Professional Documents
Culture Documents
Dimitriadis Eeg Resting State Time Varying 2012
Dimitriadis Eeg Resting State Time Varying 2012
net/publication/51921984
CITATIONS READS
36 990
5 authors, including:
Micheloyannis Sifis
University of Crete
62 PUBLICATIONS 2,103 CITATIONS
SEE PROFILE
Some of the authors of this publication are also working on these related projects:
All content following this page was uploaded by Stavros I. Dimitriadis on 23 February 2014.
1
Correspondence address: S. I. Dimitriadis, Electronics Laboratory, Department of
Physics, University of Patras, Patras 26500, Greece. E-mail:
sdimitriadis@physics.upatras.gr
5
6 NDPLS, 16(1), Dimitriadis et al.
pared during various mental tasks as a means of detecting and characterizing the
different functional modes of brain activation, as well as contrasting them
against the so-called “rest situation.” This situation refers to the state where the
brain “is doing nothing.”“ What exactly is happening in the brain during this
situation has been the matter of many studies. Berger expressed the idea that the
brain during “rest” has activity (Gloor, 1969).
The Swedish brain physiologist David Ingvar was the first to aggregate
imaging findings from resting state and notice the importance of consistent, re-
gionally specific activity patterns (Ingvar & Schwartz, 1974). Using the xenon-
133 inhalation technique to measure regional cerebral blood flow (rCBF), Ingvar
and his colleagues observed that frontal activity reached high levels during rest-
ing condition. Brain imaging studies revealed a specific set of brain regions
showing activity at rest and deactivations during cognitive tasks. Many studies,
using positron emission tomography (PET) and functional magnetic resonance
imaging (fMRI) showed the most active regions at rest and, additionally, wide-
spread activities in connection with the most active regions. The former form the
Default Mode Network (DMN) (Debener et al., 2005; Laufs et al., 2003), while
the latter the Resting State Network (RSN) (Jann et al., 2009; Mantini, Perrucci,
Del Gratta, Romani, & Corbetta, 2007). The DMN is an ensemble of brain re-
gions showing correlated, low-frequency activity during rest condition (Jann et
al., 2009; Scheeringa et al., 2008). It includes the posterior cingulated-
precuneus, medial prefrontal cortex, and bilateral inferior parietal cortex. On the
other hand, the RSN is a widespread extension of the DMN (Laufs et al., 2003;
Mantini et al., 2007). Several fMRI studies have shown coherent fluctuations in
the resting brain (Chang & Glover, 2010) and established the belief that they
constitute the dynamical substrate of the resting brain.
These fluctuations are visible in fMRI at low frequency (< 0.1 Hz).
Nevertheless, these fluctuations are considered correlated with the electrical
activity of brain (Cordes et al., 2001). By analyzing signals from combined
EEG/fMRI recordings, the self-similarity of brain dynamics at resting state was
revealed both in space and time (Mantini et al., 2007). Brain seems to operate
through transitions, wavering between an excessive cortical integration and seg-
regation (Rubinov, Sporns, van Leeuwen & Breakspear, 2009). The resting state
is a condition of undirected wakefulness that may encompass varying levels of
attention, mind – wandering and arousal. Hence, one may hypothesize that the
connectivity between and within sub-networks may undergo substantial changes
(Mantini et al., 2007; Scheeringa et al., 2008). In a recent fMRI study, the tem-
poral variability in the relationship between nodes of the DMN and its anticor-
related network was examined (Chang & Glover, 2010).
In this study, we attempted to characterize the resting state from the
perspective of complex network analysis and with high temporal resolution. The
main purpose was to add information related to the dynamics of associated brain
connectivity based on EEG signals form different frequency bands (δ, , 1, 2,
β, ). The realized experimentations aimed at the comparative examination of
these bands and followed a recently developed methodology for time-varying
NDPLS, 16(1), Brain Connectivity Dynamics 7
network-analysis of functional connectivity (Dimitriadis, Laskaris, Tsirka,
Vourkas, Micheloyannis & Fotopoulos, 2010), denoted hereafter as “TVFCA”.
TVFCA facilitated the detection of systematics behind the emergence of hubs
and the formation of functional modules via phase-coupling. Summarizing our
enterprise: We detected a restricted repertoire of segregation motifs and revealed
the deterministic character of changes in functional segregation by adopting en-
tropic measures reflecting the time evolution of brain’s modular structure.
METHODS
Introducing Time in the Analysis of Functional Connectivity.
Brain connectivity may be modulated by rapid changes in time and, ad-
ditionally, in a frequency-dependent manner. The necessity to track such a
dynamic behaviour has been recently confirmed (Boccaletti, Latora, Moreno,
Chavez, & Hwang, 2006). In this regard, selecting the appropriate window for
estimating the time-frequency dependent network-properties is crucial for under-
standing the neural underpinnings of various cognitive functions. However, pre-
vious studies confined themselves to a firm selection for the time window
(regardless of frequency) and connectivity analysis was performed in a piece-
wise manner (using consecutive signal segments without any overlap in time).
This might be a severe drawback in the case of functional connectivity data
derived from high temporal-resolution brain-imaging modalities like EEG/MEG.
Based on our TVFCA methodology, we first adopted a frequency dependent cri-
terion to define the width for the moving time-window. This is defined based on
the lower frequency limit that corresponds to the - possibly - synchronized oscil-
lations of each brain rhythm and equals the time interval of two cycles. Con-
nectivity analysis was then realized in a sliding mode by using, each time, the
signal segments enclosed inside the window in order to estimate a functional
connectivity graph (FCG) and analyze it via graph-theoretic operators.
Elements of Graph Theoretical Analysis
Functional Connectivity Networks and Related Topological Properties
To detect and precisely characterize neural synchrony between distinct
recording sites, we employed a nonlinear estimator, the Phase Locking Index
(PLI; see Appendix A.1) over the corresponding signals. These measures are
applied, using signals filtered within a particular frequency band, to every
possible pair. The derived quantities are tabulated in an [NxN] matrix, in which
an entry conveys the strength of functional connection between a particular pair.
Such a matrix has a natural graph representation, the functional connectivity
graph (FCG), with nodes being the recording sites and edges the in-between
links weighted by the tabulated value. In order to characterize a FCG, we used
two well-known topological metrics established for weighted connectivity
graphs: global/local efficiency (GE/LE) reflecting correspondingly integration
and segregation tendencies (Latora & Machiori, 2001).
8 NDPLS, 16(1), Dimitriadis et al.
The global efficiency for each node GEi is defined as:
( dij )1 (1)
GE i jN , j i
N 1
that is the inverse of the harmonic mean of the shortest path lengths (dij) be-
tween the i-th node and each other node in the graph. GEi reflects the contribu-
tion of the particular node to the global efficiency of parallel information trans-
fer in the network (Achard and Bullmore,2007; Latora and Machiori, 2001).
The local efficiency for each node LEi is defined as:
( d jh )1 (2)
j , hGi
LE i
ki ( ki 1)
where ki denotes to the total number of neighbours of the i-th node, N is the set
of all nodes in the network and djh denotes the shortest path length between
every possible pair in the neighbourhood of the current node (Gi denotes the spa-
tial neighborhood and includes all the nodes that are directly connected to the i-
th node according to the sensors’ physical locations). LEi can be understood as a
measure of the fault tolerance of the network, indicating how well each sub-
graph exchanges information when the indexed node is eliminated (Achard &
Bullmore, 2007).
Identifying Significant Edges Based on Dijkstra’s Algorithm
To compute the adjacency matrix from a weighted connectivity graph,
traditionally, a threshold is applied. A variety of thresholding schemes has been
introduced in network analysis literature. In our TVFCA methodology, we have
introduced an alternative technique to identify the most significant edges based
on Dijkstra’s algorithm (Dijkstra, 1959). According to this, an edge is consider-
ed significant (and hence used in the adjacency matrix) if it participates in the
formation of, at least, one of the shortest paths spanning the FCG. Connections
between electrodes located along the midline, are eliminated before executing
Dijkstra’s algorithm.
Identifying Hubs
An additional, useful, topological characteristic is the set of hubs (i.e.
nodes of principal role in the overall communication) in the network. Hubs are
readily identified from the adjacency graph with the following detection scheme.
The average (μ) and standard deviation (σ) of the degree for all nodes are first
derived and then used to detect those nodes with excess connectivity, i.e. with
degree higher than μ+σ (Prabhakaran, Smith, Desmond, Glover, & Gabrieli,
1997). Here, we extended this thresholding scheme so as to apply to the GE (and
LE) value of the nodes instead of the degree. After thresholding, the nodes that
play a significant role to the functional integration (and segregation) in resting
state condition are identified. Since the above procedure is repeated for each
NDPLS, 16(1), Brain Connectivity Dynamics 9
instance of FCG (and its adjacency matrix counterpart), we have established two
different algorithmic procedures to describe the ensemble.
The first procedure is based on computing the empirical probability of
each node i to act as a hub (HubProbi). This is assessed by dividing the number
of times a node is identified as hub (employing either GE or LE), with the total
number of FCGs. This gives rise to a spatially defined function, which can be
represented topographically in the format of Fig. 1 (where values of HubProb
function have been averaged across subjects).
The second procedure goes beyond averaging and follows an aggrega-
tion scheme that detects, within two sequentially coupled steps, consistent hubs.
Based on replicator dynamics technique (originated from evolutionary game
theory (Weibull, 1995), commonalities were first detected along time (for a sin-
gle subject data) and then across subjects. This technique constitutes an integral
part of our TVFCA methodology and a detailed description can be found in
(Dimitriadis et al., 2010).
Quantifying Fluctuations in Modular Structure
Modularity is an important concept in network analysis that reflects
segregation and depends on the exact size and composition of network compo-
nents. We applied a variant of a spectral community detection algorithm
(Newman, 2006) to identify modules (communities) within each network. New-
man’s algorithm (Newman, 2006) is known to be quite accurate and sufficiently
fast for small-sized networks. Here, we adopted its implementation from Brain
Connectivity Toolbox (Rubinov & Sporns, 2009) and applied it, independently,
to each one of the adjacency matrices (derived as described above). In this way,
a time-evolving community structure was derived, and the dynamics of segrega-
tion could be studied based on the corresponding time-series of groupings. Ιt is
important to stress here that the particular implementation can deal with the case
of unknown number of communities and even of no-community at all.
To quantify the contrast regarding community structure at two
successive (in time) instances, we employed a novel metric called Variation of
Information (VI) which is an information theoretic criterion that quantifies the
dissimilarity between two distinct clusterings (see Appendix A.2). This gives
rise to a signal that can be thought of as reflecting the “instantaneous” rate-of-
change in functional segregation (see Fig. 3).
EXPERIMENTAL DATA
EEG signals from 18 right-handed volunteers (students of the medical
school of Iraklion/Greece; the study was approved by the local ethical
committee and written informed consent was obtained from each participant)
were recorded using 30 electrodes according to the international 10/20 system:
FP2, F4, FC4, C4, CP4, P4, O2, F8, FT8, T4, TP8, PO8, Fz, FCz, Cz, CPz, Pz,
Oz, FP1, F3, FC3, C3, CP3, P3, O1, F7, FT7, T3, TP7, PO7, and A1 + A2 as
reference. Vertical and horizontal eye movements and blinks were monitored
10 NDPLS, 16(1), Dimitriadis et al.
through a bipolar montage from the supraorbital ridge and the lateral canthus.
The signals were filtered online with a 0.1-200 Hz band pass and digitized at
500 Hz. During the acquisition, all subjects underwent a resting state recording
period for which they were instructed only to keep their eyes closed and remain
awake. EEG segments of 20s duration, without visible artefacts, were selected
from each subject. EEG-signal was split into 6 different bands, which are
traditionally defined and denoted as follows: δ (0.5 – 4 Ηz), θ (4-8 Hz), α1 (8-10
Hz), α2 (10-13Hz), β (13-30 Hz) and γ (30-45 Hz).
Next, artifact reduction was performed using independent component
analysis (ICA) (Onton, Westerfield, Townsend, & Makeig, 2006). Working on
independently for each subject and using EEGLAB (the command runica
(http://sccn.ucsd.edu/eeglab/allfunctions/runica.html) that implements the
extended Informax algorithm (Delorme & Makeig, 2004)), we zeroed the signal
components that were associated with artifactual activity from eyes.
Components related to eye movements were identified based on their scalp
topography which included frontal sites and their temporal course which
followed the EOG signals (for further details see Jung et al., 1998).
RESULTS
Hub Distribution as Reflected Over the Scalp
After Averaging Across Time
After quantifying the HubProb for every node based on the time-
evolving graphs and representing it topographically as shown in Fig. 1, we
detected brain regions active (i.e. participating in integration or segregation pro-
cesses) during brain’s self-organization at resting state. Figure 1 depicts, for
each frequency band independently, the HubProb of each node averaged across
subjects, with top/bottom row corresponding to the network characteristic of
global/local efficiency. It can be seen from the included scalp topographies that
various brain regions shows high probability (HubProb > 0.5) to host hubs. Over
frontal regions, for all the bands and both characteristics, hubs appear perma-
nently with high probability. The rest regions did not show any consistency
regarding the emergence of hubs. Apparently, there are not significant dif-
ferences in HubProb distribution among the frequency bands. We followed a
statistical comparison at the level of individual electrodes, by applying one-
tailed paired t-test (based on single subjects’ measurements) and failed to detect
a frequency-dependent difference in HubProb values (data not shown).
After detecting consistent hubs
With the aggregation step (based on replicator dynamics and described
above) applied to the time-series reflecting the sequence of detected hubs, we
identified the brain regions that consistently (over time and across subjects) play
crucial role in integration/segregation during rest state. The procedure was re-
peated for every frequency-band independently and the results are provided in
Fig. 2. The scalp topographies therein, showed a similar widespread distribution
NDP
PLS, 16(1), Brrain Connectivvity Dynamics 11
ontal predominaance with the topographies
and fro t inn Figure 1. Mooreover, there is a
noticeaable resemblance across frequ
uency bands annd network chaaracteristics.
Fig. 1. HubProb func ction, for each frequency bannd, after averaging across su
ub-
jects. Top
T and bottomm rows relate to computatio ons based on global and loccal
ncy, respectively (darker indicates higher Hu
efficien ubProb).
Fig. 3. Fluctuations in
n modular-struccture quantified
d via VI metric for every subje
ect
and fre
equency band. Individual VI values
v have be en normalized according to tthe
overall maximum VIm max (the brighte
er the higher VII value).
NDP
PLS, 16(1), Brrain Connectivvity Dynamics 13
Table 1. Relative frequency of the segregation motifs observed in delta band for
a single subject. The four motifs can be seen in first row of Fig.5.
Probability of
No of Motif Motifs
1st 0.374
2nd 0.276
rd
3 0.205
th
4 0.145
θ 2.274 0.356
α1 2.132 0.412
α2 2.145 0.432
β 2.175 0.678
γ 2.346 0.712
DISCUSSION
We examined the dynamical behavior of the functional networks cor-
responding to EEG frequency bands using a nonlinear connectivity estimator
and tools derived from the graph theory. The appearance and behavior of hubs in
the cortex (as reflected at the EEG channels), and their evolution in time were
studied during the resting, “eyes closed,” condition. Additionally, the evolution
of modules for each individual was assessed. The results show that the probabil-
ity for a node (i.e. the electrode position) to be a hub during the time evolution
follows an irregular widespread distribution. Consistent hubs associated with
16 NDPLS, 16(1), Dimitriadis et al.
both local, and global efficiency appear to be located frontally and for all fre-
quency bands. Moreover, the evolution of functional connectivity can be
described via short-lasting bimodal functional segregations. Based on a distance
function that compares clusterings, we discovered that these segregations are
recurrent. By adopting an entropic measure for the segregation motifs, we
revealed that the apparent fluctuations are subject to intrinsic constraints and
that order emerges from spatially extended interactions. This was a novel way to
describe the complexity in brain-activity measurements. Deviating from pre-
vious approaches in which various entropic estimators, like approximate entro-
py, had been applied to EEG-signals (Rezek & Roberts, 1998), we aimed at de-
scribing the evolution of functional connectivity changes.
The resting state of the brain has been studied for many years based on
various neuroimaging techniques and bioelectrical signal recordings. Recently,
resting condition brain activity is studied based, exclusively, on fMRI measure-
ments. With fMRI active brain regions and low frequency diffused fluctuations
are visible (Chang & Glover, 2010). Since there is bioelectrical signal related to
these fluctuations, the study of DMN and RSN through related measurements is
worth pursuing. EEG signals are easily recordable and the extracted information
has a high temporal resolution. The present study explores the dynamical behav-
ior of the neural networks as this is reflected over the surface of the head. Par-
ticular electrode positions appeared to act as hubs. Consistent hubs were located
mainly in frontal brain regions. In previous studies, the EEG signal during the
resting state was studied alone or in combination with the low frequency fMRI
fluctuations. It is difficult to compare the results of these previous studies with
our results since we studied different parameters giving information about the
dynamical network organization of the EEG bands and their changes in time.
The previous studies showed EEG power band correlations with different fMRI
resting fluctuations (Debener et al., 2005; Laufs et al., 2003; Mantini et al.,
2007). The EEG patterns can show differences during the rest situation (Laufs et
al., 2003; Mantini et al., 2007). Additionally, the choice of the reference elec-
trode can give different patterns of the EEG DMN (Qin, Xu, & Yao, 2010). The
spectral power measurements, associated to regional activities of the DMN, that
were described recently (about 80 years after the Berger’s original description of
EEG) gave a more detailed picture about the topographical distributions of the
different bands (Chen, Feng, Zhao, Yin, & Wang, 2008). In the present study
and in accordance with a recent one (Chen et al., 2008), the slow wave activity
was identified, mainly, frontally. We found hubs for all the bands over frontal,
parietal and occipital areas with high (HubProbi) and based on both the local
and the global efficiency. Global and local efficiency are network metrics that
quantify the functional integration/segregation of each node. The fact that we
identified brain regions as hubs (mainly frontal, parietal and occipital) by both
measures, implies that they play an important role in the communication of the
whole network and also within their spatial neighborhood (Fig.1). Moreover,
based on individual HubProbi values, we revealed the functional core of hubs
consistent across time and subjects which includes mostly frontal sites (Fig.2)
NDPLS, 16(1), Brain Connectivity Dynamics 17
(Laufs et al., 2003; Mantini et al., 2007). It is worthwhile noticing that previous
studies (Chen et al., 2008; Dimitriadis, Laskaris, Tsirka, Vourkas, &
Micheloyannis 2010) found an increase of power frontally, only, in the delta
band, during an “eyes –open” recording condition. On the contrary, here we de-
tected hubs with high (HubProbi ) frontally in all bands under investigation.
Patterns of functional connectivity in the brain (Friston, Frith, Liddle,
& Frackowiak, 1993) are believed to reflect the patterns of interaction between
transiently formed neuronal assemblies (Fingelkurts, Fingelkurts, & Kahkonen,
2005) and to be associated with attention, perception, cognition (Varela,
Lachaux, Rodriguez, & Martinerie, 2001) and eventually with consciousness
(Fingelkurts & Fingelkurts, 2001,2006; Fingelkurts, Fingelkurts, & Neves, 2009,
2010; Fingelkurts & Fingelkurts ,2011). Changes in functional brain modules
due to ageing and performing a cognitive task have been recently identified
(Meunier, Achard, Morcom, & Bullmore, 2009). In the present study, the inter-
esting finding is the fluctuations of interconnections in the modules and between
them as well as their differences in different bands and different individuals.
Delta band shows relative high stability in the connections of modules and their
interconnections and for all the individuals compared to gamma band which
show low stabilities in most individuals. The behavior of the other bands lies
between the behavior observed in delta and gamma band. Higher fluctuations
are evident as we move from lower to higher bands. The observed changes do
not show periodicity or alternations between constancy and transitions. They re-
flect continuous change. This finding shows a “connectivity microfluctuation”
behavior on the surface of the cortex. It has been already shown that resting state
functional connectivity assessed using fMRI is not static in time (Honey et al.,
2009) and functional connectivity can reconfigure within a few hundred millise-
conds (Basset, Meyer-Lindenberg, Achard, Duke, & Bullmore, 2006). Compar-
ing functional time-dependent signatures in a systematic way revealed fluctua-
tions modulated by frequency. Evolution of functional connectivity can be des-
cribed via bimodal functional segregations. Employing a distance measure that
compares clusterings, we discovered that these segregations are recurrent. More-
over, observed fluctuations are subject to spatially extended interactions leading
to order along the axis of time-evolution. The trace of connectivity microfluctua-
tion at rest should be compared with the dynamics associated with cognition and
this might open a new window to the neural correlates of behavior.
Finally, we need to stress here that the presented observations were
based on a particular estimator of functional dependence, namely the Phase
Locking Index. It is, in general, considered a suitable measure for studying
neural synchrony through oscillatory activity. However, functional connectivity
could be derived via alternative estimators as well. Some of them can provide, in
addition, directionality information regarding the coupling among distinct re-
cording sites (Astolfi et al., 2004; Babiloni et al., 2005). By extending this work,
with the incorporation of such estimators, further insights regarding the transient
character of brain’s functional organization at rest can be provided.
18 NDPLS, 16(1), Dimitriadis et al.
APPENDIX A: PHASE LOCKING INDEX
PLI computation is based on estimates of instantaneous phase obtained
from the convolution of Morlet wavelet with the EEG signals xi(n) filtered
within one of the frequency bands under study. The resulting Dyadic Wavelet
Transform of a discrete sequence x(n) sampled with time spacing δt and
consisting of N data points (n=0,1,..N-1) is denoted as:
N1
W X (n, s) t / s
n'0
x(n' )0* ((n'n)t / s) (A.1)
where “*” denotes complex conjugation with the consecutive scaled and
translated versions of the principal wavelet function, the complex Morlet
wavelet ψo(n):
2
0 (n ) 1 / 4 e iω n e n
0 /2
(A.2)