Progress in Neurobiology 83 (2007) 375–400

www.elsevier.com/locate/pneurobio

Clinical neurophysiology of aging brain:

From normal aging to neurodegeneration
Paolo M. Rossini a,b,c,*, Simone Rossi d, Claudio Babiloni c,e,f, John Polich g
a
Clinica Neurologica University Campus Bio-Medico, Rome, Italy
b
IRCCS Centro S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy
c
AFaR, Dept. Neurosci, Ospedale Fatebenefratelli, Isola Tiberina, Rome, Italy
d
Dipartimento di Neuroscienze, Sezione Neurologia, University of Siena, Italy
e
Dept. Human Physiology and Pharmacology, University ‘‘La Sapienza’’, Rome, Italy
f
San Raffaele Cassino – Tosinvest Sanità, Cassino (FR), Italy
g
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA, USA
Received 7 February 2007; received in revised form 3 May 2007; accepted 26 July 2007

Abstract
Physiological brain aging is characterized by a loss of synaptic contacts and neuronal apoptosis that provokes age-dependant decline of sensory
processing, motor performance, and cognitive function. Neural redundancy and plastic remodelling of brain networking, also secondary to mental
and physical training, promotes maintenance of brain activity in healthy elderly for everyday life and fully productive affective and intellectual
capabilities. However, age is the main risk factor for neurodegenerative disorders such as Alzheimer’s disease (AD) that impact on cognition.
Oscillatory electromagnetic brain activity is a hallmark of neuronal network function in various brain regions. Modern neurophysiological
techniques including electroencephalography (EEG), event-related potential (ERP), magnetoencephalography (MEG), and transcranial magnetic
stimulation (TMS) can accurately index normal and abnormal brain aging to facilitate non-invasive analysis of cortico–cortical connectivity and
neuronal synchronization of firing and coherence of rhythmic oscillations at various frequencies. The present review provides a perspective of these
issues by assaying different neurophysiological methods and integrating the results with functional brain imaging findings. It is concluded that
discrimination between physiological and pathological brain aging clearly emerges at the group level, with applications at the individual level also
suggested. Integrated approaches utilizing neurophysiological techniques together with biological markers and structural and functional imaging
are promising for large-scale, low-cost and non-invasive evaluation of at-risk populations. Practical implications of the methods are emphasized.
# 2007 Elsevier Ltd. All rights reserved.

Keywords: Aging; Alzheimer’s disease; Neurophysiology; EEG; ERPs; TMS; rTMS; Plasticity

Contents

1. Historical survey and aims of the review . . . . . . . . . . .. .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

2. Main neurophysiological techniques . . . . . . . . . . . . . . .. .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
2.1. Laplacian transformation and coherence analysis of EEG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
2.2. Event-related EEG changes . . . . . . . . . . . . . . . .. .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
2.3. LORETA source recontruction . . . . . . . . . . . . . .. .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
2.4. Event-related potentials: P300 background . . . . .. .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
2.4.1. Normative P300 data . . . . . . . . . . . . . .. .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379

Abbreviations: AD, Alzheimer’s disease; CAT, computerized axial tomography; CNS, central nervous system; CSP, cortical silent period; DLPFC, dorsolateral
prefrontal cortex; DTF, direct transfer function; ECD, equivalent current dipole; EEG, electroencephalography; ERD/ERS, event-related desynchronization/
synchronization; ERP, event-related potential; EMG, electromyography; ICI/ICF, intracortical inhibition/facilitation; LORETA, low resolution electromagnetic
tomography; LTP/LTD, long-term potentiation/depression; MCI, mild cognitive impairment; MEG, magnetoencephalography; MMSE, mini-mental state evaluation;
MRI/fMRI, magnetic (functional) resonance imaging; Nold, normal old; PET, positron emission tomography; rTMS, repetitive transcranial magnetic stimulation;
SAI, short-latency afferent inhibition; SPECT, single photon emission computerized tomography; TMS, transcranial magnetic stimulation.
* Corresponding author at: University Campus Bio-Medico, Via Álvaro del Portillo, 21 I-00128 Rome, Italy.
E-mail address: paolomaria.rossini@afar.it (P.M. Rossini).

0301-0082/$ – see front matter # 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.pneurobio.2007.07.010
376 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400

2.5. Magnetoencephalography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380

2.6. Transcranial magnetic stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
2.6.1. TMS variables measurable following individual stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
2.6.2. TMS variables measurable following paired-pulses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
2.6.3. Repetitive TMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
2.7. An integrated approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
3. Physiological aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
3.1. EEG and MEG rhythms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
3.2. Event-related EEG–MEG rhythms during behavioral tasks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
3.3. ERPs and brain aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
3.3.1. P300 clinical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
3.4. Cerebral cortex excitability as revealed by TMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
3.4.1. Encoding of elementary motor-related memories as revealed by TMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
3.4.2. Interference with cortical functions as revealed by repetitive TMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
4. Pathological aging: neurophysiological markers of dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
4.1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
4.2. Neurophysiological studies with the brain ‘‘at rest’’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
4.3. Event-related EEG–MEG rhythms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
4.4. P300 and Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
4.5. The reappraisal of brain excitability in dementia as revealed by TMS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
5. Mild cognitive impairment and preclinical dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
5.1. ‘‘Resting’’ EEG–MEG rhythms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
5.2. Event-related EEG–MEG rhythms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392
5.3. Excitability of cerebral cortex as revealed by TMS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
6. Summary and conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

1. Historical survey and aims of the review
Since its introduction, the electroencephalogram (EEG) was
viewed with a great enthusiasm as the only methodology
allowing a direct, on-line view of the ‘‘brain at work’’ (Berger,
1929). It offers appreciable promise as a means to characterize
significant deviations from the ‘natural’ aging found in
Alzheimer and other dementias (Berger, 1938). From the
1970s and 1980s with the introduction of structural imaging
technologies such as computer assisted tomography (CAT) and
magnetic resonance imaging (MRI), these newer methods
produced non-invasive views of in vivo brain anatomy with
considerable resolution that contributed to their clinical and
therefore economic utility. Over the course of the following two
decades, development of regional metabolic methods such as
positron emission tomography (PET), single photon emission
computed tomography (SPECT), and the ability to map oxygen
consumption and regional blood flow in specific neural
locations with functional magnetic resonance imaging (fMRI)
have supplanted the role of EEG in basic and clinical studies.
However, these functional brain imaging methods with their
high spatial resolution for anatomical details are relatively
limited in their temporal resolution when measuring functional
brain activation (seconds to minutes). Thus, these neuroima-
ging techniques cannot discriminate in series or parallel
activation of different relays within a distributed network
(Rossini and Dal Forno, 2004).
As these imaging methods were being developed, similar
advances were being made for EEG measures in part because
neuroelectric signals can track information processing with
millisecond precision. Indeed, the development of advanced
processing analysis and display techniques for EEG, sensory
evoked potential (EP), and cognitive event-related potential
(ERP) methods progressed remarkably (Desmedt and Cheron,
1981; Halliday et al., 1972; Kutas et al., 1977; Näätänen and
Alho, 1995). However, despite all such improvements none of
the techniques can fully determine whether a given ‘‘activated’’
brain region is causally related to the task under investigation.
Transcranial magnetic stimulation (TMS) – primarily in its
repetitive modality – can provide informative clues toward
understanding neurophysiological brain in normal and abnor-
mal aging (Walsh and Cowey, 2000; Rossi and Rossini, 2004).
Table 1 contains a summary of these methods. Advances in
EEG signal analysis permit relatively precise localization of
brain neural sources and the ability to track their hierarchical
connectivity in sustaining a given function. This information
can be integrated with structural and functional imaging
provided by PET and fMRI. Such integrated measures can
index patterns of neural activation responsible for sensory
perception, attention, memory, movement, and higher mental
operations including language and thought, since electromag-
netic signals change in parallel over time and task, and can be
impaired directly during such activity.
A major challenge of modern neuroscience is to identify
patterns of neuronal activity underlying cognitive function and
to disentangle these actions from ongoing electromagnetic
brain signals unrelated to task performance, background
activity, and function-related activity. This issue is complicated
 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400 377

Table 1
Survey of the different neurophysiological approaches to investigate brain function in normal and pathological aging
Technique Resolution Integrability with Computational Information on Causality Clinical utility Clinical utility
other neuroimaging complexity functional coupling of a brain in group on the single
Spatial Temporal techniques of brain areas region studies patient
EEG ++ ++++ ++++ + ++ (Lapalacian) + ++ +
Spectral + + ++ + + + +++ ++
Coherence ++ +++ ++++ ++ ++++ (DTF) ++ ++ +
ERP (EEG, MEG) ++ ++++ ++ ++ ++ + ++ +
ERD/ERS (EEG, MEG) ++ +++ ++ ++ +++ + ++ +
CNV/BP (EEG, MEG) + ++ + ++ ++ + + +
EP (EEG, MEG) +++ ++++ ++ ++ ++ ++ ++ +
TMS, single +++ ++++ +++ +++ (mapping) + ++ +++ ++
TMS, double ++ ++++ +++ ++ +++ +++ +++ ++
TMS, repetitive ++ ++++ ++++ + +++ ++++ ++ ++

further as these processes undergo maturation in infancy,
childhood, adolescence, and adult aging with dramatic
alterations produced by neurodegeneration in dementing
disorders (Celesia et al., 1987). It is important, therefore, to
implement techniques that are able to measure natural brain
aging and to discriminate it from neurodegeneration.
The present review outlines the impact of neurophysiolo-
gical techniques for the measurement of physiological and
pathological brain aging and attempts to provide a reasonably
comprehensive analysis of brain aging by integrating the
contemporary methodological descendants of the EEG. Thus,
the major goal is to highlight the emerging neurophysiological
findings to determine whether they provide sufficient innova-
tive and potentially useful information for the assessment of
normal aging and dementia, both at a group- and single-subject
level.
2. Main neurophysiological techniques
This section is not intended to represent a complete survey of
modern neurophysiological techniques but highlights those
most frequently used to assess brain aging. The focus is
therefore relatively specific rather than broad but does provide a
general overview of how neuroimaging methods have been
used to assess normal aging and neurodegeneration.
2.1. Laplacian transformation and coherence analysis of
EEG
Advanced EEG analysis techniques can illustrate changes in
specific rhythms oscillating at various frequencies over time,
provide quantitative measurements of individual rhythms, and
allow control over the contribution of volume currents from far-
field generators (Nunez, 2000; Babiloni et al., 2001). Hence,
EEG signals generated from extracerebral sources (e.g.,
electrocardiogram, electromyogram, electroretinogram, etc.)
can be isolated from those produced by the brain, with a direct
measure of the recorded neuroelectric signals (Babiloni et al.,
2001). EEG coherence or synchronicity of rhythmic signals
from separate electrodes in different frequency bands generated
in different cortical areas also can be measured. The spatial
resolution of the signals has been reduced from about 7–2 cm
by applying surface Laplacian estimation with a regularized 3D
spline function, which reduces the low spatial EEG frequencies
contributed by volume conduction and eliminates electrode
reference influence (Babiloni et al., 1995, 1996, 2003; Nunez,
1995; Nunez and Srinivasan, 2006). Compared to other linear
or nonlinear modelling analysis techniques of cortical sources
of EEG–MEG, surface Laplacian estimation provides a rough
representation of the neural currents without an explicit model
of the generators (i.e., shape, number, location) by using a
model of the head as a volume conductor (Babiloni et al., 1995,
1996). However, surface Laplacian methods cannot disentangle
the activity of two spatially adjacent cortical zones such as
primary somatosensory and motor areas that are contiguous
over the central sulcus or deep cortical sources in secondary
somatosensory and insular cortices. Surface Laplacian estima-
tion also is unreliable when computed at the borders (i.e.,
temporo-parietal electrodes), and its maxima often do overlie
cortical sources of EEG potentials, since the influence of
tangential relative to radial oriented generators is greater
(Babiloni et al., 1995, 1996; Nunez, 1995).
Spectral coherence analysis indexes the temporal synchro-
nization of two EEG time series among electrodes in the
frequency domain and permits characterization of linear
functional cortico–cortical connectivity. In general, decreased
coherence reflects reduced linear functional connections and
information transfer (i.e., functional uncoupling) among
cortical areas or modulation of common areas by a third
region. In contrast, coherence increase is interpreted as
augmented linear functional connections and information
transfer (i.e., functional coupling), which reflects the interac-
tion of different cortical structures for a given task. Finally, the
direction of the information flow within the coupled EEG
rhythms can be estimated by a direct transfer function (DTF;
Kaminski and Blinowska, 1991; Kaminski et al., 1997;
Korzeniewska et al., 1997; Mima et al., 2000; Babiloni
et al., 2004a,b).
2.2. Event-related EEG changes
Event-related desynchronization (ERD) and event-related
synchronization (ERS) of EEG or MEG brain rhythms describe
neuroelectric events preceding and following a task execution
378 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400

(Pfurtscheller and Aranibar, 1979; Klimesch, 1999; Pfurtschel-
ler and Lopez da Silva, 1999). ERD/ERS is defined as
reduction/increase in EEG power during event (sensory, motor,
cognitive) when compared to baseline immediately preceding
it, at a certain frequency band.
Fig. 1 illustrates an outcome of this approach. For example,
within a Hanning window of 1 s and sampling before stimulus
presentation or an internal trigger (e.g., mental finger move-
ment), this method can yield a frequency resolution of 1 Hz in
the alpha band (Pfurtscheller and Aranibar, 1979; Pfurtscheller
and Neuper, 1994; Pfurtscheller et al., 1997; Pfurtscheller and
Lopez da Silva, 1999). Detailed topographic maps of the alpha
ERD/ERS can be produced using a 3D quasi-realistic cortical
model using a spline interpolating function (Babiloni et al.,
1999), which has been derived from MRI scans digitized at
Brain Imaging Center of the Montreal Neurological Institute
(SPM96, www.mni.mcgill.ca).
2.3. LORETA source recontruction
Source reconstruction of the electromagnetic brain scalp
signals can be achieved via different methods. Relevant
literature on brain aging is particularly linked to the use of low-
resolution electromagnetic tomography algorithm (LORETA)

Fig. 1. Mean amplitude color maps of spatially enhanced movement-related potentials (MRPs) and alpha (10–12 Hz) event-related desynchronization (ERD)
computed in subject 2 during the preparation and execution of a voluntary self-paced right finger extension. The spatially enhanced potential distributions were
projected over a realistic subject’s cortical surface model constructed from magnetic resonance images. Color scales: maximum negativity (100%; violet) and
positivity (+100%; red) for the MRPs; maximum ERD (violet) and ERS (red) for the alpha ERD. Acronyms for the MRPs: Bereithschaftspotential or readiness
potential, RP readiness potential, RP; negative slope, NS; motor potential, MP; movement-related response 1, MRR1. Corresponding acronyms for the alpha ERD
(‘‘RP’’, ‘‘NS’’, ‘‘MP-MRR1’’) (from Babiloni et al., 1999, with permission).
 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
technique that computes 3D linear solutions from multi-
channel input to localize generators in the brain from the EEG
field distribution on the scalp by employing a three-shell
spherical head model of the scalp, skull, and brain compart-
ments (Pascual-Marqui et al., 1994, 1999, 2002). Source
analysis is reference free, since the same source distribution is
obtained for EEG data referenced to any electrode including a
common average. It also can be used from data collected by low
spatial sampling (e.g., 19 electrodes) when cortical sources are
estimated from resting EEG rhythms (Isotani et al., 2001;
Mientus et al., 2002; Babiloni et al., 2004c; Saletu et al., 2004).
LORETA solutions consist of voxel z-current density values
that are used to predict EEG spectral power density at scalp
electrodes. A normalization method yields current density at
each voxel for the power density averaged across all
frequencies (0.5–45 Hz) of electromagnetic brain rhythms
and voxels of the brain volume.
2.4. Event-related potentials: P300 background
P300 is a brain potential generated by changes in the neural
representation of the stimulus environment when sensory input
engages attention and working memory to update the
‘‘context’’ of neural representations in a fashion based on
Sokolov’s model of the orienting response (Donchin, 1981).
P300 amplitude has been linked with memory processes but is
perhaps more sensitive to the amount of attentional resources
engaged during the task (Gonsalvez and Polich, 2002; Wickens
et al., 1983). P300 latency indexes stimulus classification speed
Fig. 2. Scattergrams of P300 (Pz) amplitude (upper) and latency (lower) and age from a large (N = 120) normative aging study that used auditory and visual stimuli.
P300 amplitude declines and latency increases with aging (after Polich, 1997a, with permission).
379
(Kutas et al., 1977), reflects stimulus more than response
processing (Duncan-Johnson, 1981; McCarthy and Donchin,
1981), and is generally independent of behavioural response
time (Ilan and Polich, 1999; Verleger, 1997). Hence, peak
latency can be used as a motor-free measure of cognitive
function and has been found to be correlated negatively with
mental function in normal subjects. Shorter latencies are
associated with superior cognitive performance from neuro-
psychological tests of attention and immediate memory (e.g.,
Polich et al., 1983, 1990a,b; Polich and Martin, 1992;
Reinvang, 1999; Stelmack and Houlihan, 1994); increased
latency is found for normal aging and increases in dementia
(Fjell and Walhovd, 2001; Polich et al., 1986). Thus, theoretical
and empirical support exists for the application of P300 as a
measure of individual variation of cognitive function.
2.4.1. Normative P300 data
Fig. 2 illustrates P300 data from a large study of normal
adults with equal numbers of each gender and ERPs elicited
by auditory and visual stimuli in an oddball task (Polich,
1997a). The findings indicate that P300 amplitude declines,
and peak latency increases linearly with increased age.
However, normative age-related ERP variability is greater
than the variation observed for sensory evoked potential
measures (Fein and Turetsky, 1989; Polich and Starr, 1984). A
meta-analytical review of the extant P300 normative aging
studies was performed to characterize the sources of ERP
inter-study variability (Polich, 1996). A major goal was the
identification of moderator variables based on obvious
380 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
Table 2
Summary of moderator variable effects on normative aging P300/latency studies
Moderator variable
Sample characteristics
Size (N)
Density (mean n/decade)
Male/female (%males)
Stimulus factors
Modality (stimulus type)
Number of stimuli (n)
Probability (target)
Target-standard difference
Stimulus intensity
Duration (ms)
Task conditions
Response type
Task difficulty
Reprinted with permission from Polich (1996).
classification schemes (e.g., male versus female, number of
rare stimuli, etc.) or derived from the variable’s low-to-high
values (e.g., stimulus intensity, duration, etc.) across studies.
Table 2 presents a summary of the significant moderator
influences. These findings suggest that P300 latency variability
across normative age could be reduced by proper evaluation of
sample and task characteristics. Both auditory and visual
stimulus modalities should be used to elicit ERPs in separate
conditions. Assessment of P3a as well as P3b using a three-
stimulus paradigm will also be beneficial for evaluating patients
(cf. Polich, 2003; Conroy and Polich, 2007), with application of
single-stimulus procedures useful for children or difficult
patients (Polich, 2004). Thus, acquisition of normative ERP
data should be made in a more focused way than effected
previously.
2.5. Magnetoencephalography
Magnetoencephalography (MEG) is a non-invasive techni-
que that permits spatial identification of neuronal activity
stemming from spontaneous brain states at rest or triggered by
an external stimulus. MEG signal characteristics are not
influenced by extracerebral tissue layers (i.e., meninges, skull,
scalp, muscles). MEG signals originate from current flow of
tangential dipoles as created by parallel pyramidal cells in
cortical gyri and sulci (Romani et al., 1982; Hari and
Lounasmaa, 1989). The signals reflect the spatial and temporal
production of a dipolar source modelled as an equivalent
current dipole (ECD). This method provides three-dimensional
localization of dipolar field distributions over the scalp with
time resolution of milliseconds (Williamson and Kaufman,
1990). Hence, MEG signals can directly estimate the number of
active neural pools and provide accurate measures of the
intracellular currents in a limited shallow brain region below
the recording sensor without influence from volume conduc-
tion. ECD spatial properties not only indicate location of neural
sources but also their orientation and strength. This occurs
because restriction or enlargement of the brain area activated by
Comment
Large (n > 80) samples more variable than small (n < 40) samples
Equal and moderately unequal densities most effective
Equal numbers of male and female subjects best
Auditory stimuli produce best general measure
Two-stimulus oddball better than three-stimulus paradigms
0.20 better than <0.20 conditions
Medium/large stimulus differences better than small
Medium/high intensity levels better than low
Short/medium durations better than long
Count > press but produces more performance errors
Medium > hard > easy levels
impulse arrival is usually secondary to dynamic phenomena
such as use-dependent modulation of synaptic efficacy, changes
of excitatory/inhibitory input from adjacent/remote brain areas,
or from sensory flow (Rossini et al., 1994a,b; Tecchio et al.,
2000; Stavrinou et al., 2007). Co-registration of MEG with
structural MRI provides insights into the neuroanatomical
substrate of sensory and motor function. However, MEG
recordings cannot be made simultaneously with structural or
functional MRI acquisition, whereas EEG recordings now can
be acquired at the same time with special devices.
2.6. Transcranial magnetic stimulation (TMS)
TMS was introduced by Barker et al. (1985) and is a safe,
painless, and non-invasive technique increasingly employed in
brain functions studies (Kobayashi and Pascual Leone, 2003;
Rossini and Rossi, 2007). Only TMS variables used for the
investigation of the normally and pathologically aging brain are
reviewed here. The mechanisms underlying TMS-related
effects are often obtained using integrated approaches in
which drugs with experimentally identified mechanisms of
action are administered with the aim to produce specific and
physiologically detectable, changes of brain excitability.
2.6.1. TMS variables measurable following individual
stimuli
A single TMS pulse applied over M1 produces a series of
epidurally recordable corticospinal volleys, reflecting the
transsynaptic activation of superficial cortical neurons, whose
temporal summation at the spinal motoneuron level elicit a
motor evoked potential (MEP) in contralateral target muscles
(Di Lazzaro et al., 2001). The minimal intensity to induce an
MEP with muscle relaxation with an amplitude of about 50 mV
with a probability of 0.50 in a stimulation sequence defines the
excitability threshold at rest (Rossini et al., 1994a,b). This
approach reflects either the excitability and the local density of
a central core of excitatory interneurons and corticospinal
neurons (‘hot spot’) or of small and slow-propagating
 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
pyramidal neurons and is therefore a good parameter to
investigate the action of neuroactive drugs (Rossini et al.,
1994a,b; Hallett, 2000; Ziemann, 2004), and of the disease
process itself, involving regulatory mechanism of cortical
excitability.
Cortical mapping procedures with single TMS pulses focally
applied on several scalp positions overlying the motor cortex
take into account the number of cortical sites eliciting MEPs
and its ‘‘center of gravity’’ (Rossini et al., 1994a,b). They are
useful to track plastic changes originating from physiological
manipulations—i.e., changing the sensory feedback or during
motor learning or secondary to a disease process involving the
motor system (Pascual-Leone et al., 1995; Rossi et al., 1998).
Each MEP recorded during a voluntary contraction of the target
muscle is followed by a suppression of the electromyographic
(EMG) activity. This phenomenon is called the cortical silent
period (CSP), and indexes, after an early phase of spinal origin,
the activation of inhibitory (mainly GABAb) cortical inter-
neurons (Cantello et al., 1992; Siebner et al., 1998; Werhahn
et al., 1999).
2.6.2. TMS variables measurable following paired-pulses
Intracortical inhibitory and excitatory mechanisms can be
tested by a paired-pulse protocol in which a conditioning sub-
threshold TMS stimulus precedes a supra-threshold test
stimulus by a programmable interstimulus interval (ISI)
typically between 1 and 15 ms in duration. The amplitude
modulation of the test MEP allows the intracortical evaluation
of inhibitory (ISIs 1–4 ms = intracortical inhibition, ICI) and
facilitatory (at longer ISIs = intracortical facilitation, ICF)
phenomena, which are likely mediated by GABAa and
glutamate, respectively (Kujirai et al., 1993; Ziemann,
2004). If the conditioning pulse is applied on the median
nerve at the wrist and precedes the TMS test pulse by 20–25 ms
(a time compatible to the activation of the primary sensorimotor
cortex), the resulting MEPs are generally inhibited with respect
to those by the test pulse alone. This phenomenon has been
termed the short-latency afferent inhibition (SAI) technique
and is cortical in origin (Mariorenzi et al., 1991; Stefan et al.,
2000; Tokimura et al., 2000). Its generation seems to depend on
central cholinergic activity being abolished by scopolamine, a
potent muscarinic antagonist (Di Lazzaro et al., 2000).
2.6.3. Repetitive TMS (rTMS)
Single TMS pulses delivered in trains with a constant
frequency and intensity for a given time is the principle of
rTMS. This approach can influence transiently the function of
the underlying brain area by either potentiating or ‘‘knocking-
out’’ activity. It currently is the only in vivo method available to
demonstrate non-invasively the causality of a given cortical
relay in a particular task (Hallett, 2000; Walsh and Cowey,
2000; Rossi and Rossini, 2004). Repetitive TMS also has
therapeutic and rehabilitative capabilities, since after-effects of
repeated applications may persist in time. Depending on the
frequency of application, rTMS is known to increase or
decrease the level of cortical excitability, which is the basis for
the reported clinical benefits in diseases linked with brain
381
excitability dysfunctions (Post and Keck, 2001; Hoffman and
Cavus, 2002).
2.7. An integrated approach
A major advantage of integrating several neurophysiological
techniques such as EEG, MEG, and TMS is that each method
provides a different view of the same phenomenon. Computer-
assisted analysis facilitates online neuronavigation and off-line
reconstruction of the neurophysiological data, which can be used
to integrate and produce anatomical and flow/metabolic brain
images from individual subjects. These advances have spurred
additional modelling techniques wherein human cortical activity
from combined high-resolution EEG, MEG, and fMRI data have
been developed (Babiloni et al., 2001). Advanced methods for
the estimation of cortical connectivity from combined high-
resolution EEG and fMRI data also have been implemented
(Babiloni et al., 2005a). Cortical connectivity can be measured
by computing DTF derived from the estimated cortical current
density waveforms modelled cortical mantle over the regions of
interest. This method unveils the direction of the information
flow between the cortical areas, as it is directional in nature and
detects time-related changes of information flow between
cortical regions in different frequency bands.
3. Physiological aging
3.1. EEG and MEG rhythms
Resting EEG changes across physiological aging, with
gradual modifications in spectral power profile indicating a
pronounced amplitude decrease of alpha (8–13 Hz) and a
global ‘‘slowing’’ of the background EEG, with increases in
power and topographic location in the slower delta (2–4 Hz)
and theta (4–8 Hz) frequency ranges (Dujardin et al., 1994,
1995; Klass and Brenner, 1995; Klimesch, 1999). A recent
study in a large sample of healthy subjects (N = 185, 18–85
years) confirmed an age-dependent power decrement of low-
frequency alpha rhythms (8–10.5 Hz) in parietal, occipital, and
temporal regions, as well as a decrease of occipital delta
rhythms (Babiloni et al., 2006a).
Aging effects on parieto-occipital alpha rhythms presum-
ably reflect the activity of dominant oscillatory neural network
in the resting awake brain. This activity is modulated by
thalamo–cortical and cortico–cortical interactions facilitating/
inhibiting the transmission of sensorimotor information and the
retrieval of semantic information from cortical storage
(Steriade and Llinas, 1998; Brunia, 1999; Pfurtscheller and
Lopez da Silva, 1999). Low frequency alpha is primarily related
to subject’s global attentive readiness, whereas high-frequency
alpha reflects the oscillation of specific neural systems for the
elaboration of sensorimotor or semantic information (Kli-
mesch, 1996, 1997, 1999). Over the course of ‘‘natural’’ aging,
the power decrease of the occipital alpha rhythms might be
associated with changes in the cholinergic basal forebrain
system function, which sustain the excitatory activity in the
cholinergic brainstem pathway (Sarter and Bruno, 1998).
382 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
Despite the relative consensus on alpha decrease, there is no
general agreement on the modulation of delta and theta activity
in brain aging (Hartikainen et al., 1992). Recently, distribution
and age variation of spontaneous slow frequency activity (4–
8 Hz, theta) has been investigated in normal subjects of
different age with a 151-channel whole-head MEG device
(Puligheddu et al., 2005). Slow frequencies were divided in two
sub-bands (slow theta = 4–6 Hz, fast theta = 6–8 Hz) and data
from all trials fitted to a simple model of a single electric current
embedded in a spherically symmetric conductor to the
magnetic fields and projected onto an averaged MRI. Theta
spectral power generally was distributed over the posterior
parietal and occipital areas with fast theta sub-band dominance.
Dipole analysis resulted in a mid-sagittal distribution, though
the youngest group displayed more posterior theta dipoles
compared to the elderly (Puligheddu et al., 2005).
Neuroelectric output does not scale linearly with inputs
received, so that assessment of nonlinear EEG interactions is
important, as this method can provide information on the
strength, direction, and topography of the interdependencies.
Spatial organization of nonlinear interactions between different
brain regions has been investigated to compare anterior–
posterior intrahemispheric and left–right interhemispheric
interactions across physiological aging. Differences were
found in the rates of interdependencies between the left pre-
frontal and the right parietal regions between young and elderly,
suggesting that the aging brain engages right parietal region to
assist the pre-frontal cortex (Terry et al., 2004).
3.2. Event-related EEG–MEG rhythms during behavioral
tasks
Behavioral studies have found that compared to younger
subjects, healthy elderly subjects evince a slowing down of
information processing and a decline of short-term memory
(Bashore and Ridderinkhof, 2002), with a parallel reduction of
‘‘on-line’’ retention or manipulation of information (Fisk and
Warr, 1996; Keefover, 1998). EEG studies also have demon-
strated that memory load decreases alpha power in parietal and
frontocentral midline regions for young and elderly subjects,
respectively (McEvoy et al., 2001).
EEG recorded during a source memory study was analyzed
in the frequency domain to characterize functional networks of
alpha band activity related to performance and cortical
reorganization across physiological aging. Healthy young
and elderly participants were instructed to remember noun pairs
embedded in sentences grouped into two temporally distinct
lists. In response to subsequent noun probes, participants made
old/new judgments, followed by source judgments about list.
Alpha rhythms accompanying recognition and source retrieval
epochs were evaluated by spatial covariance analysis (Moeller
et al., 1998). For young subjects, the regional covariance
pattern involved coactivation of right anterior and left posterior
scalp recording sites. Source memory retrieval performance
was predicted by the subject difference in pattern expression
between epochs involving correct and incorrect source
attribution. The elderly adults also exhibited significant
coactivation over right anterior and left posterior areas. No
compensatory activation sites were identified for elderly
subjects who performed near chance in source retrieval (Luber
et al., 2004). More important, EEG spatial distribution
displayed an increasing uniformity with age. This effect was
attributed to an increased number of coupling interactions
among cortical areas, which may reflect loss of lateralized
(right/left hemispheres) and localized abilities such that
distributed networks are engaged for performing cognitive
tasks at the same level as the younger subjects (Babiloni et al.,
2000; Rossi et al., 2004). In a related study, delayed choice
response time tasks were used to assay ERD changes for theta
and alpha frequency activity across normal aging (Babiloni
et al., 2004d). The task required indication of which subsequent
stimulus was going to be presented as the cue stimulus. In the
‘‘memory’’ condition, a cue stimulus was memorized and a
delay period of a few seconds occurred. In the ‘‘non-memory’’
condition, the cue stimulus remained available during the entire
delay period. The explicit task requirement was visuo-spatial,
but the retention could be based on phonological and
somatosensory coding. Performance measures were highly
accurate, although somewhat better for the young compared to
elderly subjects. During the delay period, theta and alpha ERD
from correct responses were found in both groups, with alpha
ERD larger and longer during memory than non-memory task.
Fronto-parietal theta and parietal alpha ERD were larger in
young than elderly subjects for both tasks. Notably, the frontal
alpha ERD was negligible in the elderly group. These findings
imply that in the elderly subjects, (i) there is a weaker
involvement of parahippocampal–cortical circuits thought to be
related to theta ERD, and (ii) a weaker involvement of
‘‘executive’’ thalamo–cortical circuits as revealed by frontal
alpha ERD (Babiloni et al., 2004d) and that EEG measures
provide interesting indices of memory operations at different
ages.
3.3. ERPs and brain aging
Neuroelectric measures can provide direct imaging of
central nervous system (CNS) function. In particular, the P300
component has been widely used to study neurologic and
psychiatric cognitive impairment, although its utility has been
limited because normative data and standard acquisition
methods have not been clinically established (for specific
reviews, see DeBoer et al., 2005; Jeon and Polich, 2003; Oken,
1997; Polich, 2004; Verleger, 2003).
3.3.1. P300 clinical applications
The early suggestion that the P300 might be used to assess
cognitive function originated from studies of dementing
illness, since peak latency from patients was prolonged
compared to age-matched normal subjects (Goodin et al.,
1978). Most brain disorders affect the fundamental cognitive
operations of attention allocation and immediate memory, and
therefore influence P300 amplitude or latency measures (cf.
Goodin, 1990; Pfefferbaum et al., 1990). A systematic
evaluation of normative P300 measures compared to routine
 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
biomedical assay found them quite similar (Polich and Herbst,
2000). Indeed, P300 latency reflects less homogeneity than
many clinical tests, such as a blood-screening panel. Thus,
despite a lack of clinical specificity for P300, development of
an objective and relatively inexpensive means to assess
cognitive efficiency should be highly useful in clinical settings
(Katada et al., 2004; Polich, 2004). Additional considerations
for ERP clinical studies should include: (i) patient disease
characteristics and medication; (ii) sample characteristics such
as female and male proportions, education, age, and other
demographic data; (iii) food intake time, body temperature,
physical/mental fatigue level, and related biological factors, so
that these variables can be controlled directly or used as
covariates in the statistical analysis. Further, stimulus, task and
measurement methods need to be established empirically (e.g.,
Polich, 1997b; Polich and Kok, 1995; Salisbury et al., 2001),
with both P300 amplitude and latency measured and reported
at least for the midline electrodes (Fz, Cz, Pz). As peak latency
varies systematically across the scalp with component ampli-
tude, P300 latency values need to be obtained from individual
electrodes (Fjell and Walhovd, 2001; Polich et al., 1997).
3.4. Cerebral cortex excitability as revealed by TMS
Physiological aging is associated with more complex
activations of the motor system to compensate the reduced
movement skills (Ward and Frackowiack, 2003; Babiloni et al.,
2000). Therefore, TMS variables can provide useful clues to
investigate causally subclinical changes of cortical excitability
at the motor cortex level. Most of single-pulse TMS studies
have not found differences in excitability threshold of the
primary motor cortex between young and elderly (Pepin et al.,
1999; Pitcher et al., 2003; Rossi et al., 2004; Oliviero et al.,
2006). Others suggest an association between healthy aging and
increased motor thresholds (Rossini et al., 1992; Peinemann
et al., 2001). Such discrepancies likely originate from technical
and experimental differences. Input–output properties of the
aging brain reflect neural changes that can produce decreases in
MEP amplitude (Pitcher et al., 2003; Oliviero et al., 2006). This
result may originate from an increased distance of the excitable
elements within the motor cortex stemming from physiological
cortical atrophy. Alternatively, it may reflect a decreased
number of corticospinal motoneurons being activated in older
subjects or to a less synchronous activation of the same number
of motoneurons leading to phase cancellation of unit potentials
in the surface electromyogram (Rossini et al., 1992; Pitcher
et al., 2003). Amplitude reduction of the peripheral compound
muscle action potential (cMAP), a frequent finding in older
people due to physiological loss of large motor nerve peripheral
fibres, also may contribute to MEP amplitude reduction
(Kimura, 2001).
Studies specifically investigating MEP/cMAP ratios in
healthy aging are lacking, and few reports have examined
the effect of aging on intracortical inhibitory circuits. The CSP
seems to be shortened in the elderly (Oliviero et al., 2006), a
finding associated to similar CSP/MEP amplitude ratios in
young and elder subjects which may suggest that overlapping
383
mechanisms would account for both changes. Other inhibitory
GABAergic intracortical mechanisms revealed by ICI have
been found reduced in elderly subjects (Peinemann et al., 2001;
Hortobagyi et al., 2006). These results likely reflect compen-
satory phenomena to maintain motor skills, but the reduction of
ICI has not been confirmed in larger populations (Wassermann,
2002; Oliviero et al., 2006). Short latency afferent inhibition, a
cortical phenomenon relying on cholinergic activity, seems to
be preserved in healthy aging (Di Lazzaro et al., 2000;
Tokimura et al., 2000; Oliviero et al., 2006).
3.4.1. Encoding of elementary motor-related memories as
revealed by TMS
Traces of elementary motor-related memories, reflecting
synaptic adapting properties, can be revealed by TMS. A
paradigmatic experimental protocol includes a short period of
training, consisting of simple and voluntary repetitive thumb
movements in a specific direction opposite to the direction of
the thumb twitch elicited by TMS in untrained conditions. This
method is used to elicit reorganization within the cortical
representation of the thumb that encodes the kinematic details
of the practiced movement (Classen et al., 1998). After such
training, the thumb twitch direction evoked by TMS of the
contralateral motor cortex transiently reverse its direction
according to the practiced movements, with a return toward the
untrained condition within the following 30 min. Most studies
have demonstrated that formation of this elementary motor
memory is associated with changes in the balance of excitation
and inhibition within the primary motor cortex involving
GABAergic, cholinergic, alpha-adrenergic and dopaminergic
systems (Classen et al., 1998; Butefisch et al., 2000; Sawaki
et al., 2002, 2003a; Ziemann et al., 2004; Floel et al., 2005).
What is most relevant, however, is that the ability to encode
elementary motor-related memories seems to be age-dependent
as it progressively diminishes with increasing age (Sawaki
et al., 2003b).
3.4.2. Interference with cortical functions as revealed by
repetitive TMS
Neuroimaging findings suggest that lateralization of pre-
frontal cortex activation associated with episodic memory is
reduced by aging. It is debated whether this loss of asymmetry
during memory encoding and retrieval reflects compensatory
mechanisms or de-differentiation processes. This issue was
addressed by using rTMS to assess causal relationships
between performance and stimulated brain regions. The effects
of rTMS applied to the left or right dorsolateral prefrontal
cortex (DLPFC) simultaneously to the presentation of
memoranda on visuospatial recognition memory task were
compared in a population of healthy subjects divided in two
classes of age (<45 and >50 years). In the younger subjects,
rTMS of the right DLPFC interfered with retrieval more than
left DLPFC stimulation. The asymmetry of the effect
progressively vanished with aging, as indicated by bilateral
interference effects on recognition performance. Conversely,
the predominance of left DLPFC effect during encoding was
not abolished in the older subjects, thereby indicating its causal
384 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
role for encoding along the life span. Findings with rTMS
suggest that the bilateral engagement of the DLPFC has a
compensatory role on episodic memory performance across the
age span (Rossi et al., 2004).
4. Pathological aging: neurophysiological markers of
dementia
4.1. Background
Dementia is one of the most frequent chronic diseases of the
elderly. Its prevalence increases with age and affects nearly
30% of all octogenarians (Vicioso, 2002), with heavy social
costs and impact on family and caregivers. Neuropathological
hallmarks indicating Alzheimer’s dementia (AD) include
macroscopic signs characterized by reduced brain weight with
cortical atrophy and ventricular enlargements primarily due to
neuronal loss in the temporal and parietal structures.
Microscopic signs include neurofibrillary tangles (intracellular
aggregations of tau protein filaments) and amyloid plaques
(extracellular aggregates of amyloid beta-peptides) that are
particularly concentrated in the hippocampus, entorhinal
cortex, and post-central parietal neocortex (Iqbal et al.,
2002). Tangles are mainly found in hippocampal and
parahippocampal limbic structures, whereas extensive diffuse
and neuritic amyloid plaques – circumscribed by proinflam-
matory and proapoptotic reactions – form deposits throughout
the cortex (Goedert and Spillantini, 2006). A progressive
decrease of use-dependent synaptic plasticity and of inter-
neuronal connectivity and its association with the degree of
dementia is considered the neurophysiological hallmark of
brain aging (Cook and Leuchter, 1996). However, in pre-
clinical conditions plastic compensatory remodelling appears
to continue that maintains neural function, such that the
neuronal and synaptic death may occur in the absence of
dementia symptoms for an unknown duration.
The concept of ‘‘plasticity’’ applied to neurobiology
typically denotes the potential for change in addition to the
mechanisms of self-repair and/or of reorganization of neural
connections. Neural plasticity underlies learning as well as
endogenous brain function repair (Rossi et al., 1998; Rossini
et al., 2003; Pascual-Leone et al., 1995; Elbert et al., 1995;
Tecchio et al., 2000). CNS plasticity includes a number of
cellular and anatomical mechanisms that reflect synaptic
efficacy and synaptic redundancy, the true anatomical
distribution that underlies a neural network being much larger
than the usual area of functional influence (Bastian et al., 2004).
The functional status and distribution of a network appears to
depend on the balance between neural excitation and inhibition,
with some areas appearing silent or ‘‘masked’’ by a mechanism
of active tonic inhibition mediated through GABAergic input.
This active inhibition can be altered or removed, causing a rapid
change of the functional network, a process termed ‘‘unmask-
ing’’ (Jacobs and Donoghue, 1991). Modifications of the
neuronal membrane excitability, through changes in the Na+
channel, possibly mediated by protein kinase C activation, may
also play a role (Halter et al., 1995). Additional mechanisms
include long-term potentiation (LTP) and long-term depression
(LTD), which contribute to the functional strengthening or
weakening of existing synapses by which information is stored
in the CNS (Lisman and Spruston, 2005). LTP has been
regarded as the prototypic mechanism of modified synaptic
efficacy, and it can occur differently via modification of the
input to a postsynaptic cell, the concomitant synchronous input
to the synapse from another cell, or postsynaptic depolarization
(Asanuma and Pavlides, 1997; Rauschecker, 1995). LTD stems
from Na+ or Ca2+ channels at least for short-term changes,
while LTP-like mechanisms include glutamate dependent
NMDA receptor activation for long-term changes, a process
that can be antagonized by GABA-inhibition (Ziemann et al.,
1998). Another plasticity-related process is neuronal sprouting
and formation of new synapses, a process strongly influenced
by local neurotransmitter and neurotrophic factors release, and
synaptic protein synthesis (Deller and Frotscher, 1997). In
particular, dendrites and related spines with synaptic connec-
tions undergo continuous remodelling most likely also
modulated by interaction with neighbouring astrocytes
(Pfrieger and Barres, 1996).
4.2. Neurophysiological studies with the brain ‘‘at rest’’
When compared to healthy normal elderly (Nold) subjects,
AD patients evince high power for delta and theta and low
power for posterior alpha (8–12 Hz) and/or beta (13–30 Hz)
frequencies (Dierks et al., 2000; Huang et al., 2000;
Ponomareva et al., 2003; Jeong, 2004; Babiloni et al.,
2004c; Prichep, 2005). Some of these EEG changes could
discriminate among different dementia diagnoses, as a strong
decline of posterior slow-frequency alpha sources appears
specific for mild AD group compared to the vascular dementia
and normal elderly groups. In addition, abnormal wide theta
sources characterized cerebro-vascular dementia patients
(Babiloni et al., 2004c). EEG abnormalities were associated
with altered regional blood flow/metabolism and with impaired
global cognitive function as evaluated by mini-mental state
examination (MMSE; Sloan et al., 1995; Rodriguez et al., 1998,
1999; Jeong, 2004).
MEG also has provided contributions to the understanding
of the cortical rhythms in pathological aging. Parieto-temporal
delta and theta sources are enhanced in power in AD compared
to Nold subjects in association with hippocampal atrophy
(Fernandez et al., 2002, 2003). Furthermore, AD subjects
demonstrated a decrease of alpha sources in parieto-occipital
region possibly compensated by an increase of temporal alpha
sources (Osipova et al., 2005). It is noteworthy that delta
measurements contributed to a classification rule between AD
and Nold subjects with an estimated sensitivity and specificity
given by 68% and 76%, respectively (Fernandez et al., 2006).
When beta sources were added the classification improved with
an estimated sensitivity and specificity given by 81% and 80%,
respectively (Fernandez et al., 2006). This classification
improved to 90% and 100% for sensitivity and 100% specificity
when the model used both spectroscopic magnetic resonance
(myoinositol/N-acetyl aspartate) and delta dipole density from
 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
temporo-parietal cortical regions (Fernandez et al., 2005).
Finally, cortical theta and alpha rhythms as revealed by MEG
have discriminated severity level of AD and distinguished it
from Lewy body dementia (Franciotti et al., 2006).
Genetic risk factors such as Apo-E alleles are associated
with EEG rhythms abnormalities in AD (Jelic et al., 1997;
Lehtovirta et al., 1996, 2000; Almkvist et al., 2001). Patients
with e4 demonstrated faster theta and lower beta spectral power
than those with the e2 or e3 alleles (Lehtovirta et al., 1996).
Furthermore, AD with e2 or e3 compared to AD patients with
e4 showed demonstrated larger theta and lower beta power at
baseline and higher delta and lower alpha power after 3 years at
follow-up (Lehtovirta et al., 2000). For AD patients, ApoE e4
has been related to selective decrease in functional cortico–
cortical connectivity, which was suggested by the reduction of
right and left temporoparietal, right temporofrontal, and left
occipitoparietal alpha coherence (Jelic et al., 1997). Thus,
genetic risk factors for AD may affect EEG measures in
relatively specific ways.
EEG power per se does not capture one of the main features
of AD, namely the impairment of functional neural con-
nectivity. It has been reported that AD patients present an
abnormal linear coupling of EEG rhythms among cortical
regions, as revealed by spectral EEG coherence (Jelic et al.,
1997; Locatelli et al., 1998; Wada et al., 1998a,b; Knott et al.,
2000; Adler et al., 2003), suggesting a linear temporal
synchronicity of coupled EEG rhythms from simultaneously
engaged neural sources. Such findings imply that functional
coupling of cortical rhythms is modulated by cholinergic
systems, and that a decrease of cortical EEG coherence may be
a fine-grained marker of AD, since it is characterized by
defective basal forebrain cholinergic inputs to cortex and
hippocampus (Stam et al., 2006).
Most EEG studies of AD have reported a prominent decrease
of alpha band coherence (Leuchter et al., 1987, 1992; Cook and
Leuchter, 1996; Locatelli et al., 1998; Wada et al., 1998a,b;
Jelic et al., 1997, 2000; Knott et al., 2000; Adler et al., 2003).
This result also has been found to be associated with ApoE
genetic risk, which is hypothesized to be mediated by
cholinergic deficit (Jelic et al., 1997). However, delta and
theta band coherence changes in AD is not homogeneous, as
some studies demonstrate a decrease of slow-band EEG
coherence, whereas others find an increase (Leuchter et al.,
1992; Locatelli et al., 1998; Adler et al., 2003; Brunovsky et al.,
2003). To improve the functional coupling evaluation EEG and
MEG data have been analyzed with procedures inspired by the
theory of nonlinear dynamics (Stam, 2005). AD patients
produce a nonlinearly defined ‘‘complexity’’, which is a
measure of signal dynamic coordination. Brain rhythms loose
the usual modulation in complexity as observed by eyes-open
versus eyes-close comparisons, as a reflection of neuronal
death, deficiency in neurotransmission, and/or loss of
connectivity in local neuronal networks (Besthorn et al.,
1995; Jeong et al., 1998). Nonlinear analysis also has been used
to model brain flexibility in information processing, defined as
the capability to affect information processing states from
identical initial conditions. AD patients demonstrate a decrease
385
in information processing flexibility, so that EEG complexity
decrease in AD might be attributable to decreased nonlinear
dynamics that are associated with cognitive decline. Among the
techniques for nonlinear brain dynamics, synchronization
likelihood combines sensitivity to linear and nonlinear
functional coupling of EEG/MEG rhythms (Stam, 2005). This
measure has been shown to be significantly decreased at 10–
12 Hz, 14–18 Hz, and 18–22 Hz bands when comparing AD to
MCI and/or Nold subjects (Stam et al., 2002; Babiloni et al.,
2004e, 2006b; Pijnenburg et al., 2004). When applied to MEG
data, global synchronization likelihood has been found to be
lower in mild AD compared to Nold subjects at upper alpha
(10–14 Hz), upper beta (18–22 Hz), and gamma (22–40 Hz)
bands (Stam, 2005).
In addition or in parallel to the cortico–cortical uncoupling
progression, a decrease of synaptic coupling is likely to
contribute to reducing selective EEG coherence for faster
rhythms, as observed in healthy humans by transient use of a
cholinergic synaptic blocker like scopolamine (Kikuchi et al.,
2000). Animal models suggest that acetylcholine loss produces
a decrease of high-frequency EEG couplings and an increase of
slow-frequency couplings (Villa et al., 2000). Loss or a
significant drop in EEG synchronization in faster rhythms also
has been correlated with decreased MMSE scores in MCI and
AD patients (Stam, 2005). Linear and nonlinear EEG analysis
improves classification accuracy of AD compared to unaffected
controls, and these methods correlate with disease severity
(Babiloni et al., 2004e, 2006b; Stam, 2005).
Few studies have assessed EEG measures over the course of
dementia progression. A significant increase of delta and theta
power in conjunction with decrease of alpha and beta power
over a period of 30 months from diagnosis have been found
(Coben et al., 1985). The length of the follow-up is of
paramount importance and indicates the reason for a lack of
findings over a 12-month period (Soininen et al., 1989). The
major question in this context is: ‘‘Which is the physiological
mechanism at the basis of abnormal resting brain rhythms in
MCI and AD?’’ Abnormality of resting EEG rhythms may
originate from impairment in the cholinergic neural projections
from basal forebrain, which is a pivotal aspect of AD
(Mesulam, 2004). Resting EEG alpha power is decreased
from experimental damage to this cholinergic pathway
(Holschneider et al., 1998). Furthermore, the cholinergic basal
forebrain has been found to be responsive to the treatment with
cholinesterase inhibitors more for AD than other dementias
(Tanaka et al., 2003). Conversely, brainstem cholinergic
innervations of the thalamus are relatively spared in AD
patients (Mesulam, 2004). Long-term (1 year) treatment of
acetylcholinesterase inhibitors (AChEI) demonstrate less
temporal and occipital alpha reduction for responders
compared to non-responders and a combined effect on delta
and low alpha (Babiloni et al., 2006c; Rodriguez et al., 2002).
Hence, increasing cholinergic tone was related to restoring
temporal and occipital alpha rhythms in responders. Brain
cholinergic systems also appear to improve primarily cerebral
blood flow with a functional impact on attentional and memory
functions (Classen and Jansen, 2006).
386 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
4.3. Event-related EEG–MEG rhythms
EEG rhythms have been assessed for each harmonic
response during photic stimulation (white flickers at 5, 10
and 15 flashes/s) in younger subjects, non-demented elderly
subjects, and AD patients. Analysis indicated that the elderly
subjects generally demonstrated more absolute power than the
younger subjects and AD patients during photo stimulation
(Kikuchi et al., 2002a). Similar results have been reported for
interhemispheric and intrahemispheric coherence at alpha
frequencies (Wada et al., 1998a,b; Kikuchi et al., 2002b). These
results suggest that AD is not the end result of normal aging of
the brain, at least for the functional organization produced by
photo stimulation.
Cognitive function in dementia has been assayed by delayed
response tasks in which the subject is instructed to remember a
‘‘cue’’ stimulus, with a related motor response made after a
delay period to an imperative ‘‘go’’ stimulus (Goldman-Rakic,
1995). Frontoparietal and midline alpha power decreased in
young and elderly healthy subjects during the delay (Filipovic
et al., 2001; Bastiaansen et al., 2002; Babiloni et al., 2004c,d).
Different types of neurophysiological techniques have demon-
strated abnormalities in AD during memory tasks: (i) a
hyperactivation of prefrontal and midline activity (Grady et al.,
2001), (ii) a functional disconnection between prefrontal cortex
and hippocampus (Grady et al., 2001), and (iii) a stronger
activation of the left temporal cortex (Grossman et al., 2003).
These findings provide evidence for the clinical benefit of
neuroelectric measures in the assessment of AD, although a
clear interpretation is still being sought.
MEG measures using two delayed-response tasks also have
been used to investigate ERD of frontocentral midline alpha
rhythms in AD (Babiloni et al., 2005b). This approach was
employed to determine whether ‘easy’ cognitive tasks that
minimize fatigue/distraction and maximize the rate of correct
responses would induce an abnormal recruitment of cortical
neuronal resources at an early dementia stage. A low rate of
correct performances was observed in AD (35%) compared
both to young (97%) and elderly (71%) healthy subjects. The
most frequent error was obtained for the delayed response,
which may reflect slowing of decisional and visuo-motor
processes in the demented compared to the normal subjects.
This outcome is consistent with decline of the correct memory/
cognitive performances from neurophysiological and patholo-
gical aging (McEvoy et al., 2001; West and Craik, 2001; Grady
et al., 2001). During the delay period of both tasks, the alpha
ERD was stronger in AD than in normal young and elderly
subjects (Babiloni et al., 2005b). The absence of ERD
differences between the two conditions suggests that task
difficulty for the delayed response tasks was stronger than
changes in memory load.
Alpha band hyper-reactivity in AD as indexed by
increased alpha ERD suggests an abnormal increase of the
cortical excitation or disinhibition even during simple
cognitive demands. Such findings agree with previous
functional neuroimaging studies on memory that demon-
strated a stronger allocation of cortical resources in AD when
compared to Nold subjects (Backman et al., 1999; Grady
et al., 2001; Grossman et al., 2003). In addition, they are
consonant with other findings of abnormal central rhythms
when processing sensory stimuli or performing voluntary
movements and with hyper-reactivity of AD primary motor
cortex as revealed by TMS (Ferri et al., 1996; Babiloni et al.,
2004f, 2000; see Section 4.5). Frontocentral midline alpha
ERD recovered in all groups during the late phase of the
delay period, but more in demented and normal elderly than
in the young subjects (Babiloni et al., 2005b). The late phase
of the delay period was characterized by stable ERS
measures or just a reduction of the ERD that did not affect
ERS values. Thus, alpha recovery in this task may indicate
that both neural inhibition and removal of the excitatory
activity associated with GABA-ergic and glutamate-ergic
processes, respectively (Comi and Leocani, 1999; Hummel
et al., 2002; Rau et al., 2003).
During delay period frontocentral midline alpha ERD
accompanying correct responses, was stronger in AD than in
controls, so that simple delayed response tasks are quite
difficult for patients in the early dementia stage and induce a
frontocentral midline hyper-reactivity possibly originating
from hyper-excitation or disinhibition. In addition, abnor-
mally strong values of frontal and ipsilateral central
sensorimotor rhythms have been found during a unimanual,
self-paced finger movement in mild AD. This result suggests
that compared with healthy controls, they have unreactive
and abnormally low interhemispheric EEG coherence as well
as an unreactive and abnormally high frontoparietal EEG
coherence, which supports the hypothesis of an impaired
mechanism of sensorimotor cortical coupling in mild AD
(Babiloni et al., 2004f).
4.4. P300 and Alzheimer’s disease
Some early reports indicate that ERP measures can
distinguish between subcortical and cortical dementias
(Rosenberg et al., 1985; Goodin and Aminoff, 1986), and that
P300 latency can separate individuals with dementia from those
with depression-associated pseudodementia (Brown et al.,
1982; Patterson et al., 1988). However, not all studies find these
effects (Polich et al., 1986). Discrimination between patients
with early AD from normal subjects also has been reported
(Holt et al., 1995; Polich et al., 1990a,b). Relatively
sophisticated cognitive paradigms have been applied to these
populations with some success, but no neuroelectric disease
markers have been established.
Table 3 summarizes ERP studies that elicited the P300 using
an oddball paradigm in AD and unaffected elderly control
subjects (see also Jeong, 2004; Olichney and Hillert, 2004).
Early studies typically employed a mental counting task,
whereas latter reports used a button press response that permits
averaging of only those trials to which subjects respond. The
sample populations, stimuli, methods, and recording conditions
varied appreciably across studies, but the majority of papers
found differences between AD and controls: P300 amplitude
was typically smaller for AD patients and latency was
 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400 387

Table 3
Summary of ERP studies on Alzheimer and elderly control subjects
Study (year) Sample size Paradigm ALZ 6¼ CTL
ALZ CTL Modality Task Amplitude Latency
a b
Brown et al. (1982) 11 24 Auditory Count NR +
Syndulko et al. (1982) 12a 45 Auditory Count NR +
Duffy et al. (1984) 9 15 Auditory Count + 
St. Claire et al. (1985) 15 23 Auditory Count + +
Gordon et al. (1986) 19a 55 Auditory Count NR +
Blackwood et al. (1987) 20 23 Auditory Count + +
Neshige et al. (1988) 13 27 Auditory Press  +
Patterson et al. (1988) 15a 15 Auditory Press  +
Ball et al. (1989) 18 15 Auditory Count  +
Surwillo and Iyer (1989) 33 5 Auditory Passive  +
O’Donnell et al. (1990) 30 20 Auditory Count NR +
Marsh et al. (1990) 18 17 Auditory Count NR +
Polich et al. (1990a,b) 16 16 Auditory Press + +
Ito (1991) 67 43 Auditory Count  +
Onofrj et al. (1991) 30 30 Auditory and visual Count  +
Verleger et al. (1992) 7 20 Auditory and visual Press  
Holt et al. (1995) 26 26 Auditory Count + +
Ford et al. (1996) 12 12 Auditory Count + /+ c
Kraiuhin et al. (1996) 11 15 Auditory Press NR 
Kazmerski and Friedman (1998) 16 16 Auditory Press  NR
Kazmerski et al. (1997) 16 16 Auditory Press + NR
Knott et al. (1999) 32 15 Auditory Passive  
Yamaguchi et al. (2000) 32 18 Auditory Press + +
Daffner et al. (2001) 10 20 Visual Press + 
Saito et al. (2001) 10 10 Visual Press + 
Frodl et al. (2002) 30 43 Auditory Press + +
Boller et al. (2002) 10 12 Auditory Press + +
Reprinted with permission from Polich and Corey-Bloom (2005). For reference citations, please see original publication.
a
Alzheimer + a few multi-infarct patients.
b
NR, not reported; +, significant group difference; , non-significant group difference.
c
Significant effects for some conditions/analyses.

consistently longer in AD compared to unaffected controls
(Polich, 2004; Polich and Corey-Bloom, 2005).
Fig. 3 illustrates grand averages from AD and unaffected
controls in a study designed to characterize oddball difficulty
and stimulus modality, as these variables affect P300 values and
interact with normal aging (Polich, 1996; Vesco et al., 1993).
P300 amplitude was smaller and latency longer for the AD,
with no other task-related group effects obtained. The strongest
differences between AD and control groups were obtained with
the relatively easy oddball task—especially for P300 ampli-
tude. Peak latency group differences were not robust and were
eliminated for the hard oddball task. Indeed, component
amplitude rather than latency produced the more consistent
difference between AD and control subjects, peak timing was
affected by the task and modality factors but in an additive
rather than interactive fashion. This outcome indicates that
P300 measures for AD are stable, almost regardless of task or
stimulus modality conditions. The scalp topographic distribu-
tion of P300 amplitude was affected by the group factor, such
that AD produced appreciably less frontal-to-parietal increase
across task difficulty. P300 latency was relatively unaffected by
scalp topography other than the usual increase from the frontal-
to-parietal electrodes. Thus, at the group level P300 can
discriminate between AD and healthy controls.
4.5. The reappraisal of brain excitability in dementia as
revealed by TMS
TMS can be used to assess cortical excitability, intracortical
facilitatory and inhibitory mechanisms resulting from the
balance among neurotransmitters, and dynamic synaptic
adaptations to progressive neuronal loss. However, TMS
studies in AD have not yielded converging findings. Motor
threshold is generally reduced in AD compared to healthy age
matched controls and is similarly reduced in subcortical
ischemic vascular dementia (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). Several
reports have not found reduction of motor thresholds (Liepert
et al., 2001; Ferreri et al., 2003; Pierantozzi et al., 2004;
Nardone et al., 2006), with one study noting increased rather
than decreased motor thresholds in AD (Perretti et al., 1996).
Global cortical hyperexcitability while the brain is ‘‘at rest’’ in
AD is a stable result (Ferreri et al., 2003; Di Lazzaro et al.,
2004), which seems to occur independently of gabaergic and
cholinergic corticocortical mechanisms dysfunction as reduced
motor thresholds and ICI and SAI are uncorrelated (Di Lazzaro
et al., 2004). Since TMS does not provide specific pathophy-
siological information but is sensitive to the ‘‘global weight’’ of
388 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400

Fig. 3. Grand averaged event-related potentials for the early Alzheimer disease and unaffected matched controls (n = 16/group) for the single-stimulus, easy oddball,
medium oddball, and hard oddball tasks that were presented in the auditory (upper) and visual (lower) modalities (after Polich and Corey-Bloom, 2005, with
permission).

several neurotransmitters as well as subcortical and cortical
motor inputs, interpretation of cortical hyperexcitability in AD
is not yet possible.
Although early TMS studies suggested cholinergic deficit as
the main candidate in AD (Pepin et al., 1999; Liepert et al.,
2001), a recent hypothesis is that excitatory glutamatergic
system is dysfunctional and stems from an imbalance between
non-NMDA and NMDA neurotransmission (Ferreri et al.,
2003; Di Lazzaro et al., 2003a). Ketamine is a glutamatergic
agent that enhances non-NMDA transmission through an
increase in the release of endogenous glutamate to induce
cortical hyperexcitability in normal subjects, which supports a
pivotal role of glutamate and the regulation of its (NMDA and
AMPA) receptors (Farlow, 2004; Di Lazzaro et al., 2003b;
Hynd et al., 2004; Voisin et al., 2004). A consistent finding is
that normal ICF occurs in AD (Pierantozzi et al., 2004; Liepert
et al., 2001), making glutamatergic hypothesis and the more
widely accepted and complex cholinergic deficit difficult to
support as the only cause of cortical hyperexcitability in AD
(De Sevilla et al., 2002). Converging evidence implies that SAI
is reduced in AD and that AChEI can normalize it (Di Lazzaro
et al., 2002, 2006; Nardone et al., 2006). Moreover, SAI is
preserved in other forms of cognitive impairment as
frontotemporal dementia (Di Lazzaro et al., 2006). Post-
mortem studies do not show central cholinergic deficits or
dementia with Lewy bodies, in which the cholinergic deficit
seems to be mainly presynaptic (Perry et al., 1991; Procter
et al., 1999; Nardone et al., 2006). Assessment of GABA-a
 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400 389

mediated ICI mechanisms by paired-pulse TMS impaired
intracortical inhibitory transmission in AD has been demon-
strated (Liepert et al., 2001; Di Lazzaro et al., 2002; Pierantozzi
et al., 2004; Nardone et al., 2006), but the finding was not
replicated in frontotemporal dementia or in dementia with
Lewy bodies (Pierantozzi et al., 2004; Nardone et al., 2006).
Impaired ICI mechanisms therefore may be reversed by
middle-term treatment with galantamine and other AChEI,
suggesting that cholinergic (and not only GABAergic) deficit
might play a role in reduction of corticocortical inhibition
(Pierantozzi et al., 2004; Liepert et al., 2001; Di Lazzaro et al.,
2004). Other reports failed to find changes of ICI between
unaffected controls and AD patients (Di Lazzaro et al., 2004),
which supports the concept that GABAergic neurons and
receptors are relatively preserved in AD (Nagga et al., 1999;
Rissman et al., 2003). This outcome implies that most but not
all studies showed that the CSP in AD is preserved (Liepert
et al., 2001; Alagona et al., 2004; Inghilleri et al., 2006; Perretti
et al., 1996). Thus, subtle GABAergic dysfunctions can be
characterized by paired-pulse TMS studies (but not by the
majority of CSP studies), which could reflect an epiphenome-
non of the complex cortical excitability balance unrelated to
age, disease duration, and degree of cognitive impairment
(Nardone et al., 2006).
The majority of these TMS results indicate that the cortex of
AD patients is hyperexcitable, and that such hyperexcitability
even may offer clues for the differential diagnosis from other
dementias in which the cholinergic deficit is not predominant.
An intriguing issue that can be addressed by TMS is the study of
cortical reorganization of the motor output in AD. Indeed,
motor cortex physiological organization is early involved in
AD, despite the lack of clinically evident motor deficits which
only appear later (Suva et al., 1999). This observation is not
surprising considering that the motor cortex, through muscari-
nic receptors and cholinergic terminals, receives a major input
from the nucleus basalis of Meynert (Selden et al., 1998).
Mapping of motor output in mild AD patients asymptomatic for
motor deficits has demonstrated frontal and medial shift of the
cortical motor maps for hand muscles. In healthy controls the
centre of gravity of motor cortical output is coincident with
the site of maximal excitability (hot spot; Cicinelli et al., 1997),
whereas in AD patients it shifts toward frontal and a medial
regions in the absence of changes in ‘hot spot’ (Fig. 4; Ferreri
et al., 2003). An altered synaptic plasticity in AD also has been
demonstrated by applying brief trains of high-frequency
rTMS to motor cortex and recording of MEPs from the
contralateral hand muscles. This procedure can induce a
progressive increase in MEP size in normal age-matched
controls, but it produces opposite changes in AD (Inghilleri
et al., 2006). This finding was interpreted as an altered short-
term synaptic enhancement in excitatory circuits of the motor
cortex. Additional assessment of these findings will be required
by evaluating AD patients after different pharmacological
treatments (e.g., cholinergic versus drugs acting on NMDA
glutamate receptors).
In summary, TMS assays of cortical disinhibition in AD as a
dysfunction of a single neurotransmitter in a single neural
circuit or as the net effect of a complex involvement of more

Fig. 4. Schematic representation of the mean centers of gravity of cortical TMS mapping in 16 patients with AD (panel a) and in 13 control subjects (panel b). For
each group of subjects, Cartesian values (panel c) of center of gravity for the extensor communis digitorum muscle (ECD) and abductor digiti minimi muscle (ADM)
are shown. The cross intersection corresponds to the overlapping of the hot spot and centers of gravity. Deviations are expressed in cm. Because of the absence of
interhemispheric asymmetries in cortical mapping, measures refer to the ‘‘average hemisphere’’. Note that in control there is a slight medial shift, whereas in AD
patients a clear anteromedial shift of the motor area representation can be appreciated (from Ferreri et al., 2003, partly modified).
390 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400

than one neurotransmitter system in several brain areas likely
reflects a single facet of a pathological mosaic. A lasting pre-
clinical condition under the attack of pro-degenerative agents
could produce the AD brain as alternative strategies of
functioning belonging to the brain reserve even for the
execution of simple motor tasks (Babiloni et al., 2000; Ferreri
et al., 2003). The emerging evidence indicates that the
‘‘stressed synapses’’ may acquire a different function both in
terms of effects and of utilized neurotransmitter and may be
strongly dependent by the sampling time of the tested patients
(Armstrong et al., 2003).
5. Mild cognitive impairment and preclinical dementia
5.1. ‘‘Resting’’ EEG–MEG rhythms
Assessing pre-clinical dementia is of keen interest as a clinical
research issue, since MCI often precedes frank dementing illness.
As the selective cognitive impairments characteristic of MCI are
primarily memory-related and not severe enough to exceed
standard clinical criteria for AD, their prodromal qualities do not
greatly impair daily functioning and can be identified by refined
clinical and neuropsychological evaluation. Consistent MCI
symptoms 3–5 years following their identification either remain
stable or decrease in 30–50% of the cases, whereas the remaining
cases progress toward a frank AD condition. Epidemiological
and clinical follow-up studies confirm that MCI reflects a
transition state towards mild AD and prompts the idea that early
identification of MCI patients can facilitate rehabilitative or
pharmacological interventions to slow disease progression
(Winblad et al., 2004; Gauthier et al., 2006; Portet et al.,
2006). Fig. 5 illustrates MCI effects for low-frequency alpha (8–
10.5 Hz) activity from parietal, occipital, and limbic areas that
demonstrate an intermediate magnitude in MCI compared to
mild AD and normal elderly (Babiloni et al., 2006d). Increase of
slow EEG power coupled with a decrease in alpha activity is
linked to cognitive performance decline in MCI compared to
Nold. More important, the magnitude of these sources is
correlated negatively with MMSE scores across subjects of the
three groups, suggesting that EEG evidence of alpha power
decrease in MCI compared to normal subjects is related to
behavioral cognition (Jelic et al., 1996, 2000; Huang et al., 2000;
Grunwald et al., 2001; Kwak, 2006; Rossini et al., 2006). The
relative decrease of posterior low-frequency alpha sources in
MCI may be related to an initial selective impairment of the
cholinergic basal forebrain, which could induce a sustained
increase of the excitatory activity in the cholinergic brainstem
pathway (Sarter and Bruno, 1998; Kikuchi et al., 2000; Villa
et al., 2000). As a consequence, the increased excitability of
thalamocortical connections would desynchronize the resting
alpha rhythms and enhance the cortical excitability as seen in AD
(see Section 4.5). Hence, changes of low-frequency alpha power
in MCI and mild AD suggest a progressive impairment of the
thalamo–cortical and cortico–cortical systems that govern visual
attention. This hypothesis is consistent with clinical findings of
increasing deficits of visuo-spatial abilities in MCI and mild AD
(Arnaiz and Almkvist, 2003). Similarly, limbic sources imply a
progressive impairment of thalamo–cortical and cortico–cortical
systems regulating attention tone for memory functions.
Decreases in cortico–thalamic modulation and increase of
slow EEG rhythms secondary to progressive cortical hypo-
perfusion have been found in AD (Rodriguez et al., 1999,

Fig. 5. Grand average of LORETA solutions (i.e., normalized relative current density at the cortical voxels) modeling the distributed EEG sources for delta, theta,
alpha 1, alpha 2, beta 1, and beta 2 bands in normal elderly (Nold), mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD) groups. The left side of the
maps (top view) corresponds to the left hemisphere. Legend: LORETA, low-resolution brain electromagnetic tomography. Color scale: all power estimates were
scaled based on the averaged maximum value (i.e., alpha 1 power value of occipital region in Nold). The maximal value of power is reported under each column (from
Babiloni et al., 2006d, with permission).
 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400 391

2004). Abnormal delta and alpha sources in the posterior brain
regions could therefore index the progressive decline of
cognitive visuo-spatial functions across MCI and mild AD
thereby supporting a transition between these conditions
(Winblad et al., 2004; Gauthier et al., 2006; Portet et al.,
2006). An intriguing aspect includes the peculiar magnitude
increase of the parieto-occipital high-frequency (10.5–13 Hz)
alpha sources in MCI compared to mild AD and normal elderly
(Babiloni et al., 2006d). Furthermore, prospective studies have
demonstrated that increased delta/theta activity, decreased
alpha and beta, and slowed mean frequency may be predictors
of progression from MCI to dementia (Huang et al., 2000; Jelic
et al., 2000). These findings imply that neuroelectric indices
could be developed for the preclinical assessment of dementia,
as their acquisition are inexpensive, easily implemented,
entirely non-invasive and very well suited for large-scale
screening and follow-up of at-risk populations. Fig. 6 illustrates
the findings from a major EEG study of these factors in MCI
subjects. The hypothesis that presence of e4 affects sources of
resting EEG rhythms in MCI and AD was assessed in 89 MCI
with 34.8% e4 incidence and 103 AD with 50.4% e4 incidence
(Babiloni et al., 2006e). Alpha 1 and 2 sources in occipital,
temporal, and limbic areas were of lower amplitude in subjects
carrying the e4 allele. For AD homozygous for ApoE e4 allele,
abnormal temporo-parietal and occipitoparietal EEG or MEG
rhythms were found (Jelic et al., 1997; Stam, 2005). However,
in addition to ApoE e4 allele, another important genetic risk
factor for late-onset AD is haplotype B of CST3 (the gene

Fig. 6. Grand average of LORETA solutions (i.e., normalized relative current density at the cortical voxels) modeling the distributed EEG sources for delta (2–4 Hz), theta
(4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 Hz) bands in MCI and AD groups, both subdivided in two genetic sub-groups:
MCI/AD not carrying the ApoE e4 and MCI+/AD+ carrying the e4 allele. The left side of the maps (top view) corresponds to the left hemisphere. Legend: LORETA,
low-resolution brain electromagnetic tomography. Color scale: all power estimates was scaled based on the averaged maximum value (i.e., alpha 1 power value of occipital
region in MCI not carrying the ApoE e4 allele). The maximal power value is reported under each column (from Babiloni et al., 2006c, with permission).
392 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
coding for cystatin C—a neurotrophic protein), which was
investigated to establish eventual links with cortical rhythmi-
city (Babiloni et al., 2006f). EEG measures were obtained from
84 MCI with 42% B haplotype and 65 AD with 40% B
haplotype. Slow alpha (from parietal, occipital, temporal areas)
and fast alpha (from occipital areas) power were statistically
lower in CST3 B carriers. A trend was observed for occipital
delta power sources as stronger in CST3 B carriers than in non-
carriers for both MCI and AD patients.
Association between the presence and amount of hippocam-
pus atrophy in AD and MCI subjects and changes in sources of
posterior slow rhythms has been observed by EEG and whole-
head MEG (Fernandez et al., 2003; Wolf et al., 2003; Helkala
et al., 1996). Less known is the relationships between
impairments of white matter and slow rhythms across the
continuum from MCI to AD. This issue has been addressed with
EEG assessments in MCI (N = 34) and AD (N = 65) cases
(Babiloni et al., 2006a). Delta activity was related to the amount
of cortical atrophy revealed by MRI voxel-to-voxel volumetry of
lobar brain volume (white and gray matter), such that as delta
power increased brain volume decreased. Thus, changes in brain
structure and function could be found for MCI and AD patients.
As life expectancy and elderly populations in Western
countries are increasing, the incidence of MCI that may predict
AD or vascular dementia is rising. Cognitive impairment
associated with MCI or AD at least at the group level is
associated with decreased power and coherence in the alpha/
beta band. This observation suggests the occurrence of a
functional disconnection among cortical areas, since both
power and coherence in the delta and theta bands increase with
cortical deafferentiation from subcortical structures (Spiegel
et al., 2006). However, the extent to which features of
neuroelectric activity can be used to predict the conversion
from MCI to AD in single subjects is as yet unclear. When EEG
theta power (3.5–7.5 Hz) is higher in MCI subjects who will
convert to AD compared to MCI subjects who will not, an
overall predictive accuracy of 90% is obtained between
baseline EEG features and probability of future decline
(Prichep et al., 2006). Furthermore, spectral EEG coherence
or other EEG features have shown to contribute to the
discrimination of Nold from mild AD with 89–45% of success,
from MCI to AD with 92–78% of success, and the conversion of
MCI subjects to AD with 87–60% of success (Nuwer, 1997;
Claus et al., 1999; Jelic et al., 2000; Huang et al., 2000; Bennys
et al., 2001; Adler et al., 2003; Brassen et al., 2004; Lehmann
et al., 2007; Missonnier et al., 2006). These findings are
encouraging for future development of this prognostic and
perhaps diagnostic approach (Buscema et al., 2007).
Rossini et al. (2006) investigated whether combined analysis
of EEG power and coherence provide early and reliable
discrimination of MCI subjects who will convert to AD after a
relatively brief follow-up. Cortical connectivity using spectral
coherence measures and LORETA were used to characterize
EEG sources at baseline in 69 MCI cases that were reassessed
clinically after about 14 months. At follow-up, 45 subjects were
classified as MCI stable whereas the remaining 24 had
converted to AD. Fronto-parietal midline coherence as well
as delta (temporal), theta (parietal, occipital and temporal), and
slow alpha (central, parietal, occipital, temporal, limbic)
sources were reliably weaker than the patients who had
converted from MCI to AD. Moreover, low midline coherence
and weak temporal source was associated with low (about 10%)
annual rate AD conversion; conversion rate steeply increased
up to 60% when strong temporal delta source and high midline
gamma coherence were present. This outcome indicates that
quantitative EEG is able to predict with a good approximation
MCI progression to AD in the short run.
5.2. Event-related EEG–MEG rhythms
Evaluation of brain rhythms in MCI has been extended to
assess neural synchronization in the working brain (Comi and
Leocani, 1999). Opening of the eyes is a simple task that
induced a modulation of EEG power explaining several
cognitive deficits in MCI and AD subjects (van der Hiele et al.,
2007). EEG power in Nold and amnestic MCI was obtained
during three different memory conditions: word memory,
picture memory, and animal fluency (van der Hiele et al.,
2007a). More alpha ERD was found for the Nold than for MCI
during picture memory activation, which may be related to an
insufficient cortical information processing at the pre-clinical
stage of AD and the absence of compensatory neural processes.
This outcome is consonant with theta ERS during n-back
working memory task and neuropsychological follow-up after 1
year, wherein stable MCI subjects demonstrated greater theta
ERS than MCI subjects who evinced cognitive decline across
the year (Missonnier et al., 2006). Indeed, theta ERS was
significantly related to the cognitive outcome explaining 15.5%
of its variability over the scalp, which implies that these
changes are a generalized deficit. This view is challenged by the
following lines of evidence: first, ERD accompanying episodic
short-term memory scanning demands was measured in MCI
and AD compared to Nold subjects (Karrasch et al., 2006).
During the encoding phase, beta ERD (10–20 Hz) was higher in
MCI than Nold, consistent with the interpretation that the task
is more difficult at that pre-clinical stage of dementia. During
the retrieval phase, alpha-beta ERD (7–17 Hz) was practically
absent in AD, suggesting it is associated with deficient lexical-
semantic processing during the retrieval phase in working
memory tasks (Karrasch et al., 2006). Second, functional
coupling (synchronization likelihood) of resting state EEG has
shown that cognitive dysfunction in AD and its precursor MCI
are associated with a loss of functional connectivity at high
(upper alpha and beta) frequency bands not only at rest but also
during visual working memory demands (Pijnenburg et al.,
2004). At both rest and memory conditions, the synchronization
likelihood was significantly decreased at high frequency alpha
(10–12 Hz) and beta (12–30 Hz) bands in AD compared to
healthy persons with subjective memory complaints while MCI
showed higher alpha ERD during the only working memory
task (Pijnenburg et al., 2004). Third, EEG data were recorded at
rest and during three levels of working memory load in MCI
and in Nold (Jiang, 2005). EEG power from theta to beta was
higher in MCI than Nold at rest and during working memory
 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
tasks. In addition, only during working memory tasks, the EEG
coherences at all bands were significantly higher in the MCI
than Nold (Jiang, 2005). Fourth, inter- and intra-hemispheric
EEG coherence values were separately evaluated in a
subsequent study (Jiang and Zheng, 2006). During working
memory tasks, these parameters from delta to beta were both
higher in MCI than Nold, indicating higher degree of functional
connectivity between and within hemispheres during working
condition. Taken together, the results suggest that MCI may be
associated with compensatory information processing as
revealed by ERD and band coherence during memory demands.
5.3. Excitability of cerebral cortex as revealed by TMS
Application of rTMS is an innovative strategy to improve
cognitive performance in patients with MCI. In a recent
study, 40 participants underwent two fMRI sessions in which
they were administered two equivalent face-name memory
tasks (Solé-Padullé et al., 2006). Following each fMRI
session, subjects were asked to match faces with their
corresponding proper name. Between sessions sham or real
off-line 5 Hz rTMS trains were applied randomly in a double-
blind design. Improvement in the associative memory task
occurred only for subjects who received active rTMS and was
associated with recruitment of right prefrontal and bilateral
posterior cortical regions as indicated by the second fMRI
session. Repetitive TMS on dorsolateral prefrontal cortex
also has been demonstrated to improve action (but not object)
naming in mild AD (Cotelli et al., 2006). These findings
reflect the potential of rTMS to recruit compensatory
networks that underlie the memory-encoding process and
suggest that rTMS in helpful in restoring brain function
(Rossi and Rossini, 2004).
6. Summary and conclusions
The present review highlights the use of modern neuro-
physiological techniques that report assessment of physiolo-
gical and pathological brain aging. Electromagnetic brain
signals during mental rest and cognitive engagement provide
significant insights on the aging processes and cognitive decline
from neurodegeneration. In addition, cortical excitability and
the causative role of relevant cortical areas within a cognitive
task reliably can be performed using TMS techniques. ERP
measures also provide considerable information about cogni-
tion that is quantitatively comparable to other clinically used
biomedical assays. Indeed, P300 variability with respect to both
task and biological determinants has been well characterized,
such that refinement of ERP methods for clinical applications is
now feasible. Elaboration of how the P300 and other cognitive
components reflect neuropsychological processes will help to
increase their clinical relevance.
Neurophysiological data also can be fused with structural
and metabolic/flow information using contemporary software
that can produce a comprehensive view of brain function in
space and time. Moreover, risk factors including genetic causes
correlate with neurophysiological findings to reinforce their
393
causative role in diagnosis and prognosis of pathologic brain
aging. Unfortunately, this remarkable literature suffers from the
partial lack of integration of various low-cost and non-invasive
neurophysiological techniques within a unique frame of goal-
directed test for evaluation of physiological brain aging and
discrimination from abnormal scenarios heralding neurode-
generation. In the near future, systematic evaluation of
Alzheimer’s and other dementing disorders relative to normal
aging using refined and integrated neuroimaging methods will
help to coalesce these methodologies and improve diagnostic
utility. If this approach can provide clinically useful informa-
tion at the individual level, such methods should prompt design
of an instrument widely available for large-scale population-
based screening studies. The results would be welcome for
prognosticating disease progression and providing an objective
evaluation of innovative pharmacological and cognitive
rehabilitation treatments for dementing illness.
Acknowledgements
Preparation of this chapter was supported by NIH Grants
RO1-DA018262 and 3 P50 AA06420 to J.P. and by Association
Fatebenefratelli for Research (AFaR). John Polich thanks Maya
Cano for very helpful editorial comments.
References
Adler, G., Brassen, S., Jajcevic, A., 2003. EEG coherence in Alzheimer’s
dementia. J. Neural Transm. 9, 1051–1058.
Alagona, G., Bella, R., Ferri, R., Carnemolla, A., Pappalardo, A., Costanzo, E.,
Pennisi, G., 2001. Transcranial magnetic stimulation in Alzheimer’s dis-
ease: motor cortex excitability and cognitive severity. Neurosci. Lett. 314,
57–60.
Alagona, G., Ferri, R., Pennisi, G., Carnemolla, A., Maci, T., Domina, E.,
Maertens de Noordhout, A., Bella, R., 2004. Motor cortex excitability in
Alzheimer’s disease and in subcortical ischemic vascular dementia. Neu-
rosci. Lett. 362, 95–98.
Almkvist, O., Jelic, V., Amberla, K., Hellstrom-Lindahl, E., Meurling, L.,
Nordberg, A., 2001. Responder characteristics to a single oral dose of
cholinesterase inhibitor: a double-blind placebo-controlled study with
tacrine in Alzheimer patients. Dement. Geriatr. Cogn. Disord. 12, 22–32.
Armstrong, D.M., Sheffield, R., Mishizen-Eberz, A.J., Carter, T.L., Rissman,
R.A., Mizukami, K., Ikonomovic, M.D., 2003. Plasticity of glutamate and
GABAA receptors in the hippocampus of patients with Alzheimer’s disease.
Cell. Mol. Neurobiol. 23, 491–505.
Arnaiz, E., Almkvist, O., 2003. Neuropsychological features of mild cognitive
impairment and preclinical Alzheimer’s disease. Acta Neurol. Scand. Suppl.
179, 34–41.
Asanuma, H., Pavlides, C., 1997. Neurobiological basis of motor learning in
mammals. Neuroreport 8 .
Babiloni, F., Babiloni, C., Fattorini, L., Carducci, F., Onorati, P., Urbano, A.,
1995. Performances of surface Laplacian estimators: a study of simulated
and real scalp potential distributions. Brain Topogr. 8, 35–45.
Babiloni, F., Babiloni, C., Carducci, F., Fattorini, L., Onorati, P., Urbano, A.,
1996. Spline Laplacian estimate of EEG potentials over a realistic magnetic
resonance-constructed scalp surface model. Electroencephalogr. Clin. Neu-
rophysiol. 98, 363–373.
Babiloni, C., Carducci, F., Cincotti, F., Rossini, P.M., Neuper, C., Pfurtscheller,
G., Babiloni, F., 1999. Human movement-related potentials vs. desynchro-
nization of EEG alpha rhythm: a high-resolution EEG study. Neuroimage
10, 658–665.
Babiloni, C., Babiloni, F., Carducci, F., Cincotti, F., Del Percio, C., De Pino, G.,
Maestrini, S., Priori, A., Tisei, P., Zanetti, O., Rossini, P.M., 2000. Move-
394 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
ment-related electroencephalographic reactivity in Alzheimer disease. Neu-
roimage 12, 139–146.
Babiloni, F., Carducci, F., Cincotti, F., Del Gratta, C., Pizzella, V., Romani,
G.L., Rossini, P.M., Tecchio, F., Babiloni, C., 2001. Linear inverse source
estimate of combined EEG and MEG data related to voluntary movements.
Hum. Brain Mapp. 14, 197–209.
Babiloni, F., Babiloni, C., Carducci, F., Cincotti, F., Rossini, P.M., 2003. ‘The
stone of madness’ and the search for the cortical sources of brain diseases
with non-invasive EEG techniques. Clin. Neurophysiol. 114, 1775–1780.
Babiloni, C., Vecchio, F., Babiloni, F., Brunelli, G.A., Carducci, F., Cincotti, F.,
Pizzella, V., Romani, G.L., Tecchio, F.T., Rossini, P.M., 2004a. Coupling
between ‘‘hand’’ primary sensorimotor cortex and lower limb muscles after
ulnar nerve surgical transfer in paraplegia. Behav. Neurosci. 118, 214–222.
Babiloni, C., Babiloni, F., Carducci, F., Cincotti, F., Vecchio, F., Cola, B., Rossi,
S., Miniussi, C., Rossini, P.M., 2004b. Functional frontoparietal connectiv-
ity during short-term memory as revealed by high-resolution EEG coher-
ence analysis. Behav. Neurosci. 118, 687–697.
Babiloni, C., Binetti, G., Cassetta, E., Cerboneschi, D., Dal Forno, G., Del
Percio, C., Ferreri, F., Ferri, R., Lanuzza, B., Miniussi, C., Moretti, D.V.,
Nobili, F., Pascual-Marqui, R.D., Rodriguez, G., Romani, G.L., Salinari, S.,
Tecchio, F., Vitali, P., Zanetti, O., Zappasodi, F., Rossini, P.M., 2004c.
Mapping distributed sources of cortical rhythms in mild Alzheimer’s
disease. A multicentric EEG study. Neuroimage 22, 57–67.
Babiloni, C., Babiloni, F., Carducci, F., Cappa, S.F., Cincotti, F., Del Percio, C.,
Miniussi, C., Vito Moretti, D., Rossi, S., Sosta, K., Rossini, P.M., 2004d.
Human cortical rhythms during visual delayed choice reaction time tasks. A
high-resolution EEG study on normal aging. Behav. Brain Res. 153, 261–
271.
Babiloni, C., Ferri, R., Moretti, D.V., Strambi, A., Binetti, G., Dal Forno, G.,
Ferreri, F., Lanuzza, B., Bonato, C., Nobili, F., Rodriguez, G., Salinari, S.,
Passero, S., Rocchi, R., Stam, C.J., Rossini, P.M., 2004e. Abnormal fronto-
parietal coupling of brain rhythms in mild Alzheimer’s disease: a multi-
centric EEG study. Eur. J. Neurosci. 19, 2583–2590.
Babiloni, C., Miniussi, C., Moretti, D.V., Vecchio, F., Salinari, S., Frisoni, G.,
Rossini, P.M., 2004f. Cortical networks generating movement-related EEG
rhythms in Alzheimer’s disease: an EEG coherence study. Behav. Neurosci.
118, 698–706.
Babiloni, F., Cincotti, F., Babiloni, C., Carducci, F., Mattia, D., Astolfi, L.,
Basilisco, A., Rossini, P.M., Ding, L., Ni, Y., Cheng, J., Christine, K.,
Sweeney, J., He, B., 2005a. Estimation of the cortical functional connec-
tivity with the multimodal integration of high-resolution EEG and fMRI
data by directed transfer function. Neuroimage 24, 118–131.
Babiloni, C., Cassetta, E., Chiovenda, P., Del Percio, C., Ercolani, M., Moretti,
D.V., Moffa, F., Pasqualetti, P., Pizzella, V., Romani, G.L., Tecchio, F.,
Zappasodi, F., Rossini, P.M., 2005b. Alpha rhythms in mild dements during
visual delayed choice reaction time tasks: a MEG study. Brain Res. Bull. 65,
457–470.
Babiloni, C., Frisoni, G., Steriade, M., Bresciani, L., Binetti, G., Del Percio, C.,
Geroldi, C., Miniussi, C., Nobili, F., Rodriguez, G., Zappasodi, F., Carfagna,
T., Rossini, P.M., 2006a. Frontal white matter volume and delta EEG
sources negatively correlate in awake subjects with mild cognitive impair-
ment and Alzheimer’s disease. Clin. Neurophysiol. 117, 1113–1129.
Babiloni, C., Ferri, R., Binetti, G., Cassarino, A., Forno, G.D., Ercolani, M.,
Ferreri, F., Frisoni, G.B., Lanuzza, B., Miniussi, C., Nobili, F., Rodriguez,
G., Rundo, F., Stam, C.J., Musha, T., Vecchio, F., Rossini, P.M., 2006b.
Fronto-parietal coupling of brain rhythms in mild cognitive impairment: a
multicentric EEG study. Brain Res. Bull. 69, 63–73.
Babiloni, C., Cassetta, E., Dal Forno, G., Del Percio, C., Ferreri, F., Ferri, R.,
Lanuzza, B., Miniussi, C., Moretti, D.V., Nobili, F., Pascual-Marqui, R.D.,
Rodriguez, G., Luca Romani, G., Salinari, S., Zanetti, O., Rossini, P.M.,
2006c. Donepezil effects on sources of cortical rhythms in mild Alzheimer’s
disease: responders vs. non-responders. Neuroimage 31, 1650–1665.
Babiloni, C., Binetti, G., Cassetta, E., Dal Forno, G., Del Percio, C., Ferreri,
F., Ferri, R., Frisoni, G., Hirata, K., Lanuzza, B., Miniussi, C., Moretti,
D.V., Nobili, F., Rodriguez, G., Romani, G.L., Salinari, S., Rossini, P.M.,
2006d. Sources of cortical rhythms change as a function of cognitive
impairment in pathological aging: a multicenter study. Clin. Neurophy-
siol. 117, 252–268.
Babiloni, C., Benussi, L., Binetti, G., Cassetta, E., Dal Forno, G., Del Percio,
C., Ferreri, F., Ferri, R., Frisoni, G., Ghidoni, R., Miniussi, C., Rodriguez,
G., Romani, G.L., Squitti, R., Ventriglia, M.C., Rossini, P.M., 2006e.
Apolipoprotein E and alpha brain rhythms in mild cognitive impairment:
a multicentric electroencephalogram study. Ann. Neurol. 59, 323–
334.
Babiloni, C., Benussi, L., Binetti, G., Bosco, P., Busonero, G., Cesaretti, S., Dal
Forno, G., Del Percio, C., Ferri, R., Frisoni, G., Ghidoni, R., Rodriguez, G.,
Squitti, R., Rossini, P.M., 2006f. Genotype (cystatin C) and EEG phenotype
in Alzheimer disease and mild cognitive impairment: a multicentric study.
Neuroimage 29, 948–964.
Backman, L., Andersson, J.L., Nyberg, L., Winblad, B., Nordberg, A., Almk-
vist, O., 1999. Brain regions associated with episodic retrieval in normal
aging and Alzheimer’s disease. Neurology 52, 1861–1870.
Barker, A.T., Jalinous, R., Freeston, I.L., 1985. Non-invasive magnetic stimula-
tion of the human motor cortex. Lancet 1, 1106–1107.
Bashore, T.R., Ridderinkhof, K.R., 2002. Older age, traumatic brain injury, and
cognitive slowing: some convergent and divergent findings. Psychol. Bull.
128, 151–198.
Bastiaansen, M.C., Posthuma, D., Groot, P.F., de Geus, E.J., 2002. Event-related
alpha and theta responses in a visuo-spatial working memory task. Clin.
Neurophysiol. 113, 1882–1893.
Bastian, J., Chacron, M.J., Maler, L., 2004. Plastic and nonplastic pyramidal
cells perform unique roles in a network capable of adaptive redundancy
reduction. Neuron 41, 767–779.
Bennys, K., Rondouin, G., Vergnes, C., Touchon, J., 2001. Diagnostic value
of quantitative EEG in Alzheimer disease. Neurophysiol. Clin. 31, 153–
160.
Berger, H., 1929. Über das Elektroenkephalogramm des Menschen. Archiv für
Psychiatrie und Nervenkrankheiten 87, 527–570.
Berger, H., 1938. Das Elektroenkephalogramm des Menschen. Halle an der
Saale, Buchdruckerei des Waisenhauses, volume 6, No. 38 of Nova acta
Leopoldina. Neue Folge.
Besthorn, C., Sattel, H., Geiger-Kabisch, C., Zerfass, R., Forstl, H., 1995.
Parameters of EEG dimensional complexity in Alzheimer’s disease. Elec-
troencephalogr. Clin. Neurophysiol. 95, 84–89.
Brassen, S., Braus, D.F., Weber-Fahr, W., Tost, H., Moritz, S., Adler, G., 2004.
Late-onset depression with mild cognitive deficits: electrophysiological
evidences for a preclinical dementia syndrome. Dement. Geriatr. Cogn.
Disord. 18, 271–277.
Brown, W.S., Marsh, J.T., LaRue, A., 1982. Event-related potentials in psy-
chiatry: differentiating depression and dementia in the elderly. Bull. L.A.
Neurol. Soc. 47, 91–107.
Brunia, C.H., 1999. Neural aspects of anticipatory behavior. Acta Psychol.
(Amst.) 101, 213–242.
Brunovsky, M., Matousek, M., Edman, A., Cervena, K., Krajca, V., 2003.
Objective assessment of the degree of dementia by means of EEG.
Neuropsychobiology 48, 19–26.
Buscema, M., Rossini, P., Babiloni, C., Grossi, E., 2007. The IFAST model, a
novel parallel nonlinear EEG analysis technique, distinguishes mild cog-
nitive impairment and Alzheimer’s disease patients with high degree of
accuracy. Artif. Intell. Med. 40 (2), 127–141.
Butefisch, C.M., Davis, B.C., Wise, S.P., Sawaki, L., Kopylev, L., Classen, J.,
et al., 2000. Mechanisms of use-dependent plasticity in the human motor
cortex. Proc. Natl. Acad. Sci. 97, 3661–3665.
Cantello, R., Gianelli, M., Civardi, C., Mutani, R., 1992. Magnetic brain
stimulation: the silent period after the motor evoked potential. Neurology
42, 1951–1959.
Celesia, G.G., Kaufman, D., Cone, S., 1987. Effects of age and sex on pattern
electroretinograms and visual evoked potentials. Electroencephalogr. Clin.
Neurophysiol. 68, 161–171.
Cicinelli, P., Traversa, A., Bassi, A., et al., 1997. Interhemispheric differences
of hand muscle representation in human motor cortex. Muscle Nerve 20,
535–542.
Classen, J.A., Jansen, R.W., 2006. Cholinergically mediated augmentation of
cerebral perfusion in Alzheimer’s disease and related cognitive disorders:
the cholinergic-vascular hypothesis. J. Gerontol. A: Biol. Sci. Med. Sci. 61,
267–271.
 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
Classen, J., Liepert, J., Wise, S.P., Hallett, M., Cohen, L.G., 1998. Rapid
plasticity of human cortical movement representation induced by practice. J.
Neurophysiol. 79, 1117–1123.
Claus, J.J., Strijers, R.L., Jonkman, E.J., Ongerboer de Visser, B.W., Jonker, C.,
Walstra, G.J., Scheltens, P., van Gool, W.A., 1999. The diagnostic value of
electroencephalography in mild senile Alzheimer’s disease. Clin. Neuro-
physiol. 110, 825–832.
Coben, L.A., Danziger, W., Storandt, M., 1985. A longitudinal EEG study of
mild senile dementia of Alzheimer type: changes at 1 year and at 2.5 years.
Electroencephalogr. Clin. Neurophysiol. 61, 101–112.
Comi, G., Leocani, L., 1999. Neurophysiological imaging techniques in
dementia. Ital. J. Neurol. Sci. 20 (Suppl.), S265–S269.
Conroy, M.A., Polich, J., 2007. Normative variation of P3a and P3b from a large
sample (N = 120): gender, topography, and response time. J. Psychophysiol.
21, 22–32.
Cook, I.A., Leuchter, A.F., 1996. Synaptic dysfunction in Alzheimer’s disease:
clinical assessment using quantitative EEG. Behav. Brain Res. 78, 15–23.
Cotelli, M., Manenti, R., Cappa, S.F., Geroldi, C., Zanetti, O., Rossini, P.M.,
Miniussi, C., 2006. Effect of transcranial magnetic stimulation on action
naming in patients with Alzheimer disease. Arch. Neurol. 63, 1602–1604.
De Carvalho, M., de Mendoza, A., Miranda, P., Garcia, C., De Lourdes, M.,
1997. Magnetic stimulation in Alzheimer’s disease. J. Neurol. 244, 304–
307.
De Sevilla, D.F., Cabezas, C., De Prada, A.N., et al., 2002. Selective muscarinic
regulation of functional glutammatergic Schaffer collateral synapses in rat
CA1 pyramidal neurons. J. Physiol. 545, 51–63.
DeBoer, T., Scott, L.S., Nelson, C.A., 2005. ERPs in developmental popula-
tions. In: Handy, T.C. (Ed.), Event-related Potentials: A Methods Hand-
book. MIT Press, Cambridge, MA, pp. 263–297.
Deller, T., Frotscher, M., 1997. Lesion-induced plasticity of central neurons:
sprouting of single fibres in the rat hippocampus after unilateral entorhinal
cortex lesion. Prog. Neurobiol. 53, 687–727.
Desmedt, J.E., Cheron, G., 1981. Non-cephalic reference recording of early
somatosensory potentials to finger stimulation in adult or aging normal man:
differentiation of widespread N18 and contralateral N20 from the prero-
landic P22 and N30 components. Electroencephalogr. Clin. Neurophysiol.
52, 553–570.
Di Lazzaro, V., Oliviero, A., Profice, P., et al., 2000. Muscarinic receptor
blockade has different effects on the excitability of intracortical circuits in
human motor cortex. Exp. Brain Res. 135, 455–461.
Di Lazzaro, V., Oliviero, A., Profice, P., Meglio, M., Cioni, B., Tonali, P.,
Rothwell, J.C., 2001. Descending spinal cord volleys evoked by transcranial
magnetic stimulation of the motor cortex leg area in conscious humans. J.
Physiol. 537, 1047–1058.
Di Lazzaro, V., Oliviero, A., Tonali, P.A., Marra, C., Daniele, A., Profice, P.,
Saturno, E., Pilato, P., Fasullo, C., Rothwell, J.C., 2002. Non-invasive in
vivo assessment of cholinergic cortical circuits in AD using transcranial
magnetic stimulation. Neurology 59, 392–397.
Di Lazzaro, V., Oliviero, A., Pilato, F., Saturno, E., Di leone, M., Tonali, P.A.,
2003a. Motor cortex hyperexcitability to transcranial magnetic stimulation
in Alzheimer’s disease: evidence of impaired glutammatergic
neurotransmission? Ann. Neurol. 53, 824.
Di Lazzaro, V., Oliviero, A., Profice, P., et al., 2003b. Ketamine increases motor
cortex excitability to transcranial magnetic stimulation. J. Physiol. 547,
485–496.
Di Lazzaro, V., Oliviero, A., Pilato, F., Saturno, E., Dileone, M., Marra, C.,
Daniele, A., Ghirlanda, S., Gainotti, G., Tonali, P.A., 2004. Motor cortex
hyperexcitability to transcranial magnetic stimulation in Alzheimer’s dis-
ease. J. Neurol. Neurosurg. Psychiatry 75, 555–559.
Di Lazzaro, V., Pilato, F., Dileone, M., Saturno, E., Oliviero, A., Marra, C.,
Daniele, A., Ranieri, F., Gainotti, G., Tonali, P.A., 2006. In vivo cholinergic
circuit evaluation in frontotemporal and Alzheimer dementias. Neurology
66, 1111–1113.
Dierks, T., Jelic, V., Pascual-Marqui, R.D., Wahlund, L., Julin, P., Linden, D.E.,
Maurer, K., Winblad, B., Nordberg, A., 2000. Spatial pattern of cerebral
glucose metabolism (PET) correlates with localization of intracerebral
EEG-generators in Alzheimer’s disease. Clin. Neurophysiol. 111, 1817–
1824.
395
Donchin, E., 1981. Surprise!. . .Surprise? Psychophysiology 18, 493–513.
Dujardin, K., Bourriez, J.L., Guieu, J.D., 1994. Event-related desynchronization
(ERD) patterns during verbal memory tasks: effect of age. Int. J. Psycho-
physiol. 16, 17–27.
Dujardin, K., Bourriez, J.L., Guieu, J.D., 1995. Event-related desynchronization
(ERD) patterns during memory processes: effects of aging and task diffi-
culty. Electroencephalogr. Clin. Neurophysiol. 96, 169–182.
Duncan-Johnson, C.C., 1981. P300 latency: a new metric of information
processing. Psychophysiology 18, 207–215.
Elbert, T., Pantev, C., Wienbruch, C., Rockstroh, B., Taub, E., 1995. Increased
cortical representation of the fingers of the left hand in string players.
Science 270, 305–307.
Farlow, M.R., 2004. NMDA receptor antagonists. A new therapeutic approach
for Alzheimer’s disease. Geriatrics 59, 22–27.
Fein, G., Turetsky, B., 1989. P300 latency variability in normal elderly: effects
of paradigm and measurement technique. Electroencephalogr. Clin. Neu-
rophysiol. 72, 384–394.
Fernandez, A., Maestu, F., Amo, C., Gil, P., Fehr, T., Wienbruch, C., Rockstroh,
B., Elbert, T., Ortiz, T., 2002. Focal temporoparietal slow activity in
Alzheimer’s disease revealed by magnetoencephalography. Biol. Psychiatry
52, 764–770.
Fernandez, A., Arrazola, J., Maestu, F., Amo, C., Gil-Gregorio, P., Wienbruch,
C., Ortiz, T., 2003. Correlations of hippocampal atrophy and focal low-
frequency magnetic activity in Alzheimer disease: volumetric MR imaging-
magnetoencephalographic study. AJNR Am. J. Neuroradiol. 24, 481–487.
Fernandez, A., Garcia-Segura, J.M., Ortiz, T., Montoya, J., Maestu, F., Gil-
Gregorio, P., Campo, P., Viano, J., 2005. Proton magnetic resonance
spectroscopy and magnetoencephalographic estimation of delta dipole
density: a combination of techniques that may contribute to the diagnosis
of Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 20, 169–177.
Fernandez, A., Turrero, A., Zuluaga, P., Gil, P., Maestu, F., Campo, P., Ortiz, T.,
2006. Magnetoencephalographic parietal delta dipole density in mild
cognitive impairment: preliminary results of a method to estimate the risk
of developing Alzheimer disease. Arch. Neurol. 63, 427–430.
Ferreri, F., Pauri, F., Pasqualetti, P., Fini, R., Dal Forno, G., Rossini, P.M., 2003.
Motor cortex excitability in Alzheimer’s disease: a transcranial magnetic
stimulation study. Ann. Neurol. 53, 102–108.
Ferri, R., Del Gracco, S., Elia, M., Musumeci, S.A., Spada, R., Stefanini, M.C.,
1996. Scalp topographic mapping of middle-latency somatosensory evoked
potentials in normal aging and dementia. Neurophysiol. Clin. 26, 311–319.
Filipovic, S.R., Jahanshahi, M., Rothwell, J.C., 2001. Uncoupling of contingent
negative variation and alpha band event-related desynchronization in a go/
no-go task. Clin. Neurophysiol. 112, 1307–1315.
Fisk, J.E., Warr, P., 1996. Age and working memory: the role of perceptual
speed, the central executive, and the phonological loop. Psychol. Aging 11,
316–323.
Fjell, A., Walhovd, K., 2001. P300 and neuropsychological tests as measures of
aging: scalp topography and cognitive changes. Brain Topogr. 14, 25–40.
Floel, A., Breitenstein, C., Hummel, F., Celnik, P., Gingert, C., Sawaki, L.,
et al., 2005. Dopaminergic influences on ormation of a motor memory. Ann.
Neurol. 58, 121–130.
Franciotti, R., Iacono, D., Della Penna, S., Pizzella, V., Torquati, K., Onofrj, M.,
Romani, G.L., 2006. Cortical rhythms reactivity in AD, LBD and normal
subjects: a quantitative MEG study. Neurobiol. Aging 27 (8), 1100–1109.
Gauthier, S., Reisberg, B., Zaudig, M., Petersen, R.C., Ritchie, K., Broich, K.,
Belleville, S., Brodaty, H., Bennett, D., Chertkow, H., Cummings, J.L., de
Leon, M., Feldman, H., Ganguli, M., Hampel, H., Scheltens, P., Tierney,
M.C., Whitehouse, P., Winblad, B., 2006. International Psychogeriatric
Association Expert Conference on mild cognitive impairment. Mild cog-
nitive impairment. Lancet 367, 1262–1270.
Goedert, M., Spillantini, M.G., 2006. A century of Alzheimer’s disease. Science
314, 777–781.
Goldman-Rakic, P.S., 1995. Cellular basis of working memory. Neuron 114,
477–485.
Gonsalvez, C.J., Polich, J., 2002. P300 amplitude is determined by target-to-
target interval. Psychophysiology 39, 388–396.
Goodin, D.S., 1990. Clinical utility of long latency ‘cognitive’ event-related
potentials P300: the pros. Electroencephalogr. Clin. Neurophysiol. 76, 2–5.
396 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
Goodin, D.S., Aminoff, M.J., 1986. Electrophysiological differences between
subtypes of dementia. Brain 109, 1103–1113.
Goodin, D.S., Squires, K.C., Starr, A., 1978. Long latency event-related
components of the auditory evoked potential in dementia. Brain 101,
635–648.
Grady, C.L., Furey, M.L., Pietrini, P., Horwitz, B., Rapoport, S.I., 2001. Altered
brain functional connectivity and impaired short-term memory in Alzhei-
mer’s disease. Brain 124, 739–756.
Grossman, M., Koenig, P., Glosser, G., DeVita, C., Moore, P., Rhee, J., Detre, J.,
Alsop, D., Gee, J., fMRI study, 2003. Functional magnetic resonance
imaging. Neural basis for semantic memory difficulty in Alzheimer’s
disease: an fMRI study. Brain 126, 292–311.
Grunwald, M., Busse, F., Hensel, A., Kruggel, F., Riedel-Heller, S., Wolf, H.,
Arendt, T., Gertz, H.J., 2001. Correlation between cortical theta activity and
hippocampal volumes in health, mild cognitive impairment, and mild
dementia. J. Clin. Neurophysiol. 18, 178–184.
Hallett, M., 2000. Transcranial magnetic stimulation and the human brain.
Nature 406, 147–150.
Halliday, A.M., McDonald, W.I., Mushin, J., 1972. Delayed visual evoked
response in optic neuritis. Lancet 1, 982–985.
Halter, J.A., Carp, J.S., Wolpaw, J.R., 1995. Operantly conditioned motoneuron
plasticity: possible role of sodium channels. J. Neurophysiol. 73, 867–871.
Hari, R., Lounasmaa, O.V., 1989. Recording and interpretation of cerebral
magnetic fields. Science 244, 432–436.
Hartikainen, P., Soininen, H., Partanen, J., Helkala, E.L., Riekkinen, P., 1992.
Aging and spectral analysis of EEG in normal subjects: a link to memory
and CSF AChE. Acta Neurol. Scand. 86, 148–155.
Helkala, E.L., Hanninen, T., Hallikainen, M., Kononen, M., Laakso, M.P.,
Hartikainen, P., Soininen, H., Partanen, J., Partanen, K., Vainio, P., Riekki-
nen Sr., P., 1996. Slow-wave activity in the spectral analysis of the
electroencephalogram and volumes of hippocampus in subgroups of Alz-
heimer’s disease patients. Behav. Neurosci. 110, 1235–1243.
Hoffman, R.E., Cavus, I., 2002. Slow transcranial magnetic stimulation, long-
term depotentiation, and brain hyperexcitability disorders. Am. J. Psychia-
try 159, 1093–1102.
Holschneider, D.P., Leuchter, A.F., Scremin, O.U., Treiman, D.M., Walton,
N.Y., 1998. Effects of cholinergic deafferentation and NGF on brain
electrical coherence. Brain Res. Bull. 45, 531–541.
Holt, L., Raine, A., Pa, G., Schneider, L., Henderson, V., Pollock, V.E., 1995.
P300 topography in Alzheimer’s disease. Psychophysiology 32, 257–
265.
Hortobagyi, T., Del Olmo, M.F., Rothwell, J.C., 2006. Age reduces cortical
reciprocal inhibition in humans. Exp. Brain Res. 171, 322–329.
Huang, C., Wahlund, L., Dierks, T., Julin, P., Winblad, B., Jelic, V., 2000.
Discrimination of Alzheimer’s disease and mild cognitive impairment by
equivalent EEG sources: a cross-sectional and longitudinal study. Clin.
Neurophysiol. 111, 1961–1967.
Hummel, F., Andres, F., Altenmuller, E., Dichgans, J., Gerloff, C., 2002.
Inhibitory control of acquired motor programmes in the human brain. Brain
125, 404–420.
Hynd, M.R., Scott, H.L., Dodd, P.R., 2004. Glutammate-mdiated excitotoxicity
and neurodegeneration in Alzheimer’s disease. Neurochem. Int. 45, 583–
595.
Ilan, A.B., Polich, J., 1999. P300 and response time from a manual Stroop task.
Clin. Neurophysiol. 110, 367–373.
Inghilleri, M., Conte, A., Frasca, V., Scaldaferri, N., Gilio, F., Santini, M.,
Fabbrini, G., Principe, M., Berardelli, A., 2006. Altered response to rTMS in
patients with Alzheimer’s disease. Clin. Neurophysiol. 117, 103–109.
Iqbal, K., Alonso Adel, C., El-Akkad, E., Gong, C.X., Haque, N., Khatoon, S.,
Pei, J.J., Tsujio, I., Wang, J.Z., Grundke-Iqbal, I., 2002. Significance and
mechanism of Alzheimer neurofibrillary degeneration and therapeutic
targets to inhibit this lesion. J. Mol. Neurosci. 19, 95–99.
Isotani, T., Tanaka, H., Lehmann, D., Pascual-Marqui, R.D., Kochi, K., Saito,
N., Yagyu, T., Kinoshita, T., Sasada, K., 2001. Source localization of EEG
activity during hypnotically induced anxiety and relaxation. Int. J. Psycho-
physiol. 41, 143–153.
Jacobs, K.M., Donoghue, J.P., 1991. Reshaping the cortical motor map by
unmasking latent intracortical connections. Science 251, 944–947.
Jelic, V., Shigeta, M., Julin, P., Almkvist, O., Winblad, B., Wahlund, L.O.,
1996. Quantitative electroencephalography power and coherence in Alz-
heimer’s disease and mild cognitive impairment. Dementia 7, 314–
323.
Jelic, V., Julin, P., Shigeta, M., Nordberg, A., Lannfelt, L., Winblad, B.,
Wahlund LO, 1997. Apolipoprotein E epsilon4 allele decreases functional
connectivity in Alzheimer’s disease as measured by EEG coherence. J.
Neurol. Neurosurg. Psychiatry 63, 59–65.
Jelic, V., Johansson, S.E., Almkvist, O., Shigeta, M., Julin, P., Nordberg, A.,
Winblad, B., Wahlund, L.O., 2000. Quantitative electroencephalography in
mild cognitive impairment: longitudinal changes and possible prediction of
Alzheimer’s disease. Neurobiol. Aging 21, 533–540.
Jeon, Y.-W., Polich, J., 2003. Meta-analysis of P300 and schizophrenia:
patients, paradigms, and practical implications. Psychophysiology 40,
684–701.
Jeong, J., 2004. EEG dynamics in patients with Alzheimer’s disease. Clin.
Neurophysiol. 115, 1490–1505.
Jeong, J., Kim, S.Y., Han, S.H., 1998. Non-linear dynamical analysis of the EEG
in Alzheimer’s disease with optimal embedding dimension. Electroence-
phalogr. Clin. Neurophysiol. 106 (3), 220–228.
Jiang, Z.Y., 2005. Study on EEG power and coherence in patients with mild
cognitive impairment during working memory task. J. Zhejiang Univ. Sci. B
6, 1213–1219.
Jiang, Z.Y., Zheng, L.L., 2006. Inter- and intra-hemispheric EEG coherence in
patients with mild cognitive impairment at rest and during working memory
task. J. Zhejiang Univ. Sci. B 7, 357–364.
Kaminski, M.J., Blinowska, K.J., 1991. A new method of the description
of the information flow in the structures. Biol. Cybern. 65, 203–
210.
Kaminski, M.J., Blinowska, K.J., Szclenberger, W., 1997. Topographic analysis
of coherence and propagation of EEG activity during sleep and wakeful-
ness. Electroencephalogr. Clin. Neurophysiol. 102, 216–227.
Karrasch, M., Laine, M., Rinne, J.O., Rapinoja, P., Sinerva, E., Krause, C.M.,
2006. Brain oscillatory responses to an auditory-verbal working memory
task in mild cognitive impairment and Alzheimer’s disease. Int. J. Psycho-
physiol. 59, 168–178.
Katada, E., Sata, K., Ojika, K., Ueda, C., 2004. Cognitive event-related
potentials: useful clinical information in Alzheimer’s disease. Curr. Alz-
heimer Res. 1, 63–70.
Keefover, R.W., 1998. Aging and cognition. Neurol. Clin. 16, 635–648.
Kikuchi, M., Wada, Y., Koshino, Y., Nanbu, Y., Hashimoto, T., 2000. Effects of
scopolamine on interhemispheric EEG coherence in healthy subjects:
analysis during rest and photic stimulation. Clin. Electroencephalogr. 31,
109–115.
Kikuchi, M., Wada, Y., Koshino, Y., 2002a. Differences in EEG harmonic
driving responses to photic stimulation between normal aging and Alzhei-
mer’s disease. Clin. Electroencephalogr. 33, 86–92.
Kikuchi, M., Wada, Y., Takeda, T., Oe, H., Hashimoto, T., Koshino, Y., 2002b.
EEG harmonic responses to photic stimulation in normal aging and
Alzheimer’s disease: differences in interhemispheric coherence. Clin. Neu-
rophysiol. 113, 1045–1051.
Kimura, J., 2001. Principles and variation of nerve conduction studies. In:
Electrodiagnosis in Diseases of Nerve and Muscle. Principle and Practice,
3rd ed. Oxford University Press, pp. 91–129.
Klass, D.W., Brenner, R.P., 1995. Electroencephalography of the elderly. J.
Clin. Neurophysiol. 12, 116–131.
Klimesch, W., 1996. Memory processes, brain oscillations and EEG synchro-
nization. Int. J. Psychophysiol. 24, 61–100.
Klimesch, W., 1997. EEG-alpha rhythms and memory processes. Int. J.
Psychophysiol. 26, 319–340.
Klimesch, W., 1999. EEG alpha and theta oscillations reflect cognitive and
memory performance: a review and analysis. Brain Res. Brain Res. Rev. 29,
169–195.
Knott, V., Mohr, E., Mahoney, C., Ilivitsky, V., 2000. Electroencephalo-
graphic coherence in Alzheimer’s disease: comparisons with a control
group and population norms. J. Geriatr. Psychiatry Neurol. 13, 1–8.
Kobayashi, M., Pascual Leone, A., 2003. Transcranial magnetic stimulation in
neurology. Lancet Neurol. 2, 145–156.
 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
Korzeniewska, A., Kasicki, S., Kaminski, M., Blinowska, K.J., 1997. Informa-
tion flow between hippocampus and related structures during various types
of rat’s behavior. J. Neurosci. Methods 73, 49–60.
Kujirai, T., Caramia, M.D., Rothwell, J.C., Day, B.L., Thompson, P.D., Ferbert,
A., Wrose, S., Asselamnn, P., Marsden, C.D., 1993. Corticocortical inhibi-
tion in human motor cortex. J. Physiol. 471, 501–519.
Kutas, M., McCarthy, G., Donchin, E., 1977. Augmenting mental chronometry:
P300 as a measure of stimulus evaluation time. Science 197, 792–795.
Kwak, Y.T., 2006. Quantitative EEG findings in different stages of Alzheimer’s
disease. J. Clin. Neurophysiol. 23, 456–461.
Lehmann, C., Koenig, T., Jelic, V., Prichep, L., John, R.E., Wahlund, L.O.,
Dodge, Y., Dierks, T., 2007. Application and comparison of classification
algorithms for recognition of Alzheimer’s disease in electrical brain activity
(EEG). J Neurosci. Methods 161, 342–350.
Lehtovirta, M., Partanen, J., Kononen, M., Soininen, H., Helisalmi, S., Man-
nermaa, A., Ryynanen, M., Hartikainen, P., Riekkinen Sr., P., 1996. Spectral
analysis of EEG in Alzheimer’s disease: relation to apolipoprotein E
polymorphism. Neurobiol. Aging 17, 523–526.
Lehtovirta, M., Partanen, J., Kononen, M., Hiltunen, J., Helisalmi, S., Harti-
kainen, P., Riekkinen Sr., P., Soininen, H., 2000. A longitudinal quantitative
EEG study of Alzheimer’s disease: relation to apolipoprotein E polymorph-
ism. Dement. Geriatr. Cogn. Disord. 11, 29–35.
Leuchter, A.F., Spar, J.E., Walter, D.O., Weiner, H., 1987. Electroencephalo-
graphic spectra and coherence in the diagnosis of Alzheimer’s-type and
multi-infarct dementia. A pilot study. Arch. Gen. Psychiatry 44, 993–998.
Leuchter, A.F., Newton, T.F., Cook, I.A., Walter, D.O., Rosenberg-Thompson,
S., Lachenbruch, P.A., 1992. Changes in brain functional connectivity in
Alzheimer-type and multi-infarct dementia. Brain 115, 1543–1561.
Liepert, J., Bar, K.J., Meske, U., Weiller, C., 2001. Motor cortex disinhibition in
Alzheimer’s disease. Clin. Neurophysiol. 112, 1436–1441.
Lisman, J., Spruston, N., 2005. Postsynaptic depolarization requirements for
LTP and LTD: a critique of spike timing-dependent plasticity. Nat. Neu-
rosci. 8, 839–841.
Locatelli, T., Cursi, M., Liberati, D., Franceschi, M., Comi, G., 1998. EEG
coherence in Alzheimer’s disease. Electroencephalogr. Clin. Neurophysiol.
106, 229–237.
Luber, B., Habeck, C., Trott, C.T., Friedman, D., Moeller, J.R., 2004. A ghost of
retrieval past: a functional network of alpha EEG related to source memory
in elderly humans. Brain Res. Cogn. Brain Res. 20, 144–155.
Mariorenzi, R., Zarola, F., Caramia, M.D., Paradiso, C., Rossini, P.M., 1991.
Non-invasive evaluation of central motor tract excitability changes follow-
ing peripheral nerve stimulation in humans. Electroencephalogr. Clin.
Neurophysiol. 81, 90–101.
McCarthy, G., Donchin, E., 1981. A metric for thought: a comparison of P300
latency and reaction time. Science 211, 77–80.
McEvoy, L.K., Pellouchoud, E., Smith, M.E., Gevins, A., 2001. Neurophysio-
logical signals of working memory in normal aging. Brain Res. Cogn. Brain
Res. 11, 363–376.
Mesulam, M., 2004. The cholinergic lesion of Alzheimer’s disease: pivotal
factor or side show? Learn. Mem. 11, 13–19.
Mientus, S., Gallinat, J., Wuebben, Y., Pascual-Marqui, R.D., Mulert, C., Frick,
K., Dorn, H., Herrmann, W.M., Winterer, G., 2002. Cortical hypoactivation
during resting EEG in schizophrenics but not in depressives and schizotypal
subjects as revealed by low resolution electromagnetic tomography (LOR-
ETA). Psychiatry Res. 116, 95–111.
Mima, T., Matsuoka, T., Hallett, M., 2000. Functional coupling of human right
and left cortical motor areas demonstrated with partial coherence analysis.
Neurosci. Lett. 287, 93–96.
Missonnier, P., Gold, G., Herrmann, F.R., Fazio-Costa, L., Michel, J.P., Deiber,
M.P., Michon, A., Giannakopoulos, P., 2006. Decreased theta event-related
synchronization during working memory activation is associated with
progressive mild cognitive impairment. Dement. Geriatr. Cogn. Disord.
22, 250–259.
Moeller, J.R., Ghez, C., Antonini, A., Ghilardi, M.F., Dhawan, V., Kazumata,
K., Eidelberg, D., 1998. Brain networks of motor behavior assessed by
principal component analysis. In: Carson, R.E., Daube-Witherspoon,
M.E., Herscovitch, P. (Eds.), Quantitative Functional Brain Imaging
with Positron Emission Tomography. Academic, San Diego.
397
Näätänen, R., Alho, K., 1995. Mismatch negativity—a unique measure of
sensory processing in audition. Int. J. Neurosci. 80, 317–337.
Nagga, K., Bogdanovic, N., Marcusson, J., 1999. GABA transporters (GAT-1)
in Alzheimer’s disease. J. Neural Transm. 106, 1141–1149.
Nardone, R., Bratti, A., Tezzon, F., 2006. Motor cortex inhibitory circuits in
dementia with Lewy bodies and in Alzheimer disease. J. Neural Transm.
113, 1679–1684.
Nunez, P.L., 1995. Neocortical Dynamics and Human EEG Rhythms. Oxford
University Press, New York.
Nunez, P.L., 2000. Toward a quantitative description of large-scale neocortical
dynamic function and EEG. Behav. Brain Sci. 23, 371–398 discussion 399–
437.
Nunez, P.L., Srinivasan, R., 2006. Electric Fields of the Brain: The Neuro-
physics of EEG. Oxford University Press, New York, USA.
Nuwer, M., 1997. Assessment of digital EEG, quantitative EEG and brain
mapping: report of the American Clinical Neurophysiology Society. Neu-
rology 49, 277–292.
Oken, B., 1997. Endogenous event-related potentials. In: Chiappa, K. (Ed.),
Evoked Potentials in Clinical Medicine. Lippincott-Raven Publishers, New
York, pp. 529–563.
Olichney, J.M., Hillert, D.G., 2004. Clinical applications of cognitive event-
related potentials in Alzheimer’s disease. Phys. Med. Rehabil. Clin. 15,
205–233.
Oliviero, A., Profice, P., Tonali, P.A., Pilato, F., Saturno, E., Dileone, M.,
Ranieri, F., Di Lazzaro, V., 2006. Effects of aging on motor cortex
excitability. Neurosi. Res. 55, 74–77.
Osipova, D., Ahveninen, J., Jensen, O., Ylikoski, A., Pekkonen, E., 2005.
Altered generation of spontaneous oscillations in Alzheimer’s disease.
Neuroimage 27, 835–841.
Pascual-Leone, A., Dang, N., Cohen, L.G., et al., 1995. Modulation of muscle
responses evoked by transcranial stimulation during the acquisition of new
fine motor skills. J. Neurophysiol. 74, 1037–1045.
Pascual-Marqui, R.D., Michel, C.M., Lehmann, D., 1994. Low resolution
electromagnetic tomography: a new method for localizing electrical activity
in the brain. Int. J. Psychophysiol. 18, 49–65.
Pascual-Marqui, R.D., Lehmann, D., Koenig, T., Kochi, K., Merlo, M.C., Hell,
D., Koukkou, M., 1999. Low resolution brain electromagnetic tomography
(LORETA) functional imaging in acute, neurolepticnaive, first-episode,
productive schizophrenia. Psychiatry Res. 90, 169–179.
Pascual-Marqui, R.D., Esslen, M., Kochi, K., Lehmann, D., 2002. Functional
imaging with low resolution brain electromagnetic tomography (LORETA):
a review. Methods Find. Exp. Clin. Pharmacol. 24, 91–95.
Patterson, J.V., Michalewski, H.J., Starr, A., 1988. Latency variability of the
components of auditory event-related potentials to infrequent stimuli in
aging, Alzheimer type dementia, and depression. Electroencephalogr. Clin.
Neurophysiol. 71, 450–460.
Peinemann, A., Lebner, C., Conrad, B., Siebner, H.R., 2001. Age-related
decrease in paired-pulse intracortical inhibition in the human primary motor
cortex. Neurosci. Lett. 313, 33–36.
Pennisi, G., Alagona, G., Ferri, R., Greco, S., Santocito, D., Pappalardo, A.,
Bella, R., 2002. Motor cortex excitability in Alzheimer disease: one-year
follow-up study. Neurosci. Lett. 329, 293–296.
Pepin, J.L., Bogacz, D., De Pasqua, V., Delwaide, P.J., 1999. Motor cortex
inhibition is not impaired in patients with Alzheimer’s disease: evidence
from paired transcranial magnetic stimulation. J. Neurol. Sci. 170, 119–
123.
Perretti, A., Grossi, D., Fragassi, N., Lanzillo, B., Nolano, M., Pisacreta, A.I.,
Caruso, G., Santoro, L., 1996. Evaluation of the motor cortex by magnetic
stimulation in patients with Alzheimer disease. J. Neurol. Sci. 135, 31–37.
Perry, E.K., Mc Keith, I., Thompson, P., Marshall, E., Kerwin, J., Jabeen, S.,
et al., 1991. Topography, extent, and clinical relevance of neurochemical
deficits in Lewy body type, Parkinson’s disease, and Alzheimer disease.
Ann. N.Y. Acad. Sci. 649, 197–202.
Pfefferbaum, A., Ford, J., Kraemer, H.C., 1990. Clinical utility of long latency
‘cognitive’ event-related potentials P300: the cons. Electroencephalogr.
Clin. Neurophysiol. 76, 6–12.
Pfrieger, F.W., Barres, B.A., 1996. New views on synapse–glia interactions.
Curr. Opin. Neurobiol. 6, 615–621.
398 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
Pfurtscheller, G., Aranibar, A., 1979. Evaluation of event-related desynchro-
nization (ERD) preceding and following voluntary self-paced movement.
Electroencephalogr. Clin. Neurophysiol. 46, 138–146.
Pfurtscheller, G., Lopez da Silva, F., 1999. Event-related EEG/MEG synchro-
nization and desynchronization: basic principles. Clin. Neurophysiol. 110,
1842–1857.
Pfurtscheller, G., Neuper, C., 1994. Event-related synchronization of mu
rhythm in the EEG over the cortical hand area in man. Neurosci. Lett.
174, 93–96.
Pfurtscheller, G., Neuper, C., Andrew, C., Edlinger, G., 1997. Foot and hand
area mu rhythms. Int. J. Psychophysiol. 26, 121–135.
Pierantozzi, M., Panella, M., Palmieri, M.G., Koch, G., Giordano, A., Marciani,
M.G., Bernardi, G., Stanzione, P., Stefani, A., 2004. Different TMS patterns
of intracortical inhibition in early onset Alzheimer dementia and fronto-
temporal dementia. Clin. Neurophysiol. 115, 2410–2418.
Pijnenburg, Y.A., v d Made, Y., van Cappellen van Walsum, A.M., Knol, D.L.,
Scheltens, P., Stam, C.J., 2004. EEG synchronization likelihood in mild
cognitive impairment and Alzheimer’s disease during a working memory
task. Clin. Neurophysiol. 115, 1332–1339.
Pitcher, J.B., Ogston, K.M., Miles, T.S., 2003. Age and sex differences in human
motor cortex input–output characteristics. J. Physiol. 546, 605–613.
Polich, J., 1996. Meta-analysis of P300 normative aging studies. Psychophy-
siology 33, 334–353.
Polich, J., 1997a. EEG and ERPs in normal aging. Electroencephalogr. Clin.
Neurophysiol. 104, 228–243.
Polich, J., 1997b. On the relationship between EEG and P300: individual
differences, aging, and ultradian rhythms. Int. J. Psychophysiol. 26, 299–317.
Polich, J., 2003. Overview of P3a and P3b. In: Polich, J. (Ed.), Detection of
Change: Event-related Potential and fMRI Findings. Kluwer, Boston, MA,
pp. 83–98.
Polich, J., 2004. Clinical application of the P300 event-related potential. Phys.
Med. Rehabil. Clin. 15, 133–161.
Polich, J., Corey-Bloom, J., 2005. Alzheimer’s disease and P300: review and
evaluation of task and modality. Curr. Alzheimer Res. 2, 515–525.
Polich, J., Herbst, K.L., 2000. P300 as a clinical assay: rationale, evaluation, and
findings. Int. J. Psychophysiol. 38, 3–19.
Polich, J., Kok, A., 1995. Cognitive and biological determinants of P300: an
integrative review. Biol. Psychol. 41, 103–146.
Polich, J., Martin, S., 1992. P300, cognitive capability, and personality: a
correlational study of university undergraduates. Pers. Indiv. Differ. 13,
533–543.
Polich, J., Starr, A., 1984. Evoked potentials in aging. In: Alpert, M.L. (Ed.), The
Clinical Neurology of Aging. Oxford University Press, New York, pp. 149–
177.
Polich, J., Howard, L., Starr, A., 1983. P300 latency correlates with digit span.
Psychophysiology 20, 665–669.
Polich, J., Ehlers, C., Otis, S., Mandell, A., Bloom, F., 1986. P300 latency
reflects the degree of cognitive decline in dementing illness. Electroence-
phalogr. Clin. Neurophysiol. 63, 138–144.
Polich, J., Ladish, C., Burns, T., 1990a. Normal variation of P300 in children:
age, memory span, and head size. Int. J. Psychophysiol. 9, 237–248.
Polich, J., Ladish, C., Bloom, F.E., 1990b. P300 assessment of early Alzhei-
mer’s disease. Electroencephalogr. Clin. Neurophysiol. 77, 179–189.
Polich, J., Alexander, J.E., Bauer, L.O., Kuperman, S., Rohrbaugh, J., Mozarati,
S., O’Connor, S.J., Porjesz, B., Begleiter, H., 1997. P300 topography of
amplitude/latency correlations. Brain Topogr. 9, 275–282.
Ponomareva, N.V., Selesneva, N.D., Jarikov, G.A., 2003. EEG alterations in
subjects at high familial risk for Alzheimer’s disease. Neuropsychobiology
48, 152–159.
Portet, F., Ousset, P.J., Visser, P.J., Frisoni, G.B., Nobili, F., Scheltens, P., Vellas,
B., Touchon, J., MCI Working Group of the European Consortium on
Alzheimer’s Disease (EADC), 2006. Mild cognitive impairment (MCI) in
medical practice: a critical review of the concept and new diagnostic
procedure. Report of the MCI Working Group of the European Consortium
on Alzheimer’s Disease. J. Neurol. Neurosurg. Psychiatry 77, 714–718.
Post, A., Keck, M.E., 2001. Transcranial magnetic stimulation as a therapeutic
tool in psychiatry: what do we know about the neurobiological
mechanisms? J. Psychiatr. Res. 35, 193–215.
Prichep, L.S., 2005. Use of normative databases and statistical methods in
demonstrating clinical utility of QEEG: importance and cautions. Clin. EEG
Neurosci. 36, 82–87.
Prichep, L.S., John, E.R., Ferris, S.H., Rausch, L., Fang, Z., Cancro, R.,
Torossian, C., Reisberg, B., 2006. Prediction of longitudinal cognitive
decline in normal elderly with subjective complaints using electrophysio-
logical imaging. Neurobiol. Aging 27, 471–481.
Procter, A.W., Qurne, M., Francis, P.T., 1999. Neurochemical features of
frontotemporal dementia. Dement. Geriatr. Cogn. Disord. 10 (Suppl. 1),
80–84.
Puligheddu, M., de Munck, J.C., Stam, C.J., Verbunt, J., de Jongh, A., van Dijk,
B.W., Marrosu, F., 2005. Age distribution of MEG spontaneous theta
activity in healthy subjects. Brain Topogr. 17, 165–175.
Rau, C., Plewnia, C., Hummel, F., Gerloff, C., 2003. Event-related desynchro-
nization and excitability of the ipsilateral motor cortex during simple self-
paced finger movements. Clin. Neurophysiol. 114, 1819–1826.
Rauschecker, J.P., 1995. Compensatory plasticity and sensory substitution in the
cerebral cortex. Trends Neurosci. 18, 36–43.
Reinvang, I., 1999. Cognitive event-related potentials in neuropsychological
assessment. Neuropsychol. Rev. 9, 231–248.
Rissman, R.A., Mishizen-Ebetrz, A.J., Carter, T.L., et al., 2003. Biochemical
analysis of GABA-A receptor subunit alpha 1, alpha 5, beta 1, beta 2 in the
hippocampus of patients with Alzheimer’s disease neuropathology. Neu-
roscience 120, 695–704.
Rodriguez, G., Vitali, P., Nobili, F., 1998. Long-term effects of boxing and judo-
choking techniques on brain function. Ital. J. Neurol. Sci. 19, 367–372.
Rodriguez, G., Nobili, F., Copello, F., Vitali, P., Gianelli, M.V., Taddei, G.,
Catsafados, E., Mariani, G., 1999. 99mTc-HMPAO regional cerebral blood
flow and quantitative electroencephalography in Alzheimer’s disease: a
correlative study. J. Nucl. Med. 40, 522–529.
Rodriguez, G., Vitali, P., De Leo, C., De Carli, F., Girtler, N., Nobili, F., 2002.
Quantitative EEG changes in Alzheimer patients during long-term done-
pezil therapy. Neuropsychobiology 46, 49–56.
Rodriguez, G., Vitali, P., Canfora, M., Calvini, P., Girtler, N., De Leo, C.,
Piccardo, A., Nobili, F., 2004. Quantitative EEG and perfusional single
photon emission computed tomography correlation during long-term done-
pezil therapy in Alzheimer’s disease. Clin. Neurophysiol. 115, 39–49.
Romani, G.L., Williamson, S.J., Kaufman, L., 1982. Tonotopic organization of
the human auditory cortex. Science 216, 1339–1340.
Rosenberg, C., Nudleman, K., Starr, A., 1985. Cognitive evoked potentials P300
in early Huntington’s disease. Arch. Neurol. 42, 984–987.
Rossi, S., Rossini, P.M., 2004. TMS in cognitive plasticity and the potential for
rehabilitation. Trends Cogn. Sci. 8, 273–279.
Rossi, S., Tecchio, F., Pasqualetti, P., Sabato, A., Rossini, P.M., 1998. Modula-
tion of corticospinal output to human hand muscles following deprivation of
sensory feed-back. Neuroimage 8, 163–175.
Rossi, S., Miniussi, C., Pasqualetti, P., et al., 2004. Age-related functional
changes of prefrontal cortex in long-term memory. A repetitive transcranial
magnetic stimulation (rTMS) study. J. Neurosci. 24, 7939–7944.
Rossini, P.M., Dal Forno, G., 2004. Integrated technology for evaluation of
brain function and neural plasticity. Phys. Med. Rehabil. Clin. N. Am. 15,
263–306.
Rossini, P.M., Rossi, S., 2007. Transcranial magnetic stimulation: diagnostic,
therapeutic and research potential. Neurology 68, 484–488.
Rossini, P.M., Desiato, M.T., Caramia, M.D., 1992. Age-related changes of
motor evoked potentials in healthy humans: non-invasive evaluation of
central and peripheral motor tract excitability and conductivity. Brain Res.
593, 14–19.
Rossini, P.M., Martino, G., Narici, L., Pasquarelli, A., Peresson, M., Pizzella, V.,
Tecchio, F., Torrioli, G., Romani, G.L., 1994a. Short-term brain ‘plasticity’
in humans: transient finger representation changes in sensory cortex soma-
totopy following ischemic anesthesia. Brain Res. 642, 169–177.
Rossini, P.M., Barker, A.T., Berardelli, A., Caramia, M.D., Caruso, G., Cracco,
R.Q., Dimitrijevic, M.R., Hallett, M., Katayama, Y., Lucking, C.H., et al.,
1994b. Non-invasive electrical and magnetic stimulation of the brain, spinal
cord and roots: basic principles and procedures for routine clinical applica-
tion. Report of an IFCN committee. Electroencephalogr. Clin. Neurophy-
siol. 91, 79–92.
 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
Rossini, P.M., Calautti, C., Pauri, F., Baron, J.C., 2003. Post-stroke plastic
reorganisation in the adult brain. Lancet Neurol. 2, 493–502.
Rossini, P.M., Del Percio, C., Pasqualetti, P., Cassetta, E., Binetti, G., Dal Forno,
G., Ferreri, F., Frisoni, G., Chiovenda, P., Miniussi, C., Parisi, L., Tombini,
M., Vecchio, F., Babiloni, C., 2006. Conversion from mild cognitive
impairment to Alzheimer’s disease is predicted by sources and coherence
of brain electroencephalography rhythms. Neuroscience 143, 793–803.
Saletu, M., Anderer, P., Saletu-Zyhlarz, G.M., Mandl, M., Arnold, O., Zeitlho-
fer, J., Saletu, B., 2004. EEG-tomographic studies with LORETA on
vigilance differences between narcolepsy patients and controls and sub-
sequent double-blind, placebo-controlled studies with modafinil. J. Neurol.
251, 1354–1363.
Salisbury, D.F., Rutherford, B., Shenton, M.E., McCarley, R.W., 2001. Button
pressing affects P300 amplitude and scalp topography. Clin. Neurophysiol.
112, 1676–1684.
Sarter, M., Bruno, J.P., 1998. Cortical acetylcholine, reality distortion, schizo-
phrenia, and Lewy body dementia: too much or too little cortical
acetylcholine? Brain Cogn. 38, 297–316.
Sawaki, L., Boroojerdi, B., Kaelin-Lang, A., Burstein, A.H., Butefisch, C.M.,
Kopylev, L., et al., 2002. Cholinergic influences on use-dependent plas-
ticity. J. Neurophysiol. 87, 166–167.
Sawaki, L., Werhahn, K.J., Barco, R., Kopylev, L., Cohen, L.G., 2003a. Effect
of an alpha(1)-adrenergic blocker on plasticity elicited by motor training.
Exp. Brain Res. 148, 504–508.
Sawaki, L., Yaseen, Z., Kopylev, L., Cohen, L.G., 2003b. Age-dependent
changes in the ability to encode a novel elementary motor memory.
Ann. Neurol. 53, 521–524.
Selden, N.R., Gitelman, D.R., Salamon-Muruyama, N., et al., 1998. Trajec-
tories of cholinergic pathways within the cerebral hemispheres of the human
brain. Brain 121, 2249–2257.
Siebner, H.R., Dressnandt, J., Auer, C., Conrad, B., 1998. Continuous intrathe-
cal baclofen infusions induced a marked increase of the transcranially
evoked silent period in a patient with generalized dystonia. Muscle Nerve
21, 1209–1215.
Sloan, E.P., Fenton, G.W., Kennedy, N.S., MacLennan, J.M., 1995. Electro-
encephalography and single photon emission computed tomography in
dementia: a comparative study. Psychol. Med. 25, 631–638.
Soininen, H., Partanen, J., Laulumaa, V., Helkala, E.L., Laakso, M., Riekkinen,
P.J., 1989. Longitudinal EEG spectral analysis in early stage of Alzheimer’s
disease. Electroencephalogr. Clin. Neurophysiol. 72, 290–297.
Solé-Padullé, C., Bartres-Faz, D., Junqué, C., Clemente, I.C., Molinuevo, J.L.,
Bargalló, N., Sanchez-Aldeguer, J., Bosch, B., Falcon, C., Valls-Solé, J.,
2006. Repetitive transcranial magnetic stimulation effects on brain function
and cognition among elders with memory dysfunction. A randomized sham-
controlled study. Cereb. Cortex 161, 1487–1493.
Spiegel, A., Tonner, P.H., Renna, M., 2006. Altered states of consciousness:
processed EEG in mental disease. Best Pract. Res. Clin. Anaesthesiol. 20,
57–67.
Stam, C.J., 2005. Nonlinear dynamical analysis of EEG and MEG: review of an
emerging field. Clin. Neurophysiol. 116, 2266–2301.
Stam, C.J., van Cappellen van Walsum, A.M., Pijnenburg, Y.A., Berendse,
H.W., de Munck, J.C., Scheltens, P., van Dijk, B.W., 2002. Generalized
synchronization of MEG recordings in Alzheimer’s disease: evidence for
involvement of the gamma band. J. Clin. Neurophysiol. 19, 562–574.
Stam, C.J., Jones, B.F., Manshanden, I., van Cappellen van Walsum, A.M.,
Montez, T., Verbunt, J.P., de Munck, J.C., van Dijk, B.W., Berendse, H.W.,
Scheltens, P., 2006. Magnetoencephalographic evaluation of resting-state
functional connectivity in Alzheimer’s disease. Neuroimage 32, 1335–
1344.
Stavrinou, M.L., Della Penna, S., Pizzella, V., Torquati, K., Cianflone, F.,
Franciotti, R., Bezerianos, A., Romani, G.L., Rossini, P.M., 2007. Temporal
dynamics of plastic changes in human primary somatosensory cortex after
finger webbing. Cereb. Cortex 17, 2134–2142.
Stefan, K., Kunesh, E., Cohen, L.G., Benecke, R., Classen, J., 2000. Induction
of plasticity in the human motor cortex by paired associative stimulation.
Brain 123, 572–584.
Stelmack, R.M., Houlihan, M., 1994. Event-related potentials, personality, and
intelligence: concepts, issues, and evidence. In: Saklofske, D.H., Zaidner,
399
M. (Eds.), International Handbook of Personality and Intelligence. Plenum
Press, New York, pp. 349–365.
Steriade, M., Llinas, R.R., 1998. The functional states of the thalamus and the
associated neuronal interplay. Physiol. Rev. 68, 649–742.
Suva, D., Favre, I., Kraftsik, R., et al., 1999. Primary motor cortex involvement
in Alzheimer disease. J. Neuropathol. Exp. Neurol. 58, 1125–1134.
Tanaka, Y., Hanyu, H., Sakurai, H., Takasaki, M., Abe, K., 2003. Atrophy of the
substantia innominata on magnetic resonance imaging predicts response to
donepezil treatment in Alzheimer’s disease patients. Dement. Geriatr. Cogn.
Disord. 16, 119–125.
Tecchio, F., Bicciolo, G., De Campora, E., Pasqualetti, P., Pizzella, V., Indovina,
I., Cassetta, E., Romani, G.L., Rossini, P.M., 2000. Tonotopic cortical
changes following stapes substitution in otosclerotic patients: a magne-
toencephalographic study. Hum. Brain Mapp. 10, 28–38.
Terry, J.R., Anderson, C., Horne, J.A., 2004. Nonlinear analysis of EEG during
NREM sleep reveals changes in functional connectivity due to natural
aging. Hum. Brain Mapp. 23, 73–84.
Tokimura, H., Di Lazzaro, V., Tokimura, Y., Oliviero, A., Profice, P., Insola, A.,
Mazzone, P., Tonali, P., Rothwell, J.C., 2000. Short latency inhibition of
human hand motor cortex by somatosensory inputs from the hand. J.
Physiol. 523, 503–553.
van der Hiele, K., Vein, A.A., van der Welle, A., van der Grond, J., Westendorp,
R.G., Bollen, E.L., van Buchem, M.A., van Dijk, J.G., Middelkoop, H.A.,
2007. EEG and MRI correlates of mild cognitive impairment and Alzhei-
mer’s disease. Neurobiol. Aging 28, 1322–1329.
van der Hiele, K., Vein, A.A., Kramer, C.G., Reijntjes, R.H., van Buchem,
M.A., Westendorp, R.G., Bollen, E.L., van Dijk, J.G., Middelkoop, H.A.,
2007a. Memory activation enhances EEG abnormality in mild cognitive
impairment. Neurobiol. Aging 28, 85–90.
Verleger, R., 1997. On the utility of P3 latency as an index of mental
chronometry. Psychophysiology 34, 131–156.
Verleger, R., 2003. Event-related EEG potential research in neurological
patients. In: Zani, A., Proverbio, A.M. (Eds.), The Cognitive Electrophy-
siology of Mind and Brain. Academic Press, Amsterdam, pp. 309–341.
Vesco, K., Bone, R., Ryan, J., Polich, J., 1993. P300 in young and elderly
subjects: auditory frequency and intensity effects. Electroencephalogr. Clin.
Neurophysiol. 88, 302–308.
Vicioso, B.A., 2002. Dementia: when is it not Alzheimer disease? Am. J. Med.
Sci. 324, 84–95.
Villa, A.E., Tetko, I.V., Dutoit, P., Vantini, G., 2000. Non-linear cortico–cortical
interactions modulated by cholinergic afferences from the rat basal fore-
brain. Biosystems 58, 219–228.
Voisin, T., Reynish, E., Portet, F., Feldman, H., Vellas, B., 2004. What are the
treatment options for patients with severe Alzheimer’s disease? CNS Drugs
18, 575–583.
Wada, Y., Nanbu, Y., Kikuchi, M., Koshino, Y., Hashimoto, T., Yamaguchi, N.,
1998a. Abnormal functional connectivity in Alzheimer’s disease: intrahe-
mispheric EEG coherence during rest and photic stimulation. Eur. Arch.
Psychiatry Clin. Neurosci. 248, 203–208.
Wada, Y., Nanbu, Y., Koshino, Y., Yamaguchi, N., Hashimoto, T., 1998b.
Reduced interhemispheric EEG coherence in Alzheimer disease: analysis
during rest and photic stimulation. Alzheimer Dis. Assoc. Disord. 12, 175–
181.
Walsh, V., Cowey, A., 2000. Transcranial magnetic stimulation and cognitive
neuroscience. Nat. Rev. Neurosci. 1, 73–79.
Ward, N.S., Frackowiack, R.S., 2003. Age-related changes in the neural
correlates of motor performance. Brain 126, 873–888.
Wassermann, E.M., 2002. Variation in the response to transcranial magnetic
stimulation in the general population. Clin. Neurophysiol. 113, 1165–
1171.
Werhahn, K.J., Kunesch, E., Noachtar, S., Benecke, R., Classen, J., 1999.
Differential effects on motorcortical inhibition induced by blockade of
GABA uptake in humans. J. Physiol. (Lond.) 517, 591–597.
West, R., Craik, F.I., 2001. Influences on the efficiency of prospective memory
in younger and older adults. Psychol. Aging 16, 682–696.
Wickens, C., Kramer, A., Vanasse, L., Donchin, E., 1983. The performance of
concurrent tasks: a psychophysiological analysis of the reciprocity of
information processing resources. Science 221, 1080–1082.
400 P.M. Rossini et al. / Progress in Neurobiology 83 (2007) 375–400
Williamson, S.J., Kaufman, L., 1990. Evolution of neuromagnetic topographic
mapping. Brain Topogr. 3, 113–127.
Winblad, B., Palmer, K., Kivipelto, M., Jelic, V., Fratiglioni, L., Wahlund,
L.O., Nordberg, A., Backman, L., Albert, M., Almkvist, O., Arai, H.,
Basun, H., Blennow, K., de Leon, M., DeCarli, C., Erkinjuntti, T.,
Giacobini, E., Graff, C., Hardy, J., Jack, C., Jorm, A., Ritchie, K., van
Duijn, C., Visser, P., Petersen, R.C., 2004. Mild cognitive impairment—
beyond controversies, towards a consensus: report of the International
Working Group on Mild Cognitive Impairment. J. Intern. Med. 256, 240–
246.
Wolf, H., Jelic, V., Gertz, H.J., Nordberg, A., Julin, P., Wahlund, L.O., 2003. A
critical discussion of the role of neuroimaging in mild cognitive impairment.
Acta Neurol. Scand. Suppl. 179, 52–76.
Ziemann, U., 2004. TMS and drugs. Clin. Neurophysiol. 115, 1717–1722.
Ziemann, U., Hallett, M., Cohen, L.G., 1998. Mechanisms of deafferentation-
induced plasticity in human motor cortex. J. Neurosci. 18, 7000–7007.
Ziemann, U., Iliac, T.V., Pauli, C., Meintzschel, F., Ruge, D., 2004. Learning
modifies subsequent induction of long-term potentiation-like and long-term
depression-like plasticity in human motor cortex. J. Neurosci. 24, 1666–
1672.