Efficacy of repetitive transcranial magnetic stimulation/
transcranial direct current stimulation in cognitive
Carlo Miniussi, PhDa, Stefano F. Cappa, MDb, Leonardo G. Cohen, MDc,
Agnes Floel, MDd, Felipe Fregni, MD, PhDe, Michael A. Nitsche, MDf,
Massimiliano Oliveri, MDg, Alvaro Pascual-Leone, MD, PhDe, Walter Paulus, MDf,
Alberto Priori, MDh, Vincent Walsh, PhDi
aDepartment of Biomedical Sciences and Biotechnology, National Institute of Neuroscience-Italy, University of Brescia and
Cognitive Neuroscience Section, IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy
bDepartment of Neuroscience, Vita Salute University-National Institute of Neuroscience-Italy and San Raffaele Scientific
Institute, Milan, Italy
cHuman Cortical Physiology Section and Stroke Neurorehabilitation Clinic, NINDS, National Institutes of Health,
dDepartment of Neurology and IZKF, University of Mu ¨nster, Mu ¨nster, Germany
eBerenson-Allen Center for Noninvasive Brain Stimulation, Department of Neurology, Beth Israel Deaconess Medical
Center, and Harvard Medical School, Boston, Massachusetts
fDepartment of Clinical Neurophysiology, Georg-August University, Go ¨ttingen, Germany
gDepartment of Psychology University of Palermo and Fondazione ‘‘Santa Lucia’’ IRCCS, Roma, Italy
hClinical Center for Neuronanotechnology and Neurostimulation, Department of Neurological Sciences, University of
Milan and IRCCS Ospedale Maggiore Policlinico, Milan, Italy
iInstitute of Cognitive Neuroscience and Department of Psychology, University College London, London, United Kingdom
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 perfor-
mance. They all reflect the potential of these methods to improve the subject’s ability to relearn or to
Correspondence: Prof. Carlo Miniussi, University of Brescia, Biomedical Sciences and Biotechnologists, Viale Europa 11, Brescia, 25123, Italy.
E-mail address: email@example.com
Submitted May 22, 2008; revised July 21, 2008. Accepted for publication July 21, 2008.
1935-861X/08/$ -see front matter ? 2008 Elsevier Inc. All rights reserved.
Brain Stimulation (2008) 1, 326–36
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.
? 2008 Elsevier Inc. All rights reserved.
cranial magnetic stimulation; transcranial direct current stimulation
cognitive deficits; cognitive rehabilitation; memory; attention; language; repetitive trans-
Cognitive dysfunction after a brain insult constitutes one
of the major causes of disability worldwide, exerts a major
impact on the lives of affected individuals and their
families, and represents a major public health and financial
burden for society. Therefore, the rehabilitation of disorders
of cognitive functions related to language, attention, or
memory is a clinically important and promising area. So
far, the studies available in this area are few in number,
preliminary in nature and the results are often inconclu-
sive.1,2With the maturing fields in cognitive neurosciences,
the combination of different expertises and methodologies
has yielded a new interdisciplinary approach. The central
nervous system responds dynamically to degenerative or
focal lesion-induced cognitive deficits, thus explaining the
clinical observation that, at least in some cases, disturbed
or lost functions can be partially or fully restored. Studies
of functional neuroimaging have shown that cerebral reor-
ganization may occur after specific rehabilitation interven-
tions.3-5Moreover, a number of investigations indicate that
interacting with cortical activity by means of cortical stim-
ulation can positively affect the cognitive performance of
patients affected by aphasia, unilateral neglect, and other
cognitive disorders. In this article, we will present an over-
view of recent developments in rehabilitation of cognitive
function by means of noninvasive brain stimulation.
Transcranial magnetic stimulation
Transcranial magnetic stimulation (TMS) is a technique that
uses a magnetic field, inducing an electrical current in the
underlying brain tissue,6which interacts with ongoing activ-
ity in the neural tissue. Trains of repetitive stimuli (rTMS),
present the opportunity to interact even more effectively
with cortical activity.7-9
Interference with cognitive processing when TMS is
applied during performance of a task is called online
TMS.10In contrast, in the case of offline stimulation,
TMS is applied for several minutes before the subject is
tested on the task. The ability of TMS to temporarily dis-
able neuronal function, thereby interrupting information
processing, allows one to investigate the relationship
between cortical areas and behavior and to trace the tempo-
ral course of the activity of a particular cortical region that
contributes to a given task. This allows the mapping of the
functional connectivity among brain regions and of the ex-
tent of neural reorganization (compensatory plasticity) after
an insult.9,10The idea is that TMS delivered during the ex-
ecution of a cognitive task triggers a synchronous activity
in a subpopulation of neurons located under the stimulating
coil, with the net result of disrupting the task-related pattern
of activity that occurred at the time of the stimulation.12,13
However, this simplified interpretation cannot explain
the observation that sometimes the performance of a
cognitive task can also be facilitated by rTMS.14,15It
must be underlined that behavioral facilitation does not
necessarily imply enhanced cortical activity. Behavior after
a brain insult is primarily a manifestation of how the un-
damaged brain adapts to the injury to sustain function.
Such adaptive changes can themselves limit recovery (mal-
adaptive changes) and in such instances behavioral facilita-
tion may result from disruption or inhibition of brain
activity (paradoxical functional facilitation).16
In any case, facilitatory behavioral effects related to
TMS are important in two different respects. First, they can
provide reassuring proof of principle that the stimulated
brain region is part of a circuit critical for performing the
task under investigation. However, facilitation effects could
be due to unspecific factors such as a general arousal
caused by rTMS, and these need to be carefully excluded in
the experimental design. The RT enhancements caused by
rTMS could, in many cases, be related to auditory inter-
sensory facilitating influences of the auditory click occur-
stimulator.17,18Nevertheless, these effects can be clearly
discarded as an explanation of rTMS-induced facilitation
in accuracy because it has been shown that the facilitation
effects are clearly specific for task, site, type (sham vs real)
of stimulation and stage of cognitive decline.15,19,20
The second important point, and the most interesting
concerning neurorehabilitation, is that this facilitatory
function may in fact be used to enhance disrupted function.
Although most of these effects are transient, their applica-
tion in concomitance with a learning process may
of the magnetic
Neurorehabilitation with rTMS/tDCS 327
perpetuate the facilitatory effect beyond even after the end
The modification of cortical excitability for an adequate
period may affect/promote adaptive organization or affect/
disrupt maladaptive functional reorganization, inducing
a new balance in the system and enhancing behavioral
Online TMS applied over cortical areas involved in verbal
processing (perisylvian cortex of the dominant, usually left
hemisphere) has been reported to facilitate picture naming
and other language-related tasks in healthy subjects,22-29as
well as in epileptic patients.15Similar facilitatory effects of
online rTMS were observed with picture naming after stim-
ulation of prefrontal cortices (PFCs) in healthy volunteers15
and in patients with Alzheimer’s disease (AD).30The latter
experiment was based on three experimental blocks of
naming of pictures of objects and actions (for this and the
following experiments, details in Table 1). Anomia is com-
mon in the early stages of AD, and in the study by Cotelli et
al,30patients were instructed to name the picture as quickly
as possible while trains of high-frequency rTMS were
delivered simultaneously with picture presentation. The
main result was that the action-naming performance was
improved during TMS applied to both left and right PFC
(mean 17%), as compared with sham stimulation, whereas
no effect was present for the object-naming performance.
A following study by the same group19aimed to assess
the effect of rTMS in patients with AD with different de-
grees of cognitive decline. The authors found improved
naming accuracy for both classes of stimuli (actions and
objects) in the moderate-to-severe group, whereas in the
previous experiment, mild AD performance was facilitated
only in the case of action naming. These results suggest that
effects induced by rTMS influenced performance as long as
it did not reach a ceiling at baseline, as in the case of object
naming in patients with mild AD. Moreover, the ameliora-
tion was short-lived, lasting in the order of minutes.
Although the effect size on action naming was quite robust,
the underlying mechanisms remain unclear, and the basis
for the facilitatory effects of rTMS on lexical retrieval re-
main essentially unknown. It must be underlined that in
healthy subjects a shortening of naming latency for actions
was found only after stimulation of left PFC.15On the other
hand, the improvement of action naming in the AD group
was observed after rTMS to both left and right PFC. This
result could be attributed to the presence of a compensatory
mechanism based on the recruitment of right hemispheric
resources to support residual naming performance, suggest-
ing that the brains of the patients with AD retain a signifi-
cant degree of functional plasticity.31,32A crucial role in
supporting language performance after left hemispheric
damage has been traditionally assigned to the right hemi-
sphere, and recent studies have indicated an increase in
right hemispheric activation in progressive aphasia.33
Although we do not expect that the online experimental
procedure used in the current experiments (high-frequency
online rTMS) will have a lasting effect on language (ie,
beyond the end of the trial, to improve subsequent perfor-
mance), we believe that the transient response to online
rTMS may be a promising method for patient selection.
For language function, it has been shown that the type of
brain lesion determines the degree to which the activity
of the right language areas are compensatory.34,35There-
fore, it might be possible to use online rTMS over the
right/left language areas to separate maladaptive activation
from compensatory activation and to identify those patients
who will benefit from this treatment.
The changes in behavioral response may be related to
changes in cortical excitability, dominated by the area
stimulated, or due to secondary effects on an area afferent
or efferent to the area stimulated. These factors are in turn
dependent on a number of variables, such as the timing of
stimulation (ie, before, in the initial or final phase of the
task; this is probably the most important factor), stimulus
frequency (a relatively unexplored factor), and intensity.
Moreover, an important point is that the effects of TMS on
cognitive performance are also dependent on task and
subject-related factors (eg, young vs old).
The effects induced by online stimulation are generally
short lived, probably in the order of a few hundred
milliseconds to a few seconds.26Therefore, this approach
should not be considered a neurorehabilitation intervention,
but may represent a suitable methodology for studying can-
didates in whom offline rTMS might be applied for cogni-
tive rehabilitation or for identifying possible routes for
neurorehabilitation. In the latter case rTMS is applied for
several minutes (on average 10-15 minutes) before the sub-
ject is tested on the task of interest. Obviously this possibil-
ity has generated interest as a tool to potentially ameliorate
clinical deficits.36,37It has been shown that by using offline
rTMS, it is possible to transiently modulate neural excita-
bility, with the net effect dependent on the stimulation
frequency. Generally, from a physiologic point of view,
low-frequency (% 1 Hz) results in inhibition, whereas
high-frequency (R 5 Hz) stimulation results mainly in ex-
citatory changes in the stimulated area.38,39However, ro-
bust parameters and measures of excitatory and inhibitory
consequences of different frequencies remain to be docu-
mented in detail.
However, several studies have demonstrated that both
types of stimulation (low- and high- frequency) may have
similar, positive effects on subjects’ performance depend-
ing on the site of applications.40-46This does not mean that
328C. Miniussi et al
of the site
Cotelli et al30
AD15 Left and right
Left and Right
Left PFC/sham 6 cm anterior
Double-70rTMS20 Online90%MT 600 ms
Cotelli et al19
AD 24 Double-70rTMS20 Online90%MT600 ms
Naeser et al53
(5-11 y ps)
4 Double-70rTMS1 Offline90%MT 20 min 102 -8 mon Picture
and 1 cm
ventral to M1a
5 cm anterior
w5 min 10
trains of 2
s 1 30 s ISI
25 min 50
trains of 2
s 1 28 s ISI
5 45 d Sentence-
Triggs et al55
10Left PFCDouble-70 rTMS 20Offline80%MT10 3 monOral word
Oliveri et al58
(1-4 mon ps)
14 Left and Right
PFC and PC
Oliveri et al59
(1-12 mon ps)
8Left PFC and
Oliveri et al61
(1-48 wks ps)
7 PC/sham10/20 EEG
Double-7025 Online115%MT400 ms
(3-5 mon ps)
3 Left posterior
Double-45 rTMS1Offline90%MT15 min1415 d
Shindo et al62RBD neglect
(6 mon ps)
2Left PFC 10/20 EEG
Double-70 rTMS0.9 Offline95%MT
w17 min6 2-6 wks
5 cm anterior
Double-70rTMS 10Offline100%MT 3 x w3 min
15 trains of
1s 1 10 s ISI
5 min 10 trains
of 10 s 1 20
40 Bilateral PFC
5 cm anterior
AD 5 Alzheimer disease; DLPFC5 dorsolateral prefrontal cortex; MRI 5 magnetic resonance imaging; rTMS 5 repetitive transcranial magnetic stimulation; MT 5 motor threshold; PFC 5 prefrontal cortex; M1 5
primary motor cortex; ISI 5 interstimulu interval; RBD 5 right-brain damage with extinction; ps 5 poststroke; PC 5 parietal cortex; EEG 5 electroencephalogram; CVD 5 cerebrovascular disease and mild
executive impairment; d 5 days; wks 5 weeks; mon 5 months; y 5 years.
aFunctional identification of M1 for the first dorsal interosseous muscle in the left hemisphere.
bIn a single patient an MRI was performed after TMS to verify the stimulated site.
Neurorehabilitation with rTMS/tDCS
both low and high frequencies have the same effects on
cortical response, but rather that the effects are strictly cor-
related to the role of the stimulated cortex and its ‘‘activa-
tion state’’ during stimulation.47Therefore, we should keep
separate the concept of inhibitory/excitatory-induced activ-
ity from detrimental/beneficial behavior because both types
of activity can induce a beneficial effect. In particular, it has
been proposed that in patients with unilateral hemispheric
damage, in motor descending pathways, the homotopic
contralateral area may be in a state of abnormally high ac-
tivation and may exert an inhibitory effect on the damaged
hemisphere.48,49In other words, a focal lesion, such as a
stroke, may produce a state of hemispheric imbalance in
some patients in the chronic stage. The hypothesis is that
rTMS can be used to restore this disequilibrium by enhanc-
ing excitability in the ipsilesional motor areas or decreasing
it in contralesional motor areas. This postulation is sup-
ported by neuroimaging studies in patients affected by
stroke-induced aphasia showing a decrease of cortical
blood flow in the language areas, as well as an abnormally
increased activation of their right hemispheric homo-
logues.48,50,51Martin et al50hypothesized that this activa-
tion was correlated with defective recovery of nonfluent
aphasia.34,35, 52,53Therefore, the prediction was that the ap-
plication of offline low-frequency stimulation over the right
homologue of Broca area may result in an improved ability
to name pictures. Four chronic aphasic patients were in-
cluded in the study.52,53All of them were assigned to a
low-frequency TMS treatment on anterior portion of right
Broca’s homologue (Table 1). A significant improvement
was observed in picture naming at 2 months post-rTMS,
with lasting benefit at 8 months in three patients. No
sham stimulation as control was used.
The complementary approach was applied on a single
patient with a probable diagnosis of primary progressive
aphasia.54High-frequency offline rTMS was applied to the
left hemisphere, with the aim of inducing facilitation di-
rectly on the language areas (Table 1). After 5 days of stim-
ulation to the left PFC, the patient’s performance improved
for verb production, whereas 5 days of sham stimulation
did not showed any beneficial effect. The beneficial effect
lasted over the following month.
It is also noteworthy that one study55in depressed pa-
tients found a significant facilitation on oral word associa-
tions task after 2 weeks of high-frequency rTMS, on the left
PFC (Table 1). But these data are probably because of a
general unspecific effect related to a return to a premorbid
baseline cognitive condition
In summary, these studies should be considered as
preliminary, because of the low number of patients, the
absence of critical control conditions and the amelioration
of only restricted abilities, suggest the need for adopting a
parsimonious view when evaluating the effects of TMS on
language performance. Nevertheless, considering the po-
tential benefit induced by TMS, that it is noninvasive and
with remissionof the
well-tolerated, further studies on large patient populations
and with controlled sham or control TMS conditions are
needed, to elucidate the possible roles for TMS in the
treatment of language disorders caused by stroke or
Enhancement of visual attention functions has been found
in healthy subjects after stimulation of the parietal
cortex.14,56,57RTMS can be seen in this area as a interven-
tional tool in sensory extinction58,59or unilateral neglect60-
62patients. Unilateral neglect can be defined as a defective
ability to orient, detect, and report novel stimuli presented
in the hemispace contralateral to the brain lesion, in which
cannot be attributed to sensory-motor impairment functions
(ie, hemianopsia or hemiplegia). The disorder usually
follows right parietotemporal lesions. There are many inter-
pretations of the physiopathologic mechanisms responsible
for the neglect. One of the hypotheses is that unilateral ne-
glect is the consequence of selective impairment of global
attention inducing an imbalance in the control of the
contralateral, generally left, hemispace.
A first study that used online single-pulse TMS, found
improved performance during the execution of a tactile
detection task in right brain-damaged patients (Table 1)
with extinction.58TMS was applied to the left unaffected
frontal, prefrontal, or parietal cortices, 40 milliseconds after
a bilateral tactile stimulation. Only left frontal stimulation,
as compared with other sites, significantly reduced extinc-
tion in these patients. In a following study59the same re-
searchers, using single- and paired-pulse TMS in a group
of right brain-damaged patients with extinction (1-12
months poststroke), found similar results but using different
timing between tactile stimulation and TMS. It was found
that parietal stimulation reduced the amount of extinction
earlier (at 20-30 milliseconds) than frontal stimulation
(40 milliseconds). Moreover, paired TMS at 1 millisecond
of ISI improved the patients’ performance more than sin-
gle-pulse TMS, whereas paired TMS at 10 milliseconds
of ISI induced a decline of performance. In short, the
authors demonstrated that it was possible to test the chro-
nometry of these beneficial effects. These results can be
explained as induction of transient inhibition of the unaf-
fected hemisphere reducing the lesion-related interhemi-
spheric attentional imbalance in analyzing the tactile
stimuli. Along similar lines Oliveri et al61applied high-
frequency rTMS over the unaffected parietal cortex of
seven neglect patients. The trains started synchronously
with the appearance of visual stimuli on the monitor that
consisted of black horizontal lines bisected by a marker.
After stimulus presentation patients made a forced-choice
decision about the respective length of the two segments
330C. Miniussi et al
bisected by the marker with three response possibilities:
equal, longer right, or longer left. The result showed that
rTMS of the unaffected parietal site reduced contralateral
neglect compared with sham or baseline condition. Never-
theless, amelioration was short lived.
The same task described before was also used to evaluate
an offline protocol by Brighina et al60in three unilateral
visual neglect patients (Table 1) using low-frequency
rTMS. Patients were tested 15 days before, immediately
preceding, at the end and 15 days after stimulation. rTMS
induced a significant improvement of visuospatial peform-
ance that persisted 15 days after. Finally, a similar study62
tested the efficacy of low-frequency rTMS (Table 1) over
the unaffected parietal cortex, in two unilateral visual
neglect patients. Assessment of attention deficits were per-
formed with the Behavioral Inattention Test and perfor-
mance improved from 2-4 weeks after the end of rTMS
treatment. At 6 weeks, the scores of this test still remained
above pre-rTMS levels.
Overall, these results suggest that the hemispheric
imbalance caused by unilateral brain damage can be
diminished by distractive/inhibitory stimulation of the
unaffected hemisphere, thus down-regulating the atten-
tional imbalance characteristic of hemispatial neglect
Even though these positive results are presented as
evidence to support the use of this approach to treat
attentional deficits, these studies should, nevertheless, be
considered as preliminary because they are open label
without controls or sham stimulation and with a low
number of patients.
Many studies have used TMS, in healthy young subjects,
during the execution of memory tasks.63,64Only a few of
them have found facilitatory effects by using high-fre-
quency online rTMS on working memory20,65or episodic
To the best of our knowledge, there is no published
evidence of rTMS-induced ameliorations of memory def-
icits in patients with memory impairments. The memory
changes associated with physiologic aging were the focus
of an article by Sole `-Padulles et al.67Using offline rTMS
and functional magnetic resonance imaging (fMRI) in a
group of elderly participants, they investigated the effects
of rTMS on memory performance and brain activity. Be-
tween fMRI sessions, sham or real offline rTMS trains
were applied randomly in a double-blind design. The use
of a double cone allowed the stimulation of bilateral
PFC. Trains of rTMS at high-frequency were used (Table
1). Behavioral improvement of recognition accuracy in an
associative memory task (ie, association face-name) oc-
curred only for subjects who received active, as opposed
to sham, rTMS. The effect was associated with the recruit-
ment of right PFC and bilateral posterior cortical regions,
as indicated by the second fMRI session. Several fMRI
studies have shown a reduction of the asymmetrical activa-
tion of PFC, during episodic memory tasks, in older adults
compare with young subjects.68,69The results of an fMRI
study suggest that high-performing older adults counteract
age-related neural decline through plastic reorganization
of the complex neural networks involved in encoding and
retrieval of information. These include, besides the medial
temporal regions, the prefrontal cortex.68Converging evi-
dence of such reorganization also comes from an rTMS
study of interference with the encoding and recognition
of pictures.70The general idea is that some older subjects
showing a performance comparable with that of young sub-
jects are able to compensate for structural loss. These
results can thus be interpreted as an rTMS induction of
activation of areas, which were not recruited previously,
to solve the task. The compensation mechanisms elicited
by TMS may therefore result in a bilateral recruitment of
PFC, counteracting structural loss as a form of ‘‘functional
In conclusion, based on the currently available evidence,
the use of TMS to improve memory performance in
patients with memory impairments is still an important
open field in which much basic work remains to be done.
A positive effect on executive functions of offline rTMS has
been reported in patients with cerebrovascular disease who
have mild executive dysfunction.71High-frequency rTMS
was applied either over the left PFC or over the left motor
cortex (control stimulation site) in one of two sessions.
Each patient participated in two stimulation sessions
(days 1 and 4). A short battery of neuropsychologic tests
was performed before and after each rTMS session.
Psychomotor speed, executive function, and memory were
evaluated. The only mild but significant stimulation site-
specific effect of rTMS was observed in the Stroop interfer-
ence results after the stimulation of PFC compare with
baseline.71Evidence of this one session pilot study needs
to be replicated in adequate clinical trials.
Transcranial direct current stimulation
At the end of the last century, another stimulation technique
received renewed attention from the scientific commu-
nity,72,73although knowledge of its existence and documen-
tation of its clinical applications date back, at least, at the
beginning of the 19th century.74This method relies on ap-
plication of direct currents (DC) and is known as transcra-
nial DC stimulation (tDCS).73,75,76Electrical currents are
Neurorehabilitation with rTMS/tDCS331
applied constantly at low intensities (1-2 mA) over a long
period, usually in minutes (5-30 minutes), to achieve
changes in cortical excitability by influencing spontaneous
neural activity. In this respect, several studies on animal
models77-79suggest that cathodal stimulation reduces spon-
taneous neuronal firing rates, whereas anodal stimulation
has the opposite effect. Similar effects have also been
shown in humans. Nitsche and Paulus75have found that
cathodal polarization reduces motor cortex excitability,
whereas anodal polarization increases it, and these changes,
like those induced by rTMS, last beyond the end of stimu-
lation. Excitatory anodal after effects,80measured in terms
of MEP size, increase the need for longer stimulation than
inhibitory cathodal after effects.81
In comparison with rTMS, tDCS has some advantages
and disadvantages. The main advantages are that this is a
simple, nonexpensive procedure, which is painless and
allows inducing effects of opposite directions (facilitation
or inhibition) on different parts of the brain. It has a reliable
sham condition, therefore providing more robust double-
blind clinical trials than TMS.82In addition, tDCS is a good
tool to be used simultaneously with cognitive training as it
induces much less scalp sensation than rTMS and therefore
is not prey to aspecific effects on attention. The major lim-
itation of tDCS is that it is less focal than TMS. DC is gen-
erally delivered over the scalp through relatively large
electrodes (20-35 cm2). Therefore, it is not focal enough
to target localized areas and to map cognitive functions
accurately. Recently, it has been demonstrated that by
reducing electrode size, it can also be as focal as TMS,83
although results in this trial showed a greater variability
on motor cortical excitability compare with a trial that
used larger electrodes.
Like rTMS, tDCS has been used to modulate cognitive
performance in healthy subjects. The results shows that it is
possible to produce interaction between task execution and
stimulation, thereby reducing or improving subject perfor-
mance, depending on the type of stimulation applied
(anodal vs cathodal). Nitsche et al81showed that anodal po-
larization over the motor cortex speeds the implicit learning
of a motor sequence or a visuomotor coordination task.84In
a later study,85it was found that the same type of stimula-
tion induced facilitation on a probabilistic learning task.
Improved long-term memory consolidation for word pairs
during sleep86or enhanced working memory;87,88interfer-
ence with deception89have also been found.
Similar facilitatory effects were demonstrated in healthy
subjects during language learning,90as well as in other lan-
guage-related tasks such as verbal fluency91or picture nam-
ing,92and during performance of tactile discriminative
tasks.93Nevertheless, like rTMS, it is clearly too simplistic
to consider that anodal tDCS is beneficial and cathodal
tDCS disruptive with regard to behavior in general. Other
important factors such as the type of task, the site of appli-
cation, the excitability status of the underlying cortical
tissue, and the timing of stimulation are critical for the
results. The effects might also depend on task characteris-
tics as demonstrated by several studies.84,94-96
Recently, Monti et al97reported the effects of tDCS in
chronic aphasia after stroke. Cathodal stimulation, applied
to the left frontotemporal cortex of nonfluent aphasic
patients (Table 2), resulted in a 34% improvement in the
ability to name object pictures correctly97with no effects
after anodal and sham stimulation. The authors suggested
that the facilitatory effects on naming performance of the
left-sided tDCS are due to the suppression of inhibitory
interneurons in the lesioned hemisphere. The seemingly
paradoxical improvement is in line with other findings on
detectability of randomly moving dots. Here it was argued
that unspecific cathodal inhibition of all cells involved
increased the signal-to-noise ratio.84
The same group98investigated also the effects of tDCS
in patients with AD (Table 2). Results showed that after
anodal tDCS in temporoparietal areas, accuracy on a
word recognition memory task increased, whereas after
cathodal tDCS, it decreased and after sham tDCS it re-
mained unchanged. The authors concluded that tDCS
over the temporoparietal areas can specifically affect recog-
nition memory performance in patients with AD.
The use of tDCS in cognitive neurorehabilitation is
appealing. However, the data to date are insufficient to
of tDCSin cognitive
The effects induced by rTMS or tDCS stimulation on
cortical function are complex. The observed behavioral
modifications reflect changes in cortical activity, which are
dependent on a number of variables, such as the frequency
of stimulation, its polarity, duration, intensity, and the site
of stimulation. Moreover, we should bear in mind that the
brain does not react passively to cortical stimulation, but
that the response depends on its state of activation. It has
been shown that offline rTMS induces modulations of
neuronal threshold, or even a rearrangement of synaptic
efficiency, and these mechanisms are generally expressed
as a form of functional plasticity or metaplasticity.47,99,100
The effects of rTMS or tDCS may be related to the direct
change of activity in the areas immediately underlying
the stimulation site, or to the level of connected neural net-
works. Neuroimaging, (EEG), and sensitivity studies have
shown that rTMS induces efficient, sometimes long-lasting
modifications of cortical activity both locally99,101-103and
at distant sites.102-105Anodal tDCS induces widespread
changes in regional neuronal activity, measured by in-
creased regional cerebral blood flow. This activity is pre-
sent in many cortical and subcortical regions compared
with cathodal tDCS106and it is related to an increase in
the firing rates of spontaneously active cells. Therefore,
there might be differences between the effects induced in
332C. Miniussi et al
the brain by these two stimulation methods. All these
aspects should be considered when interpreting the effects
induced by cortical stimulation.
In addition, several studies52,53,62suggest that, in the
case of cognitive disorders associated with unilateral hemi-
spheric damage, different approaches of stimulation are ef-
fective. Therefore, they cannot only be used to up-regulate
the excitability within the cortex of the lesioned hemi-
sphere, but also to down-regulate the excitability in the con-
tralateral intact hemisphere, resulting in an improvement of
the damaged function (also see studies from the motor
system42,46,86,107,108). The improved cognitive performance
after rTMS/tDCS may be attributed to a suppression of in-
terhemispheric inhibition. In this respect, it has been dem-
onstrated that a rightward shift of language may be caused
by a reduced transcallosal inhibition109of the language
dominant left hemisphere. However, it is too soon to be
prescriptive and many other combinations of interhemi-
spheric interactions remain to be explored as a function
of timing, task, frequency, initial state, and whether one
hemisphere is stimulated or both are stimulated at different
times. The use of rTMS/tDCS may disrupt an established,
but behaviorally maladaptive pattern of brain activity, and
thus provide an opportunity for the establishment of a
new, more adaptive strategy, therefore pursing the network
toward a new pattern of activation restoring interhemi-
spheric equilibrium and resulting in the improvement of
We should also consider that the goal of the treatment
may not be to restore the functionality of impaired compo-
nents, but rather to exploit the preserved abilities to
compensate for the deficit. Instead of simple cortical
stimulation, future applications will include combined
rTMS/tDCS-induced modifications of cortical responsive-
ness with a specific cognitive training, like the approach
used to improve motor performance in patients with hem-
iplegia.46,110,111It must be underlined that all these proto-
cols are to be considered as additional treatment options
and are not designed to replace conventional treatments.
To summarize, several possible mechanisms can account
for the effects of TMS and tDCS on cognitive performance.
They all reflect the potential of these methods to improve
brain functions. In general, modifications of brain activity
may be sufficient to assist the brain to relearn by inhibiting
competing regions, facilitating local activity, or suppressing
activity to promote changes. Taken together, all these data
suggest that we could, theoretically, extend the general
framework for using rTMS or tDCS presented here in
pathologies that hinder cognitive functions.
Nevertheless, as mentioned previously, changes induced
in cortical response are dependent on a number of technical
variables. Although some of these parameters meet relative
consensus in the scientific community as critical determi-
nants, others are still subject of much debate, especially for
tDCS because there are fewer studies present in literature.
Moreover, it may be that given parameters that induce a
of the site
Type of stimulation
2 mA 10 min
2 mA 10 min
ps 5 poststroke; AD 5 Alzheimer disease; EEG 5 electroencephalogram; sham 5 the stimulator was turned off after 10 seconds; d 5 days; y 5 years.
Neurorehabilitation with rTMS/tDCS333
clear result in a normal system lead to an opposite pattern
of results in a pathologic system.
Previous results from depression trials112,113suggest that
at least 4 weeks of treatment are necessary to achieve clin-
ically meaningful benefits. Therefore, the duration of treat-
ment remain a key point in further studies. RTMS or tDCS
can be applied in combined protocols. Combining facilita-
tion and inhibition effects for priming effects. So far there
are no studies that used combined rTMS/tDCS-induced
modifications of cortical responsiveness with traditional re-
habilitation strategies. An additional possibility is to com-
bine brain stimulation with drugs that can improve
performance as an add-on treatment.114-116
Finally, the risk of rTMS use should be assessed care-
published safety guidelines117especially in stroke patients
who are seizure prone. Safety issues should be considered
also in using tDCS although there is no evidence that it
induces side effects with current stimulation parame-
ters,82,91,118but current density at cortical level may induce
The general conclusion is that TMS and tDCS promote
exogenous plasticity that, combined with endogenous
mechanisms, may prove to have a ‘‘potentiation effect’’
on the, generally modest, effects of cognitive rehabilitation.
As this brief consensual overview shows, there is both a lot
of promise and a lot of uncovered ground in the possibility
of TMS and tDCS in rehabilitation. At this point in time, it
is not possible to say which cognitive disorders are most
likely to yield the optimal combination of brain stimulation
and rehabilitation, but there can be no doubt that it is an
area with foundations worth building upon.
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