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http://nnr.sagepub.com/Repair
Neurorehabilitation and Neural
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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Neurorehabilitation and
Neural Repair111
The Author(s) 2014Reprints and permissions:
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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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4 Neurorehabilitation and Neural Repair
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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6 Neurorehabilitation and Neural Repair
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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8 Neurorehabilitation and Neural Repair
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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10 Neurorehabilitation and Neural Repair
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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