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DEMENTIAS - REVIEW ARTICLE
Transcranial magnetic stimulation in Alzheimer’s disease:
a neurophysiological marker of cortical hyperexcitability
Giovanni Pennisi •Raffaele Ferri •Giuseppe Lanza •Mariagiovanna Cantone •
Manuela Pennisi •Valentina Puglisi •Giulia Malaguarnera •Rita Bella
Received: 4 September 2010 / Accepted: 29 November 2010 / Published online: 5 January 2011
ÓSpringer-Verlag 2010
Abstract Recently, neuropathological studies have
shown an important motor cortex involvement in Alzhei-
mer’s disease (AD), even in its early stages, despite the
lack of clinically evident motor deficit. Transcranial mag-
netic stimulation (TMS) studies have demonstrated that
cortical excitability is enhanced in AD patients. This cor-
tical hyperexcitability is believed to be a compensatory
mechanism to execute voluntary movements, despite the
progressive impairment of associative cortical areas.
At present, it is not clear if these motor cortex excit-
ability changes might be the expression of an involvement
of intracortical excitatory glutamatergic circuits or an
impairment of inhibitory cholinergic and, to a lesser extent,
gabaergic activity. Although the main hypothesis for the
pathogenesis of AD remains the degeneration of the basal
forebrain cholinergic neurons, the development of specific
TMS protocols, such as the paired-pulse TMS and the
study of the short-latency afferent inhibition, points out
the role of other neurotransmitters, such as gamma-
amino-butyric acid, glutamate and dopamine. The potential
therapeutic effect of repetitive TMS in restoring or com-
pensating damaged cognitive functions, might become a
possible rehabilitation tool in AD patients. Based on
different patterns of cortical excitability, TMS may be
useful in discriminating between physiological brain aging,
mild cognitive impairment, AD and other dementing dis-
orders. The present review provides a perspective of these
TMS techniques by further understanding the role of dif-
ferent neurotransmission pathways and plastic remodelling
of neuronal networks in the pathogenesis of AD.
Keywords Transcranial magnetic stimulation
Cortical excitability Aging Alzheimer’s disease
Neurotransmission Neuroplasticity
Transcranial magnetic stimulation in Alzheimer’s
disease: an overview
Alzheimer’s disease (AD) is a neurodegenerative disorder
clinically characterized by a progressive cognitive decline
that affects memory and other cognitive functions, as well
as mood and behavior (Borson and Raskind 1997). Positron
emission tomography of regional cerebral metabolism
revealed that the posterior associative areas are the first to
be affected, while the frontal areas become affected in the
following stages (Friedland et al. 1985). Indeed, memory
disturbances appear early: first, the ability to learn and
retrieve information is affected; later, impairment in recog-
nition memory and attention occurs (Morris et al. 2001;
Tales et al. 2002). With the progression of the disease,
other neurological symptoms and signs become evident
(Becker et al. 1994); for instance, abnormal motor mani-
festations, such as gait disturbances, bilateral spasticity at
lower limbs, myoclonus and presence of an extensor
plantar response are frequently observed in advanced
phases of AD (Funkenstein et al. 1993). Such a delayed
involvement of the motor system has been previously
G. Pennisi (&)G. Lanza M. Cantone V. Puglisi
G. Malaguarnera R. Bella
Department of Neuroscience, University of Catania,
Catania, Italy
e-mail: pennigi@unict.it
R. Ferri
Department of Neurology I.C., Oasi Institute for Research on
Mental Retardation and Brain Aging (IRCCS), Troina, Italy
M. Pennisi
Department of Chemistry, University of Catania, Catania, Italy
123
J Neural Transm (2011) 118:587–598
DOI 10.1007/s00702-010-0554-9
explained by a smaller burden of neuropathological chan-
ges in the motor cortices compared with other brain areas
(Rogers and Morrison 1985; Arnold et al. 1991). However,
recent neuropathological studies have shown that the den-
sity of neurofibrillary tangles and senile plaques in the
motor cortex is approximately equivalent to other areas
considered to be specific targets for AD abnormalities
(Suva et al. 1999). These features suggest that the primary
motor cortex (M1) is involved in the neurodegenerative
process (Pepin et al. 1999) presumably at the level of large
cortical pyramidal neurons (Hardy et al. 1986).
Although the involvement of multiple neurotransmitter
systems is likely to occur in the pathogenesis of AD,
the most accepted hypothesis is that of the degeneration of
the basal forebrain cholinergic neurons, especially of the
Meynert’s nucleus (Bartus et al. 1982; Kasa et al. 1997),
which provides the major cholinergic input to hippocampal
and cortical regions (Davies and Maloney 1976; White-
house et al. 1981). The consequent decreased cholinergic
neurotransmission is thought to be related to amyloid
deposition and plaque formation (Geula 1998), phenomena
linked to memory loss and cognitive impairment (Perry
et al. 1978; Mesulam et al. 1983). Mesulam et al. (2004)
demonstrated that neurodegeneration is a very early event
in the course of the continuum that leads from aging to
mild cognitive impairment (MCI) and AD, although there
are only few in vivo studies and most of these changes have
been described in brains of late-stage AD. Muscarinic
cholinergic receptors and cholinergic terminals are present
in the M1 area (Lidow et al. 1989), suggesting that the
cholinergic deficit in AD could modify excitability and
function of the motor system (Liepert et al. 2001). These
data led several investigators to study cortical excitability
by means of transcranial magnetic stimulation (TMS).
TMS is a non invasive neurophysiological method spe-
cifically able to evaluate the primary motor cortex and the
cortico-spinal tract. In recent years, TMS and related
techniques have been used for studying patterns of cortical
excitability in normal (Peinemann et al. 2001; Disterhoft
and Oh 2007) and pathological brain aging (Ferreri et al.
2003; Rossini et al. 2007; Kobayashi and Pascual-Leone
2003). A single TMS pulse applied over the M1 elicits a
motor evoked potential (MEP) in the contralateral target
muscles (Di Lazzaro et al. 2001). The minimal intensity to
induce a MEP at rest with an amplitude of about 50 lV
with a probability of 50% in a stimulation sequence defines
the motor threshold at rest (rMT) (Rossini et al. 1994a,b).
Resting MT reflects the site of maximal density and
excitability of excitatory interneurons and corticospinal
neurons (‘‘hot spot’’) (Rossini et al. 2007). MEP recorded
during a voluntary contraction of the target muscle is fol-
lowed by a suppression of the electromyographic activity, a
phenomenon called cortical silent period (CSP) which
reflects after an early phase of spinal origin, the activation of
inhibitory cortical interneurons mainly mediated by gamma-
amino-butyric acid (GABA)-B transmission (Cantello et al.
1992; Werhahn et al. 1999).
Intracortical inhibitory and excitatory mechanisms can
be tested by a paired-pulse TMS (pp-TMS) in which a
conditioning subthreshold stimulus precedes a supra-
threshold test stimulus by a programmable interstimulus
interval (ISI). The amplitude variation of the test MEP
allows the evaluation of inhibitory and facilitatory intra-
cortical phenomena, which are likely to be mediated by
GABA-A and glutamate, respectively (Kujirai et al. 1993;
Ziemann 2004). At short ISI (1-4 ms), the conditioning
stimulus determines an intracortical inhibition (ICI) with
respect to the test stimulus, whereas at longer ISI ([5 ms),
the effect is an intracortical facilitation (ICF). ICI is
attributed to an activation of GABA-A neuronal system
transmission, whereas ICF to both gabaergic and gluta-
matergic influences (Abbruzzese and Trompetto 2002).
Using the pp-TMS technique, inhibitory/facilitatory curves
at various ISI reflect M1 excitability.
If an electric conditioning pulse is applied on the median
nerve at wrist and precedes the cortical TMS test pulse by
20–25 ms (a time compatible with the activation of the
primary sensorimotor cortex), the resulting MEPs are
generally inhibited. This phenomenon, termed short-
latency afferent inhibition (SAI), is cortical in origin
(Mariorenzi et al. 1991; Stefan et al. 2000; Tokimura et al.
2000) and considered as a putative marker of central cho-
linergic activity because it is abolished by scopolamine, a
potent muscarinic antagonist (Di Lazzaro et al. 2000).
Single TMS pulses delivered in trains are the principle
of repetitive TMS (rTMS), an approach that can transiently
influence the function of stimulated and connected brain
areas (Paus et al. 1997; Strafella et al. 2001), mainly
depending on the frequency of stimulation. Repetitive TMS
at high frequency (C5 Hz) transiently enhances motor
excitability (Pascual-Leone et al. 1994), whereas slow
rTMS (1 Hz) transiently depresses excitability (Chen et al.
1997), although both frequencies of stimulation may have
similar positive effects in some pathological conditions,
depending on the site of stimulation (Fitzgerald et al.
2003). Repetitive TMS might have therapeutic and reha-
bilitative applications, since the effects of repeated sessions
may persist in time (Rossini et al. 2007). Repetitive TMS
as a therapeutic approach has been suggested for psychi-
atric disorders (Chibbaro et al. 2005; Scho
¨nfeldt-Lecuona
et al. 2010). The mechanisms of these changes are not
clear, but seem to be related to synaptic long-term poten-
tiation (LTP) and long-term depression (LTD) in the cen-
tral nervous system. In an experimental model of cortical
plasticity in humans, Ziemann et al. (1998) argued that
plasticity involves rapid downregulation of GABA-related
588 G. Pennisi et al.
123
inhibitory circuits and short-term changes in synaptic
efficacy dependent on Na
?
and Ca
??
channels. The rTMS-
induced long-lasting ([60 min) reduction in ICI involved
N-methyl-D-aspartate acid receptor (NMDAR) activation
and was probably related to LTP-like mechanism. LTD is
also predominantly mediated by activation of synaptic
NMDAR or by metabotropic glutamate receptors (mGluR)
at the level of the hippocampal CA3:CA1 synapses
(Gladding et al. 2009). Other forms of LTD can also be
induced in the hippocampus and other brain areas that are
independent of NMDAR and mGluR activation (Berretta
and Cherubini 1998). Furthermore, LTD regulation can be
dependent on nonglutamatergic receptors, such as adeno-
sine receptors (de Mendonc¸a et al. 1997; Kemp and Bashir
1999), adrenergic receptors and muscarinic receptors
(Kirkwood et al. 1999).
Cortical excitability to transcranial magnetic
stimulation in Alzheimer’s disease
In recent years, many studies were carried out with the aim
to understand better the changes in motor cortex excit-
ability in AD patients by means of TMS techniques;
however, they did not produce converging findings.
Table 1shows a list of selected peer-reviewed articles on
cortical excitability to TMS in AD patients, compared to
age-matched control subjects.
Motor threshold and cortical silent period
in Alzheimer’s disease
Most studies reported that rMT is generally reduced in AD,
compared to healthy age-matched subjects, and this was
interpreted to be a marker of increased motor cortex
excitability (de Carvalho et al. 1997; Pepin et al. 1999;
Alagona et al. 2001,2004; Pennisi et al. 2002; Di Lazzaro
et al. 2002,2004,2006; Inghilleri et al. 2006; Di Lazzaro
et al. 2007; Martorana et al. 2008,2009). Other reports
have found a tendency towards a reduced rMT although
without statistically significant difference (Liepert et al.
2001; Ferreri et al. 2003; Nardone et al. 2006; Sakuma
et al. 2007; Battaglia et al. 2007; Nardone et al. 2008;
Alberici et al. 2008; Olazara
´n et al. 2010), whereas two
studies noted no difference in rMT between AD patients
and controls (Pierantozzi et al. 2004; Julkunen et al. 2008)
and one found increased rMT in AD (Perretti et al. 1996).
Ten of these studies (de Carvalho et al. 1997; Pennisi
et al. 2002; Ferreri et al. 2003; Alagona et al. 2001,2004;
Pierantozzi et al. 2004; Sakuma et al. 2007; Nardone et al.
2008; Alberici et al. 2008; Martorana et al. 2008) obtained
the rMT by increasing the stimulator output intensity by
5% steps, according to internationally established standards
(Rossini et al. 1994a; Rothwell et al. 1999); other studies
did not specify the measurement method employed
(Perretti et al. 1996; Liepert et al. 2001; Di Lazzaro et al.
2002,2004,2006; Inghilleri et al. 2006; Battaglia et al.
2007; Nardone et al. 2008; Olazara
´n et al. 2010), whereas
four studies used 1% steps (Pepin et al. 1999; Di Lazzaro
et al. 2007; Julkunen et al. 2008; Martorana et al. 2009).
This heterogeneity in methodological procedure may have
contributed to affect the significance of the different rMT
values found in the studies, since the difference in rMT
between AD and controls can be subtle (i.e., Martorana
et al. 2009).
In 1996, Perretti et al. (1996) noted increased rMT and
reduced CSP in 6 of 15 AD patients, compared to controls,
suggesting that loss or dysfunction of motor cortex neurons
may occur in AD before clinical signs become evident.
However, 5 of these 6 patients were at the most advanced
stage of the disease with neuroradiological evidence of
severe cortical atrophy that involves an increase in the
distance between the stimulating magnetic coil and the
brain cortical surface. Moreover, rMT values were not
adjusted for the scalp–cortex distance and, as a conse-
quence, they do not provide an accurate index of cortical
excitability (Stokes et al. 2007) because the effect of TMS
is inversely proportioned to the distance from the stimu-
lating coil (Jalinous 1991). One year later, it was reported
that increased motor cortical excitability could be related to
a degeneration of inhibitory gabaergic terminals (de
Carvalho et al. 1997). This finding could not be explained
by an abnormal spinal motor neuron activity in AD patients
because spinal excitability, tested with H reflex and F
waves, was not increased. Post-synaptic changes in the
GABA-A receptors might also affect gabaergic transmis-
sion, since alterations in the GABA-A receptor complex
have been observed in the enthorinal cortex and in other
regions of AD patients’ brains (Jansen et al. 1990). In a
following study by Alagona et al. (2001) in 21 patients
enrolled at different stage of AD, it was found that the
reduction of rMT correlates with the severity of the dis-
ease. So, the more severe stage could represent the elec-
trophysiological aspect of synapse loss with consequent
deficient inhibitory control, as supported by the significant
reduction of CSP in patients but not in controls. However,
it can not be excluded that the methodology employed for
measuring CSP in this study may have contributed to the
observed CSP reduction. Indeed, Alagona et al. (2001)
elicited CSP with a circular coil and at a stimulus intensity
of 30% above rMT; therefore, given the well-known
dependence of CSP duration on stimulus intensity and type
of stimulating coil (Kimiskidis et al. 2005), this approach
might lead to factitious CSP changes. The construction of
stimulus–response curves of CSP using a figure-of-eight
coil and a wide range of stimulus intensities provides a
Transcranial magnetic stimulation in Alzheimer’s disease 589
123
Table 1 Selected peer-reviewed articles on cortical excitability to transcranial magnetic stimulation in Alzheimer’s disease patients compared to age-matched control subjects
Study Demographic and clinical characteristics TMS parameters
Authors No. of
patients
Mean age Stage of disease
(neuropsychological assessment)
Type of
coil
Mean rMT (%) CSP (ms) ICI (%) ICF (%) SAI (%)
Perretti et al. (1996) 15 67.2 ±7.8 Moderate–severe (Reisberg’s global
deterioration scale
a
)
Circular L 68.3 ±17.7* L 97.2 ±39.3 **
de Carvalho et al. (1997) 14 67.8 ±6 Mild–moderate
(Blessed dementia scale
b
)
Figure of eight R 77.9 ±7.8
L 78.6 ±6.9*
Pepin et al. (1999) 17 70.7 ±6.6 Mild–moderate–severe (Reisberg’s
global deterioration scale
a
)
Figure of eight 34.9 ±6.5** NS NS
Alagona et al. (2001) 21 72 (55–81)
c
Mild–moderate–severe
(Blessed dementia scale
b
)
Circular R 36 (24–58)* R 114 (36–168.6)**
L 36 (23–53)** L 119 (36–178)*
Liepert et al. (2001) 11 74.8 ±9.7 Mild–moderate (CDR) Circular NS NS 68.7 ±29.6* NS
Pennisi et al. (2002) 17 74 (55–82)
c
Mild–moderate–severe (MMSE) Circular R 38.41 ±10.02*
L 37.94 ±9.41**
Di Lazzaro et al. (2002)15 69±5.3 Mild–moderate (MMSE) Figure of eight 50.2 ±6.4* NS NS NS 85.7 ±15.8**
Ferreri et al. (2003)1675±6.9 Mild–moderate (CDR) Figure of eight NS
Di Lazzaro et al. (2004) 28 71.3 ±6.8 Mild–moderate (MMSE) Figure of eight 49.9 ±10.9* NS 86.6 ±18.2**
Alagona et al. (2004) 20 72.2 ±7.53 Mild–moderate (MMSE) Circular 36 ±3.02** NS
Pierantozzi et al. (2004) 12 65.2 ±3.5 Mild (CDR) Figure of eight NS ** NS
Di Lazzaro et al. (2005) 20 70.5 ±6.9 Mild–moderate (MMSE) Figure of eight 86.2 ±21.3**
Di Lazzaro et al. (2006) 20 69.5 ±6.5 Mild–moderate (MMSE) Figure of eight 47.2 ±7.4* 89.1 ±16.5**
Inghilleri et al. (2006)20 71±2.1 Mild–moderate (MMSE) Figure of eight 54.4 ±1.74** NS
Sakuma et al. (2007) 12 – Mild (MMSE) Figure of eight NS 86 ±35**
Battaglia et al. (2007) 10 70.1 ±7.4 Mild–moderate (MMSE) Figure of eight NS
Di Lazzaro et al. (2007) 10 72.1 ±4.4 Mild-moderate (MMSE) Figure of eight * NS 90.8 ±14.9**
Alberici et al. (2008) 8 74.5 ±7.3 Mild–moderate (MMSE) Circular NS NS NS
Julkunen et al. (2008) 5 73.2 ±8.1 Mild (CDR) Figure of eight 41.2 ±4.6*
Martorana et al. (2008)11 73±9.2 Moderate (CDR) Figure of eight ** ** NS
Nardone et al. (2008) 17 68.4 (58–74) Mild (CDR) Figure of eight NS NS NS 67.4 ±14.2*
Martorana et al. (2009) 10 72.5 ±6.1 Moderate (CDR) Figure of eight 45.9* *
Olazara
´n et al. (2010) 11 77.2 ±4.4 Very mild (CDR) Circular NS * NS
Results are shown as mean ±SD with ranges given in parentheses
NS Not significant, MMSE Mini mental state examination (Folstein et al. 1975), CDR Clinical dementia rating scale (Hughes et al. 1982), RRight hemisphere, LLeft hemisphere, rMT Resting motor
threshold, CSP Cortical silent period, ICI Intracortical inhibition, ICF Intracortical facilitation, SAI Short-latency afferent inhibition
a
(Reisberg and Ferris 1982)
b
(Blessed et al. 1968)
c
Median value and range
*p\0.05
** p\0.01
590 G. Pennisi et al.
123
much more accurate and comprehensive estimate of brain
inhibitory mechanisms, independently of rMT (Kimiskidis
et al. 2005). In the 1-year follow-up study by Pennisi et al.
(2002), the mean rMT values of AD patients treated with a
cholinesterase inhibitor drug (ChEI) showed a decrease
significantly correlated with the severity of cognitive
impairment. This suggested that treatment did not stop the
neurophysiological and clinical progression of the disease
and that changes in rMT following neuronal degeneration
rather than the patient’s neuropsychological performance.
Moreover, Di Lazzaro et al. (2002) found that SAI of the
motor cortex was significantly reduced in AD patients. SAI
of the motor cortex is thought to depend on the integrity of
cortico-cortical inhibitory circuits (Tokimura et al. 2000),
thus the reduction of SAI might reflect the cholinergic
involvement in AD.
Finally, studies concerning the correlation between rMT
and the stage of the disease are still inconclusive. Some of
the modifications occurring in cortical excitability detected
by TMS may be variable, ranging from the preclinical-
initial stages of the disease to the advanced-end stages.
Interestingly, rMT values can be taken into account in
patients compared to controls: normal (Sakuma et al. 2007)
or increased rMT (Julkunen et al. 2008) in MCI; normal or
slightly reduced rMT in very mild and mild AD (Pier-
antozzi et al. 2004; Sakuma et al. 2007; Nardone et al.
2008; Olazara
´n et al. 2010); significantly reduced rMT in
moderate AD (de Carvalho et al. 1997; Pepin et al. 1999;
Alagona et al. 2001,2004; Pennisi et al. 2002; Di Lazzaro
et al. 2002,2004,2006; Inghilleri et al. 2006; Di Lazzaro
et al. 2007; Martorana et al. 2008,2009); and increased
rMT in advanced AD (Perretti et al. 1996). It is feasible
that, in the early stages, mechanisms related to rMT are
preserved (Pierantozzi et al. 2004) or that rMT changes
reflect a functional, but not structural, damage of the
cortical motor neurones. In the subsequent progression
of AD, the decrease in rMT might be compensatory to the
loss of motor cortex neurones (Pepin et al. 1999; Ferreri
et al. 2003) whereas, in the most advanced AD cases, the
increase of rMT is probably due to cortical atrophy
(Perretti et al. 1996). In this perspective, rMT could be
used as a neurophysiological marker identifying the degree
of cognitive impairment.
Intracortical inhibition and facilitation
in Alzheimer’s disease
As demonstrated by Pepin et al. (1999) using pp-TMS, ICI
of the motor cortex is normal in AD patients, suggesting
that cortical hyperexcitability might originate in some in-
tracortical excitatory circuits or in dysfunction of other
inhibitory circuits. Other authors found that AD patients
tended to have less pronounced ICI than controls, without
statistical significance (Di Lazzaro et al. 2002). On the
contrary, Liepert et al. (2001) demonstrated that AD
patients exhibited reduced ICI compared to an age-matched
control group and that this motor cortex disinhibition was
more evident in moderate than in mild demented patients.
In the late stage of disease, a reduced motor excitability
was observed, due to severe cortico-spinal fiber loss
(Perretti et al. 1996). Thus, the pattern of cortical hyperex-
citability in AD seems to be stage-dependent and might turn
into a loss of excitability during further progression of the
disease. The same authors did not find significant changes in
rMT and CSP, suggesting that ICI and CSP are mediated by
different inhibitory circuits, as reported in other diseases
(Liepert et al. 1998). The administration of the ChEI
donepezil resulted in an increase of ICI, supporting the
hypothesis that motor cortex disinhibition in mildly to
moderately affected AD patients might be reversible, even if
1 year of treatment did not stop the progressive increase in
motor cortex excitability (Pennisi et al. 2002).
It has been demonstrated (Di Lazzaro et al. 2002) that a
single dose of the ChEI rivastigmine significantly increased
SAI in the six patients in whom it was tested and there was
no correlation between rMT and the administration of
rivastigmine (Di Lazzaro et al. 2004), as already noted
(Pennisi et al. 2002). In a subsequent study, Di Lazzaro
et al. (2005) evaluated whether SAI might be useful in
identifying AD patients likely to respond to treatment. At
baseline, an abnormal SAI that was not greatly increased
by rivastigmine was invariably associated with a poor
response to long-term treatment, whereas an increase after
treatment was associated with a favorable response in most
of the patients.
Transcranial magnetic stimulation and synaptic
plasticity in Alzheimer’s disease
Taken together, the overall results of TMS and related
protocols studies have demonstrated that motor cortex
excitability is enhanced in AD patients, but what is the
meaning of this hyperexcitability?
Physiological aging cannot explain this hyperexcitabil-
ity because healthy elderly patient showed normal (Pepin
et al. 1999; Pitcher et al. 2003; Rossi et al. 2004; Oliviero
et al. 2006) or increased rMT (Rossini et al. 1992; Peine-
mann et al. 2001) and decrease of hippocampal pyramidal
neurons excitability (Disterhoft and Oh 2007).
In AD patients, the functional meaning of cortical
hyperexcitability might be searched for in a compensatory
mechanism to execute voluntary movements when assis-
tance from associative cortical areas is impaired (Pepin
et al. 1999). As subsequently hypothesized (Ferreri et al.
2003), precentral regions, including premotor and supple-
mentary motor areas, may be recruited even for movements
Transcranial magnetic stimulation in Alzheimer’s disease 591
123
of low level of complexity, in order to preserve motor
performance. This finding fits well with the observation of
a frontal shift of electroencephalogram (EEG) rhythms in
early AD patients (Babiloni et al. 2000). In healthy sub-
jects, the main motor cortical output is coincident with the
‘‘hot spot’’ (Cicinelli et al. 1997), whereas in AD patients it
shifts toward the frontal and medial regions in the absence
of changes in the ‘‘hot spot’’ (Ferreri et al. 2003). Alter-
natively, although not in a mutually exclusive way, this
cortical recruitment may be caused by aberrant dendritic
arborization with a functional enlargement of motor-
devoted circuitries (Arendt et al. 1995; Arendt et al. 1997)
and a loss of transcallosal inhibition (Lakmache et al.
1998). An altered cortical plasticity in excitatory circuits
within the motor cortex was also suggested by Inghilleri
et al. (2006) in a rTMS study in 20 elderly patients with
mild-moderate AD, compared to healthy subjects. They
found that facilitatory rTMS in patients failed to elicit the
normal MEP facilitation; conversely, inhibitory responses
were similar in the two groups. These findings suggest that
the lack of MEP facilitation at high frequency in AD
patients is a disease-related marker, indicating abnormal
cortical motor area plasticity likely to be mediated by
short-term potentiation (STP) and LTP and probably
caused by altered glutamate transmission, as previously
suggested by Di Lazzaro et al. (2003,2004). Another
interesting finding in this study is that in patients CSP
increased normally (Berardelli et al. 1999; Romeo et al.
2000) over the rTMS train, suggesting normal plasticity of
the cortical inhibitory circuits.
Inhibitory gabaergic dysfunction may affect the com-
plex balance of cortical excitability in AD patients. Bio-
chemical investigations of biopsy brain tissues from
patients in the early phases of AD have not shown signif-
icant alterations in the concentration of GABA (Lowe et al.
1988,1990) and no disturbance of GABA transporters
(Na
¨gga et al. 1999; Ohyama et al. 1999). Most, but not all,
studies showed that CSP in AD is preserved (Liepert et al.
2001; Peinemann et al. 2001; Di Lazzaro et al. 2002;
Alagona et al. 2004; Inghilleri et al. 2006), and, because
CSP reflects GABA-mediated inhibitory motor cortical
circuits (Inghilleri et al. 1993; Werhahn et al. 1999), it is
possible to conclude that the motor cortex hyperexcitability
of AD, at least in the early stage, is not caused by gabaergic
intracortical dysfunction (Pepin et al. 1999; Liepert et al.
2001; Inghilleri et al. 2006). In order to further clarify
whether hyperexcitability was due to an impairment of
intracortical inhibitory or excitatory circuits, Di Lazzaro
et al. (2004) assessed motor cortex excitability in 28 AD
patients (14 non-treated and 14 treated with a single dose of
rivastigmine) and compared the data with SAI and ICI at
short ISIs (short latency ICI–SICI) in aim to evaluate
cholinergic and gabaergic transmission, respectively. This
study confirmed previous reports about the reduction of
rMT and found a significantly smaller SAI and a nonsig-
nificant decrease in ICI. Lastly, they did not find a corre-
lation between rMT and either SAI or ICI, suggesting that
change in rMT did not seem to correlate with dysfunction
of inhibitory intracortical cholinergic and gabaergic
circuits.
Conversely, Nardone et al. (2008) found that, even in
early stages of AD, SAI was significantly smaller in
patients than in controls, providing a neurophysiological
evidence of central cholinergic dysfunction early in the
course of AD. These results support the concept that cho-
linergic impairment is an early and leading event in AD.
Moreover, SAI values did not correlate significantly with
the patients’ age or duration and severity of dementia.
However, both in vivo and postmortem studies on early
cholinergic involvement in AD are inconclusive (Geula
1998; Stokin et al. 2005; Herholz et al. 2004) and, although
cholinergic fibers to associative areas appear to be signif-
icantly impaired in AD, hippocampal projections and
cholinergic cell bodies in basal forebrain appear relatively
intact (Herholz et al. 2004).
Several reports hypothesized a glutamatergic transmis-
sion dysfunction in the pathogenesis of cortical hyperex-
citability in AD. Di Lazzaro et al. (2002) reported a motor
cortex hyperexcitability to TMS in normal subjects by
administration of ketamine, a drug that blocks NMDA
glutamatergic receptor activity and enhances non-NMDA
transmission through an increased release of endogenous
glutamate (Moghaddam et al. 1997). Because non-NMDA
channels are more involved in high-frequency transmission
(Conti and Weinberg 1999), the net effect of ketamine is an
increase in high-frequency glutamatergic activity. So, the
reduction of rMT might be interpreted as a consequence of
an imbalance between non-NMDA and NMDA neuro-
transmission in favour of the former. Another hypothesis is
based on evidence indicating a reduced number of gluta-
matergic receptors (Nordberg 1992) and diminished glu-
tamate uptake by transporter proteins in AD brains (Hyman
et al. 1987; Masliah et al. 1996). Several studies, indeed,
have suggested a selective degeneration of glutamate
neurones relatively early during the course of the disease
(Hyman et al. 1987; Lowe et al. 1990; Francis et al. 1993,
1999). The disease process may impair neuronal energy
metabolism and lead to a decreased neuronal membrane
potential, allowing easier depolarization (Pepin et al.
1999). Thus, if a mild dysfunction of glutamate metabolism
is present in the brain of asymptomatic individuals, the
progressive deposition of b-amyloid in selectively vulner-
able neurons during the course of AD may enhance the
neuropathological consequences of this metabolic defect
(Gray and Patel 1995). However, it has also been demon-
strated that glutamate-mediated ICF in AD patients is
592 G. Pennisi et al.
123
normal (Pepin et al. 1999; Liepert et al. 2001; Di Lazzaro
et al. 2002; Pierantozzi et al. 2004; Alberici et al. 2008;
Martorana et al. 2008; Nardone et al. 2008; Olazara
´n et al.
2010). This finding complicates the hypothesis that the
selective impairment of the glutamatergic, cholinergic or
gabaergic transmission alone may explain AD cortical
hyperexcitability.
Recently, the demonstration that SAI is influenced by
dopaminergic drugs in patients with Parkinson’s disease
(Sailer et al. 2003) and that there is a correlation between
dopamine D2 receptors and memory dysfunction in AD
(Kemppainen et al. 2003), suggested a possible role for
dopamine in modulating AD cortical excitability (Martor-
ana et al. 2008) and cognitive processes (Martorana et al.
2009). Single oral administration of L-3,4-dihydroxyphen-
ylalanine (L-dopa) or dopamine receptor agonists (Ziemann
et al. 1997; Korchounov et al. 2007) did not significantly
modify rMT (Martorana et al. 2009), but was able to
restore loss of ICI (Martorana et al. 2008) and decrease of
SAI in AD patients (Martorana et al. 2009). Dopamine
released from terminals directly in the motor cortex could
have favorable effects on intracortical cholinergic inter-
neurons bearing receptors for dopamine (Berlanga et al.
2005), or might act at a subcortical level facilitating the
glutamatergic excitatory drive from thalamo-cortical
pathway (DeLong 1990). Impairment of dopaminergic
transmission may contribute to an imbalance among dif-
ferent neurotransmitters pathways, inducing hypoactivity
of gabaergic neurons and, as a consequence, glutamate-
mediated disinhibition of cortical pyramidal neurons
(Martorana et al. 2008). Alternatively, a lack of acetyl-
choline at the level of the Meynert’s basal nucleus could
perturb dopamine turnover, further contributing to the
imbalance between cholinergic and dopaminergic systems,
the latter being an important cause of the progression of the
cognitive decline (Calabresi et al. 2006). In this view,
the prompt effect of L-dopa on SAI should be interpreted as
the result of a momentarily restored transmitter deficiency
(Martorana et al. 2009).
Taken together, the abnormality of various neurotrans-
mitters (acetylcholine, GABA, glutamate, dopamine, etc.)
at different levels in brain areas supports the hypothesis
that AD is a complex neurodegenerative disease involving
several neurotransmission pathways.
Potential therapeutic effects of transcranial magnetic
stimulation in Alzheimer’s disease
Based on the hypothesis of synaptic plasticity and cortical
reorganization in the course of AD, suitable rTMS proto-
cols have been recently proposed to improve cognitive
performance and restore brain function of AD patients. In
normal subjects, rTMS can modulate cortical excitability,
improving or impairing cognitive performance depending
on different stimulation parameters (Maeda et al. 2000;
Brignani et al. 2008). For instance, anomia is one of the
earliest clinical manifestations of language impairment in
AD (Robinson et al. 1996; Kim and Thompson 2000).
Cotelli et al. (2006,2008) showed that rTMS applied on
both dorsolateral prefrontal cortices (DLPFCs) transiently
improved action and object naming in moderate to severe
AD patients, whereas improved action naming only in mild
AD patients. While rTMS effects in normal subjects were
limited to the left-side stimulation, in AD patients facili-
tation was bilateral, suggesting a compensatory mechanism
based on recruitment of right hemispheric resources to
support the residual naming performance. Compensatory
changes may be explained by an activation of adjacent or
distant cortical areas from the stimulated site (Cotelli et al.
2008). In order to verify whether the cognitive benefits
might persist after the end of the stimulation sessions,
Cotelli et al. (2010) assessed the long-term effects on
language performance of rTMS applied to left DLPFC in
AD patients. They identified an improvement in sentence
comprehension 8 weeks after the end of the rTMS proto-
col, providing the first data on long-lasting cognitive effect
of rTMS in AD. Repetitive TMS could induce a modula-
tion of short- and/or long-range cortical synaptic efficacy
and connectivity that potentiates the language neuronal
network (Cotelli et al. 2010).
Transcranial magnetic stimulation and mild cognitive
impairment
TMS may discriminate AD from other neurological dis-
orders, including MCI and other forms of dementia.
Table 2shows the details of the TMS studies on cortical
excitability in MCI.
Table 2 TMS studies on cortical excitability in mild cognitive
impairment
Authors Mean rMT
(%)
pSAI (%) p
Sakuma et al.
(2007)
MCI 48.06 ±12.55 NS 39 ±26 \0.001
b
AD 46.83 ±8.11 86 ±35
Controls 53 ±9.6 41 ±26
Julkunen et al.
(2008)
MCI 50.4 ±12.4 \0.05
a
AD 41.2 ±4.6
Controls 44.3 ±15.7
MCI Mild cognitive impairment, AD Alzheimer’s disease, rMT
Resting motor threshold, SAI Short-latency afferent inhibition, NS Not
significant
a
MCI versus AD
b
MCI and controls versus AD
Transcranial magnetic stimulation in Alzheimer’s disease 593
123
MCI is defined as a decline of cognitive functioning
halfway between normal aging and dementia and, even
though not all MCI patients convert to AD, it is thought to
be a sort of prodromic state of AD (Sakuma et al. 2007).
An understanding of the neurophysiological basis of MCI
might lead to the search of clinical and paraclinical
markers useful in the identification of either MCI patients
at high risk of progression in AD or AD patients in the MCI
clinical stage. Resting MT tended to be lower in MCI
patients than in controls, even without statistically signifi-
cant difference, whereas SAI was not reduced compared to
AD. These data indicate that cortical cholinergic circuits
may be normal in MCI patients, suggesting the presence of
a compensatory mechanism that keeps cerebral cholinergic
activity at the normal level (Sakuma et al. 2007). As the
disease progresses, an imbalance in the activity of the
cholinergic system, indexed by SAI, may gradually
become apparent (Sakuma et al. 2007). The critical point at
which SAI becomes abnormal might be an early and reli-
able marker to discriminate MCI patients advancing to AD
from those with no conversion, and could allow earlier
diagnosis and treatment of AD. In amnestic MCI (aMCI),
the subtype of MCI at highest risk for progression to AD
(Petersen 2004), the detection of a TMS alteration in cor-
tical motor neuron excitability to a specific linguistic task
may contribute to characterize the risk of conversion to
AD. In particular, the enhancement of the dominant M1
hand area excitability during a specific linguistic task is
suppressed in aMCI patients, whereas it is preserved in
normal elders, and this result might reflect an altered
functional connectivity (Bracco et al. 2009). Recent data
from EEG (Koenig et al. 2005; Rossini et al. 2006),
functional magnetic resonance imaging (fMRI) (Dannha-
user et al. 2005) and fluorodeoxyglucose positron emission
tomography (PET) (Chetelat et al. 2003) support the view
that disconnection between cerebral areas might start in the
early stage of neurodegeneration. Together with these
techniques, TMS may also contribute to distinguish
patients with MCI who progress into AD from stable MCI
patients. Recently, the combination of navigated brain
stimulation (NBS) technique with EEG revealed prominent
changes in functional cortical connectivity and reactivity,
providing a novel tool for examining the degree and pro-
gression of cognitive decline from MCI to AD (Julkunen
et al. 2008). All the basic components in the TMS-evoked
EEG response were visible in AD, MCI and normal groups
but the early responses, presumably reflecting cortical
reactivity and functional connectivity, were decreased in
AD patients (Julkunen et al. 2008). Moreover, EEG activity
in the AD group was less synchronized than in the controls
or MCI (Julkunen et al. 2008), a finding which is in line
with a previous report showing that the EEG synchroni-
zation decreases in relation to cognitive impairment
(Koenig et al. 2005), whereas the MCI group exhibited a
behavior about halfway between the values of AD and
controls.
TMS combined with compatible EEG can be accurately
and non-invasively applied to determine functional analy-
sis of cortico-cortical connectivity and EEG reactivity
following the spreading of electrical activity after locally
applied stimuli (Ilmoniemi et al. 1997;Ka
¨hko
¨nen et al.
2001). Previous studies have used TMS and EEG to
explore transcallosal (Cracco et al. 1989) and cerebello-
frontal (Amassian et al. 1992) connections. As altered
functional connectivity may precede structural changes, an
objective method for the investigation of early functional
changes would be useful in the diagnostics of MCI, AD and
other dementing disorders. Neurophysiological data also
can be fused with structural (MRI) and functional neuro-
imaging techniques (fMRI, PET, single photon emission
computed tomography—SPECT), improving diagnostic
utility of each method employed (Rossini et al. 2007). An
integrated approach of EEG–TMS, as proposed by the
pioneer pilot study of Julkunen et al. (2008), might be
developed since it is not invasive, low-cost, easy to
implement and suitable for screening the population at-risk.
Finally, studies with ChEI (Pierantozzi et al. 2004;
Olazara
´n et al. 2010) in MCI converted to AD-related
dementia and early-onset AD showed no modification in
rMT, ICI, and ICF except for a reduced SICI at baseline
that was reversed after treatment. The absence of rMT
variation is probably related to the very mild AD stage,
whereas the behavior of SICI after treatment with ChEI
supports the pivotal role of cholinergic dysfunction of AD
since the earliest stages. In this perspective, in the follow-
up of patients with MCI that converted to AD-related
dementia, the peculiar damage seems to be mostly dys-
functional, affecting the fine modulation of the intracortical
inhibitory circuitry of the motor cortex (Pierantozzi et al.
2004). The specific profile of SICI may be an auxiliary
neurophysiological parameter easily tested in the follow-up
of patients affected by cognitive decline and could be a
predictor of response to treatment.
Conclusion
The present review highlights the role of TMS in the
detailed assessment of the neurophysiological mechanisms
underlying AD.
Reduction of rMT in AD patients is a relatively stable
result, suggesting a pattern of global increased cortical
excitability.
At present, it is not clear if the hyperexcitability of the
motor cortex in AD is the expression of a selective
involvement of excitatory glutamatergic circuits or an
594 G. Pennisi et al.
123
impairment of inhibitory cholinergic and, to a lesser extent,
gabaergic activity. Although early TMS studies suggested
cholinergic deficit as the main accepted hypothesis, recent
results indicate that AD should be considered as a complex
neurodegenerative disease involving different neurotrans-
mitter systems.
Moreover, increased excitability and cortical reorgani-
zation of the motor output that occur in the course of AD
could explain the frontomedial shift of the excitable motor
areas, interpreted as a compensatory mechanism allowing
the preservation of motor programming and execution over
a long period, despite the clinical progression of AD.
The application of rTMS in transiently restoring or
compensating damaged cognitive functions might lead to
the development of stimulation protocols as a possible
cognitive rehabilitation method in patients with AD.
Finally, TMS and related techniques may offer clues in
evaluation and discrimination between the physiological
brain aging, MCI, and other dementing disorders based on
their different patterns of cortical excitability.
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