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Brain stimulation improves associative memory in an individual with amnestic mild cognitive impairment

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In patients with cognitive deficits, brain stimulation has been shown to restore cognition (Miniussi et al., 200810. Miniussi , C. , Cappa , S. F. , Cohen , L. G. , Floel , A. , Fregni , F. Nitsche , M. A. 2008. Efficacy of repetitive transcranial magnetic stimulation/transcranial direct current stimulation in cognitive neurorehabilitation. Brain Stimulation, 1: 326–336. [CrossRef], [PubMed], [Web of Science ®]View all references, Brain Stimulation, 1, 326). The aim of this study was to assess whether repetitive Transcranial Magnetic Stimulation (rTMS) could improve memory performance in an individual with amnestic Mild Cognitive Impairment (aMCI). Stimulation of the left parietal cortex increased accuracy in an association memory task, and this improvement was still significant 24 weeks after stimulation began. These findings indicate that rTMS to the left parietal cortex improved memory performance in aMCI.
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NEUROCASE
2012, 18 (3), 217–223
Brain stimulation improves associative memory in an
individual with amnestic mild cognitive impairment
Maria Cotelli1, Marco Calabria2, Rosa Manenti1, Sandra Rosini1, Claudio Maioli3,
Orazio Zanetti1, and Carlo Miniussi1,3
1IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
2Department of Technology, Universitat Pompeu Fabra, Barcelona, Spain
3Department of Biomedical Sciences and Biotechnologies, National Neuroscience Institute,
University of Brescia, Brescia, Italy
In patients with cognitive deficits, brain stimulation has been shown to restore cognition (Miniussi et al., 2008,
Brain Stimulation, 1, 326). The aim of this study was to assess whether repetitive Transcranial Magnetic Stimulation
(rTMS) could improve memory performance in an individual with amnestic Mild Cognitive Impairment (aMCI).
Stimulation of the left parietal cortex increased accuracy in an association memory task, and this improvement
was still significant 24 weeks after stimulation began. These findings indicate that rTMS to the left parietal cortex
improved memory performance in aMCI.
Keywords: Neurorehabilitation; Parietal cortex; Face–name association; MCI; Brain stimulation.
Recently, in patients with neurological disease, sev-
eral studies have reported enhanced performance
on specific cognitive tasks following non-invasive
brain stimulation (e.g., repetitive Transcranial
Magnetic Stimulation, rTMS) to specific cortical
areas (see Miniussi et al., 2008).
Episodic memory encoding and retrieval pro-
cesses have been linked to different networks; lesion
and functional imaging studies have indicated
that episodic memory involves a widespread net-
work of brain structures, including the prefrontal
cortex (PFC) and the posterior parietal cortex
(Cabeza, Ciaramelli, Olson, & Moscovitch, 2008).
In elderly subjects, successful memory encoding
and retrieval is associated with activation of the
left inferior parietal lobules (IPL) and the anterior
hippocampus (Kircher et al., 2008).
We wish to thank the patient for his patience and Michela Brambilla for her help with experimental assistance. This research was
supported by a project grant from the ‘Fondazione della Comunità Bresciana-ONLUS’.
Address correspondence to Maria Cotelli, PhD, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Via Pilastroni, 4, 25125 Brescia,
Italy. (E-mail: mcotelli@fatebenefratelli.it).
In healthy participants, rTMS studies have con-
firmed the role of the PFC during encoding and
retrieval of verbal or non-verbal material (Rossi
et al., 2001; Sandrini, Cappa, Rossi, Rossini, &
Miniussi, 2003). However, regarding rTMS stud-
ies in posterior brain areas, the mechanism has
not yet been elucidated. Previous studies have
demonstrated the involvement of parietal areas,
which is in contrast to rTMS studies. In particu-
lar, Rossi et al. (2006) found that the activity of
the intraparietal sulci, unlike that of the dorsolat-
eral prefrontal cortex (DLPFC), are not causally
involved in the encoding and retrieval of visual
scenes; however, by combining functional Magnetic
Resonance Imaging (fMRI) and rTMS, Manenti,
Tettamanti, Cotelli, Miniussi, and Cappa (2010)
provided the first evidence for the causal role of
c
2012 Psychology Press, an imprint of the Taylor & Francis Group, an Informa business
http://www.psypress.com/neurocase http://dx.doi.org/10.1080/13554794.2011.588176
Downloaded by [University of Sydney] at 15:42 15 August 2012
218 COTELLI ET AL.
not only prefrontal but also parietal cortices during
word retrieval.
Furthermore, Sole-Padulles et al. (2006) demon-
strated a beneficial role of high-frequency rTMS
in associative memory among elderly subjects with
memory deficits and low performance on neu-
ropsychological memory tests. The study combined
rTMS and fMRI and showed a selective behavioral
improvement in a face–name association memory
task following an off-line stimulation. Moreover,
this improvement was associated with the recruit-
ment of the right PFC and bilateral posterior
cortices.
Mild Cognitive Impairment (MCI) is widely
used to define the disorder in individuals who
have subjective cognitive deficits, objective memory
impairments, or other cognitive deficits, without
impairments in daily activities (Petersen et al.,
1999).
Despite the clinical impact, there is no published
evidence that rTMS can induce improvements
in patients with selective memory impairment.
Previous imaging and rTMS studies have shown
the involvement of the DLPFC and the parietal
cortex during memory processes, suggesting that,
in patients with memory deficits, stimulation of
these areas could induce improvements in memory.
The aim of this study was to assess whether rTMS
applied to the left parietal cortex, could induce
improvements in memory performance in an indi-
vidual with amnestic Mild Cognitive Impairment
(aMCI).
CASE REPORT
A 61-year-old man, with 18 years of education, was
referred for memory complaints. He was diagnosed
with aMCI (MMSE: 27), according to clinical cri-
teria (Petersen et al., 1999).
His evaluation included formal neuropsycholog-
ical testing (Table 1), a physician interview, and
a neurological examination. The patient had his
first clinic visit 18 months prior to enrolling in the
present study. During this period, he was exam-
ined regularly every 6 months. A physician (O.Z.)
completed a medical history and conducted gen-
eral physical, neurological, and psychiatric exam-
inations. The patient had no history of neurolog-
ical or psychiatric disorders, alcohol abuse, psy-
chosis, major depression (Hamilton Depression
Rating Scale =4), or sleep disturbances. There was
no indication of dementia, according to the clin-
ical interview with the patient and his caregiver
(Clinical Dementia Rating, CDR =0.5). The diag-
nosis of aMCI was confirmed at the follow-up
visits, and the patient had been steadily treated
with Rivastigmine Patch (9.5 mg/day) for the previ-
ous 12 months. The patient did not take any other
medication.
He was selected for this study based on the fol-
lowing criteria (Sarazin et al., 2007): (i) a subjec-
tive memory complaint assessed by the Everyday
Memory Questionnaire (Sunderland, 1984); (ii) an
objective memory impairment assessed by specific
neuropsychological memory tests; (iii) preserva-
tion of general cognitive functioning assessed by
general neuropsychological tests; (iv) a normal
Instrumental Activities of Daily Living (IADL)
score (Lawton & Brody, 1969); and (v) the absence
of the diagnostic criteria for dementia (American
Psychiatric Association, 1987). A structural brain
MRI excluded the presence of cerebrovascular dis-
ease and white matter lesions.
An experienced neuropsychologist (M.C.)
administered and evaluated a comprehensive
diagnostic set of memory tests. The cognitive
assessment included tests to screen for dementia
(Mini Mental State Examination) and neuropsy-
chological tests to assess non-verbal reasoning
(Raven Colored Progressive Matrices), language
comprehension (Token Test), verbal fluency
(phonemic and semantic), memory (Story recall;
Auditory-Verbal Learning Test, immediate and
delayed recall; Rey-Osterrieth Complex Figure,
recall; Digit Span; Spatial Span; Serial Position
Curve), apraxia and visuo-spatial abilities (De
Renzi Imitation Test; Rey-Osterrieth Complex
Figure, Copy), and attention and executive func-
tions (Trail-Making Test A and B; Wisconsin Card
Sorting Test). All of the tests were administered
and scored according to the standard procedures
(Lezak, Howieson, & Loring, 2004). The cognitive
assessment was divided into two parts, a standard
evaluation and an experimental evaluation, and
both were administered at baseline (before the
rTMS treatment), shortly after the rTMS treatment
(2 weeks), and 24 weeks after the baseline. The
results of the baseline cognitive assessment are
reported in Table 1.
For the experimental evaluation, we used an
unfamiliar face–name association task (FNAT)
composed of an encoding and a retrieval phase.
During the encoding phase, the patient was shown
a grey-scale picture of a face on a monitor followed
by a proper name. During the retrieval phase, the
patient was shown a face with two proper names
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BRAIN STIMULATION IMPROVES MEMORY 219
TABLE 1
Patient’s performance on general standard neuropsychological tests
Adjusted score
baseline
Adjusted score after
rTMS (2 weeks)
Adjusted score at follow
up (24 weeks) Cut-offs
Screening for dementia
MMSE 24.5/30 25.5/30 24.6/30 24
Non-verbal reasoning
Raven Colored Progressive
Matrices
33/36 34/36 33/36 >17.5
Memory
Story recall 12 14/28 13/28 >7.5
Auditory-Verbal Learning Test,
immediate recall
33.8/75 30.8/75 31.8/75 >28.52
Auditory-Verbal Learning Test,
delayed recall
3.6/155.4/15 3.6/15>4.68
Rey-Osterrieth Complex Figure,
Recall
9.3/368.3/366.8/36>9.46
Spatial Span 5.8 5.8 5.8 >3.50
Digit Span 7.5 5.5 5.5 >3.75
Serial position curve
Primacy effect 48 8 >4.5
Recency effect 20 22 23 >7.5
First item 1.25 4.25 0.25 >0
Language
Token Test 30.5/36 32.5/36 31.5/36 >26.25
Fluency, phonemic 56 48 44 >16.0
Fluency, semantic 52 63 59 >24.0
Praxia
Rey-Osterrieth Complex Figure,
Copy
33.5/36 36/36 33.5/36 >28.88
De Renzi Imitation test, dx 71/72 71/72 72/72 >62.0
De Renzi Imitation test, sx 67/72 68/72 71/72 >62.0
Executive funcion
Trail-Making Test A 18 13 13 <93.0
Trail-Making Test B 69 53 52 <282.0
Trail-Making Test B–A 45 34 33 186
Wisconsin Card sorting test,
Global score
23.8/128 14.8/128 20.8/128 <90.60
Wisconsin Card sorting test,
Perseverative Responses
11.2 9.2 6 <42.70
Wisconsin Card sorting test,
Non-perseverative Errors
4.6 5.6 5 <30.0
Wisconsin Card sorting test,
Failure to mantain set
1 0 0 <4.0
Age- and education-adjusted scores are reported. denotes scores below cut-off.
(i.e., the correct name and another previously pre-
sented name), and the patient had to associate the
correct name to the face. During the encoding, the
participant was required to respond if a male or
female face was presented and to encode the face–
name association. During the retrieval, the patient
was required to associate one of the two presented
proper names to the face, as was presented during
the encoding.
The FNAT was used to assess the patient’s
associative memory. Each stimulus consisted of
a grey-scale face associated with a proper name.
Faces were downloaded from an electronic dataset
on the web and processed by Adobe Photoshop 5.0
(http://www.adobe.com). The unfamiliar faces were
photographs of people unknown to the patient. A
set of 50 unfamiliar faces was identified (25 males,
25 females). These pictures were scaled to 210 ×263
pixels and presented on a computer screen (sub-
tending a visual angle of 3.15×4). With respect
to names, a set of 50 (25 males, 25 females) unfa-
miliar proper names were generated and randomly
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220 COTELLI ET AL.
assigned to the unfamiliar faces. Both the encod-
ing and the retrieval phases were comprised of two
training trials followed by three separate blocks of
16 trials, with each presented in a random order.
Gender of the stimuli were counterbalanced and
randomized across blocks. Responses were col-
lected via a response-box, and the stimuli remained
on the screen until the response was made. Finally,
to exclude any learning effects resulting from its
repeated execution, the task was conducted twice
at baseline (i.e., baseline 1 and baseline 2) before
rTMS treatment.
In addition, the same task was administered to
22 normal control (NC) subjects comparable in age
and education (age: 64 ±4; education: 13 ±4)
to investigate both the experimental performance
and the learning abilities of a healthy aging group.
The evaluation in the NC group was performed
with the same timing as that used for the patient
(i.e., baseline 1, baseline 2, and 2 weeks), with the
exception of the 24-week evaluation. The protocol
was approved by the Ethics Committee of IRCCS
Fatebenefratelli, Brescia, Italy.
rTMS PROCEDURE
Based on previous rTMS and neuroimaging studies
of episodic memory, we defined the DLPFCs and
IPL as potential target areas for rTMS treatment
(Cabeza et al., 2008; Manenti et al., 2010; Rossi
et al., 2006; Sandrini et al., 2003).
To determine the location of a target area for the
off-line rTMS treatment, we initially conducted two
on-line rTMS experimental sessions during which
each of the named areas, DLPFC and IPL, was
stimulated individually.
We localized the left and right DLPFC and
IPLs using the SofTaxic Evolution navigator system
(www.emsmedical.net).
Prior to rTMS application, the motor threshold
was defined as the lowest stimulation intensity over
the primary motor cortex that resulted in a contrac-
tion in the contralateral hand, of at least 50%, in
10 consecutive stimulations (42% of the maximum
stimulator output in our patient).
Two on-line rTMS tests (i.e., during FNAT) were
performed: one for the DLPFCs and one for the
IPLs. On-line rTMS was applied while the patient
was performing the retrieval phase of the FNAT.
We proposed that the stimulation of one of these
areas during the execution of the FNAT could mod-
ify performance (i.e., accuracy). Each on-line rTMS
test included three blocks corresponding to three
stimulation types (left, right and sham stimulation;
20 Hz for 500 ms, from the trial onset, at 100% of
the motor threshold). We found that only stimula-
tion of the left IPL improved accuracy in the FNAT
(p=.04) compared to sham.
Subsequently, the patient received daily rTMS
treatments, 5 days a week for 2 weeks (25 min-
utes per day), to the left IPL (Talairach coordi-
nates –44, –51, 43). A rapid magnetic stimulator
and a figure-eight, double 70 mm, cooled coil
(www.magstim.com) were used for rTMS admin-
istration. Fifty trains of high-frequency (20 Hz)
rTMS were delivered for 2 seconds with an inter-
stimulus interval of 28 seconds (40 stimuli/train,
50 trains, 2000 pulses/session, five sessions/week,
2 weeks). The stimulation intensity was set to 100%
of the motor threshold. These parameters are con-
sistent with the safety recommendations for rTMS
(Rossi, Hallett, Rossini, & Pascual-Leone, 2009),
and the patient reported no adverse effects.
RESULTS
For the two baseline evaluations (baseline 1 and 2;
Figure 1), the patient’s performance did not change;
therefore, no learning repetition effects were present
for the FNAT (χ2<1, df =1, p>.05). In contrast,
for the NC group, the repetition of the task resulted
in an improvement in performance, F(2, 42) =39,
p<.001. Post-hoc analyses (Bonferroni) revealed
that the NC group’s performance during the sec-
ond (2 days after baseline 1) and the third (2 weeks
after) repetitions were higher than the performance
90
80
70
CORRECT RESPONSES %
60
50
40
Baseline 1 Baseline 2 2 weeks 24 weeks
aMCI
NC
Figure 1. Percentage of correct responses (%) in a face–name
association task (FNAT) over several sessions. aMCI, amnestic
mild cognitive impairment patient; NC, normal control group.
Error bars represent the standard errors of only one side. The
dotted line indicates chance performance.
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BRAIN STIMULATION IMPROVES MEMORY 221
during the first presentation (baseline 1; p<.001);
there was no difference between the second and
third repetitions (baseline 2 vs. 2 weeks; p>.05).
Regarding the rTMS treatment, the patient’s per-
formance on the FNAT was compared, using the
non-parametric χ2statistical test (Figure 1), to
the four time points: baseline (pre-treatment; mean
between the first two repetitions of the task, base-
line 1 and 2), 2 weeks (post-treatment) and at the
follow-up (24 weeks after baseline). The analysis
showed a significant improvement in the patient’s
performance on the FNAT after 2 weeks of rTMS
(73%) with respect to baseline (54%) (χ2=6.99,
df =1, p<.001, Yates correction). The improve-
ment was still significant 24 weeks after treatment
(79%) as compared to baseline (χ2=13, df =1,
p<.001). The performance at 24 weeks was not dif-
ferent from the score obtained at 2 weeks (p>.05),
suggesting that the increased performance observed
at 2 weeks was stable until follow-up.
Compared with the NC group, the patient did
not show an improvement in performance resulting
from the repetition of the task (no difference
between the first two repetitions baseline 1 vs. 2),
but the patient did demonstrate an increased
performance after rTMS treatment. The direct
comparison between the patient’s performance and
the performance of the healthy subjects revealed
a significant difference at baseline, t(21) =5.1,
p<.001, at the second repetition, t(21) =11.6,
p<.001, and after 2 weeks, t(21) =5.0, p<.001,
while the patient’s performance after 24 weeks was
not different from the NC group after 2 weeks,
t(21) =1.9, p>.05.
In the baseline neuropsychological standard eval-
uation, the patient had scores below cut-off on
some memory tasks: delayed recall of Auditory-
Verbal Learning Test, recall of Rey-Osterrieth
Complex Figure and Primacy effect of Serial
Position Curve task. Two weeks after rTMS treat-
ment onset, we observed an improvement on
the delayed recall of Auditory-Verbal Learning
Test and the Primacy effect of Serial Position
Curve task. However, only the improvement in the
Primacy effect of Serial Position Curve task per-
sisted 24 weeks after treatment. Primacy is strongly
correlated to the consolidation of long-term
memory. The patient’s improvement in this task
suggests an increase in the ability to encode verbal
items to memory, which parallels the improvement
on FNAT.
DISCUSSION
The goal of this study was to assess whether appli-
cation of high-frequency rTMS to the left IPL for
25 minutes a day, 5 days a week, for 2 weeks
would lead to significant increases in memory per-
formance in an individual with aMCI.
Previous neuroimaging evidence suggests that, in
elderly subjects, successful memory encoding and
retrieval is associated with activation of the left
IPL and the anterior hippocampus (Kircher et al.,
2008). The present study provides direct evidence
for a putative role of the left IPL in associative
memory and its enhancement by rTMS. Similarly,
using imaging data, Sole-Padulles et al. (2006) have
shown that elderly adults who received DLPFC
rTMS temporarily improved their performance in
an association memory task by activating the pre-
frontal and posterior areas.
In this vein, it has also been suggested that the
recruitment of a larger neural network in older par-
ticipants (Dennis & Cabeza, 2010), as well as in
Alzheimer’s patients, might reflect attempts to com-
pensate for functional loss (Backman et al., 1999).
Although the mechanisms involved in enhancing
memory formation from rTMS are still specula-
tive, rTMS might interact with the brain to main-
tain or strengthen the neural connections between
regions. The present findings may reflect rTMS-
induced neuromodulation, which promotes a long-
term rearrangement of synaptic connections within
a precise network. Comparing the patient with
the NC group, which showed learning after the
first repetition, allowed us to exclude the hypoth-
esis that the patient’s improvement was due to
task repetition and therefore practice effects. The
present results are consistent with previous stud-
ies, which have shown that neuromodulation of a
specific behaviourally-activated network produces
an increase in cortical efficacy when performing a
cognitive task.
Several studies have suggested that rhythmic
transcranial stimulation can enhance cognitive
performance (Miniussi et al., 2008). A possible
mechanism might be that the modulation of corti-
cal activity through the use of rhythmic stimulation
may re-adjust pathological patterns of brain activ-
ity, which provides an opportunity to induce new,
improved activity patterns with an enhancement of
the affected functional networks (Thut & Miniussi,
2009).
Downloaded by [University of Sydney] at 15:42 15 August 2012
222 COTELLI ET AL.
The preliminary results presented here highlight
the therapeutic potential of the induction of long-
term neuromodulation using brain stimulation in
the treatment of aMCI. Our patient showed a sta-
ble aMCI diagnosis over 24 weeks, and until the
patient was studied, he did not show any other cog-
nitive or psychiatric disorder. We found that the
improvement due to rTMS treatment was specific to
the associative memory task. In addition, immedi-
ately after 2 weeks of rTMS treatment, we observed
an improvement in performing neuropsychological
tasks that assess long-term memory.
The major limitation in our study was the use of
a single case and the lack of a placebo condition.
However, several factors suggest that the cogni-
tive improvement observed in our study cannot be
solely accounted for by task practice effects. First,
it seems unlikely that the magnitude of improve-
ment found in this study is solely due to a task
practice effect. We also show the absence of any
rTMS effects on language, apraxia, visuo–spatial
abilities, and executive functions, suggesting the
specificity of the result, and the repetition learn-
ing effects cannot be explained by the present data.
Furthermore, normal control subjects, who did not
receive real rTMS treatment, did not show any sig-
nificant improvement in FNAT task when tested
after the third evaluation. We cannot exclude, how-
ever, that the absence of any additional improve-
ment on the FNAT is due to the high performance
obtained rapidly by the control group.
We acknowledge that these are preliminary find-
ings, and present data cannot entirely rule out
the practice effect, therefore future studies should
use parallel versions of the same neuropsycholog-
ical assessments to evaluate cognitive performance
pre- and post-stimulation. However, if confirmed in
larger samples, using a randomized, blinded design
(e.g., real vs. placebo rTMS), these results could
highlight the potential role of transcranial brain
stimulation in modulating and facilitating memory
performances in individuals with aMCI.
As to the long-term effects, we identified an
improvement in the formation of associative mem-
ories 20 weeks after the end of rTMS treatment
(24 weeks from the baseline). To date, this is the
first study that has shown a long-lasting cogni-
tive role of rTMS treatment in aMCI patients. A
recent study described a long-lasting (12 weeks
post-treatment) improvement on sentence compre-
hension tasks after rTMS in Alzheimer’s disease
patients (Cotelli et al., 2011), but no studies have
investigated rTMS effects in aMCI. These find-
ings may reflect a rTMS-induced modulation of
short- and/or long-range cortical synaptic efficacy
and connectivity that potentiates the functional net-
work, which leads to more effective processing. This
neuromodulation could explain the long-lasting
effects even if the mechanism behind these changes
remains poorly understood.
The possibility of using brain stimulation as a
tool to promote neuroplasticity is promising, not
only for advancing our understanding of brain
plasticity mechanisms but also for designing new
neurorehabilitation strategies.
Original manuscript received 22 July 2010
Revised manuscript accepted 11 May 2011
First published online 1 September 2011
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Cognitive Science,13, 182–189.
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... Individual coordinates in native space were transformed to MNI space using the affine and non-linear warping estimated by Melodic. The Euclidean distance was used to compute the distance from group-level left IPL and DLPFC coordinates reported in previous TMS studies (Herwig et al., 2003;Cotelli et al., 2010Cotelli et al., , 2012Fox et al., 2013). Coordinates in Talairach space were transformed to MNI space using a non-linear transformation (Lacadie et al., 2008). ...
... When using the anatomical atlas label (AAL; Tzourio-Mazoyer et al., 2002) to localize our IPL coordinates, 5 out of 13 cases corresponded to or were close to the angular gyrus (AG), five to the middle occipital gyrus (MOG), two to the inferior parietal gyrus (IPL), and one was borderline between the latter two regions ( Table 2). The median distance between individual fMRI-derived and group-level IPL coordinates was >20 mm for both the studies considered (Herwig et al., 2003;Cotelli et al., 2012). However, the distance between individual fMRI-derived and P3 coordinates (Herwig et al., 2003) significantly exceeded rTMS focality when considering the 12 mm threshold (p = 0.0002), but not the 20 mm threshold (p = 0.342; Table 2). ...
... However, the distance between individual fMRI-derived and P3 coordinates (Herwig et al., 2003) significantly exceeded rTMS focality when considering the 12 mm threshold (p = 0.0002), but not the 20 mm threshold (p = 0.342; Table 2). When compared with the IPL coordinates used in Cotelli et al. (2012), the distance significantly exceeded both rTMS focalities (all p's < 0.05; Table 2). For the DMN, green target corresponds to P3 (Herwig et al., 2003), and light-blue to IPL (Cotelli et al., 2012). ...
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A growing number of studies is using fMRI-based connectivity to guide transcranial magnetic stimulation (TMS) target identification in both normal and clinical populations. TMS has gained increasing attention as a potential therapeutic strategy also in Alzheimer’s disease (AD), but an endorsed target localization strategy in this population is still lacking. In this proof of concept study, we prove the feasibility of a tailored TMS targeting approach for AD, which stems from a network-based perspective. Based on functional imaging, the procedure allows to extract individual optimal targets meanwhile accounting for functional variability. Single-subject resting-state fMRI was used to extract individual target coordinates of two networks primarily affected in AD, the default mode and the fronto-parietal network. The localization of these targets was compared to that of traditional group-level approaches and tested against varying degrees of TMS focality. The distance between individual fMRI-derived coordinates and traditionally defined targets was significant for a supposed TMS focality of 12 mm and in some cases up to 20 mm. Comparison with anatomical labels confirmed a lack of 1:1 correspondence between anatomical and functional targets. The proposed network-based fMRI-guided TMS approach, while accounting for inter-individual functional variability, allows to target core AD networks, and might thus represent a step toward tailored TMS interventions for AD.
... Deep TMS, which has been less investigated than rTMS, is assumed to have the advantage of a wider and deeper site of stimulation and could be better suited for reaching structures, such as the cingulum, that are known to be important for memory function [31]. Interestingly, studies on the role of rTMS in episodic memory, support the involvement of a more distributed neural network sustaining this function, including the temporal lobes and parietal cortices [32]. Furthermore, it has been suggested that stimulating the medial PFC could be advantageous because it is part of the default-mode network, which is important for memory functions [33]. ...
Article
Purpose: Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique with the 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 deep TMS (dTMS) on a group of 10 patients diagnosed with amnesic MCI. Methods: We compared the effects of TMS COG treatment (dTMS delivered with H7 helmet for ten daily sessions together with cognitive training of memory and attention), with those of COG treatment (cognitive training alone) of the same duration. Results: Neuropsychological evaluation at baseline, after TMS COG treatment, after COG treatment and at six months follow up, compared with ANOVA, revealed a significant group-by-time interaction (𝑝 = 0.05), favoring the TMS COG treatment for memory tests. The improvement was kept after six months. Other neuropsychological tests were not significantly affected by treatment. Conclusions: These findings suggest that dTMS might be effective as a therapy for MCI and probably a tool to delay cognitive deterioration.
... Several studies utilized multitimepoint assessments to test the lasting effect of rTMS (Lee et al., 2016;Nguyen et al., 2017;Bagattini et al., 2020). Cotelli et al. has reported that with a 2-week rTMS stimulation over left parietal cortex, aMCI patients improved their accuracy in an association memory task and such improvement remained significant 24 weeks after stimulation began (Cotelli et al., 2012). However, there are limitations that some studies lacked of data in the control group and cannot provide a better evaluation for the effect of rTMS. ...
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Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, has been considered as a potentially effective treatment for the cognitive impairment in patients with mild cognitive impairment (MCI) and Alzheimer’s Disease (AD). However, the effectiveness of this therapy is still under debate due to the variety of rTMS parameters and individual differences including distinctive stages of AD in the previous studies. The current meta-analysis is aiming to assess the cognitive enhancement of rTMS treatment on patients of MCI and early AD. Three datasets (PubMed, Web of Science and CKNI) were searched with relative terms and finally twelve studies with 438 participants (231 in the rTMS group and 207 in the control group) in thirteen randomized, double-blind and controlled trials were included. Random effects analysis revealed that rTMS stimulation significantly introduced cognitive benefits in patients of MCI and early AD compared with the control group (mean effect size, 1.17; 95% CI, 0.76 - 1.57). Most settings of rTMS parameters (frequency, session number, stimulation site number) significantly enhanced global cognitive function, and the results revealed that protocols with 10 Hz repetition frequency and DLPFC as the stimulation site for 20 sessions can already be able to produce cognitive improvement. The cognitive enhancement of rTMS could last for one month after the end of treatment and patients with MCI were likely to benefit more from the rTMS stimulation. Our meta-analysis added important evidence to the cognitive enhancement of rTMS in patients with MCI and early AD and discussed potential underlying mechanisms about the effect induced by rTMS.
... Though clinically-speaking group B showed improvement on the MoCA test, it is important to emphasize the differences in the intergroup analysis, as they suggest the need for a larger sample to achieve a better comparison in terms of statistically-significant differences between the two study groups. For the neuropsychological domains, AG showed improvement in areas related to memory, as Cotelli et al. (2012) have reported. Attention and cognitive flexibility also showed significant intergroup differences, which could explain why this effect may not indicate the impact of CS on the sham group. ...
Article
Mild cognitive impairment (MCI) is a state between normal cognition and dementia. Currently, there is little evidence of repetitive Transcranial Magnetic Stimulation (rTMS) as an enhancing tool for Cognitive Stimulation (CS) on MCI. The importance of this study consists in its assessment of the enhancing effect of rTMS on CS in 22 MCI patients randomized and divided into two group: active (AG) and sham (SG). Diagnoses and assessments were determined during 30 sessions over a 10-week period by Montreal Cognitive Assessment (MoCA) and Neuropsí test. Results were statistically significant in the intergroup analysis with MoCA and intragroup only for AG.
... First, Cotelli et al. (2012) described the case of an 81-year-old man with amnesic MCI [48]. After two online rTMS sessions to pinpoint the location they would consistently stimulate, they found that only stimulation of the left inferior parietal cortex (IPL) improved accuracy in FNAT (Face-Name Association Test) scores. ...
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Dementia is a debilitating impairment of cognitive functions that affects millions of people worldwide. There are several diseases belonging to the dementia spectrum, most prominently Alzheimer’s disease (AD), vascular dementia (VD), Lewy body dementia (LBD) and frontotemporal dementia (FTD). Repetitive transcranial magnetic stimulation (rTMS) is a safe, non-invasive form of brain stimulation that utilizes a magnetic coil to generate an electrical field and induce numerous changes in the brain. It is considered efficacious for the treatment of various neuropsychiatric disorders. In this paper, we review the available studies involving rTMS in the treatment of these dementia types. The majority of studies have involved AD and shown beneficial effects, either as a standalone, or as an add-on to standard-of-care pharmacological treatment and cognitive training. The dorsolateral prefrontal cortex seems to hold a central position in the applied protocols, but several parameters still need to be defined. In addition, rTMS has shown potential in mild cognitive impairment as well. Regarding the remaining dementias, research is still at preliminary phases, and large, randomized studies are currently lacking.
... This research will seek to shed light on this puzzled scenario by directly testing whether empathy causally draws on AM retrieval. Cabeza & St Jacques, 2007;Cotelli et al., 2012). Furthermore, according to the systems consolidation account (Antony et al., 2017;McClelland et al., 1995), memories are first dependent on the hippocampus but, with time, can become gradually independent and stably stored in the neocortex (but see also, e.g., Barry & Maguire, 2019;Clark & Maguire, 2016). ...
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Social interactions are partly driven by our ability to empathize—the capacity to share and understand others’ inner states. While a growing body of evidence suggests a link between past experiences and empathy, to what degree empathy is dependent on our own previous experiences (autobiographical memories, AMs) is still unclear. Whereas neuroimaging studies have shown wide overlapping brain networks underpinning AM and empathic processes, studies on clinical populations with memory loss have not always shown empathy is impaired. The current transcranial magnetic stimulation (TMS) and electroencephalography study will seek to shed light on this neuropsychological puzzle by testing whether self‐perceived empathy is causally linked to AM retrieval. Cortical activity, together with self‐rating of empathy, will be recorded for scenarios that echo personal experiences while a brain region critical for AM retrieval will be transiently inhibited using TMS before task performance.
... While studies of amnesia are potentially powerful sources of evidence evaluating the role of memory in empathy, they do not provide definitive evidence about the role of AMs. This is because the retrieval of AMs does not rely only on the hippocampal cortices but is underpinned by a network of brain areas that involves the prefrontal cortex and parietal areas including precuneus, posterior parietal cortex and the retrosplenial cortex (Boccia, Teghil, & Guariglia, 2019;Cabeza & St Jacques, 2007;Cotelli et al., 2012). In line with the systems consolidation account, by which memories become gradually independent of the hippocampus and stably stored in the neocortex, at least remote memories might still be available as a source of semantic knowledge or implicit memories for the patients (Antony, Ferreira, Norman, & Wimber, 2017;McClelland, McNaughton, & O'Reilly, 1995). ...
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Empathy relies on the ability to mirror and to explicitly infer others' inner states. Theoretical accounts suggest that memories play a role in empathy, but direct evidence of reactivation of autobiographical memories (AM) in empathy is yet to be shown. We addressed this question in two experiments. In Experiment 1, electrophysiological activity (EEG) was recorded from 28 participants. Participants performed an empathy task in which targets for empathy were depicted in contexts for which participants either did or did not have an AM, followed by a task that explicitly required memory retrieval of the AM and non-AM contexts. The retrieval task was implemented to extract the neural fingerprints of AM and non-AM contexts, which were then used to probe data from the empathy task. An EEG pattern classifier was trained and tested across tasks and showed evidence for AM reactivation when participants were preparing their judgement in the empathy task. Participants self-reported higher empathy for people depicted in situations they had experienced themselves as compared to situations they had not experienced. A second independent fMRI experiment replicated this behavioural finding and showed increased activation for AM compared to non-AM in the brain networks underlying empathy: precuneus, posterior parietal cortex, superior and inferior parietal lobule, and superior frontal gyrus. Together, our study reports behavioural, electrophysiological, and fMRI evidence that robustly supports AM reactivation in empathy.
... During the encoding phase, a grey-scale picture of a face on a monitor with a proper name was presented, and the participant was required to respond if a male or female face was presented. During the retrieval phase, after 5 min from the encoding, the participant was shown a face with four proper names (i.e., the correct name and three other names), and the subject had to associate the correct name to the face, as was presented during the encoding phase, as quickly as possible [36]. With respect to names, unfamiliar proper names were generated and randomly assigned to the unfamiliar faces. ...
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Objective: To assess whether exposure to non-invasive brain stimulation with transcranial alternating current stimulation at γ frequency (γ-tACS) applied over Pz (an area overlying the medial parietal cortex and the precuneus) can improve memory and modulate cholinergic transmission in mild cognitive impairment due to Alzheimer’s disease (MCI-AD). Methods: In this randomized, double-blind, sham controlled, crossover pilot study, participants were assigned to a single 60 min treatment with exposure to γ-tACS over Pz or sham tACS. Each subject underwent a clinical evaluation including assessment of episodic memory pre- and post-γ-tACS or sham stimulation. Indirect measures of cholinergic transmission evaluated using transcranial magnetic stimulation (TMS) pre- and post-γ-tACS or sham tACS were evaluated. Results: Twenty MCI-AD participants completed the study. No tACS-related side effects were observed, and the intervention was well tolerated in all participants. We observed a significant improvement at the Rey auditory verbal learning (RAVL) test total recall (5.7 [95% CI, 4.0 to 7.4], p<0.001) and long delayed recall scores (1.3 [95% CI, 0.4 to 2.1], p=0.007) after γ-tACS but not after sham tACS. Face-name associations scores improved during γ−tACS (4.3 [95% CI, 2.8 to 5.8], p<0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission evaluated with TMS, increased only after γ-tACS (0.31 [95% CI, 0.24 to 0.38], p<0.001) but not after sham tACS. Conclusions: exposure to γ-tACS over Pz showed a significant improvement of memory performances, along with restoration of intracortical connectivity measures of cholinergic neurotransmission, compared to sham tACS.
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Background Deficits in associative memory (AM) are the earliest and most prominent feature of Alzheimer's disease (AD) and demonstrate a clear cause of distress for patients and their families. Objective The present study aimed to determine AM enhancements following accelerated intermittent theta-burst stimulation (iTBS) in patients with AD. Methods In a randomized, double-blind, sham-controlled design, iTBS was administered to the left dorsolateral prefrontal cortex (DLPFC) of patients with AD for 14 days. Measurements included AM (primary outcome) and a comprehensive neuropsychological battery. Patients were evaluated at baseline, following the intervention (week 2), and 8 weeks after treatment cessation (week 10). Results Sixty patients with AD were initially enrolled; 47 completed the trial. The active group displayed greater AM improvements compared with the sham group at week 2 (P = 0.003), which was sustained at week 10. Furthermore, higher Mini-Mental State Examination (MMSE) scores at baseline were associated with greater AM improvements at weeks 2 and 10. For the independent iTBS group, this correlation predicted improvements in AM (P < 0.001) and identified treatment responders with 92% accuracy. Most of the neuropsychological tests were markedly improved in the active group. In particular, the Montreal Cognitive Assessment and MMSE in the active group increased by 2.8 and 2.3 points, respectively, at week 2, while there was no marked change in the sham group. Conclusion In the present study, accelerated iTBS of the DLPFC demonstrated an effective and well-tolerated complementary treatment for patients with AD, especially for individuals with relatively high MMSE scores.
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Objectives To compare cognitive effects and acceptability of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) in patients with Alzheimer’s disease (AD) or mild cognitive impairment (MCI), and to determine whether cognitive training (CT) during rTMS or tDCS provides additional benefits. Methods Electronic search of PubMed, Medline, Embase, the Cochrane Library and PsycINFO up to 5 March 2020. We enrolled double-blind, randomised controlled trials (RCTs). The primary outcomes were acceptability and pre–post treatment changes in general cognition measured by Mini-Mental State Examination, and the secondary outcomes were memory function, verbal fluency, working memory and executive function. Durability of cognitive benefits (1, 2 and ≥3 months) after brain stimulation was examined. Results We included 27 RCTs (n=1070), and the treatment components included high-frequency rTMS (HFrTMS) and low-frequency rTMS, anodal tDCS (atDCS) and cathodal tDCS (ctDCS), CT, sham CT and sham brain stimulation. Risk of bias of evidence in each domain was low (range: 0%–11.1%). HFrTMS (1.08, 9, 0.35–1.80) and atDCS (0.56, 0.03–1.09) had short-term positive effects on general cognition. CT might be associated with negative effects on general cognition (−0.79, –2.06 to 0.48) during rTMS or tDCS. At 1-month follow-up, HFrTMS (1.65, 0.77–2.54) and ctDCS (2.57, 0.20–4.95) exhibited larger therapeutic responses. Separate analysis of populations with pure AD and MCI revealed positive effects only in individuals with AD. rTMS and tDCS were well tolerated. Conclusions HFrTMS is more effective than atDCS for improving global cognition, and patients with AD may have better responses to rTMS and tDCS than MCI.
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The contribution of the parietal cortex to episodic memory is a fascinating scientific puzzle. On the one hand, parietal lesions do not normally yield severe episodic-memory deficits; on the other hand, parietal activations are seen frequently in functional-neuroimaging studies of episodic memory. A review of these two categories of evidence suggests that the answer to the puzzle requires us to distinguish between the contributions of dorsal and ventral parietal regions and between the influence of top-down and bottom-up attention on memory.
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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.
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There is evidence that the human prefrontal cortex is asymmetrically involved in long-term episodic memory processing. Moreover, abstract and concrete words processing has been reported to differentially involve prefrontal and parietal areas. We implemented a two-stages functional magnetic resonance imaging (fMRI)-repetitive transcranial magnetic stimulation (rTMS) paradigm to investigate the role of the dorsolateral prefrontal cortices (DLPFCs) and parietal cortices (PARCs) in encoding and retrieval of abstract and concrete words. Using this paradigm we could select areas to be stimulated on the basis of single-subject (SS) anatomical and functional data, investigating the usefulness of this integration approach. With respect to fMRI, abstract and concrete words differed only for a greater left fusiform gyrus activation for concrete words. In turn, significant rTMS effects were found, but only for the retrieval of abstract words. Consistent with previous findings, repetitive stimulation of the right DLPFC had a specific impact on episodic retrieval. Memory retrieval performance was also disrupted when rTMS was applied to the left PARC. Finally, we found a significant positive correlation between the effect sizes of SS right PARC activations for abstract word retrieval and the consequent rTMS interference effects. Taken together these data provide for the first time evidence that also the PARC has a necessary role in episodic retrieval of abstract words. Importantly, from a methodological perspective, our data demonstrate that fMRI-guided rTMS with a SS approach provides a powerful tool to investigate the neural underpinnings of cognitive functions.
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Background Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials.Objective To characterize clinically subjects with MCI cross-sectionally and longitudinally.Design A prospective, longitudinal inception cohort.Setting General community clinic.Participants A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn.Main Outcome Measures The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale–Revised, Wechsler Memory Scale–Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, respectively.Results The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD.Conclusions Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.
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Cognitive deficits are a common consequence of neurologic disease, in particular, of traumatic brain injury, stroke, and neurodegenerative disorders, and there is evidence that specific cognitive training may be effective in cognitive rehabilitation. Several investigations emphasize the fact that interacting with cortical activity, by means of cortical stimulation, can positively affect the short-term cognitive performance and improve the rehabilitation potential of neurologic patients. In this respect, preliminary evidence suggests that cortical stimulation may play a role in treating aphasia, unilateral neglect, and other cognitive disorders. Several possible mechanisms can account for the effects of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) on cognitive performance. They all reflect the potential of these methods to improve the subject's ability to relearn or to acquire new strategies for carrying out behavioral tasks. The responsible mechanisms remain unclear but they are most likely related to the activation of impeded pathways or inhibition of maladaptive responses. Modifications of the brain activity may assist relearning by facilitating local activity or by suppressing interfering activity from other brain areas. Notwithstanding the promise of these preliminary findings, to date no systematic application of these methods to neurorehabilitation research has been reported. Considering the potential benefit of these interventions, further studies taking into consideration large patient populations, long treatment periods, or the combination of different rehabilitation strategies are needed. Brain stimulation is indeed an exciting opportunity in the field of cognitive neurorehabilitation, which is clearly in need of further research.
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Abundant research finds that in young adults explicit learning (EL) is more dependent on the medial temporal lobes (MTL) whereas implicit learning (IL) is more dependent on the striatum. Using fMRI, we investigated age differences in each task and whether this differentiation is preserved in older adults. Results indicated that, while young recruited the MTL for EL and striatum for IL, both activations were significantly reduced in older adults. Additionally, results indicated that older adults recruited the MTL for IL, and this activation was significantly greater in older compared with young adults. A significant Task × Age interaction was found in both regions-with young preferentially recruiting the MTL for EL and striatum for IL, and older adults showing no preferential recruit for either task. Finally, young adults demonstrated significant negative correlations between activity in the striatum and MTL during both the EL and IL tasks. These correlations were attenuated in older adults. Taken together results support dedifferentiation in aging across memory systems.
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This article is based on a consensus conference, which took place in Certosa di Pontignano, Siena (Italy) on March 7-9, 2008, intended to update the previous safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings. Over the past decade the scientific and medical community has had the opportunity to evaluate the safety record of research studies and clinical applications of TMS and repetitive TMS (rTMS). In these years the number of applications of conventional TMS has grown impressively, new paradigms of stimulation have been developed (e.g., patterned repetitive TMS) and technical advances have led to new device designs and to the real-time integration of TMS with electroencephalography (EEG), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Thousands of healthy subjects and patients with various neurological and psychiatric diseases have undergone TMS allowing a better assessment of relative risks. The occurrence of seizures (i.e., the most serious TMS-related acute adverse effect) has been extremely rare, with most of the few new cases receiving rTMS exceeding previous guidelines, often in patients under treatment with drugs which potentially lower the seizure threshold. The present updated guidelines review issues of risk and safety of conventional TMS protocols, address the undesired effects and risks of emerging TMS interventions, the applications of TMS in patients with implanted electrodes in the central nervous system, and safety aspects of TMS in neuroimaging environments. We cover recommended limits of stimulation parameters and other important precautions, monitoring of subjects, expertise of the rTMS team, and ethical issues. While all the recommendations here are expert based, they utilize published data to the extent possible.