Abstract and Figures

Word-retrieval difficulties commonly occur in healthy aging. Recent studies report an improved ability to name pictures after the administration of high-frequency repetitive transcranial magnetic stimulation (rTMS) in healthy younger adults and in patients with neurological disease. The aim of this study was to assess the effect of high-frequency rTMS applied to the dorsolateral prefrontal cortex (DLPFC) on picture naming in healthy older adults. High-frequency rTMS was applied to the left and right DLPFC during object and action naming in thirteen healthy older adults. The naming latency for actions was shortened after stimulation of the left and right DLPFC compared to application of the sham stimulation. Stimulation was not observed to have any effect on correctness of naming. Our data demonstrate the involvement of the left and right DLPFC in a sample of healthy aging subjects during an action-naming task. The bilateral involvement of the DLPFC in these participants is discussed together with data on younger adults and on Alzheimer’s patients.
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Frontiers in Aging Neuroscience www.frontiersin.org November 2010 | Volume 2 | Article 151 | 1
AGING NEUROSCIENC
E
Original research article
published: 24 November 2010
doi: 10.3389/fnagi.2010.00151
Mackay et al. (2002) demonstrated that when action and object
items are carefully matched for difficulty, the aging process affects
the naming of actions and objects equally.
Naming difficulty is commonly present in aphasic and demented
patients (Robinson et al., 1996; Cappa et al., 1998; Kim and
Thompson, 2000; Cotelli et al., 2006a; Crepaldi et al., 2006). Lesion
and imaging studies support the hypothesis of a central role of the
left prefrontal and parietal areas in the naming of actions (i.e., verb
processing) (Daniele et al., 1994; Perani et al., 1999b). However,
studies that establish the role of these areas in older adults are
still lacking.
Repetitive transcranial magnetic stimulation (rTMS) can induce
a brief change in a subject’s behavioral performance only if it is
applied over an area that is causally engaged in that task being
executed. Recent studies reported an improved ability to name
pictures after the administration of rTMS over the prefrontal cor-
tex in healthy younger adults and in patients with several types
of neurological diseases (Topper et al., 1998; Cappa et al., 2002;
Martin et al., 2004; Naeser et al., 2005a, b; Cotelli et al., 2006b,
2008; Finocchiaro et al., 2006). Cappa et al. (2002) reported a selec-
tive facilitation in younger adults for action naming when they
received rTMS to the left dorsolateral prefrontal cortex (DLPFC).
Specifically, they found a shortening in verbal response times com-
pared to sham (i.e., placebo) stimulation. Consistent with these
results, Cotelli et al. (2006b, 2008) applied the same protocol in
Alzheimer’s disease (AD) patients and found that rTMS to the
DLPFC improves naming performance in AD patients not only in
the early stage (Cotelli et al., 2006b) but also in a more advanced
stage of cognitive decline (Cotelli et al., 2008). Importantly, the
improvement in AD patients consisted of an increased correctness
score after left and right rTMS compared to the sham stimulation
condition. Moreover, in patients in the early stages of cognitive
INTRODUCTION
Several studies have investigated cognitive changes linked to
healthy aging and have documented an age-related decline in
naming (Goodglass, 1980; Nicholas et al., 1985; LaBarge et al.,
1986; Ardilla and Rosselli, 1989; Feyereisen, 1997) and lexical
retrieval processing abilities (Nicholas et al., 1985; Bowles et al.,
1987; Albert et al., 1988; Au et al., 1995; Ramsay et al., 1999; Barresi
et al., 2000; Mackay et al., 2002; Morrison et al., 2003; Connor
et al., 2004; Mortensen et al., 2008), generally observed after the
age of 70 (Feyereisen, 1997). A number of studies suggest that
increased picture-naming errors in older adults reflect impairment
in lexical or phonological access rather than in semantic access
(Barresi et al., 2000; Mackay et al., 2002; Mortensen et al., 2006).
Moreover, differences in the performances of younger and older
adult participants on a picture-naming task have also been related
to a slowing of the speed of processing with age. In this respect, a
number of studies have provided data consistent with the hypoth-
esis that older adults are slower than younger adults in picture-
naming tasks (Thomas et al., 1977; Mitchell, 1989; Morrison et al.,
2003). However, despite reports of word retrieval difficulties in
older adults, age-related difficulties in picture naming have not
consistently been identified (Villardita et al., 1985; LaBarge et al.,
1986; Flicker et al., 1987). Goulet et al. (1994) argued that different
methodological variables such as the age range of participants,
the study design, and the type of naming task might account for
these different results. Moreover, the material to be named could
be different between studies, and action and object naming could
give different results. Studies of retrieval abilities by grammatical
class provide evidence for dissociation between action and object
naming in the healthy aging population. In these studies, action
naming was relatively more preserved in older adults than object
naming (Nicholas et al., 1997; Barresi et al., 2000). In contrast,
Action and object naming in physiological aging:
an rTMS study
Maria Cotelli 1*, Rosa Manenti1, Sandra Rosini1, Marco Calabria1, Michela Brambilla1, Patrizia Silvia Bisiacchi2,
Orazio Zanetti1 and Carlo Miniussi1,3
1 Istituto Di Ricovero e Cura a Carattere Scientifico, Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
2 Department of General Psychology, University of Padua, Italy
3 Department of Biomedical Sciences and Biotechnologies, National Neuroscience Institute, University of Brescia, Brescia, Italy
Word-retrieval difficulties commonly occur in healthy aging. Recent studies report an improved
ability to name pictures after the administration of high-frequency repetitive transcranial magnetic
stimulation (rTMS) in healthy younger adults and in patients with neurological disease. The aim of
this study was to assess the effect of high-frequency rTMS applied to the dorsolateral prefrontal
cortex (DLPFC) on picture naming in healthy older adults. High-frequency rTMS was applied to the
left and right DLPFC during object and action naming in 13 healthy older adults. The naming latency
for actions was shortened after stimulation of the left and right DLPFC compared to application of
the sham stimulation. Stimulation was not observed to have any effect on correctness of naming.
Our data demonstrate the involvement of the left and right DLPFC in a sample of healthy aging
subjects during an action-naming task. The bilateral involvement of the DLPFC in these participants
is discussed together with data on younger adults and on Alzheimer’s patients.
Keywords: brain stimulation, naming, HAROLD
Edited by:
Hari S. Sharma, Uppsala University,
Sweden
Reviewed by:
John F. Disterhoft, Northwestern
University Medical School, USA
Ashok K. Shetty, Duke University
Medical Center, USA
*Correspondence:
Maria Cotelli, Istituto Di Ricovero e
Cura a Carattere Scientifico, Centro
San Giovanni di Dio Fatebenefratelli,
Via Piastroni, 4 25125 Brescia, Italy.
e-mail: mcotelli@fatebenefratelli.it
Frontiers in Aging Neuroscience www.frontiersin.org November 2010 | Volume 2 | Article 151 | 2
Cotelli et al. Brain stimulation in aging
decline, rTMS only improved action-naming performance, while
both action-and object-naming performance were improved in
patients in an advanced stage of cognitive decline.
The purpose of this study was to explore the effects of rTMS
applied to the DLPFC on an action and object picture-naming task
in older adults. We hypothesized that stimulation of the left DLPFC
can generate a facilitatory effect, namely a decrease in the verbal
reaction time in action picture naming, as previously found in
younger adults. Furthermore, if physiological aging implies hemi-
spheric asymmetry reduction, as previously suggested, we would
expect to find facilitation after stimulation of either the left or right
DLPFC, as found in previous studies with AD patients (Cotelli
et al., 2006b, 2008).
MATERIALS AND METHODS
EXPERIMENT 1: BEHAVIORAL ACTION AND OBJECT-NAMING TASK
The aim of Experiment 1 was to select from a larger set of pictures
a congruent subset of stimuli balanced for all variables and verbal
reaction time (vRT) .
Participants
Prior to being enrolled in the experiment, participants were admin-
istered a standard health history questionnaire and completed a
Mini Mental State Examination (MMSE) (Folstein et al., 1975).
Potential participants were excluded if they reported a history of
neurological disease, cardiovascular disease, psychiatric disorders or
alcohol or other substance abuse. Individuals who reported subjec-
tive memory complaints or scored below 27 out of 30 on the MMSE
were also excluded. Thirty (8 male, 22 female) healthy older adults
(age 60–81 years, mean 64.1 years, education mean = 13.8 years)
participated in the experiment. All participants were native Italian
speakers and had normal or corrected-to-normal vision. All partici-
pants were right-handed (Oldfield, 1971). The study was approved
by the local ethics committee, and informed consent was obtained
from all participants prior to the beginning of the experiment.
Stimuli
The stimuli used in the action and object picture-naming tasks
were taken from the Center for Research in Language-International
Picture-Naming Project corpus CRL-IPNP (Bates et al., 2000),
which contains 795 black and white two-dimensional line drawings
representing actions and objects. These items have been tested and
normed in healthy and patient populations across seven different
international sites and languages. Items are coded for a number
of variables known to influence naming difficulty. These variables
include word frequency, age of acquisition, and picture imageability
scores; the named variables were tested to see whether they signifi-
cantly influenced participants’ naming performance.
In Experiment 1, we used 54 objects and 54 actions taken from
the CRL-IPNP database. None of the action stimuli included in the
task were associated with the selected objects. The nouns and verbs
corresponding to the set of objects and actions used were matched
for target word frequency and length. The frequency, length of the
target word, visual complexity and imageability of the pictures were
matched and counterbalanced between the experimental blocks.
Ten additional objects and actions were used for a practice block
(5 actions and 5 objects).
Procedure
Subjects sat in front of a 17-inch monitor controlled by a personal
computer running Presentation software1. The trial structure of
Experiment 1 is illustrated in Figure 1. After a frame that indi-
cated the category of the stimulus to the subject (“ACTION” or
“OBJECT”), a sound 50 ms in duration was presented at the onset
of a centrally located fixation cross that was present for 1000 ms.
After the disappearance of the fixation cross, the stimulus was pre-
sented and remained on the screen for 1000 ms. A blank screen
followed for a time varying from 4000 to 5000 ms. The subject’s
task was to accurately name as fast as possible the stimuli appear-
ing on the computer screen. Verbal responses were recorded and
digitized at 44.1 kHz using the program GoldWave (V. 5.12)2. The
responses were then analyzed off-line for accuracy and vRTs. For
each stimulus, we calculated the mean vRT and the mean response
accuracy percentage.
Results
The 54 actions were, on average, named after 1132 ms (±280), whereas
the 54 objects required 823 ms (±154) to be correctly named. The mean
accuracy was 90% (±14) for actions and 97% (±4) for objects.
Based on these results, we decided to exclude the actions that
required a vRT higher than 1692 ms (i.e., mean vRT plus 2 standard
deviations) or with a mean accuracy lower than 85%. We excluded
objects with vRTs higher than 1131 (i.e., mean vRT plus 2 standard
deviations) or with a mean accuracy lower than 90%.
The obtained subset of stimuli comprised 42 actions and 42
objects. Within this final set, actions were named after 1070 ms
(±252), whereas objects required 777 ms (±108) to be correctly
named. The mean accuracy was 95% (±5) for actions and 99%
(±2) for objects. The new sets of stimuli were still matched for
frequency and length.
EXPERIMENT 2: rTMS EXPERIMENT
Participants
All the exclusion criteria used in Experiment 1 were also used in
Experiment 2. In addition, a neuropsychological battery was applied,
and a pathological score in at least one of the tests was a further
exclusion criterion. Thirteen (4 male, 9 female) healthy older adults
(age 65–78 years, mean 70.2 years, education mean = 13.8 years)
participated in the rTMS experiment. All participants were native
Italian speakers and had normal or corrected-to-normal vision. All
participants were right-handed (Oldfield, 1971) and had no con-
traindications for rTMS (Rossi et al., 2009). The study was approved
by the local ethics committee, participants were informed about the
possible risk of rTMS, and informed consent was obtained.
The neuropsychological test battery included measures to assess
non-verbal reasoning (Raven-Colored Progressive Matrices), lan-
guage comprehension (Token Test), verbal fluency (phonemic
and semantic), memory (Story Recall, Rey–Osterrieth Complex
Figure Recall, Digit Span, Spatial Span), visuo-spatial abilities (Rey–
Osterrieth Complex Figure, Copy), attention and executive func-
tions (Trail-Making Test A and B). All the tests were administered
and scored according to standard procedures (Lezak et al., 2004).
1www.neurobs.com
2www.goldwave.com
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Cotelli et al. Brain stimulation in aging
In addition, some subtests of the Battery for Analysis of Aphasic
Deficits (BADA) were applied (Miceli et al., 1994). The results of
the cognitive assessment are presented in Table 1.
Stimuli
Experiment 2 used the 84 items (42 actions and 42 objects) selected
from the previous experiment. None of the action stimuli included
in this task were associated with the selected objects. The nouns and
verbs corresponding to the set of objects and actions were matched
for target word frequency and length.
The items were divided into three blocks designed for the three
stimulation conditions (left DLPFC, right DLPFC, and sham stimu-
lation). The frequencies and lengths of the target words were coun-
terbalanced in the experimental blocks. The visual complexity and
imageability of the pictures were also matched between blocks.
Ten additional objects and actions were used for a practice block
(5 actions and 5 objects).
Procedure
The procedures of the behavioral task were exactly the same as those
used in Experiment 1 (see Figure 1). The experiment included three
blocks corresponding to three stimulation sites, left and right DLPFC
and sham stimulation, and presentation orders were counterbal-
anced across subjects. For the sham control condition, a 3-cm-thick
piece of plywood was applied to the coil (Harris and Miniussi, 2003;
Rossi et al., 2007) so that no magnetic fields reached the cortex. For
the sham condition, the junction of the two coil wings was placed
above the vertex (CZ in the EEG 10/20 international system) using
the same procedure as for the real rTMS. For left and right DLPFC,
Table 1 | Neuropsychological data of the older adults who participated
in Experiment 2.
Raw scores Cut-off
SCREENING FOR DEMENTIA
MMSE 29.5/30 24
NON-VERBAL REASONING
Raven-colored progressive matrices 30.9/36 17.5
MEMORY
Story recall 15.2/28 7.5
Rey–Osterrieth complex figure, recall 14.6/36 9.46
Digit span 5.7 3.75
Spatial span 4.9 3.55
PRAXIA
Rey–Osterrieth complex figure, copy 33.1/36 28.87
EXECUTIVE FUNCTION
Trail-making test A (s) 40.2 93
Trail-making test B (s) 117.1 282
LANGUAGE
Token test 33.6/36 26.5
Fluency, phonemic 39.6 16
Fluency, semantic 45.3 24
Oral object comprehension (BADA) 39.9/40
Oral action comprehension (BADA) 19.9/20
Written object comprehension (BADA) 39.9/40
Written action comprehension (BADA) 19.9/20
Oral object naming (BADA) 29.2/30
Oral action naming (BADA) 27.0/28
FIGURE 1 | Time course of the experiment. The initial frame indicated the
category of the next stimulus to the subject (“ACTION” or “OBJECT”). A
sound (50 ms in duration) was presented at the onset of a centrally located
fixation cross (1000 ms duration) that preceded the picture. The picture was
present on the monitor for 1000 ms while trains of rTMS (500 ms,
20 Hz, 10% subthreshold) were delivered simultaneously with the
picture presentation. Verbal reaction times were recorded with
a microphone.
Frontiers in Aging Neuroscience www.frontiersin.org November 2010 | Volume 2 | Article 151 | 4
Cotelli et al. Brain stimulation in aging
this analysis only showed a significant effect of stimulus category
[F(1, 12) = 23.38, p = 0.0004], indicating a higher accuracy for objects
(mean = 98.7 ± 0.3) than for actions (mean = 88.4 ± 2). Conversely,
with respect to vRTs, this analysis indicated significant effects of both
stimulus category [F(1, 12) = 94.01, p < 0.0001] and the interaction
of stimulus category with site [F(2, 24) = 5.46, p = 0.01].
Post hoc analysis, Fisher’s Least Significant Difference (LSD) test,
revealed that for actions, naming performance was better during
stimulation of both left (mean = 963.3 ± 20, p = 0.003) and right
(mean = 975.5 ± 40, p = 0.006) DLPFC than during sham stimula-
tion (mean = 1077.5 ± 36). However, this was not true for objects,
for which performance did not differ significantly between condi-
tions, as shown in Figure 2.
DISCUSSION
The primary finding of this study is that rTMS applied to the DLPFC
improves action-naming performance in older adults. This finding
provides further direct evidence for a causal role of DLPFC in nam-
ing, consistent with the results of previous studies on younger adults
(Cappa et al., 2002). While the rTMS effect in healthy younger adults
was limited to left-sided stimulation, the facilitation in our elderly
sample was bilateral. Functional neuroimaging studies have shown
that older adults tend to recruit regions of the contralateral hemi-
sphere in addition to regions of the specialized hemisphere used by
younger adults when performing cognitive tasks (Grady et al., 1998;
D’Esposito et al., 1999; Grady, 2000; Rypma and D’Esposito, 2000;
Cabeza et al., 2002; Logan et al., 2002; Stebbins et al., 2002; Wierenga
et al., 2008). The presence of a facilitation effect after right or left
DLPFC rTMS in older adults could be attributed to the presence
of a compensatory mechanism based on the recruitment of right
hemispheric resources to maintain task performance despite the
possible reduction in neural efficacy of a distributed naming net-
work. A shift from unilateral to bilateral engagement is consistent
with Cabeza’s (2002) model of hemispheric asymmetry reduction
in older adults (HAROLD). The HAROLD hypothesis proposes that
the Talairach coordinates of cortical sites underlying the coil were
estimated for each subject by the SofTaxic Evolution Navigator sys-
tem (V. 2.0)3. This system was used to identify the stimulation site
on the scalp above Brodmann area 8 (Talairach coordinates X = ±35,
Y = 24, Z = 48, middle frontal) as in previous studies (Cappa et al.,
2002; Cotelli et al., 2006b, 2008). The SofTaxic Navigator system per-
mits the estimation of the MRI volume from the head, allowing us
to guide the rTMS coil positioning in subjects for whom MRIs were
unavailable. The estimated MRIs are automatically calculated using
a warping procedure that operates on a generic MRI volume (tem-
plate) on the basis of a set of points digitized from the subject’s scalp.
The accuracy of this procedure has been evaluated on 28 healthy
adults (mean age 35 years) having own MRIs used as gold standard.
In this evaluation, the TMS stimulation brain site was localized using
both own and estimated MRIs, while the position of the TMS coil
was kept fixes onto the subject’s scalp. The results indicate a mean
error of 2.11 mm, with a standard deviation of 2.04 mm, lower
than TMS spatial resolution (unpublished data). To stimulate the
DLPFC, we used a 70 mm figure-eight coil and placed the junction
of the two coil wings above the target point. rTMS was delivered for
500 ms from the onset of the visual stimulus using a frequency of
20 Hz. We decided to stimulate for the first 500 ms with a frequency
of 20 Hz because we were looking for a facilitation effect, as reported
in previous studies (Wassermann, 1998; Machii et al., 2006). The
stimulation intensity used during the experiment was set at 90%
of each subject’s resting motor threshold. These parameters are in
line with safety recommendations for rTMS (Rossi et al., 2009), and
none of the subjects showed side effects of stimulation.
Results
We separately analyzed both vRTs and accuracy using a repeated-
measures ANOVA with stimulus category (action and object)
and site (sham, left and right) as factors. With respect to accuracy,
FIGURE 2 | Verbal reaction times (vRTs) following each stimulation condition, plotted separately for action and object stimuli. Asterisks indicate significant
effects (p < 0.05). vRTs for actions were consistently faster during left and right dorsolateral prefrontal cortex than during sham stimulation. No significant differences
were observed for object naming. Errors bars indicate mean standard error.
3www.emsmedical.net
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Cotelli et al. Brain stimulation in aging
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Perani, 2003; DeLeon et al., 2007). These observations have led to
the hypothesis that neural networks subserving naming involve
numerous cerebral areas including the bilateral occipito-temporo-
parietal and left frontal areas.
The present results showed a reduction in vRTs in action-
naming performance in older adults. The reduction in vRTs sug-
gests that this effect is related to a facilitation of the task that
involves recalling the semantic representation of the action and
that this facilitation speeds up task execution. Several studies have
demonstrated that the reduction in naming efficacy that occurs
in older adults reflects inefficient access to semantic knowledge
rather than a true loss of semantic representations (Barresi et al.,
2000; Mackay et al., 2002; Mortensen et al., 2006). In our experi-
ment, brain stimulation-induced cortical modulation of synaptic
efficacy and connectivity occurs, potentiating the system within
the language network and thus leading to more effective process-
ing. These observations lead us to suggest that the improvement
in performance observed after DLPFC stimulation may reflect a
facilitation of lexical retrieval processes. Thus, these data confirm
the hypothesis that the reduced efficiency in naming that occurs
in healthy aging is due to defective access rather than to semantic
loss (Jefferies et al., 2007).
In conclusion, the present study confirms that rTMS is a useful
tool that can complement traditional neuroimaging approaches
in the investigation of age-dependent modifications of the causal
engagement of cortical brain regions. Moreover, age-related decline
in performance on an action-naming task seems to be the con-
sequence of a slowing down of lexical access. Finally, our find-
ings further support the HAROLD model, which posits a bilateral
involvement of DLPFC in older adults compared with a left-sided
involvement of this area in younger adults.
ACKNOWLEDGMENTS
We wish to thank the participants in the study for their patience. This
research was supported by a project grant from the “Fondazione
della Comunità Bresciana-onlus”.
bilateral activation increases with age. There is evidence from many
cognitive tasks supporting the HAROLD hypothesis (Grady et al.,
1994; Rossi et al., 2001; Cabeza et al., 2002; Rowe et al., 2006), although
the importance of these reduced lateralization remains unclear.
In the case of language, the right hemisphere has traditionally
been assigned a crucial role in supporting performance after left
hemispheric damage (Vandenbulcke et al., 2005). Consistent with
this idea, a recent study reported that older participants activate a
larger frontal network than younger adults during word retrieval
and that they show less lateralization of activity (Wierenga et al.,
2008). In the present study, we reported a facilitation effect follow-
ing stimulation of the left or right DLPFC and showed that this
effect is consistent with recent findings in AD in which stimulation
of both DLPFCs improved picture naming compared to placebo
stimulation (Cotelli et al., 2006b, 2008). In AD patients, DLPFC
has been specifically shown to improve the number of correct
responses, whereas we found a shortening of vRT in our older
adult group. This difference could be explained by the presence of
a “ceiling” effect that decreases the likelihood of finding accuracy
effects in these healthy subjects.
The use of rTMS involves the discharge of a transient elec-
tromagnetic field through the skull. Rapidly changing magnetic
fields induce electric currents in the brain, which in turn pro-
duce transynaptic depolarization of groups of neurons located
in the superficial cortical layers (Heller and van Hulsteyn, 1992).
The effect of rTMS is believed to result from activation of these
neurons. rTMS has also been shown to be able to influence the
activity of brain centers distant from the stimulated site through
the activation of cortico-cortical or cortico-subcortical networks
(Bestmann et al., 2008; Miniussi and Thut, 2010); this observa-
tion actually provided the starting point for clinical application of
rTMS. The fact that rTMS can facilitate a network rather than a
single area is also consistent with a large number of focal lesion and
neuroimaging studies that demonstrate that the ability to name
an action or an object depends on a wide and complex cerebral
network (Perani et al., 1999a; Damasio et al., 2001; Cappa and
Frontiers in Aging Neuroscience www.frontiersin.org November 2010 | Volume 2 | Article 151 | 6
Cotelli et al. Brain stimulation in aging
with verbs in Alzheimer’s disease.
Neurology 47, 178–182.
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Frontiers in Aging Neuroscience www.frontiersin.org November 2010 | Volume 2 | Article 151 | 7
Cotelli et al. Brain stimulation in aging
Copyright © 2010 Cotelli, Manenti, Rosini,
Calabria, Brambilla, Bisiacchi , Zanetti and
Miniussi. This is an open-access article
subject to an exclusive license agreement
between the authors and the Frontiers
Research Foundation, which permits unre-
stricted use, distribution, and reproduc-
tion in any medium, provided the original
authors and source are credited.
Received: 26 July 2010; accepted: 08
November 2010; published online: 24
November 2010.
Citation: Cotelli M, Manenti R, Rosini S,
Calabria M, Brambilla M, Bisiacchi PS,
Zanetti O and Miniussi C (2010) Action
and object naming in physiological aging:
an rTMS study. Front. Ag. Neurosci. 2:151.
doi: 10.3389/fnagi.2010.00151
role of bilateral frontal and subcortical
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Conflict of Interest Statement: The
authors declare that the research was con-
ducted in the absence of any commercial or
financial relationships that could be con-
strued as a potential conflict of interest.
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... Particularly, Cotelli and colleagues explored the effect of rTMS on the dorsolateral prefrontal cortex (DLPFC) to evaluate language abilities in control and AD groups. They have found that rTMS improves performance both in controls and AD patients [9,10]. ...
... Functional connectivity of cortical sources analysis Brain connectivity was computed using exact Low Resolution Electromagnetic Tomography (eLO-RETA) [29,30] software on Regions Of Interest (ROIs) defined according to the Brodmann areas (Bas): 42 ROIs (BAs: 1, 2, 3, 4, 5, 6,7,8,9,10,11,13,17,18,19,20,21,22,23,24,25,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47). ROIs are needed for the estimation of electric neuronal activity that is used to analyze brain functional connectivity. ...
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Alzheimer’s disease (AD) is the most common neurodegenerative disorder in elderly subjects. Recent studies verified the effects of cognitive training combined with repetitive transcranial magnetic stimulation (rTMS-COG) in AD patients. Here, we analyzed neuropsychological and neurophysiological data, derived from electroencephalography (EEG), to evaluate the effects of a 6-week protocol of rTMS-COG in 72 AD. We designed a randomized, double-blind, sham-controlled trial to evaluate efficacy of rTMS on 6 brain regions obtained by an individual MRI combined with COG related to brain areas to stimulate (i.e., syntax and grammar tasks, comprehension of lexical meaning and categorization tasks, action naming, object naming, spatial memory, spatial attention). Patients underwent neuropsychological and EEG examination before (T0), after treatment (T1), and after 40 weeks (T2), to evaluate the effects of rehabilitation therapy. “Small World” (SW) graph approach was introduced allowing us to model the architecture of brain connectivity in order to correlate it with cognitive improvements. We found that following 6 weeks of intensive daily treatment the immediate results showed an improvement in cognitive scales among AD patients. SW present no differences before and after the treatment, whereas a crucial SW modulation emerges at 40-week follow-up, emphasizing the importance of rTMS-COG rehabilitation treatment for AD. Additional results demonstrated that the delta and alpha1 SW seem to be diagnostic biomarkers of AD, whereas alpha2 SW might represent a prognostic biomarker of cognitive recovery. Derived EEG parameters can be awarded the role of diagnostic and predictive biomarkers of AD progression, and rTMS-COG can be regarded as a potentially useful treatment for AD.
... Cotelli et al. (2008) also demonstrated that rTMS application over the DLPFC improved action naming even in the advanced stages of AD, and proposed that rTMS may enable the brain to recover damaged function during disease development. It has recently been reported that highfrequency rTMS (20 Hz) of the DPLFC improves language performance and object naming in patients with AD (Cotelli et al., 2010). These studies suggest both the beneficial and therapeutic effects of rTMS and its potential usefulness for behavioral and cognitive rehabilitation. ...
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Brain stimulation techniques offer powerful means of modulating the physiology of specific neural structures. In recent years, non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, have emerged as therapeutic tools for neurology and neuroscience. However, the possible repercussions of these techniques remain unclear, and there are few reports on the incisive recovery mechanisms through brain stimulation. Although several studies have recommended the use of non-invasive brain stimulation in clinical neuroscience, with a special emphasis on TMS, the suggested mechanisms of action have not been confirmed directly at the neural level. Insights into the neural mechanisms of non-invasive brain stimulation would unveil the strategies necessary to enhance the safety and efficacy of this progressive approach. Therefore, animal studies investigating the mechanisms of TMS-induced recovery at the neural level are crucial for the elaboration of non-invasive brain stimulation. Translational research done using animal models has several advantages and is able to investigate knowledge gaps by directly targeting neuronal levels. In this review, we have discussed the role of TMS in different animal models, the impact of animal studies on various disease states, and the findings regarding brain function of animal models after TMS in pharmacology research.
... 39,40 These studies were excluded as crossover trials or case reports. Still other studies confi rmed that high-frequency rTMS over the left dorsolateral prefrontal cortex decreases vocal reaction times for picture naming in healthy individuals 41,42 , increases the number of correct responses in patients with Alzheimer's disease 43,44 , and facilitates actionnaming performance in patients with progressive non-fl uent aphasia. 45 However, the effect of highfrequency rTMS in stroke aphasia patients has not yet been studied in a randomized clinical trial. ...
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Background & Objective: Aphasia—acquired loss of the ability to understand or express language—is a common and debilitating neurological consequence of stroke. Evidence suggests that transcranial magnetic stimulation (TMS) can significantly improve language outcomes in patients with aphasia. Repetitive transcranial magnetic stimulation (rTMS) has been reported to improve naming in chronic stroke patients with nonfluent aphasia since 2005. Methods: We conducted a systematic review and meta-analyses of TMS treatment studies in patients with aphasia. Eight electronic databases (PubMed, Medline, Embase, Scopus, ScienceDirect, Cochrane Central Register of Controlled Trials, Journals@ Ovid, and clinicaltrials.gov) were searched for articles. Relevant studies were further evaluated and studies that met inclusion criteria were reviewed. We included studies if were: randomized controlled blinded clinical trials, meta-analyses or crossover designs of rTMS alone or with speech therapy or any other therapy tested with rTMS. Standard mean difference (SMD) for changes in picture naming accuracy was estimated. Results: The literature search yielded 423 studies. Fifty articles were further evaluated to be included. Eleven met all inclusion criteria and were chosen for review. Eleven eligible studies involving 301 stroke patients were identified in this meta-analysis. Further analyses demonstrated prominent effects for the naming subtest (SMD = 1.26, 95% CI = 0.80 to 1.71, P=0.01), with heterogeneity (I2 = 69.101%). The meta-analysis continued to show that there was a statistically significant effect of rTMS compared with sham rTMS on the severity of aphasia. None of the patients from the 11 included articles reported adverse effects from rTMS. Conclusions: There are some strong studies evaluating the efficacy of rTMS in stroke patients but further research is required to fully establish the usefulness of this treatment. This meta-analysis indicates a clinically positive effect of rTMS with or without speech and language therapy (SLT) for patients with aphasia following stroke in overall language function and expressive language, including naming, repetition, writing, and comprehension. Low-frequency (1 Hz) rTMS over the unaffected hemisphere is effective and compatible with the concept of interhemispheric inhibition. Moreover, the treatment of 1 Hz rTMS for patients with aphasia after stroke was safe.
... For the neuropsychological assessment, we followed a common approach used in studies investigating physiological aging (see e.g., Allard et al., 2013;Bahmad et al., 2020;Cotelli et al., 2010;Molloy et al., 2019;Nyberg et al., 2003;Scalici et al., 2021), consisting of the administration of the Mini-Mental State Examination (MMSE; Folstein et al., 1975;see Measso et al., 1993 for the Italian version of the MMSE) to rule out a general cognitive impairment. The MMSE consists of 11 questions or tasks involving the examination of several cognitive domains, including orientation to time and space, encoding and recall of verbal information, attention, calculation, language, and visual construction. ...
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Whilst countless studies have shown that aging is associated with cognitive decline in the general population, near to nothing is known about this association in elderly individuals naturally exhibiting enhanced memory capabilities. The identification of a 75-year-old individual (GC) with highly superior autobiographical memory (HSAM), and his willingness to volunteer to our study over a period of five years, allowed us to investigate this issue in a single case study. At the age of 75 years, GC was screened for HSAM with the Public Events Quiz and the Random Dates Quiz, with a positive outcome. GC’s memory performance was extraordinarily higher than normal-memory control subjects (>3 standard deviations), and comparable to a group of younger HSAM individuals (mean age of 32.5 years; Santangelo et al., 2018). GC underwent general neuropsychological (Mini-Mental State Examination), personality (Personality Assessment Inventory), and brain morphological (brain volumes and lesions) assessments, showing no deviation from normal ranges. To gain insight into the brain mechanisms underlying his memory performance, GC underwent functional brain imaging during the retrieval of memories associated with random dates. The latter were also rated in terms of reliving quality and emotional valence. Similar to younger HSAM individuals, GC’s access to past memories recruited a wide network of prefrontal and temporo-parietal regions, especially during the recollection of memories associated with a lower reliving rating, suggesting a compensatory mechanism in HSAM. Increased activity in the insula was instead associated with emotionally-positive memories. Five years later, GC was tested again for HSAM and showed no sign of memory decline, whereby his memory performance was indistinguishable from the tests he performed five years earlier. GC’s case suggests that highly superior memory performance can manifest without apparent decline in physiological aging. Implications of the current findings for the extant models of autobiographical memory are discussed.
... Regions of stimulation have included the left frontal/prefrontal cortex, dorsolateral prefrontal cortex (DLPFC), and the frontotemporal region of the left hemisphere to engage the brain regions that are thought to underlie the concurrent tasks employed (oral or written and spelling therapy, individualized speech therapy (focused on naming), and narration of wordless children's books, respectively). Previous studies have shown involvement of the DLPFC in naming in healthy participants [43], whereas patients with lesions in frontal and frontotemporal regions have shown associations of decreased complexity in story narration [44]. It is important to note a gap in knowledge pertaining to the appropriate stimulation location in PPA patients and the ways in which the targeted brain region might differ between variants. ...
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Noninvasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), paired with behavioral language therapy, have demonstrated the capacity to enhance language abilities in primary progressive aphasia (PPA), a debilitating degenerative neurological syndrome that leads to declines in communication abilities. The aim of this meta-analysis is to systematically evaluate the efficacy of tDCS and TMS in improving language outcomes in PPA, explore the magnitude of effects between stimulation modalities, and examine potential moderators that may influence treatment effects. Standard mean differences for change in performance from baseline to post-stimulation on language-related tasks were evaluated. Six tDCS studies and two repetitive TMS studies met inclusion criteria and provided 22 effects in the analysis. Random effect models revealed a significant, heterogeneous, and moderate effect size for tDCS and TMS in the enhancement of language outcomes. Findings demonstrate that naming ability significantly improves due to brain stimulation, an effect found to be largely driven by tDCS. Future randomized controlled trials are needed to determine long-term effectiveness of noninvasive brain stimulation techniques on language abilities, further delineate the efficacy of tDCS and TMS, and identify optimal parameters to enable the greatest gains for persons with PPA.
... For example, Boggio et al. applied anodal tDCS over the bilateral temporal cortex for 5 days and found that AD patients improved their performance at the VRM task but not at the visual attention task (VAT) or MMSE. [21] Cotelli et al. [26] found an improvement in auditory sentence comprehension in healthy older adults when high-frequency rTMS was applied over the left DLPFC and an improvement in action-naming task when rTMS was applied over the bilateral DLPFC. Notably, in a study by Ahmed et al., a clinical benefit was present only in mild and moderate AD patients and not in severe AD patients. ...
... This model views this bilateral prefrontal activity seen in healthy older adults as compensatory, such that the activity in the contralateral hemisphere is advantageous for task performance [66,65], (Daselaar et al., 2003). Using rTMS, Cotelli et al. [12] also have found evidence for this theory, where left stimulation facilitates a naming task in younger adults and both left and right stimulation cause facilitation in older adults. ...
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Functional neuroimaging studies have found that lateralization of activity in the dorsolateral prefrontal cortex (dlPFC) is reduced with aging. In the present study, repetitive transcranial magnetic stimulation (rTMS) was used to disrupt dlPFC activity in order to test the relationship of dlPFC laterality and age in verbal working memory (WM). Young (n = 36) and older (n = 35) subjects received 1 Hz-rTMS (sham or active) to left or right dlPFC and WM performance was assessed pre- and post-stimulation via the n-back task. Significant increases in WM accuracy were observed following rTMS in the right dlPFC and sham conditions, but not with the left dlPFC stimulation. This was accompanied by a decrease in left P1 latency was also observed following left dlPFC stimulation. In contrast, older adults did not show a disruption in WM performance following rTMS in any of the stimulation conditions and exhibited increased left P3 amplitude following left stimulation. Our results show that changes in prefrontal laterality are evident with increasing age (left stimulation affects younger adults while older adults are not affected by stimulation) and this change is associated with specific neurophysiologic measures.
... An example of test is name as many words as possible that begin with the letters K, L, M in 1 minute. Based on the Dystest test (Cimlerová et al., 2014). § Semantic Fluency (SF), the ability to rapidly produce words that share semantic features.) ...
Article
Purpose: Aphasia-acquired loss of the ability to understand or express language-is a common and debilitating neurological consequence of stroke. Evidence suggests that transcranial magnetic stimulation (TMS) can significantly improve language outcomes in patients with aphasia. Repetitive transcranial magnetic stimulation (rTMS) has been reported to improve naming in chronic stroke patients with nonfluent aphasia since 2005. Methods: We conducted a systematic review and meta-analyses of TMS treatment studies in patients with aphasia. Eight electronic databases (PubMed, Medline, Embase, Scopus, ScienceDirect, Cochrane Central Register of Controlled Trials, Journals@Ovid, and clinicaltrials.gov) were searched for articles. Relevant studies were further evaluated, and studies that met inclusion criteria were reviewed. The searches were limited to human studies written in English and published between January 1960 and January 2020. In keeping with the main objective of this review, we included all studies that carried out treatment using rTMS in stroke patients with aphasia, regardless of the trial (or experimental) design of the study. Studies that implemented between-subject or randomized controlled (RCT) design, cross-over trials, and within-subject or pre-post trials were all included. Standard mean difference (SMD) for changes in picture naming accuracy was estimated. Results: The literature search yielded 423 studies. Fifty articles were further evaluated to be included. Eleven met all inclusion criteria and were chosen for review. Eleven eligible studies involving 242 stroke patients were identified in this meta-analysis. Further analyses demonstrated prominent effects for the naming subtest (SMD = 1.26, 95% CI = 0.80 to 1.71, p = 0.01), with heterogeneity (I2 = 69.101%). The meta-analysis continued to show that there was a statistically significant effect of rTMS compared with sham rTMS on the severity of aphasia. None of the patients from the 11 included articles reported adverse effects from rTMS. Conclusions: There are some strong studies evaluating the efficacy of rTMS in stroke patients but further research is required to fully establish the usefulness of this treatment. This meta-analysis indicates a clinically positive effect of rTMS with or without speech and language therapy (SLT) for patients with aphasia following stroke in overall language function and expressive language, including naming, repetition, writing, and comprehension. Low-frequency (1 Hz) rTMS over the unaffected hemisphere is effective and compatible with the concept of interhemispheric inhibition. Moreover, the treatment of 1 Hz rTMS for patients with aphasia after stroke was safe.
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Full-text available
Background Repetitive Transcranial Magnetic Stimulation (rTMS) has shown initial promise in combating age-related cognitive decline and dementia. The nature and severity of cognitive aging, however, varies markedly between individuals. Objective/hypothesis We hypothesized that the distinct constellation of brain changes responsible for individual differences in cognitive aging might influence the response to rTMS. Methods Cognitive effects of rTMS were evaluated using a rat model of cognitive aging in which aged rats are classified as Aged-Impaired (AI) or -Unimpaired (AU) relative to young (Y) according to their performance in the Morris water maze. Several weeks later, following presentation of a sample odor in an olfactory recognition task, rats received either sham (Y, n = 9; AU, n = 8; AI, n = 9) or intermittent Theta Burst Stimulation (Y, n = 8; AU, n = 8; AI, n = 9). Memory was tested 24 hours later. Results Recognition memory in the sham and stimulated conditions depended on pre-treatment cognitive status in the aged rats. Y and AU sham rats displayed robust odor recognition, whereas sham-treated AI rats exhibited no retention. In contrast, rTMS treated AI rats showed robust retention, comparable in magnitude to Y, whereas the AU stimulated scored at chance. Conclusion Our results are consistent with a perspective that the unique neurobiology associated with variability in cognitive aging modulates the response to rTMS. Protocols with documented efficacy in young adults may have unexpected outcomes in aging or neurodegenerative conditions, requiring individualized approaches.
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Neuroimaging has consistently shown engagement of the prefrontal cortex during episodic memory tasks, but the functional relevance of this metabolic/hemodynamic activation in memory processing is still to be determined. We used repetitive transcranial magnetic stimulation (rTMS) to transiently interfere with either left or right prefrontal brain activity during the encoding or retrieval of pictures showing complex scenes. We found that the right dorsolateral prefrontal cortex (DLPFC) was crucial for the retrieval of the encoded pictorial information, whereas the left DLPFC was involved in encoding operations. This 'interference' approach allowed us to establish whether a cortical area activated by a memory task actually contributes to behavioral performance.
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We used event-related fMRI to investigate age-related differences in PFC activity during separate WM task components (encoding, maintenance, retrieval) with varying memory loads of verbal information. Younger adults showed greater PFC activity than older adults only in dorsolateral PFC, only during memory retrieval. Faster young subjects showed less dorsolateral PFC activation during retrieval than slower young subjects whereas the opposite pattern was observed in older adults. This result was replicated in two additional experiments using verbal and spatial information. Age-related changes in the dorsolateral PFC regions involved in memory retrieval may mediate declines in WM performance. These results suggest a relationship between neural activation and performance that is sigmoid in nature. Age-related differences in performance may be mediated by bias shifts in this sigmoid function.
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