Brain Research Bulletin 200 (2023) 110684

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Brain Research Bulletin

journal homepage: www.elsevier.com/locate/brainresbull

Research report

Distance to criticality undergoes critical transition before epileptic

seizure attacks☆
Shun Liu a, b, c, Fali Li a, d, e, Feng Wan a, b, c, *
a
The Department of Electrical and Computer Engineering, Faculty of Science and Technology, University of Macau, Macau
b
The Centre for Cognitive and Brain Sciences, Institute of Collaborative Innovation, University of Macau, Macau
c
The Centre for Artificial Intelligence and Robotics, Institute of Collaborative Innovation, University of Macau, Macau
d
The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuro-information, University of Electronic Science and Technology of China, Chengdu,
China
e
School of Life Science and Technology, the Center for Information in Bio-Medicine, University of Electronic Science and Technology of China, Chengdu, China

A R T I C L E I N F O A B S T R A C T

Keywords: Epilepsy is a common neurological disorder characterized by recurring seizures, but its underlying mechanisms
Epileptic seizures remain poorly understood. Despite extensive research, there are still gaps in our knowledge about the rela­
Electroencephalogram (EEG) tionship between brain dynamics and seizures. In this study, our aim is to address these gaps by proposing a
Brain network
novel approach to assess the role of brain network dynamics in the onset of seizures. Specifically, we investigate
Criticality
the relationship between brain dynamics and seizures by tracking the distance to criticality. Our hypothesis is
that this distance plays a crucial role in brain state changes and that seizures may be related to critical transitions
of this distance. To test this hypothesis, we develop a method to measure the evolution of the brain network’s
distance to the critical dynamic systems (i.e., the distance to the tipping point, DTP) using dynamic network
biomarker theory and random matrix theory. The results show that the DTP of the brain decreases significantly
immediately after onset of an epileptic seizure, suggesting that the brain loses its well-defined quasi-critical state
during seizures. We refer to this phenomenon as the “criticality of the criticality” (COC). Furthermore, we
observe that DTP exhibits a shape transition before and after the onset of the seizures. This phenomenon suggests
the possibility of early warning signal (EWS) identification in the dynamic sequence of DTP, which could be
utilized for seizure prediction. Our results show that the Hurst exponent, skewness, kurtosis, autocorrelation, and
variance of the DTP sequence are potential EWS features. This study advances our understanding of the rela­
tionship between brain dynamics and seizures and highlights the potential for using criticality-based measures to
predict and prevent seizures.

1. Introduction decipher the irregular patterns of seizure dynamics, researchers have

Epilepsy is a pervasive neurological disorder characterized pre­
dominantly by the occurrence of spontaneous seizures, which result
from synchronized and uncontrolled neural activity within extensive
regions of the brain (Maturana et al., 2020). These seizures, among the
most frequent forms of neuronal abnormalities, can propagate to sur­
rounding tissue, disrupting normal brain function (Moshé et al., 2015;
Fisher et al., 2005). The mechanisms underlying seizure initiation,
however, remain elusive despite the high prevalence of epilepsy. To
examined brain signals within the context of nonlinear systems and
utilized analytical methods from the field of nonlinear science.
(Maturana et al., 2020). Despite significant advancements in research in
this area, the specific mechanisms that lead to the transition from a
normal brain state into a seizure activity still represent a significant
challenge (Kuhlmann et al., 2018; Freestone et al., 2017, 2015).
The perspective of nonlinear science suggests that abrupt state
changes may be indicative of critical transitions, with the system
approaching tipping points. Mathematical (Brock and Carpenter, 2006;

☆
This work was supported in part by The Science and Technology Development Fund, Macau SAR (File no. 0045/2019/AFJ and 0018/2019/AKP), The University
of Macau Research Committee (MYRG projects 2017-00207-FST and 2022-00197-FST), The Natural Science Foundation of Guangdong Province, China (Grant No.
2023A1515010844), Macau Young Scholars Program (No. AM2022025).
* Corresponding author at: The Department of Electrical and Computer Engineering, Faculty of Science and Technology, University of Macau, Macau.
E-mail address: fwan@um.edu.mo (F. Wan).

https://doi.org/10.1016/j.brainresbull.2023.110684
Received 15 May 2023; Received in revised form 3 June 2023; Accepted 10 June 2023
Available online 22 June 2023
0361-9230/© 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
S. Liu et al.
Biggs et al., 2009; Guttal and Jayaprakash, 2008) and experimental
(Carpenter et al., 2011; Drake and Griffen, 2010; Veraart et al., 2012;
Dai et al., 2012) studies have explored critical transitions and developed
methods to predict tipping points or critical transitions in various
real-world systems, including financial markets (McSharry et al., 2003;
Lenton et al., 2008; Scheffer et al., 2001), cell population collapse in
bacterial cultures (Dai et al., 2012), and ecosystems (Scheffer et al.,
2009). These prediction methods hinge on the hypothesis that as a
system nears a bifurcation point, the system’s state experiences a
delayed return to its stable attractor following a perturbation, a phe­
nomenon referred to as critical slowing down, causes a system to switch
back and forth between alternative states in response to relatively large
impacts. (Scheffer et al., 2009).
In neuroscience, critical dynamics have emerged as a potential
mechanism underlying normal brain functioning, given the brain’s
remarkable information processing and computational capabilities. This
concept, known as the “critical brain hypothesis” (CBH), posits that
human brain dynamics may be situated at a phase transition between
ordered and disordered activity (Cocchi et al., 2017). Theoretical and
simulation-based research has proposed that neural networks at a crit­
ical point exhibit optimal information transmission (Beggs and Plenz,
2003), storage (Haldeman and Beggs, 2005; Chen et al., 2010),
computational power (Bertschinger and Natschläger, 2004; Gollo et al.,
2013), dynamic range (Gollo et al., 2013; Kinouchi and Copelli, 2006;
Larremore et al., 2011; Publio et al., 2012; Manchanda et al., 2013;
Mosqueiro and Maia, 2013; Williams-García et al., 2014; Pei et al.,
2012), and learning capabilities (de Arcangelis and Herrmann, 2010),
while maintaining flexible yet stable dynamics (Haldeman and Beggs,
2005; Magnasco et al., 2009). This theory predicts that individuals with
stronger cognitive abilities should have neural dynamics that are closer
to criticality when compared to individuals with weaker cognitive
abilities (Ezaki et al., 2020). Some researchers have found that the brain
operates as a “quasicritical” system, optimizing its receptiveness to
stimuli to interpret information, rather than operating at a strictly crit­
ical point due to the constant influx of external stimuli (Fosque et al.,
2021).
Critical transitions have been employed to describe various aspects
of neural systems, such as the onset of depression (van de Leemput et al.,
2014), pharmacologically induced cortical state changes (Gautam et al.,
2015; Beggs and Plenz, 2003; Shew et al., 2009), the onset of spiking in
neurons (Meisel et al., 2015), and the termination of epileptic seizures
(Kramer et al., 2012). A key question is how the critical brain hypothesis
relates to pathological conditions, given its crucial role in normal brain
functioning. Some studies have suggested that epileptic seizures may
result from the failure of adaptive self-organized criticality (Meisel et al.,
2012). Therefore, the seizing brain, which alternates between normal
and seizure states, offers a unique living system for investigating the
signatures of impending critical transitions, as well as a system where
interventions can have substantial practical implications (Kramer et al.,
2012). Although extensive research has been conducted on this topic,
the debate continues as to whether epileptic seizures represent bi­
furcations in the neural system. For instance, a recent study by (Mila­
nowski and Suffczynski, 2016) examined the application of critical
slowing down indicators and discovered that only 8% of nearly 300
epileptic patients exhibited evidence of critical slowing down before
seizures. In contrast, Maturana et al. provided robust validation of
theoretical models and demonstrated that critical slowing down can
serve as a biomarker for seizure susceptibility (Maturana et al., 2020).
In this study, we present an alternative view by investigating the
position of the brain’s position relative to a critical dynamical system,
rather than adopting a binary classification of “yes” or “no” at a perfect
tipping point to determine whether the brain is in a pathological state.
We hypothesize that a healthy brain consistently resides within a well-
defined quasi-critical state zone, maintaining proximity to a critical
point, while diseased brains may be out of this region. Consequently, the
distance of criticality serves as a valuable preliminary indicator for
2
Brain Research Bulletin 200 (2023) 110684
gauging the brain’s position within the critical zone. This approach
recognizes the brain’s intricate nature as a highly efficient and adaptable
organ, operating in a broad phase space. Specifically, it postulates that
healthy brain dynamics operate at the boundary of a critical transition
between ordered and disordered phases (O’Byrne and Jerbi, 2022), and
a ideal measurement for distance to tipping points should directly show
how the system transitions between these two phases. Moreover, it is
crucial for this indicator to discern informative structures from noise is
crucial due to inherent EEG signal noise.
To solve these complex issues, we present a network-based criticality
analysis that employs the dynamical network biomarker (DNB) theory
and utilizes random matrix theory (RMT) to extract informative struc­
tures from complex and noisy data. This approach forms a novel index
called DTP, which measures the distance of high-dimensional dynamical
systems to critical dynamical systems. Rather than utilizing univariate
variable analysis, DNB theory investigates the spatio-temporal evolving
characteristics of the brain network to determine the presence of sig­
nificant differences. The DNB theory, introduced by (Chen et al., 2012),
aims to quantitatively identify the tipping point or critical state during
the high-dimensional dynamic evolution of a complex system, based on
observed data. DNB is mathematically derived from the premise that
when a complex system approaches the tipping point, a dominant group
of variables or members emerges. This dominant group satisfies the
following three necessary conditions, based on the observed data: a) The
internal correlation (PCCin) between any pair of members within the
DNB group rapidly increases; b) The external correlation (PCCout) be­
tween one member of the DNB group and any other non-DNB member
rapidly decreases; c) The standard deviation (SDin) or the coefficient of
variation for any member in the DNB group drastically increases. The
original indicator integrating these features (Chen et al., 2012) was
defined as an early warning signal (EWS) and has been used to detect the
onset of diseases (Chen et al., 2012; Liu et al., 2013), abrupt changes in
exchange markets (Oya et al., 2014), and other phenomena (Lesterhuis
et al., 2017; Yang et al., 2018). By integrating the DNB theory and
Random Matrix Theory, we devise an indicator to explore how the dis­
tance to criticality varies across distinct stages and evaluate the brain
networks’ transition between random and order.
The remainder of this paper is organized as follows: in Section 2, we
explain the theoretical background of the proposed indicator; in Section
3, we demonstrate the results of the spatiotemporal evolution of the
brain network and DTP, and identify the EWS in the DTP sequence; and
in Section 4-5, we discuss the results with our main findings and give a
conclusion.
2. Materials and methods
2.1. Data
We assess the efficacy of our proposed method using the CHB-MIT
Scalp EEG Database, which comprises long-duration EEG signal re­
cords collected at the Children’s Hospital Boston (Goldberger et al.,
2000. This database represents the largest freely accessible dataset of its
kind, forming part of the PhysioBank—a comprehensive online resource
offering a growing collection of digitized physiological signals and
related data for the biomedical research community. The CHB-MIT
dataset comprises recordings from 23 patients (5 males aged 3–22; 17
females aged 1.5–19) diagnosed with intractable seizures, yielding a
total of 24 cases due to one patient having two separate recordings taken
1.5 years apart. Each subject features between 9 and 42 continuous
sessions, some of which include one or more seizure events. Annotations
for the beginning and endpoints of each seizure have been provided.
Non-seizure records are those without any seizure events, while seizure
records contain one or more seizures. Overall, the dataset encompasses
916 h of continuous scalp EEG data, sampled at 256 Hz with 16-bit
recording precision. The EEG signals were obtained using 23 standard
EEG channels (FP1-F7, F7-T7, T7-P7, P7-O1, FP1-F3, F3-C3, C3-P3,
S. Liu et al. Brain Research Bulletin 200 (2023) 110684

P3-O1, FP2-F4, F4-C4, C4-P4, P4-O2, FP2-F8, F8-T8, T8-P8, P8-O2,

FZ-CZ, CZ-PZ, P7-T7, T7-FT9, FT9-FT10, FT10-T8, and T8-P8)
following the international 10–20 system of electrode placement. In
our study, we focus on sessions containing one seizure event for testing
purposes.

2.2. EEG pre-processing

In this study, we analyzed EEG signals of epilepsy and divided them

into three sub-datasets: normal/interictal, pre-seizure/preictal, and
seizure/ictal phases. To facilitate analysis and comparison, we extracted
3-minute EEG time series from each recording. This included 1 min of
EEG data before the seizure onset, 1 min of EEG data after the seizure
onset, and 1 min of EEG data as far away from the onset point as possible
in each trial. These three segments were concatenated to form a com­
plete EEG signal for analysis. A 3-minute EEG time series is sufficient to
capture all three stages of brain seizure activity (Li et al., 2014). Fig. 1
presents representative examples of 23-channel EEG recordings during
(A) interictal, (B) preictal, and (C) ictal phases, respectively. The
mathematical analysis was conducted using MATLAB software version
R2017a. Prior to analysis, the EEG data underwent several
pre-processing steps. Firstly, a 50 Hz notch filter was applied to remove
line noise, which is considered noise induced by the power supply.
Secondly, a band-pass filter with a frequency range of 0–60 Hz was used
to retain relevant frequency components. Additionally, the EEG data
was standardized by setting the mean of each time series to zero and the Fig. 2. The decision tree describes how the CBH and QCBH theories are asso­
variance to 1, i.e., Σxl (t) = 0; Σxl (t)2 = 1, with l representing the ciated with clinical diseases and how they can be utilized for disease detection.
channel index and t denoting the sampling time. This step ensured that
all measures were on the same scale, facilitating comparison across criticality, it may be more fitting to discuss computational trade-offs
channels and time points. associated with proximity to criticality. Different tunings along these
trade-offs could correspond to various cognitive profiles. By considering
these computational properties and trade-offs intrinsic to shifts in crit­
2.3. Criticality and brain states
icality, the distance to criticality emerges as a crucial biological variable
for understanding both healthy and pathological changes in cognition
The critical brain hypothesis (CBH) suggests that the brain leverages
and behavior, forging a direct mechanistic link between neurons and
a critical phase transition to optimize its adaptive computational prop­
neuronal ensembles at the micro-scale and computation at the macro
erties (Cocchi et al., 2017). Consequently, any loss or attenuation of
scale.
criticality in brain dynamics could lead to a decline in these properties.
This underlines the significance of the distance to the critical point/­
2.4. The dynamic network biomarker theory
tipping point (DTP) as a biological parameter for understanding cogni­
tive differences within individuals concerning brain states, between
The brain’s complexity requires the distance measures that extend
individuals with regard to psychological traits, and in relation to mental
beyond univariate variables for analyzing high-dimensional dynamical
illness (O’Byrne and Jerbi, 2022; Fosque et al., 2021). Recent findings
systems transitions. Chen et al. proposed a dynamical network
reveal that a healthy brain operates in a state of near-criticality as
biomarker (DNB) indicator, which uses fluctuations and correlations
opposed to being precisely critical and shares similar computational
between variables to identify critical points in systems across various
characteristics as the critical point, albeit with reduced intensity (Ma
fields, such as gene expression, Raman spectra, and disease progression
et al., 2019; Hahn et al., 2017; Toker et al., 2022. This hypothesis
(Chen et al., 2012). However, the original DNB calculation is chal­
sometimes is called the quasi-critical brain hypothesis (QCBH). In Fig. 2,
lenging due to the involvement of the unknown Jacobian matrix. To
we have depicted how the CBH and QCBH theories are associated with
address this, Kamal et al. (2019) proposed a modified indicator using
clinical diseases and how they can be utilized for disease detection,
only standard deviations and Pearson correlation coefficients of the
using a decision tree format Fig. 3.
DNB. Furthermore, Oku and Aihara (2018) introduced a novel
The phenomenon of near-criticality can be rationalized from a
DNB-based indicator focusing on the relationship between the Jacobian
normative perspective through several explanations as described in
matrix and the sample covariance matrix concerning eigenvalues and
O’Byrne and Jerbi (2022). Firstly, near-criticality may serve as a buffer
eigenvectors. This allows the DNB selection based on the dominant
that prevents an excessive build-up of activity from incoming inputs,
eigenvector of a sample covariance matrix (Matsumori et al., 2019).
which could otherwise drive global dynamics into the supercritical
The eigenvalues and corresponding eigenvectors has the following
phase. Secondly, since not all computational tasks are optimized at
relations:

σ2
= λCi (c)(i = 1, 2, …, n) (1)
1 − λAi (c)2

where λAi(c) is the largest eigenvalue of Jacobian matrix at c, λCi is the

eigenvalue of covariance matrix. (Oku and Aihara, 2018). Matsumori
et al. (2019) define an indicator CD(c) for detecting a transition using the
average of Cij(c) in JD as follows:
Fig. 1. An example seizure.

3
S. Liu et al. Brain Research Bulletin 200 (2023) 110684

Fig. 3. Flowchart of the study. a) The Quasi-critical brain hypothesis suggests that the brain resides in a well-defined region near the critical point. Brain states that
exceed this region can lead to brain pathology. b) Large-distance communication emerges at critical points (Beggs and Timme, 2012). c) Critical transitions are
sudden shifts triggered by small forces, which correspond to catastrophic bifurcations mathematically. These abrupt changes occur at specific thresholds in external
conditions and arise in systems with alternative stable states, where one system can have more than one possible configuration under the same external conditions. d)
We can reconstruct the dynamic brain network and identify biomarkers for detecting changes in brain connectivity over time. We divided the time course of each
subject into multiple time-windows with a one-step forward sliding window. In each window, we reconstructed the functional brain connectivity using methods such
as Pearson’s correlation coefficient computation, forming the dynamical functional connectivity (dFC). This resulted in a series of dFC matrices that capture the
dynamic changes in brain connectivity over time. The trajectory of network system’s states traditionally can be tracked by the network structures. The Jacobian
matrix of the original system, which is traditionally used to identify the transition, can be approximated by the sample covariance matrix from observed data. To
assess the dynamical properties of the dFC matrices, we compared them to a random network with a random adjacency matrix. Specifically, we calculated the
eigenvalue of the system by comparing it to the random network/random matrix. The informative eigenvalues and eigenspaces can be identified by Random Matrix
Theory (RMT) prediction. If the brain system transitions from a normal to a pathological state, it may undergo a sudden change in distance to criticality. To detect
early warning signals of these sudden changes, we can use indicators such as critical slowing down.

⃒ ⃒
1 ∑ ⃒⃒ ⃒
⃒ distance to tipping points should directly show how the system transi­
CD (c) = 2 ⃒Cij (c)⃒. (2) tions between these two areas. Moreover, due to the presence of inherent
m i,j∈JD ⃒ ⃒
noise in EEG signals, it is crucial for this indicator to effectively
discriminate informative structures from the noise. In order to achieve
where Cij(c) = vi1(c)vj1(c)λC1(c). This indicator has been successfully
this, we have utilized random matrix theory (RMT) to extract informa­
used to predict transitions in a complex network-based harvesting
tive structures from complex and noisy data.
model.
The RMT was initially introduced in the field of quantum physics by
Wigner (1955). Recently, various studies have shown that filtering the
2.5. Random matrix theory and scaled distance to criticality empirical covariance matrices can reveal the actual statistical structure
underlying data (El Karoui et al., 2008; Laloux et al., 1999; Plerou et al.,
This section introduces a novel index called DTP, which we develop 1999). If the covariance matrix C is from time series with random en­
to measure the distance to tipping points. As previously discussed, brain tries, under the restriction L → ∞, N → ∞ with fixed Q ≡ L∕N ≥ 1, the
states exist between order and disorder. An ideal measurement for the

4
S. Liu et al.
probability density ρ of eigenvalues λ of C is analytically given by the
√̅̅̅̅̅̅̅̅√̅̅̅̅̅̅̅̅
Q warning signals in the DTP sequence, we investigate two perspectives:
Marchenko-Pastur distribution, ρ(λ) = 2πσ where is the
λ+ − λ λ− λ−
2 σ2
variance of the time series (unit in this case, i.e., σ2 = 1) and λ± are the
upper bound and lower bound of eigenvalues, respectively, given by λ±
( √̅̅̅ )
= σ 2 1 + Q1 ± 2 Q1 .
Building on the eigenvalues of EEG covariance and random matrix as
well as eigenvector-based DNB’s index, we can define a distance to
tipping points as:
( ∑ )
DTP(c) = exp
− (Δλ) ∗ i,j∈JD vi1 (c)vj1 (c)
(3)
m 2
{ speed from small disturbance becomes slower and slower, resulting in
0 if λC1 (c) ≤ λ+
where Δλ = , and λ+ is the upper bound
λC1 (c) − λ+
otherwise
( √̅̅̅ )
of the eigenvalue of a random matrix, given by: λ+ = δ2 1 + Q1 + 2 Q1 .
The operation in the formula scales the DTP values between 0 and 1.
When the signals consist predominantly of white noise, their covariance
matrix can be accurately characterized by RMT, yielding a DTP value of
1. As the system approaches a tipping point, the dominant eigenvalue of
the covariance matrix tends toward infinity, causing the DTP value to
approach zero. By leveraging RMT, the DTP indicator provides a
powerful means to assess a system’s proximity to critical transitions,
offering valuable insights into the underlying dynamics. As the DTP
value transitions from 1 to 0, it indicates that the underlying system
shifts from a completely random to an ordered system. Systems posi­
tioned between order and randomness, i.e., within the range (0,1), are
considered to exhibit complexity, which is described as the “edge of
chaos” (Bak, 2013).
Based on the calculation process, the brain system states are pro­
jected onto a position between randomness (DTP = 1) and order (DTP =
0) in the phase diagram, which appears to be closely related to
complexity metrics. Consequently, we are interested in exploring the
relationship between our method and specific complexity measures,
such as entropy. In thermodynamics, it is well-established that entropy
and rate functions derived from large deviations often serve as in­
dicators that a system is approaching a critical transition. In the field of
evolutionary biology, entropy has been found to be closely related to
network topology, as demonstrated by Demetrius and Manke (2005). In
the current study, we will examine the relationship between DTP and
network entropy (West et al., 2012), a widely accepted measure
employed to quantify network functionality and fragility. Network en­
tropy appears to be particularly well-suited for brain network system
analysis and comparison with dynamic network biomarkers introduced
in this paper. We also present a comparison between distance to criti­
cality index and network entropy. Consider a stochastic matrix ϕ = (ηky),
which describes a Markov chain that characterizes transition rates from
∑
state x to state y with ηxy≥ 0 and yηxy = 1, along with its invariant
distribution π = πϕ. Network entropy can then be defined as follows:
∑ ∑
Se = π(x)S(x) with S(x) = − ηxy logηxy .
x y
In the above definition, nodal entropy S(x) is the summation only over
edges y adjacent to x, effectively discounting information from nonad­
jacent vertices.
2.6. Early warning signatures
In this study, we introduce a novel approach to forecast epileptic
seizures by investigating phase transitions in the distance to criticality
sequence at seizure onset points. Unlike previous studies that directly
detect phase transitions in the raw signal, we hypothesize that DTP
undergoes a sudden change when the brain transitions from a healthy to
a pathological state. If there is a phase transition in the DTP sequence, it
is possible to apply early warning indicators to identify early warning
5
Brain Research Bulletin 200 (2023) 110684
signals in the sequence to predict epileptic seizures. To explore early
critical slowing down-related indicators and multi-fractal indicators.
The critical slowing down-related indicators are based on the observa­
tion that the dynamics of a system near a critical point become slower as
the system approaches the critical point. The fractal indicators are based
on the observation that the DTP sequence may exhibit fractal behavior
near the critical point. By combining these two perspectives, we aim to
identify reliable early warning signals for epileptic seizures.
2.6.1. Critical slowing down
When it is close to a bifurcation or phase transition, the recovery
critical slowing down (Wissel, 1984). The approach of critical slowing
down of the dynamics of complex systems as control parameters
approach critical values is used to extract early warning signals from
univariate time series in real datasets.
When a system loses resilience, in other words, it approaches bifur­
cation or phase transition, the speed of system recovery from distur­
bance will gradually slow down. Therefore, systems that lose resilience
will show high autocorrelation and fluctuations after small disturbance.
Recently, some indexes, such as variance, skewness, autocorrelation and
kusisto, have been proposed to detect critical slowing down. The method
based on critical slowing down has attracted wide attention and has
been widely used in different complex systems, such as the earth system
(Kleinen et al., 2003, climate system (Dakos and Bascompte, 2014),
financial system (Diks et al., 2019) and neural system (Pavithran and
Sujith, 2021). In this paper, we use autocorrelation, variance, skewness
and kurtosis as the characteristics of a critical transition to explore the
phenomenon of critical slowing down. These indicators are defined as
follows.
a. Autocorrelation. Autocorrelation describes the correlation between
the original signal, p(t), and its time delayed signal, p(i− τ):
∑N
p(i)p(i − τ)
AC(τ) = i=1 2
σ
In this paper, τ is set as 1, considering the factor that low lags the
system’s short-term memory increase caused by the critical slowing
down.
b. Variance. Variance (VAR) is defined as the expectation of the
squared differences from its mean. It is a measure of the degree of a
data set spread out.
1 ∑N
VAR = (pi − p)2
N i=1
where p is the mean value and N is the number of sampled data
points.
c. Skewness. Skewness measures the symmetry degree of a probability
distribution. A symmetric distribution has similar left and right parts,
and has zero skewness. The skewness of X is defined as follows.
∑N
(pi − p)3 ∕N
Skew = i=1
σ 3
where p presents the mean, σ presents the standard deviation, and N
presents data points’ number. When the system approaches to a
tipping point, the skewness value will be non-zero because of the
asymmetric probability distributions.
d. Kurtosis. Kurtosis (K) provides information about whether the data
has a heavy tail distribution. The kurtosis of the normal distribution
is 3, and the higher the kurtosis is, the more abnormal values or
heavy tails are found in the data. Kurtosis is the fourth standard
moment, defined as follows:
S. Liu et al. Brain Research Bulletin 200 (2023) 110684

∑N
i=1 (pi − p)4 ∕N [ ]
K= 1 ∑w
σ4 F 2 (w, i) = (Yi (t) − Pi )2 .
w t=1
where p is the mean, σ presents the standard deviation and N rep­
resents the number of data points. The order 2 structure function and span w, F2w is defined as:
[ ]1∕2
2.6.2. Multifractal detrended fluctuation analysis 1 ∑ Nw

Multifractal detrended fluctuation analysis (MF-DFA) was used to F 2w = F2 (w, i)

Nw i=1
study the scaling behavior of time series. The Hurst exponent (H) related
to the fractal dimension (D) can be obtained as D = 2-H, using the MF- The step is repeated with different time scales or span w. Then we plot
DFA algorithm. The indicator could also be a potential early warning
the variation of F2w in the logarithm scale. The slope is the Hurst expo­
sign of a key shift (Stošić et al., 2015). MF-DFA has been applied in
nent (H).
various cases such as financial markets (Zorick and Mandelkern, 2013)
and neuroscience (Pavithran and Sujith, 2021).
2.7. Statistical analyses
The calculation process of MF-DFA method applying to a time series
x(t) of length N as follows: First, the mean subtracted cumulative deviate
We used the Mann-Whitney U Test (Mann and Whitney, 1947) to
series Y(k) can be defined as,
compare mean differences between different periods. This nonpara­
∑
k metric test is appropriate for variables that are either ordinal or
Y(k) = [xt − x], k = 1, 2, …, N continuous but not normally distributed. Specifically, we used the
Mann-Whitney U Test to examine differences in several early warning
t=1

where x represents the mean value. Secondly, divide Y(k) into Nw signal indicators during interictal, preictal, and ictal periods. We report
= [N∕w] non-overlapping segments of length w, where [N∕w] is the the results as significant, with an associated p-value less than 0.05. All
analyses were conducted using Matlab.
biggest integer function. Thirdly, a first order polynomial to fit (Yi ).
Then, subtract the polynomial fit from (Yi) to obtain the fluctuations.
The variance of fluctuations is defined as,

Fig. 4. Spatiotemporal evolution of the brain network during interictal, preictal, and ictal periods for a representative subject (subject 1). The first row displays the
covariance matrices for each period, while the second row shows the corresponding dynamical network biomarker (DNB) values.

6
S. Liu et al.
3. Results
3.1. Spatial-temporal evolution of EEG signal
We conducted a comprehensive analysis of EEG records obtained
from 111 measurements containing epileptic seizures in the CHB-MIT
Scalp EEG Database. The data used here are preprocessed according to
the description in the method section. Our approach involved
computing the DNB sequence within each window consisting of 256
samples, corresponding to a duration of one second, and forming the
sliding moving windows with one sample forward. This process resulted
in the creation of approximately 7000 overlapping near stationary
windows for every measurement. The DNB was initially applied to
monitor state transitions in brain networks across different periods,
based on their respective covariance matrices (Fig. 4(a)). Our findings
reveal that the mean DNB remains relatively stable when transitioning
from the seizure-free/interictal to the pre-seizure/preictal phase, but
exhibits a noticeable increase from the preictal to the seizure/ictal phase
(Fig. 4(b)).
Fig. 5 illustrates the statistical comparison of mean DTP values across
three distinct periods. Our results show a significant decrease in the DNB
index during the pre-ictal period ((0.057 ± 0.139) × 1011, mean ± std)
compared to the inter-ictal period ((0.904 ± 1.126) × 1011, p < 0.001).
Additionally, we observed a notable elevation in DNB during the ictal
period ((3.560 ± 2.621) × 1011, p < 0.001). The observation made
during the pre-ictal period seems to be correlated with the desynchro­
nization that occurs during this period, which aligns with the findings
presented in Schindler et al. (2007).
3.2. The dynamics of distance to criticality
Fig. 6 shows the mean DTP evolution during three periods. DTP does
not change significantly from the interictal period to the preictal period,
however, shortly after the seizure onset, it drops sharply afterward,
suggesting that brain network systems may closely resemble critical
dynamic systems. Fig. 6 demonstrates a substantial change in DTP after
the onset of the seizure, with mean DTP values decreasing from 0.993 in
interictal period and 0.994 in the preictal period to 0.967 (p < 0.001) in
the ictal period. Furthermore, it can be observed that there are signifi­
cant differences between normal states and epileptic seizure states,
which are accompanied by alterations in the brain’s spatiotemporal
network structure. This phenomenon may suggest that shifts in the brain
networks’ positions within the phase diagram may be a possible driver
of the observed differences, with brain networks gravitating toward
much more ordered systems during the seizure state. This supports the
Fig. 5. Statistical comparison of DNB values across interictal, preictal, and ictal
periods. All differences are significant (p < 0.0001).
7
Brain Research Bulletin 200 (2023) 110684
hypothesis that seizures cause the brain loses its well-defined quasi-
critical state exhibited during the interictal period.
3.3. Critical slowing down analysis of DTP
We performed a detailed analysis of critical slowing down (CSD) and
multifractal features within DTP sequences (Fig. 6). In Fig. 7, our results
reveal a decrease in autocorrelation across the interictal (0.980
± 0.001), preictal (0.975 ± 0.017), and ictal periods (0.939 ± 0.026).
During the preictal period, the relative variance of DTP decreased to
0.789 compared to the interictal period, and during the ictal period, it
increased to 3.096 compared to the interictal period’s DTP. Although the
difference in autocorrelation and variance between periods is significant
(p < 0.001), these typical CSD indicators cannot be directly identified as
a CSD phenomenon, as one would expect these indicators to increase
during the preictal period. Further research is necessary to investigate
the underlying mechanisms. Fig. 6 also shows kurtosis and skewness
values for the DTP exhibited a consistent pattern of increase from the
interictal period (2.459 ± 1.087, − 0.182 ± 0.411, respectively) to the
preictal period (2.598 ± 2.645, − 0.136 ± 0.528, respectively), fol­
lowed by a decrease during the ictal period (2.542 ± 0.850, − 0.172
± 0.310, respectively). The statistical tests confirmed that changes in
these indicators across different periods were significant (p < 0.001).
3.4. Multifractal analysis and Hurst exponent of DTP sequence
The multifractal analysis (Fig. 8) indicates a significant decrease in
the Hurst exponent, as it declined from the interictal state (0.673
± 0.010) to the preictal state (0.660 ± 0.014), eventually reaching a
considerably lower value (0.453 ± 0.008) during the ictal state. The
Mann-Whitney U test verifies that all of these changes during different
periods are statistically significant (p < 0.001). The considerable
decrease in the Hurst exponent shortly before and after the onset of a
seizure provides further quantitative evidence supporting its effective­
ness as a potential early warning signal for epileptic seizures.
3.5. Correlation between network entropy and DTP
Although the primary objective of this work is to examine criticality
levels in various epileptic seizure phases, our introduced metric seems to
belong to the category of complexity indicators, such as network en­
tropy, which is well utilized as a measurement of network functionality
and fragility. We determined the Spearman correlation between the two
time series, which yielded a correlation coefficient of − 0.35
(p = 0.0008). The findings demonstrate that a higher DTP corresponds
to an increase in the network entropy, suggesting that the brain system
becomes more fragile and less functional. Furthermore, it is evident that
DTP offers substantial benefits in distinguishing seizure phases.
4. Discussion
The investigation of the relationship between brain dynamics and
epileptic seizures is of paramount importance, as it has the potential to
considerably enhance our comprehension of seizure prediction, pre­
vention, and management strategies. In this study, we introduced a
novel approach to explore the relationship between brain dynamics and
seizures by examining the distance to the criticality of brain networks.
Our methodology combines dynamic network biomarker theory and
random matrix theory to quantify the trajectory of the brain network’s
DTP, with a focus on the dynamics during epileptic seizures. The results
demonstrated a significant decrease in DTP immediately after seizure
onset, suggesting that the brain loses its quasi-critical state during sei­
zures. Furthermore, we identified several early warning signals in the
DTP sequences as potential biomarkers for predicting seizure onset. Our
analysis offers valuable insights into the underlying mechanisms gov­
erning brain network systems during various seizure periods and holds
S. Liu et al. Brain Research Bulletin 200 (2023) 110684

Fig. 6. The mean DTP calculated using dynamical biomarker theory and random matrix theory. The sliding window size is 1 s (256 sample points) and shifts by one
point each time, resulting in 45,569 overlapping windows per three-minute EEG. The figure illustrates a significant change in DTP values following seizure onset.

Fig. 7. The four subplots display the average values for each CSD measure, including autocorrelation, variance, kurtosis, and skewness, across these distinct periods,
i.e., interictal, preictal, and ictal periods.

promise for the development of sophisticated seizure prediction tools preictal period, followed by a sharp increase during the ictal period. This
such as the potential of criticality-based measures for seizure prediction suggests that the brain undergoes a brief period of inhibition before
and prevention. becoming excessively excited prior to the onset of a seizure. Tradition­
Figs. 4 and 5 illustrate a decrease in DNB from the interictal to the ally, hypersynchrony covering large brain regions is considered a

8
S. Liu et al.
Fig. 8. Multifractal analysis of Hurst exponent values during interictal, pre­
ictal, and ictal periods. The figure highlights a significant decrease in Hurst
values before and after the epileptic seizure phase, as well as between the
seizure-free phase and the pre-epileptic seizure phase, suggesting its potential
as an early warning signal for seizure prediction.
hallmark of generalized seizures. Previous studies have identified hy­
perexcitability and hypersynchrony as the two hallmarks of seizure
generation. However, recent research suggests an initial stage of
desynchronization followed by synchronization towards seizure termi­
nation Schindler et al. (2007). It aligns with our observations. Con­
flicting views may arise due to differences in datasets, recording
techniques, and computational measures used to construct connectivity
maps across a broad frequency range (Jiruska et al., 2013).
Additionally, Fig. 6 shows a significant decrease in DTP post-seizure
onset, indicating a shift in the brain networks’ position within the phase
diagram, moving towards a more ordered system during the seizure
state. This finding supports the hypothesis that the brain, which typi­
cally operates within a quasi-critical state during the interictal period,
deviates from this state during seizures. This deviation resonates with
Williams et al.’s findings, suggesting that deviations from the quasi-
critical region could signify or cause certain pathologies (Wil­
liams-García et al., 2014). This finding potentially leads to the devel­
opment of novel diagnostics and treatments. For example, Ezaki et al.
(2020) demonstrated that resting-state neural dynamics deviating from
criticality resulted in lower fluid intelligence. From a complexity
perspective, our results can be linked to the Fluctuation Theorem and
the theory of large deviations (Varadhan, 1984). The proximity to a
critical transition results in a lower recovery rate from deviations,
establishing a connection between entropy and DTP (Demetrius, 2013).
The correlation of activities among various elements within a network
determines its ability to maintain functionality in the face of perturba­
tions (Demetrius et al., 2004).
Our analysis of CSD indicators in DTP sequences revealed an unusual
trend. The decrease in autocorrelation and relative variance during the
preictal phase, followed by an increase in the ictal phase, challenges
traditional expectations of CSD phenomena, suggesting more complex
underlying mechanisms. Previous experimental studies have reported
critical slowing down before and after seizures in humans (Kramer et al.,
2012; Negahbani et al., 2015; Chang et al., 2018; Medeiros et al., 2014),
supporting the idea of seizures as critical transitions. Our approach,
focused on identifying criticality signatures in the DTP sequence, simi­
larly suggests that certain critical slowing down measures can serve as
early warning signals for seizures (Chang et al., 2018). However, some
recent studies have found limited evidence of critical slowing down
before seizures (Milanowski and Suffczynski, 2016; Wilkat et al., 2019),
potentially due to varying rates of control parameter changes among
individuals. Rapid changes could result in a pre-seizure phase that is too
short for detecting warning signals. Further research is needed to
9
Brain Research Bulletin 200 (2023) 110684
investigate this issue and explore the full implications of our findings for
seizure prediction and prevention (Medeiros et al., 2014).
Our multifractal analysis (Fig. 8) showed a significant decrease in the
Hurst exponent from the interictal to ictal state, supporting its potential
as an early warning signal for epileptic seizures. The negative correla­
tion between network entropy and DTP was also significant, indicating
that as the system approach to more order (higher DTP), it becomes
more fragile, highlighting DTP’s potential as a complexity indicator and
its ability to distinguish between different seizure phases. Further
research is required to explore the efficacy of these measures in real-time
seizure prediction.
The study discussed in the text has several limitations that must be
acknowledged. Firstly, the data used in the analysis is obtained from the
CHB-MIT Scalp EEG Database, which may not fully represent diverse
epilepsy phenotypes. Future research should consider various types of
epilepsy and incorporate data from other sources to ensure broader
applicability. Secondly, the study focused on analyzing scalp EEG data,
which may suffer from limitations such as low spatial resolution and
signal attenuation. Therefore, intracranial EEG data could provide
higher-resolution insights into brain dynamics during seizures. Thirdly,
the choice of parameters such as the window length for calculating DTP
may impact the results, and a comprehensive exploration of parameter
sensitivity and optimization is required to improve the robustness of the
findings. Fourthly, the limited sample size of patients may affect the
statistical power of the findings, and a larger cohort of patients is
required for more accurate estimations of the relationship between
criticality and seizures. Lastly, the study focused on identifying early
warning signals based on the mean DTP sequences, and the results may
not be universally applicable across individual patients. A more
personalized approach to seizure prediction and prevention may be
required for the development of effective clinical interventions.
5. Conclusion
In summary, our analysis of the EEG records demonstrates a strong
relationship between brain network dynamics and seizure evolutions by
tracking the distance of criticality. The observed changes in the DTP
values across different seizure periods highlight the potential of
criticality-based measures for predicting and preventing epileptic sei­
zures. Furthermore, the examination of early warning signals (EWS)
reveals the presence of statistically significant changes in CSD and
multifractal features, despite not conforming entirely to the expected
patterns of the previous theory. This suggests that further research into
these indicators may yield valuable insights into seizure prediction and
underlying mechanisms. The substantial decrease in the Hurst exponent
at the onset of a seizure further validates its potential as an early
warning signal for epileptic seizures. Overall, our results emphasize the
importance of studying brain network criticality-based measures in
understanding and predicting epileptic seizures.
CRediT authorship contribution statement
Shun Liu: Conceptualization, Methodology, Software, Writing –
original draft. Fali Li: Writing – review & editing. Feng Wan: Super­
vision, Writing – review & editing.
Declaration of Competing Interest
None.
Data Availability
The dataset used in this article is a publicly available dataset with a
detailed description provided in the Method section. It can be obtained
from the corresponding website.
S. Liu et al. Brain Research Bulletin 200 (2023) 110684

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