Mean SD Total Mean SD Total Weight

1.2.1 TBS

1.2.2 tDCS

1.2.3 rTMSCha 2016Kim 2013

16.310.4

5.33.6

109

19

58 58 100.0% −0.62 (−1.89, 0.65)

23.43.6

6.34.7

109

19

17.6%17.2%34.8%

−1.17 (−2.13, −0.20)1.55 (0.46, 2.63)

0.18 (−2.48, 2.84)

Sunwoo 2013 12.2 31.37 1010

1010

17.9%17.9%

−0.24 (−1.12, 0.64)−0.24 (−1.12, 0.64)

21.37 41.52

Fu 2015Hoch 2012Yang 2015Subtotal (95% CI)

Subtotal (95% CI)

Subtotal (95% CI)

Heterogeneity: Tau2 = 5.01; Chi2 = 29.54, df = 2 (P < 0.00001); I2 = 93%


Heterogeneity: Tau2 = 2.14; Chi2 = 43.27, df= 5 (P < 0.00001); I2 = 88%

Heterogeneity: not applicable

Test for overall effect: Z =1.18 (P = 0.24)


Test for overall effect: Z = 0.96 (P = 0.34)Test for subqroup differences: Chi2 = 1.06, df = 2 (P = 0.59), I2 = 0%


Total (96% CI)

6.2546.8918.46

5.947.964.91

10109

29

10109

29

11.7%17.9%17.6%47.3%

−6.29 (−8.64, −3.95)−0.15 (−1.03, 0.72)0.74 (−0.23,1.70)

−1.61(−4.28, 1.06)

45.2948

14.79

5.945.724.59

Favours sham

Figure 4: Sensitivity analysis of overall USN measured by the star cancellation test using TBS, single-mode tDCS, and 10Hz rTMS.

19Neural Plasticity

3.4.2. Synthesized Results from Non-RCTs. The non-RCTsdid not report data in a usable way to allow for any statis-tical analysis.

4. Discussion

4.1. Main Findings. Based on pooled data from six random-ized trials with 116 participants, we found evidence for a ben-efit in overall USN with noninvasive brain stimulation,especially with the use of rTMS in comparison to the sham(Figures 5, 7, and 8). The evidence is from moderate-quality evidence because of risk of bias due to the studies thatwere ranked as high risk of bias for both allocation sequenceand allocation concealment (Figure 2). Non-RCT studiesprovided no evidence, suggesting that future trials should

adhere to CONSORT guidelines to ensure clarity and repro-ducibility in the reporting of methods.

We presented the results of overall USN in a forest plot,which showed a statistically significant difference betweenthe noninvasive brain stimulations and sham in the followingtests: line bisection test, Motor-Free Visual Perception Test,and Albert’s test and line crossing test. Nevertheless, thestudy also showed a nonsignificant difference between thenoninvasive brain stimulations and sham on the star cancel-lation test.

Several noninvasive brain stimulations have beenexplored to determine whether some of these techniquesmight be useful in promoting recovery from USN afterstroke. The lesion of the right parietal cortex after strokecauses disinhibition of the left hemisphere and thus a



1.4.1 TBS

Subtotal (95% CI)

Subtotal (95% CI)

Fu 2015Yang 2015

11.1722.36

14.275.31

−1.42 (−2.42, −0.42)−4.96 (−6.94, −2.97)−3.08 (−6.54, 0.38)

109

19

101020

21.8%15.2%36.9%

35.7954.12

18.656.76

Subtotal (95% CI)

19.33−30

6.879.2

159

24

34.6−8.3

44.2

159

24

21.7%19.0%40.7%

−2.64 (−3.66, −1.63)

−2.73 (−3.55, −1.90)−2.89 (−4.30, −1.48)

Total (95% CI)





1.3.2 tDCSSunwoo 2013 7.05 7.45 10

101010

14.27 12.85 22.4%22.4%

−0.66 (−1.56, 0.25)−0.66 (−1.56, 0.25)

Test for overall effect: Z = 6.49 (P < 0.00001)


1.3.3 rTMSCha 2016Kim 2013

53 54 100.0% −2.33 (−3.54, −1.12)

Test for subgroup differences: Chi2 = 11.49, df = 2 (P = 0.003), I2 = 82.6%

Heterogeneity: not applicableTest for overall effect: Z = 1.42 (P = 0.15)

0 10−10 −5 5Favours noninvasive brain stimulations Favours sham

Figure 5: Meta-analysis of overall USN measured by the line bisection test.



1.4.1 TBSFu 2015Yang 2015

11.1722.36

14.275.31

109

19

35.7954.12

18.656.76

101020

21.5%16.1%37,6%

−1.42 (−2.42, −0.42)−4.96 (−6.94, −2.97)−3.08 (−6.54, 0.38)Subtotal (95% CI)

Subtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)

1.4.2 tDCS

1.4.3 rTMSCha 2016Kim 2013

19.33−36,9

6.8711.2

159

24

34.6−8.3

44.2

159

24

21.5%18.8%40.3%

−2.64 (−3.66, −1.63)−3.22 (−4.73, −1.71)−2.82 (−3.66, −1.98)

Sunwoo 2013 10.4 9.64 14.27 12.85 22.1%22.1%

−0.33 (−1.21, 0.56)−0.33 (−1.21, 0.56)

1010

1010


Heterogeneity: not applicable



Test for overall effect: Z =1.75 (P = 0.08)


Test for overall effect: Z = 3.35 (P < 0.0008)Test for subqroup differences: Chi2 = 16.74, df = 2 (P = 0.0002), I2 = 88.1% Favours noninvasive brain stimulations

58 58 100.0% −2.35 (−3.72, −0.98)

-10 -5 0 5 10

Test for overall effect: Z = 6,58 (P < 0.00001)

Favours sham

Figure 6: Sensitivity analysis of overall USN measured by the line bisection test using TBS, single-mode tDCS, and 10Hz rTMS.


pathological overactivation of the latter. This overactivationin the left depresses the neural activity by an increased inhi-bition on the right hemisphere, aggravating the perception.The rTMS can generate currents capable of depolarizing cor-tical neurons, and tDCS changes cortical activity by means ofsmall electric currents and does not evoke action potentials.The tDCS has the advantage that the device is inexpensive,portable, and easy to use, but rTMS presented more activa-tion of the neural network and induced a neuroplasticresponse for a long-term potentiation [65].

In three of four meta-analyses, rTMS was responsiblefor the improvement of overall USN, revealing that anelectric current is an effective strategy for generating last-ing promising effects in the brain. Unfortunately, we didnot find any significant TBS or tDCS effects compared tosham procedures.

4.2. Strengths and Limitation. Strengths of our review includea comprehensive search; assessment of eligibility, risk of bias,and data abstraction independently and in duplicate; assess-ment of risk of bias that included a sensitivity analysisaddressing loss to follow-up; and use of the GRADEapproach for rating the certainty of evidence for each out-come (Table 3). Furthermore, there were no language

restrictions, and translations of non-English trials wereobtained whenever possible.

The primary limitation of our review is the low certaintyconsequent to study limitations. We identified a smallnumber of RCTs with a modest number of participantsresulting in wide confidence intervals. The total numberof participants was relatively very low (RCTs n = 278,non-RCTs n = 94) due to the small sample sizes of individualtrials, which led to downgrading the quality of evidence insome instances because underpowered trials are likely tohave a greater degree of imprecision.

Moreover, selection bias and unblinding were substantial.Another limitation of this review was having an insufficientnumber of included studies to allow for the complete statisti-cal analysis that we had planned. We were not able to assesspublication bias because there were fewer than 10 eligiblestudies addressing the same outcome in a meta-analysis. Wealso planned to perform subgroup analyses according to thecharacteristics of stroke type, type of stimulation, type of fre-quency, and comparators (type of control intervention, i.e.,pharmacological therapy versus nonpharmacological). How-ever, we also were not able to conduct these analyses becausethey did not meet our minimal criteria, which was at least fivestudies available with at least two in each subgroup.



Subtotal (95% CI)

Heterogeneity: Tau2 = 0.00; Chi2 = 0.02, df = 1 (P = 0.88); I2 = 0% Test for overall effect: Z = 3.89 (P = 0.0001)

1.5.1 1Hz rTMS

Cha 2016Kim 2013

21.65.4

41.8

109

19

16.93.3

2.12.3

109

19

49.4%50.6%

100.0%

1.41 (0.41, 2.41)0.97 (−0.02, 1.96)1.19 (0.48, 1.89)

1.52 10Hz rTMS

Cha 2016Kim 2013Subtotal (95% CI)

21.66.6

41.8

109

19

16.93.3

2.12.3

109

19

53.8%46.2%

100.0%

1.41 (0.41, 2.41)1.52 (0.44, 2.60)1.46 (0.73, 2.20)

Heterogeneity: Tau2 = 0.00; Chi2 = 0.38, df = 1 (P = 0.54); I2 = 0% Test for overall effect: Z = 3.30 (P = 0.0010)

Test for subgroup differences: Chi2 = 0.28, df = 1 (P = 0.60), I2 = 0%0 10−10 −5 5

Favours sham Favours noninvasive brain stimulation

Figure 7: Meta-analysis of overall USN measured by the Motor-Free Visual Perception Test.



1.6.1 TBSKoch 2012 35.44

35.33 2.9 1515

25 25 100.0% 1.01 (−1.00, 3.02)

27.33 4.55 1515

49.8% 2.04 (1.14, 2.95)2.04 (1.14, 2.95)49.8%

1.01 1010

1010

50.2%50.2%

−0.01 (−0.89, 0.87)−0.01 (−0.89, 0.87)

35.45 0.65Subtotal (95% CI) Heterogeneity: not applicableTest for overall effect: Z = 0.03 (P = 0.98)

1.6.2 rTMSCha 2016Subtotal (95% CI)

Total (95% CI)Heterogeneity: Tau2 = 1.90; Chi2 = 10.19, df = 1 (P = 0.001); I2 = 90% Test for overall effect: Z = 0.99 (P = 0.32)

Heterogeneity: not applicableTest for overall effect: Z = 4.42 (P < 0.00001)

Test for subgroup differences: Chi2 = 10.19, df = 1 (P = 0.001), I2 = 90.2%0 10−10 −5 5

Favours sham Favours noninvasive brain stimulation

Figure 8: Meta-analysis of overall USN measured by Albert’s test and the line crossing test.

21Neural Plasticity

Although this review presents several limitations, theissue is whether one should dismiss these results entirely orconsider them bearing in mind the limitations. The latterrepresents our view of the matter.

4.3. Relation to Prior Work. The research question we inves-tigated in our review has been addressed before from differ-ent perspectives using our population of interest but with adifferent intervention (i.e., pharmacological intervention)[7] or investigating either the intervention or the controlarms explored in this review but with a different population(e.g., idiopathic Parkinson’s disease (IPD) [48], panic disor-der in adults [66], or amyotrophic lateral sclerosis or motorneuron disease) [13].

Two Cochrane reviews [21, 49] evaluated the effect oftDCS in people after stroke but not in comparison withrTMS; instead, the authors compared tDCS with placebo,sham tDCS, no intervention, or conventional motor rehabil-itation. The first review’s [49] authors found evidence ofeffect regarding activities of daily living performance at theend of the intervention period and at the end of follow-up.However, the results did not persist in a sensitivity analysisincluding only trials of good methodological quality. In thesecond review [21], the authors found that there were nostudies examining the effect of tDCS on cognition in strokepatients with aphasia.

Another Cochrane review [22] that addressed the use ofrTMS compared to sham treatment or other conventionaltreatment for improving function after stroke revealed thatrTMS treatment was not associated with improved activitiesof daily living, nor did it have a statistically significant effecton motor function.

Three additional Cochrane reviews also discussed theeffects of both tDCS [48] and rTMS [13, 66] but in differentpopulations—in Parkinsonism [48], in patients with amyo-trophic lateral sclerosis or motor neuron disease [13], and inadults with panic disorder [66]. All reviews suffered frompoormethodological quality, imprecision, and hence low confi-dence in the estimate of the true effect to draw a consistentconclusion on the effects of noninvasive brain stimulations.

4.4. Implications. Moderate-quality evidence shows thatrTMS, at 1Hz, is more efficacious than sham for unilateralspatial neglect after stroke measured by Motor-Free VisualPerception Test. Furthermore, low-quality evidence also sug-gests a benefit of noninvasive brain stimulation, particularlywith the use of rTMS, for overall USN measured by the linebisection test, Albert’s test, and the line crossing test. Futuretrials should adhere to CONSORT guidelines to ensure clarityand reproducibility in the reporting of methods [67].

Disclosure

The funding agencies played no role in conducting theresearch or preparing the manuscript.

Conflicts of Interest

The authors have no conflicts of interest.

Authors’ Contributions

Flávio Taira Kashiwagi, Regina El Dib, Adriana Bastos Con-forto, Gustavo José Luvizutto, and Rodrigo Bazan conceivedthe review. Erica Aranha Suzumura, Taís Regina da Silva,and Fernanda Cristina Winckler undertake searches. HudaGomaa, Juli Thomaz de Souza, and Nermeen Gawishscreened search results. Flávio Taira Kashiwagi, Regina ElDib, and Gustavo José Luvizutto organized the retrieval ofpapers. Flávio Taira Kashiwagi, Huda Gomaa, NermeenGawish, Erica Aranha Suzumura, Taís Regina da Silva, andRodrigo Bazan helped in screening retrieved papers againstinclusion criteria. Flávio Taira Kashiwagi, Huda Gomaa,Nermeen Gawish, Erica Aranha Suzumura, Taís Regina daSilva, Fernanda Cristina Winckler, Juli Thomaz de Souza,and Rodrigo Bazan appraised the quality of papers. FlávioTaira Kashiwagi, Erica Aranha Suzumura, Taís Regina daSilva, and Fernanda Cristina Winckler extracted data fromthe papers. Flávio Taira Kashiwagi, Huda Gomaa, NermeenGawish, and Erica Aranha Suzumura helped in writing tothe authors of papers for additional information. Flávio TairaKashiwagi, Gustavo José Luvizutto, Juli Thomaz de Souza,and Nermeen Gawish provided additional data about thepapers. Flávio Taira Kashiwagi, Erica Aranha Suzumura, TaísRegina da Silva, Nermeen Gawish, and Huda Gomaaobtained and screened the data of unpublished studies. FlávioTaira Kashiwagi, Regina El Dib, Gustavo José Luvizutto, andRodrigo Bazan managed the data for the review. Flávio TairaKashiwagi, Regina El Dib, Erica Aranha Suzumura, GustavoJosé Luvizutto, and Rodrigo Bazan entered the data intoReview Manager (RevMan). Regina El Dib, Gustavo JoséLuvizutto, Adriana Bastos Conforto, and Rodrigo Bazan ana-lyzed the RevMan statistical data. Flávio Taira Kashiwagi,Huda Gomaa, Nermeen Gawish, Erica Aranha Suzumura,Adriana Bastos Conforto, Gustavo José Luvizutto, Regina ElDib, and Rodrigo Bazan interpreted the data. Flávio TairaKashiwagi, Regina El Dib, Huda Gomaa, Nermeen Gawish,Erica Aranha Suzumura, Gustavo José Luvizutto, andRodrigo Bazan made statistical inferences. Flávio TairaKashiwagi, Gustavo José Luvizutto, Regina El Dib, Erica Ara-nha Suzumura, and Rodrigo Bazan wrote the review. FlávioTaira Kashiwagi, Huda Gomaa, Nermeen Gawish, EricaAranha Suzumura, Gustavo José Luvizutto, Adriana BastosConforto, and Rodrigo Bazan take the responsibility forreading and checking the review before submission.

Acknowledgments

The authors would like to acknowledge São Paulo ResearchFoundation (FAPESP) (2015/14231-0) and National Councilfor Scientific and Technological Development (CNPq)(423924/2016-8) for the grants and financial support.

References

[1] R. Bonita, “Epidemiology of stroke,” Lancet, vol. 339, no. 8789,pp. 342–344, 1992.

[2] E. C. Jauch, J. L. Saver, Adams HP Jr et al., “Guidelines for theearly management of patients with acute ischemic stroke: a


guideline for healthcare professionals from the AmericanHeart Association/American Stroke Association,” Stroke,vol. 44, no. 3, pp. 870–947, 2013.

[3] N. Gorgoraptis, Y. H. Mah, B. Machner et al., “The effects ofthe dopamine agonist rotigotine on hemispatial neglect follow-ing stroke,” Brain, vol. 135, no. 8, pp. 2478–2491, 2012.

[4] P. Chen, K. Hreha, P. Fortis, K. M. Goedert, and A. M. Barrett,“Functional assessment of spatial neglect: a re

Documents

Noninvasive Brain Stimulations for Unilateral Spatial ...downloads.hindawi.com/journals/np/2018/1638763.pdf · Background. Unilateral spatial neglect (USN) is the most frequent perceptual