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An overview of repetitive transcranial magnetic stimulation (rTMS) in Alzheimer’s disease

  • Secretariat of the Mexican Board of Mental Health


Background Alzheimer’s disease (AD) is the most frequent neurocognitive disorder. It affects 50% to 75% of the cases of dementia, and is characterized by a progressive cognitive decline that hinders behavior and functionality. Its etiology is still uncertain, and the efficiency of treatments is limited. Repetitive transcranial magnetic stimulation (rTMS) has been used as an alternative therapeutic strategy, but the clinical impact on Alzheimer’s disease has hardly been studied. Objective To describe the effects of rTMS on cognition, the behavioral and psychological symptoms of dementia (BPSD), and functionality, considering the various modes of application. Method The PubMed, ScienceDirect, and PsycInfo databases were consulted using key words relating to the topic of study. Articles published between 2006 and 2016 were selected. Results The studies that have assessed the clinical effect of rTMS have used various parameters to stimulate and compare the different cortical areas, principally the dorsolateral prefrontal cortex. A variety of benefits have been proposed for patients with Alzheimer’s disease in cognitive domains such as language and episodic memory, as well as behavior and functionality in everyday activities. Discussion and conclusion rTMS has been suggested as a possible treatment for AD, and the results indicate the need for further studies with different methodological designs and more participants, in addition to cognitive rehabilitation techniques. The objective is to identify the most efficient parameters for stimulation and to explore new cortical targets.
171Vol. 40, No. 4, julio-agosto 2017
An overview of repetitive transcranial
magnetic stimulation (rTMS) in Alzheimer’s disease
Ruth Alcalá Lozano,1 Erik Daniel Morelos Santana,1 Orely Osorio Rojas,1
Jorge Julio González Olvera1
Background. Alzheimer’s disease (AD) is the most frequent neurocognitive disorder. It affects 50% to 75%
of the cases of dementia, and is characterized by a progressive cognitive decline that hinders behavior and
functionality. Its etiology is still uncertain, and the efficiency of treatments is limited. Repetitive transcranial
magnetic stimulation (rTMS) has been used as an alternative therapeutic strategy, but the clinical impact on
Alzheimer’s disease has hardly been studied. Objective. To describe the effects of rTMS on cognition, the be-
havioral and psychological symptoms of dementia (BPSD), and functionality, considering the various modes
of application. Method. The PubMed, ScienceDirect, and PsycInfo databases were consulted using key words
relating to the topic of study. Articles published between 2006 and 2016 were selected. Results. The studies
that have assessed the clinical effect of rTMS have used various parameters to stimulate and compare the
different cortical areas, principally the dorsolateral prefrontal cortex. A variety of benefits have been proposed
for patients with Alzheimer’s disease in cognitive domains such as language and episodic memory, as well as
behavior and functionality in everyday activities. Discussion and conclusion. rTMS has been suggested as
a possible treatment for AD, and the results indicate the need for further studies with different methodological
designs and more participants, in addition to cognitive rehabilitation techniques. The objective is to identify the
most efficient parameters for stimulation and to explore new cortical targets.
Keywords: Alzheimer’s disease, repetitive transcranial magnetic stimulation, cognition.
Antecedentes. La enfermedad de Alzheimer (EA) es el trastorno neurocognitivo más frecuente. Afecta de 50
a 75% de los casos de demencia y se caracteriza por un declive cognitivo progresivo que perjudica la con-
ducta y funcionalidad. Su etiología es aún incierta y la eficacia de los tratamientos limitada. La estimulación
magnética transcraneal repetitiva (EMTr) se ha utilizado como una estrategia terapéutica alternativa, pero se
ha estudiado poco el impacto clínico que tiene en la EA. Objetivo. Describir los efectos de la EMTr sobre la
cognición y los síntomas psicológicos y conductuales de la demencia (SPCD), así como en la funcionalidad,
considerando las diferentes modalidades de aplicación. Método. Se consultaron las bases de datos PubMed,
ScienceDirect y PsycInfo utilizando palabras clave relacionadas con el tema de estudio. Se seleccionaron
los artículos publicados de 2006 a 2016. Resultados. Los estudios que han evaluado el efecto clínico de la
EMTr han utilizado diferentes parámetros de estimulación y comparaciones de diferentes áreas corticales,
principalmente de la corteza prefrontal dorsolateral. Se postulan diferentes beneficios en pacientes con EA en
dominios cognitivos como el lenguaje y la memoria episódica, así como en la conducta y en la funcionalidad
de las actividades de la vida diaria. Discusión y conclusión. La EMTr se ha sugerido como posible trata-
miento para la EA. Los resultados favorecen la necesidad de realizar nuevos estudios con diferentes diseños
metodológicos y mayor número de participantes, en combinación con técnicas de rehabilitación cognitiva. La
perspectiva es identificar los parámetros de estimulación más eficaces y explorar nuevas dianas corticales.
Palabras clave: Enfermedad de Alzheimer, estimulación magnética transcraneal repetitiva, cognición.
1 Subdirección de Investigaciones
Clínicas, Instituto Nacional de
Psiquiatría Ramón de la Fuente
Jorge Julio González Olvera
Subdirección de Investigaciones
Clínicas, Instituto Nacional de
Psiquiatría Ramón de la Fuente
Calz. México-Xochimilco 101, Col.
San Lorenzo Huipulco, Del. Tlal-
pan, C.P. 14370, Ciudad de Méxi-
co, México.
Phone: +52 (55) 4160-5349
Received rst version: December 30,
Second version: May 19, 2017
Accepted: July 13, 2017
Alcalá Lozano et al.
172 Vol. 40, No. 4, julio-agosto 2017
Alzheimer’s disease is a neurocognitive disorder character-
ized by chronic, progressive deterioration in cognition and
functionality. It also presents signicant psychological and
behavioral symptoms, and is the most common type of de-
mentia, appearing in 50% to 75% of the cases (“WHO &
Alzheimer’s Disease International [ADI], 2012”; Prince et
al., 2015). AD is a heterogeneous process that develops in
a preclinical period over the course of several decades. It
has been theorized that its etiopathology is secondary to the
extracellular overproduction and accumulation of beta-am-
yloid plaques and due to the hyperphosphorylation of tau
protein, which causes the formation of neurobrillary tan-
gles (Dubois et al., 2010; McKhann et al., 2011).
The treatment of Alzheimer’s disease is generally phar-
macological and based on the use of acetylcholinesterase
inhibitors (AChEI): donepezil, rivastigmine, and galantam-
ine, for the treatment of mild to moderate AD. Memantine
(the antagonist of the NMDA glutamate receptor) is used
for moderate to severe AD. These drugs have demonstrated
a positive eect on the manifestation of the disease. How-
ever, the treatment is still ineective in slowing, stopping
or reversing the progress of Alzheimer’s disease, and many
substances under study have been proposed to treat it, yet
have failed to produce the expected results (NICE, 2011;
Stanzione & Tropepi, 2011).
The challenge of treating AD has been approached with
not only pharmacological strategies, but also various neu-
romodulation techniques as adjuvant, alternative or com-
plementary therapeutic strategies, which seek to inhibit or
modify specic neuronal circuits. Among these techniques
is repetitive transcranial magnetic stimulation (rTMS),
which consists in inducing a pulsating electric current to
the cerebral cortex, which allows the non-invasive, focused,
safe, and painless stimulation of the brain (Freitas et al.,
2011; Rotenberg et al., 2014). In rTMS, several successive
pulses are applied rhythmically in the same sequence, and
allow the modulation of cortical excitability (Rossi et al.,
2009). A frequency is considered to have a low stimulation
when it is equal to or above one pulse per second (1 Hz),
which fosters inhibitory activity, and to have a high stimu-
lation when it is between 5 Hz and 20 Hz, which causes an
increase in cortical excitability (Cotelli, Manenti, Zanetti,
& Miniussi, 2012; Higgins, 2008; Hsu, Ku, Zanto & Gaz-
zaley, 2015; Manenti, Cotelli, Robertson & Miniussi, 2012;
Nardone et al., 2014).
rTMS has demonstrated its benet for various neuro-
psychiatric disorders such as cerebral infarction, depres-
sion, and anxiety. It has principally an eect on mood, ex-
ecutive functions, learning, memory, and attention. A study
of rTMS conducted among young adults, elderly adults,
and persons with memory impairment examined memory
processes, and established the role of the right dorsolateral
prefrontal cortex (DLPFC), concluding that it is involved in
recovering information from the episodic memory. The role
of the left DLPFC was determined during the codication
of new events, in terms of both precision and reaction times.
This nding demonstrated the role of the DLPFC and sug-
gests that it is a fundamental element for memory perfor-
mance induced by semantic processing (Devi et al., 2014;
Innocenti et al., 2010; Manenti et al., 2012).
It has been suggested that the long-term eect of rTMS
is due to changes in activity in a network of cortical and
subcortical areas, rather than simply the local inhibition or
excitement of an individual area. The evidence indicates
that the brain operates through networks distributed in a
exible, interactive manner, which have an impact on both
cognition and behavior. It has therefore been considered
that the modication of one node of a network could aect
the entire network, and that the results in one area could
have eects on various functions based on the node of ac-
tivation or on which interconnected networks are activated
(Miniussi & Ruzzoli, 2013).
rTMS in Alzheimer’s has been shown to induce pro-
longed functional changes in the cerebral cortex with var-
ious studies that have evaluated changes in cortical excit-
ability, but very few studies have addressed the possible
clinical impact on cognitive yield, BPSD, and functionality
in patients with AD. Accordingly, there is a need to dene
the parameters for the estimulation to be used, which could
be recognized as an indication for the treatment of the dis-
ease (Lefaucheur et al., 2014; Miniussi & Ruzzoli, 2013;
Nardone et al., 2012).
This review aims to show the most relevant results and
provide information on the stimulation applied thus far in
various studies. This will make it possible to understand the
current situation and propose future studies.
This update aims to describe the eects of rTMS on
cognition, the behavioral and psychological symptoms of
dementia (BPSD), and functionality in patients with AD,
considering the various modes of application.
Search strategy
To integrate this revision, a search was conducted in several
databases (PubMed, ScienceDirect, and PsycInfo) of arti-
cles published between 2006 and 2016. The following route
was used: “Alzheimer’s disease” AND “transcranial mag-
netic stimulation” AND “cognition” NOT “motor cortex”
NOT “deep brain stimulation”. The terms “motor cortex”
and “deep brain stimulation” were excluded, as this revi-
sion did not consider studies that analyzed motor regions by
applying TMS or interventions with deep cerebral stimula-
tion. The articles considered for the revision were clinical
Repetitive transcranial magnetic stimulation and Alzheimer’s disease
173Vol. 40, No. 4, julio-agosto 2017
trials, case reports, narrative reviews, systematic reviews,
and meta-analyses.
Selection of articles
Articles with the following inclusion criteria were reviewed:
1. measuring the eects of rTMS on cognition using instru-
ments to evaluate cognitive functioning or state and/or; 2.
measuring the eects of rTMS on other clinical variables
such as functionality (basic, instrumental or advanced ac-
tivities) and psychological and behavioral symptoms in
patients with AD, using clinimetric instruments to evaluate
these aspects; 3. articles published in English. Articles that
used other techniques of neuromodulation, studies that only
addressed changes in cortical excitability, and those with
non-human subjects were excluded.
A qualitative analysis was undertaken of the type of vari-
ables, that is, descriptions of the improvement or increase
in cognitive functions, BPSD and/or functionality were
considered as indicators of intervention using rTMS. There
is also a description of the design and parameters of stimu-
lation used in the various studies conducted thus far on AD
(localization, frequency, pulses, number of sessions).
A total of 294 articles were identied, which are disaggre-
gated by search engines for scientic information in Fig-
ure 1. Of these, 267 were excluded because they presented
repeated records, dierent neuromodulation techniques to
rTMS, non-human subjects of study, book chapters or let-
ters to the editor. Of the remaining 27 articles, the title and
abstract were reviewed in a second lter and nine articles
were excluded for various reasons mentioned in Figure 1.
Finally, 18 articles were included in the narrative review.
Table 1 shows the clinical trials and a case report in
which rTMS was applied in patients with AD, and which
studied cognition, behavior or functionality.
Modalities and eects of repetitive
transcranial magnetic stimulation (rTMS)
in Alzheimer’s disease
The rst studies of rTMS and AD were conducted by Cotel-
li et al. in 2006 and 2008. The former included 15 patients
with moderate AD, and assessed the eect of rTMS applied
on the left DLPFC and right DLPFC at high frequencies (20
Hz), compared with a placebo. It observed the eects of ap-
plying a session on linguistic designation and performance
during the performance of designation tasks as a cognitive
measurement. The study showed an improvement in desig-
nating the action after the stimulation in comparison with
the placebo group. In the second study, this test was only
replicated on patients with mild AD; the study included 24
patients with mild and moderate to severe AD. In both stud-
ies, since the rTMS was applied in a single session, long-
term eects were not evaluated. Moreover, in both cases,
rTMS was applied during the task, which aects the mod-
ulation of cortical excitation and attempts to change cogni-
tive performance. These studies suggested that rTMS can
restore or compensate for damaged function, and proposed
this alternative as a tool for cognitive rehabilitation (Cotelli,
Manenti, Cappa, Zanetti & Miniussi, 2008; Cotelli et al.,
A trial designed to compare the long-term eciency of
rTMS at high frequencies versus low frequencies, applied
on the bilateral DLPFC, studied the cortical excitability and
cognitive function of patients with mild to moderate Alz-
heimer’s disease. All the patients received a daily session
for ve consecutive days. The group that was stimulated
at high frequencies (20Hz) improved signicantly more
than the group stimulated at low frequencies (1 Hz) in the
evaluations conducted through the Mini Mental State Ex-
amination, Scale for Instrumental Everyday Activities, and
Scale for Geriatric Depression, and their eect remained
three months after the end of the treatment. Thus, the au-
thors conclude that rTMS applied at high frequencies can
be a useful instrument for treating mild to moderate AD
(Ahmed, Darwish, Khedr, El serogy & Ali, 2012).
SearchFirst lterSecond lterInclusion
Articles identied
through database search
(n = 294)
Registers excluded
(duplicates, dierent
topic or other format)
(n = 267)
Registers selected
for eligibility
(n = 27)
Articles included
for narrative review
(n = 18)
Reason for articles
excluded and number
Dierent objective: 6
Language other
than English: 3
Reading of title
and abstract.
Regiters excluded (n = 9)
Number of articles
identied by database:
• PubMed:8
• ScienceDirect:75
• PsycInfo:211
Figure 1. Flow chart of selection process for narrative review.
Alcalá Lozano et al.
174 Vol. 40, No. 4, julio-agosto 2017
Table 1
Studies of repetitive transcranial magnetic stimulation conducted on Alzheimer’s disease
Age in years
Average (DE)
(rTMS/placebo) MMSE Localization
rTMS frequency/
total pulses
of sessions
Improvement or increase in cognitive
functions, BPSD and./or functionality.
Cotelli et. al.,
15 76.6 (6.0) 17.8 Left / right FC 20 Hz (600 ms)
*On line
1↑ Designation of action between groups.
Cotelli et. al.,
24 76.6 (5.8) /
75.0 (6.2)
Mild AD 19.7 /
Moderate AD
Left DLPFC 20 Hz
*On line
1 Designation of action in the mild AD
group in comparison with the moderate.
Cotelli et .al.,
10 71.2 (6.1) /
74.4 (3.8)
EMTr 16.2 /
placebo 16.0
Left DLPFC 20 Hz / 2000 Group 1: 20
Group 2:
10 of rTMS
and 10 placebo
↑ Auditory comprehension of phrases
after 2 weeks of treatment.
↑ Auditory comprehension of phrases 8
weeks after end of treatment.
Bentwich et al.,
8 75.4 (4.4) 18 - 24 Day 1:
Broca Wernicke
Day 2:
Bilateral PSAC
10 Hz / 1200 30 (Day 1 and 2
6 follow-up
every 15 days
↑ 4.2 points after 6 weeks and 4 points
after 4.5 months of treatment.
↑ 4.9 points after 6 weeks and 1.6 points
after 4.5 months of treatment.
↑ 3.4 points after 6 weeks and 2.4 after
4.5 months of treatment.
HAM-D and NPI do not present signi-
cant dierences.
Ahmed et al.,
45 20 Hz
65.9 (5.9);
1 Hz
68.6 (6.7) /
68.3 (4.9)
Moderate AD
Group 20Hz
rTMS 14.7 /
placebo 13
Group 10 Hz
rTMS 12.7 /
placebo 13.9
Bilateral DLPFC 20 Hz
1 Hz / 1200
5 MMSE, Everyday activities and
GDS-Y in 20 Hz group in comparison
with 1 Hz group.
Haen et al.,
1 75 20 Left DLPFC 10 Hz / 2000 10 MMSE (episodic memory and informa-
tion processing speed) and other psycho-
logical tests.
Possible eects one month after treat-
Rabey et .al.,
15 76.6 (8.9) /
75.4 (9.07)
18 - 24 Day 1:
Broca Wernicke
Day 2:
Bilateral SP
10 Hz / 1300 30 (Day 1 and 2
6 follow-up
every 15 days
↑ 3.7 points after 6 weeks and 3.52
points after 4.5 months of treatment.
3.57 points and 3.6 after 4.5 months
of treatment NPI without signicant dif-
Lee et al.,
rTMS +
72.1 (7.6) /
70.3 (4.8)
Mild AD 18-20 /
Moderate AD
Day 1:
Broca Wernicke
Day 2:
Bilateral PSAC
10Hz / 1300 30 (Day 1 and 2
↑ 4.28 points for mild AD compared to
moderate AD. Eect maintained for 6
weeks after the rTMS.
Recovery of words, recognizing
words, orientation, designating objects,
ngers and orders, with rTMS+TC,
compared with placebo.
↑ 1.5 after 6 weeks and 2 after 6 weeks
with rTMS+TC.
2.4 after 6 weeks and 2.6 later, with
GDS-Y did not improve signicantly.
Wu et al.,
71.4 (4.9 /
71.9 (4.8)
rTMS 15.3 /
placebo 15.2
Left DLPFC 20 Hz / 1200 20 BEHAVE-AD improved 73.1% versus
42.3 of the placebo group.
↑ 5.21 Total.
↑ 3.85 Subscale for memory.
↑ 3.19 Subscale for language.
↑ 1.61 Subscale for praxis.
↑ 1.04 Subscale for attention.
Note: n = number of subjects; aDesign = Randomized, double blind and controlled with placebo; bCase report; *On line = administering rTMS during performance of task ; CT = Cognitive
training; DLPFC = dorsolateral prefrontal cortex; PSAC = Parietal Sensory Association Cortex; ADAS-cog = Alzheimer Disease Assessment Scale-cognitive section; ADAS-ADL = Alzheimer
Disease Assessment-Activities of Daily Living; MMSE = Mini Mental State Examination; CGIC = Clinical Global Impression of Change; HAM-D = Hamilton Rating Scale for Depression; NPI
= Neuropsychiatric Inventory; GDS-Y = Geriatric Depression Scale; BEHAVE-AD = Behavioral Pathology in Alzheimer’s Disease Rating Scale; ↑ = increase/improvement.
Repetitive transcranial magnetic stimulation and Alzheimer’s disease
175Vol. 40, No. 4, julio-agosto 2017
A case report was undertaken using rTMS as an ad-
juvant treatment for mild AD, where the left DLPFC was
stimulated. Improvements were observed in cognitive per-
formance, in particular episodic memory, and information
processing speed tests. Moreover, the spouse reported im-
provements in functionality and in beginning activities such
as walking, writing or using the telephone, and no adverse
eects were reported, as the treatment was well tolerated
(Haen et al., 2012).
In addition to the DLPFC, other targets have been pro-
posed to apply rTMS in patients with AD. The areas includ-
ed are Wernike and Broca, as well as the cortical regions
of somatosensory association in the right and left parietal
lobes, in alternating stimulation sessions. In a trial that stim-
ulated these areas, improvements were reported for up to
4.5 months of follow-up in cognition and general function-
ing measurements. This study researched the combination
of rTMS with cognitive training (CT) in patients with Alz-
heimer’s disease and evaluated a possible synergic eect
of CT associated with rTMS, comparing it with only CT
in a sample of eight patients with mild and moderate AD.
It was applied in a combined treatment regimen for ve
sessions a week for six weeks, followed by maintenance
sessions (twice a week) for six months. It was applied in
the aforementioned areas and CT tasks adjusted to these
areas were developed. Even considering the sample size,
improvements were observed in the evaluation scales, but
without statistical signicance: Alzheimer´s Disease As-
sessment Scale (ADAS-cog), Clinical Global Impression of
Change (CGI), Mini Mental State Examination (MMSE),
Evaluation Scale of Daily Activities, and Hamilton Depres-
sion Scale. There were no changes in the Cummings neuro-
psychiatric inventory (NPI) (Bentwich et al., 2011).
Another randomized and double-blind trial included 15
patients and compared the eciency and safety of rTMS
with CT against simulated stimulation. rTMS was applied
to the treatment group for an hour, ve sessions a week,
followed by bimonthly sessions for three months. There
were improvements in the average score for ADAS-cog and
the average of CGI after six weeks and after 4.5 months
of treatment, in comparison with the simulated stimulation
group. Again, there were no signicant dierences when
these were evaluated with the NPI (Rabey et al., 2013).
In a study published recently, in which a larger sam-
ple of 26 patients was used, CT was combined with rTMS
and applied in the same areas as the Bentwich group. The
results showed a signicant improvement in the domains of
memory and language with the combination of both treat-
ments (Lee, Choi, Oh, Sohn & Lee, 2016). In the three trials
mentioned, in which various areas of stimulation were pro-
posed, these were localized by a neuronavigator. It is pro-
posed that CT and rTMS localized with a neuronavigator
and the system called “NeuroAD” oer a new, safe, and
ecient therapy to improve cognitive function, which rep-
resents an adjuvant therapy to AChEIs, in particular in the
mild phase of AD (Anderkova & Rektorova, 2014; Fonse-
ca, Navatta, Bottino & Miotto, 2015).
As regards the number of sessions administered, the
study conducted to evaluate the improvement in language
performance in AD after rTMS showed that administering
rTMS for four weeks did not produce additional improve-
ment in performance, in comparison with the application
of rTMS during two weeks. This suggests that two weeks
of rTMS provide sucient evidence of an improvement in
behavior in patients with AD (Cotelli et al., 2011).
A trial examined the eect of rTMS at 20 Hz on BPSD
in patients with AD, and also evaluated the cognitive eect.
Twenty sessions were applied (ve sessions a week for four
weeks) on the left DLPFC, and 27 patients, to whom rTMS
and 1mg of risperidone was applied, were compared with
another 27 patients who had received the simulated maneu-
ver and 1 mg of risperidone. After four weeks, half the to-
tal scores on both the Behavioral Pathology in Alzheimer´s
Disease Rating Scale (BEHAVE-AD), used to measure be-
havioral symptoms, and the ADAS-cog in the two groups
decreased when compared to the baseline. However, in the
group to which rTMS was applied, the dierence was 30%
higher in BPSD and signicantly higher in the ADAS-cog
scores (Wu et al., 2015).
Other studies on the treatment of dementia have imple-
mented similar treatment to that for depression, including
ve sessions per week for two, four, and six weeks, some
with maintenance and follow-up evaluations. Since the
protocols for the treatment of depression have been eec-
tive, similar results are expected for dementia. One exam-
ple of this is described in a comparative study that applies
high-frequency and low-frequency rTMS (20 Hz vs. 1Hz)
and a group of simulated stimulation applied in the DLPFC
bilaterally for patients with AD. All the patients received
one session a day for ve consecutive days, and displayed
signicant improvements on the scales of geriatric depres-
sion, MMSE, and the evaluation of instrumental everyday
activities (Ahmed et al., 2012).
One publication suggested that the optimal specica-
tions for the use of rTMS as treatment for depression are
very similar to those employed in studies to treat AD. In-
deed, the intensities used to treat dementia are between 90
and 110%, which is a similar range to that used in depres-
sion, which is 90 to 120%; the frequencies suggested for
depression are between 5 and 20 Hz, and frequencies of 10
and 20 Hz have been used to treat dementia (Fitzgerald &
Daskalakis, 2013).
Since Alzheimer’s disease aects millions of persons and
its incidence is increasing, it is crucial for new therapeutic
Alcalá Lozano et al.
176 Vol. 40, No. 4, julio-agosto 2017
approaches to be developed as there is currently no treat-
ment that prevents or halts the eects of AD completely.
Due to the need for dierent options to those approved by
the FDA (acetylcholine-esterase inhibitors and memantine)
and other health regulation agencies across the world, stud-
ies were conducted with rTMS to consider it as a therapeu-
tic alternative capable of improving cognition, BPSD, and
consequently functionality. This would enable families to
be closer to patients and decrease polypharmacy; it has also
shown to be a safe technique since few adverse eects have
been reported.
Accordingly, there is growing interest in neuromod-
ulation techniques applied to AD, including rTMS, which
will require a study of its physiological impact. The evi-
dence suggests that this involves: a) The modication of
synaptic plasticity through long-term reinforcement and in-
hibition mechanisms. The evidence obtained from studies
that have addressed changes in cortical excitability suggests
that early intervention using rTMS could favor the resto-
ration of partially lost connections. Compensation networks
could be restored to recover deteriorated function, and these
networks could include perilesional areas or contralateral
counterpart cortical regions with a similar anatomic struc-
ture, which could thus perform the impaired functions.
b) An increase in cerebral blood ow when stimulated at
a high frequency. c) The repetitive aspects of TMS could
have positive eects on cognitive performance through the
modication of cortical oscillatory activity. It has also been
postulated that neurotrophic factors could participate as a
mechanism induced by rTMS. rTMS could oer a reliable
method to characterize important neurophysiological and
physiopathological aspects of AD, and a decrease in cortical
plasticity and connectivity/reactivity has been identied in
comparison with healthy persons and even with other de-
mentias. As a result, rTMS can be proposed as a promising
therapy for AD (Bentwich et al., 2011; Brem et al., 2013;
Freitas et al., 2011).
In this regard, a decrease in cellular plasticity could be
the basis for the motor symptoms of AD, and the result of a
decit of neurotransmission depending on N-methyl-D-as-
partate (NMDA) receptors, as these are primary compo-
nents in cellular plasticity (Freitas et al., 2011).
The dorsolateral prefrontal cortex (DLPFC) has been
an area of interest for the application of rTMS, as it is a re-
gion localized in the lateral face of the interior frontal gyrus,
which makes it accessible to stimulation by the rTMS coil.
It is also closely interconnected with structures of the limbic
system that have been indicated as important intermediar-
ies in the modulation of feelings and executive functions.
Numerous neuroimaging studies have clearly demonstrated
the existence of a more widely distributed neuronal network
that includes the bilateral dorsolateral prefrontal cortex, me-
dial temporal lobes, and parietal cortexes that maintain the
functioning of the memory (Rossi et al., 2009). As a result
of its interconnection with other regions of the brain, the
DLPFC plays an important role in executive functions. This
region coordinates functions with the rest of the brain. The
DLPFC also plays a role in working memory, choice, and
decision-making, functions that are aected by dementia
(Rutherford, Gole & Moussavi, 2013).
rTMS could be used as a potent tool not only for re-
search into the participation of cerebral areas in a specic
cognitive task, but also the design of interventionist ther-
apies in persons with a deterioration in cognition and AD
(Manenti et al., 2012).
Treatment using rTMS has achieved signicant im-
provement in the scores on the ADAS-cog scale in a com-
parable manner to the treatments suggested by international
guidelines. However, it is not known how long the eect
lasts, as there have not been enough studies to determine
this in the long term. It is known that the typical annual
deterioration in patients without treatment is 2 to 4 points of
the MMSE and 7 points of the ADAS-cog scale.
Studies conducted with rTMS thus far have shown
an improvement in various stages of the disease, which
may have a clinical impact not only for AD but also for
its prodromal stages, based on the general hypothesis that
the mechanisms of cortical plasticity and altered cerebral
networks are the proximal causes of cognitive decline and
make a critical contribution to the disease.
The few studies conducted on rTMS in Alzheimer’s
disease to date display considerable variations in the meth-
odological design. For example, selection criteria vary from
one study to another (age of onset of disease, length, and
type of treatment previous to the start of the study and all
the risk factors associated with AD), which makes it di-
cult to obtain homogeneous samples. The same occurs with
some of the measurement instruments: the selection of neu-
ropsychological tests used to measure cognitive functions,
BPSD, and even functional variables are not standardized
(Nardone et al., 2014). The lack of multicenter studies may
cause another limitation, as one of the advantages of these
studies is establishing a better basis for the subsequent gen-
eralization of ndings. On the other hand, when stimulation
is applied, there is a variety in the parameters and pulses
used, the frequencies ‒ranging from low to high frequency
(5 Hz, 10 Hz, 20 Hz)‒, the areas of application and type of
location (10-20 system or by neuronavigation), the moment
of application and of evaluation (during or after stimula-
tion), the duration of the eect, and whether there is also
a comparison with currently approved drugs or cognitive
rehabilitation or stimulation techniques.
Clinical trials conducted with rTMS on patients with
Alzheimer’s disease, although mainly preliminary, show
promising results and require more research to conrm
them and identify the most ecient method, comparing re-
sults by including various, less studied cortical areas, and
assessing how long the results remain in cognitive symp-
Repetitive transcranial magnetic stimulation and Alzheimer’s disease
177Vol. 40, No. 4, julio-agosto 2017
toms, BPSD, and functionality (Lefaucheur et al., 2014).
Importantly, there are other limitations in the samples stud-
ied in the various trials that have examined the use of rTMS,
including the heterogeneity of AD and its many comorbid-
ities, in addition to the lack of accurate knowledge on the
action mechanism of rTMS.
The overview suggests that future studies with im-
proved experimental designs (larger samples, with an eval-
uation of various stimulation parameters), using clinical,
cognitive, and behavioral instruments and neurophysiolog-
ical measurements with greater sensitivity and specicity
will achieve more solid interventions and make better com-
parisons in the studies. It is also necessary to determine how
long the eect remains for the dierent modalities of appli-
cation, and the number of sessions required for treatment,
since AD is a chronic, degenerative process, which makes
it dierent from other conditions such as depression, which
are resistant to treatment, for which rTMS has already been
approved as a method of treatment by the FDA (Brem et al.,
2013; Freitas et al., 2011).
The studies presented in this review suggest the thera-
peutic potential of rTMS in patients with mild to moderate
AD by observing the eects that benet some of the cogni-
tive domains aected by AD, improve the BPSD, and lead
to better performance in functionality. The specic benets
of rTMS can translate into benets for patients in their ev-
eryday activities, notably their ability to communicate with
the caregiver and the behavior associated with the disease,
thus improving their quality of life and even limiting the use
of medical services for early conditions and institutional-
ization. More controlled studies are required with dierent
methodological designs and more participants, principally
in conjunction with cognitive rehabilitation techniques, to
obtain clearer data, identify the most ecient parameters
for stimulation, and compare results with the participation
of less studied cortical areas. This will make it possible to
describe how long the eect of the treatment lasts and deter-
mine the precise mechanism of action in cognitive deterio-
ration processes. These results will be employed to design
new research as strategies for treating and rehabilitating
patients with AD.
Conicts of interest
The authors state that there are no conicts of interest.
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... Clinical trials using rTMS in AD have found positive effects on cognition, behavior and function (2)(3)(4). High frequency (HF) rTMS applied on the right or left DLPFC has shown improvement in language abilities, in cognitive function, functionality and behavior for up to 3 months (5). Other studies have shown similar results on cognition, behavior and function using HF applied over several cortical sites in a complex design (6). ...
Full-text available
Brackground Current treatments for Alzheimer’s disease (AD) have a limited clinical response and methods, such as repetitive transcranial magnetic stimulation (rTMS), are being studied as possible treatments for the clinical symptoms with positive results. However, there is still seldom information on the type of rTMS protocols that deliver the best clinical improvement in AD. Objetive To compare the clinical response between a simple stimulation protocol on the left dorsolateral prefrontal cortex (lDLPFC) against a complex protocol using six regions of interest. Methods 19 participants were randomized to receive any of the protocols. The analysis of repeated measures evaluated the change. Results Both protocols were equally proficient at improving cognitive function, behavior and functionality after 3 weeks of treatment, and the effects were maintained for 4 weeks more without treatment. Conclusion We suggest rTMS on the lDLPFC could be enough to provide a clinical response, and the underlying mechanisms should be studied.
... Although a number of studies have suggested that brain stimulation may represent a promising tool targeting cognitive impairments in AD and other dementing illnesses [4], there is still seldom and contrasting information on the therapeutic potential and the mechanism of action of these techniques. A handful of studies reported that increasing excitation over temporal/parietal and prefrontal areas using excitatory brain stimulation methods, such as anodal tDCS or high-frequency rTMS enhances cognitive functions in patients with mild cognitive impairment (MCI) and AD, as well as in elderly with subjective memory complaints [12][13][14][15][16][17][18][19][20][21] Looking specifically at the effects of anodal tDCS on episodic memory in AD, Ferrucci et al. [22] reported an improvement in a word recognition memory test in ten mild AD patients following bilateral anodal tDCS delivered over the temporo-parietal areas. Boggio et al. [23] reported enhanced visual recognition memory performance in ten mild-tosevere AD patients after anodal tDCS applied over the temporal and the prefrontal cortices. ...
Background: The lack of effective pharmacological or behavioral interventions for memory impairments associated with Alzheimer's disease (AD) emphasizes the need for the investigation of approaches based on neuromodulation. Objective: This study examined the effects of inhibitory repetitive transcranial magnetic stimulation (rTMS) of prefrontal cortex on recognition memory in AD patients. Methods: In a first experiment, 24 mild AD patients received sham and real 1Hz rTMS over the left and right dorsolateral prefrontal cortex (DLPFC), in different sessions, between encoding and retrieval phases of a non-verbal recognition memory task. In a second experiment, another group of 14 AD patients underwent sham controlled repeated sessions of 1Hz rTMS of the right DLPFC across a two week treatment. Non-verbal recognition memory task was performed at baseline, at the end of the two weeks period and at a follow up of 1 month. Results: Right real rTMS significantly improved memory performance compared to right sham rTMS (p = 0.001). Left real rTMS left the memory performance unchanged as compared with left sham rTMS (p = 0.46). The two sham conditions did not differ between each other (p = 0.24). In the second experiment, AD patients treated with real rTMS showed an improvement of memory performance at the end of the two weeks treatment (p = 0.0009), that persisted at 1-month follow-up (p = 0.002). Conclusion: These findings provide evidence that inhibitory rTMS over the right DLPFC can improve recognition memory function in AD patients. They also suggest the importance of a new approach of non-invasive brain stimulation as a promising treatment in AD.
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Background: Behavioral and psychological symptoms of dementia (BPSD) occur in 70-90% of patients at different stages of Alzheimer's Disease (AD), but the available methods for managing these problems are of limited effectiveness. Aim: Assess the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS), applied over the left dorsolateral prefrontal cortex (DLPFC), on BPSD and cognitive function in persons with AD. Methods: Fifty-four patients with AD and accompanying BPSD were randomly divided into an intervention group (n=27) and a control group (n=27). In addition to standard antipsychotic treatment, the intervention group was treated with 20Hz rTMS five days a week for four weeks, while the control group was treated with sham rTMS.The Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog), and the Treatment Emergent Symptom Scale (TESS) were administered by raters who were blind to the group assignment of patients before and after four weeks of treatment. Results: Twenty-six subjects from each group completed the study. After four weeks of antipsychotic treatment with adjunctive real or sham rTMS treatment, the mean (sd) total BEHAVE-AD scores and mean total ADAS-Cog scores of both groups significantly decreased from baseline. After adjusting for baseline values, the intervention group had significantly lower scores (i.e., greater improvement) than the control group on the BEHAVE-AD total score, on five of the seven BEHAVE-AD factor scores (activity disturbances, diurnal rhythm, aggressiveness, affective disturbances, anxieties and phobias), on the ADAS-Cog total score, and on all four ADAS-Cog factor scores (memory, language, constructional praxis, and attention). The proportion of individuals whose behavioral symptoms met a predetermined level of improvement (i.e., a drop in BEHAVE-AD total score of > 30% from baseline) in the intervention group was greater than that in the control group (73.1% vs.42.3%, X (2)=5.04, p=0.025). Conclusion: Compared to treatment of AD with low-dose antipsychotic medications alone, the combination of low-dose antipsychotic medication with adjunctive treatment with high frequency rTMS can significantly improve both cognitive functioning and the behavioral and psychological symptoms that often accompany AD.
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Background: There is a close genetic relationship between Alzheimer's disease (AD) and Down syndrome (DS), AD being the most severe mental disorder affecting ageing individuals with DS. The objective of the present study was to evaluate the efficacy of cognitive rehabilitation interventions in DS patients with AD by means of a critical literature review. Summary: Because AD is progressive and irreversible, treatment is aimed at delaying and reducing the cognitive and functional decline in order to preserve or improve quality of life. The effects that pharmacological treatments and cognitive interventions have on elderly individuals with AD are well documented. Recent clinical trials have investigated the use of pharmacological treatment in DS patients with AD, generating preliminary results that have been unfavourable. Key messages: There is a clear lack of studies addressing the efficacy of cognitive rehabilitation interventions in DS patients with AD, and there is an urgent need for studies providing evidence to inform decisions regarding the appropriate choice of treatment strategies.
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Background and purpose: Repetitive transcranial magnetic stimulation (rTMS) has been examined as a potential treatment for many neurological disorders. High-frequency rTMS in particular improves cognitive functions such as verbal fluency and memory. This study explored the effect of rTMS combined with cognitive training (rTMS-COG) on patients with Alzheimer's disease (AD). Methods: A prospective, randomized, double-blind, placebo-controlled study was performed with 27 AD patients (18 and 8 in the treatment and sham groups, respectively, and 1 drop-out). The participants were categorized into mild [Mini-Mental State Examination (MMSE) score=21-26] and moderate (MMSE score=18-20) AD groups. The rTMS protocols were configured for six cortical areas (both dorsolateral prefrontal and parietal somatosensory associated cortices and Broca's and Wernicke's areas; 10 Hz, 90-110% intensity, and 5 days/week for 6 weeks). Neuropsychological assessments were performed using the AD Assessment Scale-cognitive subscale (ADAS-cog), Clinical Global Impression of Change (CGIC), and MMSE before, immediately after, and 6 weeks after the end of rTMS-COG treatment. Results: Data from 26 AD patients were analyzed in this study. There was no significant interactive effect of time between the groups. The ADAS-cog score in the treatment group was significantly improved compared to the sham group (4.28 and 5.39 in the treatment group vs. 1.75 and 2.88 in the sham group at immediately and 6 weeks after treatment, respectively). The MMSE and CGIC scores were also improved in the treatment group. Based on subgroup analysis, the effect of rTMS-COG was superior for the mild group compared to the total patients, especially in the domains of memory and language. Conclusions: The present results suggest that rTMS-COG represents a useful adjuvant therapy with cholinesterase inhibitors, particularly during the mild stage of AD. The effect of rTMS-COG was remarkable in the memory and language domains, which are severely affected by AD.
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A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.
Transcranial Magnetic Stimulation seeks to enable new and existing practitioners to learn and follow established TMS protocols. The individual chapters in this detailed volume describe methods for single and multiple pulse TMS as well as methods for TMS coupled with associated techniques, from electromyography to neuroimaging. The collection promises to facilitate growth and exploration of clinical and experimental TMS. As a volume in the popular Neuromethods series, chapters include the kind of expert implementation advice that encourages successful and reproducible results. Authoritative and practical, Transcranial Magnetic Stimulation will serve not only as a good methodological introduction for those new to this growing field, but also as a source of continual reference for experienced practitioners when re-visiting older, exploring novel, or developing new concepts.