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http://nnr.sagepub.com/content/early/2014/02/05/1545968314521009The online version of this article can be found at:

DOI: 10.1177/1545968314521009

published online 6 February 2014Neurorehabil Neural RepairKarim

Eman M. Khedr, Noha Abo El-Fetoh, Anwer M. Ali, Dina H. El-Hammady, Hosam Khalifa, Haisam Atta and AhmeA Randomized, Double-Blind Clinical Trial

al-Hemisphere Repetitive Transcranial Magnetic Stimulation for Rehabilitation of Poststroke Aph

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Original Article

Introduction

Repetitive transcranial magnetic stimulation (rTMS) has

been used in many studies as a novel intervention to treat

disorders associated with stroke, including paralysis or

dysphagia, hemispatial neglect, pain, and aphasia.1-12

Approximately 20% of stroke patients have speech and

language problems, including hesitant, poorly articulated,agrammatic speech with word-finding problems (nonfluent

aphasia).13

The language network includes Brocas and Wernickes

areas in the left hemisphere and homologous areas in the

right side of the brain, the prefrontal and premotor areas in

the frontal regions, and the lower part of the parietal

region.14,15In the subacute phase after stroke (8 weeks), the

bilateral activation was detected by positron emission

tomography in 7 out of 11 patients. In a separate investiga-

tion on aphasic patients 12 days after stroke, increased

functional magnetic resonance imaging (fMRI) activity in

both the inferior frontal gyri and the temporal gyri were

detected.16

An increasing number of studies have demonstrated that

low-frequency rTMS over the unaffected hemisphere can

009 NNRXXX10.1177/1545968314521009Neurorehabilitation and Neural RepairKhedr eta l

1Department of Neuropsychiatry, Assiut University Hospital, Assiut,

Egypt2Department of Rheumatology and Rehabilitation, Assiut University

Hospital, Assiut, Egypt3Department of Radiology, Assiut University Hospital, Assiut, Egypt4Department of Prevention and Health Psychology, Riedlingen

University, Riedlingen, Germany5Department of Psychiatry and Psychotherapy, University Clinic

Tbingen, Tbingen, Germany

Corresponding Author:

Eman M. Khedr, Department of Neurology, Faculty of Medicine, Assiut

University Hospital, Assiut 15117, Egypt.

Email: [email protected]

Dual-Hemisphere Repetitive TranscranialMagnetic Stimulation for Rehabilitation ofPoststroke Aphasia: A Randomized, Double-Blind Clinical Trial

Eman M. Khedr, MD1, Noha Abo El-Fetoh, MD1, Anwer M. Ali, MD1,

Dina H. El-Hammady, MD2, Hosam Khalifa, MD1, Haisam Atta, MD3,

and Ahmed A. Karim, PhD4,5

Abstract

Background. Recent neuroimaging studies on poststroke aphasia revealed maladaptive cortical changes in both hemispheres,

yet their functional contribution in language recovery remains elusive. The aim of this study was to evaluate the long-term

efficacy of dual-hemisphere repetitive transcranial magnetic stimulation (rTMS) on poststroke aphasia. Methods. Thirtypatients with subacute poststroke nonfluent aphasia were randomly allocated to receive real or sham rTMS. Each patient

received 1000 rTMS pulses (1 Hz at 110% of resting motor threshold [rMT] over the right unaffected Brocas area and 1000

pulses (20 Hz at 80% rMT) over the left affected Brocas area for 10 consecutive days followed by speech/language training.

The language section of the Hemispheric Stroke Scale (HSS), the Stroke Aphasic Depression QuestionnaireHospitalVersion (SADQ-H), and the National Institutes of Health Stroke Scale (NIHSS) were measured before, immediately after

the 10 sessions, and 1 and 2 months after the last session. Results. At baseline, there were no significant differences

between groups in demographic and clinical rating scales. However, there was a significantly greater improvement in the

HSS language score as well as in the SADQ-H after real rTMS compared with sham rTMS, which remained significant2 months after the end of the treatment sessions. Conclusion. This is the first clinical study of dual-hemisphere rTMS in

poststroke aphasia. Combining dual-hemisphere rTMS with language training might be a feasible treatment for nonfluent

aphasia; further multicenter studies are needed to confirm this result.

Keywords

aphasia, stroke, transcranial magnetic stimulation (TMS), hemispheric role, Brocas area, neurorehabilitation, corticalplasticity

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2 Neurorehabilitation and Neural Repair

be useful for enhancing recovery in aphasic patients.6-11

Excitatory rTMS over the damaged hemisphere induces

improvements in poststroke aphasia.12,17

We hypothesized that simultaneous application of low-

frequency rTMS over the nondominant speech area and

high-frequency (facilitatory) rTMS over the dominant

speech area would have a beneficial effect on improvingspeech performance, particularly if we applied it early after

stroke in combination with language training at a time

when neural plasticity might be maximal. The aim of this

study was therefore to evaluate the therapeutic role of dual-

hemisphere rTMS in subacute ischemic stroke aphasia, and

to study the changes of cortical excitability after treatment

sessions.

Methods

This trial is reported following 2010 CONSORT guidelines.

A participants flow diagram is shown in Figure 1.

PatientsForty-seven patients with poststroke nonfluent aphasia

were recruited consecutively during the period from May

2010 to December 2012. All patients were admitted to the

Stroke Unit, Department of Neurology, Assiut University

Hospital, Assiut, Egypt. Each patient fulfilled the eligibility

criteria as follows: subacute hemiplegia with nonfluent

aphasia, single thromboembolic nonhemorrhagic infarction

Figure 1. CONSORT 2010 flow diagram.



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Khedr et al 3

documented by computed tomography in the distribution of

middle cerebral artery. Exclusion criteria included head

injury or neurological disease other than stroke, unstable

cardiac dysrhythmia, fever, infection, hyperglycemia, and

prior administration of tranquilizer plus contraindications

for rTMS according to the safety guidelines.18,19The proto-

col was approved by the Assiut Medical School Ethical

Review Board and all participants gave written consent.

Seventeen patients were excluded because 15 did not

meet the inclusion criteria and 2 refused to participate. All

patients were right-handed according to the Edinburgh

Handedness Inventory.20

Fourteen men and 16 women with

subacute poststroke aphasia were admitted to the trial. The

mean stroke interval was 5 3.2 weeks, ranging from 1 to

12 weeks at study onset; aphasia was recognized in neuro-

psychological assessments with language deficits ranging

from 0 to 5 points according to the the Aphasia Severity

Rating Scale (ASRS).21Zero represents no usable speech

or auditory comprehension and 5 represents minimal dis-

cernible speech/ language handicaps. The mean age was57.3 12.5 years. Twenty patients received real rTMS (one

of them did not complete the follow-up) and 10 patients

received sham rTMS.

Clinical Assessment

A detailed case history and neurological examination was

performed for each patient. Hand strength and the language

assessment section of Hemispheric Stroke Scale (HSS)22

were evaluated for each patient. Additional scales used

were the Stroke Aphasic Depression Questionnaire

Hospital Version (SADQ-H; asking about presence of

depressive symptoms within the last week of stroke to be

present all the days or frequent from 4 to 6 days, or infre-

quent from 1 to 4 days, or not at all)23 and the National

Institutes of Health Stroke Scale (NIHSS)24 to assess the

functional disability of each patient.

Cortical Excitability

Cortical excitability (resting motor threshold [rMT] and

active motor threshold [aMT]) was measured with a mono-

phasic magnetic stimulator (Magstim model 200; Magstim,

Whitland, UK) connected to a 90-mm outer diameter fig-

ure-of-8 coil, which had a maximal output of 2.2 tesla. Welocated the optimal scalp location of each hemisphere from

which TMS evoked motor-evoked potentials of greatest

amplitude by moving the figure-of-8 coil systematically in

1-cm steps to determine the site of maximum peak-to-peak

motor-evoked potentials in the first dorsal interosseous.

The coil was positioned tangentially to the scalp and ori-

ented so that the induced electrical currents would flow

approximately perpendicular to the central sulcus, at a 45

angle from the mid-sagittal line. Single-pulse TMS was

then delivered at the optimal location starting at supra-

threshold intensity and decreasing in steps of 1% of the

stimulator output to determine motor thresholds as defined

by Rothwell et al.25

We used silversilver chloride surface electrodes, using

a muscle belly-tendon montage, with a 3-cm diameter cir-

cular ground electrode placed on the wrist. A Nihon Kohden

Machine model 9400 (Tokyo, Japan) was used to amplify

and record the signals. Electromyography parameters

included a bandpass of 20 to 1000 Hz and a recording time

window of 200 ms. The electromyogram was monitored

online for 20 seconds prior to stimulation to confirm muscle

relaxation.

Randomization (Parallel Design)

Group allocations (real or sham with ratio 2:1) were placed

in serially numbered opaque closed envelopes. Each patientwas placed in the appropriate group after opening the cor-

responding sealed envelope.

Repetitive Transcranial Magnetic Stimulation

Procedure

Real rTMS was applied for 10 sessions (5 days per week).

A session of stimulation consisted of sequential stimulation

of each hemisphere; one continuous 1-Hz train at 110% of

the RMT over the unaffected right Brocas area with 1000

total pulses (500 pulses over pars triangularis followed by

500 pulses over pars opercularis) followed by 10 trains of20-Hz stimulation, each lasting for 5 seconds with an inter-

train interval of 30 seconds given through a figure-of-8 coil

(9-cm diameter loop) positioned over the left Brocas area

of the affected hemisphere (5 trains over pars triangularis

followed by 5 trains over pars opercularis). We chose these

areas based on the results of Gough et al,26

who used TMS

to define an anteroposterior division within the left inferior

frontal cortex for semantic and phonological processing of

words. The intensity of stimulation was set at 80% of the

rMT for the first dorsal interosseous of unaffected hemi-

sphere. Sham rTMS was applied using the same parameters,

but with the coil held so that the edge was in contact with

the head while the remainder was rotated 90 away from thescalp in the sagittal plane to reproduce the noise of the stim-

ulation.27,28Moreover, as the patients had never experienced

rTMS previously, they did not know whether they were

receiving real or sham rTMS. This was supported by self-

report in a poststimulation survey. All patients, whether in

the real or sham group, received single-pulse TMS to deter-

mine their RMT. Those patients in the sham group who had

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received single-pulse TMS were informed that the rTMS

therapy would use a much lower intensity of stimulation

than was required for testing, and that they would experi-

ence no muscle twitching during stimulation. During rTMS,

all patients wore earplugs to protect the ears from the noise

associated with the discharge of the stimulation coil.

We stimulated sequentially 2 parts of Brocas area

homologue: the anterior part (pars triangularisPTr) and

posterior part (pars opercularisPOp). To target the regions

of interest precisely, we positioned the coil on the scalp

according to the coordinates used by Gough et al.26 The

anterior stimulation site was 2.5 cm posterior to the canthus

along the canther-tragus line and 3 cm superior to this line;the posterior stimulation site was 4.5 cm posterior and 6 cm

superior to the canther-tragus line. The stimulation was

applied in the same session with 500 pulses over pars trian-

gularis followed by 500 pulses over pars opercularis in each

hemisphere. The position of the TMS coil over the left

Brocas area and the right homologue of Brocas area was

validated in 3 patients using a 3-dimensional MRI sequence

with vitamin E capsules in place29

(see Figure 2).

All the treatments were administered by only one inves-

tigator who was not involved in aphasia assessment and

therapy. Immediately after the end of each session, each

patient received speech and language training for 30

minutes.

Language Training Program

The rehabilitation program focused on specific training to

stimulate various aspects of the language system. The fol-

lowing subtests of the Boston Diagnostic Aphasia

Examination (BDAE)21were used for training: (a) Visual

Confrontation, Naming, Words Retrieval, Verbal Fluency

(naming); (b) Repetition of Words, Phrases, and Sentences

(repetition); and (c) Word Discrimination, Body-PartIdentification, Command, Comprehension, and Complex

Ideational Material (auditory comprehension).

The general nature of the therapy method was similar for

all patients, but the level of difficulty and types of exercises

differed depending on the patients symptoms. Assessment

and language training was performed by a speech and lan-

guage therapist who was not aware of the patients group

randomization. Therefore, any influence of the individual

features of the therapist or differences in rehabilitation

approach was minimized. The rational for combining rTMS

Figure 2. Experimental design. Real repetitive transcranial magnetic stimulation (rTMS) was applied for 10 sessions (5 days perweek). A session consisted of one continuous 1-Hz rTMS train over the unaffected right Brocas homologue with 1000 pulses (panelA) followed by 10 trains of 20-Hz rTMS over the affected left Brocas area. Each train lasted for 5 seconds with an intertrain intervalof 5 seconds (panel B). The position of the TMS coil was confirmed using a 3-dimensional magnetic resonance imaging sequence withvitamin E capsules in place. Immediately after the end of the applied stimulation protocol, each subject received speech and languagetraining for 30 minutes (panel C). The control group received language training with sham rTMS as placebo control.



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Khedr et al 5

with a training procedure is based on a previous study of

Karim et al30 showing for the first time that combining

rTMS with operant learning can induce persistent after-

effects not achievable neither with rTMS alone nor with

operant learning alone. Figure 2A-C illustrates the experi-

mental design.

Follow-up and Outcomes

All stroke patients were followed up clinically, after the end

of last session and then at 1 and 2 months after the end of

treatment with language rating scores as primary outcome

and the other rating scales as secondary outcomes. All

patients completed the evaluations except a male patient

from the real group (see Figure 1). The evaluation was per-

formed blindly by a neurologist who was unaware of the

type of rTMS group. We also assessed resting and active

motor thresholds and recruitment 1 hour after the last ses-

sion. No patient developed seizures during the study or on

follow-up.

Statistical Analysis

At the baseline assessment (ie, before rTMS), the mean

values of different scales between both groups were

compared using the MannWhitney test for independent

samples. Means standard error were used to represent

data. The level of significance was set at P< .05. Two-

factor analysis of variance (ANOVA) for repeated mea-

surements analysis of variance with treatment (ie, real

or sham rTMS) and time (before, versus after the end

of last treatment session, 1-month and 2-month follow-

up) as the main factors was used to compare the differen-

tial effects of the rTMS conditions (real rTMS vs sham

rTMS) on changes in language rating scores and other

rating scales. When necessary, a GreeenhouseGeisser

correction was applied to correct for nonsphericity. Post

hoc unpaired ttests were carried out for comparisons at

each time point of assessment. For MT analysis; 2-way

ANOVA and post hoc paired t tests were used to com-

pare the rMT and aMT between groups and time.

Spearmans correlation was calculated between the

changes (pre 2-month point of assessment) in different

rating scores.

Results

At baseline, there was no significant difference between the

groups in age, sex distribution, duration of onset of stroke,

site of infarction, HSS (language section comprehension,

naming, repetition, and fluency), ASRS, SADQ-H, grip

strength, and NIHSS (Table 1).

However, there was a significant improvement in the

ASRS in the real rTMS group compared with the sham

group. The ASRS in the real group increased by a mean of

1.8 1.2 points (range 0-4), while in sham group it only

increased by a mean of 0.9 0.3 points (range 0-1). This

was confirmed in a repeated-measures ANOVA that showed

a significant Time (pre, post session, 1-month and 2-month

postsession) Group (real vs sham) interaction (F= 4.5,

df= 1.85, andP= .018).

There was a significantly greater improvement in the

HSS language score in the real rTMS group compared with

the sham group both immediately after the end of treatment

as well as at the 1- and 2-month follow up measurements

(Figure 3A). This effect was confirmed in a repeated-mea-

sures ANOVA that showed a significant Time (pre, post

session, 1- and 2-month post-session) Group (real vs

sham) interaction (F = 7.1, df = 1.6, 42.7 and P = .004).

Post hoc t tests revealed that in the real rTMS group the

obtained scores were significantly lower than in the sham

group concerning the three post-treatment assessment time

points (P= .006,P= .003, andP= .01, respectively). This

finding was supported by a significantly greater reductionof the HSS language score (mean change [pre 2-month

point assessment] = 8 vs 3 points in the TMS vs sham

group, respectively). However, 5 cases in the real rTMS

group showed no changes in HSS, all of them had percep-

tive and nonfluent aphasia (severity grade 0), 3 of them had

extensive infarction (cortical and subcortical infarction)

and 1 had cortical infarction (operculum) with NIHSS

ranging from 7 to 13 at baseline with minimal changes in

their score (0-3 points).

The scores on the SADQ-H behaved similarly, with a

significant Time Group interaction (F= 4.9, df= 1.45,

andP= .02) and significant differences in scores at post-

treatment session and 1-month but not at 2 months after

the treatment session (P = .006, P = .04, and P = .05,

respectively, Figure 3B). These results were supported by

a significant reduction in the points of the SADQ-H after

real rTMS compared with sham stimulation (mean change

= 25 vs 15 points). There was also a significant Time

Group interaction for the overall NIHSS (F= 3.8, df= 1.8,

andP= .03, respectively); however, there were no differ-

ences in NIHSS posttreatment and the significant interac-

tion was driven mostly by baseline differences in scores

(Figure 3C). In contrast to the effects on language func-

tion, there was no significant Time Group interaction

(F = 1.37, df = 0.9, and P = .3) for hand grip strength,indicating a similar increase in strength in both groups of

patients (Figure 3D).

Analysis of the subscores of the HSS language scale

showed that there were significantly greater improvements

in the rTMS than in the sham groups in all 4 main items of

comprehension, naming, repetition, and fluency (Time

Group interactions:F= 3.49, df= 1.7,P= .04;F= 4.8, df=

2.16,P= .01;F= 8.6, df= 1.5,P= .002; andF= 4.9, df=

1.3,P= .025, respectively; see Figure 4A-D).



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Cortical Excitability

We assessed 13 patients in the real rTMS group and 7 cases

in the sham group. Three cases in the real group plus 1 casein sham group had no motor-evoked potential from the

affected hemisphere.

There was a significant increase in cortical excitability

of the affected hemisphere when tested immediately after

the last treatment session as demonstrated by reduced the

rMT and the aMT in the TMS group (F= 8.28, df= 1,P=

.015 andF= 10.5,P= .008 for rMT and aMT, respectively)

while no such changes were recorded in the sham group

(F= 1.3,P= .30 andF= 1.5,P= .25, for rMT and aMT,

respectively). A 2-way ANOVA Time (prepost) Group

(TMS vs sham) showed significant differences for mea-

sures of both the rMT and the aMT in the affected hemi-

sphere (F = 9.6, P = .008 and F = 7.2, P = .018,respectively).

In contrast, there was a significant mild inhibition in

the unaffected hemisphere of the TMS group; however,

the ANOVA did not show an interaction, just an effect of

TIME, thus we have to conclude that there was a small

increase in threshold in both groups (Figure 5).

Moreover, there was a significant correlation between

the change in the rMT (prepost session) for all patients

for the affected hemisphere and the change in the language

score (prepost session) with r= 0.51 andP= .04.

Discussion

Direct manipulation of cortical brain activity by rTMS has

the potential to serve as an efficacious complimentary reha-bilitatory treatment for poststroke aphasia.

The main finding in this present study was the signifi-

cantly greater improvement in language recovery (word

comprehension, naming, repetition, and frequency) and in

the aphasia severity rating scale (ASRS) in the group receiv-

ing real rTMS (dual stimulation) compared with the sham

group. This effect occurred immediately after the treatment

sessions and persisted for 2 months. We used a bihemi-

spheric approach in which low-frequency rTMS (1 Hz) was

given over the right Brocas area in an attempt to remove

the inhibitory effect from the nondominant to the dominant

hemisphere, combined with high-frequency stimulation

over left Brocas area, in an attempt to strengthen neuralconnections within an area of metabolic dysfunction. The

parameters that we chose for rTMS were within current

safety guidelines.19Despite the absence of any rTMS side

effects in this series, electroencephalography would be an

important monitor to include in future studies to warn of

possible seizure onset.

Our experimental design differs from previous work in

the following ways. First, we targeted an early-stroke

patients cohort, whereas most of the previous studies were

done on chronic patients7,9,11,31-35

and few were conducted

Table 1. Demographic Data, Clinical Data, and Different Rating Scales of the Investigated Groups.

Real rTMS Group (n = 19) Sham rTMS Group (n = 10) PValue

Age in years (mean SD) 61.0 9.8 57.4 9.6 .321

Gender (n)

Male 8 5 .684

Female 11 5

Duration of stroke in weeks(mean SD)

5.8 4.08 4.0 2.6 .500

Site of ischemic infarction (n)

Cortical 5 4

Subcortical 4 2 .995

Cortical and subcortical 10 4

Type of aphasia (n)

Expressive (nonfluent aphasia) 3 3 .459

Mixed (perceptive andnonfluent aphasia)

16 7

NIHSS 11.9 6.3 9.3 5.1 .367

Hand strength 3.7 2.2 4.6 1.2 .217

SADQ-H 21 54.32 12.5 52.3 14.3 1.000

Total HSS language score 17.3 3.8 18.9 1.1 .499 Comprehension 3.9 1.8 4.7 0.5 .447

Naming 4.6 1.0 5 0 .126

Repetition 4.6 1.0 5 0 .193

Fluency 4.4 1.0 4.2 1 .656

ASRS 0.47 0.51 0.5 0.53 .899

Abbreviations: rTMS, repetitive transcranial magnetic stimulation; SD, standard deviation; NIHSS, National Institutes of Health Stroke Scale; SADQ-H,Stroke Aphasic Depression QuestionnaireHospital Version; HSS, Hemispheric Stroke Scale; ASRS, Aphasia Severity Rating Scale.



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Khedr et al 7

in the subacute stages.8,10

To maximize patient recruitment

and compliance, this study was conducted during their ini-

tial hospital admission within the first few weeks of the

stroke. Although functional recovery is not stable until sev-

eral months after a stroke, early intervention might maxi-

mize the potential benefit. Second, we used the simultaneousbihemispheric approach (stimulating the unaffected then

affected hemisphere) rather than limiting stimulation to one

hemisphere. The rationale for keeping the stimulation order

fixed was to reduce right hemisphere hyperactivity and

transcallosal inhibition exerted on the left Brocas area in

order to prepare it for further facilitation (using high fre-

quency rTMS) to return the balance between both hemi-

spheres. Third, each stimulation session was followed by

speech and language training. The rationale for combining

rTMS with a training procedure is based on a previous study

of Karim et al30

showing for the first time that combining

rTMS with operant learning can induce persistent after-

effects not achievable neither with rTMS alone nor with

operant learning alone.

A number of studies have examined the effect of 1 Hz

rTMS of the contralesional right inferior frontal gyrus.Weiduschat et al7reported a beneficial effect of 2 weeks

rTMS in a heterogeneous series of subacute aphasic patients.

However, this was not replicated by Seniw et al6in their

double-blind, placebo-controlled pilot study of 40 patients

with subacute poststroke aphasia. However, they did report

improvement (minimal word namingand significant in rep-

etition) when tested 15 weeks after the rTMS procedure.

This was consistent with an fMRI study demonstrating

altered patterns at 3 months poststroke that continued up to

46 months poststimulation.33Thiel et al10studied 24 patients

Figure 3. Changes in mean different rating scores of (A) Hemispheric Stroke Scale (HSS) language score, (B) Stroke Aphasic

Depression QuestionnaireHospital Version (SADQ-H 21), (C) National Institutes of Health Stroke Scale (NIHSS), and (D) handgrip strength at the 4 assessment points for the 2 groups of patients with stroke. The first assessment was immediately prior tocommencing repetitive transcranial magnetic stimulation (rTMS) treatment (Pre), the second (Post session) was immediately after theend of the 10th session of rTMS, the third and fourth assessment were immediately after the end of the first and the second months,respectively. Each group separately shows significant improvement. However the mean scores of the patients who received real rTMSare significantly better than sham group over the course of the treatment in HSS language score and SADQ-H 21, while hand gripstrength showed no significant differences (P= .3). Data are expressed as mean standard error.



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with subacute poststroke aphasia in a double-blind random-

ized trial. A 10-day protocol followed by 45 minutes of

speech and language therapy revealed a significantly greater

improvement in the global Aachen Aphasia Test score

observed in the rTMS group. They also found greater acti-

vation of the left hemisphere using O2positron emission

tomography (PET) compared with sham-treated patients.Instead of inhibiting the right hemisphere, 3 rTMS stud-

ies attempted to restore the left hemisphere networks and

perilesional neuronal activity in the injured Brocas area by

applying excitatory rTMS protocols (either intermittent

theta burst stimulation or high-frequency rTMS) on the left

inferior frontal gyrus of aphasic patients.12,17,35

They showed

favorable effects in patients with nonfluent chronic aphasia.

In the first study, intermittent theta burst stimulation trains

were delivered under fMRI-guided navigation to the

Brocas area.12

Clinical improvement (increased fluency)

was associated with concomitant fMRI changes showing a

relative increase in the activity of the lesioned inferior fron-

tal gyrus, which was stimulated.12 Cotelli et al35 applied

excitatory high-frequency rTMS over the left dorsolateral

prefrontal cortex combined with speech therapy and

observed a significant improvement in object naming.Interestingly in the present study; 5 cases in the real

rTMS group did not improve in HSS or NIHSS (4 cases had

extensive infarction and 1 case had operculum infarction).

This means that those patients with complete middle cere-

bral artery occlusion are not suitable to receive dual-hemi-

sphere stimulation and perhaps would benefit more from

high-frequency rTMS to the unaffected hemisphere to

enhance activation of the right homologue of Bocas area

because the left Brocas area is severely damaged.

Figure 4. Changes in mean different rating scores of comprehension (A), naming, (B) repetition (C), and fluency (D) in real andsham groups along the course of the treatment and follow-up. The first assessment was immediately prior to commencing repetitivetranscranial magnetic stimulation (rTMS) treatment (Pre), the second (Post session) was immediately after the end of the fifth sessionof rTMS, the third was immediately after the end of the first and the fourth assessment at the end of the second month. Each groupseparately shows significant improvement. However, the mean scores of the patients who received real rTMS are significantly betterthan those of the sham group (P= .04, P= .01, P= .002, and P= .025, respectively). Data are expressed as mean standard error.



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Khedr et al 9

Several neuroimaging studies with chronic, nonfluent

aphasia patients during language tasks have observed highactivation and possibly overactivation in parts of the right

Brocas area and other regions such as the right perisylvian

language homologues, which may be maladaptive.31,36

When 1-Hz rTMS is applied to right hemisphere cortical

regions of interest, including M1 mouth area, the superior

temporal gyrus and subregions within the Brocas area such

as pars triangularis posterior and pars opercularis, rTMS

may suppress transcallosal inhibition from these areas onto

the damaged hemisphere, and thereby permit reactivation of

some areas in the left hemisphere and facilitate functional

recovery.37

In contrast, high-frequency stimulation has beenshown to cause regeneration of the left damaged part of the

brain assessed by diffusion tensor imaging.38Stimulating

neurons in the perilesional zone with appropriate parame-

ters could increase the neuronal survival rate and facilitate

clinical recovery.37

Thus, both high- and low-frequency

rTMS could induce neuroplasticity.39,40

Moreover, the observed improvement of speech and

depression in this study could be explained on a reciprocal

basis: improvement of speech could improve depression

Figure 5. There was a significant increase in cortical excitability of the affected hemisphere as demonstrated in decreased resting andactive motor thresholds in the TMS group compared with the sham group (F= 8.28, df= 1, P= .015 and F= 10.5, df= 1, P= .008 forthe resting motor threshold [rMT] and the active motor threshold [aMT], respectively). A significant decrease in cortical excitabilityof the unaffected hemisphere (as demonstrated in increased rMT and aMT) were only observed in the real TMS group, while no suchchanges were found in the sham group.



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and vice versa. However, it should also be noted that stimu-

lation of the left Brocas area could spread to stimulate the

left dorsolateral prefrontal cortex either directly or through

functional connectivity. rTMS of dorsolateral prefrontal

cortex has been reported to improve depression in previous

studies.41Thus, rTMS may be able to enhance stroke recov-

ery in general by acting directly on the underlying cortical

regions or through its connections with other structures.

Alternatively, there may have been indirect effects of rTMS

in reducing patients depression as assessed by the SADQ-H,

thereby increasing compliance with the treatment.

Conclusion and Recommendation

Repetitive TMS has some potential to be an adjuvant ther-

apy for subacute poststroke expressive nonfluent aphasia.

The present study was exploratory and followed only a

small number of patients for a short time. Further studies

are needed with a larger sample size to confirm the results.

Cortical excitability changes and neuroimaging studieswould be helpful to study bihemispheric changes in lan-

guage recovery.

Acknowledgments

The authors would like to thank Prof John Rothwell for useful

discussion during the preparation of this article and Prof Andreas

J. Fallgatter for his valuable comments.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect

to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, author-

ship, and/or publication of this article.

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