Clinical Linguistics & Phonetics

ISSN: 0269-9206 (Print) 1464-5076 (Online) Journal homepage: https://www.tandfonline.com/loi/iclp20

Neuronavigated theta burst stimulation for
chronic aphasia: two exploratory case studies
Anastasios Georgiou, Nikos Konstantinou, Ioannis Phinikettos & Maria
Kambanaros
To cite this article: Anastasios Georgiou, Nikos Konstantinou, Ioannis Phinikettos & Maria
Kambanaros (2019): Neuronavigated theta burst stimulation for chronic aphasia: two exploratory
case studies, Clinical Linguistics & Phonetics, DOI: 10.1080/02699206.2018.1562496
To link to this article: https://doi.org/10.1080/02699206.2018.1562496

Published online: 24 Jan 2019.

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CLINICAL LINGUISTICS & PHONETICS
https://doi.org/10.1080/02699206.2018.1562496

Neuronavigated theta burst stimulation for chronic aphasia:
two exploratory case studies
Anastasios Georgiou, Nikos Konstantinou, Ioannis Phinikettos, and Maria Kambanaros
Department of Rehabilitation Sciences, Cyprus University of Technology, Limassol, Cyprus
ABSTRACT

The present study reports the findings of a 10-day neuronavigated
continuous theta burst stimulation (cTBS) over the right pars triangularis for two individuals with chronic aphasia after a single left
hemispheric stroke. Baseline language and quality of life measures
were collected prior to the treatment study, post-treatment and at
3-month follow up. Therapy was tolerated well by both participants
and no side effects were noticed during and after treatment. Results
from one individual showed potential for positive change in performance in comprehension and expressive language both posttreatment and at the follow-up stage. Also, a trend towards improvement post-treatment was noticed in discourse and sentence productivity, and grammatical accuracy. In the follow up stage, grammatical
accuracy showed a trend towards improvement; discourse productivity decreased and; sentence productivity skills showed mixed results.
Results from the other participant showed potential for positive
change in comprehension post-treatment, that was maintained at
the follow-up stage. However, a decline in expressive language posttreatment and at follow-up, stronger post-treatment, was
noticed. Regarding quality of life measurements, participant one
appeared to have improved as his performance increased in the
overall, physical and communication domains, but decreased slightly
in the psychosocial domain. The second participant improved in the
physical and communication domains and declined overall and in the
psychosocial domains. Findings from this study indicate that cTBS
over the right pars triangularis may have the potential to improve
various language skills in patients suffering from chronic aphasia
post-stroke. However, the potential benefits of this fast, noninvasive brain stimulation protocol on improvement of language
abilities post-stroke need further exploration.

ARTICLE HISTORY

Received 8 October 2018
Revised 5 December 2018
Accepted 19 December 2018
KEYWORDS

Transcranial magnetic
stimulation (TMS);
neuronavigation; receptive
and expressive language;
quality of life; case-based
approach

Introduction
Aphasia is an acquired communication disorder resulting from damage to brain areas
responsible for language comprehension and/or production in spoken and written
form. Being a significant sequela of stroke, aphasia affects more than a third of all
stroke survivors (Dickey et al., 2010; Heiss & Thiel, 2016). In the context of Cyprus
where this research was carried out, prevalence of post-stroke aphasia is unknown yet,
on average 1200–1400 people each year suffer a stroke and years of healthy life lost due
to stroke disability is estimated between 20 and 30 years (Cyprus WHO, 2017). Aphasia
CONTACT Anastasios Georgiou
Technology, Limassol 3041, Cyprus
© 2019 Taylor & Francis Group, LLC

anastasios.georgiou@cut.ac.cy

Faculty of Health Sciences, Cyprus University of

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A. GEORGIOU ET AL.

is associated with limitations in activities of daily living, loss of independence and
a decrease in social participation (Northcott, Marshall, & Hilari, 2016). If aphasia does
not improve over time and becomes chronic, this leads to long-term disability
(Gialanella, Bertolinelli, Lissi, & Prometti, 2011) and dependency (American Heart
Association, 2010), increased societal burden (Northcott, Moss, Harrison, & Hilari,
2016), family carer strain (Kniepmann & Cupler, 2014) and poor quality of life
(Hilari, Needle, & Harrison, 2012). Speech and language therapy (SLT) robustly
remains the gold standard treatment for rehabilitation of aphasia. Intensive SLT is
known to improve language skills in all stages post-stroke independent of severity and
aphasia type (Saxena & Hillis, 2017). Nonetheless, more research is needed to define
the optimal approach, type, frequency and duration of SLT (Brady, Kelly, Godwin,
Enderby, & Campbell, 2016). Currently, there is a need to develop novel cost-effective
treatments to address the impact of aphasia.
Rehabilitation research exploring non-invasive brain stimulation techniques (NIBS),
such as transcranial magnetic stimulation (TMS) and transcranial direct current
stimulation (tDCS) as a treatment method for language deficits as consequence of
stroke is on the rise (Georgiou, Lada & Kambanaros, in press). This is because even if
SLT is proven to be efficacious, many patients are left with residual language and
communication deficits (Saxena & Hillis, 2017) upon discharge from speech-language
therapy services. Depending on the frequency, intensity, and duration of the stimulation, TMS can lead to transient increases or decreases in excitability of the affected
brain areas. When multiple TMS stimuli are delivered in trains (repeated single
magnetic pulses of the same intensity), the term “repetitive TMS (rTMS)” is used.
Results on MEP measurements in healthy people have led to the consensus that low
frequency stimulation (≤1 Hz) induces inhibition, whereas high frequencies (≥5 Hz)
induce excitation (Lefaucheur et al., 2014). It is assumed that excitation and inhibition
represent changes in synaptic efficacy that are related to the after-effects of rTMS
(Lenz, Muller-Dalhaus & Vlachos, 2016).
For treatment of aphasia post-stroke, both high- and low-frequency paradigms have
been used. Inhibitory rTMS has been applied to the right hemisphere in order to
increase language activity of the undamaged left hemisphere structures by suppressing
competing right hemisphere language activation or simply by diminishing inhibitory
processes in the right hemisphere. Most studies use a frequency between 1 and 4 Hz of
rTMS to inhibit increased activation of the homologous BA45 and others have targeted
right superior temporal areas (Shah-Basak & Hamilton, 2016). Over the last few years,
there is robust evidence for the positive effects of low frequency (1 Hz) rTMS over the
right triangular part of the inferior frontal gyrus (IFG) on language abilities (e.g.
naming) as measured by standardized language tests in individuals with aphasia in
the sub-acute phase after first-time stroke (Rubi-Fessen et al., 2015; Thiel et al., 2006;
Weiduschat et al., 2011). Significant improvement following rTMS treatment, either
inhibitory or excitatory, is reported in the literature also for naming accuracy (Thiel
et al., 2006); language comprehension (Kakuda, Abo, Momosaki, & Morooka, 2011);
spontaneous speech (Naeser et al., 2012); and fluency (Abo et al., 2012). Several of the
most recent rTMS studies for aphasia neurorehabilitation combine TMS with SLT (e.g.
Naeser et al., 2012; Rubi-Fessen et al., 2015; Seniow et al., 2013). Providing SLT as an

CLINICAL LINGUISTICS & PHONETICS

3

adjunct treatment to rTMS may have a truly synergic outcome and boost language
abilities, but it can also mask the actual therapeutic effects of rTMS.
Of major clinical interests are the positive findings from recent studies using short
rTMS burst protocols, such as theta burst stimulation (TBS) paradigms, that have
shown positive results in aphasia recovery (e.g. Griffis, Nenert, Allendorfer, &
Szaflarski, 2016; Kindler et al., 2012; Vuksanovic et al., 2015). The TBS paradigm
was first introduced by Huang et al. in 2005. It was developed in animal experiments
to mimic the normal pattern of neuronal firing in the hippocampus of the rodent
(Huang & Rothwell, 2007). Research in humans (Oberman, Edwards, Eldaief, &
Pascual-Leone, 2011) has revealed that TBS protocols promote sustained changes in
cortical activity that last well beyond the duration of TMS conditioning. TBS protocols
are speedier than other rTMS paradigms, which require much longer periods of
conditioning and higher stimulus intensities in order to elicit changes in cortical
excitability of a similar duration to TBS (Huang & Rothwell, 2007). There are two
TBS paradigms; (i) intermittent TBS (iTBS), the basic TBS pattern delivered in a short
train lasting for 2 seconds (secs) (i.e. 10 bursts in total), repeated every 10 secs for 20
cycles for a total of 600 pulses and (ii) continuous TBS (cTBS) that delivers the basic
TBS pattern in a continuous, uninterrupted train lasting for a total of 40 secs (i.e. 200
bursts with a total 600 pulses). Huang, Edwards, Rounis, Bhatia, and Rothwell (2005)
have demonstrated that in the iTBS pattern, motor evoked potential (MEP) size is
facilitated for about 15 minutes, whereas in the cTBS paradigm, an important reduction of MEP size is observed which lasts for close to 60 minutes.
Recent TBS studies provide evidence that this quick NIBS protocol induces positive
functional language changes. Griffis et al. (2016) applied iTBS over the residual
language responsive cortex in or near the left inferior frontal gyrus (IFG), as identified
using an fMRI language task, for five consecutive days over the course of two weeks.
One-week post-iTBS, the researchers found that treatment was associated with (i)
increases in left IFG activation magnitudes and decreases in right IFG activation
magnitudes during covert verb generation, (ii) reduced right to left IFG connectivity
during covert verb generation, and improvements in fluency. Vuksanovic et al. (2015)
applied for 15 daily sessions, cTBS over the Broca’s area homologue of the right
hemisphere and immediately after, applied iTBS over the left hemisphere Broca’s
area in a right-handed patient with chronic non-fluent aphasia post-stroke. The
researchers found improvement in several language functions, most notably in propositional speech, semantic fluency, short-term verbal memory, and verbal learning.
Kindler et al. (2012) applied cTBS over the right Broca’s homologue in 18 patients
with aphasia in different post-stroke phases. Their cTBS protocol included 801 pulses
delivered in 267 bursts and each burst contained 3 pulses at 30 Hz, repeated with an
interburst interval of 100 ms. Total duration of a train was 44 seconds. The researchers
found that naming performance was significantly better, and naming latency was
significantly shorter post-cTBS than post sham intervention.
The aim of this research was the investigation of possible changes in language performance using cTBS as a stand-alone treatment for aphasia rehabilitation in two patients
with chronic aphasia post-stroke. We hereby report language and quality of life outcomes
at pre-therapy (baseline), post-therapy and follow up (three months post-treatment). In
this exploratory research an rTMS protocol similar to Kindler et al. (2012) was followed.

4

A. GEORGIOU ET AL.

Materials and methods
The Template for Intervention Description and Replication (TIDieR) 12 item checklist
and guide (Hoffmann et al., 2014) was adhered to improve the reporting of the intervention study, and for the future replicability of the study (see Appendix 1 for the TIDieR
checklist completed by the authors). Ethical approval was given by the Cyprus National
Bioethics Committee prior to the commencement of the research.

Participant 1
The first participant was a 61-year-old male who had suffered a left middle cerebral artery
(MCA) stroke 20 months prior. He presented with mild to moderate anomic aphasia, had
attended twice weekly speech and language therapy sessions for 8 months, and withdrew
from treatment two weeks before enrolling in the present study.

Participant 2
The second participant was a 39-year-old female who had suffered a left MCA stroke 25 months
prior. She presented with severe global aphasia. She had attended twice weekly speech and
language therapy sessions for ten months and withdrew from therapy two weeks before
enrolling in this study. Table 1 presents the background demographics of the participants.
Both participants were enrolled in the study as they met the following inclusion criteria: (1)
they were native speakers of (Cypriot) Greek (to avoid confounding the study with bilingual
issues); (2) a recent brain magnetic resonance imaging (MRI) confirmed a first-ever stroke in
the left (dominant) hemisphere; (3) they had chronic aphasia (time elapsed since
stroke > 6 months); (4) the presence of aphasia was diagnosed using the Greek version of
the Boston Diagnostic Aphasia Examination – Short Form (BDAE-SF) (Messinis, Panagea,
Papathanasopoulos, & Kastellakis, 2013); (5) chronological age was no greater than 75 years.
In addition, a key prerequisite for participation in the study was the willingness to withdraw
from any speech and language therapy for the whole duration of the program (i.e. four
months). Exclusion criteria were as follows: (1) non-native Greek speakers; (2) symptomatic
prior cerebrovascular accidents (CVAs); (3) standard MR imaging, TMS and tDCS exclusion
criteria; (4) severe comprehension deficits; (5) severe apraxia of speech or dysarthria affecting
intelligibility; (6) auditory or visual deficits and (6) cognitive disorders known before the
stroke.
Table 1. Demographic and clinical characteristics of the participants.
Age Education
Participant Sex (years) (years)
1
M
61
12
2

F

39

12

Months
Severity
SLT
post Lesion Type of
of
prior to
stroke
site Aphasia Aphasia
enrolment
20
LMCA Anomic Mild to
8 months – two times per
moderate week – 45 min of SLT
25

LMCA Global

Severe

Termination
of SLT
15 days
before
enrolment
10 months – two times per 15 days
week – 45 min of SLT
before
enrolment

Note: LMCA = Left Middle Cerebral Artery; PWA = people with aphasia; SLT = speech-language therapy

CLINICAL LINGUISTICS & PHONETICS

5

Background language measures
The Boston diagnostic aphasia examination (BDAE-SF)
For the purposes of the study, the primary outcome measure that determined the
presence, type and severity of aphasia was the Greek BDAE-SF (Messinis et al., 2013).
The battery includes evaluation of language comprehension (e.g. words, commands, small
paragraphs), expressive language (spontaneous speech, picture description, naming, word
and sentence repetition, automatized sequences) reading and writing. Obtained scores can
be converted into a language deficit score and a measure of aphasia severity for language
functioning assessment in acute and sub-acute stroke. The tool has satisfactory psychometric properties (Messinis et al., 2013). For the purposes of the present study, written
language was not assessed.
Multilingual Assessment Instrument for Narratives (MAIN) and Quantitative
Production Analysis protocol (QPA)
The Multilingual Assessment Instrument for Narratives (MAIN) (Gagarina et al., 2012)
was used to measure spontaneous language abilities. Narratives are considered an ecologically valid measure that represent functional communication or language (production of
phrases, sentences) as used in everyday life tasks (Brady et al., 2016). For the purposes of
this study, both participants were asked to tell the experimenter the ‘Baby Goat’ story
using a series of six-coloured pictures presented in a cartoon strip. See Appendix 1. The
MAIN Baby Goat story depicts a mother goat saving her baby goat from drowning and
from a hungry fox, that is also chased away from eating the baby goat by a bird. The story
is controlled for cognitive and linguistic complexity and has a moral meaning similar to an
Aesop fable. The MAIN was developed for children but can also be used with adults as the
pictures are appropriate for adults (see Appendix 1). The story has episodic structure and
provides macrostructure and microstructure information (Gagarina et al., 2012).
Spontaneous speech samples from the MAIN were audio-recorded, then transcribed in
standard orthography and in phonemic transcription by a linguist, native speaker of Cypriot
Greek, and later analysed using the Quantitative Production Analysis Protocol (QPA) (Saffran,
Berndt, & Schwartz, 1989) as adapted by Varkanitsa (2012). The QPA measures the formal/
structural characteristics of language production, yielding structural complexity scores and
description of error types. For the two participants with aphasia, utterances were subdivided
into sentences with verbs, sentences without verbs, and single word utterances. Following on
from Varkanitsa’s proposed modification of the protocol, utterances consisting of just a single
verb and no other lexical items were classified as sentences with verb, taking into account the
null-subject nature of Greek. The mean length of utterance (MLU) was calculated by measuring
the number of words in each utterance and calculating its average. The number of syntactically
well-formed sentences with verb was recorded and a proportion was calculated by dividing the
number of well-formed sentences by the total number of sentences produced with a verb. For
each narrative sample, the words were categorised as nouns, verbs, pronouns (including strong
and weak clitic forms), adjectives, adverbs, prepositions, or as closed class words (a grouping
that included determiners, auxiliaries and other functional vocabulary which do not have full
lexical meaning, and that belong to word categories that do not easily admit new members
through neologism or derivation). The number of tokens that belonged to each category was
recorded and the proportions were calculated in relation to the total number of narrative words.

6

A. GEORGIOU ET AL.

This categorisation into word types allowed for the observation of differentiated performance
patterns between the two participants. The sentences containing a verb were further analysed by
calculating the ‘AUX Score’ metric (as adapted for Greek by Varkanitsa, 2012), which is
calculated by assigning one point for each of the features MODAL, TENSE, ASPECT, NEGATION as
encoded by the Main (Matrix) Verb of each independent clause and calculating the average
score. The AUX Score Index is the average AUX Score minus one (one is subtracted to account
for the base form of the verb). The verbs were scored based on the presence of the feature, and
not their syntactical or semantic felicity as the goal is to measure the complexity of the produced
verbs (Saffran et al., 1989). Concerning the verb phrase, two more complexity scores were
calculated: the Embedding Index, and the Elaboration Index. The Embedding Index was the
average of embedded clauses (clauses introduced by a subordinating particle, or a relative
pronoun, or clauses used as verb objects) produced across the total number of sentences. The
Elaboration Index was calculated by measuring the average number of Open Class words (i.e.
Nouns, Verbs, Adjectives, and Adverbs) and of Pronouns (either strong pronouns or clitics) in
the Subject Noun Phrase and in the Verb Phrase. The two averages are added together to
calculate the total Elaboration Index. In addition to the QPA, we followed Varkanitsa (2012) and
calculated the proportion of errors-by-type produced (and left unrepaired) in each sample. The
error types were the following: (i) phonological, (ii) morphosyntactic, (iii) semantic, (iv) lexical,
(v) uninterpretable neologisms and (vi) extended circumlocutions. The two samples recorded
before the treatment were averaged to produce a baseline score for comparison with the posttreatment and follow-up performance.
Stroke and aphasia quality of life scale-39 item (SAQOL-39)
The Greek version of the SAQOL-39 was administered (Kartsona & Hilari, 2007). This
questionnaire has been adapted and linguistically validated as a measurement of QoL in
Greek speaking people with aphasia after stroke. The psychometric properties of the Greek
version have been tested in its generic form (SAQOL-39g) (i.e. the exact same tool tested
with a generic stroke population with and without aphasia) and was found to be a valid
and reliable scale that can be used as an outcome measure (Efstratiadou et al., 2012).
Procedures
The pre- and post- therapy procedures were the same for both participants. A certified
speech and language pathologist, blind to the study, carried out the language assessment
and QoL measures (baseline, post-treatment, follow up), and later analyzed the data for all
time points. The first author administered the rTMS protocol. Specifically, QoL measurements were obtained at two time points: baseline and at follow-up. Both participants
struggled to respond to the SAQOL-39g questions because of mild-moderate comprehension deficits, so proxy (spouses) ratings were used to evaluate QoL. Even though unbiased
self-reports are the most appropriate source of QoL, ratings by proxies can provide
clinicians with useful information if patients are unable to self-report (Ignatiou,
Christaki, Chelas, Efstratiadou, & Hilari, 2012).
After completion of the treatment period (10 consecutive days), participants were asked
not to participate in any formal aphasia rehabilitation program. Instead, they were encouraged
to actively engage in conversations with their families and friends. Such activities were not
monitored by the researchers.

CLINICAL LINGUISTICS & PHONETICS

7

cTBS treatment
Resting motor threshold (RMT) was assessed using surface electromyography (EMG) for which
electrodes were placed over the first dorsal interosseous (FDI) muscle of the left hand. The coil
was then placed over the right primary motor cortex and stimulated, with a single-pulse, at the
optimal site for obtaining a motor evoked potential (MEP) of at least 50 μV in five or more of 10
consecutive stimulations of the FDI of the left hand. Motor threshold levels were used to
determine stimulation parameters as they are considered an indication of cortical excitability.
After obtaining RMTs, participants underwent cTBS at 80% of their individual RMT, using
the Magstim Rapid2® stimulator (Magstim Co., Wales, UK) connected to a 70 mm Double Air
Film Coil. Stimulation parameters were in accordance with the guidelines proposed by
Wassermann (1998). However, before stimulation, a T1-weighted MRI image was obtained
from each patient. The position of the stimulation coil was guided by a frameless stereotactic
neuronavigation system (ANT NEURO) that used the individual patient’s MRI scan to precisely
localize the target area for stimulation. Both participants received inhibitory rTMS (cTBS) to the
pars triangularis (Tr) of the right inferior frontal gyrus (homologous BA45) following the
protocol suggested by Huang et al. (2005). This paradigm uses a theta burst stimulation pattern
(TBS) in which three pulses of stimulation are given at 50 Hz, repeated every 200 ms. In the
cTBS, a 40 sec train of uninterrupted TBS is given (600 pulses in total). In total, the program for
each patient consisted of 10 daily stimulation treatments (10 consecutive days). To ensure
treatment fidelity, we monitored and measured how well the treatment protocol was implemented using the TIDieR checklist as reported in Appendix 2.

Results
Language outcome measures are reported in Table 2 for both participants.

Participant 1
Auditory comprehension showed a trend towards improvement post-treatment that was
sustained in the follow-up stage. Expressive language improved significantly posttreatment and even though it decreased in the follow-up stage, it was slightly higher
compared to baseline. Naming scores remained stable post-treatment and in the followup. Regarding narration analysis (see Table 3), compared to baseline, the participant
produced a higher number of narrative words in the post-treatment assessment. The
elaboration index of sentence productivity showed a trend in increase for the embedding
index. The proportion of well-formed utterances increased, and the AUX complexity
index remained stable. The proportion of errors remained stable. In the follow-up stage,
the number of narrative words decreased compared to baseline. Regarding sentence
productivity, the elaboration index remained increased as in the post-treatment phase
and the embedding index reverted to baseline. The proportion of well-formed utterances
increased compared to baseline and post-treatment phases and the proportion of errors
remained stable.
The QoL for this participant improved post TMS as it was higher in all areas assessed
compared to baseline, but the psychosocial score had decreased. Outcomes for QoL
measures are shown in Table 4.

Item
Auditory comprehension
Expressive language (Boston naming test –
excluded)
Boston naming test – Accuracy

Post TMS
scores
26/32
25/435
10/15

Baseline
scores
25/32
19/35
10/15

10/15

Follow up
scores
27/32
21/35

Participant 1

14.76/15 (SD = .622)

Normal Controls (age
60–82)
30.97/32 (SD = 1.02)
32.45/33 (SD = 1.00)
2/15

Baseline
scores
14/32
11/48

Table 2. Language outcomes at post-treatment and follow-up compared to baseline for each participant.

1/15

Post TMS
scores
17/32
7/48

1/15

Follow up
scores
17,5/32
9/48

Participant 2

15/15 (SD = .000)

Normal Controls (age
25–39)
31.91/32 (SD = .28)
33/33 (SD = .000)

8
A. GEORGIOU ET AL.

CLINICAL LINGUISTICS & PHONETICS

9

Table 3. A detailed linguistic analysis of spontaneous language for
participant 1.
Participant 1
Category
Lexical Selection
Closed class:
Nouns:
Adjectives:
Prepositions:
Adverbs:
Pronouns:
Verbs:
Sentence Productivity
MLU:
Elaboration Index:
Embedding Index:
Discourse Productivity
Narrative words:
Grammatical Accuracy
Prop of S with V:
Prop of U w/o V:
Prop of Single Word U:
Prop of well-formed U:
AUX Complexity Index:
Error Types:
Phonological:
Morphosyntactic:
Semantic:
Lexical:
Neologisms:
Circumlocution:
Phonological %:
Morphosyntactic %:
Semantic %:
Lexical %:
Neologisms %:
Circumlocution %:
All Errors %:

1

Post

Follow-up

23
13

24
16

9
7
21

9
2
17
23

11
11
2
5
2
8
13

5,21
1,5
0,3

5,06
2,06
0,39

4,73
2
0,27

73

91

52

14
0
0
0,36
1,00

17
1
0
0,47
1,00

10
1
0
0,6
1,00

0
1
0
2
2
0
0,00
0,01
0,00
0,03
0,03
0,00
0,07

1
0
1
5
0
0
0,01
0,00
0,01
0,05
0,00
0,00
0,07

1
3
0
1
0
0
0,01
0,06
0,00
0,01
0,00
0,00
0,08

Key: prop = proportion; s = sentences; V = verbs; U = utterances; w/o = without

Table 4. Quality of life for each participant at pre-treatment (baseline) and at 3 months follow-up using
the SAQOL-39g.
Participant 1

Participant 2

Item
3 months post TMS
(max score: 5)
Baseline measure 3 months post TMS (follow up) Baseline measure
(follow up)
SAQOL – 39 g Mean score
3.61
3.92
2.89
2.56
Physical score
3.25
3.93
2.68
3.00
Communicate score
4.28
4.71
1.71
2.00
Psychosocial score
3.68
3.56
3.62
2.37

Participant 2
Auditory comprehension improved post-treatment and this improvement was sustained
in the follow-up stage. Expressive language decreased significantly post-treatment, but at
follow-up showed a trend towards improvement. Naming scores decreased slightly posttreatment and during follow-up. With regards to the narrative analysis, the samples could

10

A. GEORGIOU ET AL.

not be analysed because they consisted only of one pronoun “toutos” (translation ‘him’),
and some automatized expressions. Spontaneous speech samples for both participants are
reported in Appendix 3.
In terms of her QoL scores, outcomes showed that the psychosocial score had significantly decreased. Outcomes for QoL measures are shown in Table 4.

Discussion
In this explorative study, two participants were recruited to pilot whether cTBS as
a stand-alone treatment (without SLT) has the potential to improve language symptoms
in the chronic stage of aphasia. We followed a similar protocol to Kindler et al. (2012)
but differed in that we used neuronavigated TMS and more sessions in total. Therapy
was tolerated well by both participants and no side effects were noticed during and
after treatment. The first participant had mild to moderate anomic aphasia and showed
potential for positive change in performance in comprehension and expressive language
both post-treatment and at the follow-up stage. The change in expressive language
performance was stronger post-treatment. Naming accuracy remained stable throughout treatment. Narration analysis revealed that post-treatment the participant showed
a positive trend towards improvement in discourse, sentence productivity, and grammatical accuracy. In the follow up stage, discourse productivity decreased and; the
elaboration index of sentence productivity increased, while the embedding index
reverted to baseline. Grammatical accuracy also showed a trend towards improvement.
Regarding QoL measurements, participant 1 appeared to have improved as his performance in the overall, physical and communication domains increased, but in the
psychosocial domain it decreased. The second participant had global aphasia and
showed potential for positive change in comprehension post-treatment, that was maintained at the follow-up stage. However, she showed a decline in expressive language
post-treatment and at follow-up, that was stronger post-treatment. Naming accuracy
scores also showed a trend for decline post-treatment and follow-up. Analysis of
narratives was not possible for this participant because of her limited verbal output.
However, she showed improvement in the QoL physical and communication domains
but a decline in the psychosocial domain.
Considering the unequal demographic variables (e.g. age), aphasia types (anomic vs.
global) and only two participants an attempt to draw conclusions on cTBS effects in
chronic aphasia would be problematic. However, the trend towards improvement that was
noticed in comprehension (in both participants) and expression (in one participant) in
our study is in accordance with findings from recent TBS studies, either iTBS (Griffis et al.,
2016; Szaflarski et al., 2011), cTBS (Kindler et al., 2012) or bilateral iTBS and cTBS
(Vuksanovic et al., 2015) that support positive changes in various language domains poststroke. Particularly relevant to our study, Kindler et al. (2012) investigated the effects of
cTBS in one group of stroke patients that were in the subacute phase of stroke recovery
compared to a second group of stroke patients in the chronic phase. Both groups
significantly improved and the subacute group showed a greater improvement in naming
accuracy and reaction time compared to the group with chronic aphasia compared to
a sham group. Even though the findings of this study favoured the use of cTBS for
treatment of aphasia post-stroke, the lack of a follow-up assessment was an important

CLINICAL LINGUISTICS & PHONETICS

11

drawback since the possible long-term effects of this type of therapy are unknown, and the
contribution of spontaneous recovery cannot be excluded.
Positive changes (Naeser et al., 2005; Rubi-Fessen et al., 2015; Weiduschat et al., 2011)
and trends toward improvements in specific groups of patients with aphasia (Seniow et al.,
2013, Waldowski, Seniów, Bilik, & Członkowska, 2009) in several language domains are
also associated with other inhibitory rTMS protocols applied in aphasia post-stroke. There
are several reasons reported for the variability in response to TMS amongst different
patients with aphasia, such as aphasia type, aphasia chronicity, site of stimulation, TMS
stimulation parameters, and the use of SLT combined with TMS (Coslett, 2016); and even
age, gender and genetics can also play a role in the biological and clinical effects of rTMS
protocols (Lefaucheur et al., 2014). Therefore, the failure or success of rTMS protocols can
be attributed to either extrinsic and/or intrinsic therapeutic factors.
With regards to stimulation parameters in particular, the dichotomy between lowfrequency stimulation (≤1 Hz) related induced inhibition and high frequencies (≥5 Hz)related induced excitation is not 100% correct as there is evidence that both conditions
can have mixed excitatory and inhibitory results (Houdayer et al., 2008). For instance,
doubling the duration of stimulation on the motor cortex can reverse excitation to
inhibition and vice versa (Gamboa, Antal, Moliadze, & Paulus, 2010). In addition, the
cellular and molecular mechanisms underpinning rTMS based therapies are not fully
understood in clinical populations (Muller-Dahlaus & Vlachos, 2013). What complicates
the elucidation of such mechanisms even more is that in chronic patients, when prolonged
therapeutic effects (i.e. up to several months) are observed, placebo effects (that reflect
a complex mixture of neurobiological effects (Benedetti, 2010; Krummenacher, Candia,
Folkers, Schedlowski, & Schönbächler, 2010), should also be taken into consideration
(Lefaucheur et al., 2014). In our case, our first participant was highly motivated to take
part to the study and hoped to improve post-treatment.
People with aphasia form a highly heterogeneous group with large individual differences in post-stroke linguistic profiles, severity, type of aphasia and recovery patterns
(Brady et al., 2016), making accurate prognosis difficult. Generally, several factors are
thought to influence recovery of language functions, but the evidence so far is not
straightforward. For example, conflicting evidence exists in relation to the impact of sex
(Sohrabji, Park, & Mahnke, 2017), age (Lazzarino, Palmer, Bottle, & Aylin, 2011), handedness and educational background (Henseler, Regenbrecht, & Obrig, 2014) on language
recovery. Also, there is research that places additional importance on the initial aphasia
profile (severity, modalities involved) as a contributing factor of the type of language
recovery (Gialanella & Prometti, 2009).
In our study, in addition to standardized language assessments, we also employed an
assessment of narrative production as we aimed at assessing not only the effects of rTMS
on experimental language tasks, but also on an everyday life task, as functional communication is based on production of phrases, sentences and on narration. To our knowledge, only Medina, Hamilton, Norise, Turkeltaub, and Coslett (2011) assessed discourse
productivity (narrative words, closed-class words, open-class words), sentence productivity, grammatical accuracy and lexical selection. The use of QPA in this study exhibited
some predictive power, but some concerns about its applicability to Greek arose: the AUX
score measure, even with the modifications by Varkanitsa (2012), relies on the rate of
omission of verb features such as tense and aspect to score their complexity. Unlike

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A. GEORGIOU ET AL.

English, tense and aspect omissions are not common, since the morphemes that express it
are obligatory parts of the verb and not auxiliaries. Additionally, tense in Greek verbs is
expressed syncretically with person and number, which might make it more salient and
less likely to be omitted. Moreover, complex subject noun phrases containing subordinated clauses were not present, since those were not elicited directly even though
opportunities for them to be used were provided by the story the participants were
asked to tell. This measure was later removed from the elaboration index formula we
used since there was no effect.
Overall, the trends in the present study towards improvement in specific language
domains from baseline to post-treatment and follow-up assessments (comprehension in
both participants post-treatment and at follow up and; expressive language in one
participant post-treatment and at follow-up) might be due to the TBS treatment.

Conclusion
Continuous TBS was successfully applied to two individuals with chronic aphasia poststroke and no adverse effects were noticed during treatment and follow-up periods. We
tentatively suggest that TBS shows has potential to facilitate recovery of language abilities
in chronic aphasia despite its short application.
Further investigation is warranted and specific functional markers and biomarkers of
good responders to non-invasive brain stimulation methods need to be explored and
established.

Statement of interest
The authors report no conflict of interest.

References
Abo, M., Kakuda, W., Watanabe, M., Morooka, A., Kawakami, K., & Senoo, A. (2012). Effectiveness
of low-frequency rTMS and intensive speech therapy in poststroke patients with aphasia: A pilot
study based on evaluation by fMRI in relation to type of aphasia. European Neurology, 68(4),
199–208. doi:10.1159/000338773
Benedetti, F. (2010). No prefrontal control, no placebo response. Pain, 148, 357–358. doi:10.1016/j.
pain.2009.10.009
Brady, M., Kelly, C., Godwin, H., Enderby, J., & Campbell, P. (2016). Speech and language therapy
for aphasia following stroke. Cochrane Database for Systematic Reviews, 6, CD000425.
Dickey, L., Kagan, A., Lindsay, M. P., Fang, J., Rowland, A., & Black, S. (2010). Incidence and profile
of inpatient stroke-induced aphasia in Ontario, Canada. Archives of Physical Medicine and
Rehabilitation, 91(2), 196–202. doi:10.1016/j.apmr.2009.09.020
Efstratiadou, E. A., Chelas, E. N., Ignatiou, M., Christaki, V., Papathanasiou, I., & Hilari, K. (2012).
Quality of life after stroke: Evaluation of the Greek SAQOL-39g. Folia Phoniatrica Et
Logopaedica, 64(4), 179–186. doi:10.1159/000340014
Gagarina, N., Klop, D., Kunnari, S., Tantele, K., Välimaa, T., Balčiūnienė, I., … Walters, J. (2012).
MAIN: Multilingual Assessment Instrument for Narratives [Part I]/download materials to be
used for assessment IIa) pictorial stimuli; IIb) adaption of MAIN in different languages:
Guidelines for assessment; protocols, scoring sheets for cat, dog, baby birds, baby goats; background questions; story scripts [Part II] (ZAS Papers in Linguistics 56). Berlin: ZAS.

CLINICAL LINGUISTICS & PHONETICS

13

Gamboa, O. L., Antal, A., Moliadze, V., & Paulus, W. (2010). Simply longer is not better: Reversal of
theta burst after-effect with prolonged stimulation. Experimental Brain Research, 204, 181–187.
doi:10.1007/s00221-010-2293-4
Georgiou, A. G., Lada, E., & Kambanaros, M. (in press). Evaluating the quality of conduct of
systematic reviews on the application of transcranial magnetic stimulation (TMS) for post-stroke
aphasia rehabilitation. Aphasilogy.
Gialanella, B., Bertolinelli, M., Lissi, M., & Prometti, P. (2011). Predicting outcome after stroke:
The role of aphasia. Disability and Rehabilitation, 33(2), 122–129. doi:10.3109/
09638288.2010.488712
Gialanella, B., & Prometti, P. (2009). Rehabilitation length of stay in patients suffering from aphasia
after stroke. Topics in Stroke Rehabilitation, 16(6), 437–444. doi:10.1310/tsr1606-437
Griffis, J. C., Nenert, R., Allendorfer, J. B., & Szaflarski, J. P. (2016). Interhemispheric plasticity
following intermittent theta burst stimulation in chronic poststroke aphasia. Neural Plasticity,
4796906, 20–23.
Heiss, W. D., & Thiel, A. (2016). Basic principles of rTMS in aphasia treatment after stroke. In
T. Platz (Ed.), Therapeutic rTMS in Neurology. Principles, evidence, and practice recommendations
(pp. 73–85). New York, NY: Springer.
Henseler, I., Regenbrecht, F., & Obrig, H. (2014). Lesion correlates of patholinguistic profiles in
chronic aphasia: Comparisons of syndrome-, modality- and symptom-level assessment. Brain,
(awt374). doi:10.1093/brain/awt374
Hilari, K., Needle, J. J., & Harrison, K. L. (2012). What are the important factors in health-related
quality of life for people with aphasia? A systematic review. Archives of Physical Medicine and
Rehabilitation, 93(1), S86–S95. doi:10.1016/j.apmr.2011.05.028
Hoffmann, T. C., Glasziou, P. P., Boutron, I., Milne, R., Perera, R., Moher, D., … Michie, S. (2014).
Better reporting of interventions: Template for intervention description and replication (TiDieR)
checklist and guide. British Medical Journal, 348, 1–12. doi:10.1136/bmj.g1687
Houdayer, E., Degardin, A., Cassim, F., Bocquillon, P., Derambure, P., & Devanne, H. (2008). The
effects of low- and high-frequency repetitive TMS on the input/output properties of the human
corticospinal pathway. Experimental Brain Research, 187(2), 207–217. doi:10.1007/s00221-0081294-z
Huang, Y. Z., Edwards, M. J., Rounis, E., Bhatia, K. P., & Rothwell, J. C. (2005). Theta burst
stimulation of the human motor cortex. Neuron, 45, 201–206. doi:10.1016/j.
neuron.2004.12.033
Huang, Y.-Z., & Rothwell, J. C. (2007). Theta burst stimulation. In M. A. Marcolin & F. Padberg
(Eds.), Transcranial magnetic stimulation for treatment of psychiatric disorders. Advances in
biological psychiatry (pp. 187–203). Basel, Switzerland: Karger.
Ignatiou, M., Christaki, V., Chelas, E. V., Efstratiadou, E. A., & Hilari, K. (2012). Agreement
between people with aphasia and their proxies on health-related quality of life after stroke,
using the Greek SAQOL-39g. Psychology, 3(3), 686–690. doi:10.4236/psych.2012.39104
Kakuda, W., Abo, M., Momosaki, R., & Morooka, A. (2011). Therapeutic application of 6-Hzprimed low frequency rTMS combined with intensive speech therapy for post-stroke aphasia.
Brain Injury, 25(12), 1242–1248. doi:10.3109/02699052.2011.608212
Kartsona, A., & Hilari, K. (2007). Quality of life in aphasia: Greek adaptation of the stroke and
aphasia quality of life scale-39 item (SAQOL-39). Europa Medicophysica, 43(1), 27–35.
Kindler, J., Schumacher, R., Cazzoli, D., Gutbrod, K., Koenig, M., Nyffeler, T., … Muri, M. R.
(2012). Theta burst stimulation over the right Broca’s homologue induces improvement of
naming in aphasia patients. Stroke, 43(8), 2175–2179. doi:10.1161/STROKEAHA.111.647503
Kniepmann, K., & Cupler, M. H. (2014). Occupational changes in caregivers for spouses with stroke
and aphasia. British Journal of Occupational Therapy, 77(1), 10–18. doi:10.4276/
030802214X13887685335463
Krummenacher, P., Candia, V., Folkers, G., Schedlowski, M., & Schönbächler, G. (2010). Prefrontal
cortex modulates placebo analgesia. Pain, 148(3), 368–374. doi:10.1016/j.pain.2009.09.033

14

A. GEORGIOU ET AL.

Lazzarino, A. I., Palmer, W., Bottle, A., & Aylin, P. (2011). Inequalities in stroke patients’ management in English public hospitals: A survey on 200,000 patients. PloS one, 6(3), e17219.
doi:10.1371/journal.pone.0017219
Lefaucheur, J. P., Andre-Obadia, N., Antal, A., Ayache, S. S., Baeken, C., Benninger, D. H., …
Garcia-Larrea, L. (2014). Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clinical Neurophysiology, 125(11), 2150–2156. doi:10.1016/j.
clinph.2014.05.021
Lenz, M., Müller-Dahlhaus, F., & Vlachos, A. (2016). Cellular and molecular mechanisms of rTMSinduced neural plasticity. In T. Platz (Ed.), Therapeutic rTMS in neurology (pp. 11–22).
Switzerland: Springer Charm.
Medina, J., Hamilton, R. H., Norise, C., Turkeltaub, P. E., & Coslett, H. B. (2011). Transcranial
magnetic stimulation improves discourse productivity in individuals with non-fluent aphasia.
Procedia - Social and Behavioral Sciences, 23, 167–168. doi:10.1016/j.sbspro.2011.09.222
Messinis, L., Panagea, E., Papathanasopoulos, P., & Kastellakis, A. (2013). Boston diagnostic aphasia
examination-short form in Greek language. Patras: Gotsis.
Muller-Dahlaus, F., & Vlachos, A. (2013). Unravelling the cellular and molecular mechanisms of
repetitive magnetic stimulation. Frontiers in Molecular Neuroscience, 6, 1–7.
Naeser, M. A., Martin, P. I., Ho, M., Treglia, E., Kaplan, E., Bashir, S., & Pascual-Leone, A. (2012).
Transcranial magnetic stimulation and aphasia rehabilitation. Archives of Physical Medicine and
Rehabilitation, 93(1), S26–S34. doi:10.1016/j.apmr.2011.04.026
Naeser, M. A., Martin, P. I., Nicholas, M., Baker, E. H., Seekins, H., Kobayashi, M., … PascualLeone, A. (2005). Improved picture naming in chronic aphasia after TMS to part of right Broca’s
area: An open-protocol study. Brain and Language, 93(1), 95–105. doi:10.1016/j.
bandl.2004.08.004
Northcott, S., Marshall, J., & Hilari, K. (2016). What factors predict who will have a strong social
network following a stroke? Journal of Speech, Language, and Hearing Research, 59(4), 772–783.
doi:10.1044/2016_JSLHR-L-15-0201
Northcott, S., Moss, B., Harrison, K., & Hilari, K. (2016). A systematic review of the impact of
stroke on social support and social networks: Associated factors and patterns of change. Clinical
Rehabilitation, 30(8), 811–831. doi:10.1177/0269215515602136
Oberman, L., Edwards, D., Eldaief, M., & Pascual-Leone, A. (2011). Safety of theta burst transcranial
magnetic stimulation: A systematic review of the literature. Journal of Clinical Neurophysiology,
28(1), 67–74. doi:10.1097/WNP.0b013e318205135f
OECD/European Observatory on Health Systems and Policies. (2017). Cyprus: Country Health
Profile 2017. Brussels: State of Health in the EU, OECD Publishing; Paris: European
Observatory on Health Systems and Policies.
Rosamond, W., Flegal, K., Furie, K., Go, A., & Greenlund, K. et al. (2010). American heart
association. Executive Summary: Heart Disease and Stroke Statistics 2010 Update. Circulation,
121, 948–954.
Rubi-Fessen, I., Hartmann, A., Huber, W., Fimm, B., Rommel, T., Thiel, A., & Heiss, W. D. (2015).
Add-on effects of rTMS on subacute aphasia therapy: Enhanced improvement of functional
communication and basic linguistic skills. A randomized controlled study. Archives of Physical
Medicine and Rehabilitation, 96, 1935–1944. doi:10.1016/j.apmr.2015.06.017
Saffran, E. M., Berndt, R. S., & Schwartz, M. F. (1989). The quantitative analysis of agrammatic
production: Procedure and data. Brain and Language, 37(3), 440–479.
Saxena, S., & Hillis, A. E. (2017). An update on medications and noninvasive brain stimulation to
augment language rehabilitation in post-stroke aphasia. Expert Review of Neurotherapeutics, 17
(11), 1091–1107. doi:10.1080/14737175.2017.1373020
Seniow, J., Waldowski, K., Lesniak, M., Iwanski, S., Czepiel, W., & Czlonkowska, A. (2013).
Transcranial magnetic stimulation combined with speech and language training in early aphasia
rehabilitation: A randomized double-blind controlled pilot study. Topics in Stroke Rehabilitation,
20(3), 250–261. doi:10.1310/tsr2003-250
Shah-Basak, P. P., & Hamilton, R. H. (2016). Therapeutic applications of rTMS for aphasia after
stroke. In T. Platz (Ed.), Therapeutic rTMS in Neurology (pp. 87–114). USA: Springer Charm.

CLINICAL LINGUISTICS & PHONETICS

15

Sohrabji, F., Park, M. J., & Mahnke, A. H. (2017). Sex differences in stroke therapies. Journal of
Neuroscience Research, 95(1–2), 681–691. doi:10.1002/jnr.23855
Szaflarski, J. P., Vannest, J., Wu, S. W., DiFrancesco, M. W., Banks, C., & Gilbert, D. L. (2011).
Excitatory repetitive transcranial magnetic stimulation induces improvements in chronic
post-stroke aphasia. Medical Science Monitor, 17(3), CR132–139.
Coslett, 2016. Noninvasive Brain Stimulation in Aphasia Therapy. In G. Hickok & S. L Small,
Neurobiology of Language, 1035–1054. USA: Elsevier.
Thiel, A., Habedank, B., Herholz, K., Kessler, J., Winhuisen, L., Haupt, W. F., & Heiss, W. D.
(2006). From the left to the right: How the brain compensates progressive loss of language
function. Brain and Language, 98(1), 57–65. doi:10.1016/j.bandl.2006.01.007
Varkanitsa, M. (2012). Quantitative and error analysis of connected speech: Evidence from
Greek-speaking patients with aphasia and normal speakers. Current Trends in Greek
Linguistics, 313–338.
Vuksanovic, J., Jelic, M. B., Milanovic, S. D., Kacar, K., Konstantinovic, L., & Filipovic, S. R. (2015).
Improvement of language functions in a chronic non-fluent post-stroke aphasic patient following
bilateral sequential theta burst magnetic stimulation. Neurocase, 21(2), 244–250. doi:10.1080/
13554794.2014.890731
Waldowski, K., Seniów, J., Bilik, M., & Członkowska, A. (2009). Transcranial magnetic stimulation
in the therapy of selected post-stroke cognitive deficits: Aphasia and visuospatial hemineglect.
Neurologia i neurochirurgia polska, 43(5), 460–469.
Wassermann, E. M. (1998). Risk and safety of repetitive transcranial magnetic stimulation: Report
and suggested guidelines from the international workshop on the safety of repetitive transcranial
magnetic stimulation, June 5- 7,1996. Electroencephalography and Clinical Neurophysiology, 108
(1), 1–16.
Weiduschat, N., Thiel, A., Rubi-Fessen, I., Hartmann, A., Kessler, J., Merl, P., … Heiss, W. D.
(2011). Effects of repetitive transcranial magnetic stimulation in aphasic stroke: A randomized
controlled pilot study. Stroke, 42(2), 409–415. doi:10.1161/STROKEAHA.110.597864