Effects of Low Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) on Gamma Frequency...

NeuroRehabilitation 28 (2011) 113–128 113DOI 10.3233/NRE-2011-0640IOS Press

The effects of low frequency RepetitiveTranscranial Magnetic Stimulation (rTMS)and sham condition rTMS on behaviourallanguage in chronic non-fluent aphasia: Shortterm outcomes

Caroline H.S. Barwooda,∗, Bruce E. Murdocha, Brooke-Mai Whelana, David Lloyda,b, Stephan Riekb,John O’Sullivanc, Alan Coulthardd, Andrew Wongc,e,f , Phil Aitkenf,h and Graham Hallf,g

aCentre for Neurogenic Communication Disorders Research, School of Health and Rehabilitation Sciences,University of Queensland, AustraliabSchool of Human Movement Studies, University of Queensland, AustraliacDepartment of Neurology and Neurosurgery, Royal Brisbane and Women’s Hospital, Queensland, AustraliadDepartment of Medical Imaging, Royal Brisbane and Women’s Hospital, Queensland, AustraliaeDepartment of Neurology, Princess Alexandra Hospital, Queensland, AustraliafAcute Stroke Unit, Princess Alexandra Hospital, Queensland, AustraliagDepartment of Medicine, Princess Alexandra Hospital, Queensland, AustraliahDepartment of Geriatric Medicine, Princess Alexandra Hospital, Queensland, Australia

Abstract. Introduction: The application of low frequency (1 Hz) Repetitive Transcranial Magnetic Stimulation (rTMS) to righthemisphere (RH) language homologues in non-fluent aphasic populations has yielded improvements in behavioural languagefunction, up to 43 months post stimulation 32. Functional imaging studies have demonstrated RH language homologue “overac-tivation” post left inferior frontal gyrus (IFG) damage, inchronic non-fluent aphasia. The effects of low frequency (inhibitory)rTMS are postulated to be as a result of a reduction of overactivation in RH language homologues, facilitating the reorganisationof neural language networks.Methods: Low frequency (1 Hz) rTMS was applied to the anterior portionof a Broca’s area homologue (pars triangularis),for 20 minutes per day for 10 days, using a stereotactic neuronavigational system. Twelve non-fluent aphasic patients (six realstimulation and six sham), 2–10 years post stroke were stimulated. Behavioural language outcome measures were taken atbaseline and 1 week post rTMS.Results:Comparisons between the real stimulation and sham conditions indicated significant main effects between the stimulationand sham groups to 1 week post stimulation for naming accuracy, latency and repetition.Conclusions:This study indicates that rTMS has the capacity to modulate neural language networks, to facilitate improvementsin behavioural language function, 1 week post TMS.

Keywords: Transcranial Magnetic Stimulation (TMS), aphasia, stroke rehabilitation, language

∗Corresponding author: Caroline Barwood, Centre for Neuro-genic Communication Disorders Research, School of Health and Re-hab ilitation Sciences, University of Queensland, Brisbane St Lucia,

QLD 4072, Australia. Tel.: +617 3365 6162; Fax: +617 3365 1877;E-mail: [email protected].

ISSN 1053-8135/11/$27.50 2011 – IOS Press and the authors. All rights reserved

114 C.H.S. Barwood et al. / Effects of low frequency rTMS in chronic non-fluent aphasia

1. Introduction

In recent years, low frequency repetitive Transcra-nial Magnetic Stimulation (rTMS) has been safelyand successfully applied to patients with chronic non-fluent aphasia, modulating neural language networksto improve language performance, subsequent to lefthemisphere (LH) stroke. The resulting effects on be-havioural language function show significant improve-ments in picture naming performance up to 43 monthspost stimulation [32,39]. To date, some TMS re-searchers have proposed that the inhibition of righthemisphere (RH) language homologues using low fre-quency rTMS and the subsequent improvements innaming may be due to transcallosal disinhibition [55]where a decrease of overactivation in RH perisylviansites may promote increased LH perilesional activa-tions and function [32,38,39]. There may be additionalexplanations for functional reorganisation of languagepost rTMS nonetheless current evidence from chronicnon-fluent aphasia populations substantiates the neuro-physiological and behavioural changes associated withtranscallosal disinhibition. Current functional neu-roimaging evidence offers valuable insight into recov-ery mechanisms post LH infarction however, has failedto resolve many issues regarding the functional rolesof both the LH and RH and the integration of bilateralnetworks in recovery of language in the aphasic brain.Both the LH and RH are believed to assist languagerecovery after stroke [9,15,44,56]. Despite this, in thechronic stage of aphasia RH activations are thought tobe a maladaptive process indicating faulty recovery oflanguage systems [4].

1.1. Evidence for the modulation of language usingrTMS in normal control and aphasic populations

rTMS modulates neural activity in brain regionswhere it is applied with effects ranging from excitationto inhibition, depending on the frequency [3]. Modula-tion of language using rTMS has been demonstrated inboth normal control and aphasic populations. A previ-ous study by Thiel et al. [54] applied low frequency (in-hibitory) rTMS to the left inferior frontal gyrus (IFG) inright (R) handed normal controls demonstrating inter-ferences in semantic processing and repetition priming.Such studies involving the creation of temporal lesionsin neurologically healthy individuals using rTMS haveestablished causal links between neural language sitesand language behaviour.

rTMS has been applied to LH language sites and RHlanguage homologues to investigate the role of bothhemispheres in language processing after neurologicalinsult (e.g., stroke and brain tumour). Winhuisen etal. [63] applied 4 Hz rTMS to maximal activation sitesidentified on PET scans in L and R IFG in LH strokepatients with aphasia. Patients were stimulated within2 weeks post stroke, to elucidate the acute activationpatterns and behavioural interference using a rTMS. Bi-lateral hemispheric activations were reported for mostpatients in response to semantic based paradigm. WhenrTMS was applied to the L IFG, significantly longerlatencies were reported indicating disruptions of thebrain region responsible for language processes. Simi-lar results were reported in a follow-up investigation onthe same patient sample 8 weeks post stroke [64], fur-ther reiterating the importance of residual LH functionin the recovery of language in aphasia.

rTMS studies targeting patients with chronic non-fluent aphasia have reported significantly improved be-havioural language function post stimulation [32,37–39,64]. Such studies have demonstrated the success-ful modulation of behavioural language function insome patients following administration of low frequen-cy (1 Hz) rTMS to inhibit counterproductiveRH activa-tion. Naeser et al. [38] demonstrated significantly im-proved picture naming function in a cohort of four non-fluent aphasic patients when rTMS was applied to theanterior portion of pars triangularis, (right Brodmannarea 45 [R BA45]), for 20 minutes per day over 10days. Improvements in behavioural language functionwere reported up to 8 months post stimulation, signi-fying reorganisation of neural language networks overtime. Additionally, case study evidence substantiatesthe use of rTMS on global aphasic patients to remediateimpaired language function [39].

In more recent rTMS research, improvements in spe-cific picture naming function have been documented upto 43 months post TMS [32]. Functional magnetic res-onance imaging evidence accompanying these rTMSapplications has identified a significant reduction in RHactivation with a concurrent increase in LH perilesionalactivation, up to 46 months post rTMS stimulation [32].Such evidence verifies the long term, potentially pos-itive neuromodulatory effects of rTMS. Additionally,TMS has been postulated as an adjunct to tradition-al behavioural language therapy. A recent pilot studyby Martin et al. [33] combined 1 Hz rTMS and Con-straint Induced Language Therapy (CILT) to treat a sin-gle patient. Significant improvements were noted onsome naming outcome measures. Cumulatively, thesestudies substantiate the therapeutic potential of rTMSprotocols for patients with chronic non-fluent aphasia.

C.H.S. Barwood et al. / Effects of low frequency rTMS in chronic non-fluent aphasia 115

1.2. Theories to explain low frequency rTMSmodulation of language

Inhibitory forms of rTMS may be used to decreaseoveractivity in RH language homologues [38]. Previ-ous research has identified unusually high RH corti-cal activation patterns in the superior temporal gyrus(STG) [62] and the IFG [41,50,53] in association witha variety of experimental language paradigms in strokepatients. High levels of activation found in R homolo-gous language centres post stroke suggest an interhemi-spheric shift in neural language networks, to recruitundamaged neural resources in the unaffected hemi-sphere [27,57]. There is little doubt that the RH may as-sume a compensatory role in the presence of damage toLH language centres [13,63], however, the capacity towhich the RH is significant for language recovery overtime remains controversial. Paramount to the restora-tion of language function in aphasia is the reintegrationof damaged left fronto-temporal areas into functionallanguage networks [3].

Altered RH activation patterns are postulated in somestudies to be a significant compensatory mechanism tolanguage recovery in aphasia [7,36,47,49]. Compara-tively, other studies have indicated that reactivation ofipsilateral, perilesional sites is frequently a marker ofbetter recovery [4,6]. This suggests that RH integrationinto language networks may impede overall languagerecovery in some patients. Time post stroke, lesionlocation and the specific language tasks examined mayinfluence reported results and the mechanisms control-ling language recovery [44,55]. Some studies have in-dicated that high activation in RH language regions maynot be correlated with improvements in behaviourallanguage performance on specific language tasks. Ev-idence provided by Belin et al. [4] indicated abnormalactivation in homologousRH language regions in apha-sic patients compared to normal controls in response toword repetition tasks. Additionally, improvementsdur-ing the Melodic Intonation Therapy using word repeti-tion tasks accompanied increased activation in Broca’sarea and the L prefrontal cortex [4]. Similarly, Naeseret al. [37] identified increased RH activation comparedto control subjects during overt speech on a story tellingtask, suggesting that RH contribution may influenceagrammatic speech in aphasia. Contralateral areas inthe non-dominant hemisphere may have only limitedcompensatorycapabilities for language processing [47]however, a lack of consistency in the language tasksinvestigated hinders the interpretation of results in thisresearch area.

Low frequency rTMS is used to create a transient“virtual lesion” in RH language homologues (e.g., RBA45). Evidence suggests that this facilitates downregulation of overactive RH sites and the potential up-regulation of perilesional sites in the damaged LH [55].This theory is consistent with the principle of Para-doxical Functional Facilitation (PFF) which proposesthat direct or indirect damage to a particular part ofthe central nervous system may result in facilitationof behavioural outcomes [12,25]. The application of1 Hz rTMS may result in a decrease of overactivationin R BA45, promoting reduced inhibition by R BA45on adjacent and distant neural sites, resulting in modu-lation of bilateral neural networks responsible for pic-ture naming. Previous studies have verified the in-hibitory effects of 1 Hz frequency rTMS on corticalbrain tissue in humans [8,31] and the inhibitory effecton event related brain potentials after stimulation of atleast 15 minutes [18].

Abnormally high RH activation patterns in someaphasic patients post stroke may be due in part totranscallosal disinhibition, where persisting languagedeficits are caused by incomplete or faulty recov-ery mechanisms. According to Heiss and Thiel [20]changes in excitability inipsilateral andcontralateralhomologousregions of a cortical lesion occur as a re-sult of a reduction incollateral andtranscallosal inhi-bition. In normal processing, specialised neural areas(e.g. those specific to language function) inhibit regionsipsilateral, contralateral, or those in bilateral networksthat do not participate in any specialised language func-tion [40] When a specialised neural area is damaged,adaptive processes (plasticity) facilitate functional re-organisation and a cessation of disinhibitive processingto draw on resources perilesional (collateral Disinhibi-tion) and contralateral (transcallosal Disinhibition) tothe damage [65]. With respect to damage in LH lan-guage areas, transcallosal disinhibition may facilitate afunctional shift in language processes from LH to theRH language homologue. Some residual function maystill remain in the LH. Secondary to this, a reductionin collateral disinhibition is thought to allow recruit-ment of areas ipsilateral to the lesion site (in the LH) toassume compensatory language function. In patientswith extensive lesions not limited to language dedicat-ed neural sites (e.g. Broca’s area), the theory of mutualinhibition by transcallosal disinhibition in homologousareas may be less applicable. It is unlikely that suchwide areas of homologous brain tissue are participat-ing in mutual inhibitive processes instigated by a sin-gle neural site (e.g. R Broca’s area). In spite of this,previous case study evidence from global aphasia has


demonstrated improved language skills post rTMS sug-gesting that theories of inhibition may be one compo-nent at work in a complex interconnected bilateral lan-guage network, in the presence of extensive areas ofneural damage [39]. Current theories have promptedthe exploration of alternative therapeutic interventionswhich may directly target neural activity in contralater-al language homologues to induce transient or lastingcognitive and behavioural change [45].

Overactivation of RH language homologues has beenthe target of many neuroimaging investigations and ishypothesised to be a form of neural plasticity to pro-mote recovery. Despite this, evidence still suggeststhat activation and recruitment of perilesional neuronalresources in the LH remain critical to patient recov-ery [20,26,30,47], regardless of the amount of RH ac-tivation [14,63]. Recruitment of the available undam-aged areas ipsilateral to language areas in the LH e.g.STG and the supplementary motor area (SMA), appearsto facilitate better overall aphasia recovery [6,19,26,35,62]. Many factors must be considered when interpret-ing the extent of RH activation such as lesion size andsite [46] as well as time frame post stroke [23,49] Ithas also been hypothesised that the RH may have aninitial compensatory significance in the acute recoveryphase of aphasia, thus, RH activations are present at 10days and remain for up to 8 weeks after stroke [64,65].Furthermore, persisting RH activations are postulatedto be maladaptive processes, marking failed or faultyrecovery and/or a breakdown in inter-hemispheric con-trol [4].

The present study aims to investigate and charac-terise the short term behavioural language changes, 1week post stimulation, associated with a protocol ofinhibitory rTMS as defined by Naeser et al. [38,39].Specifically, it aims to improve on previous rTMS pro-tocols by incorporating a sham condition to investigatethe placebo effects of rTMS and will utilise neuronavi-gational techniques to ensure the accurate identificationof cortical targets. This study will provide a compar-ison of the short term behavioural language effects ofrTMS between stimulation and sham stimulation (con-trol) conditions based on larger sample sizes than thosepreviously published, and test current hypotheses re-garding the ability of low frequency rTMS to inhibitoveractivation in RH language homologues and inducebehavioural language improvements in picture namingfunction.

2. Methods

Twelve (12) right-handed, chronic aphasic patientsreceived rTMS. Handedness was assessed using the Ed-

inburgh Handedness Inventory (EHI) [42]. All patientshad suffered a L middle cerebral artery (MCA) strokebetween 2–10 years previously and had residual lan-guage impairments, including deficits in picture nam-ing. Patient severities ranged from mild to severe. Ta-ble 1 provides detailed biographical information aboutthe patients who participated in the present study. Ap-pendices A-D detail the language profiles of all pa-tients prior to stimulation and 1 week post stimulation.Patients were recruited through two major metropoli-tan hospitals and university research databases in theGreater Brisbane Region, Australia. Ethical clearancewas granted from hospital and university review boards.All patients gave informed consent to participate in thisresearch. A rigorous medical screening procedure (as-sisted by neurologists) was implemented to ensure thatpatients were suitable to receive rTMS.

Exclusion criteria for rTMS were derived fromguidelines published by Wasserman [61]. These in-clude: patients with a personal or family history ofepilepsy or seizures, the presence of: metal anywherein the head, cardiac pacemakers, implanted medica-tion pumps, intracardiac lines, other serious medicalconditions including serious heart disease, any medi-cations which lower neural thresholds (tricyclic anti-depressants, neuroleptic agents etc.). Patients whowere identified as having an increased risk of adverseside effects from receiving rTMS were excluded fromparticipating. A full medical history was compiled forall patients. Patients who had suffered multiple strokeswere excluded due to increased risk of adverse reac-tions to stimulation. Exclusion was on the basis of theneuroradiological report and medical history. Thosepatients who had severe visual or hearing impairmentswere also excluded.

Patients did not receive speech therapy services dur-ing their participation in this research study. Due to thechronic nature of language deficits, none of the patientcohort were receiving speech therapy immediately pri-or to participating in the study. Therefore, no thera-peutic interventions were interrupted to receive rTMS.All patients received comprehensive speech therapy in-tervention up to 4 months post stroke however, all pa-tients in the current cohort had residual language (in-cluding naming) impairments that were not alleviatedby behavioural therapy.

A double blind methodologywas employed wherebypatients were randomly assigned to one of two groupseither receivingreal conditionTMS (n = 6, aged be-tween 54 and 67 years; mean age (SD)= 60.8 (5.98)years, mean time post stroke (SD)= 3.49 (1.27) years)


Tabl

e1

Pat

ient

Sex

Age

Edi

nbur

ghH

ande

d-Y

ears

ofL

esio

nsi

teT

ime

post

stro

keH

emip

ar-

Aph

asia

Stim

ulat

ion

hand

edne

ssne

ssed

ucat

ion

toin

itial

esis

diag

nosi

sgr

oup

inve

ntor

yte

stin

g(y

ears

;(E

HI)

scor

em

onth

s)

rTM

S1

F65

80R

18L

ong

stan

ding

LM

CA

terr

itory

infa

rct

with

exvacu

odi

lata

tion

ofth

ele

ftla

tera

lven

tric

le.

4;5

No

Mild

-mod

erat

eno

n-flu

ent

Rea

l

rTM

S3

M59

50R

12L

MC

Ain

farc

twith

exva

cuo

dilta

tion

ofth

eleftla

tera

lven

tric

lean

den

ceph

alom

acia

inth

ele

ftin

sula

and

left

parie

to-o

ccip

ital

regi

on.

3;3

No

Mod

erat

e-se

vere

non-

fluen

t/glo

bal

Rea

l

rTM

S4

F66

100

R14

LM

CA

infa

rct

with

ence

phal

omac

iaan

dex

vac

uodi

lata

tion

ofth

ele

ftla

tera

lven

tric

le.

The

sylv

ian

fissu

reis

enla

rged

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heence

phal

o-m

alac

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tend

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perio

rlyan

dm

edia

llyto

invo

lve

the

med

ial

aspe

ctof

the

left

mot

orst

rip.

5;8

Yes

Mod

erat

eno

n-flu

ent

Rea

l

rTM

S9

M67

100

R16

Sig

nific

ant

LM

CA

terr

itory

infa

rct

with

enc

epha

lom

alac

iaan

dex

-va

cuo

dila

tatio

nof

the

left

late

ral

vent

ricle

.T

heB

asal

nucl

eiar

ela

rgel

ysp

ared

.

2;6

No

Sev

ere

non-

fluen

t/glo

bal

Rea

l

rTM

S10

M54

60R

10M

atur

eL

MC

Ain

farc

text

endi

ngla

tera

llyfr

omth

epo

ster

ior

horn

ofth

ele

ftla

tera

lven

tric

lew

ithen

ceph

alom

alac

iaan

dex

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cuo

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ta-

tion

ofth

eve

ntric

le.

Sm

alll

acun

arty

pein

farc

tsbi

late

rally

.N

orm

alpo

ster

ior

foss

ast

ruct

ures

.

3;5

Yes

Sev

ere

non-

fluen

t/glo

bal

Rea

l

rTM

S13

M54

100

R10

LM

CA

terr

itory

infa

rct

with

asi

gnifi

cant

are

aof

ence

phal

omac

iain

the

left

fron

tall

obe

and

asso

ciat

edex

vacu

odi

lata

tion

of

the

left

vent

ricle

and

left

cere

bral

pedu

ncle

redu

ctio

n.

2;5

Yes

Mild

-mod

erat

eno

n-flu

ent

Rea

l

rTM

S2

M72

100

R14

Lin

ferio

rdiv

isio

nM

CA

infa

rctw

ithac

com

panyi

ng

tem

pero

-par

ieta

len

ceph

alom

acia

.4;

0N

oM

ild-m

oder

ate

non-

fluen

tS

ham

rTM

S5

F51

100

R13

LC

VA,

tota

lan

terio

rci

rcul

atio

nin

farc

t,exte

nsiv

ele

fthe

mis

pher

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CA

/str

oke

with

gros

sen

ceph

alom

alac

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The

reis

ahy

perin

tens

eco

llect

ion

over

the

left

hem

isph

ere

whi

chis

assu

med

tore

pres

ent

asu

bacu

tesu

bdur

alha

emat

oma.

The

right

hem

isph

ere

appe

ars

nor-

mal

.T

here

isat

roph

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the

left

cere

bral

pedu

ncle

and

left

sid

eof

the

pons

,in

keep

ing

with

Wal

leria

nde

gene

ratio

n.

3;4

Yes

Mod

erat

eno

n-flu

ent

Sha

m

rTM

S8

M77

100

R13

LM

CA

terr

itory

infa

rctw

ithsu

bacu

terig

htocci

pita

l(po

ster

iorc

ere-

bral

arte

ry)

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itory

infa

rct.

Aco

uple

ofsm

allg

lobu

larfoc

iare

seen

inth

ede

epw

hite

mat

ter

ofbo

thce

rebr

alhe

mis

pher

esco

nsis

tent

with

chro

nic

isch

emia

rela

ted

tom

icro

vasc

ular

dise

ase.

2;2

No

Mild

-Mod

erat

eno

n-flu

ent

Sha

m

rTM

S11

M66

80R

12L

MC

Ate

rrito

ryin

frac

tw

ithen

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alom

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cia

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onta

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oder

ate

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vacu

odi

lata

tion

ofth

ele

ftla

tera

lve

ntric

le.

The

right

hem

isph

ere

and

the

post

erio

rfo

ssa

str

uctu

res

appe

arre

lativ

ely

norm

al(W

alle

rian

dege

nera

tion

note

dle

ftup

per

brai

nst

em).

2;3

Yes

Mod

erat

eno

n-flu

ent

Sha

m

rTM

S14

M71

100

R10

Sig

nific

antL

MC

Ate

rrito

ryin

farc

twith

mode

rate

exva

cuo

dila

tatio

nof

the

left

vent

ricle

and

tem

pero

-par

ieta

lenc

epha

lom

acia

.2;

9Y

esM

oder

ate-

seve

reno

n-flu

ent

Sha

m

0rT

MS

15M

6310

0R

15L

arge

LM

CA

terr

itory

infa

rct

with

sign

ificant

tissu

elo

ssw

ithex

vacu

odi

lata

tion

ofth

ele

ftve

ntric

le.

The

right

hem

isph

ere

and

post

erio

rfo

ssa

stru

ctur

esap

pear

norm

al.

6;3

Yes

Sev

ere

non-

fluen

t/glo

bal

Sha

m


Fig. 1. Structural 3T MRI scans for two patients of the twelvepatient cohort, demonstrating the range of lesion severities A) PatientrTMS 15;left extensive middle cerebral (MCA) territory infarct with ex vacuo dilatation of the left ventricle. Patient has a severe non-fluent/ global aphasia.B) PatientrTMS 13; L MCA territory infarct with a significant area of encephalomacia in the left frontal lobe and associated ex vacuo dilatationof the left ventricle and left cerebral peduncle reduction.Patient has a mild- moderate non-fluent aphasia.

or a placeboTMS (using a SHAM coil) (n =6, agedbetween 51 and 77 years; mean age (SD)= 66.6 (9.09)years, mean time post stroke (SD)= 3.46 (1.53) years).All recorded language measures were scored by an ex-ternal researcher who was not aware of the conditionor testing occasion of each patient, to reduce observerbias. The sham stimulation group in this study served asa placebo condition to measure the effects of real con-dition stimulation. The sham coil employed (Magstim,Carmarthenshire, Wales, UK) was identical in shapeand size to the real stimulation coil and produced nomagnetic field. Thus it is hypothesised that the place-bo TMS condition does not induce neuro-physiologicalchanges to influence behavioural language function.Each patient only received ONE type of stimulation.Sham stimulation was utilised to verify the effects ofthe real stimulation protocol as a control condition.

Prior to stimulation, all subjects were required to un-dertake a 3-Tesla structural magnetic resonance imag-ing (MRI) scan, to aid target localisation and provideadditional information on the size, extent and compo-sition of the lesion. Figure 1 shows examples of MRIsfrom two of the stimulated patients. Acquisition pa-rameters were as follows: TR= 19, TE= 4.92, ma-

trix size = 256× 256, number of slices= 128, slicethickness= 2 mm. The study neuroradiologist pro-vided a radiological report to specify affected neuralregions. A computerised MRI visualisation and anal-ysis system [51] was then employed to visually marktarget areas (R BA45 and the motor hand knob) witha crosshair (i.e., +). This software program permits aTalairach transformation of each subject’s brain, gen-erating voxel and Talairach co-ordinates in referenceto general neuroanatomical landmarks and Brodmannareas within designated “hot spots,” which may then bemarked for future reference. In this research study, suchmarkings assist in defining the orientation of the TMScoil on the skull using the neuronavigational system.

The language related cortical area in the contralater-al (right) hemisphere (i.e., homologue R BA) was es-tablished as the stimulation target. The foot of the 3rdfrontal convolution represents the classical definitionof Broca’s area [5]. Within the L IFG, this region in-corporates the structures pars triangularis and pars op-ercularis, also known as Brodmann areas 45 (BA 45)and 44 (BA 44), respectively. The cytoarchitecture ofBroca’s area was informed by papers from Amunts etal. [1,2]. Previous studies have revealed TMS of BA


Fig. 2. A 3D brain surface reconstruction from 3T StructuralMRI scan of patientrTMS 5. The target for stimulation has been marked in theunaffected, healthy right hemisphere. The target is definedas the apical portion of R Brodmann area 45, delimited ventrally by the horizontalramus of the Sylvian fissure and laterally by the vertical ramus of Sylivan fissure.

45 (pars triangularis) and not BA 44 (pars opercularis)significantly increases the accuracy and decreases re-action time of picture naming in aphasic patients [37,38]. The apical portion of right BA 45 was thereforeselected as the specific stimulation point for the presentstudy, delimited ventrally by the horizontal ramus ofthe Sylvian fissure [11], and laterally by the verticalramus of Sylivan fissure. Figure 2 shows the stimula-tion target marked on 3D reconstruction of the patient’sbrain.

The resting motor threshold (rMT) for stimulationwas determined using one of the hand muscles. TheTMS coil (bi-phasic stimulation) was placed on themotor “hot spot” for the first dorsal interosseous (FDI)muscle in the left hand (i.e. knob within pre-centralgyrus) in the contralateral hemisphere as determinedby MRI marking and Stealthstation software (Medtron-ic, USA). Motor evoked potentials (MEPs) were thenelicited via TMS and surface EMG recorded fromFDI via Ag/AgCl electrodes (1 cm in diameter), posi-tioned over the belly of the muscle and the metacarpo-phalangeal joint of the index finger, respectively. Theground electrode was attached over a bony prominenceon a distal region of the radius. The coil was posi-tioned tangentially to the skull above the left M1 withthe handle pointing backward and laterally at an angleof about 45◦ to the sagittal plane inducing an electricalcurrent in the brain tissue with a posterior–lateral toanterior–medial direction roughly perpendicular to thecentral sulcus. This current orientation is known to beoptimal for evoking a motor response in the contralat-eral hand [34]. The location and exact orientation atwhich stimuli was applied at suprathreshold intensityconsistently yielded maximal MEPs in the contralat-eral FDI muscle. rMT was defined as the minimumstimulus intensity eliciting 5 responses of about 50µV

out of 10 consecutive trials (50% successful MEPS) inthe relaxed contralateral FDI [48]. Trials commencedwith a suprathreshold value and subsequent TMS in-tensities were decreased in steps of 2% until no reliableMEPs were recorded. For the present research studyon lesioned stroke patients, stimulation was applied at90% of the rMT attained [37]. Patient stimulation in-tensities in the present study ranged between 35–55%of maximum stimulator output.

Once the target was marked on the image, the MRIswere imported into theStealthstation Treon(Medtron-ic, USA), a frameless stereotactic image guidance sys-tem designed for neurosurgical application but adaptedfor our purposes via several custom software modifica-tions. Within the Stealthstation, the “hot spots” wereconverted to target plans. In brief, reflective markersattached to the subject’s head were detected via an in-frared tracking camera, subsequently logging the po-sition of the head in space. The software then co-registered the position of the subject’s head with theMRI data set and target plans were established. Eachplan consists of a perpendicular line from the “hot spot”to the external skull surface. It is reported that the max-imum electric field produced by a figure of eight coilcan be measured at the point of the cortex lying perpen-dicular to the midline of the centre of the coil [21]. A3D model of the head was then constructed with rele-vant target plans depicted. Reflective markers were al-so attached to the TMS coil, subsequently allowing thecoil to be positioned on the head and tracked, relevantto these predetermined target plans.

Low frequency, 1 Hz rTMS was applied to patientsfor 20 minutes per day (1200 pulses), for 2 weeks (10sessions) as defined by Naeser et al. [38] and used instudies to remediate depression [28]. The stimulationprotocol aimed to down regulate RH overactivation in


homologous language sites. The TMS target was theanterior portion of the homologue of pars triangularis(R Brodmann area 45), in the Broca’s homologue ascited in previous rTMS studies [32,37,39]. A figure ofeight, 70 mm diameter rTMS coil and identical shamcoil were utilised (Magstim, Carmarthenshire, Wales,UK). The coil was placed over the marked region ofinterest on the MRI scan (on the gyrus immediatelyrostral to the anterior (vertical) ascending ramus of thesylvian fissure). The coil was held by hand and positionrelative to the head was maintained using realtime feed-back from the stereotatic guidance system, the StealthStation Treon. As the Stealth Station gives continuousfeedback of coil position relative to head position, therewas no need to fixate the participant’s head. Accordingto Naeser et al. [38], the approximate size of the corticalarea stimulated utilising a 70 mm coil is 1 cm× 1 cm.

Standardised language assessments were utilised tomeasure changes in behavioural language function as-sociated with rTMS treatment. 1 week prior to stim-ulation (baseline), and 1 week post stimulation pa-tients were tested using the standard form of the BostonNaming Test (BNT) [24] and selected subtests of theBoston Diagnostic Aphasia Examination (BDAE) [17]were administered according to a protocol outlined byNaeser et al. [38]. Receptive and expressive languageabilities were tested. The subtests administered were:picture description (Cookie Theft Picture) (analysis ofcomplexity index and longest number of words perphrase length), word comprehension,word comprehen-sion by category, commands, complex ideational ma-terials, repetition (single words, non-words and sen-tences), responsive naming, naming screening of spe-cial categories, naming colours, naming actions, nam-ing animals, naming tools and implements. The overallscore on the above BDAE was also collated. Thosesubtests containing culturally sensitive materials wereomitted from the testing battery. This was a com-prehensive language battery that provided a detailedoverview of each patient’s language profile. Appen-dices A-D outline individual patient assessment results.

Additionally, a set of 144 black and white line draw-ings of objects, taken from a previously published com-mon object picture inventory [52] were used to measurechanges in lexical-semantic function at baseline and 1week post stimulation. Pictures were administered inlists of 48 words, balanced for average response la-tency, syllable length, frequency and visual complexi-ty and percentage agreement from normal control sin-gle pulse TMS studies previously administered in ourlaboratory. Norms pertaining to these variables were

obtained from the online International Picture Nam-ing Database. The entire picture set was randomisedeach time it was presented and patients were given restbreaks during administration. Pictures were present-ed on a 20” LCD computer monitor where the patientsat approximately 30 cm from the screen. Each pic-ture was preceded by a preparatory dot on screen for200 msec. The picture appeared for 5 sec, with an ad-ditional 5 sec recording for responses and a 1sec inter-stimulus interval. Verbal responses were recorded via amicrophone positioned approximately 10 cm from thesubject’s mouth. Responses was digitised via a custommadeSound Detectprogram (Matlab version 6.5) at a16 bit resolution and a sampling rate of 22kHz, whichproduced acoustic waveforms on a computer screen foranalysis. As per Topper’s [57] methodology, an ampli-tude filter was used to remove all acoustic signals withan amplitude of less than 7.5% of the maximum soundlevel. Acoustic onset time/naming latency (i.e., time inmsec from presentation of picture to acoustic onset ofaccurate response) was calculated.

Using the digitised naming responses, the mean re-action time and accuracy of naming (i.e., no. of pic-tures named correctly) for the picture set at baselineand 1 week post stimulation was calculated. Accordingto Naeser et al. [38] the learning and priming effects onresponse times for the Snodgrass and Vanderwart [52]pictures are negligible, thus, the repeated exposure ofpatients to the same picture set was justified.

3. Results

A comparison of performance between the stimula-tion and sham groups across baseline and 1 week postrTMS is shown in Fig. 3. A series of two-way re-peated measures analysis of variances (ANOVA) wereconducted for all BDAE subsets, BNT, picture namingaccuracy and latency, by time of testing (baseline, priorto TMS vs. 1 week post TMS) and group (real stimu-lation vs. sham). Table 2 outlines mean values, stan-dard deviations, significant main effects and effect sizedemonstrated on the ANOVA statistical analyses. Sig-nificant differences in the interactions between groupand time were found on the following subtests: BDAEnaming actions (p < 0.05), BDAE naming tools andinstruments (p < 0.05), BDAE repetition of sentences(p < 0.05), Cookie Theft picture description complex-ity index (p < 0.05), Cookie Theft picture descrip-tion longest words per phrase (p < 0.01), Commands(p < 0.05), the overall score calculated from the BDAE


Table 2Overview of significant results baseline to 1 week post stimulation

Language subtest Baseline Pre- 1 week ANOVA ANOVA Group Effect sizerTMS post rTMS × Time Cohen’s

Stim Sham Stim Sham f df (P) (d)

BDAE naming actions Mean 5.50 6.66 7.50 6.17 5.95 10 0.035 0.393SD 4.72 5.27 5.43 4.87

BDAE Naming tools and Mean 5.83 6.67 7.66 6.67 9.31 10 0.012 0.469instruments SD 3.54 4.17 4.23 4.27BDAE repetition of sentences Mean 2.83 4.0 4.67 4.0 9.31 10 0.012 0.502

SD 3.19 3.58 4.08 3.41Picture description complexity Mean 1.21 1.12 1.55 1.12 5.13 10 0.043 0.777index SD 0.39 0.30 0.58 0.26Picture description longest Mean 4.17 4.00 5.00 3.83 18.00 10 0.002 0.392word per phrase SD 2.23 2.61 2.00 2.40Commands Mean 7.67 5.83 9.5 5.83 7.857 10 0.019 0.378

SD 5.16 1.72 4.50 1.72BDAE overall score Mean 147.83 156 166.33 156.17 23.00 10 0.001 0.319

SD 58.33 45.93 57.65 44.88Boston Naming Test (BNT) Mean 29.17 28.33 36.00 28.67 5.107 10 0.047 0.283

SD 23.27 22.20 25.12 22.54Snodgrass and Vanderwart Mean 1770.76 1838.89 1469.96 1914.45 8.14 10 0.005 0.543picture naming latency (msec) SD 558.83 165.72 549.96 154.79Snodgrass and Vanderwart Mean 88.33 79.50 94.50 80.00 5.93410 0.035 0.107picture naming accuracy SD 56.97 61.73 58.36 61.53

subtests administered (p < 0.01), Snodgrass and Van-derwart [52] picture naming latency (p < 0.01) andSnodgrass and Vanderwart [52] picture naming accu-racy (p < 0.05). No significant results within the shamgroup across time were found.

Post Hoc analyses were conducted between the twogroups (independent samples) at baseline and 1 weekpost rTMS and within sample groups across baseline to1 week post rTMS (repeated measures t-test). All anal-yses at baseline demonstrated no significant differencesbetween the real stimulation and sham conditions. At 1week post stimulation, significant differences betweenthe stimulation and sham groups were found for somepicture naming and repetition subtests. Within the re-al stimulation group significant differences across time(baseline to 1 week post stimulation) were found for:BDAE naming of tools and instruments (t = −3.379,p = 0.020), BDAE overall score (t = −4.959,p =

0.004), BDAE repetition of sentences (t = −3.379,p = 0.020), Commands (t = −2.803,p = 0.038), theSnodgrass and Vanderwart [52] picture naming laten-cy (t = 4.073,p = 0.015) and Snodgrass and Van-derwart [52] picture naming accuracy (t = 2.750,p =

0.04).

4. Discussion

The present study incorporated a sample size oftwelve patients, including a sham (control) group to in-

vestigate the behavioural language effects of rTMS onlanguage function 1 week post stimulation in a popula-tion of chronic non-fluent aphasic patients. To date, thisis the largest chronic aphasic sample population whichrTMS has been applied to, with a placebo stimulationgroup as a comparative control measure. Comparisonbetween the real stimulation and sham conditions in-dicated significant main effects between the stimula-tion and sham group one week post-stimulation, withthe former group, but not the sham group, demonstrat-ing significantly improved performance on the picturenaming and repetition subtests of the BDAE [17] andnaming accuracy and latency on a standardised pictureinventory [52]. Results from the present study indicatethat low frequency, 1 Hz rTMS to R BA 45 (pars trian-gularis) has a positive effect on behavioural languagefunction 1 week post stimulation. The improvementsreported 1 week post stimulation are noteworthy, withsignificant differences between the means of the realstimulation and sham groups at 1 week post stimulationfor many subtests, directly relating to picture namingfunction. These results are consistent with those pre-viously reported by Naeser et al. [38,39] and Martinet al. [32], which exemplify improvements in picturenaming function associated with PFF effects inducedby low frequency rTMS.

It is hypothesised that the effect of rTMS on the LIFG lesioned brain is due to down-regulation of overactivity in R Broca’s homologue in chronic aphasic pa-tients, and potential up regulation of LH perilesional


Fig. 3. Graphs showing means at baseline and 1 week post stimulation for real and sham stimulation groups across subtestsadministered fromBoston Diagnostic Aphasia Examination [17] and Snodgrass and Vanderwart [52] picture naming inventory.

resources. The present study proposes that the sup-pression of R pars triangularis using rTMS will mod-ulate prefrontal and temporo-parietal neural connec-tions responsible for naming processes, to facilitate be-havioural improvements in naming function. Semanticbased experimental paradigms have previously elicitedactivations in L Broca’s area, (including pars opercu-laris (BA 44) and pars triangularis (BA 45)) and theL posterior temporal lobe structures in normal controlsubjects [15,44] and in aphasic patients [44]. rTMScan facilitate decreased RH activations in the R SMAand increased LH in the L SMA compared to baselinemeasures [32]. This study demonstrates the potentialneuromodulatory advantage of rTMS over time.

The theory of compensatorybrain responses in apha-sia recovery provides a beneficial framework on whichto base further experimental rTMS research. Howev-er, some pertinent issues within the present stimulationand sham patient samples must be addressed. Patientsin both samples were in the stable, chronic phase ofaphasia, and were well past the spontaneous recoveryperiod of 3–6 months post stroke [10]. As a result ofstrict randomisation procedures, differences were not-ed into the mean age of each group (the sham meanage was higher than the stimulation group mean). Ad-

ditionally, the variability of ages within the sham sam-ple was much greater than that in the stimulation sam-ple which may impact the capacity for neural and ul-timately behavioural language change (e.g., as a resultof age related atrophic changes). Heterogeneity, par-ticularly in small sample populations is also a majorconfounding factor to results obtained in all rTMS re-search, including the present study. A widely diverserange of: lesions sites, lesion size, aging effects onbrain tissue, time post stroke, severity of language im-pairment and neurobiological factors such as tissue dis-tribution affecting stimulation parameters [58] cautionthe interpretation of results. Many of these differencesbetween groups and within groups in the present studycan be attributed to randomisation of the sample pop-ulation. Particularly noteworthy are individual patientresponses to rTMS, which in this study and have beenreported previously to be linked to the severity of lan-guage impairment. Those patients with severe non-fluent or global aphasia have shown the least capacityfor neurological or behavioural change in response torTMS [32]. This may be due to an inability to rerecruitresources within the LH or adequately integrate RHsites in bilateral language networks. Despite the limi-tations discussed the capacity of behavioural language


change over time (as a result of neuromodulation) canbe accurately measured through repeated behaviouralassessments in which patients act as their own control.

The sham group in the present study showed no sig-nificant improvements across baseline to 1 week poststimulation for any subtests on the BDAE or picturenaming inventories. Some minor improvements werenoted in individual patient’s data e.g. BNT. Further lon-gitudinal research on this sham population will deter-mine the effects of sham stimulation over time. Insome cognitive and motor cortex TMS studies, im-provements in sham group performance are reported.These are postulated to be a result of “activation” ofneurons rather than stimulation, whereby, sham formsof TMS may induce neuronal activity to modulate cor-tical activity through somatosensory input e.g. audito-ry click [60]. This may explain any minor individualchanges in language function in the present study how-ever, the results of the present sham group are not sig-nificant when compared to the real stimulation groupon a number of behavioural language outcome mea-sures. Reproducibility of these sham results on dif-ferent aphasic populations is paramount to verify thatsham conditions may be employed as a reliable con-trol measure of TMS neuromodulation, particularly inmodulation of cognitive measures such as language.

Clearly, further research to investigate the capaci-ty of rTMS to modulate neural language networks tofacilitate long-term improvements in behavioural lan-guage function post-stroke is warranted. Future re-search however, needs to address a number of inherentinadequacies in many of the studies reported to date.Firstly, by far the majority of previous studies involveonly very small numbers. Indeed, the present study isthe largest study of rTMS in relation to language func-tion completed to date. Further, many studies have notutilised appropriate and accurate techniques to identi-fy cortical targets for rTMS stimulation. Neuronavi-gational approaches to TMS coil placement have beenrecognised as essential to localise cortical targets withbenchmark precision [22]. Finally few studies haveexamined the longer-term effects of rTMS on languagefunction. The current research represents an unprece-dented attempt to study the effects of rTMS on word re-trieval processes in a larger cohort of aphasic individu-als using a state-of-the-art neuronavigational guidancesystem (Stealthstation) for stimulus target localisation.Future studies applying rTMS to patients with aphasiashould incorporate larger sample sizes, further longi-tudinal data collection and test variations of stimula-tion protocols (intensity and length of stimulation) andbrain sites to establish the most efficacious methods ofneuromodulation for the greatest number of patients.

5. Conclusions

The present research provides evidence to show thatrTMS can be utilised to facilitate improved behaviourallanguage function, in particular picture naming perfor-mance, in patients with non-fluent aphasia through thesuppression of RH language homologues. As indicat-ed by the results, the short term effects of real con-dition rTMS are significant across baseline to 1 weekpost stimulation, when compared to a sham stimula-tion group. The incorporation of a sham control groupverified the positive behavioural effects of real condi-tion stimulation. The effects of sham stimulation onbehavioural language function are postulated to be low,however, the results may be specific to this sampleaphasic population and impacted by the small samplesize. Further longitudinal research on both the realstimulation and sham groups is necessary to charac-terise the long term effects of TMS on behavioural lan-guage measures and clarify its role in neurorehabilita-tion of post stroke aphasia. Future research incorpo-rating electrophysiological measures may be advanta-geous to identify subtle changes in language process-ing in chronic non-fluent aphasia associated with rTMSapplications.

Acknowledgement

We acknowledge the assistance of the Communica-tion Disability Centre’s Aphasia Registry, in recruitingparticipants for this project.

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Appendix D. Patient results of picture naming accuracy and la-tency measured on 144 pictures selected from the Snodgrass andVanderwart, (1980) picture naming inventory

Snodgrass and Vanderwart Picture Naming Inventory

Patient Naming accuracy Naming latencyTotal= 144 (msec)

STIM Baseline Post TMS Baseline Post TMS

rTMS 1 118 132 1823.76 1256.14rTMS 3 123 134 1233.02 1099.76rTMS 4 124 124 1568.64 1344.31rTMS 9 25 32 2695.38 2441.31rTMS 10 6 8 2765.90 2513.54rTMS 13 134 137 1522.87 1209.68

SHAM Baseline Post TMS Baseline Post TMS

rTMS 2 86 88 1636.46 1629.70rTMS 5 138 136 1491.20 1601.53rTMS 8 112 112 1420.39 1480.59rTMS 11 134 136 1237.63 1289.36rTMS 14 6 7 2386.94 2298.22rTMS 15 1 1 2880.22 3004.11

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