multisensory stimulation to improve low- and higher-level ... · sensory deficits after stroke: a...

REVIEW

Multisensory Stimulation to Improve Low- and Higher-LevelSensory Deficits after Stroke: A Systematic Review

Angelica Maria Tinga1 & Johanna Maria Augusta Visser-Meily2 &

Maarten Jeroen van der Smagt1 & Stefan Van der Stigchel1 &

Raymond van Ee3,4,5 & Tanja Cornelia Wilhelmina Nijboer1,2

Received: 31 May 2015 /Accepted: 1 October 2015 /Published online: 21 October 2015# The Author(s) 2015. This article is published with open access at Springerlink.com

Abstract The aim of this systematic review was to integrateand assess evidence for the effectiveness of multisensorystimulation (i.e., stimulating at least two of the followingsensory systems: visual, auditory, and somatosensory) as apossible rehabilitation method after stroke. Evidence wasconsidered with a focus on low-level, perceptual (visual, audi-tory and somatosensory deficits), as well as higher-level, cog-nitive, sensory deficits. We referred to the electronic databasesScopus and PubMed to search for articles that were publishedbefore May 2015. Studies were included which evaluated theeffects of multisensory stimulation on patients with low- orhigher-level sensory deficits caused by stroke. Twenty-onestudies were included in this review and the quality of thesestudies was assessed (based on eight elements: randomization,inclusion of control patient group, blinding of participants,

blinding of researchers, follow-up, group size, reportingeffect sizes, and reporting time post-stroke). Twenty ofthe twenty-one included studies demonstrate beneficialeffects on low- and/or higher-level sensory deficits afterstroke. Notwithstanding these beneficial effects, the qualityof the studies is insufficient for valid conclusion that multisen-sory stimulation can be successfully applied as an effectiveintervention. A valuable and necessary next step would be toset up well-designed randomized controlled trials to examinethe effectiveness of multisensory stimulation as an interven-tion for low- and/or higher-level sensory deficits after stroke.Finally, we consider the potential mechanisms of multisensorystimulation for rehabilitation to guide this future research.

Keywords Stroke . Hemianopia . Perceptual disorders .

Neglect . Rehabilitation .Multisensory . Review

AbbreviationsADL Activities of Daily LivingfMRI Functional Magnetic Resonance ImagingMSI Multisensory IntegrationRCT Randomized Controlled TrialA AuditoryAV Audiovisuald DaysFr Frontalh HoursLH Left Hemispherem Monthsms MillisecondsOc OccipitalP ProprioceptivePa ParietalRH Right Hemisphere

This study was performed at the Helmholtz Institute Utrecht, theNetherlands.The manuscript or substantially similar work, has not been published andis not under consideration for publication elsewhere.Artworkwas created inAdobe PhotoshopCS6 andMicrosoftWord 2010.

* Tanja Cornelia Wilhelmina [email protected]

1 Department of Experimental Psychology, Hemholtz Institute, UtrechtUniversity, Utrecht, The Netherlands

2 Brain Center Rudolf Magnus, and Center of Excellence forRehabilitation Medicine, University Medical Center Utrecht,and De Hoogstraat Rehabilitation, Utrecht, The Netherlands

3 Department of Brain, Body & Behavior, Philips ResearchLaboratories, Eindhoven, The Netherlands

4 Department of Biophysics, Donders Institute, Radboud University,Nijmegen, The Netherlands

5 Laboratory of Experimental Psychology, University of Leuven,Leuven, Belgium

Neuropsychol Rev (2016) 26:73–91DOI 10.1007/s11065-015-9301-1

http://crossmark.crossref.org/dialog/?doi=10.1007/s11065-015-9301-1&domain=pdf

S SomatosensorySC SubcorticalSign. Statistically SignificantTe TemporalV Visualv Years

Introduction

In the last decade there has been a considerable increase infundamental cognitive neuroscience studies on multisensoryintegration (MSI; Van der Stoep et al. 2015). Most of thesestudies indicate that multisensory integration allows fora coherent representation of the environment and that itenhances detection and localization of external events(see Stein 2012 for an overview). Combining informationfrom different sensory modalities can be especially beneficialin supporting behavior when the signal from a single modalityis only weakly able to induce a behavioral response, or when asensory system as a whole is weakened (Stein 2012). Basedon these findings, we hypothesize that stimulating multiplesensory modalities (i.e., multisensory stimulation) has the po-tential to be beneficial in improving sensory deficits after braindamage, as information from a normally functioning sensorymodality might aid the processing of information from theimpaired sensory modality. In this way, multisensory stimula-tion might have the potential to aid rehabilitation of patientssuffering from stroke.

Integration of multisensory information is an important as-pect of multisensory stimulation. Animal studies have led tothe formulation of three fundamental rules of MSI (Stein2012): first, the temporal rule states that maximal MSI occurswhen multimodal stimulations occur approximately at thesame time; second, the spatial rule states that maximal MSIoccurs when multimodal stimulations originate from the samelocation; and third, the rule of inverse effectiveness states thatmaximal MSI occurs when each of the constituent unisensorystimuli are suboptimally effective in evoking responses.

Electrophysiological and anatomical findings in animalsand non-invasive neuroimaging findings in humans haveidentified multiple brain areas that contribute to MSI (Amediet al. 2001; Keysers et al. 2003; Rockland and Ojima 2003;Shore 2005; Nagy et al. 2006; Beauchamp et al. 2008; Allmanet al. 2009; Cappe et al. 2009; Falchier et al. 2010). Two basicneural mechanisms by which multisensory processing canarise have been proposed. First, multisensory processingmay be accomplished when primary sensory areas are activatedand project to multisensory convergence areas (red arrows inFig. 1), followed by feedback projections from the latter to theformer. Second, neurophysiological studies in animals havedemonstrated that there is a direct neural connectivity betweenthe primary sensory cortices (Rockland andOjima 2003; Allman

et al. 2009; Falchier et al. 2010), which implies that sensorymodalities can also modulate each other’s responses at a lowcortical level of processing (blue arrows in Fig. 1). Moreover,several fMRI (functional magnetic resonance imaging) studieshave reported an increase or decrease in brain activity of theprimary sensory cortices during multisensory stimulation(Macaluso et al. 2000; Amedi et al. 2002; Watkins et al.2006; Martuzzi et al. 2007). For a more detailed discussionof brain areas that contribute to MSI, see for exampleBolognini et al. (2013) and Klemen and Chambers (2012).

In general, the brain can use alternative routes to by-pass adamaged area after stroke and in this way adapt to the damage(e.g., Nudo et al. 1996; Dancause et al. 2005; Wilde et al.2012; Buma et al. 2013). We expect that multisensory infor-mation could still be combined to some extent in the case ofdamage to multimodal association areas as well as whenthe damage affects sensory-specific cortices, because many(even sensory-specific) brain regions would still be able toassist in combining this information. Multisensory stimula-tion might even enhance residual neuronal activity withinsuch a damaged area when information comes from mul-tiple senses. This increase in neuronal activity might leadto (for instance) detection improvements, since neuronalactivity is more likely to exceed the threshold necessaryfor detection. All in all, multisensory stimulation mightprove to be a promising intervention for (sensory-specific)impairment caused by stroke, since information coming frommultiple senses might enhance detection and localization of,and responding to external events, resulting in a reduction ofthe impairment.

The aim of the current systematic review is to provide anintegrated account and quality assessment of studies that haveinvestigated multisensory stimulation as a possible rehabilita-tion method to improve low-level and higher-level sensorydeficits after stroke. Deficits in low-level processing of per-ceptual information occur at a relatively early processingstage, leading to a primary sensory deficit (e.g., visual fielddefects). Distortions at a later level of perceptual processingare causing higher-level sensory deficits, which are more cog-nitive in nature (e.g., neglect; Kandel et al. 2000). Recently,Johansson (2012) deemed multisensory stimulation in strokerehabilitation a promising approach with a focus on motorrecovery. Our focus will be on the effects of multisensorystimulation on recovery of sensory deficits. To guide futureresearch, we also consider the mechanisms of multisensorystimulation for rehabilitation (i.e., the short- and long-termeffects, transfer effects, and whether it targets compensationand/or restoration). In the next sections, studies that haveassessed the effects of multisensory stimulation in patientswith low-level visual (i.e., visual field defects), auditoryand somatosensory deficits and higher-level sensory deficits(i.e., hemi-inattention or neglect) caused by stroke will bereviewed.

74 Neuropsychol Rev (2016) 26:73–91

Methods

Literature Search and Article Selection

The literature search (Fig. 2) was conducted in the Scopus andPubMed databases for articles that have been published beforeMay 2015. Date last searchedwasMay 5, 2015. The string usedto search for articles was: (TITLE-ABS-KEY (Bmultisensory^

or Bmultimodal integration^ or Bmultimodal stimul*^ orBaudiovisual^ or Baudio-visual^ or Bvisuo-auditory^ orBvisuotactile^ or Bvisuo-tactile^ or Btactile-visual^ orBaudiotactile^ or Baudio-tactile^ or Btactile-audio^ or Bvisual*enhanc*^ or Btactile enhanc*^ or Baudit* enhanc*^ orBsomatosens* enhanc*^) AND (TITLE-ABS-KEY(Bhemianop*^ or Bvisual field defect^ or Bvisual fielddeficit^ or Bauditory disorder^ or Bauditory deficit^ or

Fig. 1 An illustration of how multisensory processing could arise fromprojections from sensory specific areas tomultisensory convergence areas(depicted in red) or from direct anatomical connections between theprimary sensory areas (depicted in blue). Lateral view on the left,medial view on the right. Depicted multimodal areas: The posterior

parietal cortex (PPC); the superior temporal sulcus (STS) the perirhinalcortex (PRC); and the superior colliculus (SC). Depicted primary sensoryareas: primary somatosensory (S1), visual (V1), and auditory (A1) cortex.See text for details

389 and 731 documents identified through Scopus and PubMed database searching respectively and 5 additional documents identified through other sources (e.g., reference lists)

104 and 347 documents excluded from the Scopus andPubMed databases respectivelythat were classified as a different article type than a journal article; that were classified as a review, systematic review or comment publication type; that were not conducted in humans; which had a different language than English; or of which the full-text was not available

608 records, after duplicates removed, screened (title and abstract)

568 documents excluded

40 full-text articles assessed for eligibility

21 studies included for review and validity evaluation

19 articles excluded:- Focus on competition of

attentional resources in patients with extinction (8)

- No multisensory stimulation by our definition (4)

- Passive stimulation (2)- Only abstract available (2)- Literature discussion (1)- No patient study (2)

Fig. 2 Schematic of the literaturesearch and article selection usedby the authors to identify studieson multisensory stimulation instroke patients

Neuropsychol Rev (2016) 26:73–91 75

Bauditory defect^ or Bsomatosensory disorder^ orBsomatosensory defect^ or Bsomatosensory deficit^ orBperceptual disorder^ or Bperceptual deficit^ or Bperceptualdefect^ or Bneglect^ or Bstroke^)) AND NOT (TITLE-ABS-KEY (Bmigraine^ or Bsynesthesia^ or Bsynaesthesia^ orBspinal cord injury^ or Bautism^ or Baphasia^ orBschizophrenia^ or Bdyslexia^)). Documents retrieved fromthis initial search that were classified as an article by Scopusor as a journal article by PubMed and as being written inEnglish were screened on their titles and abstracts. Studieswere included which evaluated the effects of multisensorystimulation on patients with low- or higher-level sensorydeficits caused by stroke. In all included studies at leasttwo sensory modalities were stimulated at the exact samemoment in time. The stimulation had to be passive and notactive (i.e., the stimulation itself had to be independent ofany action by the patient). Excluded were animal studies,studies in healthy participants (e.g., Laurienti et al. 2004;van Ee et al. 2009), reviews, and studies of which the fullarticle was not available. Articles that focused on competi-tion of multisensory attention in patients with extinctionwere excluded as well. The included articles were readcompletely and their references were scanned for relevantarticles that might also meet criteria for inclusion. In total,21 articles met the criteria for eligibility and were includedfor review and quality assessment.

Quality Assessment

The quality of the included studies was assessed based onthe following eight elements (following Spreij et al. 2014):1) randomization; 2) inclusion of control patient group; 3)blinding of participants; 4) blinding of researchers; 5)follow-up (i.e., subsequent examination of participants);6) group size; 7) reporting effect sizes; and 8) reportingtime post-stroke. Studies could score 1 or 0 on each ele-ment, when it was dealt with in a sufficient or insufficientway respectively. Additionally, an element was scored as 0if it could not be inferred from the article. If these qualityelements were not sufficiently dealt with, the effect of anintervention might have been either under- or overestimated(Tijssen and Assendelft 2008).

The criteria for sufficient randomization were randomizedallocation to an intervention or randomized or counterbalancedpresentation of the order of conditions. Inclusion of controlpatient group was sufficient if a control group of patients re-ceiving either an alternative form of treatment or no interven-tion was included. When patients and researchers wereprevented from having access to certain information that mighthave influenced them and thereby the results, the criteria forblinding of participants and blinding of researchers respective-ly were sufficiently dealt with. The criteria for sufficientfollow-up were incorporation of a follow-up in the study’s

design and disclosure of the total number of losses-to-follow-up (i.e., dropouts). The element group size was scored as 1when 10 or more patients were included in a within-subjectsdesign or when 10 or more patients were included in eachgroup in a between-subject design (this criterion is based onthe common group size in fundamental studies in healthyparticipants [10–12 participants] and is used in other re-views as well [e.g., Spreij et al. 2014]). Additionally,reporting effect sizes and reporting time post-stroke weresufficiently dealt with when effect sizes and time post-stroke respectively were reported. If none of the elementswere sufficiently dealt with, the study would receive a totalscore of 0, if all of the elements were sufficiently dealtwith, the study would receive a total score of 8. Based onthe study’s total score, its quality was classified as high(total score≥6), moderate (total score≥3 and≤5), or low(total score≤2).

Results

The specifics of the included studies are presented inTables 1–4. First, findings in patients with low-level, percep-tual deficits are addressed, including patients with visual fielddefects (Table 1), auditory deficits (Table 2) and somatosen-sory deficits (Table 3). Second, findings in patients with ne-glect are addressed (Table 4).

Visual Field Defects

Visual field defects, such as hemianopia, occur frequently af-ter stroke, as a result of a lesion in the early visual pathway(Kandel et al. 2000). Patients with visual field defects usuallyfail to adequately respond to or report contralesional visualstimuli (Halligan et al. 2003), resulting in difficulties withreading, scanning scenes, and obstacle avoidance, especiallyon their affected side (Papageorgiou et al. 2007). Eleven stud-ies were included that have examined direct and short-termeffects (i.e., effects measured during stimulation or directlyafter stimulation) and/or short-term effects and longer lastingeffects (i.e., effects measured not directly after stimulation) ofmultisensory stimulation on performance of patients withchronic and acute visual field defects. The characteristics ofthe studies are listed in Table 1.

Studies on the direct and short-term effects of multisensorystimulation by Frassinetti et al. (2005) and Leo et al. (2008)demonstrated that the addition of a coincident sound enhanceddetection of a visual target in the affected hemifield(Frassinetti et al. 2005) and vice versa (Leo et al. 2008). In arecent study by Ten Brink et al. (2015) the addition of a coin-cident sound facilitated saccades to a visual target in the un-affected hemifield of all (eight) patients, but in only one pa-tient performance in the affected hemifield was enhanced. In


Tab

le1

Studiesevaluatin

gtheeffectsof

multisensory

stim

ulationafterstroke

inpatientswith

visualfielddefects(inorderof

appearance

intext)

Study

Patients

Lesionside

Lesion

site

Tim

epost

injury

Stim

ulated

modalities

Stim

uli

Conditio

nsFrequency

ofstim

ulation

Outcome

measure

Statisticaltest/

alphalevel

Mainresults

Frassinetti

etal.

2005

7neglect,7

hemianopia,7

neglectand

hemianopia

Differentacross

patients

Fr,T

e,Pa,

Oc,SC

?VandA

V:singleLEDflash

of100ms

A:w

hite-noisebursts

of100ms

V,A

,AV(stim

uli

presented

temporally

coincident,in

sameor

different

positio

n)

2sessions

of+/−

2h,

includingall

conditions,on

2succeeding

d

Vdetection

ANOVA/p

<.001

Sign.enhancemento

fVdetectionin

the

affected

hemifield

inAVcondition

whenspatially

coincident,in

patientswith

neglecto

rhemianopia

Leo

etal.2008

12hemianopia

7RH,4

LH,1

bothLHand

RH

Fr,T

e,Pa,

Oc,SC

2m

–30

yAandV

A:p

ure-tone

bursts

of100ms

V:squares

presented

for100ms

A,V

,AV(stim

uli

presented

temporally

coincident,in

sameor

different

positio

n)

15blocks

of40

trials

includingall

conditions,on

2succeeding

d

Alocalization

ANOVA/p

<.03

Sign.improvem

ento

fAlocalizationinthe

affected

and

unaffected

hemifield

inAV

condition

when

spatially

coincident

(and

temporally

coincident,as

demonstratedby

anotherexperiment

inthisstudy)

TenBrink

etal.

2015

7hemianopia,1

quadrantanopia

4RH,4

LH

Te,P

a,Oc,SC

26–154

mAandV

A:b

roadband

noise

burstsof

500ms

(36–72

dB)

V:circles

presented

for500ms

A,A

V(stim

uli

presented

temporally

coincident,in

sameor

different

positio

n)

Experim

ent1

:40

blocks

of40

trialsincluding

allconditions

Experim

ent2

:2blocks

of480

trials,first

includingAand

AVcoincident,

second

including

AandAV

disparate

Saccade

accuracy

(toAtarget)

andlatency

(ofinitiation)

t-testsatsingle-

subjectlevel/

p≤.004

Unaf fectedhemifield:

sign.enhancement

ofsaccadeaccuracy

inAVcoincident

condition

andsign.

decrease

ofsaccade

accuracy

inAV

disparatecondition

(especially

with

high

contrastV

stim

uli);sign.

effectsof

condition

onsaccadelatency

forsomepatients

Affectedfield:

sign.

enhancem

ento

fsaccadeaccuracy

inAVcoincident

condition

forone

patient

Cecereetal.

2014

1centralfield

defectand

visualagnosia

BothLHand

RH

Pa,O

c3y

VandA

V:solid

lines

presentedfor

250ms

A:looming(rising

inintensity);

receding

(decreasingin

intensity);or

stationary

(fixed

V,A

V(A

either

loom

ing,

receding

orstationary

presentedatsame

mom

entintim

ein

eithersameor

differentp

osition

[alsoin

different

Experim

ent1

:40

blocks

of96

trials

includingall

conditions

Experim

ent2

:40

blocks

of112

trials

Experim

ent1

:Vdiscrimination

Experim

ent2

:Vdetection

Fisher’stest/p

<.038

Vdiscrimination

sensitivity

(d')in

theunaffected

visualfieldwas

sign.higherin

AV

loom

ingcondition;

Vdetectiond'inthe

unaffected

and

affected

visualfield


Tab

le1

(contin

ued)

Study

Patients

Lesionside

Lesion

site

Tim

epost

injury

Stim

ulated

modalities

Stim

uli

Conditio

nsFrequencyof

stim

ulation

Outcome

measure

Statisticaltest/

alphalevel

Mainresults

intensity

)sound

of250ms

positionin

experiment1

])was

sign.higherin

allA

Vspatially

coincident

conditions

Brownetal.

2008

2hemianopia

2RH

Te,P

a,Oc

9yand32

yVandP

V:6

plexiglass

block

objectsof

6differentsizes

P:contralesional

hand

placed

near

orfarfrom

target

location

Contralesionalh

and

placed

near

orfar

from

target

location

The

trialsforeach

combinationof

VandPstim

uli

wererepeated

6tim

es

Size

estim

ationand

grasping

Linearregression

/p≤.

047

Sign.enhancem

ento

fsize

estim

ationand

grasping

ofobjects

presentedin

theleft

(affected)

visual

fieldin

thehand-

near

condition

Schendeland

Robertson

2004

1hemianopia

1RH

Te,O

c,SC

7m

VandP

V:p

robe

of150ms

presentedat

60cm

(baseline

andnear

condition)or

at180cm

distance

(far

andtool

condition)

P:arm

inlapor

arm

extended

with

orwithouth

olding

atennisracket

Contralesionalarm

inlap(baseline),

arm

extended

(near),arm

extended

and

visualstim

uli

presentedfurther

away

(far),arm

extended

and

holdingtennis

racketandvisual

stim

ulip

resented

furtheraw

ay(tool)

6sessions

conducted

onmultipled

Vdetection

Chi-squaretest/

p<.01

Sign.im

provem

ento

fVdetectionin

the

left(affected)

visual

fieldin

near

condition

compared

tobaseline.Sign.

improvem

entin

tool

condition

comparedto

far

condition

forthe

upperleftvisual

field(after

acorrectionforfalse

alarms)

Smith

etal.

2008

5hemianopia

4RH,1

LH

Pa,Oc,

SC

3.5–32

mVandP

V:w

hitespot

(onblack

background)

P:contralesionalarm

inlapor

extended

Contralesionalarm

inlap(baseline)

orextended

(near)

Patientscompleted

adifferenttotal

amount

oftrials

rangingfrom

96to

240.Trials

weredividedin

blocks

Vdetection

ANOVA/p

≤.595

(and

analysisfor

eac h

individual

patient

with

Fish-

er’sexacto

rChi-

square

test/

p≤.85)

Nosign.differences

betweenconditions

(not

forasingle

patient)

Passamonti

etal.2009a

9hemianopia,

6neglect

6RH,9

LH

(neglect:

allR

H)

Fr,Te,P

a,Oc,SC

5–108m

AandV

A:w

hite-noise

burst

of100ms

V:singleLEDflash

of100ms

AVadaptationin

which

thestim

uli

wereeither

spatially

disparate

ofspatially

congruent

Adaptationblocks

lasted

4min,A

localizationtask

had105trials

Alocalizationbefore

andafter

adaptationandA

localizationshift

(calculatedby

subtractingmean

reported

locations

pre-adaptation

from

thosepost-

adaptation)

ANOVA/p

<.05

After

adaptationto

spatiald

isparity:A

localization

accuracy

decreased

sign.after

adaptin

gtheunaffected

field;

sign.shiftin

sound

localizationtoward

stim

ulation

locatio

n;sign.

greatershiftin

soundlocalization

towards

adapting

stim

ulus

after

adaptatio

nin

the

unaffected

than

the

affected

fieldin

hemianopia


Tab

le1

(contin

ued)

Study

Patients

Lesionside

Lesion

site

Tim

epost

injury

Stim

ulated

modalities

Stim

uli

Conditio

nsFrequencyof

stim

ulation

Outcome

measure

Statisticaltest/

alphalevel

Mainresults

patients.After

adaptationtospatial

coincidence:A

localization

accuracy

sign.

increased,

regardless

ofthe

adaptedhemifield;

sign.greater

accuracy

forsounds

presentedatthe

adaptedlocation

comparedto

the

untrainedlocations

Bolognini

etal.

2005a

8hemianopia

4RH,3

LH,1

?Fr,Te,P

a,Oc

2–4y

VandA

V:singleLEDflash

of100ms

A:w

hite-noise

burst

of100ms

V,A

,AV(stim

uli

presentedatsame

ordifferent

location).T

hetemporalinterval

intheaudiovisual

condition

was

gradually

reduced

from

500to

0ms

48trialsperblock,

totaln

umberof

blocks

differed

across

patients.

Trainingwas

conductedon

multipledaily

sessions

of+/−

4hlastingless

than

2w

Vdetection(w

ithandwithouteye

movem

ents),

Vexploration,

hemianopic

dyslexiaand

ADLassessed

before

training

andattheendof

thetraining

and

after1m

ANOVA/W

ilcoxon

signed-rank,

p<.06

Improvem

entswere

demonstratedforthe

affected

hemifield:

Vdetection

performance

during

trainingimproved

progressively.

Vdetectionwas

improved

post-

training,this

improvem

entw

assign.intheeye

movem

entcondition.

Vexplorationwas

improved

post-

trainingforvisual

search

andforthe

Num

bertest

(multiplesign.effects

werefound).Sign.

improvem

entswere

also

demonstrated

forhemianopic

dyslexiaandADL

Passamonti

etal.2009b

12hemianopia

and12

healthy

controls

5RH,5

LH,2

?Fr,Te,P

a,Oc,SC

5m

–30

yVandA

V:singleLEDflash

of100ms

A:w

hite-noise

burst

of100ms

VandAVtraining.

The

temporal

intervalin

theAV

training

was

gradually

reduced

from

300to

0ms

Trainingwas

conductedon

multipledaily

sessions

of+/−

4hlastingless

than

2w

Vdetection(w

ithandwithouteye

movem

ents),

Vexploration,

ADL,and

occulomotor

scanning

assessed

before

training,

afterVtraining,

afterAVtraining,

3m

laterand1y

later

ANOVA/p

<.05

After

theAVtraining

patientsim

proved

sign.inV

detections,

perceptual

sensitivity

and

ADL.Inadditio

n,aftertheAV

training,patients

demonstratedsign.

fewer

fixations

and

asign.reductionin


Tab

le1

(contin

ued)

Study

Patients

Lesionside

Lesion

site

Tim

epost

injury

Stim

ulated

modalities

Stim

uli

Conditio

nsFrequencyof

stim

ulation

Outcome

measure

Statisticaltest/

alphalevel

Mainresults

meansaccadic

amplitude.A

sa

consequence,V

scanning

was

more

organizedandmore

similarto

the

controlsubjects.

Trainingeffectsin

patientsremained

stableatthe3-

month

andthe1-

year

follo

w-upfor

Vdetectionand

exploration,

oculom

otor

scanning

andADL

Kellerand

Lefin-Rank

2010

13hemianopiaand7

quadrantanopia

Quadrantanopi-

a:6RH,1

LH.H

emia-

nopia:7RH,

6LH

Te,P

a,Oc

3–24

wVandA

V:singleLEDflash

of100ms

A:w

hite-noise

burst

of100ms

VandAVtraining

20sessions

ofeach

30min

over

3w

Vexploration

(for

readingand

objectsearch),

occulomotor

scanning

and

ADLassessed

before

andafter

training

ANOVA/p

≤.036

PatientsreceivingAV

training

improved

sign.m

oreon

all

outcom

emeasures


Tab

le2

Studiesevaluatin

gtheeffectsof

multisensory

stim

ulationafterstroke

inpatientswith

auditory

deficits(inorderof

appearance

intext)

Study

Patients

Lesionside

Lesion

site

Tim

epost

injury

Stim

ulated

modalities

Stim

uli

Conditio

nsFrequencyof

stim

ulation

Outcomemeasure

Statisticaltest/

alphalevel

Mainresults

Bolognini

etal.2005b

1auditory

localization

defect

1RH(tem

poral-

occipital)

Te,O

c9m

AandV

A:w

hite-noise

bursto

f100ms

V:singleLED

flashof

100ms

A,V

,AV(stim

uli

presentedin

sameposition

orin

different

positio

n)

120A,120

V,120

AV

spatially

coincident

and360AVspatially

disparatetrials.T

rials

weredistributedin

15experimentalb

locks

over

3consecutived

Percentageof

correct

responsesof

Alocalization

ANOVA/

p<.0005

Sign.im

provem

ento

fAlocalizationinthe

AVcondition

when

thestim

uliw

ere

spatially

coincident

Tab

le3

Studies

evaluatin

gtheeffectsof

multisensory

stim

ulationafterstroke

inpatientswith

somatosensory

deficits(inorderof

appearance

intext)

Study

Patients

Lesion

side

Lesion

site

Tim

epost

injury

Stim

ulated

modalities

Stim

uli

Conditio

nsFrequencyof

stim

ulation

Outcome

measure

Statisticaltest/

alphalevel

Mainresults

New

port

etal.

2001

1somatosensory

deficito

fthe

rightu

pper

limband1

healthycontrol

1LH

SC+/−

3y

PandV

P:indexfin

gerof

unseen

targethand,

placed

underneath

asurface

V:targetlocations

definedby

small

woodenpin

(Vcondition)or

view

ingsurface

adjacent

tohidden

limb

V,P

(inwhich

adjacent

surfaceto

the

to-be-detected

limbcouldnot

beseen)and

VP(inwhich

adjacent

surfacecould

beseen)

32trialsforeach

hand

ineach

condition

(total=192

trials).Patient

was

tested

in2

sessions

Localization

ofthetarget

(bypointin

g,to

aVstim

ulus

intheVcondition

andto

the

unseen

limbin

theother2

conditions)

ANOVA/

p<.0001

Forthepatient,

detectionof

the

impaired

hand

was

sign.

improved

when

theadjacent

surfacecould

beseen

(VPcondition)

Serino

etal.

2007

10somatosensory

deficitand

32healthycontrols

5RH,

5LH

Fr,T

e,Pa,S

C1–50

mSandV

S:1or

2vibrating

solenoidsattached

totheunderarm

(2:separated

by30–90mm)

V:v

iewingeitherthe

ownarm,a

neutral

objector

arubber

foot

Viewingow

narm,

view

inga

neutralo

bject

andview

inga

rubber

foot

24singletaps,24

simultaneous

doubletaps

Twopoint

discrimination

(tactileacuity)

ANOVA/p

<.03

(and

linear

regression

and

ANOVAon

the

healthycontrol

data,p

<.04)

Perform

ance

inpatients(and

insubjectswith

lowtactile

accuracy)was

sign.enhanced

whenow

narm

was

view

ed


Tab

le4

Studiesevaluatin

gtheeffectsof

multisensory

stim

ulationafterstroke

inpatientswith

neglect(in

orderof

appearance

intext)

Study

Patients

Lesion

side

Lesion

site

Tim

epost

injury

Stim

ulated

modalities

Stim

uli

Conditio

nsFrequencyof

stim

ulation

Outcome

measure

Statisticaltest

Mainresults

Calam

aroetal.

1995

8neglect,7without

neglectand

8healthycontrols

15RH

Fr,T

e,Pa,

Oc,SC

atleast1

m(not

completely

clear)

AandV

A:consonant-

vowels

V:d

ummy

loudspeaker

Astim

ulationon

theleft

orrightw

ithout

(baseline)

andwith

(experim

ental)

spatially

congruento

rincongruentV

stim

ulation

36baselin

etrials,72

experimental

trials

Aidentification

ANOVA/p

<.01

Nodifference

inidentificationof

leftAstim

ulation

betweenneglect

patientsand

controlswhen

dummyspeaker

was

presentedon

therightside

Sorokeretal.

1995

7neglect(including

auditory

neglect)

and8healthy

controls

7RH

Fr,T

e,Pa,

Oc,SC

?AandV

A:consonant-

vowels

V:m

ovieof

pronounced

syllables

Astim

ulation,AV

stim

ulation(inwhich

Astim

uliw

ere

presentedin

contralesionalspace

andVstim

uliin

ipsilesionalspace)

Max.36trialsfor

each

stim

ulation

Aidentification

ANOVAandt-test/

p≤.038

AVstim

ulation

increasedA

identificationin

both

patientsand

controls.

Improvem

entw

asbigger

whenV

stim

ulationhada

lowsaliency(i.e.,

slight

lipopening;

comparedto

high

saliency)

andwhen

Vstim

ulationwas

congruenttotheA

stim

ulation

(com

paredto

incongruent)

Passam

onti

etal.2009a

9hemianopia,6

neglect

6RH,9

LH

(neglect:

allR

H)

Fr,T

e,Pa,

Oc,SC

5–108m

AandV

A:w

hite-noise

burstof1

00ms

V:singleLED

flashof

100ms

AVadaptationin

which

thestim

uliw

ereeither

spatially

disparateof

spatially

congruent

Adaptationblocks

lasted

4min,A

localizationtask

had105trials

Alocalization

beforeandafter

adaptatio

nandA

localizationshift

(calculatedby

subtractingmean

reported

locations

pre-adaptatio

nfrom

thosepost-

adaptatio

n)

ANOVA/p

<.05

After

adaptationto

spatiald

isparity:

Alocalization

accuracy

decreased

sign.afteradapting

thenorm

alfield;

sign.shiftinsound

localizationtoward

stimulationlocation;

sign.greatershiftin

soundlocalization

towards

adapting

stimulus

after

adaptationinthe

norm

alfieldthan

the

affected

fieldin

hemianopiapatients.

Afteradaptationto

spatialcoincidence:

Alocalization

accuracy

sign.

increased,regardless

oftheadapted

hemifield;sign.

greateraccuracy

for


Tab

le4

(contin

ued)

Study

Patients

Lesion

side

Lesion

site

Tim

epost

injury

Stim

ulated

modalities

Stim

uli

Conditio

nsFrequencyof

stim

ulation

Outcome

measure

Statisticaltest

Mainresults

sounds

presentedat

theadaptedlocation

comparedtothe

untrainedlocations

Frassinetti

etal.

2002

7neglectand

8healthycontrols

7RH

Fr,T

e,Pa,

SC1m

–14

yVandA

V:singleLED

flashof

100ms

A:p

uretonesof

150ms

V,A

,AV(stim

uli

presentedin

sameor

indifferentp

osition)

8trialspercondition,

runin

2sessions

of+/−

1hon

consecutived

Vdetection

ANOVA/p

<.05

Performance

intheleft

Vfieldwas

sign.

enhanced

intheAV

condition

(mostly

whenthestim

uli

werespatially

coincident)

Frassinetti

etal.

2005

7neglect,7

hemianopia,7

neglectand

hemianopia

Different

across

patients

Fr,T

e,Pa,

Oc,SC

?VandA

V:singleLED

flashof

100ms

A:w

hite-noise

burstsof

100ms

V,A

,AV(stim

uli

presentedtemporally

coincident,insameor

differentp

osition)

2sessions

of+/−2h,

includingall

conditions,on

2succeeding

d

Vdetection

ANOVA/p

<.001

Sign.enhancemento

fVdetectionin

the

affected

hemifield

inAVcondition

whenspatially

coincident,in

patientswith

neglecto

rhemianopia

vanVleetand

Robertson

2006

1neglect

1RH

Fr,T

e,Pa,

SC8w

VandA

V:targetamong

distractors

(sharing

either

coloror

shape

featurewith

target)

A:toneof

2000

ms

(presented

atonseto

fV

search

array,

congruento

rincongruentto

Vtarget

locatio

n)

NoAstim

ulation,

bilateralsound,one-

sidedspatially

congruentsound,one-

sidedspatially

incongruentsound

(tonewas

not

predictiveof

target

location)

34trialsforeach

condition

tested

over

4sessions

Vsearch

efficiency

(presentation

latencyin

aconjunctionV

search

task

with

a75

%accurate

targetdetection)

ANOVA/p

<.01

Search

efficiency

fortargetsin

the

impaired

hemifield

was

sign.increased

inthesound

conditions,when

comparedto

the

no-sound

condition.

Inaddition,

improvem

entinthe

spatially

congruent

soundcondition

was

larger

than

intheothersound

conditions

Làdavas

etal.

1997

29patientswith

RH

damageof

which

20with

and9without

neglect

29RH

Fr,T

e,Pa,

Oc,SC

0.5–12

mVandP

V:2

8line

draw

ings

presentedleft

orright,2in

center.10

distractor

draw

ings

presentedleft

orright,2in

center.A

llview

edvia

mirror

P:leftorrighthand

passively

moved

inleft,

Lefto

rrighth

and

passivelymoved

inleft,right

orcenter

spacefordurationof

trial.The

passively

moved

hand

was

seen

onlyinthemirror(and

thus

view

edinverted)

whenin

leftor

right

space,butw

asnot

seen

atallincenter

space

6trials:1

trialp

ercondition

inwhich

thepatient

continuednaming

alltargetstim

uli

(the

line

draw

ings)until

thepatient

stated

thatalltargetshad

been

named

Videntification

ANOVA/p

<.05

Performance

ofpatientswith

neglectinnaming

linedraw

ings

onthe

leftside

ofthe

mirrorwas

sign.

moreaccuratewhen

thelefthand

was

moved

intheleft

than

intherighto

rcenter

space.There

was

nosign.effect

fortherighth

and

andfortheright

side

ofspace.The


Tab

le4

(contin

ued)

Study

Patients

Lesion

side

Lesion

site

Tim

epost

injury

Stim

ulated

modalities

Stim

uli

Conditio

nsFrequencyof

stim

ulation

Outcome

measure

Statisticaltest

Mainresults

righto

rcenter

space

patientswithout

neglectshowed

nosign.effects

diPellegrinoand

Frassinetti

2000

1left-sided

visual

extinction

(without

neglect)

1RH

Te,P

a+/−

16m

VandP

V:1

digit

presentedon

therighto

rleft,

2digits

simultaneously

presentedon

both

sides

P:indexfin

gers

placed

ontable

top,oron

screen

surface,directly

belowtarget,

whilefin

gers

wereor

were

notoccluded

from

view

Fingersfar(index

fingers

alignedwith

targetat

40cm

distance),

fingersnear

(index

fingerspositionedon

screen),fingers

covered(identicalto

fingersnear,but

with

fingersoccluded

from

view

),Vcues

(target

at40

cmdistance,

photographsof

index

fingersweredisplayed

onthescreen)

4blocks

of18

trials

foreachcondition,

tested

in4separate

sessions

Extinctionscore(i.e.,

proportio

ncorrect

identificationin

bilateraltrials

dividedby

proportio

ncorrect

inunilateraltrials)

ANOVA/p

<.0008

Extinctionscorewas

less

infingersnear

condition

than

intheotherconditions

Sambo

etal.

2012

4neglectw

ithtactile

extinctionor

somatosensory

deficits

and8

healthycontrols

4RH

Fr,T

e,Pa,

Sc1–14

mS,

PandV

S:singletaps

delivered

with

solenoids

P:lefth

andplaced

either

inleftor

righth

emi-

space

V:visionof

theleft

hand

was

either

availableor

prevented

Lefth

andplaced

inleft

(contralesional)

hemispace

orin

right

(ipsilesional)

hemispace

with

either

vision

orno

vision

ofthelefthand

320trialsequally

distributedover

8experimental

blocks

Tdetection

ANOVA/p

≤.043

Performance

ofpatientswas

sign.

faster

whentheleft

hand

was

placed

intherighthem

ispace.

Inaddition,this

effectwas

sign.

greaterwhenthe

hand

was

visible.

Health

ycontrols

weresign.faster

whenthelefthand

was

placed

inthe

lefthemispace

and

vision

hadno

sign.

effectforthese

participants


addition, Cecere et al. (2014) presented a patient with a com-plete loss of central vision and visual agnosia with differenttypes of sounds (looming, receding, and stationary) while exa-mining his visual discrimination and detection abilities. Visualdiscrimination in the unaffected, but not affected, visual fieldwas enhanced by the addition of a coincident looming sound.Visual detection was enhanced by the addition of all types ofcoincident sounds in both the unaffected and affected field.

Brown et al. (2008) demonstrated that proprioceptive in-formation provided by placing patients’ left hand near objectsimproved target size processing of these objects in thehemianopic field. Likewise, in a single case study bySchendel and Robertson (2004), visual detection in the affect-ed hemifield improved when the patient’s contralesional armwas extended into the affected field, but only for visual stimulinear the extended hand. However, these findings could not bereplicated in a sample of five patients in an otherwise largelysimilar study of Smith et al. (2008).

Apart from the direct and short-term improvements, longerlasting effects have also been reported. Passamonti et al. (2009a)found that auditory localization improved after four minutes ofadaptation to spatially congruent audiovisual stimulation, espe-cially at the location where audiovisual stimuli were presented.Bolognini et al. (2005a) presented patients with unisensory andmultisensory trials in daily sessions of about four hours for near-ly two weeks. Patients improved in visual detection, visual ex-ploration and in different tasks of daily life (relating to visualimpairments), and these improvements were stable at thefollow-up after one month. This study, however, did not ruleout that a similar improvement might have been obtained byonly using unisensory (visual) stimulation, as all the differentconditions were incorporated in the sessions. To overcome thisconfound, Passamonti et al. (2009b) incorporated an unisensory,visual training as well as an audio-visual training and showedthat audiovisual training improved visual detection and explora-tion, oculomotor scanning and activities of daily life, whereasthe visual training did not. These effects remained stable at athree-month follow-up and a one-year follow-up.

Keller and Lefin-Rank (2010) examined the effects of au-diovisual stimulation in patients in the subacute stage after braindamage. Patients received either audiovisual training or visualtraining. The audiovisual training resulted in a larger improve-ment in visual exploration compared to the visual training. Inaddition, only patients that had received audiovisual trainingshowed near normal daily living activities (relating to visualimpairments) after the training of three weeks. Yet, the role ofspontaneous recovery in these findings is not clear, as there wasno group of patients receiving no training at all.

Auditory Localization Deficits

Only a single study examining the effects of multisensorystimulation on specific auditory deficits after stroke was

included (Table 2). Bolognini et al. (2005b) investigated whe-ther a temporally congruent visual stimulus improved thelocalization of an auditory stimulus in a patient with a selec-tive deficit of auditory spatial localization, yet intact detection,in the whole auditory field. Auditory localization improved,but only when the visual stimulus was spatially congruent.

Somatosensory Deficits

Impaired somatosensory function has negative effects on ex-ploration of the environment, spontaneous use of hands, pre-cision grip and object manipulation. Additionally, it has neg-ative effects on rehabilitation outcomes, such as personal safe-ty, functional outcome and quality of life (Carey 1995; Careyand Matyas 2011). Two studies on the effect of multisensorystimulation in patients with somatosensory deficits were in-cluded (Table 3). These studies examined the effect of viewingeither a relevant body part or the surface adjacent to it. When arelevant body part or its adjacent surface is viewed, stimula-tion might be provided by descending modulatory inputs fromvisual body representation areas which could aid in the reor-ganization of damaged brain areas in somatosensory deficits.

Newport et al. (2001) investigated the effect of com-bining vision and proprioception in a patient with aunilateral somatosensory impairment of the right upperlimb, including right tactile extinction (i.e., the failure to reporta contralesional stimulus only when it is delivered togetherwith a concurrent ipsilesional stimulus [Gallace and Spence2008]). When the patient could view the surface adjacent toher hidden to-be-localized limb, detection of the impairedlimb improved compared to when she was blindfolded. Inaddition, a single case study by Serino et al. (2007) indicatedthat during invisible stimulation of the upper limb, tactilethresholds were improved when the own upper limb wasviewed compared to viewing a rubber foot or a neutral object.

Neglect

Patients with unilateral spatial neglect suffer from impairedexplicit spatial processing (i.e., reporting and/or exploring)of stimuli presented in the affected contralesional space(Gallace and Spence 2008; Ting et al. 2011). Additionally,patients with neglect can have a disrupted mental representa-tion of space, which is generally shifted to the ipsilesionalspace and therefore underrepresents the contralesional space(Mesulam 1999; Zamarian et al. 2007). Effective rehabilita-tion of neglect is of utmost importance as the disorder is as-sociated with poorer cognitive and motor recovery and pooreroutcomes on ADL (activities of daily living; Heilman et al.2000; Buxbaum et al. 2004; Nijboer et al. 2013, 2014).Neglect can occur in all perceptual domains (Kinsbourne1993) and in different regions of space (Aimola et al. 2012;Van der Stoep et al. 2013). Extinction often occurs in patients


with neglect, however, double dissociations have beenreported (Pavlovskaya et al. 2007). Nine studies wereincluded that have examined the effects of multisensory stimu-lation on performance of patients with neglect and/or extinc-tion. The characteristics of these studies are listed in Table 4.

Two early studies of Calamaro et al. (1995) and Sorokeret al. (1995) demonstrated that identification of auditorystimuli in the impaired hemispace of patients with neglectwas enhanced with additional visual stimulation in theintact hemispace. Passamonti et al. (2009a) demonstratedthat auditory localization in patients with neglect was im-proved after four minutes of adaptation to spatially con-gruent, but not spatially incongruent, audiovisual stimuli,especially at the adapted location.

Furthermore, as demonstrated in the studies of Frassinettiet al. (2002, 2005), detection of a visual stimulus improved onthe contralesional side when a spatially congruent sound waspresented simultaneously. van Vleet and Robertson (2006)demonstrated that target detection improved in the impairedhemifield when a tone was presented at the onset of the searchdisplay in a location congruent to the target location.

Làdavas et al. (1997) and di Pellegrino and Frassinetti(2000) examined whether position of the hands could modu-late visual neglect or visual extinction respectively. In the firststudy, patients with neglect viewed visual targets anddistractors via a mirror and were more accurate in identifyingtargets on the left side of the mirror when the left hand waspassively moved on the left side of space (Làdavas et al.1997). In the di Pellegrino and Frassinetti study (2000) a pa-tient’s visual extinction for left targets was reduced when thepatient’s fingers were positioned below the visual targets. Theleft-sided extinction was not reduced when the patient’s fin-gers were occluded from view.

Furthermore, Sambo et al. (2012) examined the effect ofproprioceptive and visual information on processing of tactilestimuli in patients with both neglect and left tactile extinctionor somatosensory deficits. Processing of left invisible tactilestimulation was enhanced when patients placed their left handin the ipsilesional, ‘intact’, hemispace compared to when theyplaced the hand in the contralesional, ‘impaired’, hemispace,especially when patients were able to see the hand.

Quality Assessment

In the section above the included studies on multisensorystimulation after stroke were discussed. Overall, twenty outof twenty-one studies reported a beneficial effect of multisen-sory stimulation in improving sensory deficits. In this sectionwe assess the discussed studies on 1) randomization; 2) inclu-sion of control patient group; 3) blinding of participants; 4)blinding of researchers; 5) follow-up; 6) group size; 7) reportingeffect sizes; and 8) reporting time post-stroke (Table 5).

Study Characteristics

Of the 21 discussed studies, only 1 (Keller and Lefin-Rank2010) consisted of a between-subjects design. The otherstudies were within-subjects designs, 6 (di Pellegrino andFrassinetti 2000; Newport et al. 2001; Schendel andRobertson 2004; Bolognini et al. 2005b; van Vleet andRobertson 2006; Cecere et al. 2014) of which were single casestudies. On a 8-point scale (representing the 8 elements onwhich the articles were assessed, with 8 indicating the highestand 0 the lowest possible score), the average total score for allstudies was 2 (SD=1.1, range 0–4). Based on the total scores,6 studies were of moderate quality (4 studies had a total scoreof 3, and 2 studies had a total score of 4) and fifteen were oflow quality (2 studies had a total score of 0, 4 studies had atotal score of 1, and 9 studies had a total score of 2). Theaverage score for studies on visual field defects was 2 (11studies), on auditory deficits 2 (1 study), on somatosensorydeficits 2.5 (2 studies), and on neglect 2 (9 studies). Of the21 studies, only a single study (Smith et al. 2008), whichincluded patients with hemianopia, did not report beneficialeffects of multisensory stimulation, this study was assessedwith a total score of 2.

All discussed studies included detection, localization, ex-ploration, discrimination and/or identification outcome mea-sures in their design. Only 3 of the 21 studies discussed (all onhemianopia; Bolognini et al. 2005a; Passamonti et al. 2009b;Keller and Lefin-Rank 2010) included ADL outcome mea-sures in their design, rendering the discussed studies’ focimostly experimental.

Randomization and Inclusion of Control Group

Ideally, studies investigating the effect of an interventionshould have a group of patients receiving an interventionand a control group of patients, either not receiving any inter-vention or receiving a ‘control intervention’ (Higgins et al.2011). Only a single study (Keller and Lefin-Rank 2010)had incorporated a control patient group: two randomly allo-cated groups of patients with hemianopia or quadrantanopiareceived either multisensory or unisensory training. The studydemonstrated that patients benefited more from multisensorytraining than unisensory training.

In all the other discussed studies, each patient participatedin at least two different conditions, namely an experimentalcondition (with multisensory stimulation) and a control con-dition (without multisensory stimulation). In this way, effectsof multisensory stimulation could be compared within pa-tients. Twelve of twenty within-subjects design studies(Làdavas et al. 1997; di Pellegrino and Frassinetti 2000;Newport et al. 2001; Frassinetti et al. 2002; Schendel andRobertson 2004; Bolognini et al. 2005b; Frassinetti et al.2005; van Vleet and Robertson 2006; Serino et al. 2007;


Brown et al. 2008; Smith et al. 2008; Sambo et al. 2012)reported that they had randomized or counterbalanced the dif-ferent conditions, in the other studies this was not reported.

To allow for monitoring of ‘practice effects’ and verifica-tion of improvement of performance toward normal levels, acontrol group of healthy participants is very useful. Only sixof the studies incorporated a control group of healthy subjects(Calamaro et al. 1995; Soroker et al. 1995; Newport et al.2001; Passamonti et al. 2009b; Serino et al. 2007; Samboet al. 2012) but in one study (Passamonti et al. 2009b) thehealthy control group did not receive the exact experimentaltraining as the patients. These studies demonstrated that theeffect of multisensory stimulation was larger in patients com-pared to healthy controls (Newport et al. 2001; Passamontiet al. 2009b; Sambo et al. 2012) or that patients could performon the level of healthy controls when multisensory informa-tion was presented (Calamaro et al. 1995). Moreover, thesestudies demonstrated that multisensory stimulation could leadto improvements both in patients and healthy controls(Soroker et al. 1995) or in patients and healthy controls witha low sensory acuity only (Serino et al. 2007).

Blinding of Participants and Researchers

Only three of the twenty-one studies reported that researcherswere blinded for one important aspect (vanVleet and Robertson2006; Passamonti et al. 2009b; Keller and Lefin-Rank 2010).Yet, in one of these studies (Keller and Lefin-Rank 2010) not allresearchers were blinded. The two studies that dealt withblinding of researchers sufficiently demonstrated that multisen-sory stimulation could be beneficial in patients with hemianopia(Passamonti et al. 2009b) or neglect (van Vleet and Robertson2006). None of the studies reported that patients were blinded.As a direct result of the design chosen, blinding is more difficultwhen each patient is tested in all conditions and when thedifference between the conditions is clear (for example:performing a task with or without a distinctive sound), whichwas the case in most of the discussed studies.

Follow-Up

Sufficient follow-up to the examination is of great importanceto assess the effects of the intervention over a prolonged

Table 5 Scores of the quality assessment of the discussed studies, based on eight elements a

Study Randomizationof interventionor conditions

Inclusion ofcontrol patientgroup

Blinding ofparticipants

Blinding ofresearchers

Follow-up Groupsize

Reportingeffectsizes

Reportingtimepost-stroke

Total Quality

Frassinetti et al. 2005 1 0 0 0 0 0 0 0 1 low

Leo et al. 2008 0 0 0 0 0 1 0 1 2 low

Ten Brink et al. 2015 0 0 0 0 0 0 0 1 1 low

Cecere et al. 2014 0 0 0 0 0 0 0 1 1 low

Brown et al. 2008 1 0 0 0 0 0 0 1 2 low

Schendel and Robertson2004

1 0 0 0 0 0 0 1 2 low

Smith et al. 2008 1 0 0 0 0 0 0 1 2 low

Passamonti et al. 2009a 0 0 0 0 0 0 0 1 1 low

Bolognini et al. 2005a 0 0 0 0 1 0 0 1 2 low

Passamonti et al. 2009b 0 0 0 1 1 1 0 1 4 moderate

Keller and Lefin-Rank2010

1 1 0 0 0 1 0 1 4 moderate

Bolognini et al. 2005b 1 0 0 0 0 0 0 1 2 low

Newport et al. 2001 1 0 0 0 0 0 0 1 2 low

Serino et al. 2007 1 0 0 0 0 1 0 1 3 moderate

Calamaro et al. 1995 0 0 0 0 0 0 0 0 0 low

Soroker et al. 1995 0 0 0 0 0 0 0 0 0 low

Frassinetti et al. 2002 1 0 0 0 0 0 0 1 2 low

van Vleet and Robertson2006

1 0 0 1 0 0 0 1 3 moderate

Làdavas et al. 1997 1 0 0 0 0 1 0 1 3 moderate

di Pellegrino and Frassinetti2000

1 0 0 0 0 0 0 1 2 low

Sambo et al. 2012 1 0 0 0 0 0 1 1 3 moderate

a 0=element was dealt with insufficiently; 1=element was dealt with sufficiently


period of time. Only two of the twenty-one studies discussed(Bolognini et al. 2005a; Passamonti et al. 2009b) incorporated afollow-up in their design (with no losses-to-follow-up). Theyfound that patients with hemianopia could improve in visualdetection and (oculomotor) exploration in the impaired fieldand in different tasks of daily life withmultisensory stimulation.These beneficial effects were stable at a one month (Bologniniet al. 2005a) and at a one year (Passamonti et al. 2009b) follow-up. With respect to the other studies on low-level sensory im-pairment and neglect, no follow-up results were reported.

Group Size

Studies with small groups often have large confidence inter-vals and are less able to detect clinically relevant effects sta-tistically. Group sizes in the discussed studies were relativelysmall. The average group size in the discussed studies was6.36 (SD=4.81, range 1–20). The largest group had 20patients (Làdavas et al. 1997), 9 studies (including 6 casestudies) had 1 to 5 patients, and 11 studies had 7 to 12patients. The average group size for studies on visual fielddefects was 6.7 (11 studies), on auditory deficits 1 (1 study),on somatosensory deficits 5.5 (2 studies), on neglect 6.9(9 studies). One of the twenty-one discussed studies (Smithet al. 2008) did not find a difference between unisensory andmultisensory stimulation in patients with hemianopia; thisstudy included 5 patients.

Reporting Effect Sizes and Time Post-Stroke

An important factor that should be reported is the effect size todetermine the strength of the statistically significant results.Yet, only 1 of the 21 studies discussed (Sambo et al. 2012)reported effect sizes. This study found that multisensory stim-ulation enhanced tactile detection, with an effect size (η2)ranging from 0.46 to 0.76, which is considered as a large effectsize (Cohen 1988). Another important factor that should bementioned is the time post-stroke onset to verify response totreatment in different phases of recovery. Three of the studiesdiscussed (Frassinetti et al. 2005; Calamaro et al. 1995;Soroker et al. 1995) did not report the time post-stroke of theirincluded patients. Overall, studies demonstrating beneficialeffects of multisensory stimulation included patients between0.5 months to 32 years post stroke, effects in the early acutephase were not reported.

Discussion

This review has attempted to assess and integrate evidence forthe effectiveness of multisensory stimulation as a possiblerehabilitation method for functional recovery for patients withlow- or higher-level sensory deficits after stroke. We

hypothesized that multisensory stimulation has the potentialto be beneficial for these groups of patients, as informationfrom a normally functioning sensory modality might aid theprocessing of information from the impaired sensory modali-ty. Twenty of the twenty-one included studies demonstratedbeneficial effects of multisensory stimulation on patients withlow- and/or higher-level sensory deficits. These studies dem-onstrated that detection, localization, exploration, discrimina-tion, identification, and even several activities of daily livingcould be enhanced by multisensory stimulation in both pa-tients with low- and patients with higher-level sensory impair-ments. Notwithstanding these beneficial effects, our qualityassessment classified 6 studies as being of moderate and 15studies as being of low quality. Most studies employed awithin-subjects design with small groups and more than athird of these studies did not report taking into accountrandomization/counterbalancing of the different conditions.In addition, none of the studies reported blinding all importantaspects, only two studies incorporated a follow-up in theirdesign, three studies did not report time post-stroke, and onlyone study reported effect sizes. Most importantly, thediscussed studies’ foci were mostly experimental (focusingon tasks such as signal detection or signal localization); onlythree studies measured the effect of multisensory stimulationon ADL-measures. Therefore, at present, none of the studieson multisensory stimulation after stroke are adequate to give aproper evaluation of the effectiveness of the method as anintervention. We believe that now is the time to take this lineof research to the next level and set-up well-designed random-ized controlled trials (RCTs), in which the important discussedquality elements are taken into account and in which ADL-measures are included, to examine the effectiveness of multi-sensory stimulation as an intervention after stroke.

Starting Points for Future Research

Regarding the type of stimulation, a good starting point for anRCT might be audiovisual stimulation, as most included stud-ies (13 out of 21) focused on this type of stimulation and thistype of stimulation is well controllable. Hemianopia mightthen be a suitable candidate to target first, as most studiesfocused on patients with hemianopia (10 out of 21), thisimpairment occurs relatively frequently after stroke, and theimplicated visual neural networks are well-documented(e.g., Kandel et al. 2000). Yet, recent research demonstratedthat visual spatial localization can be distorted in patientswith hemianopia (Fortenbaugh et al. 2015), which cancomplicate any spatial multisensory approach to rehabilita-tion. It is therefore essential that future studies in patientswith hemianopia include appropriate baseline conditions tomeasure also these distortions. In this way, future studies cancontrol for the influence of any comorbid (visual) disorders oneffects of multisensory stimulation. After establishing an


effective protocol for patients with hemianopia, the effective-ness of the protocol can be examined for other disorders aswell. Expanding collaborations between fundamental and clin-ical researchers might ensure that potentially interesting tech-niques can be studied in clinical populations soon after funda-mental studies demonstrate positive effects of these techniques.

Potential Mechanisms for Rehabilitation

When considering multisensory stimulation as an interven-tion, it is of importance to determine if improvements mightresult from recovery or compensatory responses. Recovery isthe reappearance of pre-stroke function and is characterizedby restitution or repair of the functionality of damaged neuralstructures (Levin et al. 2009). Compensation, on the otherhand, is the reduction of the disparity between an impairedfunction and the environmental demands characterized byactivation in alternative brain areas that are not normallyactivated in controls (Levin et al. 2009).

While most studies demonstrated short-term beneficial ef-fects of multisensory stimulation, two studies (Bolognini et al.2005a; Passamonti et al. 2009b) provided evidence that effectsof multisensory ‘training’ (of less than two weeks) can persistfor a longer period of time (up to one year). The underlyingmechanisms of these long-term effects, which are especiallyinteresting from a rehabilitation point of view, are not yetestablished. To speculate, long-term effects might mainly re-sult from restoration, as multisensory stimulation might re-cruit and, in turn, strengthen residual (sensory) pathways inthe brain and thereby might restore sensory performance andfunction (Jiang et al. 2015). Direct effects, on the other hand,might mainly result from passive compensation (e.g., multi-sensory stimuli surpassing the attention threshold, thereby‘normalizing’ sensory performance and function), as neurobi-ological recovery is known to require more time to complete(Teasell and Hussein 2014). Possibly, direct effects mightmostly reflect enhanced attention to the stimulated location.It might be especially effective to target restoration in the firstthree months post-stroke, as in this period it is most likely thatneurobiological recovery will take place (Kwakkel et al. 2004;Levin et al. 2009; Nijboer et al. 2013). Future studies shouldaim at identifying an optimal timing at which multisensorystimulation would be most effective.

Restoration of sensory performance and function mightalso lead to improvements on ADL (see Bolognini et al.2005a; Passamonti et al. 2009b; Keller and Lefin-Rank2010). Future studies should therefore examine the effects ofrestoration on cognitive (such as attention and memory) out-come measures, and to what extent the effects of multisensorystimulation are transferred (on the long-term). This could forexample be achieved by assessing these outcomes before andafter (with multiple follow-up measurements) multisensory‘training’.

When considering multisensory stimulation as an interven-tion in future research, it is also essential to determine theoptimal frequency, duration and intensity of multisensorystimulation and which patients benefit from multisensorystimulation and/or which brain regions need to be intact inorder to benefit from multisensory stimulation. The discussedstudies included patients mainly based on behavioral criteriaandwere not consistent in reporting their etiology (e.g., hemor-rhagic or ischemic stroke), another factor that may well co-determine the effects of multisensory stimulation in rehabilita-tion. Future studies would benefit from standardized tasks andoutcome measures. This could possibly contribute to establi-shing the degree of clinical relevance for observed outcomeeffects, quantified by, for example, theminimal clinically impor-tant difference (MCID). At the moment, scientific acceptancefor the MCID is not yet achieved (Gatchel et al. 2010; King2011). Establishing a quantification of clinical relevance wouldbe valuable, as effects should not only have statistical signifi-cance, but also significance in improving the patients’ lives.

Study Limitations

A limitation of the current review might be the incompleteretrieval of studies as the retrieval was limited to the selectedkeywords and databases. The selected inclusion and exclusioncriteria resulted in inclusion of studies with a specific focus,while excluding studies on related subjects. Most noteworthy,this review selected studies on passive multisensory stimula-tion in sensory recovery after stroke. Obviously, stimulatingmotor recovery to prevent functional loss is very important aswell (Nudo et al. 1996). Additionally, the type of studies in-cluded might only have been reported after a positive result.This results in a positive publication bias, which might haveled to an underrepresentation of studies showing no beneficialeffects of multisensory stimulation. A limitation regarding theincluded studies concerns the studies’ foci, which were mainlyexperimental. This resulted in an insufficient score on ourquality assessment and restricts any conclusion on the clinicalrelevance of multisensory stimulation. Yet, the lack of studiesfocused on clinical application emphasizes the need for theimplementation of proper RCTs.

Conclusion

In conclusion, in recent years there has been a tremendousincrease in fundamental cognitive neuroscience research onmultisensory integration. In addition, a number of studieshave reported promising results of multisensory stimulationin low-level as well as higher-level sensory impairments afterstroke. Yet, as the quality of these studies was insufficient, atthis moment it cannot be concluded that multisensory stimu-lation can be successfully applied as an effective intervention.


It would be a valuable next step to continue this line ofresearch with well-designed randomized controlled trials toexamine whether and how multisensory stimulation canaid recovery after stroke.

Compliance with Ethical Standards

Conflict Interests The authors declared no potential conflicts of interestwith respect to the research, authorship, and/or publication of this article.

Financial Disclosure Tanja C.W.Nijboer was supported byNetherlandsOrganization for Scientific Research grant #451-10-013. Raymond vanEe was supported by a grant from the Flemish Methusalem program(METH/08/02 assigned to J. Wagemans), the EU HealthPac grant(assigned to J.A. van Opstal), and the Flanders Scientific Organization.

The authors received no financial support for the research, authorship,and/or publication of this article.

Open Access This article is distributed under the terms of the CreativeCommons At t r ibut ion 4 .0 In te rna t ional License (h t tp : / /creativecommons.org/licenses/by/4.0/), which permits unrestricted use,distribution, and reproduction in any medium, provided you give appro-priate credit to the original author(s) and the source, provide a link to theCreative Commons license, and indicate if changes were made.

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