Improved language performance in Alzheimer disease following brain stimulation

Abstract

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a possible treatment for the cognitive deficits associated with Alzheimer disease (AD). The aim of this study was to assess the long-term effects, on cognitive performance, of rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) in AD patients.
Ten AD patients were randomly assigned to one of two study groups. Multiple-baseline design was used.The first group underwent a 4-week real rTMS stimulation protocol, while the second underwent a 2-week placebo treatment, followed by 2 weeks of real rTMS stimulation. Each session consisted of the application of rhythmic high-frequency rTMS over the DLPFC for 25 min. Sessions occurred once daily, 5 days/week. The main analysed outcome was the change in cognitive test performance at 2 and 4 weeks after rTMS treatment initiation, with a follow-up performed 8 weeks after the end of rTMS, in comparison with baseline performance.
A significant difference was found between groups over sessions in terms of the percentage of correct responses of auditory sentence comprehension. Only real treatment induced an improvement in performance with respect to baseline or placebo. Moreover, both groups showed a lasting effect on the improved performance 8 weeks after the end of treatment.
The findings provide initial evidence for the persistent beneficial effects of rTMS on sentence comprehension in AD patients. Rhythmic rTMS, in conjunction with other therapeutic interventions, may represent a novel approach to the treatment of language dysfunction in AD patients.

Full text

Improved language performance in Alzheimer disease
following brain stimulation
Maria Cotelli,
1
Marco Calabria,
1
Rosa Manenti,
1
Sandra Rosini,
1
Orazio Zanetti,
1
Stefano F Cappa,
2
Carlo Miniussi
1,3
ABSTRACT
Objectives Repetitive transcranial magnetic stimulation
(rTMS) has been proposed as a possible treatment for
the cognitive deficits associated with Alzheimer disease
(AD). The aim of this study was to assess the long-term
effects, on cognitive performance, of rTMS applied to the
left dorsolateral prefrontal cortex (DLPFC) in AD patients.
Methods Ten AD patients were randomly assigned to
one of two study groups. Multiple-baseline design was
used.The first group underwent a 4-week real rTMS
stimulation protocol, while the second underwent
a 2-week placebo treatment, followed by 2 weeks of real
rTMS stimulation. Each session consisted of the
application of rhythmic high-frequency rTMS over the
DLPFC for 25 min. Sessions occurred once daily, 5 days/
week. The main analysed outcome was the change in
cognitive test performance at 2 and 4 weeks after rTMS
treatment initiation, with a follow-up performed 8 weeks
after the end of rTMS, in comparison with baseline
performance.
Results A significant difference was found between
groups over sessions in terms of the percentage of
correct responses of auditory sentence comprehension.
Only real treatment induced an improvement in
performance with respect to baseline or placebo.
Moreover, both groups showed a lasting effect on the
improved performance 8 weeks after the end of
treatment.
Conclusion The findings provide initial evidence for the
persistent beneficial effects of rTMS on sentence
comprehension in AD patients. Rhythmic rTMS, in
conjunction with other therapeutic interventions, may
represent a novel approach to the treatment of language
dysfunction in AD patients.
INTRODUCTION
Alzheimer’s disease (AD) is a progressive disorder
that impacts memory, language and several other
cognitive functions. Given the limited effectiveness
of pharmacological treatments, non-pharmacological
interventions in AD have gained attention in recent
years, and there are currently many different
approaches under study, ranging from multistrategy
approaches to cognitive training.
1
Despite the potential therapeutic impact of
the non-pharmacological approaches, the neural
mechanisms underlying the beneficial effects of
behavioural interventions remain largely unknown.
Functional neuroimaging studies have shown that
rehabilitation in patients with developmental and
acquired cerebral damage may lead to functional
cortical reorganisation, a process mediated by
activity-dependent plasticity mechanisms.
2
These
‘plastic’mechanisms may also play a role in the
ageing brain and in AD.
3
In recent years, new techniques for studying the
human brain that allow for the non-invasive
neurostimulation have emerged. Repetitive trans-
cranial magnetic stimulation (rTMS) is a technique
that delivers several magnetic pulses in rapid
sequence up to frequencies of 100 Hz. rTMS can
modulate neuronal activity, with effects depending
on the stimulation frequency (ie, #1 Hz stimula-
tion results in inhibition, while $5 Hz stimulation
mostly leads to excitation). There have been no
studies to date that have explored the long-term
effects of rhythmic off-line rTMS in AD patients.
Therefore, the main purpose of the present study
was to investigate whether the application of high-
frequency rhythmic rTMS, for 2 or 4 weeks, to the
left dorsolateral prefrontal cortex (DLPFC) resulted
in cognitive improvements
4
in patients with AD.
More specifically, we hypothesised that this type of
stimulation may lead to improved language
performance, that is, production and/or compre-
hension. Such prediction comes from a previous
work on naming in AD patients.
56
A possible effect
on sentence comprehension was predicted on the
basis of a study in young normal subjects,
7
which
provided direct evidence of DLPFC involvement in
sentence comprehension.
In addition, an important goal of the present
study was to verify whether the cognitive benefits,
previously recorded solely during on-line rTMS,
might persist after the end of the stimulation. We
adopted a multiple-baseline design, comparing the
stimulation effects with a placebo condition (sham-
stimulation) during the first 2 weeks of treatment.
This phase was followed by 2 weeks of rTMS
stimulation in all patients, in order to evaluate
whether a longer rTMS application (4 vs 2 weeks)
would further improve the expected benefits in the
patient’s performance. Finally, we assessed the
persistence of the effects 8 weeks after the end of
the treatment (figure 1A).
SUBJECTS AND METHODS
Participants
Outpatients (n¼10) diagnosed as having probable
moderate AD, according to the NINCDS-ADRDA
8
criteria, were enrolled.
Patients with potentially confounding neurolog-
ical and psychiatric disorders, epilepsy, clinically
recorded hearing or vision impairment, or with a
history of alcohol abuse, psychosis or major
depression were not included in the study. All
patients had been on a stable dose of cholinesterase
1
IRCCS Centro San Giovanni di
Dio Fatebenefratelli, Brescia,
Italy
2
Department of Neuroscience,
Vita-Salute University and San
Raffaele Scientific Institute &
National Neuroscience Institute,
Milan, Italy
3
Department of Biomedical
Sciences and Biotechnologies,
National Neuroscience Institute,
University of Brescia, Brescia,
Italy
Correspondence to
Dr Maria Cotelli, IRCCS Centro
San Giovanni di Dio
Fatebenefratelli, Via Pilastroni,
4, Brescia 25125, Italy;
mcotelli@fatebenefratelli.it
Received 16 October 2009
Revised 12 February 2010
Accepted 13 February 2010
Cotelli M, Calabria M, Manenti R, et al.J Neurol Neurosurg Psychiatry (2010). doi:10.1136/jnnp.2009.197848 1 of 4
Short report

inhibitor (donepezil or rivastigmine) for at least 6 months prior
to the onset of the study. The use of drugs with anticolinergic
properties was used as an exclusion criterion.
rTMS
Patients were randomly assigned to one of the two groups: (1)
realereal group (RR), in which the patients received 4 weeks of
rTMS stimulation of the DLPFC; (2) placeboereal group (PR), in
which patients received DLPFC placebo stimulation during the
first 2 weeks followed by 2 weeks of real stimulation (figure 1A).
Each week of rTMS treatment consisted of five sessions (25 min
each, one per day). rTMS was delivered by a Magstim unit
featuring a double 70 mm cooled coil. Before starting the rTMS
treatment, the motor excitability stimulation threshold was
established for each subject (mean 51.5665.9%). The stimulation
intensity used during the experiment was set to 100% of each
subject’s motor threshold. Trains of rhythmic high-frequency
(20 Hz) rTMS were delivered in short periods (2 s duration)
separated by longer periods (28 s) of no stimulation, for each daily
session. The total number of pulses for each session was 2000 (40
stimuli/train, 50 trains). These parameters are consistent with
safety recommendations for rTMS.
9
Furthermore, all participants
tolerated rTMS well and did not report any adverse effects. In the
placebo condition, a sham coil was used.
10
We localised the target areas using the SofTaxic neuro-
navigator system (http://www.emsmedical.net) on an MRI
template. Based on these estimated MRIs, the average location
of the stimulating points was centred on Talairach coordinates
x¼35, y¼24, z¼48, corresponding to the DLPFC (Brodmann
Area 8/9). We chose to stimulate this area based on the results of
previous experiments.
5e7 11
To stimulate the DLPFC, the coil
was placed with the junction of the two coil wings above the
target point. During the experiment, the coil was fixed by means
of a mechanical support.
Cognitive assessment
Standard cognitive assessment was divided into two sessions.
Neuropsychological testing was administered by an experienced
examiner who was blind to patient treatment allocations. The
cognitive assessment included tests to screen for dementia,
together with neuropsychological tests for memory, executive
functions and language. The results of the cognitive assessments
at baseline, before rTMS treatment, at 2, (T2) 4 (T4) and 12
(T12) weeks after the onset of the rTMS treatment are reported
in table 1 for both experimental groups (note that T12 corre-
sponds to 8 weeks after the end of the treatment). All the tests
were administered and scored according to standard proce-
dures.
12 13
Statistical analysis
Demographic variables (age and education) of the two groups
were compared at baseline, using parametric analyses (paired t
test). A p value <0.05 was considered significant.
The behavioural effects induced by the rTMS protocol after
2 weeks of daily stimulation were assessed using a mixed-model
ANOVA, considering group (realereal vs placeboereal) as a
between-subjects factor, and time (baseline vs 2 weeks) as
a within-subject factor. Further analysis was performed to assess
the long-term efficacy of rTMS treatment using four time
instants (baseline vs 2 weeks, 4 weeks and 12 weeks) as a
within-subject factor.
RESULTS
We identified no significant differences in the demographic
variables between groups (table 1, p>0.05).
To verify the presence of short-term behavioural effects
induced by rTMS, we compared the performance of both groups
at baseline and at the 2-week evaluation. A significant difference
between groups was found in terms of the percentage of correct
responses only in auditory sentence comprehension subtest from
the Battery for Analysis of Aphasic Deficits (SC-BADA) over
time (group3time interaction: F(1, 8)¼6.07, p¼0.04;
h
p2
¼0.43).
The realereal group improved its performance (p¼0.008) at
2 weeks (77.366.5) with respect to baseline (66.668.6), whereas
the placeboereal group showed no significant differences
(p¼0.99) between baseline (66.067.1) and 2 weeks of placebo
rTMS (65.9, 69.6).
We further analysed SC-BADA scores at baseline, 2, 4 and
12 weeks to assess the long-term efficacy of rTMS in both
groups. A significant main effect of time (F(3, 24)¼3.87, p¼0.02)
was found. Post-hoc analysis, Bonferroni, showed that the
percentage of correct responses in SC-BADA at 12 weeks
(77.262.7) was still significantly different (p¼0.02) from base-
line (66.367.45) (figure 1B). No significant differences were
found for other language abilities, or for other cognitive
Figure 1 (A) Experimental paradigm. AD, Alzheimer disease; PR,
placeboereal treatment; RR, realereal treatment; T2, assessment at
2 weeks from the baseline; T4, assessment at 4 weeks from the
baseline; T12, assessment at 12 weeks from the baseline (ie, 8 weeks
after repetitive transcranial magnetic stimulation (rTMS) treatment). (B)
Comparison of percentage of correct responses on the auditory sentence
comprehension subtest from the Battery for Analysis of Aphasic Deficits
at T2, T4 and T12 between groups (realereal rTMS vs placeboereal
rTMS). T2, assessment at 2 weeks from the baseline; T4, assessment at
4 weeks from the baseline; T12, assessment at 12 weeks from the
baseline (ie, 8 weeks after rTMS treatment). The mean and SEs are
displayed. *p<0.05.
2 of 4 Cotelli M, Calabria M, Manenti R, et al.J Neurol Neurosurg Psychiatry (2010). doi:10.1136/jnnp.2009.197848
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Table 1 Demographic and neuropsychological data
Realereal
(n[5)
Placeboereal
(n[5)
p Value
Group Time Time3group
Realereal
(n[5)
Placeboereal
(n[5)
p Value
Group Time Time3group
Age (years) 71.266.1 74.463.8 0.40
Education (years) 6.461.3 4.860.4 0.06
Baseline 2 weeks Baseline 2 weeks 4 weeks 12 weeks 4 weeks 12 weeks
Mini-Mental State
Examination
16.262.7 16.063.3 16.062.0 1662.1 0.95 0.90 0.90 15.463.4 16.462.8 16.262.4 14.563.7 0.76 0.75 0.59
Basic Activities of Daily Living 1.261.2 1.261.2 2.061.2 2.061.2 0.09 ee 1.261.2 1.261.2 2.061.2 2.061.2 0.09 ee
Instrumental Activities of Daily Living 6.061.8 6.061.8 6.661.7 6.661.7 0.43 0.34 0.34 6.061.8 6.061.8 6.661.7 6.661.7 0.43 0.34 0.34
Picture-naming task
Objects 61.968.5 60.6611.5 54.767.4 55.068.7 0.37 0.95 0.75 63.0618.7 65.7619.6 51.0614.8 48.3612.7 0.18 0.82 0.22
Actions 42.269.7 48.365.2 38.267.5 40.7610.2 0.23 0.31 0.70 47.067.4 47.968.7 41.7615.0 45.0616.0 0.41 0.29 0.82
Battery for Analysis of Aphasic Deficits (correct responses, %)
Oral object naming 60.069.5 47.4610.1 0.11
Oral action naming 40.3610.5 35.668.4 0.51
Sentence comprehension* 66.767.7 77.365.8 66.066.4 66.068.6 0.22 0.04*0.04* 73.366.6 78.767.9 75.469.9 75.769.2 0.36 0.02* 0.23
Aachener Aphasie Test
Token test (errors) 21.265.1 22.667.7 19.266.2 17.668.1 0.47 0.94 0.33 25.266.7 21.2610.5 17.6610.0 19.5610.1 0.64 0.77 0.50
Repetition 137.2613.1 133.6618.0 131613.0 131.6611.4 0.68 0.43 0.28 139.867.8 136.6613.8 132.2610.8 129.5612.6 0.45 0.61 0.50
Writing 71.6615.8 77.2611.5 73.8611.0 76.8614.2 0.92 0.23 0.70 78.265.9 78.068.3 78.0610.7 77.5615.8 0.94 0.42 0.98
Naming 90.866.5 91.267.4 8864.6 90.269.7 0.68 0.63 0.74 94.265.8 99.066.0 91.6611.6 92.8610.3 0.41 0.15 0.92
Comprehension 85.663.9 92.669.1 86.463.6 90.868.4 0.90 0.07 0.64 91.669.6 94.865.6 90.2612.2 86.0614.0 0.47 0.23 0.49
Serial curve position
Primacy 3.863.2 5.064.5 5.062.6 7.064.3 0.55 0.06 0.57 3.863.6 3.464.2 6.664.8 7.062.8 0.29 0.23 0.63
Recency 4.662.6 5.862.9 5.861.6 3.861.1 0.74 0.61 0.07 7.865.4 8.267.2 4.063.1 6.662.1 0.22 0.08 0.08
First item 1.861.9 1.861.9 2.662.1 3.262.3 0.44 0.54 0.54 1.662.1 0.561.0 3.662.5 1.361.5 0.33 0.07 0.62
Cognitive estimation test
Errors 21.864.6 24.063.5 22.861.0 23.265.0 0.96 0.48 0.62 24.062.2 23.863.8 22.663.0 21.862.1 0.95 0.61 0.69
Bizarreness 9.463.1 8.662.9 9.861.9 7.663.8 0.88 0.10 0.41 9.462.7 10.662.9 7.662.5 7.563.7 0.60 0.64 0.31
*p<0.05.
Cotelli M, Calabria M, Manenti R, et al.J Neurol Neurosurg Psychiatry (2010). doi:10.1136/jnnp.2009.197848 3 of 4
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functions (such as cognitive estimation and memory). See table
1 for more details.
DISCUSSION
The main purpose of this study was to investigate whether the
application of high-frequency rTMS to the left DLPFC for
25 min a day, 5 days a week, for 2 weeks may lead to significant
cognitive improvements in patients with AD. Specifically, we
hypothesised that this protocol would result in changes in
language performance, that is, facilitation of language produc-
tion and/or comprehension. In addition, we compared the
effects of 2 or 4 weeks of stimulation to evaluate whether
a longer rTMS application would result in a greater and/or
longer-lasting effect. Finally, another important aim of the
present study was to verify whether the cognitive benefits
recorded immediately after rTMS treatment would persist
8 weeks after the end of the treatment protocol (T12).
Overall, the results of our study show a significant effect of
rTMS treatment on auditory sentence comprehension.
In contrast with our previous studies,
5 6
in the present study
we failed to observe a significant effect on naming performance
in AD. These results may be attributed to the rTMS paradigm
used (off-line vs on-line) with a short term facilitation, in our
previous study, strictly related to the timing of stimulation (that
is, a few milliseconds before the naming). In the present study,
we applied an off-line rTMS approach in which patients received
daily rTMS treatment, while in the previous studies rTMS was
applied to DLPFC during the execution of the naming task.
We also found that the administration of rTMS for 4 weeks
did not result in additional improvements in performance
compared with the application of rTMS for 2 weeks. A meta-
analysis by the Cochrane Collaboration
14
concluded that rTMS
significantly improves depression only after a minimum of
2 weeks of treatment. Our results suggest that 2 weeks of rTMS
is also sufficient to evidence behavioural improvements in AD
patients.
As regards the long-term effects, we identified an improve-
ment in sentence comprehension 8 weeks (T12) after the end of
the rTMS intervention. To date, this is the first study that shows
a long-lasting cognitive effect of rTMS treatments in AD
patients.
Another important result of our study was the absence of any
rTMS effects on memory and executive functions suggesting
that learning effects cannot explain data. Therefore, the facili-
tation effect of DLPFC rTMS in AD appears to be specific to the
language domain rather than reflecting a general, non-specific
effect on cognitive processing.
Why did rTMS induce this improvement in patient language
performance?The neurophysiological mechanisms responsible
for rTMS-induced facilitation remain unknown. A number of
investigations suggest that rhythmic transcranial stimulation
can exert positive effects on cognitive performance.
4
A possi-
bility is that the modification of cortical activity through the use
of rhythmic stimulation may readjust pathological patterns of
brain activity, thus providing an opportunity to induce new,
healthier activity patterns within the affected functional
networks.
15
The present findings may reflect an rTMS-induced modula-
tion of short- and/or long-range cortical synaptic efficacy and
connectivity that potentiates the system within the language
network, leading to more effective processing.
The present preliminary results highlight the therapeutic
potential of the induction of long-term neuromodulatory effects
using brain stimulation. They hold considerable promise, not
only for advancing our understanding of brain plasticity mech-
anisms, but also for designing new rehabilitation strategies in
patients with neurodegenerative disease.
Acknowledgement We wish to thank patients and caregivers for their patience.
Funding This research was supported by a Project grant from the ‘Ministero della
Sanita
`and from Associazione Fatebenefratelli per la Ricerca (AFaR).
Competing interests None.
Ethics approval Ethics approval was provided by the CEIOC Local Ethical Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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