Clinical Neurophysiology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

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

Structure and dynamics of functional networks in child-onset

schizophrenia
Guilherme Ferraz de Arruda a, Luciano da Fontoura Costa b, Dirk Schubert c, Francisco A. Rodrigues a,⇑
a
Departamento de Matemática Aplicada e Estatística, Instituto de Ciências Matemáticas e de Computação, Universidade de São Paulo, CEP: 13566-590, São Carlos, SP, Brazil
b
Instituto de Física de São Carlos, Universidade de São Paulo, 13560-970, São Carlos, SP, Brazil
c
Radboud University Medical Centre, Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Postbus 9101 6500 HB Nijmegen,
The Netherlands

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

Article history:
 Cortical networks in healthy and child-onset schizophrenic subjects differ significantly in only a small
Accepted 26 November 2013
Available online xxxx
number of large-scale network properties.
 Classification of networks of healthy and schizophrenic subjects yields sensitivity of 90% and specific-

Keywords:
ity of 74%.
Cortical networks  Our analysis allows reliable automatic diagnostics in patients with child-onset schizophrenia based
Schizophrenia on cortical network properties and data mining methods.
Child-onset schizophrenia
Complex networks
a b s t r a c t
Objective: Schizophrenia is a neuropsychiatric disorder characterized by cognitive and emotional deficits
and associated with various abnormalities in the organization of neural circuits. It is currently unclear
how and to which extend the global network organization is changed due to such disorder. In this work,
we analyzed cortical networks of healthy subjects and patients with child-onset schizophrenia to address
this issue.
Methods: We performed a comparison of cortical networks extracted from functional MRI data of
patients with schizophrenia and healthy subjects considering their topological and dynamical properties.
Results: Among 54 network measures tested, only four contributed substantially to a discrimination
between the classes of healthy and schizophrenic subjects, with a sensitivity of 90% and specificity of
74%. However, such classes of networks did not differ significantly with respect to the level of network
resilience and synchronization.
Conclusions: Schizophrenic subjects have cortical regions with higher variance of network centrality, but
less modular structure.
Significance: Our findings suggest that it is possible to establish data analysis routines that allow auto-
matic diagnosis of a multifaceted disease like child-onset schizophrenia based on fMRI data of individual
subjects and extracted network properties.
Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights
reserved.

1. Introduction human brain organization has allowed studying the hypothesis

The structural and functional mapping of human brain net-
works using functional magnetic resonance imaging (fMRI) and
magnetoencephalographic data has shown that cortical networks
present small-worldness, high efficiency of information transfer,
modularity, and the existence of hubs (Chen et al., 2008; Bullmore
and Sporns, 2009; Sporns, 2010). The description of the large-scale
⇑ Corresponding author. Tel.: +55 1633738626.
E-mail address: francisco@icmc.usp.br (F.A. Rodrigues).
that some neuropsychiatric disorders are related to disarrays of
connectivity between cortical areas. Indeed, aberrant structural
patterns have been verified in the brain organization of subjects
with autism, schizophrenia, depression, anxiety disorders, Alzhei-
mer’s disease and frontotemporal dementia (Supekar et al., 2008;
He et al., 2008; Bassett et al., 2008; Bassett and Bullmore, 2009;
Lynall et al., 2010; Menon, 2011). Revealing these disorder related
differences has improved the understanding of how dysfunction of
cognitive and emotion regulation processes are related to the
altered brain network organization.

1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.clinph.2013.11.036

Please cite this article in press as: de Arruda GF et al. Structure and dynamics of functional networks in child-onset schizophrenia. Clin Neurophysiol
(2014), http://dx.doi.org/10.1016/j.clinph.2013.11.036
2 G.F. de Arruda et al. / Clinical Neurophysiology xxx (2014) xxx–xxx
In addition, analysis of brain network properties derived from
fMRI data has been considered for developing methods of non-inva-
sive diagnosis of neurological disorders (Supekar et al., 2008). Diag-
nosis of neurological disorders is often hampered by ambiguous
symptoms and the necessity for long-lasting monitoring of the pa-
tients. The analysis of brain network properties may provide a way
to facilitate and accelerate diagnosis of such disorders. Neural net-
work properties derived from resting-state fMRI data have already
successfully been used for distinguishing between healthy subjects
and patients with different neurological disorders, such as amyo-
trophic lateral sclerosis (Welsh et al., 2013) major depression (Zeng
et al., 2013) antisocial personality disorder (Tang et al., 2013). In our
study we focused on child-onset schizophrenia, which is a rare form
of schizophrenia having its onset before age of 13. From first med-
ical consultation to correct diagnosis of child-onset schizophrenia it
can take years (Schaeffer and Ross, 2002) partially because the diag-
nostic challenges are with differentiating childhood-onset schizo-
phrenia from other neurological disorders or acute, transient
syndromes (for review see (Masi et al., 2006)).
In case of schizophrenia in general, data obtained from fMRI
suggest that cortical networks of schizophrenic adults are less
small-world type, less hierarchical, less clustered, less efficiently
wired (Bassett et al., 2008; Bullmore and Sporns, 2009) and have
a less hub-dominated configuration (Lynall et al., 2010). Moreover,
Basset et al. (Bassett et al., 2008) showed that multimodal network
organization of patients with schizophrenia are abnormal, present-
ing increased connection distance and reduced hierarchy. In adult
schizophrenic patients previous studies already illustrated the use-
fulness of non-invasive diagnosis based on the analysis of resting-
state fMRI data. Such analysis of brain network properties achieved
values for correct classification of up to 94% with 75% accuracy
(Tang et al., 2012; Venkataraman et al., 2012; Shen et al., 2010).
However, similar analysis of fMRI data from patients with child-
onset schizophrenia is currently lacking. Analysis of data from pa-
tients presenting child-onset schizophrenia is very important,
since it allows early diagnosis and disease monitoring. Moreover,
although these studies confirmed various structural differences
in cortical networks of schizophrenic subjects, they have not deter-
mined which network properties are most consistently affected by
schizophrenia. The two main objectives of our study are (i) analysis
and evaluation of the topological and dynamical properties of brain
networks of patients with child-onset schizophrenia and healthy
subjects and (ii) determining which network properties are most
consistently affected by schizophrenia.
One of our main findings suggests that the networks in healthy
and schizophrenic subjects differ significantly in only a small num-
ber of large-scale network properties. On the other hand, healthy
and schizophrenic networks do not differ significantly with respect
to dynamical processes such as resilience to attacks and synchroni-
zation. Therefore, the main structural alterations in the cortical
networks of patients with schizophrenia do not affect the general
network resilience and synchronization of the brain.
Finally, we showed that network measures and data-mining
methods can be useful as an imaging-based diagnosis method to
distinguish patients presenting child-onset schizophrenia from
healthy subjects. In this case, a sensitivity of 74% and specificity
of 90% were obtained. Therefore, our findings suggest that it is pos-
sible to establish a data analysis routine that allows automatic
diagnosis of this multifaceted disease based on functional MRI data
of individual subjects and the resulting cortical network properties.
2. Materials and methods
In this section, we describe the main concepts adopted in
this work regarding data mining. The concepts of network
Please cite this article in press as: de Arruda GF et al. Structure and dynamics of functional networks in child-onset schizophrenia. Clin Neurophysiol
(2014), http://dx.doi.org/10.1016/j.clinph.2013.11.036
characterization and dynamical processes are presented as supple-
mentary material. These concepts are considered to develop a net-
work-based approach for diagnosis of child-onset schizophrenia.
2.1. Data set
Our study is based on cortical network data obtained from a
study by Vértes et al. (Vértes et al., 2012). The authors used rest-
ing-state fMRI to measure low-frequency neural network oscilla-
tions in 140 cortical brain regions at the right hemisphere.
The data was obtained from a group of adolescent healthy vol-
unteers (n = 20, mean age 19.7 years; 11 male) and a group of ado-
lescent participants with childhood-onset schizophrenia (n = 19,
mean age 18.7 years; 9 male). The subjects were scanned using a
General Electric Signa MRI scanner operating at 1.5 Tesla. The
authors considered only regions in the right hemisphere to facili-
tate the approximation of the wiring length by the Euclidean dis-
tance between brain regions. Cortical networks of each subject
were constructed by determining the functional connectivity from
the correlation between each pair of regional time series using a
band-pass filter in order to define the frequency interval in the
range 0.05 – 0.111 Hz. Binary graphs were constructed by thres-
holding the wavelet correlation matrix estimated for each subject.
In order to prevent disconnection of nodes, Vértes et al. considered
the minimum spanning tree as a backbone. This procedure resulted
in 140 cortical regions whose average time series were used to
construct brain functional networks. These preprocessed data can
be downloaded via http://intramural.nimh.nih.gov/chp/articles/
matlab.html. Additional details about the database can be found
in (Vértes et al., 2012).
These functional networks were used to develop mathematical
models of functional human brain networks based on distance
penalty and connections between regions sharing similar output.
Vertés and coworkers suggested that some network properties
can be explained by an economical selection pressure to establish
connections between different brain areas. Moreover, the authors
also verified that clustering and modularity are reduced in schizo-
phrenic patients (Vértes et al., 2012).
2.2. Data mining
Before performing the classification of the cortical networks,
some pre-processing is required in order to avoid scaling effects,
since the network measures varies in different ranges. That is,
while the degree is an integer larger than zero, the clustering coef-
ficient varies in the interval ½0; 1 (see the supplementary material).
One possible method for standardization is the so called z-score
(Costa and Cesar Jr, 2000; Theodoridis and Koutroumbas, 2003).
For each observation i; i ¼ 1; . . . ; N, the transformation of the attri-
bute xi is performed as
xi  x
yi ¼ ; ð1Þ
rx
P qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
PN
where x ¼ Nj¼1 xj =N and rx ¼ 2
j¼1 ðxj  xÞ =N are the average and
standard deviation of the values of the measure x, respectively. The
probability distribution of each transformed measurement, y, pre-
sents zero mean and unit variance.
Pre-processing is also necessary for obtaining classes with the
same number of objects, since a class with the highest number of
elements can be favored in the classification process (Theodoridis
and Koutroumbas, 2003). In this way, we performed a random
sampling, which allows obtaining classes with the same number
of elements.
After the pre-processing, we analyzed the topology of functional
networks via data mining methods in order to find the most impor-
tant features, i.e., those that best discriminate between the two
 G.F. de Arruda et al. / Clinical Neurophysiology xxx (2014) xxx–xxx
types of networks. This procedure, called feature ranking, performs
a ranking of all features according to a given criterion. Here we
used two different criteria: (i) symmetrical uncertainty (U) and
(ii) the v2 statistical test. The former is based on information the-
ory, and is defined as (Yu and Liu, 2003; Witten and Frank, 2005)
2ðHðCÞ  HðCjAÞÞ
UðC; AÞ ¼ ; ð2Þ
HðCÞ þ HðAÞ
where C is the class (i.e., networks of healthy subjects or patients
presenting child-onset schizophrenia), A is the network measure
(attribute) and HðpÞ is the Shannon entropy (Shannon and Weaver,
1948) — the entropy of a discrete random variable X is given by
P (ii) Precision is the proportion of positive samples classified cor-
HðXÞ ¼  i Pðxi Þlogb ðPðxi ÞÞ, where b is the base of the logarithm
used (see the supplementary material). Symmetrical uncertainty
yields values in range [0,1] with the value 1 indicating that the net-
work measure can predict the class of the subject. The second crite-
rion is a statistical test (Theodoridis and Koutroumbas, 2003),
which evaluates the worth of an attribute by computing the value
of the Pearson’s v2 test with respect to the class. This test-statistic
measures the lack of independence between the attribute and the
class (Yang and Pedersen, 1997; Jin et al., 2006). Both criteria give
a higher value for the attributes that provide better discrimination
between the classes. Note that the ranking procedures are per-
formed considering each individual measurement at a time. Since
some of the network measures evaluated here are continuous, it
is necessary to consider a discretization procedure. We used the
minimal description length principle (MDLP) algorithm (Fayyad
and Irani, 1993; Witten and Frank, 2005), which is considered to
be one of the best general techniques for supervised discretization
(Witten and Frank, 2005) and is also used in data mining software,
such as Weka (Hall et al., 2009). Such supervised approach was con-
sidered since the classes are known. This heuristic uses the minimi-
zation of the entropy with a criterion based on the minimum
description length for definition of the partition intervals. The for-
mal derivation of this criterion has been described previously
(Fayyad and Irani, 1993). The feature ranking procedure was per-
formed by using the Weka software (Hall et al., 2009) and the
FSelector toolbox available by the R language.
After the ranking procedure, we performed the network classifi-
cation by taking into account three classifiers: (i) naive Bayes
(Witten and Frank, 2005), (ii) Bayesian networks (Witten and Frank,
2005) and (iii) C4.5 decision tree (Witten and Frank, 2005). These
classifiers are based on information theory and Bayesian concepts.
Naive Bayes assumes that the attributes are statistically indepen-
dent, which is not verified for most application cases (Theodoridis
and Koutroumbas, 2003). The Bayes network classifier tries to over-
come this deficiency by considering some dependency on the attri-
butes. On the other hand, the decision tree divides the attribute
space in hyper-rectangles based on the information gain provided
by the attribute. We evaluated the classification using the leave-
one-out procedure (Witten and Frank, 2005), which consists of
using a single sample from the original data set, i.e., a cortical net-
work of a healthy subject or a patient presenting child-onset schizo-
phrenia, as the validation sample, and the remaining networks as
the training data. This process was repeated considering the whole
data set by considering each observation at a time.
In order to evaluate the accuracy of the classifiers, we took into
account the indices true positive (TP), true negative (TN), false
positive (FP) and false negative (FN). The metrics based on these
indices are (Theodoridis and Koutroumbas, 2003):
(i) Accuracy summarizes the performance of our classifier. It is
formally defined as:
TP þ TN
Accuracy ¼ : ð3Þ
n information.
Please cite this article in press as: de Arruda GF et al. Structure and dynamics of functional networks in child-onset schizophrenia. Clin Neurophysiol
(2014), http://dx.doi.org/10.1016/j.clinph.2013.11.036
3
Table 1
Feature ranking of network measures calculated by using symmetrical uncertainty (U)
and chi-squared test (v2 ). The features are ordered according to the symmetrical
uncertainty.
UðC; AÞ v2 Feature
0.326 15.55 Variance of the closeness centrality
0.289 10.13 First moment of K-core
0.263 12.88 Modularity
0.258 12.74 Variance of the accessibility
The error is defined as  ¼ 1  Accuracy.
rectly considering all samples defined as positive. Formally,
TP
Precision ¼ : ð4Þ
TP þ FP
(iii) Recall is the accuracy rate on the positive class, i.e.,
TP
Recall ¼ : ð5Þ
TP þ FN
Recall is called sensitivity when the positive class is defined as
schizophrenic subjects. On the other hand, when the positive class
is healthy subjects, it is called specificity.
(iv) F-measure is defined in terms of precision and recall, i.e.,
2  Precision  Recall
F¼ : ð6Þ
Precision þ Recall
The classification of networks of healthy and schizophrenic sub-
jects was performed by considering the whole set of measures, as
well as only the measures selected by the ranking procedure.
3. Results
3.1. Network structure
After the standardization and random sampling procedures, we
ranked a set of 54 measures extracted from the cortical networks
in order to find those that provide the best discrimination between
healthy and schizophrenic subjects. These measures are the first
two statistical moments,1 the variance and entropy of the probabil-
ity distribution of (i) degree (the first statistical moment is the mean
degree and it is fixed for all networks, so it was excluded in our anal-
ysis), (ii) clustering coefficient, (iii) closeness centrality, (iv) node
betweenness centrality, (v) edge betweenness centrality, (vi) short-
est path length, (vii) K-core, (viii) communicability, (ix) access infor-
mation, (x) hidden information, (xi) accessibility and (xii) average
degree of the nearest neighbors. Note that we calculated all statisti-
cal moments of the distributions of network measures before apply-
ing the z-score (Eq. (1)).
Other measurements related to the large-scale network organi-
zation were also considered, including the first two spectral
moments, assortativity, central point dominance, efficiency, aver-
age search information as well as the maximum network modular-
ity. Introduction of these measures is given in the supplementary
material.
Table 1 presents the values of U and v2 for the four measure-
ments that contribute substantially to the discrimination between
the healthy and schizophrenic cortical networks. The remaining 50
networks measures (data not shown) present U and v2 equal to
1
The statistical moment of order m of a random variable X is defined as
R1
E½X m  ¼ 1 X m PðX ¼ xÞdx. The first moment is the mean and the second is related
to the variance, E½X 2  ¼ VðXÞ þ ðEðXÞÞ2 . See the supplementary material for additional
4 G.F. de Arruda et al. / Clinical Neurophysiology xxx (2014) xxx–xxx

zero. Consequently these measures did not contribute to the dis-
crimination between the two classes of networks. Note that a mea-
sure presenting similar values in different data classes has U ¼ 0
and v2 ¼ 0 (Theodoridis and Koutroumbas, 2003). Therefore, based
on these criteria, out of the 54 original network measures, only
four contributed significantly to a discrimination between the
two classes of networks, which indicates that these properties
can be related to abnormalities in cortical networks of patients
presenting child-onset schizophrenia. These measures are the var-
iance of the closeness centrality, the first moment of K-core, the
maximum modularity and the variance of the accessibility (see
Table 1). Our finding that only 4 of the tested measures contributed
to discrimination at the same time indicates that the network
properties quantified by the other 50 measures were similar in net-
works of schizophrenic and healthy subjects. Fig. 1 presents the
probability distributions of these measurements. For better visual-
ization, we considered a kernel density estimation (Gaussian ker-
nel) to smooth the densities (Parzen, 1962; Rosenblatt, 1956).
Cortical networks of schizophrenic subjects tended to present
higher values of variance of the closeness centrality and accessibil-
ity, but small values of average K-core and modularity. Therefore,
such networks have cortical regions displaying a higher variance
of central properties, but less modular structure. Note that the sep-
arations of the distributions in Fig. 1 agree with the rankings pre-
sented in Table 1. Note that U ¼ 0 and v2 ¼ 0 are zero mainly due
to the discretization method applied to the dataset during the fea-
ture ranking procedures. For additional information about the dis-
cretization procedure see Section 2.2 and (Fayyad and Irani, 1993).
Having identified the most relevant features for discrimination
of the two classes of networks, we performed a supervised classi-
fication. We evaluated the data set by considering three different
supervised classifiers, i.e., naive Bayes, Bayesian network and
C4.5 decision tree (see Section 2.2). We compared the results of
two supervised classifications: (i) a classification based on the four
most relevant measures only and (ii) a classification based on all 54
network measures. As shown in Table 2, the analysis based on the
4 most important attributes always yielded more precise classifica-
tions. Indeed, the decision tree was the most sensible one to the
selection procedure, improving the accuracy from 44.74% to
71.05%.
3.2. Dynamical processes
In addition to the structural evaluation, we performed a com-
parison between the networks obtained from healthy and schizo-
phrenic subjects in terms of two dynamical processes, i.e., the
synchronization of coupled oscillators and resilience to failures
and attacks.
The synchronization of non-identical oscillators, i.e., the Kuram-
oto model, can be considered as being related with lesion recovery
in cortical networks (Honey and Sporns, 2008). The Kuramoto
model (Acebrón et al., 2005) was considered by Honey and Sporn
(Honey and Sporns, 2008) for simulation of the effects of cortical
lesions. This model is described in the supplementary material.
The evolution of the order parameter was similar in healthy and
schizophrenic networks (Fig. 2). The differences observed may be

1200 6
Healthy Healthy
Schizophrenia Schizophrenia
1000 5

800 4
f(E[K−core])
f(V[Cc ])

600 3

400 2

200 1

0 0
0 1 2 3 4 5 2.8 3 3.2 3.4 3.6 3.8 4
−3
V[Cc ] x 10 E[K−core]

(a) (b)
−3
x 10
2
14 Healthy
Healthy
Schizophrenia
12 Schizophrenia
1.5
10
f(V[Acc])

8
f(Q)

1
6

4 0.5
2

0 0
0.4 0.5 0.6 0.7 0.8 0 1000 2000 3000 4000 5000
Q V[Acc]

(c) (d)
Fig. 1. Probability distributions of the network measures with the highest rankings for networks in healthy and schizophrenic subjects: (a) variance of the closeness
centrality, (b) first statistical moment of the K-core, (c) maximum modularity, and (d) variance of the accessibility. We considered a kernel density estimation (Gaussian
kernel) to smooth the densities for better visualization.

Please cite this article in press as: de Arruda GF et al. Structure and dynamics of functional networks in child-onset schizophrenia. Clin Neurophysiol
(2014), http://dx.doi.org/10.1016/j.clinph.2013.11.036
 G.F. de Arruda et al. / Clinical Neurophysiology xxx (2014) xxx–xxx 5

Table 2
Percentage of correct classification of networks obtained from healthy and schizophrenic subjects considering 4 or 54 measures. PC is the positive class, H. indicates the healthy
class and S., schizophrenic subjects.

Naive Bayes Bayesian network C4.5 Decision tree

54 meas. 4 meas. 54 meas. 4 meas. 54 meas. 4 meas.
Accuracy 0.74 0.76 0.71 0.78 0.45 0.71
Precision (PC: H.) 0.68 0.73 0.70 0.76 0.46 0.68
Specificity: Recall (PC: H.) 0.90 0.84 0.74 0.84 0.58 0.79
F-Measure (PC: H.) 0.77 0.78 0.72 0.80 0.51 0.73
Precision (PC: S.) 0.85 0.81 0.72 0.82 0.43 0.75
Sensitivity: Recall (PC: S.) 0.58 0.68 0.68 0.74 0.32 0.63
F-Measure (PC: S.) 0.69 0.74 0.70 0.78 0.36 0.69

1 1 1

0.8 0.8 0.8

0.6 0.6 0.6

r

r
0.4 0.4 0.4

0.2 0.2 0.2

Healthy Schizophrenia Healthy
Mean Mean Schizophrenia
0 0 0
0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100
σ σ σ
(a) (b) (c)
Fig. 2. Phase coherence calculated for networks of (a) healthy subjects and (b) patients with schizophrenia. Each point is a network. In (c), it is shown the average phase
coherence for each class, for a better visualization.

1.6 Another analysis concerning the robustness of networks was

Healthy
done by simulating random failures and attacks. Both types of net-
1.4 Schizophrenia
work had similar behaviors (Fig. 4). In order to verify these results
1.2 deeper, we calculated the second moment of the degree distribu-
2
tion of the networks (E½k ), which is related to the heterogeneity
1
of network organization. The emergence of some dynamical pro-
f(Hd)

0.8 cesses shows a critical value depending on the ratio E½k

0.6
0.4
0.2
0 bution of E½k .
2 2.5 3 3.5
Hd
Fig. 3. Probability distribution of the dynamical entropy measure for healthy and
schizophrenic cortical networks.
pffiffiffiffi
due to the fluctuations in r, which are of order Oð1= N Þ (Arenas
et al., 2008). At an N ¼ 140, we observed a fluctuation of 8.5%,
which indicates that the order parameter, which measures the net-
work synchronization, did not allow a discrimination between the
two classes of networks.
We quantified the resilience of the networks in terms of the
dynamic entropy (Demetrius and Manke, 2005), which can be con-
sidered as a measure of robustness against random failures (see the
supplementary material). Fig. 3 presents the probability distribu-
tion of this measurement obtained from cortical networks of
healthy and schizophrenic subjects. Interestingly, networks of pa-
tients with schizophrenia were slightly more robust than the net-
works of healthy subjects, confirming the results by Lynall et al.
(Lynall et al., 2010). However, this difference was not statistically
significant as we verified by performing a chi-squared statistical
test and by evaluating the symmetrical uncertainty.
, such as
E½k2 
synchronization, percolation and spreading processes (Barrat
et al., 2008). Since our data has a fixed mean degree, the second
statistical moment of the degree distribution is enough to define
the behavior of the networks. Fig. 5 presents the probability distri-
2
4 4.5 5
4. Discussion
In this study we show that cortical network measures based on
fMRI data and data-mining methods can be used to reliably distin-
guish between brain networks of patients presenting child-onset
schizophrenia and those of healthy subjects. We observed that cor-
tical networks of patients with child-onset schizophrenia pre-
sented higher values of variance of the closeness centrality and
accessibility, but small values of average K-core and modularity
(see Fig. 1 and Table 1). This fact indicates that networks of schizo-
phrenic patients contain cortical regions with higher variance of
central properties, but have less modular structure than networks
of healthy subjects. In addition, schizophrenic patients contain
some cortical regions with higher values of closeness centrality
and accessibility than the healthy ones. In contrast, large-scale
properties of the brain organization, such as small-worldness and
degree distribution, have very similar values in healthy and schizo-
phrenic subjects. This suggests that key aspects of brain topology
are highly preserved even in the presence of this putative neurode-
velopmental disorder. One can speculate that such variations are at

Please cite this article in press as: de Arruda GF et al. Structure and dynamics of functional networks in child-onset schizophrenia. Clin Neurophysiol
(2014), http://dx.doi.org/10.1016/j.clinph.2013.11.036
6 G.F. de Arruda et al. / Clinical Neurophysiology xxx (2014) xxx–xxx

1 1
Healthy Healthy
Schizophrenia Schizophrenia
0.8 0.8

0.6 0.6
E/E0

E/E0
0.4 0.4

0.2 0.2

0 0
0 0.2 0.4 0.6 0.8 0 0.1 0.2 0.3 0.4 0.5
Fraction failed Fraction attacked
(a) (b)
Fig. 4. Relative efficiency obtained from (a) random removal of nodes and (b) attacks.

expected since these features are all related to different networks

0.08
Healthy properties. More specifically, closeness centrality is based on short-
0.07 Schizophrenia est paths, accessibility on random walks, K-core on connectivity
0.06
and the modularity is related to the network modular structure.
The comparison of the networks in terms of dynamical pro-
0.05 cesses revealed that the two classes of networks do not differ sig-
f(E[k2])

0.04 nificantly with respect to synchronization and resilience (see

0.03
0.02
0.01
0 networks, as we verified by a chi-squared test. Therefore, the vari-
20 40 60 80
E[k2]
Fig. 5. Probability distribution of the second statistical moment of the degree
distribution for healthy and schizophrenic subjects.
least partially responsible for the disease pattern of schizophrenia,
but in order to test this hypothesis more accurate databases and
further studies are needed.
Regarding the remaining 50 network measures we tested in this
study, the two classes of networks were not significantly different.
Although Supekar et al. (Supekar et al., 2008) verified that the mea-
sure of the clustering coefficient could distinguish patients with
Alzheimer from the controls with a sensitivity of 72% and specific-
ity of 78%, we observed that this measure was not able to reliably
discriminate healthy patients from subjects with child-onset
schizophrenia. Moreover, our results contradict previous analysis
of networks in healthy and schizophrenic adults which showed re-
duced clustering coefficient and modularity in schizophrenic net-
works (Vértes et al., 2012; Liu et al., 2008). According to our
results, only the modularity could discriminate reliably between
both types of networks. Moreover, we also observed that the aver-
age shortest paths were similar in these two classes of networks.
Our findings imply that the schizophrenic cortical networks are
less modular but the efficiency in communication is almost the
same for both classes of networks. Therefore, network communi-
ties, formed by densely connected nodes, might be better defined
in healthy subjects than in schizophrenic ones, whereas the com-
munication between brain areas is supposed to be similar in both
classes of networks.
Our results also suggest that there is a weak statistical depen-
dence between the four selected discriminating measures, since
the performance of the naive Bayes and the Bayesian network
methods was very similar (see Table 2). This outcome was
Figs. 2 and 3). The distribution of the second moment of the degree
distribution for schizophrenic cortical networks presents higher
average, which indicates that these networks were less heteroge-
neous than the healthy networks (see Fig. 5). However, the proba-
bility distributions did not allow discriminating between the
100 ations on the network topology did not affect the dynamics of net-
works in schizophrenia, since the second moment of the degree
distribution was similar in both classes of networks. These results
agree with the simulation of synchronization and node removal
(see Figs. 2 and 4). Therefore, the networks of healthy and schizo-
phrenic subjects are not significantly different with respect to their
level of resilience and synchronization.
Our findings also indicate that the revealed differences in
cortical network organization can be explored for developing a
diagnostic aid method based on network measures. Indeed, our
classification of patients with child-onset schizophrenia achieved
a sensitivity of 90% and specificity of 74%. This finding supports
the notion that analysis based on network measures and data min-
ing methods may present a possible strategy for automatic diag-
nostics for neurological disorders Previous studies on resting-
state fMRI achieved similar levels of specificity and accuracy, not
only for schizophrenia in adults (Tang et al., 2012; Venkataraman
et al., 2012; Shen et al., 2010), but also for other neurological dis-
orders (Welsh et al., 2013; Zeng et al., 2013; Tang et al., 2013).
Regarding the limitations of our analysis, note that more accu-
rate results could be obtained if one considers data from both
hemispheres of a brain. However, such data sets are currently
not available. In addition, the use of the low-frequency oscillations,
as addressed here (0.05–0.111 Hz), may not be suitable to model
actual information transfer but probably reflect gross anatomical
connectivity plus large-scale regulation processes. A limitation in
terms of reliable and early diagnosis of child-onset schizophrenia
lies in the fact that our analysis was focused on comparing brain
networks of healthy subjects with those of child-onset schizo-
phrenic patients. A complication in diagnostics of this disease is
based on the need for differentiating child-onset schizophrenia
from other diseases such as affective disorders (both depression
and bipolar disorder) with psychotic symptoms, pervasive devel-
opmental disorders, severe personality disorders, nonpsychotic

Please cite this article in press as: de Arruda GF et al. Structure and dynamics of functional networks in child-onset schizophrenia. Clin Neurophysiol
(2014), http://dx.doi.org/10.1016/j.clinph.2013.11.036
 G.F. de Arruda et al. / Clinical Neurophysiology xxx (2014) xxx–xxx
hallucinations or delusions (for review see Masi et al., 2006).
Therefore, in future studies it has to be tested, whether the analysis
of brain network properties extracted from fMRI data is capable of
discriminating between patients that suffer from neurological dis-
eases with partially similar phenotypes. As a whole, our findings
indicate that the analysis presented here provides a reliable way
to quantify differences in networks of healthy subjects and
patients with child-onset schizophrenia, which might a first funda-
mental step towards an early diagnosis and monitoring of this neu-
ropsychiatric disorder.
Acknowledgments
F.A. Rodrigues would like to acknowledge CNPq (305940/2010-
4) and FAPESP (2010/19440-2) for the financial support given to
this research. G.F. de Arruda acknowledge Fapesp for sponsorship.
F.A. Rodrigues and L. da F. Costa acknowledge FAPESP (2011/
50761-2) and NAP eScience – PRP – USP.
The authors declare no competing financial interests.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.clinph.2013.
11.036.
References
Acebrón JA, Bonilla LL, Vicente CJP, Ritort F, Spigler R. The Kuramoto model: a
simple paradigm for synchronization phenomena. Rev Mod Phys 2005;77:137.
Arenas A, Díaz-Guilera A, Kurths J, Moreno Y, Zhou C. Synchronization in complex
networks. Phys Rep 2008;469:93–153.
Barrat A, Barthlemy M, Vespignani A. Dynamical processes on complex
networks. Cambridge University Press; 2008.
Bassett D, Bullmore E. Human brain networks in health and disease. Curr Opin
Neurol 2009;22:340.
Bassett D, Bullmore E, Verchinski B, Mattay V, Weinberger D, Meyer-Lindenberg A.
Hierarchical organization of human cortical networks in health and
schizophrenia. J Neurosci 2008;28:9239–48.
Bullmore E, Sporns O. Complex brain networks: graph theoretical analysis of
structural and functional systems. Nat Rev Neurosci 2009;10:186–98.
Chen Z, He Y, Rosa-Neto P, Germann J, Evans A. Revealing modular architecture of
human brain structural networks by using cortical thickness from MRI. Cerebral
Cortex 2008;18:2374–81.
Costa LF, Cesar Jr R. Shape analysis and classification: theory and practice. CRC Press
Inc.; 2000.
Demetrius L, Manke T. Robustness and network evolution—an entropic principle.
Phys A 2005;346:682–96.
Fayyad UM, Irani KB. Multi-interval discretization of continuous-valued attributes
for classification learning. In: Bajcsy R, editor. IJCAI. Morgan Kaufmann; 1993. p.
1022–9.
Hall M, Frank E, Holmes G, Pfahringer B, Reutemann P, Witten IH. The WEKA data
mining software: an update. SIGKDD Explorations 2009;11(1):10–8.
Please cite this article in press as: de Arruda GF et al. Structure and dynamics of functional networks in child-onset schizophrenia. Clin Neurophysiol
(2014), http://dx.doi.org/10.1016/j.clinph.2013.11.036
7
He Y, Chen Z, Evans A. Structural insights into aberrant topological patterns of large-
scale cortical networks in Alzheimer’s disease. J Neurosci 2008;28:4756–66.
Honey CJ, Sporns O. Dynamical consequences of lesions in cortical networks. Hum
Brain Mapp 2008;29:802–9.
Jin X, Xu A, Bie R, Guo P. Machine learning techniques and chi-square feature
selection for cancer classification using SAGE gene expression profiles. In:
BioDM. In: Li J, Yang Q, Tan AH, editors. Lecture Notes in Computer Science
2006;vol. 3916. Springer; 2006. p. 106–15.
Liu Y, Liang M, Zhou Y, He Y, Hao Y, Song M, Yu C, Liu H, Liu Z, Jiang T. Disrupted
small-world networks in schizophrenia. Brain 2008;131:945–61.
Lynall M, Bassett D, Kerwin R, McKenna P, Kitzbichler M, Muller U, Bullmore E.
Functional connectivity and brain networks in schizophrenia. J Neurosci
2010;30:9477–87.
Masi G, Mucci M, Pari C. Children with schizophrenia: clinical picture and
pharmacological treatment. CNS drugs 2006;20:841–66.
Menon V. Large-scale brain networks and psychopathology: a unifying triple
network model. Trends Cogn Sci 2011;15:483–506.
Parzen E. On estimation of a probability density function and mode. Ann Math Stat
1962;33:1065–76.
Rosenblatt M. Remarks on some nonparametric estimates of a density function. Ann
Math Stat 1956;27(3(1956)):832–7.
Schaeffer J, Ross R. Childhood-onset schizophrenia: premorbid and prodromal
diagnostic and treatment histories. J Am Acad Child Adolesc Psychiatry
2002;41:538–45.
Shannon CE, Weaver W. A mathematical theory of communication. Bell Syst Tech J
1948;27:623.
Shen H, Wang L, Liu Y, Hu D. Discriminative analysis of resting-state functional
connectivity patterns of schizophrenia using low dimensional embedding of
fMRI. Neuroimage 2010;49:3110–21.
Sporns O. Networks of the Brain. MIT Press; 2010.
Supekar K, Menon V, Rubin D, Musen M, Greicius M. Network analysis of intrinsic
functional brain connectivity in Alzheimer’s disease. PLoS Comput Biol
2008;4:e1000100.
Tang Y, Jiang W, Liao J, Wang W, Luo A. Identifying individuals with antisocial
personality disorder using resting-state fMRI. PloS one 2013;8:e60652.
Tang Y, Wang L, Cao F, Tan L. Identify schizophrenia using resting-state functional
connectivity: an exploratory research and analysis. Biomed Eng Online
2012;11:50.
Theodoridis S, Koutroumbas K. Pattern recognition. Academic Press; 2003.
Venkataraman A, Whitford T, Westin C, Golland P, Kubicki M. Whole brain resting
state functional connectivity abnormalities in schizophrenia. Schizophr Res
2012;139:7–12.
Vértes P, Alexander-Bloch A, Gogtay N, Giedd J, Rapoport J, Bullmore E. Simple
models of human brain functional networks. Proc Natl Acad Sci USA
2012;109:5868–73.
Welsh R, Jelsone-Swain L, Foerster B. The utility of independent component analysis
and machine learning in the identification of the amyotrophic lateral sclerosis
diseased brain. Front Hum Neurosci 2013;7(251):1–9. http://dx.doi.org/
10.3389/fnhum.2013.00251.
Witten IH, Frank E. Data mining: practical machine learning tools and
techniques. Morgan Kaufmann; 2005.
Yang Y, Pedersen JO. A comparative study on feature selection in text
categorization. In: Fisher DH, editor. Proceedings of 14th International
conference on machine learning, ICML-97. San Francisco, US: Morgan
Kaufmann Publishers; 1997. p. 412–20.
Yu L, Liu H. Feature selection for high-dimensional data: a fast correlation-based
filter solution. In: Proceedings of the Twentieth International Conference on
Machine Learning. AAAI Press; 2003. p. 856–63.
Zeng, L., Shen, H., Liu, L., Hu, D., 2013. Unsupervised classification of major
depression using functional connectivity. MRI. Hum Brain Mapp. http://
dx.doi.org/10.1002/hbm.22278.