Acta Neurol Scand 2014: 129: 351–366 DOI: 10.1111/ane.12223
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
ACTA NEUROLOGICA
SCANDINAVICA
Review Article
Transcranial magnetic stimulation
(TMS)/repetitive TMS in mild cognitive
impairment and Alzheimer’s disease
Nardone R, Tezzon F, H€
oller Y, Golaszewski S, Trinka E, Brigo F.
Transcranial magnetic stimulation (TMS)/rTMS in mild cognitive
impairment and Alzheimer’s disease.
Acta Neurol Scand 2014: 129: 351–366.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Several Transcranial Magnetic Stimulation (TMS) techniques can be
applied to noninvasively measure cortical excitability and brain
plasticity in humans. TMS has been used to assess neuroplastic
changes in Alzheimer’s disease (AD), corroborating findings that
cortical physiology is altered in AD due to the underlying
neurodegenerative process. In fact, many TMS studies have provided
physiological evidence of abnormalities in cortical excitability,
connectivity, and plasticity in patients with AD. Moreover, the
combination of TMS with other neurophysiological techniques, such
as high-density electroencephalography (EEG), makes it possible to
study local and network cortical plasticity directly. Interestingly,
several TMS studies revealed abnormalities in patients with early AD
and even with mild cognitive impairment (MCI), thus enabling early
identification of subjects in whom the cholinergic degeneration has
occurred. Furthermore, TMS can influence brain function if delivered
repetitively; repetitive TMS (rTMS) is capable of modulating cortical
excitability and inducing long-lasting neuroplastic changes.
Preliminary findings have suggested that rTMS can enhance
performances on several cognitive functions impaired in AD and
MCI. However, further well-controlled studies with appropriate
methodology in larger patient cohorts are needed to replicate and
extend the initial findings. The purpose of this paper was to provide
an updated and comprehensive systematic review of the studies that
have employed TMS/rTMS in patients with MCI and AD.
Introduction
Alzheimer’s disease (AD) is a neurodegenerative
process characterized by progressive neuronal loss,
reduced levels of several crucial neurotransmitters,
and altered forms of synaptic plasticity. Mild
cognitive impairment (MCI) is considered a transitional stage between normal aging and a diagnosis
of clinically probable AD. Single and paired-pulse
transcranial magnetic stimulation (TMS) can
assess cortical excitability, thus representing a
R. Nardone1,2, F. Tezzon2,
Y. H€oller1, S. Golaszewski1,
E. Trinka1, F. Brigo2,3
1
Department of Neurology, Christian Doppler Klinik,
Paracelsus Medical University, Salzburg, Austria;
2
Department of Neurology, Franz Tappeiner Hospital,
Merano, Italy; 3Department of Neurological,
Neuropsychological, Morphological and Movement
Sciences, Section of Clinical Neurology, University of
Verona, Verona, Italy
Key words: transcranial magnetic stimulation;
Alzheimer’s disease; mild cognitive impairment; cortical
plasticity; intracortical inhibition; afferent inhibition
R. Nardone, Department of Neurology ‘F. Tappeiner’
Hospital Meran/o, Via Rossini, 5 39012 Meran/o (BZ)
Italy
Tel.: 0473 264616
Fax: 0473 264449
e-mail: raffaele.nardone@asbmeran-o.it
Accepted for publication January 8, 2014
useful co-adjuvant diagnostic tool to noninvasively
assess in vivo neuroplastic changes. Paired
associative stimulation and cortical response to
repetitive TMS (rTMS) have provided useful
information about different aspects of cortical
plasticity. The combination of TMS with electroencephalography (EEG) or functional magnetic
resonance imaging (fMRI) can provide further
information on local cortical excitability and functional connectivity between motor cortex and
other cortical regions.
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Nardone et al.
We review the most important TMS studies
that have demonstrated abnormal cortical excitability, plasticity, or connectivity in patients with
AD and MCI.
If delivered repetitively, TMS can also induce
long-lasting effects, noninvasively modulating the
cortical excitability. rTMS was widely used to
assess and modulate a variety of cognitive functions (sustained attention/concentration, executive
functions/working memory verbal fluency/retrieval, problem solving/reasoning) in patients with
degenerative diseases, patients with psychiatric
disorders and in healthy subjects (for a review,
see 1). Memory impairment is usually the first
and more severe cognitive manifestation of these
neurodegenerative processes, and rTMS studies
have confirmed the role of the prefrontal cortex
(PFC) during the encoding and retrieval of verbal
or nonverbal material in healthy participants
(2–6). By combining fMRI and rTMS, Manenti
et al. (7) also provided evidence of a causal role
of not only the PFC but also parietal cortices
during word retrieval. It should be considered
that the research in the field of memory is limited
by the poor penetration depth of TMS (8).
In this review, we will also focus on the present, initial, findings showing that rTMS has the
potential to enhance performances in cognitive
functions that are impaired in MCI and patients
with AD.
We update here previous important reviews
(i.e., 9, 10) because in the last few years, other
studies have significantly expanded the previous
findings. We aimed thus to provide a comprehensive perspective of past and current research and
to help guide future studies.
The MEDLINE, Pubmed (1966–July 2013), and
EMBASE (1980–July 2013) electronic databases
were searched using the medical subject headings
(MeSH) ‘dementia,’ ‘Alzheimer’s disease,’ ‘mild
cognitive impairment,’ ‘transcranial magnetic stimulation,’ ‘repetitive transcranial magnetic stimulation,’ ‘cortical excitability,’ ‘cortical plasticity,’
‘motor threshold,’ ‘intracortical inhibition,’ ‘afferent inhibition,’ and ‘connectivity.’
Two review authors (SG and FB) screened the
titles and abstracts of the initially identified studies to determine whether they satisfied the selection criteria. Any disagreement was resolved
through consensus. Full-text articles were
retrieved for the selected titles, and reference lists
of the retrieved articles were searched for additional publications. In case of missing or incomplete data, principal investigators of included
trials were contacted and additional information
requested. No language restrictions were applied.
352
The two reviewers independently assessed the
methodological quality of each study and risk of
bias, focusing on blinding and other potential
sources of bias. The search strategy described
previously yielded 48 results. Only articles reporting data on studies using TMS techniques in
patients with AD or MCI were considered eligible
for inclusion. We excluded 3 studies after reading
the full published papers; thus, 45 studies contributed to this review: the earliest was published in
1997 and the most recent in 2013.
Transcranial magnetic stimulation techniques
Measures of cortical excitability
Resting motor threshold (RMT) is defined as the
minimum stimulus intensity that produces a
motor evoked potential (MEP) of more than
50 lV in 50% of 10 trials in a relaxed muscle,
whereas active motor threshold (AMT) is the
minimum stimulus intensity required to generate
a MEP (about 200 lV in 50% of 10 trials) during
isometric contraction of the tested muscle at
about 10% maximum. RMT provides information about a central core of neurons in the muscle
representation in the motor cortex. RMT is
increased by drugs that block voltage-gated
sodium channels (11, 12), but is not affected by
drugs with effect on GABAergic transmission
(11, 12), and is lowered by drugs that increase
non-N-methyl-D-aspartate (NMDA) glutamatergic transmission (13, 14). Therefore, RMT is
thought to reflect both neuronal membrane excitability and non-NMDA receptor glutamatergic
neurotransmission. AMT differs from RMT in
that excitability of motoneurons in the spinal
cord is enhanced by the voluntary muscle contraction, and thus provides a measure of corticospinal excitability with greater dependence on
the spinal segmental-level excitability (15–17).
The amplitude of the MEP reflects not only the
integrity of the corticospinal tract and the excitability of motor cortex and spinal level, but also
the conduction along the peripheral motor pathway to the muscles. That is, a dysfunction along
the corticospinal tract may therefore reveal
abnormal MEPs, while the absence of MEPs
abnormalities suggests integrity of the pyramidal
tract (15–17). It has been recently demonstrated
(18) that changes in MEP amplitudes and motor
threshold represent two different indices of motor
cortex plasticity. Whereas increases and decreases
in MEP amplitude are assumed to represent
LTP-like or LTD-like synaptic plasticity of motor
cortex output neurons, changes in motor
TMS/rTMS in MCI and AD
threshold may be considered as a correlate of
intrinsic plasticity.
Transcranial magnetic stimulation enables
mapping of motor cortical outputs. Cortical mapping procedures, performed through single TMS
pulses applied on several scalp positions overlying
the motor cortex, may be obtained with an accurate assessment of the number of cortical sites
eliciting MEPs in a target muscle, the site of maximal excitability (hot spot), and the ‘center of
gravity’ of motor cortical output, as represented
by the excitable scalp sites (19).
Besides evoking MEPs, single TMS pulses
delivered during voluntary muscle contraction
produce a period of EMG suppression known as
cortical silent period (cSP). Moreover, through
single-pulse TMS, it is possible to investigate
inhibitory motor cortical processes ipsilateral to
the stimulation side (ipsilateral silent period, iSP),
which are considered to reflect the functional
integrity of the callosal fibers connecting corresponding motor cortices (20).
Transcranial magnetic stimulation may also be
used to assess the intracortical facilitatory and
inhibitory mechanisms that influence the cortical
motor output. Some of these TMS techniques
involve paired stimuli based on a conditioningtest paradigm (21). Stimulation parameters such
as the intensity of the conditioning (CS) and test
stimulus (TS), together with the time between
them (interstimulus interval, ISI), determine interactions between stimuli. When the CS is below
and the TS is above the MT, the CS inhibits the
response to TS at ISIs of 1–5 ms (short-latency
intracortical inhibition, SICI), inducing an
increase in the test MEP amplitude at ISIs of
7–20 ms (intracortical facilitation, ICF). CS at
suprathreshold intensity inhibits the TS at ISIs of
50–200 ms and this is termed long-interval intracortical inhibition (LICI). Both SICI and cSP are
thought to reflect the excitability of inhibitory
GABAergic cortical circuits (15), and SICI is
considered to reflect mostly the GABAA-mediated
intracortical inhibitory interactions (22). Whereas
spinal inhibition contributes to the early phase of
the cSP (for its first 50–75 ms), the late part of
the SP, as well as LICI, reflect a long-lasting cortical inhibition mediated by GABAB most likely
in the motor cortex (23).
Conversely, ICF is believed to reflect intracortical excitatory neurotransmission, which is largely
mediated by NMDA receptors (24).
Short-latency afferent inhibition (SAI) refers to
the suppression of the amplitude of a MEP produced by a conditioning afferent electrical stimulus, usually applied to the median nerve at the
wrist approximately 20 ms prior to TMS of the
hand area of the contralateral motor cortex (25).
As SAI is decreased by the muscarinic receptor
antagonist scopolamine in healthy individuals
(26) and can be positively modulated by acetylcholine (Ach) in healthy individuals (27, 28), this
measure is thought to be a non-invasive way of
testing central cholinergic activity. However, SAI
may also depend on the integrity of circuits connecting sensory input with motor output (29),
and other neurotransmitters, especially dopamine,
are supposed to play a modulatory role on the
cholinergic neurotransmission.
Cortical connectivity and plasticity
Real-time integration of TMS with electroencephalography (EEG) (30–32) can provide further information on local cortical excitability and
widespread network dynamics. As a matter of fact,
EEG has an excellent temporal resolution, whereas
TMS can be applied to study local reactivity of the
brain and interactions between different brain
regions with directional and precise chronometric
information. The effects of several experimental
manipulations including TMS in rodents on EEG
rhythms have been recently reviewed to build a
knowledge platform for innovative translational
models for drug discovery in AD (33).
Several other TMS techniques are currently
used to noninvasively modulate the cortical excitability, thus shedding light on mechanisms of cortical plasticity in humans.
Paired associative stimulation (PAS) and cortical responses to rTMS also provide information
about different aspects of cortical plasticity (34).
Through PAS procedure, an electrical stimulus is
delivered to a peripheral nerve (usually the median nerve), followed by a single TMS pulse
applied over the hand area of the primary motor
cortex (M1) (35). When appropriately timed, PAS
induces an increase in corticospinal excitability
over a period of time which is interpreted as a
marker of motor cortical plasticity, where longterm plasticity (LTP)-like processes are thought
to play a major role (35). A new repetitive PAS
(rPAS) protocol facilitates and prolongs the
effects of electrical peripheral nerve stimulation
and rTMS on cortical excitability. Submotor
threshold 5-Hz repetitive electrical nerve stimulation of the right median nerve is synchronized
with subthreshold 5-Hz rTMS of the left M1 at a
constant interval for 2 min. The ISI between the
peripheral stimulus and the transcranial stimulation is set at 10 ms (5-Hz rPAS10 ms) or 25 ms
(5-Hz rPAS25 ms) (36).
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Nardone et al.
If delivered repetitively, TMS can influence
brain function. Through rTMS, a train of TMS
pulses of the same intensity are applied to a single brain area at a given frequency ranging from
1 to 20 or more stimuli per second. Depending
on the stimulation parameters, particularly the
frequency of stimulation, cortical excitability can
be modulated, thus obtaining a facilitating or
suppressing effect. RTMS can be applied as continuous trains of low-frequency (1 Hz) or bursts
of higher-frequency (≥ 5 Hz) rTMS. Generally,
low-frequency rTMS (stimulus rates ≤1 Hz)
induces inhibitory effects on motor cortical excitability leading to a reversible ‘virtual lesion’ (37,
38), whereas high-frequency rTMS (5–20 Hz)
usually promotes an increase in cortical excitability (39, 40). This modulation can last for several
minutes (depending on the overall duration of the
train itself) and provides an index of cortical
plasticity. A novel protocol of rTMS named theta
burst stimulation (TBS) (41) employs low intensities and has a robust, long-lasting effect in normal subjects (41, 42). Different patterns of
delivery of TBS (continuous vs intermittent) produce opposite effects on synaptic efficiency of the
stimulated cortex.
Studies on cortical plasticity, excitability, and
connectivity
The major findings of TMS studies published on
cortical excitability and plasticity in AD/MCI, as
well as demographic and clinical characteristics of
sample populations, are presented in Table 1.
Motor threshold
A consistent finding among TMS studies performed in patients with AD is the decreased
RMT. Most of them found significantly reduced
RMT in patients with AD compared with healthy
controls (43–55), or a tendency toward a reduced
RMT even if without statistically significant difference (56–64). Only one study noted no difference in RMT between patients with AD and
controls (65), and one found increased RMT in
AD (66).
It has been hypothesized that mechanisms
related to RMT are preserved in the early stages
(65). RMT was found to be normal also in
patients with MCI (61). Alternatively, RMT
changes might reflect a functional change, but
not structural damage of cortical motor neurones.
In the disease progression, the RMT decrease
may be compensatory to the loss of motor cortical neurones (44, 58). Perretti et al. (66) suggested
354
that, in the most advanced disease stage, the
increase in RMT can be related to cortical atrophy. In a recent combined TMS-MRI study (67)
in AD and mild cognitive impairment (MCI), the
cortical thinning was found to be related to
decreased cortical excitability, especially on the
precuneus and cuneus. In patients with AD, the
hyperexcitability on the sensorimotor cortex may
represent a protective mechanism that counteracts
the prominent loss of cortical volume. This supposed protective mechanism was found neither
on the precuneus or cuneus, nor in the MCI
group. Therefore, the authors concluded that the
progression of the dementia proceeds differently
in the structure and function of neuronal circuits
from normal condition via MCI to AD.
The AMT was assessed in fewer studies, and
the results are somewhat divergent from those for
RMT. Only two studies found significant
decreases in AMT in patients with AD as compared to healthy subjects (44, 49). These results
suggest that the excitability of spinal projections
is relatively preserved during early-course AD.
The increased excitability to TMS in patients
with AD may be the consequence of an abnormality within the glutamatergic system, and this
hypothesis was supported by a study demonstrating an abnormal response to rTMS in patients
with AD (53).
Most of the studies found no significant differences in MEP amplitude between patients with
AD and healthy individuals (46, 47, 49, 53, 54,
65, 66); significant increases in MEP amplitude in
patients with AD were detected in 3 studies
(43–45). Overall considered, the integrity of the
corticospinal tract seems not to be compromised,
at least in earlier stages of AD.
Interestingly, the ‘center of gravity’ of motor
cortical output shows a frontal and medial shift,
without changes in the hot spot location in
patients with AD (58), thus indicating functional
reorganization. The dysregulation of the inhibitory frontal centers and their integration in the
excitatory network underlying motor output was
thought to account for this finding (58).
Silent period, intracortical inhibition, and facilitation to paired
TMS
Transcranial magnetic stimulation studies exploring the inhibitory circuits by means of cSP and
SICI to paired-pulse TMS have yielded more
divergent results.
A significant reduction in SICI has been
reported in several studies (51, 55, 56, 59, 64, 65),
whereas most studies did not find any significant
TMS/rTMS in MCI and AD
Table 1 Main findings of the studies on cortical excitability and plasticity in patients with Alzheimer’s disease and mild cognitive impairment
Demographic, clinical, and radiological features
Education (y)
Disease
duration (mo)
65.0
62.5
40
72.7
40
–
4.8 0.4
–
–
9.3 3.4
–
30.7 7.3
14.4 6.7
–
28.4 14.6
8.2
7.9
8.9
9.2
9.1
–
2.3
2.9
4.5
4.9
4.3
32.0 16.8
26.8 16.4
31.9 16.3
32.0 13.1
32.0 13.1
(> 4 yrs)
–
–
–
14.2 2.8
–
9.6 3.4
–
–
7.3 4.3
–
–
–
–
–
32.2 15.5
(>6 mo)
12.4 4.5
2.7(1.9)
–
(>1 yr)
–
–
Grp
No
Alagona et al., 2001
Alberici et al., 2008
Battaglia et al., 2007
De Carvahlo et al., 1997
Di Lazzaro et al., 2002
AD
AD
AD
AD
AD
21
8
10
14
15
72.2
74.5
70.1
67.8
69.0
7.5
7.3
7.4
6.0
5.3
Di Lazzaro et
Di Lazzaro et
Di Lazzaro et
Di Lazzaro et
Di Lazzaro et
Ferreri et al.,
AD
AD
AD
AD
AD
AD
28
20
20
10
12
16
71.3
70.5
69.5
72.1
69.3
75.0
2.9
6.9
6.5
4.4
7.3
6.9
AD
AD
AD
AD
AD
MCI
AD
AD
AD
AD
AD
MCI
MCI
11
11
10
13
17
40
11
17
15
12
12
16
10
74.8
73.0
71.7
69.6
68.4
68.2
77.2
68.5
67.2
65.2
–
9.7
9.2
4.9
4.9
4.8
3.6
4.4
9.2
7.8
3.2
70
79.7 2.6
40
al., 2004
al., 2005
al., 2006
al., 2007
al., 2008
2003
Liepert et al. 2001
Martorana et al. 2008
Martorana et a. 2009
Nardone et al., 2006
Nardone et al., 2008
Nardone et al., 2011
Olazaran et al., 2010
Pepin et al., 1999
Perretti et al., 1996
Pierantozzi et al., 2004
Sakuma et al., 2007
Terranova et al., 2013
Age (y)
Gender
(%F)
Authors
–
60
50
40
–
61.5
–
–
46.15
41.1
35.0
54.5
72.7
73.3
–
–
–
33.8 16.4
TMS findings
Radiology
MRI
MRI
MRI
CT
Abnormal
RMT ↓, I/O, MEP ↑
–
–
–
–
MRI
MRI
Head techn.
or MRI
CT or MRI
MRI
MRI
PAS ↓
RMT ↓, MEP ↑
RMT, SAI ↓
RMT, SAI ↓
SAI ↓
RMT, SAI ↓
RMT, AMT, SAI ↓
RMT, SAI ↓
RMT ↓
Normal
CMCT
RMT, SICI, ICF
CMCT
AMT, I/O curve,
SP, SICI, ICF
SICI
SICI
AMT, SICI
–
–
SICI ↓
RMT, SICI ↓
RMT, SAI ↓
SICI, SAI ↓
SAI ↓
SAI ↓ in aMCI–MD
SICI ↓
RMT, AMT ↓, MEP ↑
RMT ↑, cSP ↓
SICI ↓
SAI ↓ in AD
RMT, AMT, CMCT, ICF
RMT, AMT, CMCT, SICI, ICF
RMT, AMT, CMCT, SICI, ICF
RMT, ICF, LICI
SICI, ICF
I/0 curve, MEP
RMT, AMT, I/O, ICF
RMT in AD RMT, SAI in MCI
–
PAS, SAI ↓
RMT, SAI in MCI
MRI
MRI
MRI
MRI
MT,CMCT, cSP, ICF
ICF
All values are expressed as mean (SD). No, number of subjects; y, years; mo, months;%F, percentage female; CT, computed tomography; MRI, magnetic resonance imaging;
AD, Alzheimer’s disease; MCI, mild cognitive impairment; aMCI-MD, amnestic MCI- multiple domain; RMT, resting motor threshold; AMT, active motor threshold; MEP, motor
evoked potential; I/O curve, input/output curve; cSP, cortical silent period; SICI, short-latency intracortical inhibition; LICI, long-latency intracortical inhibition; ICF, intracortical
facilitation; SAI, short-latency afferent inhibition; PAS, paired associative stimulation (induced changes in MEP amplitude); ↑, increase; ↓, decrease.
difference in SICI between patients with AD and
controls (44, 47–50, 60, 63). The amount of disinhibition can correlate with the severity of AD
(56). Conversely, most studies assessing cSP failed
to find significant abnormalities in this measure
(43, 52, 53, 56). Peripheral silent period was
examined in one single study and found not to be
altered. Taken together, these findings do not
support the possibility of an impairment in cortical GABAergic synaptic transmission. On the
other hand, a dysfunction of GABA system has
not been proven to represent a satisfactory
alternative explanation for the cortical hyperexcitability in AD. In fact, biological investigations of
biopsy brain tissue in patients with AD failed
to demonstrate alterations in the GABA concentration or disturbance of GABA transporters
(68, 69).
Significant ICF changes in AD subjects have
never been observed (44, 47, 51, 56, 59, 63, 65),
thus pointing to a normal NMDA receptordependent glutamate excitatory activity in AD.
However, several studies suggest that abnormalities of glutamatergic neurotransmission might
play a relevant role in AD. The glutamatergic
hypothesis of AD, which has been proposed as
an auxiliary mechanism to the cholinergic
hypothesis (58), is possibly related to an imbalance between the non-NMDA and NMDA neurotransmission (13, 14, 58, 70, 71).
Recently, Hoeppner et al. (55) found a significantly prolonged iSP-latency in patients with AD
compared with controls, with no differences in
iSP-duration; in this study, the iSP-latency correlated significantly with the SICI. These effects
appear to be independent from the degree of cognitive impairment and the presence of clinical
signs of motor dysfunction. Results of this study
suggest subclinical dysfunctions of motor cortical
inhibition in mild to moderate clinical AD stages,
with relevant interactions between intra- and
interhemispheric inhibitions.
Both the amount of IHI and SAI were found
to be significantly reduced also in patients with
MCI as compared to control subjects, whereas
SICI or ICF did not differ between them (72).
The degree of IHI significantly correlated with
neither the mini-mental state examination score
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Nardone et al.
nor the degree of SAI. Our results suggest that
transcallosal connection between bilateral M1 is
primarily involved in MCI, regardless of SAI
dysfunction.
Short-latency afferent inhibition
Among the parameters of motor cortical reactivity/excitability, the most consistent abnormal
finding in AD regards SAI. All the studies assessing SAI found significant decreased SAI values as
compared to healthy subjects (47–50, 59–62, 73).
These findings are consistent with postmortem
studies showing central cholinergic impairment in
AD (74–76).
A negative correlation was found between SAI
and performance in abstract thinking (49, 50)
and long-term memory (50). The reduction in this
putative marker of cholinergic activity is also correlated with euphoric manic state and disinhibition (77) in AD. This correlation can be
explained by the prevalent cholinergic dysfunction of temporo-limbic area (including hippocampus,
entorhinal
cortex,
and
amygdala),
particularly in the early stage of the disease. SAI
testing may therefore represent a useful marker
of central cholinergic dysfunction even in the initial stages of AD (60).
By contrast, SAI was found not to be significantly reduced in subjects with amnestic MCI
(61). However, it is noteworthy to consider that
in this study, the diagnosis of amnestic MCI was
based on the criteria proposed by Petersen in
1999 rather than on the revised ones (78), and
that the relationship to the different MCI subtypes was not defined. It has been recently demonstrated (79) that SAI is significantly reduced in
patients with amnestic MCI-multiple domain
when compared with the controls, while it is not
significantly different in patients with amnestic
MCI-single domain patients and in patients with
non-amnestic.
By using the neurophysiological determination
of SAI, the activation of the cerebello–thalamo–
cortical pathway by means of continuous
(inhibitory) cerebellar TBS was found to modulate central cholinergic functions (80).
Pharmacological effects
Several studies examined the acute effects of
drugs enhancing acethylcholine neurotransmission
on motor cortical excitability in patients with
AD. The effect of the acethylcholinesterase inhibitor (AchEI) rivastigmine on cortical excitability
was extensively studied by Di Lazzaro and
356
co-workers (27, 47, 48). The AchEI galantamine
was administered in another study (65). A reversal of SICI abnormalities was also detected following administration of galantamine (65), but
not after rivastigmine (48). In one study, a smaller dose of the AchEI donezepil was given to 10
patients and a higher dosage to five (56). SICI
was increased only in patients who were given the
higher dose of donezepil (10 mg). Rivastigmine
appeared to increase SAI in patients with AD
(27, 47, 48), with no effect on healthy subjects
(47), while neither rivastigmine nor galantamine
had effect on RMT (27, 47, 48, 65).
Pennisi et al. (57) found that mean RMT correlated positively with disease severity at baseline
and significantly decreased over both hemispheres
after 1 year of treatment with AChEIs administered at different dosages.
Di Lazzaro et al. (27) also reported that most
patients with abnormal SAI at baseline and who
had had an acute increase in SAI after a single
oral dose of rivastigmine benefited from prolonged administration of rivastigmine. In contrast, a normal SAI in baseline conditions, or an
abnormal SAI in baseline conditions that was not
greatly increased by a single oral dose of rivastigmine, was invariably associated with poor
response to long-term treatment. The acute
change in SAI correlated positively with an
improvement in neuropsychological tests after
1 year of treatment.
Ferreri et al. (81) compared motor cortex functionality in 10 patients with AD before and after
long-term AchEIs therapy to monitor potential
drug-related effects on cortical physiology. The
examined parameters of motor cortex excitability
remained unchanged in patients with stabilized
cognitive performances during the therapy. These
results support the theory that the frontal lobes
are among the specific targets of the neurophysiological stabilization induced by AchEIs, in agreement with quantitative EEG and SPECT studies
(82, 83). Furthermore, Trebbastoni et al. (84)
investigated changes in cortical excitability and
short-term synaptic plasticity by delivering 5-Hz
rTMS over the primary motor cortex in 11
patients with mild to moderate AD before and
after chronic therapy with rivastigmine and found
that chronic treatment with rivastigmine has no
influence on altered cortical excitability and
short-term synaptic plasticity. The authors concluded that the limited clinical benefits related to
cholinesterase inhibitor therapy in patients with
AD depend on factors other than improved plasticity within the intracortical excitatory glutamatergic circuits. Martorana and co-workers
TMS/rTMS in MCI and AD
assessed in two studies the acute effects of dopaminergic modulation on motor cortex excitability.
In the first study, the authors examined the
effects of a single dose of melevodopa on motor
threshold, SICI, and ICF in patients with AD
and healthy elderly controls (51). While melevodopa had no significant effect on RMT, AMT,
and ICF in either group, it significantly reversed
the abnormal SICI reduction in the patients with
AD, with no changes in control group. These
results suggest that dopamine may modulate cortical excitability in AD through intracortical
inhibitory circuits. In a subsequent study,
Martorana et al. (52) measured SAI after administration of a single dose of L-dopa in both AD
and healthy subjects. Normalization of SAI was
observed in AD, but no effect was noted in control subjects.
Cortical connectivity and plasticity
Inghilleri et al. (53) tested the effects of modulation of cortical motor areas induced by suprathreshold high-frequency (5 Hz) rTMS. Whereas
in controls 5-Hz rTMS elicited normal MEPs
that progressively increased in amplitude, in
patients with AD, it elicited MEPs that decreased
in size. These findings suggest the presence of an
altered cortical plasticity in excitatory circuits
within motor cortex in patients with AD. Conversely, 5-Hz rTMS induced an increase in cortical SP in both groups, thus suggesting a normal
plasticity in cortical inhibitory circuits in the
patients. Koch et al. (85) also found that lowfrequency (1 Hz) rTMS did not induce in patients
with AD the inhibitory effects which are observed
in healthy subjects. L-Dopa did not modulate the
effects of rTMS in patients with AD, showing
that synaptic potential plasticity, such as longterm depression (LTD) may play an important
role in the pathogenesis of this disease. Performing PAS with interval between peripheral nerve
stimulation and TMS set at 25 ms (PAS25),
Battaglia et al. (62) studied corticomotor LTPlike plasticity in patients with AD and healthy
controls and also performed biochemical analyses
in brain slices of amyloid precursor protein
(APP)/presenilin-1 (PS1) mice, an AD animal
model. PAS-induced plasticity was found to be
significantly reduced in patients with AD.
Moreover, 4–4.5-month-old APP/PS1 mice exhibited deficits of NMDAR-dependent neocortical
(motor and medial prefrontal) and hippocampal
LTP, and a significant alteration of NMDAR
activity. Overall considered, these findings suggest
that decreased plasticity might underlie motor
symptoms in AD, resulting from a deficit of
NMDAR-dependent neurotransmission. Also different protocols of theta burst stimulation (TBS)
are known to induce plastic changes resembling
the LTP and LTD mechanisms described in animal models. Koch et al. (86) were able to demonstrate the impairment of LTP-like together with
normal LTD-like cortical plasticity in patients
with AD. In fact, patients with AD showed consistent LTD-like effects that were comparable to
those obtained in healthy controls when submitted to continuous TBS, while they did not show
any LTP-like aftereffect when submitted to TBS
protocols that induced an LTP-like effect in
healthy controls such as intermittent TBS.
Recently, Terranova et al. (87) employed rPAS
to investigate whether abnormal M1 synaptic
plasticity is present at an early stage of AD. In
the control subjects, rPAS induced a significant
increase in MEP amplitudes and a decrease in
SAI in the APB muscle persistently for up to 1 h.
Conversely, 5-Hz rPAS did not induce any significant changes in MEP amplitudes and SAI in
mild patients with AD. These findings suggest
that sensory-motor plasticity is impaired in the
motor cortex of AD at an early stage of the
disease.
Julkunen et al. (54) studied functional connectivity between the motor cortex and other cortical
areas. Fifty single TMS pulses 3 s apart were
delivered to the motor cortex to assess spreading
of navigated TMS-evoked EEG responses
throughout the brain and found significant differences in motor cortical reactivity from averaged
left and right hemispheres in patients with AD.
In addition, using real-time integration of TMS
and EEG prominent changes in cortical connectivity in subjects with AD have been demonstrated. In particular, the TMS-evoked response
at 30–50 ms decreased significantly in patients
with AD compared with both healthy controls
and subjects with MCI over widespread brain
regions; significant differences were found in the
ipsilateral parietal cortex and contralateral
frontocentral areas. These findings of diminished
reactivity and connectivity between regions point
to a dysfunction of large-scale sensorimotor networks, perhaps with reduced synchronization of
EEG activity in patients with AD. In a subsequent study, the same authors (88) investigated
the sensitivity of the TMS-EEG to discriminate
control subjects from MCI and patients with AD
and to evaluate how the TMS-EEG response
related to the scores of the dementia rating scales
used to evaluate the severity of cognitive impairment in these subjects. The authors found that
357
Nardone et al.
the TMS-EEG response P30 amplitude correlated
with cognitive decline, showing good specificity
and sensitivity in differentiating healthy subjects
from those with MCI or AD. Recently, Bonnı
et al. (89) explored by means of bifocal TMS
parieto-frontal functional connectivity in 15
patients with AD and 12 healthy control subjects.
Conditioning stimuli were applied over the right
posterior parietal cortex (PPC) at different intensities (90% and 110% of RMT). MEPs were then
recorded from the ipsilateral M1 at different ISIs
ranging between 2 and 15 ms. Results showed
that in healthy subjects, a conditioning TMS
pulse applied over the right PPC at 90% (but not
at 110%) of RMT intensity was able to increase
the excitability of the homolateral M1. This functional interaction peaked at ISI 6 ms. Conversely,
in patients with AD, the facilitatory pattern of
parieto-motor connections was evident only when
TMS was delivered at an intensity of 110% of
RMT with a peak at ISI 8 ms. Interestingly,
treatment with AchEI did not modify significantly the strength of the connection in patients
with AD. Furthermore, the effects induced by
PPC conditioning at 110% RMT correlated with
neuropsychological measures of episodic memory
and executive functions; the patients with better
cognitive performance had thus less impaired
connectivity. These findings suggest that parietofrontal cortico-cortical functional connectivity is
altered in patients with AD.
In patients with MCI, Bracco et al. (90) found
that, unlike healthy subjects, linguistic task performance did not produce any significant MEP
modulation in patients with aMCI. These findings
suggest that functional connectivity between the
language-related brain regions and the dominant
M1(hand) may be altered in aMCI.
Neuromodulation and therapeutic interventions
In the last years, new non-invasive neurostimulation techniques have gained increased attention.
In particular, two techniques of non-invasive
brain stimulation – rTMS and tDCS – can modulate cortical excitability, inducing lasting effects
(91, 92) both have been shown to have a potential therapeutic role in cognitive neuroscience
(93).
Both techniques are known to involve mechanisms of synaptic plasticity, specifically LTP and
LTD. A link between the aftereffects induced by
rTMS and the induction of synaptic plasticity has
been recently identified (94). We focus in this
review the attention on the therapeutic applications of rTMS in patients with AD and MCI.
358
Several neuroimaging studies have demonstrated that the increased activation in right dorsolateral prefrontal cortex (DLPFC) is one of the
functional brain abnormalities associated with
memory deficits in MCI and AD (95–97); these
findings have been interpreted as demonstrating
recruitment of compensatory networks (98, 99).
DLPFC is a common target for rTMS experiments and therapeutic protocols.
Turriziani et al. (100) investigated whether
rTMS, given as inhibitory and excitatory TBS,
over the left and right DLPFC modulates recognition memory performances in 100 healthy controls and in 8 subjects with MCI. Recognition
memory tasks of faces, buildings, and words were
used in different experiments. In the healthy control subjects, inhibitory TBS of the right DLPFC
improved recognition memory performance for
both verbal and nonverbal memoranda, while
inhibitory TBS of the left DLPFC had no effect
in the recognition memory performance; in contrast, excitatory TBS of the right DLPFC
impaired nonverbal recognition memory performance in control subjects, while iTBS-excitation
of the left DLPFC had no effect on recognition
memory performance.
Repetitive transcranial magnetic stimulation
(rTMS)–inhibition of the right DLPFC thus
improved the recognition memory performance
of patients with MCI with memory deficits while,
in both the MCI and control subjects, the performance did not improve after rTMS-inhibition of
the left DLPFC. Therefore, this study revealed a
beneficial effect on memory performance when
there is reduced activity in the right DLPFC during recognition memory tasks in patients with
memory impairments.
It can be hypothesized that the previously
reported additional activation in DLPFC in MCI
and patients with AD reflects a dysfunctional use
of brain resources rather than reflecting the
recruitment of cognitive resources to maintain
task performance (e.g., 98,99). Inhibitory rTMS
over the right DLPFC may have the potential to
modulate the activity in this dysfunctional network, enhancing function in healthy subjects or
restoring an adaptive equilibrium in patients with
MCI (101).
Three studies by Cotelli and colleagues have
assessed the effects of rTMS on naming and language performance in patients with AD. In two
crossover, sham-controlled, single-session studies
(102, 103), rTMS was applied to the DLPFC during the execution of naming tasks. In the first
study, high-frequency rTMS of either left or right
DLPFC lead to a significantly improved accuracy
TMS/rTMS in MCI and AD
in action naming, but not in object naming (102).
In the second study, Cotelli et al. (103) found
that the results of the previous study were replicated only in patients with mild AD (MiniMental-State Examination (MMSE) ≥ 17/30);
conversely, both action and object naming were
facilitated in patients with moderate to severe
AD (MMSE < 17/30) after left and right DLPFC
rTMS.
In a subsequent study, Cotelli et al. (104) investigated whether the application of high-frequency
rTMS to the left DLPFC would lead to significant
facilitation of language production and/or comprehension in patients with moderate AD. Ten
patients were assigned to one of two groups in
which they received either 4-week real rTMS, or
2 weeks of sham rTMS followed by 2 weeks of real
rTMS stimulation. No significant effects were
observed on naming performance, while a significant effect was observed on auditory sentence comprehension after 2 weeks of real rTMS sessions.
After two additional weeks of daily rTMS sessions,
there was no further improvement, but a significant benefit on auditory sentence comprehension
was still detected 8 weeks after the end of the
rTMS intervention. Important findings were the
absence of any effects on memory and executive
functions, as well as the absence of any side effects
of the rTMS applications.
In a single-case study, Cotelli et al. (105) aimed
to assess whether rTMS could improve memory
performance in an individual with amnestic MCI.
Stimulation of the left parietal cortex increased
accuracy in an association memory task, and
such an improvement was still significant
24 weeks after stimulation began.
The objective of another study (106) was to
compare the long-term efficacy of high- versus
low-frequency rTMS applied bilaterally over the
DLPFC, on cortical excitability and cognitive
function of patients with AD. All patients
received one session daily for five consecutive
days. The group which received five daily sessions
of high-frequency rTMS group improved significantly more than the low-frequency and sham
groups in all assessed rating scales (MMSE,
Instrumental Daily Living Activity Scale and the
Geriatric Depression Scale) after treatment. This
improvement was maintained for 3 months. The
authors thus concluded that high-frequency
rTMS may be considered as a useful adjuvant
treatment of patients with mild to moderate AD.
Bentwich et al. (107) also investigated the combination of brain stimulation with cognitive rehabilitation (the so-called neuroAD-system) in
patients with AD. In particular, they aimed to
obtain a synergistic effect of cognitive training
(COG) associated with rTMS (rTMS-COG).
Eight subjects with mild to moderate AD were
subject to daily rTMS-COG sessions (5/week) for
6 weeks, followed by maintenance sessions
(2/week) for additional 6 months. rTMS was
applied over Broca and Wernicke areas, right and
left DLPFC, right and left parietal somatosensory
association cortex, and COG tasks were developed to fit these regions. Improvements of
Alzheimer Disease Assessment Scale-Cognitive
(ADAS-Cog) and of Clinical Global Impression
of Change (CGIC) were found. Also MMSE, the
Alzheimer Disease Assessment Scale -Activities of
Daily Living (ADAS-ADL), and the Hamilton
Depression Scale improved, but a statistical significance was not achieved, while Neuropsychiatric Inventory (NPI) did not change.
In a successive randomized, double-blind, controlled study, the same research group (108)
aimed at examining the safety and efficacy of
rTMS-COG in AD. Fifteen patients with AD
received 1-h daily rTMS-COG or sham treatment, five sessions/week for 6 weeks, followed by
bi-weekly sessions for 3 months. There was an
improvement in the average ADAS-cog score and
in the average CGIC after 6 weeks and after
4.5 months of treatment in the group receiving
real rTMS-COG compared with the placebo
group. NPI improved non-significantly. Therefore, the authors concluded that NeuroADsystem offers a novel, safe, and effective therapy
for improving cognitive function in AD.
Haffen et al. (109) reported in a single-case
study that rTMS treatment may improve cognitive
skills. rTMS was applied in the patient with initial
AD over the left DLPFC for ten stimulation sessions over 2 weeks. Cognitive improvements were
noted especially in tests of episodic memory and
speed processing. This study showed possible
effects 1 month after rTMS, and their findings suggest that brain stimulation might facilitate cognitive processes partly depending on DLPFC.
Overall considered, these studies suggest that
rTMS may be helpful in restoring brain functions, given its potential to recruit compensatory
networks that underlie the memory-encoding and
the other cognitive functions (110).
Table 2 summarizes the main findings of studies aiming at improving cognitive functions in
patients with AD and MCI using rTMS.
Discussion
The reviewed studies aiming to explore cortical
excitability and plasticity in AD illustrate that
359
Nardone et al.
360
Table 2 Main findings of studies aiming at improving cognitive performances in patients with Alzheimer’s disease and mild cognitive impairment using repetitive transcranial magnetic stimulation (rTMS)
Demographic features
Authors
Grp
Cotelli et al., 2006
AD
Cotelli et al., 2008
AD
Cotelli et al., 2010
Age (y)
Gender
(%F)
15
76.6 6.0
–
12
12
5(Real)
AD5 (sham)
15 (h-f)
15 (l-f)
15 (sham)
8
75.0
77.6
75.0
77.6
65.9
68.6
68.3
75.5
–
No
Ahmed et al., 2011
AD
Bentwich et al., 2011
AD
Haffen et al., 2012
AD
1
Turriziani et al. 2012
MCI
8
Rabey et al., 2013
AD
15
6.2
5.8
6.2
5.8
5.9
6.7
4.9
4.3
75
66.6
60.0
66.6
12.5
0
66 5.7
–
Education (y)
3.1
2.6
1.3
0.4
10.9 2.2
–
20
13.6 3.7
–
Disease
duration (y)
6.0 2.0
6.8
5.7
6.4
4.8
> 6 20%
–
Brain stimulation–Study design
Diagnosis
Parameters
–
NINCDS-ADRADA
–
NINCDS- ADRADA
–
NINCDS- ADRADA
20 Hz, 90% MT,
600 ms (+ sham)
20 Hz, 90% MT,
500 ms (+ sham)
20 Hz, 100% MT,
2000 stim/s (+sham)
20 Hz, 90% MT,
1 Hz 100%
MT (+ sham)
10 Hz, 90–110%
MT, 2 s.
10 Hz, 100%
MT, 5 s
1 Hz, 90% MT;
iTBS
10 Hz, 90–110%
MT, 2 s
3.9
4.1
4.4
2.6
2
2.3
2.3
2.5
0.6
NINCDS-ADRADA
DMS-IV
NINCDS-ADRADA
–
–
Diagnostic criteria
for MCI*
DMS-IV
Brain target
No. of
sessions
Cognitive function
L/R DLPFC
1
↑: Action naming NSE: Object naming
L/R DLPFC
1
↑: Action naming (Mi); ↑: Action-object
naming (M-S)
↑: Auditory comprehension
NSE: Naming
↑: MMSE, IALD, GDS (h-f rTMS) NSE:
MMSE, ADAS-ADL, HAMILTON, NPI
L DLPFC
L/R DLPFC
Broca’s Wernicke’sareas,
L/R DLPFC L/R pSAC
L/R DLPFC
20
5
54
↑: ADAS-COG, CGIC
10
↑: MMSE, MIS, Free and Cued Recall
Test, IST, TMT NSE: Picture naming, Copy
54
↑: ADAS-COG, CGIC
L/R DLPFC
Broca’s Wernicke’sareas,
L/R DLPFC L/R pSAC
All values are expressed as mean (SD). No, number of subjects;%F, percentage of female; y, years; L, left, R, right; MCI, mild cognitive impairment; Mi, mild (Alzheimer’s disease); M-S, moderate to severe (Alzheimer’s disease); h-f, high frequency; l-f, low frequency; Hz, Herz; MT, motor threshold; DLPFC, dorsolateral prefrontal cortex; TPC, temporoparietal cortex; TC, temporal cortex; pSAC, parietal somatosensory association cortex; ↑, enhancement; NSE, no significant effect;
NINCDS-ADRDA (national institute of neurological and communicative diseases and stroke/Alzheimer’s disease and related disorders association); DMS-IV, diagnostic and statistical manual of mental disorders, 4th edition; CDR, clinical
dementia rating; MMSE, mini-mental state examination; IALD, instrumental daily living activity; GDS, geriatric depression scale; ADAS-COG, Alzheimer’s disease assessment scale–cognitive; CGIC, clinical global impression of change; NPI,
neuroropsychiatric inventory test; *, criteria of Petersen (2001).
TMS/rTMS in MCI and AD
several TMS techniques may represent a useful
additional tool for the functional evaluation of
patients with MCI and AD. Also integrated
approaches using TMS together with others neurophysiological techniques (such as high-density
EEG) have been recently proposed as promising
tools for noninvasive evaluation of subjects with
cognitive impairment.
Among the studies focusing on motor cortical
excitability parameters, the most consistent finding
is the reduction in SAI in patients with AD. The
SAI technique can also be used to monitor AD
progression and response to treatment (27). Both
in vivo and postmortem studies on cholinergic
involvement in early AD are inconclusive (111–
113), and it remains still relatively unclear how
early in the course of the disease neurochemical
and neuropathological alterations occur. On the
other hand, neurobiological changes should be
examined earlier in the disease process, at a stage
when presumably they are more relevant for the
pathogenesis of AD. Therefore, the finding that
TMS abnormalities can also be observed in
patients with early diagnosis of AD (60, 64) and in
patients with amnestic MCI-multiple domains (79)
has potentially relevant diagnostic and therapeutic
implications. In particular, identification of SAI
abnormalities occurring early in the course of AD
or even in patients with MCI will allow earlier
diagnosis and treatment with cholinergic agents.
Several TMS techniques, as well as the combination of TMS and EEG, also enable the exploration of plasticity across different brain regions
and the characterization of the functional connectivity between different neural networks. Encouraging findings, showing impaired cortical
plasticity and functional connectivity between
motor and non-motor brain regions in AD, have
been obtained.
Overall, there are several issues that should be
more carefully addressed in future studies. First,
brain atrophy is known to occur in AD, often in
the initial stages of the disease (114, 115). Nevertheless, the potential influence of regional cortical
thinning on the TMS findings has been so far not
adequately considered. However, as the effects of
TMS depend on the distance between cortex and
scalp (93, 116), cortical thinning can significantly
modify the impact of TMS (117) because of the
greater scalp-to-brain distance. Therefore, some
reported TMS abnormalities in patients with AD
might be simply related to tissue shrinkage and
brain atrophy. In a recent study (118), higher cortical excitability was found to be associated with
lower cortical thickness and lower learning ability
in healthy older adults, in agreement with the
previous reports of increased cortical excitability
in patients with AD with cortical atrophy and
cognitive deficits.
Moreover, distinct cortical regions are differently affected in AD, especially in the earlier
stages of the disease, and in non-motor cortical
areas (e.g., temporoparietal and frontal association cortices), the abnormalities may be particularly profound and occur early in the course of
the disease, while so far principally the motor
cortex has been assessed (8).
Notably, most of the TMS findings show considerable variability between studies. TMS methodological issues, age at disease onset, duration
of disease, and also genetic factors may account
for such a marked inter-study variability. In fact,
a common single nucleotide polymorphism of the
brain-derivated neurotrophic factor (BDNF) gene
due the valine-to-methionine substitution at
codon 66 (BDNF-Val66Met) is known to differentially modulate cortical plasticity (119). Moreover, functional neuroimaging showed that the
presence of Apolipoprotein E (APOE) and its e4
allele also distinctively modulate the clinical phenotype of AD (120); therefore, similar to the
presence of BDNF-Val66Met polymorphism, also
this genetic factor could influence the cortical
reactivity and the response to rTMS. Koch et al.
(121) also investigated the correlation between
motor cortical plasticity, measured with 1-Hz
rTMS, and the levels of Ab(1–42), total tau
(t-Tau), and phosphorylated tau detected in CSF
of patients with AD. These authors found that
higher CSF t-Tau levels were associated to a
stronger inhibition of the MEPs, implying that
the expected effects of the 1-Hz rTMS protocol
were more evident in patients with more pathological t-Tau CSF levels. These findings suggest
that also CSF t-Tau modulates excitatory activity
and may alter mechanisms of cortical plasticity.
As rTMS is capable of modulating cortical
excitability and inducing lasting effects, some
researchers have tried to therapeutically use this
neuromodulatory technique to improve cognitive
performances in AD. This treatment shows considerable promise to reduce cognitive impairments, but results of the initial studies have to be
considered as still preliminary at the present time.
rTMS appears to be safe in patients with AD,
even if long-term risks have not been sufficiently
considered in all studies.
There is high between-subject and withinsubject variability also in the observed rTMS
aftereffects. Stimulation parameters and study
protocol designs varied considerably in the previous studies. Single-session studies as well as
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Nardone et al.
months-lasting studies have been performed. The
typical treatment consists of daily sessions (five
times a week) for 2 weeks. Some studies (98, 100)
have explored long-term effects up to 3 months
after the end of the rTMS intervention, and these
showed the persistence of the beneficial effects on
cognitive functions. Some rTMS interventions
were of short duration; their effects seem to be
short-lasting, and need to be replicated after
longer-duration interventions (8). Moreover,
some effects were obtained after longer-lasting
applications, but not observed after a single
rTMS session (102–104).
High-frequency stimulation has been used in
most of the studies, and the intensity of stimulation ranged from 80% to 120% of the RMT.
Important methodological differences can be
observed with regard to the coil positioning and
targeted localization. The DLPFC is the most
common target for rTMS experiments and therapeutic protocols. The coil was placed 5 cm anterior from the hand motor area on the left and
right hemispheres and held parallel to the midsagittal line.
However, the 10–20 EEG system and the conventional coil placement 5 cm anterior from the
‘hand motor area hot spot’ method cannot be
considered a precise localization of this area. For
future studies, a frameless stereotaxic navigation
system based on subject’s brain MRI is strongly
recommended (122). Interestingly, bilateral stimulation was found to be necessary to produce measurable rTMS effects in some studies (102, 103).
The effects of online and off-line rTMS also may
differ significantly. Cotelli and colleagues (104)
were able to demonstrate a significant improvement in auditory sentence comprehension only
when an off-line approach was used, while they
failed to detect any significant effect on action or
subject naming in their online studies (102, 103).
Furthermore, the heterogeneity in the selection
of neuropsychological tests that measure cognitive
functions renders the findings difficult to generalize. Two global cognitive measures, the MMSE
and ADL, were used in some controlled studies
(104, 106). In both studies, MMSE and ADL did
not change in patients with severe cognitive
impairment, thus suggesting that brain plasticity
may no longer be modifiable in these patients. It
should be considered that MMSE is a simple very
basic screening test for dementia; it is not sensitive
enough to detect subtle memory deficits and did
not examine the executive functions. For future
studies, an adequate and uniform choice of
neuropsychological outcome measures would be of
great importance to enable comparison across
362
different studies. In particular, the outcome scales
commonly used in trials of pharmacological agents
for AD, such as the cognitive subscale of the
ADAS-Cog, should also be employed to examine
the therapeutic effects of rTMS (8). Several studies
evaluated the effects of rTMS on specific cognitive
functions including associative memory (123) and
memory recognition (100), while the effects on
other cognitive functions such as episodic and
working memory, psychomotor speed and executive functions have not yet been examined in controlled studies.
Also control procedures to avoid placebo effects
can be ameliorated. Therefore, in future research,
the novel sham coils that produce an identical
scalp sensory stimulation should be employed or a
control site stimulation should be performed.
In the vast majority of the performed studies,
high-frequency rTMS was applied; only in one
controlled study (100), low-frequency rTMS was
used. Therefore, even if TMS studies showed cortical hyperexcitability in patients with AD, the
therapeutic attempts by means of rTMS are
aimed at further increasing cortical excitability.
Moreover, high-frequency rTMS might not
enhance cortical excitability in patients with AD
(8). Indeed, rTMS effects depend on the state of
activity of the brain at the time of stimulation
(124). For this reason, the baseline cortical excitability should be appropriately examined before
and after therapeutic interventions. Finally, it
seems unlikely that rTMS stimulation over a single brain area may lead to a real cognitive
enhancement of patients with AD, particularly
for those patients in more advanced stages of AD
and multiple cognitive deficits (8).
Obviously, the new safety guidelines for the
application of TMS in research and clinical settings (125) should be more thoroughly applied in
all future studies.
In conclusion, several studies from the literature suggest that TMS may contribute to better
understand the changes in cortical plasticity
underlying MCI and AD, shedding light on the
pathogenesis of the neurodegenerative process,
and might also represent a promising therapeutic
tool with potentially beneficial effects on the
impaired cognitive functions.
Acknowledgment
None.
Conflict of interest
None.
TMS/rTMS in MCI and AD
References
1. GUSE B, FALKAI P, WOBROCK T. Cognitive effects of
high-frequency repetitive transcranial magnetic stimulation: a systematic review. J Neural Transm
2010;117:105–22.
2. ROSSI S, CAPPA S F, BABILONI C et al. Prefrontal [correction of Prefontal] cortex in long-term memory: an
‘interference’ approach using magnetic stimulation. Nat
Neurosci 2001;4:948–52.
3. SANDRINI M, CAPPA SF, ROSSI S, ROSSINI PM, MINIUSSI
C. The role of prefrontal cortex in verbal episodic memory: rTMS evidence. J Cogn Neurosci 2003;15:855–61.
4. MANENTI R, COTELLI M, CALABRIA M, MAIOLI C, MINIUSSI C. The role of the dorsolateral prefrontal cortex in
retrieval from long-term memory depends on strategies:
a repetitive transcranial magnetic stimulation study.
Neuroscience 2010;166:501–7.
5. MANENTI R, TETTAMANTI M, COTELLI M, MINIUSSI C,
CAPPA SF. The neural bases of word encoding and
retrieval: a fMRI-guided transcranial magnetic stimulation study. Brain Topogr 2010;22:318–32.
6. COTELLI M, MANENTI R, ZANETTI O, MINIUSSI C. Nonpharmacological intervention for memory decline.
Front Hum Neurosci 2012;6:46.
7. MANENTI R, BRAMBILLA M, PETESI M, FERRARI C, COTELLI M. Enhancing verbal episodic memory in older
and young subjects after non-invasive brain stimulation. Front Aging Neurosci 2013;5:49.
8. SPARING R, MOTTAGHY FM. Noninvasive brain stimulation with transcranial magnetic or direct current stimulation (TMS/tDCS)-From insights into human memory
to therapy of its dysfunction. Methods 2008;44:329–37.
-LLORCA H, PASCUAL-LEONE A.
9. FREITAS C, MONDRAGON
Noninvasive brain stimulation in Alzheimer’s disease:
Systematic review and perspectives for the future. Exp
Gerontol 2011;46:611–27.
10. BOGGIO PS, VALESEK CA, CAMPANHA~ C et al. Non-invasive brain stimulation to assess and modulate neuroplasticity in Alzheimer’s disease. Neuropsychol Rehabil
2011;21:703–16.
11. ZIEMANN U, LONNECKER S, STEINHOFF BJ, PAULUS W.
The effect of lorazepam on the motor cortex excitability in man. Exp Brain Res 1996;109:127–35.
12. ZIEMANN U, LONNECKER S, STEINHOFF BH, PAULUS W.
Effects of antiepileptics drugs on motor cortex excitability in humans: a transcranial magnetic stimulation
study. Ann Neurol 1996;40:367–78.
13. DI LAZZARO V, OLIVIERO A, PILATO F, SATURNO E,
DILEONE M, TONALI PA. Motor cortex hyperexcitability
to transcranial magnetic stimulation in Alzheimer’s disease; evidence of impaired glutamatergic neurotransmission? Ann Neurol 2003;53:824.
14. DI LAZZARO V, OLIVIERO A, PROFICE P et al. Ketamine
increases human motor cortex excitability to transcranial magnetic stimulation. J Physiol 2003;547:485–96.
15. HALLETT M. Transcranial magnetic stimulation and the
human brain. Nature 2000;406:147–50.
16. KOBAYASHI M, PASCUAL-LEONE A. Transcranial magnetic
stimulation in neurology. Lancet Neurol 2003;2:
145–56.
17. GROPPA S, OLIVIERO A, EISEN A et al. A practical guide
to diagnostic transcranial magnetic stimulation: a
report of an IFCN committee. Clin Neurophysiol
2012;123:858–82.
18. DELVENDAHL I, JUNG NH, KUHNKE NG, ZIEMANN U,
MALL V. Plasticity of motor threshold and
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
motor-evoked potential amplitude – a model of intrinsic synaptic plasticity in human motor cortex? Brain
Stimul 2012;5:586–93.
ROTHWELL JC, HALLETT M, BERARDELLI A, EISEN A,
ROSSINI P, PAULUS W. Magnetic stimulation: motor
evoked potentials. The international federation of clinical neurophysiology. Electroencephalogr Clin Neurophysiol Suppl 1999;52:97–103.
FERBERT A, PRIORI A, ROTHWELL JC, DAY BL, COLEBATCH JG, MARSDEN CD. Interhemispheric inhibition
of the human motor cortex. J Physiol 1992;453:525–46.
ROSSINI PM, BARKER AT, BERARDELLI A et al. Non
invasive electrical and magnetic stimulation of the
brain, spinal cord and roots: basic principles and procedures for routine clinical application: report of IFCN
committee. Electroencephalogr Clin Neurophysiol
1994;91:79–92.
KUJIRAI T, CARAMIA MD, ROTHWELL JC et al. Corticocortical inhibition in human motor cortex. J Physiol
1993;471:501–19.
PAULUS W, CLASSEN J, COHEN LG et al. State of the
art: pharmacologic effects on cortical excitability measures tested by transcranial magnetic stimulation. Brain
Stimul 2008;1:151–63.
ZIEMANN U, PAULUS W, NITSCHE MA et al. Consensus:
motor cortex plasticity protocols. Brain Stimul
2008;1:164–82.
TOKIMURA H, DI LAZZARO V, TOKIMURA Y et al. Short
latency inhibition of human hand motor cortex by
somatosensory input from the hand. J Physiol
2000;523:503–13.
DI LAZZARO V, OLIVIERO A, PROFICE P et al. Muscarinic receptor blockade has differential effects on the
excitability of intracortical circuits in the human motor
cortex. Exp Brain Res 2000;135:455–61.
DI LAZZARO V, OLIVIERO A, PILATO F et al. Neurophysiological predictors of long term response to AChE
inhibitors in AD patients. J Neurol Neurosurg Psychiatry 2005;76:1064–9.
FUJIKI M, HIKAWA T, ABE T, ISHII K, KOBAYASHI H.
Reduced short latency afferent inhibition in diffuse
axonal injury patients with memory impairment. Neurosci Lett 2006;405:226–30.
SAILER A, MOLNAR GF, PARADISO G, GUNRAJ CA, LANG
AE, CHEN R. Short and long latency afferent inhibition
in Parkinson’s disease. Brain 2003;26:1883–94.
THUT G, IVES JR, KAMPMANN F, PASTOR MA, PASCUALLEONE A. A new device and protocol for combining
TMS and online recordings of EEG and evoked potentials. J Neurosci Methods 2005;141:207–17.
IVES JR, ROTENBERG A, POMA R, THUT G, PASCUALLEONE A. Electroencephalographic recording during
transcranial magnetic stimulation in humans and animals. Clin Neurophysiol 2006;117:1870–5.
THUT G, PASCUAL-LEONE A. A review of combined
TMS-EEG studies to characterize lasting effects of
repetitive TMS and assess their usefulness in cognitive
and clinical neuroscience. Brain Topogr 2010;22:219–
32.
BABILONI C, INFARINATO F, AUJARD F. Effects of pharmacological agents, sleep deprivation, hypoxia and
transcranial magnetic stimulation on electroencephalographic rhythms in rodents: toward translational challenge models for drug discovery in Alzheimer’s disease.
Clin Neurophysiol 2013;124:437–51.
CHEN R, UDUPA K. Measurement and modulation of
plasticity of the motor system in humans using trans-
363
Nardone et al.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
364
cranial magnetic stimulation. Mot Control 2009;13:
442–53.
STEFAN K, KUNESCH E, BENECKE R, COHEN LG, CLASSEN J. Mechanisms of enhancement of human motor
cortex excitability induced by interventional paired
associative stimulation. J Physiol 2002;543:699–708.
QUARTARONE A, RIZZO V, BAGNATO S et al. Rapid-rate
paired associative stimulation of the median nerve and
motor cortex can produce long-lasting changes in
motor cortical excitability in humans. J Physiol
2006;575:657–70.
PASCUAL-LEONE A, VALLS-SOLE J, BRASIL-NETO JP. Akinesia in Parkinson’s disease. II. Effects of subthreshold
repetitive transcranial motor cortex stimulation. Neurology 1994;44:892–8.
LEE L, SIEBNER HR, ROWE JB et al. Acute remapping
within the motor system induced by low-frequency
repetitive transcranial magnetic stimulation. J Neurosci
2003;2003(23):5308–18.
BERARDELLI A, INGHILLERI M, ROTHWELL JC et al.
Facilitation of muscle evoked responses after repetitive
cortical stimulation in man. Exp Brain Res
1998;122:79–84.
PASCUAL-LEONE A, TORMOS JM, KEENAN J, TARAZONA
F, CANETE C, CATALA MD. Study and modulation of
human cortical excitability with transcranial magnetic
stimulation. J Clin Neurophysiol 1998;15:333–43.
DI LAZZARO V, PILATO F, SATURNO E et al. Theta-burst
repetitive transcranial magnetic stimulation suppresses
specific excitatory circuits in the human motor cortex.
J Physiol 2005;565:945–50.
HUANG YZ, EDWARDS MJ, ROUNIS E, BHATIA KP,
ROTHWELL JC. Theta burst stimulation of the human
motor cortex. Neuron 2005;45:201–6.
DE CARVALHO M, DE MENDONC
ß A A, MIRANDA PC, GARCIA C, LUIS MC. Magnetic stimulation in Alzheimer’s
disease. J Neurol 1997;244:304–47.
PEPIN JL, BOGACZ D, DE PASQUA V, DELWAIDE PJ.
Motor cortex inhibition is not impaired in patients with
Alzheimer’s disease: evidence from paired transcranial
magnetic stimulation. J Neurol Sci 1999;170:119–23.
ALAGONA G, BELLA R, FERRI R et al. Transcranial
magnetic stimulation in Alzheimer disease: motor cortex excitability and cognitive severity. Neurosci Lett
2001;314:57–60.
ALAGONA G, FERRI R, PENNISI G et al. Motor cortex
excitability in Alzheimer’s disease and in subcortical
ischemic vascular dementia. Neurosci Lett 2004;362:
95–8.
DI LAZZARO V, OLIVIERO A, TONALI PA et al. Noninvasive in vivo assessment of cholinergic cortical circuits in
AD using transcranial magnetic stimulation. Neurology
2002;59:392–7.
DI LAZZARO V, OLIVIERO A, PILATO F et al. Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer’s disease. J Neurol Neurosurg
Psychiatry 2004;75:555–9.
DI LAZZARO V, PILATO F, DILEONE M et al. Functional
evaluation of cerebral cortex in dementia with Lewy
bodies. Neuroimage 2007;37:422–9.
DI LAZZARO V, PILATO F, DILEONE M et al. In vivo functional evaluation of central cholinergic circuits in vascular dementia. Clin Neurophysiol 2008;119:2494–500.
MARTORANA A, STEFANI A, CALMIERI MG et al. L-dopa
modulates motor cortex excitability in Alzheimer’s disease patients. J Neural Transm 2008;115:1313–9.
52. MARTORANA A, MORI F, ESPOSITO Z. Dopamine modulates cholinergic cortical excitability in Alzheimer’s
disease patients. Neuropsychopharmacology 2009;34:
2323–8.
53. INGHILLERI M, CONTE A, FRASCA V et al. Altered
response to rTMS in patients with Alzheimer’s disease.
Clin Neurophysiol 2006;117:103–9.
-PUNNONEN S
54. JULKUNEN P, JAUHIAINEN AM, WESTEREN
et al. Navigated TMS combined with EEG in mild cognitive impairment and Alzheimer’s disease: a pilot
study. J Neurosci Methods 2008;172:270–6.
55. HOEPPNER J, WEGRZYN M, THOME J et al. Intra- and
inter-cortical motor excitability in Alzheimer’s disease.
J Neural Transm 2012;119:605–12.
€ KJ, MESKEA U, WEILLER C. Motor cor56. LIEPERT J, BAR
tex disinhibition in Alzheimer’s disease. Clin Neurophysiol 2001;112:1436–41.
57. PENNISI G, ALAGONA G, FERRI R et al. Motor cortex
excitability in Alzheimer disease: one year follow-up
study. Neurosci Lett 2002;329:293–6.
58. FERRERI F, PAURI F, PASQUALETTI P, FINI G, DAL
FORNO G, ROSSINI PM. Motor cortex excitability in
Alzheimer’s disease: a transcranial magnetic stimulation
study. Ann Neurol 2003;53:102–8.
59. NARDONE R, BRATTI A, TEZZON F. Motor cortex inhibitory circuits in dementia with Lewy bodies and in Alzheimer’s disease. J Neural Transm 2006;113:1679–84.
60. NARDONE R, BERGMANN J, KRONBICHLER M et al.
Abnormal short latency afferent inhibition in early Alzheimer’s disease: a transcranial magnetic demonstration. J Neural Transm 2008;115:1557–62.
61. SAKUMA K, MURAKAMI T, NAKASHIMA K. Short latency
afferent inhibition is not impaired in mild cognitive
impairment. Clin Neurophysiol 2007;118:1460–3.
62. BATTAGLIA F, WANG HY, GHILARDI MF et al. Cortical
plasticity in Alzheimer’s disease in humans and
rodents. Biol Psychiatry 2007;62:1405–12.
63. ALBERICI A, BONATO C, CALABRIA M et al. The contribution of TMS to frontotemporal dementia variants.
Acta Neurol Scand 2008;118:275–80.
64. OLAZARAN
J, PRIETO J, CRUZ I, ESTEBAN A. Cortical
excitability in very mild Alzheimer’s disease: a longterm follow-up study. J Neurol 2010;257:2078–85.
65. PIERANTOZZI M, PANELLA M, PALMIERI MG et al. Different TMS patterns of intracortical inhibition in early
onset Alzheimer dementia and frontotemporal dementia. Clin Neurophysiol 2004;15:2410–8.
66. PERRETTI A, GROSSI D, FRAGASSI N et al. Evaluation
of the motor cortex by magnetic stimulation in
patients with Alzheimer disease. J Neurol Sci
1996;135:31–7.
€ A
€ S et al. New
€ ONEN
€
M, MA€ ATT
67. NISKANEN E, KON
insights into Alzheimer’s disease progression: a combined TMS and structural MRI study. PLoS ONE
2011;6:e26113.
68. LOWE SL, BOWEN DM, FRANCIS PT, NEARY D. Ante
mortem cerebral amino acid concentrations indicate
selective degeneration of glutamate-enriched neurons in
Alzheimer’s disease. Neuroscience 1990;38:571–7.
69. LOWE SL, FRANCIS PT, PROCTER AW, PALMER AM,
DAVISON AN, BOWEN DM. Gamma-aminobutyric acid
concentrations in brain tissue at two stages of Alzheimer’s disease. Brain 1988;111:785–99.
70. FARLOW MR. NMDA receptor antagonists: a new therapeutic approach for Alzheimer’s disease. Geriatrics
2004;59:22–7.
TMS/rTMS in MCI and AD
71. HYND MR, SCOTT HL, DODD PR. Glutamate-mediated
excitotoxicity and neurodegeneration in Alzheimer’s
disease. Neurochem Int 2004;45:583–95.
72. TSUTSUMI R, HANAJIMA R, HAMADA M et al. Reduced
interhemispheric inhibition in mild cognitive impairment. Exp Brain Res 2012;218:21–6.
73. DI LAZZARO V, PILATO F, DILEONE M et al. In vivo cholinergic circuit evaluation in frontotemporal and Alzheimer dementias. Neurology 2006;66:1111–3.
74. DAVIES P, MALONEY AJ. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 1976;2:1403.
75. WHITEHOUSE PJ, PRICE DL, STRUBLE RG, CLARK AW,
COYLE JT, DELON MR. Alzheimer’s disease and senile
dementia: loss of neurons in the basal forebrain. Science 1982;215:1237–9.
76. COYLE JT, PRICE DL, DELONG MR. Alzheimer’s disease: a disorder of cortical cholinergic innervation. Science 1983;219:1184–90.
77. MARRA C, QUARANTA D, PROFICE P et al. Central cholinergic dysfunction measured ‘in vivo’ correlates with
different behavioral disorders in Alzheimer’s disease
and dementia with Lewy body. Brain Stimul.
2012;5:533–8.
78. PETERSEN RC, DOODY R, KURZ A et al. Current concepts in mild cognitive impairment. Arch Neurol
2001;58:1985–92.
79. NARDONE R, BERGMANN J, CHRISTOVA M et al. Short
latency afferent inhibition differs among the subtypes
of mild cognitive impairment. J Neural Transm
2012;119:463–71.
80. DI LORENZO F, MARTORANA A, PONZO V et al. Cerebellar theta burst stimulation modulates short latency
afferent inhibition in Alzheimer’s disease patients.
Front Aging Neurosci 2013;5:2.
€ A
€ S et al. Motor cor81. FERRERI F, PASQUALETTI P, MA€ ATT
tex excitability in Alzheimer’s disease: a transcranial
magnetic stimulation follow-up study. Neurosci Lett
2011;492:94–8.
82. CARPENTER P, LAVENU I, PASQUIER F, STERLING M. Alzheimer’s disease and frontotemporal dementia are differentiated by discriminant analysis applied to (99 m)
Tc HmPAO SPECT data. J Neurol Neurosurg Psychiatry 2000;69:661–3.
83. NOBILI F, KOULIBALY M, VITALI P et al. Brain perfusion
follow-up in Alzheimer’s patients during treatment with
acetylcholinesterase
inhibitors.
J
Nucl
Med
2002;43:983–90.
84. TREBBASTONI A, GILIO F, D’ANTONIO F et al. Chronic
treatment with rivastigmine in patients with Alzheimer’s disease: a study on primary motor cortex excitability tested by 5 Hz-repetitive transcranial magnetic
stimulation. Clin Neurophysiol 2012;123:902–9.
85. KOCH G, ESPOSITO Z, CODECA C et al. Altered dopamine modulation of LTD-like plasticity in Alzheimer’s
disease patients. Clin Neurophysiol 2011;122:703–7.
86. KOCH G, DI LORENZO F, BONNI S, PONZO V, CALTAGIRONE C, MARTORANA A. Impaired LTP- but not LTD
in Alzheimer’s disease patients. J Alzheimers Dis
2012;31:593–9.
87. TERRANOVA C, SANTANGELO A, MORGANTE F et al.
Impairment of sensory-motor plasticity in mild Alzheimer’s disease. Brain Stimul 2013;6:62–6.
€
€ ONEN
€
€
M, PA€ AKK
ONEN
88. JULKUNEN P, JAUHIAINEN AM, KON
A, KARHU J, SOININEN H. Combining transcranial
magnetic stimulation and electroencephalography may
contribute to assess the severity of Alzheimer’s disease.
Int J Alzheimers Dis 2011;2011:654794.
89. BONNI S, LUPO F, LO GERFO E et al. Altered parietalmotor connections in Alzheimer’s disease patients.
J Alzheimers Dis 2013;33:525–33.
90. BRACCO L, GIOVANNELLI F, BESSI V et al. Mild cognitive impairment: loss of linguistic task-induced changes
in motor cortex excitability. Neurology 2009;72:928–34.
91. NITSCHE MA, PAULUS W. Excitability changes induced
in the human motor cortex by weak transcranial direct
current stimulation. J Physiol 2000;527:633–9.
92. FITZGERALD PB, FOUNTAIN S, DASKALAKIS ZJ. A comprehensive review of the effects of rTMS on motor
excitability and inhibition. Clin Neurophysiol
2006;117:2584–96.
93. WAGNER T, VALERO-CABRE A, PASCUAL-LEONE A. Noninvasive human brain stimulation. Annu Rev Biomed
Eng 2007;9:527–65.
94. HOOGENDAM M, RAMAKERS GM, DI LAZZARO V. Physiology of repetitive transcranial magnetic stimulation of
the human brain. Brain Stimul 2010;3:95–118.
95. WANG L, ZANG Y, HE Y et al. Changes in hippocampal
connectivity in the early stages of Alzheimer’s disease:
evidence from resting state fMRI. Neuroimage
2006;31:496–504.
96. BAI F, ZHANG Z, WATSON DR et al. Abnormal functional
connectivity of hippocampus during episodic memory
retrieval processing network in amnestic type mild cognitive impairment. Biol Psychiatry 2009;65:951–8.
97. SPERLING RA, DICKERSON BC, PIHLAJAMAKI M et al.
Functional alterations in memory networks in early Alzheimer’s disease. Neuromolecular Med 2010;12:27–43.
98. GRADY CL, MCINTOSH AR, BEIG S, CRAIK FI. An
examination of the effects of stimulus type, encoding
task, and functional connectivity on the role of right
prefrontal cortex in recognition memory. Neuroimage
2001;14:556–71.
99. SMITH GE, PANKRATZ VS, NEGASI S et al. A plateau in
pre-Alzheimer memory decline: evidence for compensatory mechanisms? Neurology 2007;69:133–9.
100. TURRIZIANI P, SMIRNI D, ZAPPALA G, MANGANO GR,
OLIVERI M, CIPOLOTTI L. Enhancing memory performance with rTMS in healthy subjects and individuals
with Mild Cognitive Impairment: the role of the right
dorsolateral prefrontal cortex. Front Hum Neurosci
2012;6:62.
101. FREGNI F, PASCUAL-LEONE A. Technology insight: noninvasive brain stimulation in neurology-perspectives on
the therapeutic potential of rTMS and tDCS. Nat Clin
Pract Neurol 2007;3:383–93.
102. COTELLI M, MANENTI R, CAPPA SF, GEROLDI C,
ZANETTI O, ROSSINI PM. Effect of transcranial magnetic stimulation on action naming in patients with
Alzheimer disease. Arch Neurol 2006;63:1602–4.
103. COTELLI M, MANENTI R, CAPPA SF, ZANETTI O, MINIUSSI C. Transcranial magnetic stimulation improves
naming in Alzheimer disease patients at different stages
of cognitive decline. Eur J Neurol 2008;15:1286–92.
104. COTELLI M, CALABRIA M, MANENTI R et al. Improved
language performance in Alzheimer disease following
brain stimulation. J Neurol Neurosurg Psychiatry
2011;82:794–7.
105. COTELLI M, CALABRIA M, MANENTI R et al. Brain stimulation improves associative memory in an individual
with amnestic mild cognitive impairment. Neurocase
2012;18:17–23.
106. AHMED MA, DARWISH ES, KHEDR EM, EL SEROGY
YM, ALI AM. Effects of low versus high frequencies
of repetitive transcranial magnetic stimulation and
365
Nardone et al.
107.
108.
109.
110.
111.
112.
113.
114.
115.
366
functional excitability in Alzheimer’s dementia. J Neurol 2011;259:83–92.
BENTWICH J, DOBRONEVSKY E, AICHENBAUM S et al.
Beneficial effect of repetitive transcranial magnetic
stimulation combined with cognitive training for the
treatment of Alzheimer’s disease: a proof of concept
study. J Neural Transm 2009;118:463–71.
RABEY JM, DOBRONEVSKY E, AICHENBAUM S, GONEN O,
MARTON RG, KHAIGREKHT M. Repetitive transcranial
magnetic stimulation combined with cognitive training
is a safe and effective modality for the treatment of
Alzheimer’s disease: a randomized, double-blind study.
J Neural Transm 2013;120:813–9.
HAFFEN E, CHOPARD G, PRETALLI JB et al. A case
report of daily prefrontal repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment
for Alzheimer disease. Brain Stimul 2012;5:264–6.
ROSSI S, ROSSINI PM. TMS in cognitive plasticity and
the potential for rehabilitation. Trends Cogn Sci
2004;8:273–9.
€
€A
€ T et al. Brain aceRINNE JO, KAASINEN V, JARVENP
A
tylcholinesterase activity in mild cognitive impairment
and early Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2003;74:113–5.
HERHOLZ K, WEISENBACH S, ZUNDORF G, LENZ O,
€
SCHRODER
H, BAUER B. In-vivo study of acetylcholineesterase in basal forebrain, amygdala, and cortex in mild to
moderate Alzheimer disease. Neuroimage 2004;21:136–
43.
STOKIN GB, LILLO C, FALZONE TL et al. Axonopathy
and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 2005;307:1282–8.
DICKERSON B, DICKERSON C, BAKKOUR A et al. The
cortical signature of Alzheimer’s disease: regionally
specific cortical thinning relates to symptom severity in
very mild to mild AD dementia and is detectable in
asymptomatic amyloid-positive individuals. Cereb Cortex 2009;19:497–510.
BAKKUR A, MORRIS JC, DICKERSON BC. The cortical
signature of prodromal AD: regional thinning predicts
mild AD dementia. Neurology 2009;72:1048–55.
116. WAGNER T, GANGITANO M, ROMERO R et al. Intracranial measurement of current densities induced by transcranial magnetic stimulation in the human brain.
Neurosci Lett 2004;354:91–4.
117. WAGNER T, EDEN U, FREGNI F et al. Transcranial magnetic stimulation and brain atrophy: a computer-based
human brain model study. Exp Brain Res 2008;186:
539–50.
€
118. LIST J, KUBKE
JC, LINDENBERG R et al. Relationship
between excitability, plasticity and thickness of the
motor cortex in older adults. Neuroimage, 2013;83:
809–16.
119. CHEERAN B, TALELLI P, MORI F et al. A common polymorphism in the brain-derived neurotrophic factor
gene (BDNF) modulates human cortical plasticity and
the response to rTMS. J Physiol 2008;586:5717–25.
120. WOLK DA, DICKERSON BC. Apolipoprotein E (APOE)
genotype has dissociable effects on memory and attentional-executive network function in Alzheimer’s disease. Proc Natl Acad Sci USA 2010;107:10256–61.
121. KOCH G, ESPOSITO Z, KUSAYANAGI H et al. CSF tau
levels influence cortical plasticity in Alzheimer’s disease
patients. J Alzheimers Dis 2011;26:181–6.
€
122. HERWIG U, PADBERG F, UNGER J, SPITZER M, SCHONFELDT-LECUONA C. Transcranial magnetic stimulation
in therapy studies: examination of the reliability of
‘standard’ coil positioning by neuronavigations. Biol
Psychiatry 2001;50:58–61.
-FAZ D, JUNQUE
C et al.
123. SOLE -PADULLES
C, BARTRES
Repetitive transcranial magnetic stimulation effects on
brain function and cognition among elders with memory dysfunction. A randomized sham-controlled study.
Cereb Cortex 2006;16:1487–93.
124. SILVANTO J, PASCUAL-LEONE A. State-dependency of
transcranial magnetic stimulation. Brain Topogr
2008;21(1):1–10.
125. ROSSI S, HALLETT M, ROSSINI PM, PASCUAL-LEONE A,
Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of
transcranial magnetic stimulation in clinical practice
and research. Clin Neurophysiol 2009;120:2008–39.