Dement Neuropsychol 2023;17:e20230021 Case Report

[Link]

Use of transcranial magnetic

stimulation in the treatment of nonfluent
primary progressive aphasia:
a case report
Natália Maria Lins Martins1 , Tathiana Baczynski1 , Larissa Sena1 , Romário de Macedo Espíndola1 ,
Natia Horato1 , Antonio Egidio Nardi2 , Valeska Marinho1

ABSTRACT. Primary progressive aphasia comprises a group of neurodegenerative diseases characterized by progressive
speech and language dysfunction. Neuroimaging (structural and functional), biomarkers, and neuropsychological assessments
allow for early diagnosis. However, there is no pharmacological treatment for the disease. Speech and language therapy is the
main rehabilitation strategy. In this case report, we describe a female patient diagnosed with nonfluent primary progressive
aphasia who underwent sessions of high-frequency transcranial magnetic stimulation in the left dorsolateral prefrontal cortex
and showed improvement in depression scores, naming tasks in oral and written speech, and comprehension tasks in oral
and written discourse.
Keywords: Primary Progressive Aphasias; Dorsolateral Prefrontal Cortex; Transcranial Magnetic Stimulation.

Uso da estimulação magnética transcraniana no tratamento da afasia progressiva primária não fluente: um
relato de caso
RESUMO. As afasias progressivas primárias (APP) representam um grupo de doenças neurodegenerativas caracterizadas
por disfunção progressiva da fala e da linguagem. A neuroimagem (estrutural e funcional), os biomarcadores e as avaliações
neuropsicológicas permitem o diagnóstico precoce. No entanto, não há tratamento farmacológico para a doença. A terapia
fonoaudiológica é a principal estratégia de reabilitação. Neste relato de caso, descrevemos uma paciente com diagnóstico de
APP não fluente que foi submetida a sessões de estimulação magnética transcraniana de alta frequência no córtex pré-frontal
dorsolateral esquerdo e apresentou melhora nos escores de depressão, nas tarefas de nomeação da fala oral e escrita e nas
tarefas de compreensão da fala oral e escrita.
Palavras-chave: Afasia Primária Progressiva; Córtex Pré-Frontal Dorsolateral; Estimulação Magnética Transcraniana.

INTRODUCTION • Nonfluent PPA (NFPPA);

P rimary progressive aphasia (PPA) com-

prises a group of neurodegenerative
diseases characterized by progressive speech
•
•
Semantic or fluent PPA (PPAS); and
Logopenic PPA3.

and language dysfunction with preserved Despite advances in terms of diagnosis

functionality until advanced stages 1,2 . and early detection of the disease, there is a
Three subtypes differing in clinical presen- lack of specific treatment for this condition.
tation, language dysfunction, and anatomo- Pharmacological treatment for neuropsy-
pathological basis have been identified and chiatric symptoms and speech and language
described, namely: therapy are currently the standard of care for

This study was conducted at the Center for Alzheimer’s Disease and Related Disorders at the Institute of Psychiatry of the Universidade Federal do Rio de Janeiro, RJ, Brazil.
1
Universidade Federal do Rio de Janeiro, Instituto de Psiquiatria, Centro para Doença de Alzheimer, Rio de Janeiro RJ, Brazil.
2
Universidade Federal do Rio de Janeiro, Instituto de Psiquiatria, Laboratório de Pânico e Respiração, Rio de Janeiro RJ, Brazil.
Correspondence: Natália Maria Lins Martins; Email: natmlm85@[Link].
Disclosure: The authors report no conflicts of interest.
Funding: Public funding of the Institute of Psychiatry of the Federal University of Rio de Janeiro.
Received on March 17, 2023; Received in its final form on August 07, 2023; Accepted on August 28, 2023.

Martins NML, et al.   Use of TMS in the treatment of NFPPA.   1

 Dement Neuropsychol 2023;17:e20230021

PPA4,5. Recently, some reports have described a positive complete a sentence”. After the initial symptoms, lan-
effect of repetitive transcranial magnetic stimulation guage deficits compelled her to quit her job. During the
(rTMS) on language and behavioral issues in PPA6,7, both few months before the presentation, her language issues
over the left dorsolateral prefrontal cortex (DLPFC)7 and became exacerbated, and she required assistance with
over the right and left DLPFC6. The rTMS is a safe meth- writing. Her behavior remained unaltered, but she
od that can be used to promote a focal stimulus and gen- began to experience difficulty carrying out day-to-day
erate an electromagnetic field through good shots using activities due to her language deficits.
a coil. This method has a low risk of side effects, such as At the first consultation, in addition to language
scalp pain, headache, and, rarely, epilepsy; furthermore, problems, the patient also reported a depressed mood
the side effects have been reported to be tolerable8. for the past three months, and she had been prescribed
According to the previously reported data6,7, we mirtazapine at a dosage of 30 mg/day. She did not have
hypothesized that rTMS over the left DLPFC could any other psychiatric or neurological disorders, and
improve language parameters, and considering the her clinical and neurological evaluations were normal.
well-known effects of rTMS on depressive symptoms, The patient had been receiving language therapy for
a secondary beneficial effect on behavioral symptoms more than six months. Biomarkers and complemen-
was supposed. tary tests needed for a precise diagnosis of PPA were
We describe a case report of a middle-aged woman requested and are described below.
diagnosed with NFPPA with a pathogenic mutation The neuropsychological evaluation at the moment
identified in the LRRK2 gene who underwent rTMS sec- of her first consultation revealed grammatical, praxis,
tions with positive results both in language parameters and verbal fluency deficits, keeping naming and word
and behavioral symptoms. comprehension ability preserved. The fluorodeoxyglu-
cose-positron emission tomography (FDG-PET) revealed
a moderate/marked reduction in glycolytic metabolism
CASE REPORT in the lateral regions of the temporal lobes and the lower
A 55-year-old female, divorced, who worked as a uni- portions of the parietal lobes; there was an asymmetrical
versity teacher sought medical care due to “difficulty pattern due to greater left-side involvement, especially
communicating”. Her symptoms began during the in the lateral portion of the prefrontal cortex, in the
previous four years with progressive difficulties in sen- posteromedial portions of the parietal lobes and in the
tence construction, and she reported “finding it hard to posterior gyrus of the cingulate cortex (Figure 1).

 
Figure 1. Fluorodeoxyglucose-positron emission tomography (FDG-PET) sequences showing moderate/marked reduction
in glycolytic metabolism in the lateral regions of the left temporal lobes and the lower portions of the parietal lobes.

2   Use of TMS in the Treatment of NFPPA.   Martins NML, et al.

 Dement Neuropsychol 2023;17:e20230021

Magnetic resonance imaging (MRI) of the skull re- Ethics Committee, CAAE: 61534322.5.0000.5263.
vealed gliosis due to atherosclerotic microangiopathy The participant was informed about the procedure and
and prominent cisterns, fissures, and cortical grooves; signed the informed consent form.
additionally, compensatory ectasia of the lateral ventri- The rTMS protocol consisted of one daily 15-min-
cles was observed (Figure 2). ute session across three to five consecutive days
Cerebrospinal fluid (CSF) analysis showed an increase per week for six consecutive weeks (a total of 28
in total tau (t-tau) levels (496,9 pg/ml/I.R.: <300 pg/ml sessions). The patient kept her daily routine as
(21–50 years); <450 pg/ml (51–70 years); <500 pg/ml usual including conventional speech and language
(71–93 years) and phosphorylated tau (p-tau) protein therapy. She had submitted to this therapy, focusing
(107,2 pg/ml/I.R.: <61 pg/ml), a decrease in beta-amyloid on discourse and language production, of one-hour
protein Aβ1-42 levels (338,7 pg/ml/I.R.: >500 pg/ml), duration, every week for the last six months. The pa-
and a decrease in Aβ1-40 levels (3919 pg/ml/I.R.: 7755– tient underwent 28 high-frequency rTMS (HF-rTMS)
16715 pg/ml). Nonetheless, the Aβ1-42/Aβ1-40 ratio sessions to the left DLPFC. The stimulation intensity
(0,086 pg/ml/I.R.: >0,069 pg/ml) was within the normal was gradually increased, to reduce any discomfort
range. A genetic panel was performed for several genes, associated with the procedure, with no change in the
including some already related to neurodegenerative dis- motor threshold (MT) over the weeks of stimulation.
eases and a pathogenic variant was found: c.6055G>A (p. Thus, for the first four sessions, an intensity of 100%
Gly2019Ser). This variant was identified in leucine-rich of the calculated MT was used; for the next four ses-
repeat kinase 2 (LRRK2). Pathogenic mutations in the sions, the intensity was 110% of the MT; and, for the
LRRK2 gene are associated with Parkinson’s disease, and last 20 sessions, the intensity was 120% of the MT,
some reports describe preliminary evidence correlating which was kept stable until the last rTMS procedure.
with Corticobasal Syndrome (CBS) and PPA9,10. The following parameters were also used: 10 Hz fre-
quency; 5s series duration; 25s interval duration; and
15-min total session duration. The rTMS protocol,
METHODS including stimulus duration and number of sessions,
The project was approved by the IPUB/UFRJ (Instituto was based on the approved rTMS protocols by the
de Psiquiatria da Universidade Federal do Rio de Janeiro) Brazilian Federal Council of Medicine in 2012 11.
No changes in prescription patterns and/or lan-
guage therapies were allowed during the procedure.
Eleven days before and four days after the last rTMS,
the patient completed depression symptom scales
(Cornell Scale and the Geriatric Depression Scale –
GDS), global cognitive measures (Alzheimer’s Disease
Assessment Scale — Cognitive Subscale — ADAS-Cog
and Mini-Mental State Examination — MMSE), and
a specific language evaluation conducted by a speech
therapist (Montreal-Toulouse Language Assessment
Battery — MTL)12.
A table containing the results of the MRL-BR, Brazil-
ian version (MTL-Brazil) pre- and pos-rTMS procedure
is available as Supplementary Material.

RESULTS
The patient showed reductions in depression symp-
toms on both the Cornell Scale (7 points and 2 points
 at pre- and post-rTMS, respectively) and the GDS (12
Figure 2. Magnetic Resonance Images of rare foci with signal on T2 fluid- points and 6 points at pre- and post-rTMS, respectively).
attenuated inversion recovery, suggestive of minimal gliosis/ischemia due to The patient also improved in global cognitive function
degenerative microangiopathy, scattered in the periventricular white matter and on the MMSE (18/30 and 20/30 at pre- and post-rTMS,
frontal and parietal lobes (Fasekas 1). Hippocampus of normal volume and signal respectively) and the ADAS-Cog (42,7 and 35,7 at pre-
intensity (MTA:1). Cortical grooves, fissures and basal cisterns accentuated. and post-rTMS, respectively).

Martins NML, et al.   Use of TMS in the treatment of NFPPA.   3

 Dement Neuropsychol 2023;17:e20230021

Furthermore, the patient presented improvements Table 1. Montreal-Toulouse Language Assessment Battery, Brazilian
in the following language parameters as assessed by the version results, pre- and pos- repetitive transcranial magnetic stimulation.
MTL-Brazil: oral and written comprehension of sentenc- PRE- POS- Total
es, copy, writing under dictation, sentence repetition, rTMS rTMS score
read-aloud sentences, naming abilities for nouns and Direct interview 20 20 26
verbs, manipulation of objects under verbal order, and Automatic speech (form) 6 6 6
written naming for nouns. The patient showed decreases Automatic speech (content) 6 6 6
in oral narrative speech, semantic verbal fluency, phono-
Oral comprehension 12 16 19
logical/orthographic verbal fluency, written nomination
Words 5 5 5
for verbs, reading numbers, written narrative speech
Sentences 7 11 14
number of words, and written text comprehension.
No difference was found in automatic speech for form Oral narrative speech (nº words) 59 41 -
and content, oral comprehension for nouns, number of Total IU 3 3 10
information units (IU), scenes, written words compre- Total scenes 0 0 3
hension, word repetition and reading, nonverbal praxis, Written comprehension 10 11 13
recognition of body parts and notions of right and left, Words 5 5 5
listening comprehension, written narrative speech Sentences 5 6 8
and text comprehension, and numerical calculation Copy 6 8 8
(Figure 3 and Table 1). Writing under dictation 10 14 22
The patient was also asked to rate her condition after
Repetition 10 24 33
the procedure and report an improvement in her daily
Words 11 11 11
life activities.
Sentences 7 13 22
Read aloud 32 33 33
DISCUSSION Words 12 12 12
This case study revealed the beneficial effects of rTMS Sentences 20 21 21
applied to the left DLPC in a 55-year-old woman with Semantic verbal fluency 9 8 -
NFPPA related to LRRK2 pathogenic mutations. The re- Non-verbal praxis 24 24 24
sults indicated reductions in depressive symptoms and Oral nomination 26 30 30
improvements in both global cognitive function and Nouns 22 24 24
language parameters. Verbs 4 6 6
Considering the scarcity of therapeutic approaches
Manipulation of objects under verbal order 11 14 16
that can modify or stop the evolutionary course of
Phonological/orthographic verbal fluency 8 7 -
PPA13, and based on the promising results of rTMS in
Recognition of body parts and notions of R/L 8 8 8
other neuropsychiatric disorders14, the present case
report sheds light on this noninvasive neuromodulation Body segments 4 4 4
R/L perceptions 4 4 4
Written nomination 21 28 30
WZͲƌdD^ WK^ͲƌdD^ dŽƚĂůĞƐĐŽƌĞ Nouns 15 21 24
ϭϰϬ Verbs 6 4 6
ϭϮϬ Listening comprehension of the text 2 2 9
ϭϬϬ Numbers dictation 5 5 6
ϴϬ Reading numbers 6 5 6
ϲϬ Written narrative speech (nº words) 37 22 -

ϰϬ IU Total 3 3 10

ϮϬ Scene score 0 0 3

Ϭ
Written text comprehension 4 0 9
ŽƌŶĞůů '^ ^ͲŽŐ DD^ Numerical calculation 0 0 12

Abbreviations: rTMS, repetitive transcranial magnetic stimulation; GDS, Geriatric Depression Mental 0 0 6
Scale; ADAS, Alzheimer’s Disease Assessment Scale; MMSE, Mini-Mental State Examination. Numerical 0 0 6
Figure 3. Pre- and pos- repetitive transcranial Abbreviations: rTMS, repetitive transcranial magnetic stimulation; IU, information units;
magnetic stimulation and total score. R/L, right/left.

4   Use of TMS in the Treatment of NFPPA.   Martins NML, et al.

 Dement Neuropsychol 2023;17:e20230021

method as a treatment option for PPA. The best-es- positive results in object naming and syllable tasks for
tablished indication for rTMS is depression treatment subjects in the active group17.
via stimulation of the left dorsolateral prefrontal cor- PPA is a rare condition with different clinical sub-
tex15. Our report is in line with these results since an types, language-related symptoms, and various asso-
improvement in depressive symptoms was observed. ciated anatomopathologies, with no pharmacological
The scores on the GDS and Cornell Scale were lower treatment currently available. Recent data suggest
after the procedure. Global cognitive function and lan- the benefits of speech therapy for trained words13.
guage parameters were also improved as assessed by The present case study revealed the positive effects of
the ADAS-Cog, MMSE, and MTL-Brazil. The positive supplementing speech therapy with rTMS as a poten-
effects on cognition could be a direct effect of rTMS tial option to improve mood and cognitive function.
or a secondary effect due to mood benefits generated Future randomized placebo-controlled studies with
by the procedure. However, benefits in cognition and large sample sizes should be conducted to evaluate the
language production were measured before and after potential of rTMS over the left DLPFC as an adjuvant
stimulation and resulted in benefits for global cogni- to speech-language therapy in PPA.
tion, action, and object naming abilities and language A limitation of the present study include the case-re-
skills such as comprehension of sentences, copying, port design describing rTMS benefits for a single NFPPA
and writing under dictation. These results corroborate patient, which precludes generalization to other PPA
previous studies that reported direct cognitive effects patients and to other clinical PPA variants. A possible
with rTMS in PPA6,7,16,17. Finocchiaro et al. described the placebo effect cannot be ruled out, as the study lacks a
first clinical case report of PPA with HF-rTMS applied control condition of neuromodulation. The single case
to the left prefrontal cortex. The patient was evaluated report method prevents a comparator for other subjects,
with a language battery of tests before and after treat- and as no information about disease progression was
ment, and the results showed significant improvements available, a comparator for the patient herself could
in vocal production after rTMS16. not be made. Besides this lack of baseline measures,
In 2012, Cotelli et al. conducted a clinical trial of another possible limitation is the absence of functional
ten NFPPA subjects who underwent rTMS applied neuroimages before and after the stimulus procedure
to the DLPFC. The results pointed to effects on ac- that could have added neurobiological measures of
tion naming performance for patients who received efficacy. The patient remained on her usual treatment
stimulation. No facilitating effect of rTMS object with speech and language therapy, so a possible benefi-
naming was observed6. Margolis et al. carried out a cial effect of such behavioral intervention could not be
single-blind study including six NFPPA subjects sub- ruled out. Further, evaluations were performed shortly
mitted to HF-rTMS sham and rTMS applied to the after stimulation, and the duration of the effects was
right or left DLPFC. The most consistent result was a not examined. Thus, the present report has encouraging
statistically significant improvement in action naming findings that are limited to the patient described herein.
post-rTMS applied to the left DLPFC but not to the There is a need for more robust and longitudinal studies
right DLPFC. There were no benefits for object naming of rTMS on PPA patients.
after right or left DLPFC rTMS stimulation. There was
an improvement in global cognitive performance in
both groups as measured by the Montreal Cognitive ACKNOWLEDGEMENTS
Assessment (MoCA). The results pointed to benefits in The authors would like to express their sincere thanks to
naming actions and global cognitive improvement for Rafael Tavares MD at Clínica de Medicina Nuclear Vilela
rTMS to the left DLPFC, suggesting that stimulation Pedras for helping with FDG-PET images.
to the left DLPFC may be more beneficial than to the
right DLPFC7.
The first randomized placebo-controlled study AUTHORS’ CONTRIBUTIONS
included 20 nonfluent and semantic PPA patients en- NMLM: methodology, project administration, writing –
rolled in active- versus control-site rTMS in a crossover original draft. TB: methodology, project administration,
design. Despite being a more robust study design, the writing – original draft. LS: project administration.
stimulation protocol used was heterogeneous, asso- RME: project administration. NH: formal analysis. AEN:
ciated with multiple foci, in addition to excitatory or conceptualization, methodology, writing – review &
inhibitory stimuli. This study found improvement in editing. VM: conceptualization, methodology, writing
spontaneous speech as a primary outcome and other – review & editing.

Martins NML, et al.   Use of TMS in the treatment of NFPPA.   5

 Dement Neuropsychol 2023;17:e20230021

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6   Use of TMS in the Treatment of NFPPA.   Martins NML, et al.