Hindawi Publishing Corporation
Behavioural Neurology
Volume 2015, Article ID 287843, 13 pages
http://dx.doi.org/10.1155/2015/287843
Clinical Study
Transcranial Magnetic Stimulation to Address Mild Cognitive
Impairment in the Elderly: A Randomized Controlled Study
Hellen Livia Drumond Marra,1 Martin Luiz Myczkowski,1 Cláudia Maia Memória,2
Débora Arnaut,1 Philip Leite Ribeiro,1 Carlos Gustavo Sardinha Mansur,1
Rodrigo Lancelote Alberto,1 Bianca Boura Bellini,1 Adriano Alves Fernandes da Silva,1
Gabriel Tortella,1 Daniel Ciampi de Andrade,1,3 Manoel Jacobsen Teixeira,1,3
Orestes Vicente Forlenza,2 and Marco Antonio Marcolin1,3
1
Transcranial Magnetic Stimulation Laboratory, Institute of Psychiatry, Faculty of Medicine, University of São Paulo,
Rua Dr. Ovidio Pires de Campos 785, 05402-010 São Paulo, SP, Brazil
2
Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo,
Rua Dr. Ovidio Pires de Campos 785, 05402-010 São Paulo, SP, Brazil
3
Division of Neurological Surgery, Pain Center, Department of Neurology, University of São Paulo,
Avenida Dr. Enéas de Carvalho Aguiar 255, Sala 5084, Cerqueira César, 05403-900 São Paulo, SP, Brazil
Correspondence should be addressed to Hellen Livia Drumond Marra; hellen.marra@gmail.com
Received 14 November 2014; Revised 5 February 2015; Accepted 1 April 2015
Academic Editor: Liana Palermo
Copyright © 2015 Hellen Livia Drumond Marra et al. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique with potential to improve memory. Mild
cognitive impairment (MCI), which still lacks a specific therapy, is a clinical syndrome associated with increased risk of dementia.
This study aims to assess the effects of high-frequency repetitive TMS (HF rTMS) on everyday memory of the elderly with MCI. We
conducted a double-blinded randomized sham-controlled trial using rTMS over the left dorsolateral prefrontal cortex (DLPFC).
Thirty-four elderly outpatients meeting Petersen’s MCI criteria were randomly assigned to receive 10 sessions of either active TMS
or sham, 10 Hz rTMS at 110% of motor threshold, 2,000 pulses per session. Neuropsychological assessment at baseline, after the
last session (10th) and at one-month follow-up, was applied. ANOVA on the primary efficacy measure, the Rivermead Behavioural
Memory Test, revealed a significant group-by-time interaction (𝑝 = 0.05), favoring the active group. The improvement was kept
after one month. Other neuropsychological tests were heterogeneous. rTMS at 10 Hz enhanced everyday memory in elderly with
MCI after 10 sessions. These findings suggest that rTMS might be effective as a therapy for MCI and probably a tool to delay
deterioration.
1. Introduction
Mild cognitive impairment (MCI) is an intermediary status
between normal aging and very early dementia [1], wherein
individuals have subjective cognitive deficits and objective
memory impairment, without affecting their daily activities
[2].
MCI is not necessarily a prodrome of Alzheimer’s disease
(AD), although evidence suggests that patients with the
amnesic subtype (a-MCI) are likely to progress to AD [1, 3–7].
Episodic memory decline is the most frequent impairment
in patients who will progress to AD (MCI due to AD)
[8, 9]. Patients with MCI typically show impairment in
delayed recall [10]. A combination of multivariate episodic
memory tests increases the prediction of AD converters
and identifies the profile associated with each MCI subtype
[11]. Likewise, everyday memory, which includes episodic
memory, is impaired [12]. Difficulties in episodic memory are
common in healthy aging [13], and studies revealed that the
Rivermead Behavioural Memory Test (RBMT), a brief battery
2
test for everyday memory, is able of differentiate between
individuals with MCI, AD, and healthy controls [12, 14].
Even though some older adults perform as well as young
adults [15], memory processing declines with senescence,
particularly in episodic memory tasks, which involve encoding and retrieval of information. Episodic memory processes
is dependent on the integrity of the medial temporal lobe
and the interaction with lateral prefrontal cortex (PFC) [13,
16]. The posterior parietal cortex is also involved in this
network [3, 4, 17]. Imaging studies have evidenced that
neural activity reductions occur primarily in the left PFC
and temporooccipital regions during encoding, and right
PFC was important for retrieval [18–21]. This rationale is
clinically consistent with the HERA (hemispheric encoding/retrieval asymmetry) model, which predicts that the
younger adults’ left PFC specializes in encoding and the
right PFC specializes in retrieval [15, 18, 19, 21]. In normal
aging, PFC activation tends to be less asymmetric during
memory tasks, as indicated by the HAROLD (hemispheric
asymmetry reduction in older adults) model. Cabeza et al.
[15] compared PFC activity in younger adults and in low/high-performing older adults during memory tasks using
PET and fMRI. The results suggest that low-performing
older adults recruited a similar network as young adults but
used it inefficiently, whereas high-performing older adults
counteracted age-related neural decline through a plastic
reorganization of neurocognitive networks.
Such cognitive deficits, even mild, cause great distress to
the elderly with MCI, who feel that their autonomy, independence, and ability to lead high-quality lives are negatively
affected. These impairments are often considered the most
debilitating aspect of aging [22].
Transcranial magnetic stimulation (TMS) emerges as a
therapeutic tool with clinical benefits in neurological and
psychiatric diseases. The method is based on generating
a rapidly variable magnetic field over the scalp in awake
subjects, which induces a transitory electric current in the
cortical surface and modulating neuronal function directly
underneath the coil, and in connected brain regions [23–25].
Repetitive TMS (rTMS) at low frequencies (<1 Hz) reduce
cortical excitability, whereas high-frequency rTMS (>1 Hz)
facilitates neuronal excitability [26, 27].
Thereby, TMS fulfills an important contribution for
studying mechanisms of cognitive function and behavioral
plasticity in the human brain [28]. As rTMS can interfere
transiently with cortical processing [29], change in behavioral
and cognitive performances occurs conversely. Repetitive
TMS (rTMS) promote modulation of cortical circuits by
inducing changes in synaptic plasticity and reorganization of
the cortex, modulating neuronal activity beyond the stimulation period [30–32]. The after-effects of repeated sessions
may outlast for days and even weeks [4, 33]. Evidence suggests
that off-line rTMS might outlast the stimulation period by
synaptic LTP and LTD mechanisms [34–36], even at brain
sites distant from those stimulated [18, 37].
HF rTMS induces upregulation of N-methyl-Daspartate (NMDA) receptor activity and increases gammaaminobutyric acid (GABA) mediated inhibition [38, 39].
rTMS might reach other neuronal processes, such as genetic
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and protein regulation, and circuit-level patterns, such as
network oscillations [40] and changes in neural signaling
by triggering the activation of neuromodulators, such as
acetylcholine, dopamine, norepinephrine, and serotonin
[41]. Moreover, rTMS also leads to nonneuronal processes,
such as changes in blood flow [40, 42]. Brain derived
neurotrophic factor (BDNF) is part of the neural signals
for synaptic plasticity [34, 43]. It is, however, unclear by
which mechanism rTMS induces lasting effects on the brain.
Nevertheless, such effects are often described as LTD- or
LTP-like, respectively, long-term depression and potentiation
[30].
With regard to TMS and memory studies, Turriziani et
al. [18] reported improvement in recognition memory (verbal
and nonverbal) performance after online LF rTMS over right
DLPFC of healthy and MCI individuals. Manenti et al. [19]
studied the effect of online HF rTMS (20 Hz, 90% MT) during
encoding or retrieval of associated and nonassociated word
pairs. A predominance of left DLPFC over right DLPFC was
observed in the low-performing elderly. The same research
group [44] conducted a trial with young subjects, using
online HF rTMS (10 Hz, 90% MT) during retrieval phase of
a face-naming task (episodic memory retrieval). The results
suggest a recruitment of left DLPFC during retrieval without
using retrieval strategies, whereas there is a shift to the right
DLPFC if retrieval strategies were needed. Solé-Padullés et
al. [45] combined functional magnetic resonance imaging
(MRI) and off-line HF rTMS (5 Hz, 80% MT) of the left
and right DLPFC before memory tasks, improving learning
of face-name associations in the elderly with memory dysfunction, with increased metabolic activation of the right
DLPFC. However, an angled active coil was used in the sham
condition [46, 47], and a double-cone coil was used. Rossi et
al. [48] compared the effect of online HF rTMS to the right
and left DLPFC (20 Hz, 90% MT) on visuospatial recognition
memory of subjects <45 and >50 years old. They reported a
greater interference of rTMS to the right DLPFC compared
to to the left DLPFC, in younger subjects. This asymmetry
is progressively vanished as the age increases. The bilateral
interference effects found in the older group corroborates this
reasoning and HAROLD model, which the neural retrieval
correlates modify along aging as a compensatory functioning
of the DLPFC in elders for episodic memory performance.
A recent article [34] reviewed studies on TMS as diagnostic and as therapeutic tool in patients with MCI and AD,
suggesting that rTMS can improve or restore several impaired
cognitive functions in AD and MCI.
Manenti et al. [49] conducted a systematic review on
studies of TMS and episodic memory addressing young and
elderly adults and subjects with memory dysfunction. They
report that, despite numerous studies on the role of the
DLPFC in episodic memory, there are many studies also
demonstrating the involvement of a more distributed neural
network, sustaining this function involving the temporal
lobes and parietal cortices. For example, Cotelli et al. [3], in a
single-case report, applied sessions of HF rTMS (20 Hz, 100%
MT) to the left parietal cortex of one male patient with aMCI, in 10 consecutive days. The observed improvement on
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association memory tasks persisted significantly for 24 weeks
after stimulation.
Finally, [50] conducted a systematic review on cognitive
effects of HF rTMS studies and its potential long-term
effects. The authors included only off-line rTMS studies
using more than a single rTMS session. Baseline subjects
diagnoses addressed young and older subjects, clinical (neurologic/psychiatric) or not. They verified that HF rTMS (10–
20 Hz) is most likely to cause significant cognitive improvement when applied over the left DLPFC, within a range of
10–15 successive sessions and an individual 80–110% MT.
In the present study, we used several neuropsychological
measures, including a very sensitive measure of everyday
memory (RBMT). We firstly aimed to investigate whether
HF rTMS over the left DLPFC improve everyday memory
of elderly patients with MCI and, secondly, to evaluate the
effects of rTMS in executive functions. We have chosen the
left DLPFC as the target area based on previous rTMS and
functional neuroimaging studies of memory in healthy and
in MCI patients. To date, there has been no randomized
controlled double-blind study in this population.
2. Materials and Methods
2.1. Inclusion Criteria. Thirty-four elderly subjects, both
sexes, age ranging between 60 and 74 years, with education
level ≥ 4 years, meeting clinical/neuropsychological criteria
for MCI for at least one year, were recruited from the community, through media advertisements, between October 2010
and June 2011.
The study protocol was approved by the Local Ethics
Committee and all subjects signed informed-consent forms
before enrolling in the trial and registering at Clinicaltrials.gov NCT01292382.
2.1.1. Screening Tests: Part I. In the first step of the screening
(part I), we used the Montreal Cognitive Assessment test
(MoCA test) [51], the Clinical Dementia Rating (CDR) Scale
[28], the 15-item Geriatric Dementia Scale (GDS-15) [52],
the 17-item Hamilton Depression (HAMD-17) Scale [53], and
the14-item Hamilton Anxiety (HAMA-14) Scale [54]. GDS-15
is a diagnostic assessment and evaluates depressive symptoms
in the elderly. The HAMD-17 scale is not a diagnostic instrument but quantifies the severity of depression, comprising
somatic and psychological parameters, and allows a followup of the patient. We use the two scales for screening
due to their different approaches of the depressive disorder,
often underestimated in a geriatric clinical evaluation. The
respective cut-off points for the tests and scales are in Table 1.
2.1.2. Screening Tests: Part II. The second step of the screening
(part II) included lab tests, cerebral MRI scan, and neuropsychological evaluation.
(1) Lab Tests. Lab tests were performed for clinical screening
in order to detect and exclude clinical secondary causes
of dementia or cognitive deficits, such as hypothyroidism,
SIDA, vitamin B12 and folate deficiency, excessive alcohol
3
Table 1: Screening tests for MCI cut-off points.
Screening battery
MoCA Test1
CDR2
GDS-153
HAMD-174
HAMA-145
1
Cut-off scores
≤24
=0
<5
<7
<8
MoCA test: Montreal Cognitive Assessment test; 2 CDR: Clinical Dementia
Rating; 3 GDS-15: 15-Item Geriatric Dementia Scale; 4 HAMD-17: 17-Item
Hamilton Depression Scale; 5 HAMA-14: 14-Item Hamilton Anxiety Scale.
consumption, syphilis, and risk factors for cardiovascular
disease, such as atherosclerosis and diabetes. The results were
required to be normal: complete blood count (CBC), thyroidstimulating hormone (TSH), T3, T4, folic acid, vitamin B12,
albumin, total cholesterol, HDL/LDL, triglycerides, alanine
transaminase (ALT), aspartate transaminase (AST), gammaglutamyl transferase (GGT), sodium, potassium, urea, creatinine, fasting glucose, VDRL, and ELISA anti-HIV test.
(2) Brain MRI Scan. All the patients were examined through
brain MRI scans, analyzed by two experts MD. MRI based
exclusion criteria were evidence of focal or lacunar ischemia,
expansive brain tumors, and hydrocephalus. Changes related
to normal aging, such as foci of rare nonspecific gliosis, were
accepted. All participants had ischemic score Hachinski <7
(original) and <5 (modified by Loeb).
(3) Neuropsychological Examination. Next, a neuropsychological and functional activity battery was applied as inclusion
and outcome criteria: IQCODE, Informant Questionnaire on
Cognitive Decline in the Elderly [55]; B-ADL, Bayer Activities
of Daily Living Scale [56].
Memory Tests. (1) MMSE, Minimental State Examination
[57], an effective 11-question test used as a screening instrument to separate patients with cognitive impairment from
those without it and (2) RBMT, the Rivermead Behavioural
Memory Test [58], a brief test battery to assess everyday
memory, with high level of ecological validity and good
correlation with traditional episodic memory, were carried
out [59, 60]. The RBMT consists of 12 subtests each of which
addresses an important aspect of everyday memory function,
mimicking daily life situations, recalling the first and last
names; immediate and delayed recalling of a route, of a short
story, and of a message (remembering to pick up an envelope
and place it in a specific place); remembering to retrieve a
personal belonging at the end of the examination and to
ask for an appointment when an alarm sounds; immediate
and delayed recalling of photographs of people, and nine
questions about time and spatial orientation. (3) Logical
memory (LM) I and II subtests of Wechsler Memory Scale
[61], to measure encoding, retrieval, and logical memory
ability were carried out. In LM I subtest, two short stories
are presented and the examinee is asked to retell each one
from memory immediately after hearing it. On the other
hand, in LM II the delayed condition assesses long-term
4
narrative memory with free recall and recognition tasks;
(4) RAVLT, Rey Auditory-Verbal Learning Test [62–64], to
evaluate short-term auditory-verbal memory, rate of learning, learning, and retrieval was carried out. Subjects repeat
lists of 15 unrelated words over five different trials and then
again after 30 minutes. From Wechsler Adult Intelligence
Scale III [65], we applied two working memory subtests [66]:
(1) letter-number sequencing test, where the participant is
presented with a series of numbers and letters in random
order and is instructed to repeat back letters and numbers
combinations, first numbers in ascending order and then
letters in alphabetical order [66] and (2) digit span, where
the examinee repeats in direct and reverse order two series
of three and two digits, respectively, read by the examiner.
Executive function tests (frontal lobe tasks) were carried
out. (1) Trail Making Test (TMT) A/B [67–70], to evaluate
psychomotor speed, focus, visual search, mental flexibility,
and sequencing, was carried out. In TMT-A, participants
are asked to draw lines sequentially connecting 25 encircled
numbers; task requirements are similar for TMT-B except for
the fact that the person must differentiate between numbers
and letters. The score represents the amount of time required,
in seconds, to complete each task. (2) Verbal fluency tests,
FAS and animal naming [71], to assess, respectively, the measure of total number of words generated in one minute for the
letters F, A, and S (phonemic fluency) and of animal names
(semantic fluency) were carried out; (3) Victoria Stroop Test
[72] involves three trials. Three cards are presented in the
same sequence and the examinee is instructed to read or call
out the color name as quickly as possible. First, in the “word
trial,” the subject reads words of color names (e.g., red and
blue) printed in black ink; secondly, in the “color trial,” they
identify colors (e.g., rectangles printed in red or blue). Finally,
in the “color-word” response inhibition trial, they must name
the color in which a word is presented, while ignoring the
printed word.
All the scores were adjusted according to age, gender,
and education level, and the tests were administered in
accordance with the standard procedures.
2.2. Exclusion Criteria. The exclusion criteria are listed as
follows: psychiatric disorders (except remitted depression ≥
12 months) and alcohol and/or drug abuse, according to
SCID-P [73], neurological conditions, severe uncontrolled
organic disease, use of pacemaker, history of seizures, history
of major head trauma, history of neurosurgery, and cerebral
metallic artifacts.
2.3. TMS Procedures. Participants were randomly assigned
in a double-blind condition to receive either active or sham
rTMS. Randomization was performed through a random
number generator (http://www.random.org) by a third-party
investigator. Patients and rater were blinded to patients’
treatment.
We used a high-speed magnetic stimulator (MagPro
X100, MagVenture A/S, Farum, Denmark) with a figure-ofeight coil.
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We used for the sham group a placebo coil, with a
mechanical outline and sound level (click) identical to the
active one. The placebo coil’s magnetic shield provides a field
reduction of approximately 90% [46, 74]. The motor threshold (MT) for each patient was determined by contraction
of the right abductor of pollicis brevis muscle of the thumb,
following the method described by Wassermann et al. [75].
rTMS was applied over the left DLPFC at the point located
approximately 5 cm in a parasagittal plane parallel to the
point of maximum stimulation of the short abductor of the
thumb, with the lowest possible intensity in five of ten stimuli.
Subjects assigned to the active group received 10 Hz rTMS
at 110% of MT, each train lasting 5 seconds, with 25-second
intervals (2,000 pulses/day) for 10 consecutive weekdays. The
sham group received the same protocol using a placebo coil.
At the end of the study period, after blinding was
removed, the sham patients were given the option of receiving
active rTMS treatment.
Security and side effects scales were assessed through
a questionnaire as well as clinical evaluation, based on the
most frequent adverse effects of TMS by The Safety of TMS
Consensus Group [33].
2.4. Blind Condition. Patients and team raters were blinded to
the assignment condition; however, for technical reasons, the
clinicians who administered the rTMS were not. The rater was
an experienced neuropsychologist, blinded to the treatment
status and with no contact with the treatment team.
After completing the sessions, patients were asked what
treatment they thought they received and why.
A lab researcher (C. G. M.) generated and concealed the
random allocation sequence, and a secretary (S. L. F.) enrolled
and assigned participants to interventions. The effectiveness
of the blinding was assessed after the follow-up period.
2.5. Efficacy Variables. The primary outcome variable was the
RBMT, for assessing everyday memory.
The secondary efficacy outcome variables were other
neuropsychological domains assessments.
2.6. Statistical Analysis. Statistical analysis was performed by
the SPSS v. 14 (Statistical Package for the Social Sciences,
Chicago, IL, 2005). The Kolmogorov-Smirnov test was conducted to assess whether continuous variables followed a
normal distribution. Statistical significance for all analyses
was set to 𝛼 = 5%.
Descriptive statistical analysis was performed for demographics: contingency tables for categorical variables (gender,
comorbidity, marital status, and education level) and descriptive measures (mean and standard deviation) for continuous
variables (age). The Fisher’s exact test was used to verify
the association of categorical variables. A Student’s 𝑡-test
was used to compare the mean of continuous normally
distributed variables of both groups; the Mann-WhitneyWilcoxon test was used when the variables did not follow a
normal distribution. Two-way analysis of variance (ANOVA)
for repeated measures compared group and time effect, as
compared to the normal distribution of the data or residues.
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5
Table 2: Study structure timing.
(T-2) = screening part I
Clinical and demographic data
MoCA test1 , CDR2 , and GDS-153
HAMD-174 and HAMA-145
Signed informed-consent forms
(T-1) = screening part II
IQCODE6 and B-ADL7
Lab blood sample analysis
Brain MRI/Hachinsky Ischemic Score
SCID DSM-IV8
Randomization
(T0) = 1st cognitive assessment battery§ (baseline)
1st rTMS session
Collateral effects scale
(T1) = 10th rTMS session
2nd cognitive assessment batery
Collateral effects scale
(T2) = one month after T1
3rd cognitive assessment battery
IQCODE and B-ADL
1
MoCA test: Montreal Cognitive Assessment test; 2 CDR: Clinical Dementia
Rating; 3 GDS-15: 15-Item Geriatric Dementia Scale; 4 HAMD-17: 17-Item
Hamilton Depression Scale; 5 HAMA-14: 14-item Hamilton Anxiety Scale;
6
IQCODE: Informant Questionnaire on Cognitive Decline in the Elderly;
7
B-ADL: Bayer Activities of Daily Living Scale; 8 SCID-DSM-IV: Structured
Clinical Interview for DSM-IV Axis I Disorders-Diagnostic and Statistical
Manual of Mental Disorders, fourth edition. § Cognitive assessment battery: MMSE: Minimental State Examination; RBMT: Rivermead Behavioral
Memory Test; WMS: Wechsler Memory Scale; WAIS: Wechsler Adult Intelligence Scale; RAVLT: Rey Auditory-Verbal Learning Test; Stroop: Stroop
Color-Word Interference Test; Trail Making Test A/B.
Table 3: Causes of exclusion in the screening phase.
Excluded
MoCA1 > 26
Education level <4 years
Depressive symptoms (GDS-152 > 5)
Effective bipolar disorder (SCID-DSM IV3 )
Anxiety
Alcoholism
Chronic benzodiazepine use
Sleep disorders
Epilepsy
History of traumatic brain injury
Cerebral MRI4 disorders
Normal pressure hydrocephalus
Lacunar infarct/ischemic stroke
Frontoparietal meningioma
Cerebellar cyst
Neurocysticercosis
Frontal granuloma
Hemorrhagic lesion
Frontal lobe atrophy
Mild AD5
Parkinson disease
Frontotemporal dementia
2.7. Flow Chart. Table 2 shows the overall structure of this
study.
3. Results
3.1. Subjects. Out of 109 screened subjects, 73 did not fulfill
the enrollment criteria. Among the 36 subjects left, 17 were
randomly assigned to the active group and 19 to the sham
group. In the active group, two drop-out subjects, after the
first session, were excluded due to inability to follow the
protocol. Therefore, 34 subjects entered the treatment phase
(Figure 1). Among them, 31 were classified as a-MCI and three
as nonamnesic-MCI (two in the sham group and one in the
active group).
Causes of exclusion are listed in Table 3.
In the first step of the screening phase, no statistically significant difference was observed among the selected subjects
(Table 4). There were no diagnostic cases of late life depression, nor present depression, excluded by various validated
Percentage
9.59%
2.74%
34.25%
9.59%
13.70%
6.85%
1.37%
5.48%
5.48%
2.74%
20.55%
2.74%
10.96%
1.37%
1.37%
1.37%
1.37%
1.37%
1.37%
4.11%
4.11%
1.37%
1
MoCA: Montreal Cognitive Assessment; 2 GDS-15: 15-items Geriatric
Depression Scale; 3 SCID: Structured Clinical Interview for Axis I DisordersDiagnostic and Statistical Manual of Mental Disorders, fourth edition; 4 MRI:
magnetic resonance imaging; 5 AD: Alzheimer’s disease.
Table 4: Subjects screening: part I.
Test/scale
The blind control was evaluated by Cohen’s kappa coefficient
of agreement to assess patients’ views of whether or not they
belonged to a given group.
𝑛
7
2
25
7
10
5
1
4
4
2
15
2
8
1
1
1
1
1
1
3
3
1
MoCA1
GDS-152
HAMD-173
HAMA-144
Active rTMS
n = 15
(mean ± SD∗ )
Sham
n = 19
(mean ± SD)
p-value∗∗
24.5 ± 1.8
1.7 ± 1.7
1.7 ± 2.1
1.7 ± 1.1
24.2 ± 2.3
1.4 ± 1.3
1.5 ± 2.1
1.4 ± 1.5
0.605
0.559
0.781
0.532
∗
SD: standard deviation; ∗∗ Student’s t-test. 1 MoCA: Montreal Cognitive
Assessment; 2 GDS-15: 15-item Geriatric Depression Scale; 3 HAMD–17, 17item Hamilton Depression Scale; 4 HAMA–14, 14-item Hamilton Anxiety
Scale.
tests in preliminary evaluation, such as GDS, HAMD-17, and
SCID DSM-IV.
Clinical and demographic characteristics were also similar in both groups, as seen in Table 5. At baseline, groups were
homogeneous in terms of neuropsychological examination,
except for digit span (𝑝 = 0.040).
3.2. Blind Integrity. An assessment of the effectiveness of the
blinding revealed that most patients did not guess correctly,
when asked to which group they believed they were assigned.
The Kappa coefficient was equal to 0.190, which indicates a
low correlation and blind integrity.
6
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Enrollment
screening
n = 109
Excluded
(unmet eligibility criteria)
n = 73
Allocation
n = 36
T0
rTMS
T0
Sham
n = 17
n = 19
Drop out
(refused to continue)
n=2
T1
rTMS
n = 15
n = 19
T2
rTMS
T2
Sham
n = 15
n = 19
T1
Sham
Figure 1: Flow diagram of referred and enrolled patients.
3.3. Tolerability and Safety. rTMS at 10 Hz with 110% of the
MT was safe and well tolerated. A zero value presented in
almost all cells of the side effects precludes any statistical
analysis beyond a descriptive one. Side effects were mild
and transient prevailing in the active group. However, a
gradual reduction in side effects was observed throughout the
sessions (see Table 6).
3.4. Outcome Variables. Four neuropsychological tests
showed heterogeneous statistical improvement along time
(Table 7).
The primary outcome variable RBMT was statistically
higher in the active group after the 10th session and after onemonth follow-up (Figure 2).
Although final scores of the logical memory II were similar, initial values for the sham group indicate a significance
favoring them (Figure 3).
Figure 4 shows initial improvement in letter-number
sequencing test for the sham group (T0-T1). Nevertheless,
the gain for the active group at T2 did not show a significant
difference at the end of follow-up (T2).
In TMT-B, an initial improvement in the sham group
was showed as well as, conversely, a later improvement in
the active rTMS group (T1-T2). No definitive effect was shown
in either group from basal to last evaluation (Figure 5).
Transient improvement was observed in the sham group
in verbal fluency/animal naming, at T2. However, the final
scores were similar in both groups and quite heterogeneous
in T0 (Figure 6).
4. Discussion
We report improvement in everyday memory after 10 sessions
of HF rTMS, in a double-blind, randomized sham-controlled
study. The duration of the improvement persisted at least for
30 days after the last rTMS session, assessed by the RBMT.
This is the first randomized, controlled, double-blind study
on early and late after-effects of rTMS on everyday memory of
the elderly with MCI. This result suggests a sustained gain in
episodic memory. The RBMT aids to identify compensatory
strategies and to design specific neuropsychological rehabilitation programs. As the tasks mimic daily life situations,
RMBT analyses individuals’ tasks performances and how
memory impairment affects everyday activities [76].
Nevertheless, others memory tests, logical memory (LM)
II and letter-number sequencing (LNS) exhibited different
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7
Table 5: Demographic data.
Age, years (mean ± SD)
Gender, n (%)
Male
Female
Education level, years
(mean ± SD)
Marital status, n (%)
Married
Single
Widow
Divorced
Residence
Living alone, n (%)
Living with family, n (%)
Professional activities, n (%)
Not retired
Retired
Physical activity, n (%)
(≥twice a week, ≥1 year)
Comorbidities, n (%)
Hypertension
Diabetes mellitus
Dyslipidemia
Thyroid disease
Osteoporosis
Tobacco consumption
Neoplasia
Active
rTMS
(n = 15)
Sham
(n = 19)
p-value
65.1 ± 3.5
65.2 ± 4.1
0.9541
0.7242
6 (40.0)
9 (60.0)
6 (31.6)
13 (68.4)
15.1 ± 4.4
12.4 ± 4.7
24.00
18.00
0
T0
0.2882
5 (26.3)
14 (73.7)
9 (60.0)
12 (63.2)
5
10
T1
15
20
Days
25
30
>0.9992
Comparison of means logical memory II
0.0802
>0.9992
0.5102
0.1512
>0.9992
>0.9992
>0.9992
T0 × T2
p = 0.002
SD: standard deviation; 1 Student’s t-test; 2 Fisher’s test.
28.00
T0 × T1
26.00
p = 0.033
24.00
22.00
Score
5 (26.3)
2 (13.3)
9 (47.4)
4 (21.1)
5 (26.3)
1 (5.3)
2 (1.5)
40
T2
Figure 2: Comparison of RBMT means scores in T0, T1, and T2.
Two-way ANOVA for repeated measures. Timing of procedures: T0:
baseline cognitive assessment and 1st rTMS; T1: 10th rTMS session
and 2nd cognitive assessment; T2: 30 days after T1 and 3rd cognitive
assessment. Student’s 𝑡-test for comparison of rTMS versus sham
basal means, 𝑝 = 0.292.
30.00
9 (60.0)
2 (10.5)
9 (60.0)
7 (46.7)
3 (20.0)
1 (6.7)
1 (6.7)
35
Sham
rTMS
7 (36.8)
12 (63.2)
7 (46.7)
8 (53.3)
21.00
19.00
8 (42.1)
4 (21.1)
4 (21.1)
3 (15.8)
0.0532
1 (67)
14 (93.3)
22.00
20.00
0.0941
0.9092
8 (53.3)
2 (13.3)
3 (20.0)
2 (13.3)
T0 × T2
p = 0.029
T0 × T1
p = 0.042
23.00
Score
Features
Comparison of means RBMT
25.00
20.00
18.00
16.00
14.00
Table 6: Side effects after rTMS sessions.
Side effects§
# Sessions
Group
∗
12.00
1
𝑛 (%)
5
𝑛 (%)
10
𝑛 (%)
Headache
Active rTMS
Sham
5 (33.3)
5 (33.3)
4 (26.7)
0 (0)
1 (5.3)
0 (0)
Cervical pain
Active rTMS
Sham
0 (0)
1 (5.3)
0 (0)
0 (0)
0 (0)
0 (0)
Scalp pain
Active rTMS
Sham
5 (33.3)
1 (5.3)
2 (13.3)
1 (5.3)
2 (13.3)
0 (0)
Burning scalp
Active rTMS
Sham
0 (0)
1 (5.3)
0 (0)
0 (0)
0 (0)
0 (0)
Concentration
difficulties
Active rTMS
Sham
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
Symptoms related to rTMS application; ∗ side effects after the 1st, 5th, and
10th rTMS sessions, respectively.
§
outcomes. Sham group improvement in LM II is probably
due a tendency to different baseline scores between both
0
T0
5
10
T1
15
20
Days
25
30
35
40
T2
Sham
rTMS
Figure 3: Comparison of logical memory II means scores in T0,
T1, and T2. Two-way ANOVA for repeated measures. Timing of
procedures: T0: baseline cognitive assessment and 1st rTMS; T1: 10th
rTMS session and 2nd cognitive assessment; T2: 30 days after T1 and
3rd cognitive assessment. Student’s 𝑡-test for comparison of rTMS
versus sham basal means, 𝑝 = 0.087.
groups. A gain in the score of the active group in T2 is
noted and can suggest a lag practice effect compared to that
which may occur in sham group. In LNS test, we have an
improvement of sham group at T1 and impairment at T2.
Conversely, active group performance suggested a temporary
deterioration soon after rTMS protocol (T1), followed by lag
amelioration at T2.
8
Behavioural Neurology
Table 7: Comparison of the statistically significant neuropsychological outcomes.
T0
RBMT
Logical memory II
(delayed)
Letter-number
sequencing test
Trail making test B
Verbal
fluency/animal
naming
T1
Mean
SD
Mean
SD
Mean
SD
Active rTMS
Sham
Group effect
20.87
21.58
2.10
1.77
22.60
22.16
1.68
1.57
22.87
22.11
1.36
1.29
Active rTMS
Sham
Group effect
21.87
17.58
Active rTMS
Sham
Group effect
10.20
9.16
Active rTMS
Sham
Group effect
99.13
110.89
Active rTMS
Sham
Group effect
18.47
15.95
6.40
7.50
21.67
22.68
2.08
2.57
9.80
9.74
29.26
49.31
107.13
93.79
4.49
3.66
18.00
17.58
T0 × T1
p-value§
T1 × T2
T0 × T2
0.042∗
0.593
0.029∗
0.033∗
0.821
0.002∗
0.130
0.039∗
0.489
0.036∗
0.023∗
0.988
0.095
0.613
0.029∗
T2
6.79
6.44
1.74
2.08
47.87
30.84
5.66
4.69
25.47
26.89
6.56
6.81
10.87
9.32
2.36
2.79
95.40
107.32
31.58
46.45
18.80
19.00
5.65
5.08
∗
Analysis performed with two-way ANOVA for repeated measures (p > 0.05); statistically significant group effect; SD: standard deviation; timing of
procedures: T0: baseline cognitive assessment before 1st rTMS; T1: 2nd cognitive assessment (after 10th rTMS session); T2: 3rd cognitive assessment (30 days
after T1).
§
Comparison of means letter-number sequencing
13.00
T1 × T2
p = 0.039
12.00
10.00
Time (s)
Score
11.00
9.00
8.00
7.00
6.00
0
T0
5
10
T1
15
20
Days
25
30
35
40
T2
Sham
rTMS
Figure 4: Comparison of letter-number sequencing means scores
in T0, T1, and T2. Two-way ANOVA for repeated measures. Timing
of procedures: T0: baseline cognitive assessment and 1st rTMS; T1:
10th rTMS session and 2nd cognitive assessment; T2: 30 days after
T1 and 3rd cognitive assessment. Student’s 𝑡-test for comparison of
rTMS versus sham basal means, 𝑝 = 0.211.
Concerning the two frontal tasks, TMT-B and the verbal
fluency test animal naming, the results showed some discrepancies. In TMT-B, there was an initial impairment in the
active TMS group, followed by a great improvement after a
month. Conversely, in animal naming test, the sham group
had a gain and then impairment at the last evaluation, but
the improvement of sham group may be due a tendency to
statistical difference between baseline scores, which should
require a larger sample to better define the result.
Comparison of means TMT-B
130.00
125.00
120.00
115.00
110.00
105.00
100.00
95.00
90.00
85.00
80.00
T0 × T1
p = 0.036
0
T0
5
10
T1
T1 × T2
p = 0.023
15
20
Days
25
30
35
40
T2
Sham
rTMS
Figure 5: Comparison of Trail Making Test B means scores in T0,
T1, and T2. Two-way ANOVA for repeated measures. Timing of
procedures: T0: baseline cognitive assessment and 1st rTMS; T1:
10th rTMS session and 2nd cognitive assessment; T2: 30 days after
T1 and 3rd cognitive assessment. Mann-Whitney-Wilcoxon test for
comparison of rTMS versus sham basal means, 𝑝 = 0.986.
Anyway, this raises the possibility that the rTMS could
have, at least in a short term, some negative effect on
some performances. Even if most of the TMS findings show
considerable variability, genetic factors can be argued. The
presence of BDNF-Val66Met polymorphism could influence the protein synthesis, affecting cortical reactivity with
decreased experience-dependent plasticity induced by rTMS.
Thereby, this genetic variation in the normal population can
Behavioural Neurology
Comparison of means animal naming
24.00
Number of words in 60 seconds
9
T0 × T2
p = 0.029
22.00
20.00
18.00
16.00
14.00
12.00
10.00
0
T0
5
10
T1
15
20
Days
25
30
35
40
T2
Sham
rTMS
Figure 6: Comparison of semantic verbal fluency/animal naming
means scores in T0, T1, and T2. Two-way ANOVA for repeated
measures. Timing of procedures: T0: baseline cognitive assessment
and 1st rTMS; T1: 10th rTMS session and 2nd cognitive assessment;
T2: 30 days after T1 and 3rd cognitive assessment. Student’s 𝑡-test for
comparison of rTMS versus sham basal means, 𝑝 = 0.081.
produce significant differences in the after-effects of rTMS
protocols [34, 43]. Koch et al. investigated the correlation
between motor cortical plasticity (with TMS) and the levels
of Ab, total tau (t-Tau), and phosphorylated tau detected in
cerebrospinal fluid (CSF) of patients with AD. They identified
that higher CSF t-Tau levels were associated with a stronger
inhibition of the MEPs, suggesting that also CSF t-Tau
modulates excitatory activity and may alter mechanisms of
cortical plasticity. In one study of HF rTMS to bilateral PFC
of patients with depression, Loo et al. [77] found an individual
temporary deterioration in executive function/planning in
the HF rTMS; two years later, the same group manifested a
selective deterioration in the retention of verbal material [78].
One of the strengths of our study is its ecological validity.
The patients recruited actively sought healthcare for memory
disturbance in the community, through the media (radio and
newspapers) and ads in the subway and buses, even by referral
of fellow physicians or participants themselves.
Some peculiarities about rTMS efficacy in elderly populations are consistent with our data. It is well described that
there is a better response to higher frequencies and intensity
pulses rTMS, which should be explained by the greater
prefrontal atrophy in the elderly. Due to cerebral atrophy,
the distance from the skull to the PFC increases with age in
greater proportion than the motor cortex [34, 79–82]. So, also,
longer treatment protocols may be more effective [42, 83].
Moreover, patients tend to reach a greater improvement than
healthy participants [50].
The duration of off-line rTMS after-effects in cognitive
performance seems to indicate that longer trains induce
longer-lasting and more robust effects, and rTMS parameters
used in this study were consistent with those recommended
on the induction of long-term cognitive effects (off-line
paradigm) after more than one session of HF rTMS [30, 84].
Besides distant activations via neural pathways projections from the target of stimulation, the length of action
of rTMS also depends on the rTMS “dose,” that is, the
intensity of stimulation [37], which is directly related to the
interindividual resting motor threshold.
Specific particularities influencing the interpretation of
the results should be considered. First, due to the presence
of a continuum of memory impairment from normal aging
to MCI [85], the problem of high heterogeneity within our
sample might be an important issue. Second, the “5 cm
rule,” presents many limitations [86–88]. Third, we did not
use different versions of RBMT, possibly introducing a bias
although the practice effect is also present in all neuropsychological batteries. Finally, a selection bias may have occurred,
due a diagnostic revision in a consensus meeting with the
neuropsychology team. The initial goal was a sample of
patients with a-MCI, that is, MCI subtype which is most
susceptible to conversion to AD [1]. However, to keep the
randomization, we maintained the three patients (9%) with
nonamnesic MCI.
Interventional therapies studies for improving cognitive
skills are of paramount importance and are likely to have a
great impact on public health. The growing proportion of
older people and the length of life increase through the world
rapidly. Such issue requires the development of interventions
to improve well-being, social engagement, and independence
for ageing people [89].
There is a great interest in neuromodulation by rTMS
due the persistence of after-effects induced by LTP mechanism [27, 30, 34, 37, 90–92]. LTP is an increase in the
synaptic strength that could last for days or even weeks
and months. Once induced and expressed, LTP is divided
in two forms: early-LTP (E-LTP) and late-LTP (L- LTP). ELTP is an increase in synaptic strength that persists for 30–
60 minutes after induction, depending on modifications of
existing proteins, for example, protein phosphorylation. LLTP could last for hours, days, or even weeks and includes
other mechanisms like changes in gene expression and the
synthesis of proteins [30]. The duration of rTMS after-effect
is proportional to the length of stimulation [84].
Most studies on healthy aging are focused on prevention.
rTMS can be viewed as a tool for cognitive enhancement of
the elderly with MCI, reversing or compensating cognitive
deficits [4, 93] and improving quality of life. rTMS may
interact synergistically with cognitive training to lead to even
greater neurocognitive enhancement [93–95]. The elderly
might benefit from cognitive rehabilitation with rTMS as an
add-on instrument in cognitive training programs of a variety
of neurological and cognitive disorders [96].
5. Conclusion
In conclusion, this study suggests that 10 consecutive sessions
or HF rTMS to the left DLPFC at 10 Hz in the elderly with
MCI selectively improve everyday memory. The improvement was sustained for at least a month. rTMS may be a
promising useful tool for interventional single (or combined)
therapy for individuals with MCI or with memory decline.
10
Further research is necessary to replicate these findings with
larger sample size and also to investigate rTMS combined
with other cognitive training therapies.
Behavioural Neurology
[13]
Conflict of Interests
All authors reported no financial conflict of interests.
[14]
Acknowledgments
The authors thank Mrs. Julia Tizue Fukushima for precious
paper suggestions, Mr. Bernardo dos Santos for statistical
analysis, and Mrs. Sandra de Lima Falcon for the carefully
working on recruitment of volunteers.
[15]
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