Clinical Neurophysiology 127 (2016) 1261–1268

Contents lists available at ScienceDirect

Clinical Neurophysiology
journal homepage: www.elsevier.com/locate/clinph

EEG characteristics in ‘‘eyes-open” versus ‘‘eyes-closed” conditions:

Small-world network architecture in healthy aging and age-related brain
degeneration
Francesca Miraglia a,⇑, Fabrizio Vecchio a, Placido Bramanti b, Paolo Maria Rossini a,c
a
Brain Connectivity Laboratory, IRCCS San Raffaele Pisana, Rome, Italy
b
IRCCS Centro NeurolesiBonino-Pulejo, Messina, Italy
c
Institute of Neurology, Catholic University, Rome, Italy

See Editorial, pages 999–1000

a r t i c l e i n f o h i g h l i g h t s

Article history:

Graph analysis tools for the study of the brain as a complex network.
Accepted 31 July 2015

Cortical sources of resting EEGin eyes-closed and eyes-open conditions could be different in mild cog-
Available online 25 September 2015
nitive impairment (MCI) and Alzheimer’s disease (AD) patients with respect to normal elderly people.

Small worldnessy modulation in eyes-open EEG reactivity in pathological aging.
Keywords:
Graph theory
Small-world networks
Functional connectivity a b s t r a c t
EEG
eLORETA Objective: Applying graph theory, we investigated how cortical sources small worldness (SW) of resting
Resting state EEG in eyes-closed/open (EC/EO) differs in amnestic mild cognitive impairment (aMCI) and Alzheimer’s
disease (AD) subjects with respect to normal elderly (Nold).
Methods: EEG was recorded in 30 Nold, 30 aMCI, and 30 AD during EC and EO. Undirected and weighted
cortical brain network was built to evaluate graph core measures. eLORETA lagged linear connectivity
was used to weight the network.
Results: In Nold, in EO condition, the brain network is characterized by more SW (higher SW) in alpha
bands and less SW (lower SW) in beta2 and gamma bands. In aMCI, SW has the same trend, except for
delta and theta bands where the network shows less small worldness. AD shows a similar trend of
Nold, but with less fluctuations between EO/EC conditions. Furthermore, in both conditions, aMCI SW
architecture presents midway properties between AD and Nold. At low frequencies (delta e theta bands)
in EC, aMCI group presents network’s architecture similar to Nold, while in EO aMCI, SW is superimpos-
able to AD ones.
Conclusions: In resting state condition, aMCI small-world architecture presents midway topological prop-
erties between AD subjects and healthy controls, confirming the hypothesis that aMCI is an intermediate
step along the disease progression.
Significance: We proposed the application of graph theory to EEG in reactivity to EO in order to find a
marker of diagnosis that – in association with other techniques of neuroimaging – could be sensitive
to the progression of MCI or conversion into AD.
Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights
reserved.

⇑ Corresponding author at: Brain Connectivity Laboratory, IRCCS San Raffaele
Pisana, Via Val Cannuta, 247, 00166 Rome, Italy. Tel.: +39 06 52253767.
E-mail addresses: fra.miraglia@gmail.com, francesca.miraglia@sanraffaele.it
(F. Miraglia).
1. Introduction
The identification of specific and quantitative biomarkers for
the assessment of brain disease severity has utmost importance
to understand age-related brain dysfunctions and to develop new

http://dx.doi.org/10.1016/j.clinph.2015.07.040
1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1262 F. Miraglia et al. / Clinical Neurophysiology 127 (2016) 1261–1268
therapeutic approaches; in particular, Connectomics can signifi-
cantly contribute to this development (Bullmore and Sporns,
2009; Griffa et al., 2013), to map brain from structure to function,
for understanding how cognitive processes emerge from their mor-
phological substrates, and for better understanding of structural
causes of dysfunction (Sporns et al., 2005).
1.1. Graph theory approach
One of the aims of the early graph theoretical studies has been
to promote a change of perspective in how we look at the brain. If
brain architecture is equalized to network, graph theory provides
measures that describe the overall white matter organization and
its alterations at different scales of investigation (Griffa et al.,
2013). Graph theory is primarily concerned with the topology of
the system, – that is, a general set of elements endowed with some
relationship among them, not with its already known anatomy
(Papo et al., 2014). Previous studies have applied this modern tech-
nique of graph theory to EEG data investigating for both physiolog-
ical and pathological aging brain network organization; a
continuous line from normal elderly (Nold) subjects to demented
patients passing through mild cognitive impairment was found
(Vecchio et al., 2014b,c) in the measures of both integration (char-
acteristic path length) and segregation (clustering coefficient). On
this basis, it was concluded that both global and local measures
can discriminate cortical network features distinguishing physio-
logical from pathological neurodegenerative brain aging (Mantini
et al., 2007). Given that the small-world model supports both spe-
cialized and integrated information processing in the brain (Bassett
and Bullmore, 2006; Sporns et al., 2004), in this study, the first aim
was to describe the effect of cognitive decline on topological prop-
erty of small-worldness characteristics derived from EEG connec-
tivity data.
This new approach allows the assessment of functional connec-
tivity patterns and aims to specify whether or not an optimal bal-
ance between local independence and global integration can be
found in the system, representing favorable conditions for infor-
mation processing (Gaal et al., 2010).
1.2. Subjects and conditions
Based on recent findings of graph theory applications in healthy
humans (Bassett et al., 2006; Sporns and Zwi, 2004; Stam and
Reijneveld, 2007), in different types of brain pathology
(Micheloyannis et al., 2006; Ponten et al., 2007), and in studies
on Alzheimer’s disease (AD) patients (He et al., 2008; Stam et al.,
2009; Supekar et al., 2008), the second goal of this study was to
address the differences in functional brain networks between
eyes-closed (EC) and eyes-open (EO) states in Nold people, amnes-
tic mild cognitive impairment (aMCI) (Petersen et al., 2001), and
AD patients, in order to find a neurophysiological marker, which
is sensitive to the progression of aMCI or conversion into AD
(Toth et al., 2014). In particular, it could be very interesting to test
the hypothesis that the dementia-related slowing in cognitive
processing speed represented by the decrease of reactivity in the
EC–EO model (Knyazev et al., 2015)could be described by the
small-worldness characteristics of the network topology approach.
In fact, the term ‘‘mild cognitive impairment” (MCI) convention-
ally applies to a condition in which the decline of cognitive abilities
is more apparent than that seen in normal aging, but it still does
not satisfy the criteria of dementia, whereas MCI maybe regarded
as a transitional state from which AD may develop (De Carli, 2003).
Furthermore, opening and closing the eyes are fundamental
behaviors for directing attention to the external versus internal
world (Xu et al., 2014). Recent findings have demonstrated that
there are distinct mental states related to the EO and EC states.
Specifically, there is an ‘‘exteroceptive” mental activity state char-
acterized by attention and ocular motor activity during EO, and an
‘‘interoceptive” mental activity state characterized by imagination
and multisensory activity during EC (Marx et al., 2004, 2003; Zhang
et al., 2015). Xu and colleagues (Xu et al., 2014) suggested that the
topological organization of human brain networks dynamically
switches corresponding to the information processing modes when
the brain is visually connected/disconnected to the external
environment.
However, it remains unclear whether the states of EO relative to
EC are associated with different topological organizations of func-
tional neural networks for exteroceptive and interoceptive pro-
cessing (processing the external world and internal state,
respectively).
Although fMRI studies have found different influences of EO and
EC on brain flow-metabolism characteristics (Marx et al., 2004,
2003; Wiesmann et al., 2006; Yang et al., 2007), and functional
connectivity (Van Dijk et al., 2010; Yan et al., 2009; Zou et al.,
2009), brain network topological organizations and corresponding
information fluxes exchanged underlying these two states had not
yet been fully elucidated. Furthermore, although some authors had
already proposed graph theory approach in the study of EO EEG
reactivity (Gaal et al., 2010; Knyazev et al., 2015; Tan et al.,
2013; Toth et al., 2014), the topic of this reactivity influence in
pathological aging has not yet been fully explored.
We expect, for the second aim of this study, to find topological
differences in EO EEG reactivity in the three groups; in particular,
we aimed to find in the small-worldness parameter a marker that
could describe the progressive loss of information flow as repre-
sented by the cortical neuronal firing functional impairment across
Nold, MCI, and AD subjects in a transversal study.
2. Methods
Ninety subjects were analyzed (coming from Neuropsychologi-
cal and Alzheimer Unit of Catholic University for memory and cog-
nitive disorders). Patient groups included 30 AD (MMSE 22.3) and
30 aMCI (MMSE 26.8). A control group composed of 30 normal
people Nold (MMSE 28.9) was also enrolled. The mean age was
about 70 years in the groups (Table 1). All subjects were right-
handed at Handedness Questionnaire (Salmaso and Longoni,
1985), and they had informed consent. The study (approved by
local ethical committee) conformed to the Declaration of Helsinki
and national guidelines.
2.1. Inclusion criteria
All subjects participated in a battery of neuropsychological tests
to assess cognitive performance such as attention, memory, execu-
tive function, visuoconstruction abilities, and language: immediate
and delayed recall measure of the Rey Auditory Verbal Learning
Test (Carlesimo et al., 1996), delayed recall of Rey figures (Rey,
1968), delayed recall of a three-word list (Chandler et al., 2004),
and delayed recall of a story (Babiloni et al., 2009; Spinnler and
Tognoni, 1987). Each subject was visited by expert neurologists,
and they underwent complete clinical tests such as brain
neuroimaging (CT or MRI), neuropsychological interview, Mini-
Table 1
Demographic and neuropsychological data of healthy elderly (Nold), mild cognitive
impairment (aMCI), and mild Alzheimer’s disease (AD) subjects.
Group Age (years) Female/male Education MMSE
(years)
Nold 65.4 (±1.75SE) 14/16 9.53 (±0.70SE) 28.90 (±0.16SE)
aMCI 70.7 (±1.26SE) 17/13 8.04 (±0.86SE) 26.84 (±0.30SE)
AD 72.0 (±1.48SE) 20/10 8.17 (±0.72SE) 22.34 (±0.97SE)
 F. Miraglia et al. / Clinical Neurophysiology 127 (2016) 1261–1268
Mental State Evaluation (MMSE) (Folstein et al., 1975), clinical
dementia rating (CDR) (Hughes et al., 1982), geriatric depression
scale (GDS) (Yesavage et al., 1982), Hachinski Ischemic Score
(HIS) (Rosen et al., 1980), and Instrumental Activities of Daily Liv-
ing scale (IADL) (Lawton and Brody, 1969) to confirm diagnosis and
to exclude other causes of dementia, such as frontotemporal
dementia, vascular dementia, extrapyramidal syndromes, reversi-
ble dementias, and Lewy body dementia, in order to have patient
groups clinically homogeneous. AD subjects were diagnosed
according to NINCDS-ADRDA (McKhann et al., 1984) and DSM IV
criteria. aMCI was diagnosed according to guidelines and clinical
standards (Flicker et al., 1991; Petersen et al., 2001, 1997; Portet
et al., 2006; Zaudig, 1992). Benzodiazepines, antidepressants,
and/or antihypertensive drugs (when present) were withdrawn
for about 24 h before the EEG, in order to pair the period from
the last assumption of the drugs and EEG recording (Vecchio
et al., 2013).
Nold subjects were recruited mostly from non-consanguineous
patients’ relatives. They underwent physical and neurological
examinations and cognitive screening (including MMSE and
GDS). Subjects affected by chronic systemic illnesses, those receiv-
ing psychoactive drugs, or those with a history of neurological or
psychiatric disease were excluded. All Nold subjects had a GDS
score lower than 14 (no depression).
2.2. Data recordings and preprocessing
EEG recordings were performed at rest during the late morning,
with closed eyes and open eyes in ‘‘no task” conditions (5 min for
each condition). Recording and analysis procedures are the same as
those of previous works (Vecchio et al., 2014a, 2015a,b,c), and here
we give a brief description for reader convenience. Subjects were
seated and relaxed in a sound-attenuated and dimly lit room. Dur-
ing EO condition, they were instructed to fix a point in front of
them. EEG was recorded from 19 Ag–AgCl electrodes (according
to the International 10–20 system), and skin/electrode impedances
were lowered below 5 KX. Eye movements were monitored by ver-
tical and horizontal EOG. Data were analyzed by Matlab R2011b
software (MathWorks), using scripts based on EEGLAB 11.0.5.4b
toolbox (http://www.sccn.ucsd.edu/eeglab). Recordings were
band-pass filtered (FIR, 0.1–47 Hz), and the sampling rate fre-
quency was set up at 256 or 512 Hz. In order to avoid potential bias
in the results, we obtained the same sampling frequency across the
whole study downsampling at 256 Hz. EEG data were then frag-
mented in 2-s epochs, cleaning artifacts (i.e., eye movements,
EKG activity, and muscle contraction) using an independent com-
ponent analysis (ICA) procedure performed in EEGLAB Infomax
ICA algorithm (Bell and Sejnowski, 1995). Subjects with at least
80 artifact-free epochs for both conditions were selected.
2.3. Graph theory estimates
2.3.1. Functional connectivity analysis
EEG functional connectivity analysis was conducted by exact
low-resolution electromagnetic tomography eLORETA
(Pascual-Marqui et al., 2011) software. This is a linear inverse
solution algorithm for EEG with no localization error to point
sources under ideal (noise-free) conditions (Pascual-Marqui,
2002). Connectivity analysis was obtained by Lagged Linear Coher-
ence algorithm as a measure of functional physiological connectiv-
ity (Pascual-Marqui, 2007a,b; Pascual-Marqui et al., 2011). For
each subject, brain connectivity was computed in 84 regions of
interest (ROIs) defined according to the available 42 Brodmann
areas (BAs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 17, 18, 19, 20, 21,
22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,
41, 42, 43, 44, 45, 46, 47), for left and right hemispheres
1263
(Talairach and Tournoux, 1988). Intracortical Lagged Linear
Coherence, extracted by ‘‘all nearest voxels” method (Pascual-
Marqui, 2007a; Pascual-Marqui et al., 2011), was individually com-
puted between all possible pairs of the 84 ROIs for each of EEG fre-
quency bands (Kubicki et al., 1979; Niedermeyer and da Silva,
2005): 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), beta 2 (20–30 Hz), and gamma
(30–45 Hz). Lagged Linear Coherence in the frequency band x is
defined by the equation (Pascual-Marqui, 2007a;Pascual-Marqui
et al., 2011):
½ImCovðx; yÞ2
LagR2xyw ¼ ð1Þ
VarðxÞ  VarðyÞ  ½ReCovðx; yÞ2
(x and y: time series of two BAs, Im and Re: imaginary and real part,
Var and Cov: variances and covariance).
2.3.2. Graph analysis
Core measures of graph theory were computed from http://
www.brain-connectivity-toolbox.net, adapted by own Matlab
scripts. Segregation refers to the degree to which network ele-
ments form separate clusters and correspond to clustering coeffi-
cient (C) (Rubinov and Sporns, 2010). Integration refers to the
capacity of network to become interconnected and exchange infor-
mation (Sporns, 2013), and it is defined characteristic path length
(L) coefficient (Rubinov and Sporns, 2010).
The clustering (C) around a vertex i is quantified by the number
of triangles in which vertex i participates, normalized by the max-
imum possible number of such triangles (Onnela et al., 2005;
Rubinov and Sporns, 2010).
As triangles are one type of subgraph, the definition of C may be
used to yield the weighted clustering coefficient Cw by replacing
the number of triangles with the sum of triangle intensities as
(Onnela et al., 2005; Rubinov and Sporns, 2010) follows:
1 X 2t W
CW ¼ i
ð2Þ
n i2N ki ðki  1Þ
where
1X
i ¼
tw ðwij wih wjh Þ1=3
2 j;h2N
is the geometric mean of triangles around i, wij are connection
weights associated to links (i, j), assuming that weights are normal-
ized, such that 0 6 wij 6 1 for all i and j. The mean clustering coef-
ficient is computed for all nodes of the graph and then averaged.
It is a measure for the tendency of network elements to form local
clusters (de Haan et al., 2009).
Characteristic path length of the network and weighted charac-
teristic path length Lw are defined as (Onnela et al., 2005; Rubinov
and Sporns, 2010) follows:
X W
dij
1 X j2N;j–i
LW ¼ ð3Þ
n i2N n  1
with
w
X
dij ¼ auv 2 g w
i$j f ðwuv Þ
that represents the shortest weighted path length between i and
j. f is a map (e.g., an inverse) from weight to length and g w
i$j is the
shortest weighted path between i and j.
Small-worldness (Sw) parameter is defined as the ratio between
normalized C and L  Cw and Lw with respect to the frequency
bands. To obtain individual normalized measures, we divided the
values of the characteristic path length and of the clustering coef-
ficient by the mean values obtained by the average values of each
1264 F. Miraglia et al. / Clinical Neurophysiology 127 (2016) 1261–1268

parameter in all frequency bands of each subjects. This procedure

could be a possible cause also of the fact that the profiles of L
and C seem similar, and it could emphasize the effect in the alpha
band as the most powerful. As a limitation of this approach, it
should be stressed that a normalization of the data with respect
to surrogate networks could not be done due to the weighted val-
ues of the considered networks.
The Sw coefficient describes the balance between local connect-
edness and global integration of a network. When Sw is larger than
1, a network has small-world properties. Small-world organization
is intermediate between that of random networks, the short overall
path length of which is associated with a low level of local cluster-
ing, and that of regular networks or lattices, and the high level of
clustering of which is accompanied by a long path length Fig. 1. Mean values and standard errors of ANOVA interaction of the normalized
(Vecchio et al., 2014c). This means that nodes are linked through characteristic path length coefficient among the factors Band (delta, theta, alpha 1,
relatively few intermediate steps, and most nodes maintain few alpha 2, beta 1, beta 2, gamma) and Condition (eyes-open, eyes-closed) in Nold. The
direct connections. eyes-open condition is represented by the continuous blue line, the eyes-closed
condition by the dashed red line. (For interpretation of the references to color in this
In this study, cortical networks were designed as undirected
figure legend, the reader is referred to the web version of this article.)
and weighted. Nodes are represented by the 84 BAs, and edges
are weighted by lagged linear connectivity values. We computed
Lw and Cw as a measure of integration and segregation of network
in Nold group in rest conditions (EO vs.EC), and Sw as a measure of
global brain network organization in each group of subjects (Nold,
aMCI, and AD).

2.4. Statistical comparisons of the EEG cortical sources as estimated by

eLORETA

Analysis of variance (ANOVA) was used between graph indices

computed in three populations (Nold, aMCI, and AD) for all fre-
quency bands and for the two resting conditions. ANOVA was cho-
sen as it is known to be robust with respect to the departure of
normality and homoscedasticity of data being treated (Zar, 1984).
Greenhouse and Geisser correction was used for protection against
the violation of sphericity assumption in the repeated-measure
ANOVA. Besides, posthoc analysis with Duncan’s test and signifi-
cance level at 0.05 were performed. All the statistical analyses
were performed using the software Statistica v.7 (StatSoft Inc.,
http://www.statsoft.com). Several statistical analyses were per-
formed. The first one was a two-way ANOVA to compare each of
the following relativized variables: Cw, Lw, and Sw in the Nold group
between the factors: Band (delta, theta, alpha 1, alpha 2, beta 1,
beta 2, and gamma) and Condition (EO and EC). The second one
included two-way ANOVA for Sw value separately for AD and aMCI
in the same selected factors: Band and Condition. The third one
was represented by two-way ANOVA for Sw value in two selected
factors: Group (Nold, aMCI, and AD) and Band for a focus in EO
and EC conditions separately.
3. Results
3.1. Nold subjects
The ANOVA for the evaluation of the global connectivity (nor-
malized characteristic path length Lw) showed a statistically signif-
icant interaction (F(6174) = 11.98; p < 0.00001) among the factors
Condition (EC/EO) and Band (delta, theta, alpha 1, alpha 2, beta 1,
beta 2, and gamma). Fig. 1 shows the Lw values relative to this sta-
tistical interaction in the ANOVA. Duncan posthoc testing showed
in Nold subjects an increase of path length in alpha 1 (p < 0.00009)
and alpha 2 (p < 0.05) and a decrease in beta 2 (p < 0.012) and
gamma (p < 0.0125) bands in EC with respect to EO condition.
The ANOVA for the evaluation of the local connectivity (normal-
ized clustering coefficient Cw) showed a statistically significant
interaction (F(6174) = 11.45; p < 0.00001) among the factors Con-
ditions and Band. Fig. 2 shows the Cw values relative to this statis-
Fig. 2. Mean values and standard errors of ANOVA interaction of the normalized
clustering coefficient among the factors Band (delta, theta, alpha 1, alpha 2, beta 1,
beta 2, gamma) and Condition (eyes-open, eyes-closed) in Nold subjects. The eyes-
open condition is represented by the continuous blue line, the eyes-closed
condition by the dashed red line. (For interpretation of the references to color in
this figure legend, the reader is referred to the web version of this article.)
tical interaction in the ANOVA. Duncan planned posthoc testing
showed an increase of Cw coefficient in EC with respect to EO con-
dition in alpha 1 (p < 0.00009) band and vice versa a decrease in
beta 2 (p < 0.0156) and gamma bands (p < 0.016).
Finally, Sw presented a significant interaction between Condi-
tion and Band (F(6174) = 8.2, p < 0.00001). Duncan posthoc testing
suggested that Sw decreased in alpha 1 (p < 0.0027) and alpha 2
(p < 0.003) bands in EC with respect to EO condition, and vice versa
increased in beta 2 (p < 0.00007) and gamma (p < 0.002) bands. The
first panel on the left of Fig. 3 shows Sw values relative to this sta-
tistical interaction.
3.2. aMCI and AD patients
In order to evaluate the modulation of the small-world param-
eter, we decided to evaluate the EEG reactivity between EO and EC
conditions for AD and aMCI subjects also. In aMCI group, ANOVA
for Sw showed a statistically significant interaction (F(6174)
= 9.62; p < 0.00001) among Condition (EC/EO) and Band (delta,
theta, alpha 1, alpha 2, beta 1, beta 2, and gamma). The middle
panel of Fig. 3 shows Sw values relative to this statistical interaction
in the ANOVA. The Duncan posthoc testing showed in aMCI sub-
jects an increase of Sw in delta (p < 0.0057), theta (p < 0.0125), beta
2 (p < 0.0024), and gamma (p < 0.0007) bands, and a decrease in
alpha 1 (p < 0.0025) and alpha 2 (p < 0.0015) bands in the EC con-
dition with respect to EO condition.
 F. Miraglia et al. / Clinical Neurophysiology 127 (2016) 1261–1268 1265

Fig. 3. Mean values and standard errors of ANOVA interaction of the small-world parameter among the factors Band (delta, theta, alpha 1, alpha 2, beta 1, beta 2, gamma) and
Condition (eyes-open, eyes-closed) of Nold, aMCI, and AD groups in the left, middle, and right panel, respectively. The eyes-open condition is represented by the continuous
blue line, the eyes-closed condition by the dashed red line. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this
article.)

In AD, ANOVA for Sw showed a statistically significant interac-
tion (F(6174) = 7.88; p < 0.00001) among Condition and Band. The
last panel on the right side of Fig. 3 shows Sw values relative to this
statistical interaction in the ANOVA. Duncan planned posthoc test-
ing showed an increase of small-world parameter in beta 2
(p < 0.00001) and gamma bands (p < 0.0004) and a decrease in
alpha 2 (p < 0.0075) band in EC with respect to EO condition.
3.3. Three-group comparisons
Finally, in order to evaluate the effect of brain pathological
aging, we performed separate analyses for EO and EC conditions
to compare together Nold, AD, and aMCI subjects.
Comparing the three groups (Nold, aMCI, and AD) in EO condi-
tion, ANOVA for Sw presented statistically significant interaction (F
(15,522) = 2.14; p < 0.0134) between the factors Group and Band
(delta, theta, alpha 1, alpha 2, beta 1, beta 2, and gamma). The left
panel of Fig. 4 shows Sw values relative to this statistical interaction
in the ANOVA for EO condition. Duncan planned posthoc testing
showed that the pattern Nold > aMCI and Nold > AD was fitted in
delta band (Nold vs aMCI, p < 0.0156; Nold vs AD, p < 0.01) and
theta bands (Nold vs aMCI, p < 0.038; Nold vs AD, p < 0.04).
In EC condition, ANOVA suggested that Sw showed statistically
significant interaction (F(12,522) = 2.12; p < 0.0144) between fac-
tors Group and Band. The right panel of Fig. 4 shows Sw values rel-
ative to this statistical interaction in the EC condition. Duncan
planned posthoc testing showed that the pattern Nold and
aMCI > AD was fitted in delta band, but not in theta band; namely,
Nold and AD presented significant differences in delta (p < 0.0025)
and theta bands (p < 0.0106), whereas aMCI and AD showed statis-
tically significant difference only in delta band (p < 0.024).
4. Discussion
Several studies have shown that graph theory provides an
excellent tool to characterize neuronal network capacities for cou-
pling parameters of time-varying signals obtained during resting
state electroencephalography (EEG) (Micheloyannis et al., 2006),
magnetoencephalography (MEG) (Stam et al., 2009) or functional
magnetic resonance imaging (fMRI)(van den Heuvel et al., 2009).
Despite the fact that task-specific neuronal firing synchronization
and functional coupling are well-established concepts, less is
known about the role of spontaneous activity. An increasing num-
ber of experimental studies have characterized the dynamics of
spontaneous activity at rest, that is, intrinsic, and not stimuli- or
task-evoked, with different methods including EEG (Babiloni
et al., 2010a,b; D’Amelio and Rossini, 2012), optical imaging
(Arieli et al., 1996; Kenet et al., 2003), single unit (Engel and
Singer, 2001), and fMRI (Biswal et al., 1995; Fox and Raichle, 2007).
Recent EEG and fMRI studies emphasize the importance of
spontaneous or intrinsic ongoing activity for brain functions
(Babiloni et al., 2011; Fox and Raichle, 2007). Furthermore, previ-
ous studies (Bassett and Bullmore, 2006; de Haan et al., 2009;
Ponten et al., 2007; Sporns and Zwi, 2004; Stam, 2004) have shown
that healthy functional as well as structural brain networks have
small-world properties, which are degraded by a brain disease.

Fig. 4. Left panel: Mean values and standard errors of ANOVA interaction of the small-world parameter among the factors Band (delta, theta, alpha 1, alpha 2, beta 1, beta 2,
gamma) and Group (Nold, aMCI, AD) in eyes-open condition. Right panel: Mean values and standard errors of ANOVA interaction of the small-world parameter among the
factors Band (delta, theta, alpha 1, alpha 2, beta 1, beta 2, gamma) and Group (Nold, aMCI, AD) in eyes-closed condition. Nold group is represented by a continuous blue line,
aMCI group with a dashed red line, AD group with a continuous green line. (For interpretation of the references to color in this figure legend, the reader is referred to the web
version of this article.)
1266 F. Miraglia et al. / Clinical Neurophysiology 127 (2016) 1261–1268
The present study aims to demonstrate that the processes of cere-
bral integration and segregation undergo variations with opening
eyes, and that Sw values – which describes the topology of net-
works based on functional connectivity strength in the wake–rest-
ing state EEG – change in the brain during pathological respect to
physiological brain aging. The results of the present study showed
that small-world properties of cerebral networks had different pat-
terns in pathological aging in the open eyes EEG reactivity, with
different trends in the frequency bands. In all three groups, in
the ‘‘EO condition,” the cerebral network shows less small world-
ness in the high-frequency bands (beta 2 and gamma bands),
whereas there is more small worldness in alpha 2 bands.
In Nold and aMCI, in EO condition, the brain network shows
more small worldness in alpha 1 band compared with the EC con-
dition. The lack of alpha 1 band reactivity following EO differenti-
ates Nold and aMCI subjects from AD patients. In fact, low alpha
rhythm as a characteristic oscillation of resting state is shown to
be abnormal in dementia and AD and aMCI (Scheeringa et al.,
2012), indicating that the flexibility of neural circuits involved in
this process shows a decline in parallel with brain degeneration,
which might become even more conspicuous in aMCI (Toth et al.,
2014). In line with our results, the lack of alpha 1 band reactivity
seen in AD could be interpreted as the brain fails to respond appro-
priately to unspecific visual stimulation now reported in several
studies (Qi et al., 2010; Stam, 2010).
Furthermore, only aMCI group presented a significant network
differentiation in the low-frequency delta e theta bands, with less
small-worldness characteristics in the EO. Pathological changes of
theta oscillation are mainly reported in association with memory
deficits (involved in some cognitive functions such as declarative
memory and attentional control processes).
We also reported the three-group comparison in EC and EO con-
ditions separately. According to some studies (Pijnenburg et al.,
2004; Rossini et al., 2008; Toth et al., 2014), the most affected fre-
quencies in AD and aMCI during cognitive tasks were found to be
in the delta and theta bands. Moreover, AD brain topology is char-
acterized by regions (and their long-range connections) primarily
affected due to their specific disease-related vulnerability (de
Haan et al., 2012), causing the known brain cognitive impairments.
de Haan and colleagues (de Haan et al., 2012) found intermediate
connectivity values in aMCI with respect to Nold and AD, explain-
ing that this increasing functional connectivity might well be a part
of the degeneration process itself. In line with this study, we found
an intermediate trend of the aMCI group, that is, in EC condition,
aMCI displays more small worldness with respect to AD and nearer
to Nold’s network topology, whereas in the EO, aMCI shows less
small worldness with a pattern superimposable to the AD’s one.
The cognitive impairment of aMCI is probably causing small-
world architecture alteration, and the effect seen on the EO reactiv-
ity could lead to the absence of the brain’s ability to react as rapidly
and efficiently as normally when the brain is visually connected to
the external environment. In fact, decreasing local and global con-
nectivity parameters, the large-scale functional brain network
organization deviates from the small-world network structure
seen in the healthy toward a more ‘‘ordered” type. This is associ-
ated with less efficient information exchange between brain areas,
supporting the disconnection hypothesis of AD. This trend also
supports the idea of a functional impairment of cortical neural syn-
chronization due to the disease processes and the hypothesis of a
progressive impairment of cortical reactivity across aMCI and AD
subjects.
The present findings are also in line with our previous studies
(Vecchio et al., 2014c) in which small-world characteristics were
found to be decreased in AD patients with respect to aMCI subject
in low-frequency band, namely the aMCI connectivity pattern
being more small worldnessy than that of the AD group. The nov-
elty of the present study is represented by the fact that we
reported in graph analysis the already known observations of
EEG spectral power analysis regarding the opening of the eyes. In
particular, we evaluated the modulations of brain network archi-
tecture during EO, in both physiological aging and neurodegenera-
tive disorders.
Furthermore, we can speculate on this observation as a stronger
local specialization, which when combined with the decreased net-
work efficiency would result in a suboptimal brain topological
organization, suggesting localized and widespread damages of
functional connectivity. This interpretation is also in line with a
model of AD (Stricker et al., 2009) in which the degeneration of
fiber tracts would follow an inverse path with respect to the myeli-
nation process occurring during brain maturation, where fibers
connecting association brain areas develop later (Hagmann et al.,
2012, 2010). The loss of white matter integrity may show up in
the impairment of connectivity between cortical regions; hence,
the study of connectivity can provide insight into functional orga-
nization from which age-related changes in processing speed may
emerge (Ash and Rapp, 2014).
Finally, as a methodological remark, the use of weighted graph
analysis in this study ensured that no arbitrary threshold had to be
set as with unweighted graph analysis. Furthermore, it should be
stressed that EEG recordings were taken from a clinical database,
and for this reason they have just 19 EEG derivations. This limita-
tion will be considered in future studies increasing the number of
recording sites. The gender of the subjects should also be taken
into account in a further study in which a higher number of sub-
jects should be recruited (Miraglia et al., 2015).
5. Conclusions
AD is often preceded by a prodromal state known as mild cog-
nitive impairment (MCI) usually characterized by memory loss.
MCI is considered an intermediate stage between normal aging
and dementia, and its characterization is of considerable interest
for early therapeutic/rehabilitative interventions. We proposed
the application of graph theory to EEG data in order to find a mar-
ker of diagnosis that – in association with other techniques of neu-
roimaging – could be sensitive to the progression of MCI or
conversion into AD in reactivity to EO. The present study provided
further evidence that functional brain networks exhibit robust
small-world properties regardless of the selection of resting condi-
tions, EC or EO.
Acknowledgments
Dr. Francesca Miraglia participated in this study in the frame-
work of her Ph.D. program at the Doctoral School in Neuroscience,
Department of Neuroscience, Catholic University of Rome, Italy.
This article is partially funded by the Italian Ministry of Instruction,
University and Research MIUR (‘‘Approccio integrato clinico e sper-
imentale allo studio dell’invecchiamento cerebrale e delle malattie
neurodegenerative: basi molecolari, epidemiologia genetica, neu-
roimaging multimodale e farmacogenetica” and ‘‘Functional con-
nectivity and neuroplasticity in physiological and pathological
aging [ConnAge]” Prot. 2010SH7H3F PRIN project).
Conflict of interest: There are no conflicts of interest, or financial
disclosures.
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