Phase-Lags in Large Scale Brain Synchronization: Methodological Considerations and In-Silico Analysis

RESEARCH ARTICLE
Phase-lags in large scale brain

synchronization: Methodological
considerations and in-silico analysis
Spase Petkoski1*, J. Matias Palva2, Viktor K. Jirsa1*
1 Aix-Marseille Université, Inserm, INS UMR_S 1106, Marseille, France, 2 Neuroscience Center, Helsinki
Institute of Life Science, University of Helsinki, Helsinki, Finland
* spase.petkoski@univ-amu.fr (SP); viktor.jirsa@univ-amu.fr (VKJ)

a1111111111
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a1111111111 Abstract
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Architecture of phase relationships among neural oscillations is central for their functional
significance but has remained theoretically poorly understood. We use phenomenological
model of delay-coupled oscillators with increasing degree of topological complexity to iden-
tify underlying principles by which the spatio-temporal structure of the brain governs the
OPEN ACCESS
phase lags between oscillatory activity at distant regions. Phase relations and their regions
Citation: Petkoski S, Palva JM, Jirsa VK (2018)
of stability are derived and numerically confirmed for two oscillators and for networks with
Phase-lags in large scale brain synchronization:
Methodological considerations and in-silico randomly distributed or clustered bimodal delays, as a first approximation for the brain
analysis. PLoS Comput Biol 14(7): e1006160. structural connectivity. Besides in-phase, clustered delays can induce anti-phase synchroni-
https://doi.org/10.1371/journal.pcbi.1006160 zation for certain frequencies, while the sign of the lags is determined by the natural frequen-
Editor: Daniele Marinazzo, Ghent University, cies and by the inhomogeneous network interactions. For in-phase synchronization faster
BELGIUM oscillators always phase lead, while stronger connected nodes lag behind the weaker during
Received: December 21, 2017 frequency depression, which consistently arises for in-silico results. If nodes are in anti-
Accepted: April 29, 2018 phase regime, then a distance π is added to the in-phase trends. The statistics of the phases
is calculated from the phase locking values (PLV), as in many empirical studies, and we
Published: July 10, 2018
scrutinize the method’s impact. The choice of surrogates do not affects the mean of the
Copyright: © 2018 Petkoski et al. This is an open
observed phase lags, but higher significance levels that are generated by some surrogates,
access article distributed under the terms of the
Creative Commons Attribution License, which cause decreased variance and might fail to detect the generally weaker coherence of the
permits unrestricted use, distribution, and interhemispheric links. These links are also affected by the non-stationary and intermittent
reproduction in any medium, provided the original synchronization, which causes multimodal phase lags that can be misleading if averaged.
author and source are credited.
Taken together, the results describe quantitatively the impact of the spatio-temporal connec-
Data Availability Statement: All relevant data are tivity of the brain to the synchronization patterns between brain regions, and to uncover
within the paper and its Supporting Information
mechanisms through which the spatio-temporal structure of the brain renders phases to be
files, and data and codes are also available at
https://gitlab.thevirtualbrain.org/spase.petkoski/ distributed around 0 and π.
plos_PLSNS. Trial registration: South African Clinical Trials Register: http://www.sanctr.gov.za/
Funding: This work was funded by the European SAClinicalbrnbspTrials/tabid/169/Default.aspx, then link to respiratory tract then link to
Union’s Horizon 2020 Framework Programme for tuberculosis, pulmonary; and TASK Applied Sciences Clinical Trials, AP-TB-201-16 (ALO-
Research and Innovation under the Specific Grant PEXX): https://task.org.za/clinical-trials/.
Agreement No. 720270 (Human Brain Project
SGA1), L0 Agence nationale de la recherche (ANR)
under the Grant No ANR-14-CE13-0018-03, and
No. 785907 (Human Brain Project SGA2) and the
PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1006160 July 10, 2018 1 / 30

Phase-lags in large scale brain synchronization
Academy of Finland (Grant No. 253130), http://

webfocus.aka.fi/ibi_apps/WFServlet?IBIF_ex=x_ Author summary
HakKuvaus&CLICKED_ON=&HAKNRO1=
253130&UILANG=fi&IBIAPP_app=aka_ Functional connectivity, and in particular, phase coupling between distant brain regions
ext&TULOSTE=HTML. The funders had no role in may be fundamental in regulating neuronal processing and communication. However,
study design, data collection and analysis, decision phase relationships between the nodes of the brain and how they are confined by its spa-
to publish, or preparation of the manuscript. tio-temporal structure, have been mostly overlooked. We use a model of oscillatory
Competing interests: The authors have declared dynamics superimposed on the space-time structure defined by the connectome, and we
that no competing interests exist. analyze the possible regimes of synchronization. Limitations of data analysis are also con-
sidered and we show that the choice of the significance threshold for coherence does not
essentially impact the statistics of the observed phase lags, although it is crucial for the
right detection of statistically significant coherence. Analytical insights are obtained for
networks with heterogeneous time-delays, based on the empirical data from the connec-
tome, and these are confirmed by numerical simulations, which show in- or anti-phase
synchronization depending on the frequency and the distribution of time-delays. Phase
lags are shown to result from inhomogeneous network interactions, so that stronger con-
nected nodes generally phase lag behind the weaker.
Introduction
Many processes in nature are oscillatory, from heart beats and birds flapping their wings, to
firing of neurons [1] and brain rhythms [2]. Oscillators are rarely isolated and they interact
when coexisting in the same environment, thus synchronizing by adjusting their rhythms [3].
Synchronization, or consistent phase relationships, of distant regions of the brain has been
detected by a variety of measures and may be a key mechanism for the regulation of cortical
processing and communication [4, 5]. Advances of non-invasive structural brain imaging [6,
7] have made feasible large-scale network modeling approaches using biologically realistic
connectivity, defined by the connection topology and delays, the so-called connectome, which
is a crucial determinant of the network behavior [8–13]. The Kuramoto model (KM) [14] as a
paradigm for the emergent group dynamics of coupled oscillatory subsystems [15, 16] is well
suited for assessing how the connectome governs the brain oscillatory dynamics [17–22],
which is then reflected in the phase relationship between brain regions.
Studies of networks dynamics predominantly focus on the synchronization properties,
while the actual phase relationship between the oscillators is typically ignored, especially in
complex networks with delays [16, 23]. For the tractable case of all-to-all equally coupled phase
oscillators in thermodynamic limit, the phases of each oscillator are either constantly shifted
from the mean phase, or non-uniformly rotate with a speed dependent on their natural fre-
quencies, while still preserving the overall stationary distribution [14]. For heterogeneous cou-
plings, phases become multimodal [24] and thus imply multimodal phase shifts for stationary
synchronization, and for couplings of mixed signs [25], the oscillators generally split at dis-
tance π, but for strong coupling they form a traveling wave. Glassy states with ordered, but uni-
formly distributed phases for each frequency also appear for distributed parameters [26], and
for structured networks multiple mean fields appear with oscillating, bounded or unbounded
phase differences between them [27].
A number of computational studies on brain functional connectivity use neural masses
connected with connectome-defined delays and weights. This yields intermittent in- or anti-
phase synchronization [8] and a good agreement with experimental studies of phase relation-
ship between local node dynamics and their degree in healthy subjects [28], and for Alzhei-
mer’s disease [29]. Time-delays have been employed as a necessary condition for modeling

anti-phase spatio-temporal patterns in the brain [11, 30], and for pair-wise coherence in con-
nectome networks of phase oscillators that reproduce resting state patterns in BOLD fMRI
[19], MEG [31] and EEG [21, 32, 33].
Oscillatory processes are particularly sensitive to delays, because shifts in phasing may ren-
der excitatory connections to inhibitory, and vice versa. The impact of time-delays on the syn-
chronization, and indirectly to the phase-lags, has been studied for a single delay [34, 35] or
for homogeneously distributed delays [36, 37], but so far only for all-to-all connectivities or for
simple motifs. Spatially heterogeneous delays are particularly important for number of sys-
tems, foremost the brain [10, 11, 13]. Depending on their distribution, time-delays impose
phase-shifted, in- or anti- phase clusters of oscillators, but their impact for phase-lags in large-
scale neural synchronization has not been properly investigated. Stronger connected network
nodes have been demonstrated to lag behind the weaker for randomly distributed delays
shorter than a quarter period of the oscillators [22], but this restricts a large portion of the rele-
vant frequencies.
In the current study we identify the relationship of the brain topology and its spatio-tempo-
ral structure, with the phase lags between the brain regions at any frequency of the brain
processes. Analytical insights of synchronization on networks with distributed delays and het-
erogeneous couplings and frequencies, are applied to in-silico large-scale brain dynamics.
Phase lockings and lags are studied in consideration to the limitations of time-series analysis
that depend on the regime and levels of coherence. Inhomogeneous interactions due to the
connectome are shown to drive the phase relationship, whilst the regimes of synchronization
are constrained by the organization of the time-delays. Besides in-phase, these include anti-
phase locking that for weak coherence depends on the length of the links, while for strong cou-
pling is prevalent for the nodes of opposite hemispheres.
Model
Spatio-temporal organization of delay-coupled oscillatory networks is often studied via phase
oscillators that arise for weak interactions [14, 38–40]. The delays are reduced to phase shifts
when they are small [38, 39, 41], but they appear inside the state variables when they are of the
order of 1/coupling-strength [38, 39], yielding
y_ i ðtÞ ¼ oi þ hi ðy1 ðt ti;1 Þ; y2 ðt ti;2 Þ . . . yn ðt ti;N Þ; Ki;1 ; Ki;2 . . . Ki;N Þ; i ¼ 1 . . . N; ð1Þ
where ωi are the natural frequencies, and for each link Kij and τij are coupling strengths and
time-delays. Phase models still exhibit rich behavior and a direct link to more complex bio-
physical models, while admitting analytic approaches [40–43]. A special case is the Kuramoto
model, which keeps only the first sine term of the Fourier series of hi and that has been worked
out to allow full analytical tractability. A large class of oscillators that are near an Andronov-
Hopf bifurcation can be exactly transformed to the KM [14, 44], as well as Wilson–Cowan net-
works [41, 45]. Although the KM is not explicitly a brain model, it has been applied as one [18,
19, 21, 31–33] since it is perfectly suited to describe large-scale network synchronization. The
utilized model therefore reads
1X N
y_ i ¼ oi þ K sin½yj ðt tij Þ yi ; i ¼ 1 . . . N; ð2Þ
N j¼1 ij
where network interactions are symmetric with Kij = Kji and τij = τji. The aim of the model is
to show correspondence to the empirical results for phase difference. These are often captured
by phase locking values [46], which are a statistical measure for similarity between phases of

two signals. For 1: 1 synchronization, which is of main interest in the empirical studies, PLV is
defined as
1X M
cPLV ij PLV ij eiij ¼ eiDyij ðpÞ ; ð3Þ
M p¼1
where the phase difference Δθij(p) = θi(p) − θj(p) is calculated at times p = 1. . .M.
Numerical analysis and statistics

Numerical integrations utilize a Heun scheme adapted to time delays. The time-step is set as
0.01/(max([max(K), 0.05μ, D, 1])), with noise intensity D and mean of the natural frequencies
μ, thus assuring that it is never larger than 0.01s and it is accordingly decreased for larger cou-
plings, frequencies or noise. All time series are down-sampled to twice the Nyquist frequency
of the fastest oscillator.
Complex phase locking values, Eq (3), are calculated at sliding windows of length equal to
10 periods of the mean entrainment frequency and with 75% overlap. Qualitatively similar
results are obtained for windows lengths between 5 and 10 periods, and for overlapping
between 50% and 90%, although longer windows yield systematically lower level for statistical
significance [47].
Signals can often be coherent just by chance and statistical testings are necessary to cor-
rectly identify the coherence due to the mutual interactions [46, 47]. The level of significance
for PLV is calculated as the 95th percentile of maximum values in 100 surrogate signals using
two different procedures, followed by the same processing as for the original time-series. The
first surrogates, which yield less strict level of significance are obtained by shuffling the time
series of the phases of one of the oscillators. The second, generally stricter level is obtained by
two independent uncoupled oscillators with the same frequencies, fixed or time-varying, as the
original oscillators, with the same level of noise. The problem with the latter is that in empirical
analysis the parameters of the uncoupled oscillators and the noise intensity can be unknown,
although the noise intensity could be obtained from the variance of the signal under assump-
tions of stationarity.
Results
We first analyze the case with two phase oscillators with time-varying coupling strengths and
natural frequencies [48]. This is valid if network interactions are either unknown, or too weak
to cause synchronization, and hence assumed to be encompassed in the inherent dynamics of
each oscillator, as additive noise and/or non-autonomous (NA) forcing. Then the analysis is
extended to homogeneous and delay-imposed networks with bimodal δ time delays and log-
normally distributed node strengths, as observed in the brain. Analytical findings are numeri-
cally validated and are used to explain phase statistics for simulated dynamics over the human
connectome.
Two oscillators
The simplest case of two delay-coupled phase oscillators with constant parameters reads
y_ 1;2 ðtÞ ¼ o1;2 K sin½y1;2 ðtÞ y2;1 ðt tÞ: ð4Þ
Steady synchronization occurs when the oscillators start oscillating with a same adjusted

frequency O, preserving a constant phase shift ϕ1,2 = θ1 − θ2, which becomes

8
o1 o2 < ð p2 ; p2Þ; if K cos Ot > 0;
1;2 ¼ arcsin 2 ð5Þ
2K cos Ot : ð p ; 3pÞ; if K cos Ot < 0;
2 2
where O is described by a transcendental function and the critical coupling reads

Kc ¼ jo2 o1 j=j2 cos Otj ð6Þ
Oscillators can be locked in- or anti- phase, depending on the sign of K cos Oτ, so that for the
phase shift it holds
8 8 p

>
> < 2 0; 2 if K cos Ot > 0; ðin‐phaseÞ;
>
>
>
> o o )
>
>
2 1
:
>
< 2 p2 ; p if K cos Ot < 0; ðanti‐phaseÞ:
8 ð7Þ
>
> 2 p
; 0 if K cos Ot > 0; ðin‐phaseÞ;
>
> < 2
>
>
>
> o o )
>
:
2 1
:
2 p; 3p2 if K cos Ot < 0; ðanti‐phaseÞ:
The model is made more realistic by allowing deterministic variability of the frequencies
and the coupling, and additive, independent, Gaussian noise
y_ 1;2 ðtÞ ¼ o1;2 þ 1;2 sin o

^ 1;2 t ^ K tÞ sin½y1;2 ðtÞ
ðK þ K sin o y2;1 ðt tÞ þ Z1;2 ðtÞ: ð8Þ
Here hηi(t)i = 0 and hη1(t)η2(t0 )i = 2Dδ(t − t0 )δ1,2, with h i denoting time-average operator,
while ω1,2 and K are harmonically modulated. In adiabatic limit without noise [48] effective
coupling Keff ðtÞ ¼ ðK þ K sin o ^ K tÞcosOt and frequencies oeff 1;2 ðtÞ ¼ o1;2 þ 1;2 sin o
^ 1;2 t and
Δωeff1,2(t) = ωeff1(t) − ωeff2(t), can quantify the synchronization instead of fixed parameters in
Eqs (5) and (6), but they give insight into the level of coherence even for stochastic dynamics,
and for non-adiabatic response that occurs due to the large inherent time-scale close to inco-
herence. The stochastic dynamics with constant parameters is shown through the evolution of
instantaneous and time-averaged phase lags, and PLVs in Fig 1.
The oscillators in panel (A) are identical and the only variability is due to the noise, which
causes time-varying cPLV and phases. Nevertheless, phase lags are close to zero during the
periods of significant PLV, as seen by the red and magenta lines for a shorter interval in (a),
and for the whole time series in (b). Thus, for a sufficient number of time-points the lags for
in-phase synchronization will have a mean at 0, as seen in their histograms and estimated
probability density distributions (PDF), (d, e). The mean phase difference in (B) is in the
interval (−π/2, 0), as predicted by Eq (7) for in-phase locking and different natural frequen-
cies with ω1 < ω2. The results also indicate that statistical significance has no influence on the
mean of the observed lags, but only impacts their variance. Hence, lower significance levels
would improve the statistics of short time-series, by increasing the number of significant data
points.
Non-autonomicity causes intermittent epochs of in- or anti-phase synchronization, Fig 2.
These are still well captured by |2Keff| ≷ |Δωeff|, as predicted by Eq (6) for fixed parameters,
with periods of insignificant coherence, (c, j), corresponding to |2Keff| ≲ |Δωeff|, (d, k). In both
examples the coupling is explicitly modulated with o ^ K , but also implicitly through the NA fre-
quency of synchronization included in cos O(t)τ, whilst hωeff2i is clearly larger than hωeff1i for
averaging over the times of significant coherence. The latter ensures the phase lags to be in the
ranges predicted by Eqs (5) and (7) for ω2 ω1, although they are wider distributed than for

Fig 1. Evolution and statistics of phase metrics for two noisy oscillators with (A) identical and (B) different frequencies. (a, b, f, g) Phase difference, Δθ1,2, (black),
and angle of the cPLV, ϕ1,2, (red and magenta for significant PLV and blue otherwise), with the top plots depicting zoomed phases of the shaded area in the lower plots.
(c, h) PLV (blue) and its mean value (black), and two levels of significance (magenta and red). (d, e, i, j) PDF (dashed red and full magenta line), histograms of phase
differences Δθ1,2 and angle ϕ1,2 during epochs of synchronization, and their circular mean values (red and magenta arrows). Two different surrogates procedures (high
surr and low surr) are used for the levels of significance. Parameters: τ = 0.01s, D = 5, K = 30 (A) ω1,2 = 12 2π rad/s; (B) ω1,2 = 12 [0.95, 1.05] 2π rad/s.
https://doi.org/10.1371/journal.pcbi.1006160.g001
fixed parameters, due to the varying frequency mismatch. The distribution of Δθ is addition-
ally broader due to the noise-induced variability, which gets partially averaged out for ϕ. As
in Fig 1, instantaneous and averaged phases from cPLV have very similar statistics, shown
through histograms for significant phase lags in regard to the both levels of significance, calcu-
lated at 50 equally spaced bins in the interval [−π, π], as it is the case in the later figures. This
implies that shorter time-windows would affect observed phase shifts only indirectly, through
the levels of PLV.
Results for time-varying parameters, Eq (8), in Fig 2 confirm that the theoretical insights,
Eqs (5) and (7), can be also used to describe the statistics for noisy and NA parameters, which
resemble the intermittent coherence observed in the real data. The distribution of phase lags
depends on the time-delay compared with the frequency of synchronization, and the average
ratio of the natural frequencies. The former dictates the regime of synchronization, in- or
anti-phase, whereas the latter specifies in which quadrant the mean of the phases will be
located.

Fig 2. Evolution and statistics of phase metrics for two NA oscillators being (A) in- and (B) anti-phase synchronized. (a, b, h, i) Phase differences Δθ1,2(t), (black) and
ϕ1,2(t), (red and magenta for significant PLV, and blue otherwise) with top plots zooming the shaded interval of the lower plots. (c, j) PLV (blue) and its mean value
(black), and levels of significance (magenta and red). (d, k) Effective coupling strength, Keff (black) compared with the absolute value of the frequency difference, Δωeff,
(blue if ω1 < ω2 and red otherwise), and (e, l) effective natural frequencies (red for ω1 and blue for ω2). (f, g, m, n) PDF (dashed red and full magenta line), histograms of
phase differences during epochs of synchronization and their means (arrows). Parameters: ω1,2 = 12 [1.03, 0.97] 2π rad/s, 1,2 = [3.6, 3.6], o^ K ¼ 0:63 rad=s, D = 5 (A)
τ = 0.01s, o^ 1;2 ¼ ½0:48; 0:74 rad=s, K = 25, K = 5; (B) τ = 0.03s, o
^ 1;2 ¼ ½0:42; 0:60 rad=s, K = 30, K = 6.
Networks of oscillators
First we derive analytical results for two spatial configurations of time-delays in all-to-all con-
nected oscillators with heterogeneous natural frequencies and coupling strengths. Then we

generalize and numerically validate those results for a more biologically plausible scenario
with stochastic inhomogeneities.
The system Eq 2 cannot be solved for general [Kij, τij], such as the connectome. Still, based
on certain assumptions, we characterize phase relations between different nodes, depending
on their location and strength. Firstly we approximate coupling inhomogeneity by the average
coupling strength of each oscillator [49], which also allows for sparse networks. The model Eq
2 is henceforth reduced to
K X
N
y_ i ¼ oi þ i sin½yj ðt tij Þ yi ; i ¼ 1 . . . N: ð9Þ
N j¼1
Next, global and local order parameters [13, 36], are defined
1X N
zðtÞ rðtÞeiFðtÞ ¼ eiyj ; ð10Þ
N j¼1
1X N
xi ðtÞ Ri ðtÞeiCi ðtÞ ¼ eiyj ðt tij Þ
: ð11Þ
N j¼1
Here r is the global coherence or the strength of the instantaneous mean field, Ri is the local
coherence or the mean field strength felt by each oscillator, whilst F and Ci are the phases of
the global and the local mean-fields. Introducing these in Eq 9, the mean-field character of the
model emerges
y_ i ¼ oi þ Ki Imðxi e iyi
Þ ð12Þ
To facilitate the analysis steady partial synchronization [24] is assumed, as opposed to the
so-called standing waves [50]. We build on [13] and we derive analytical results for randomly
distributed bimodal-δ delays and delay-imposed symmetrical biclusters. The PDF of the time
delays with equal peaks hence reads
hðtÞ ¼ ½dðt t1 Þ þ dðt t2 Þ=2: ð13Þ
The delays are either spatially homogeneous with the same independent probability for any
link, or they are heterogeneously organized so that two identical subpopulations emerge with
same internal and external time-delays, Fig 3. Besides representing distinct phenomenological
structures, these topologies are motivated from the connectome. Its simplest decomposition
Fig 3. Sketch of spatial distribution of the delays and connectivity matrices. Bimodal δ distributed delays with τ1
(blue) τ2 (red). (a) Spatially homogeneous (random) delays and (b) heterogeneous, delay-imposed structure.

on a left and a right hemispheres identifies the peaks in the delays distribution as intra- and
inter- hemispheric links (see Fig 9(d)–9(f)), leading to the clustered organization as a first
approximation. However, this division is not strict, and many links are randomly distributed,
corresponding to spatial homogeneity.
Due to the spatial homogeneity of the random network and of the internal links of ordered
subpopulations, Fig 3, the global order parameter, Eq (10), in both cases is
zðtÞ ¼ ðz I þ zII Þ=2: ð14Þ
For the former zI, II = z can represent any proportion of nodes, while for the latter they corre-
spond to the different delay-imposed subpopulations.
Bimodal-δ spatially homogeneously distributed delays. Because of the spatial homoge-
neity, steady synchronization for random delays implies
ri ðtÞ ¼ rðtÞ ¼ RðtÞ ¼ const; FðtÞ ¼ Ot; ð15Þ
where the initial phase of the mean field is set to 0 without losing generality. This allows rela-
tive phases to be introduced, ϕi = θi − Ot, and considering that contribution of links with dif-
ferent delays can be separated for each oscillator [13], Eq (12) is rewritten as
_ i ¼ oi O Ki r sinði þ O~t Þ cosð ODtÞ; ð16Þ
where we have introduced ~t ¼ t1 þt

2
2
; Dt ¼ t2 2 t1 > 0:
For steady synchronization fixed point appears in Eq (16), and considering its stability, rela-
tive phases read
8
< p
; p2 ; if ODt 2 p
; p2 ;
oi O 2 2
i þ O~t ¼ arcsin 2 ð17Þ
Ki r cos ODt : p ; 3p; if ODt 2 p ; 3p :

2 2 2 2
Thus, OΔτ and O~t are always in the same complex half-plane (left or right), as also shown by
the examples in Figs 5 and 6, and the limits of synchronization are defined as
Ki r cos ODt > joi Oj ð18Þ
Taking into account the signs of cos OΔτ and arcsin(x), Fig 4(a), relative phases read
8 8 p
>
> < 0; 2 ; for oi O;
> if ODt 2 p ; 3p;
>
> i þ O~t 2
>
> 2 2
:
>
> p
< 2
;0 ; for oi O:
8 p ð19Þ
>
> for oi O;
>
>
> < 2;p ;
>
> if ODt 2 p
; p
; þ O~
t 2
>
> 2 2 i
: 3p
:
p; 2 Þ; for oi O:
Moreover, considering the changing of arcsin(x) in those ranges, Fig 4(a), the following rules
appear for the phases depending on the nodes strengths and frequencies
(
Ki % and=or oi & , i & for oi > O;
ð20Þ
Ki % and=or oi % , i % for oi < O;
where up/down pointing arrows indicate to the increase/decrease of the preceding parameter.
Note that for any angles Oτ1,2, the values for OΔτ and O~t , which appear due to the summa-
tion sin(ϕi + Oτ1) + sin(ϕi + Oτ2), can be represented on the opposite side of the imaginary

Fig 4. (a) Values of the arcsine function and (b) an example for transformation of OΔτ and O~ t . (a) Blue for arcsin
(x) 2 [−π/2, π/2] and red for arcsin(x) 2 [π/2, 3π/2] in the Cartesian plane. (b) Values of Oτ1,2 (black) and OΔτ and O~ t
(red), and OΔτ = OΔτ ± π and O~t ¼ O~ t p (blue), which appear due to the summation sin(Oτ1 + ϕi) + sin(Oτ2 +
ϕi + 2π).
axis. This can be shown by adding 2π to any of the angles, so that the result of the sum is not
changed, while it can be transformed to read
sinði þ Ot1 Þ þ sinði þ Ot2 Þ ¼ sinði þ Ot1 þ 2pÞ þ sinði þ Ot2 Þ ¼
¼ sinði þ Ot1 Þ þ sinði þ Ot2 þ 2pÞ ¼ 2 sinði þ O~t þ pÞ cosðODt þ pÞ:
Hence, none of the above results will change if both, sin OΔτ and cos OΔτ, get opposite signs
by rotating the angles OΔτ and OΔτ by π, Fig 4(a). In addition, since for stable solutions OΔτ
and OΔτ need to be on the same side of the imaginary axis, only cases when they are in the
right half-plane can be considered without any loss of generality.
Numerical results in Fig 5 are for constant couplings, Ki = K, and Lorentzian distributed
natural frequencies with mean μ and scale γ
2
gðoÞ ¼ g=p=½ðo mÞ þ g2 :
Regardless of angles O~ t and OΔτ being in the right or left complex half-planes, panels (A) and
(B), phases are as predicted by Eqs (19) and (20) with slower oscillators being closer to the
mean field. Time-evolution of entrained and two closest to them unsynchronized oscillators
(a, b, e, f), as well as the position of the phases in the complex plane, (c, g), are shown for the
rotating reference frame O.
The same populations are simulated in Fig 6, but with equal frequencies and Gaussian
noise with a same heterogeneity for the critical coupling for instantaneous interactions [15],
i.e. D = γ. Node’s strengths, Ki = ∑j Kij/N, are log-normal
2
1 ðln K mÞ
GðKÞ ¼ pffiffiffiffiffi exp ; K > 0;
Ks 2p 2s2
pffiffiffiffiffiffiffiffiffiffiffiffi qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
with mean and variance given as mK ¼ lnðm= 1 þ ms2 Þ, sK ¼ ln 1 þ ms2 :They are assigned
to the outgoing links of each node i, whereas the symmetric connectivity is enforced by setting
Kij = (Kij + Kj,i)/2.
The stochastic frequency heterogeneity averages out over time, hence for the time-averaged
phase shifts of the synchronized oscillators we approximately derive
m O þ Zi ðtÞ m O
hi ðtÞi þ O~t ¼ harcsinð Þi ≊ arcsinð Þ: ð21Þ
Ki r cos ODt Ki r cos ODt

Fig 5. Delay-coupled heterogeneous oscillators with homogeneous bimodal-δ delays. Synchronization at frequency (A) O < μ and (B) O > μ. (a, b, e, f)
Relative phases ϕi(t) of the synchronized and two unsynchronized oscillators (black) closest to the limits O ± Kr cos OΔτ. For comparison ±(O − μ)t are shown
with dashed lines. Oscillators with (a, e) ωi < O and (b, f) ωi > O. (c, g) Geometric representation of ϕi of the synchronized oscillators (different shades of red
diamonds for ωi < O and blue circles for ωi > O) at the end of the simulations. Limits p=2 O~ t ; 3p=2 O~ t and O~ t are dashed red. The arrows show the
complex order parameter (black), angles Oτ1,2 (blue), and O~ t and OΔτ (red). (d, h) PDF of the natural frequencies, the frequency O (black vertical line), and the
limits of synchronization O ± rK cos OΔτ (red). Entrained (blue and red) and the first two un-synchronized (black) oscillators are consistent across the plots,
and the rest are green. Parameters: Number of oscillators: N = 300, Lorentzian natural frequencies with μ = 1Hz and γ = 1 (A) τ = [0.02, 0.37]s, K = 6, (B) τ =
[0.07, 0.63]s, K = 8.
The stability condition is the same as for the deterministic case, while the criterion for syn-
chronization is Kir cos OΔτ > |μ − O|. Predictions from Eq (20) still hold, with stronger oscilla-
tors lagging for O~t in the right quadrant, Fig 6(A), and leading otherwise, Fig 6(B). Compared
to the Lorentzian frequencies that have an infinite variance, the statistics of noise is homoge-
neous, but due to the couplings heterogeneity not all oscillators always synchronize, Fig 6(A).
Decreasing the noise, while fixing other parameters, Fig 6(c), improves the compliance with
the theory, c.f. plots (b) and (l), which is also manifested in the dependency of the phases to the
in-strengths, Fig 6(m)–6(o). Similar effect occurs if the simulation time is increased, Fig 6(D),
due to the better statistics for longer observations, which averages out the noise.
Time-delays imply multistable solutions for the level and frequency of synchronization,
often with no analytical solutions [13, 34, 35]. For all-to-all equally coupled oscillators, low-
dimensional evolution of the dynamics [13] reads
z_ ¼ ðim gÞz K=4½ðz 2 zt t1 zt t1 Þ þ ðz 2 zt t2 zt t2 Þ: ð22Þ
From here the frequency of steady synchronization is given as

O¼m K=2ðr2 þ 1ÞsinðO~t Þcosð ODtÞ; ð23Þ
Even though this expression is exact only for Lorentzian natural frequencies, it can be used to
determine whether the frequency of synchronization is larger or smaller than the natural fre-
quencies, i.e. O ≷ μ. This inequality depends solely on the signs of sin O~ t and cos OΔτ, Eq
(23), and governs the general relation of the phase shifts, Eq (21). Hence, taking also into
account the stability of ϕi, Eqs (17) and (21), the behavior of arcsin(x), Fig 4(a), and the trans-
formation of sine summation, Fig 4(b), we obtain the directions of change of the relative
phases as nodes strength increases, Table 1. All combinations of delays are considered, because
phases Oτ1,2 might still be longer than a full cycle, despite internal delays being set shorter than
the external.

Fig 6. Identical noisy phase oscillators coupled with homogeneous bimodal-δ delays and log-normal coupling strengths. Synchronization at frequency (A, C, D) O
> μ and (B) O < μ. (a, f, k, p) Phases ϕi(t) of the synchronized (colored coded with the in-strength) and unsynchronized (dashed black) oscillators, and the mean phase,
±(O − μ)t (dashed lines). (b, g, l, q) Scatter plot of averaged relative phases and nodes in-strengths, showing synchronized (red) and unsynchronized (green) oscillators.
Black line is the theoretical prediction Eq (21) and blue is the linear fit of the correlation. (c, h, m, r) Node strengths color-coded with their phases (filled circles are
synchronized, and empty squares are unsynchronized), and their PDF. (d, i, n, s) Phases of synchronized oscillators color-coded with their in-strength, and their PDF, ρ
(ϕ) and (e, j, o t) geometric representation and the complex order parameter (black arrow). Parameters: N = 300, simulation time (A-C) tfin = 200s and (D) tfin = 2000s.
(A, B, D) D = 1, (C) D = 0.1. Log-normally distributed in-strengths with σK = 2μK, (A, C, D) μK = 6 and (B) μK = 8. Delays (A, C, D) τ = [0.02, 0.37]s, (B) τ = [0.07, 0.63]s.
Results from Table 1 can be summarized by the geometrical mean of the time-delays eiO~t ,
which can be always transformed to be in the right complex half-plane. If eiO~t or eiðO~t pÞ is in
first quadrant, then O < μ and stronger nodes phase lag, whilst if it is in the fourth quadrant,
then O > μ and stronger nodes lead. This is confirmed with Fig 6, where the angles are in the
same quadrants as for Fig 5.
Two clusters with identical bi-modally distributed delays. For fully ordered delay-
imposed clusters, the mean field felt by the ith oscillator is sum from the delayed mean fields of

Table 1. Change of the relative phases ϕi for increasing coupling strengths for spatially random delays.
Oτ2 I II III IV
Oτ1
I & unstable unstable %
& % &
II unstable unstable unstable unstable
& &
III unstable unstable unstable unstable
% %
IV % unstable unstable %
& & %
Results are shown for angles Oτ1,2 in the different quadrants, during synchronization.
https://doi.org/10.1371/journal.pcbi.1006160.t001
each population
xi ðtÞ ¼ xI ðtÞ þ xII ðtÞ ¼ ½zint ðt t1 Þ þ zext ðt t2 Þ=2; ð24Þ
where the subscripts correspond to the mean field from its own (internal), and from the other
(external) subpopulation. Assuming steady synchronization with frequency O for both clus-
ters, due to the symmetry it follows that
RI;II ¼ r I;II ¼ r; FI;II ¼ Oðt t1 Þ þ c1;2 ; ð25Þ
where ψ1,2 is the phase shift of each cluster and the first is set to zero initial phase without loss
of generality, ψ1 = 0. In [13] it was shown that ψ2 = 0 ± π depending on the sign of cos Oτ2,
with a stability criterion
8
p
< 0; if Ot2 2 2
; p2 þ 2np;
c2 ¼ ð26Þ
:p if Ot2 2 p2 ; 3p2 þ 2np; n ¼ 0; 1 . . .
Thus, from Eq (12), synchronized oscillators in the reference frame O, Eq (25), follow
8
p
< oi O Ki r sinði þ O~t Þcos ODt; if Ot2 2 2
; p2 ;
_ i ¼ 0 ¼ ð27Þ
: o O þ K r cosð þ O~t Þsin ODt; if Ot2 2 p2 ; 3p2 :
i i i
In phase synchronization. Stable in-phase solutions of Eq (27) are identical to the case of
spatially homogeneous delays, Eq (17), with the same condition for synchronization, Eq (18).
Since these are stable only for eiO~t and eiOΔτ on the same side of the imaginary axis, the trans-
formation of the sine sum and the properties of arcsin(x), lead to
8
< oi > O , i þ O~t 2 0; p2 ) Ki % and=or oi & , i &
ð28Þ
: o < O , þ O~t 2 p
;0 ; ) Ki % and=or oi % , i %;
i i 2
which is the same relation as for spatially random delays, Table 1. These results are numerically
confirmed in Fig 7(A) and 7(B), where for identical coupling strengths, faster oscillators phase
lead the slower ones. The limits of synchronization are also confirmed, as well as the behavior
of the phases for ωi ≷ O as predicted by Eq (28).

Fig 7. Delay-imposed populations of coupled heterogeneous phase oscillators. (A, B) In- and (C, D) anti- phase synchronized clusters, at frequency (A, C) O < μ and
(B, D) O > μ. (a, b, e, f, i, j, m, n) Phases ϕi(t) of the synchronized (red and blue) and two unsynchronized oscillators (black) closest to the limits of synchronization, and
±(O − μ)t (dashed). (c, g, k, o) Geometric representation of ϕi of the synchronized oscillators (different shades of red diamonds for ωi < O and blue circles for ωi > O).
Limits p=2 O~ t ; 3p=2 O~ t and O~ t are dashed red, the arrows are for the complex order parameter (black) of each subpopulation (they overlap for in-phase), angles
Oτ1,2 (blue), and O~t and OΔτ (red). (d, h, l, p) PDF of the natural frequencies, frequency of synchronization O (black vertical line), and limits of synchronization (red).
Entrained oscillators are blue and red, the first two un-synchronized on both sides are black, and the rest are green. The colors of each oscillator are consistent across the
plots. Parameters: N = 300, K = 7, Lorentzian natural frequencies with μ = 1Hz and γ = 1. (A) τ = [0.05, 0.2]s, (B) τ = [0.7, 0.95]s, (C) τ = [0.22, 0.47]s, and (D) τ = [0.04,
0.27]s.
Anti phase synchronization. For Oτ2 in the left complex half-plane, clusters are anti-phase
locked with mean fields at distance π and same frequency and level of synchronization. Rela-
tive phases are the stable solutions of Eq (27), which read
8
p p
oi O < ð0; pÞ; if ODt 2 2
; 2
;
i þ O~t ¼ arccosð Þ 2 ð29Þ
Ki r sin ODt : ðp; 2pÞ; if ODt 2 p
; 3p
;
2 2
whilst the criterion for entrainment of single oscillators is Kir|sin OΔτ| > |μ − O|. As before,
transforming eiO~t and eiOΔτ to be in the right half-plane, without any loss of generality we focus

Fig 8. Delay-imposed clusters of identical noisy phase oscillators. (A, B) In- and (C, D) anti- phase synchronization, with log-normally distributed coupling
strengths Kij. (a, f, k, p) Phases ϕi(t) of synchronized oscillators (color-coded with their in-strength) and the mean phase, ±(O − μ)t (dashed). (b, g, l, k) Scatter
plot of averaged relative phases and nodes strength. Oscillators of the different populations are with opposite pointing triangles. Black line is the theoretical
prediction, Eq (33), blue is the linear fit for each population. (c, h, m, r) Node strengths color-coded with their relative phases and their PDF. (d, i, n, s) Phases
of the synchronized oscillators (color-coded with their in-strength) and their PDF, and (e, j, o, t) their geometric representation and complex order parameter
(black arrow). Parameters: N = 300, K = 7, D = 1. (A) τ = [0.05, 0.2]s, (B) τ = [0.7, 0.95]s, (C) τ = [0.22, 0.47]s, and (D) τ = [0.04, 0.27]s.
only on the interval (0, π), yielding

8 p
< oi > O , i þ O~t 2 ;p ; 2
) Ki % and=or oi & , i &;
ð30Þ
: o < O , þ O~t 2 0; p; ) Ki % and=or oi % , i % :
i i 2
Hence, the phase shifts within the same cluster have the same dependence from the sign of
ωi − O, as for in-phase synchronization, Figs 7 and 8.
Next we analyze the sign of μ − O, which for deterministic bell-shaped frequency distribu-
tion or for stochastic frequencies implies the sign of ωi − O for a large majority of oscillators.
For all-to-all equal couplings and Lorentzian frequencies [13], the low-dimensional dynamics

Table 2. Change of the relative phases ϕi for increasing coupling strengths for delay-imposed structure.
Oτ2 I II III IV
Oτ1
I & % & %
& &
II unstable unstable unstable unstable
& & & &
III unstable unstable unstable unstable
% % & %
IV % % % %
& &
Results are shown for angles Oτ1,2 in the different quadrants, during in and anti-phase synchronization.
https://doi.org/10.1371/journal.pcbi.1006160.t002
reads
z_ I;II ¼ ðim gÞz I;II K=4½ðz I;II 2

ztI;IIt1 ztI;IIt1 Þ þ ðz I;II 2 ztII;It2 ztII;It2 Þ: ð31Þ
Taking also into account Eq (25), the frequency of steady synchronization becomes
8 K 2 p

< m 2 ðr þ 1Þ sin O~t cos ODt;
> if Ot2 2 2
; p2 ;
O¼ ð32Þ
: m þ K ðr 2 þ 1Þ cos O~t sin ODt;
>
if Ot2 2 p2 ; 3p2 :
2
This allows evaluating increase/decrease of phases ϕi as function of the nodes strength Ki in Eq

(27). Results for in- and anti-phase synchronization, Eqs (28) and (30), are summarized in
Table 2. Note again that node-strength dependent change of the phases is identical for both
models, Tables 1 and 2, when Oτ2 is in the right complex half-plane.
To compare nodes from different hemispheres during anti-phase regime, the π shift
between the mean phases need to be considered in relations in Eqs (27) and (30). Henceforth,
due to the periodicity of phases, the nodes whose phases lag the most in one cluster, will be
closest to the leading nodes in the other. Similarly, for ωi > O stronger and slower nodes will
be further away from the mean of the opposite cluster, although they will be closer to their
own mean phase. This is illustrated in Fig 7(C) and 7(D) with nodes of the opposite ends in
the frequency spectrum for each population being closest to each other—light red and light
blue nodes are furthest apart within, but closest to each other between clusters.
Phases for distributed coupling strengths and stochastic inhomogeneities read
8
>
> harcsin m Oþxi ðtÞ
i ≊ arcsin m O
; if Ot2 2 p
; p2 ;
< Ki r cos ODt Ki r cos ODt 2
hi þ O~t i ¼ ð33Þ
>
>
: harccos m Oþxi ðtÞ i ≊ arccos m O
; if Ot 2 2 p
; 3p
;
Ki r sin ODt Ki r sin ODt 2 2
with a same stability criterion as for deterministic case, while synchronization limits accord-
ingly become Kir|cos OΔτ| > |μ − O| and Kir|sin OΔτ| > |μ − O|. Plots in Fig 8, show the same
examples as in Fig 7, but with stochastic frequency inhomogeneity and log-normally distrib-
uted coupling strengths that dictate phase offsets. As predicted by Eqs (28) and (30), within the
same population stronger nodes phase lag the weaker for μ > O, and otherwise. For the nodes
belonging to different clusters during anti-phase regime, periodicity causes weaker nodes of
one cluster to be closer to stronger nodes of the other, Fig 8(n), 8(o), 8(s) and 8(t).

Results for both types of networks, Figs 6 and 8, indicate that only if both delays are in the
first quadrant, stronger brain regions will always phase-lag behind the weaker ones, in agree-
ment with [22]. For this also the natural frequencies of each region are supposed to be equal
on average, so that they will be all locked at a lower frequency than their natural. Hence,
assuming realistic range of conduction velocities, this would hold only for lower bands of the
EEG frequencies.
The above analysis and the results for bimodal δ time-delays, homogeneous or clustered,
can be generalized for any multimodal δ distributed delays, or for combination of random and
clustered delays. However these are not supposed to bring qualitatively new types of steady
synchronization, while making the analysis more cumbersome.
Connectome based modeling (numerical results)

General analysis for networks with time-delays is practically impossible to this date. Analytic
approaches exist only for certain types of complex networks [16] combined with special delay
heterogeneities [13, 36], but they are still limited to the thermodynamic limit or require aver-
aging. Besides, the connectome typically consists of less than 100 nodes, rarely going above
several hundreds, and the state of art large-scale brain-modeling considers personalized con-
nectomes [51]. Therefore, numerical simulations scrutinized by the analytical insights for sim-
pler network topologies are a reasonable direction to proceed with the analysis of the brain
networks dynamics.
In-silico oscillatory neural activity is explored over connectome based architecture to better
understand the phase relation between signals from distant brain areas. A human connectome,
Fig 9, is randomly chosen from a list of 1200 publicly available healthy subjects part of the
Human Connectome project [52]. The subject was scanned on a customized 3 T scanner at
Washington University and the structural connectivity was constructed using a publicly avail-
able pipeline [53] that applies spherical deconvolution method to a probabilistic streamlines
tracking algorithm [54]. The obtained connectome consists of few million tracts spatially aver-
aged to connect 68 cortical regions defined according to Desikan-Kiliany atlas [55]. Note how-
ever, that different parcellations are also possible, for example by subdividing each of the
Fig 9. Connectome of a healthy subject. (a) Normalized weights, (b) logarithmic weights and (c) lengths of the tracks. (d) Joint
distribution of weights and lengths, and histograms of weighted lengths for (e) intra- and (f) inter-hemisphere links.

cortical regions [56], and these can consist of several thousand nodes [57], but are not com-
monly used in simulations because of the computational cost.
For each link, weights are numbers of individual tracts, Fig 9(a), and lengths are their aver-
ages, Fig 9(b). Spatial distribution of the track lengths show that they are bimodaly distributed,
Fig 9(d), with the modes being spatially heterogeneous, and as a first approximation corre-
sponding to the intra- and inter-hemispheric links, Fig 9(e) and 9(f). This insight suggests that
some of the aspects of the large-scale brain dynamics are expected to be explained by the
results for fully ordered delays.
The propagation velocity is fixed within the realistic range [2, 58] at 5m/s, and dynamics are
analyzed at different frequencies and coherence levels. The latter are additionally constrained
by the noise and the global coupling strength that multiplies the normalized weights of the
connectome. Since the distribution of natural frequencies across brain regions is generally
unknown, equal values with stochastic inhomogeneities are assumed at each node. Moreover,
even band-pass filtered recordings of neural activity in most of the cases consist of several
overlapping rhythms, which are time-varying and activity-dependent, henceforth equal on
average for long recordings.
Time delays cause coexistence of multiple stable frequencies of synchronization, larger or
smaller than the natural, and can lead to amplitude and oscillation death in more complex sys-
tems [59]. However, we observe that unlike for the networks with bi-modally distributed
delays, all numerical simulations on the connectome evolve towards a state with lower fre-
quency than the natural, as often reported for different configurations of delay-coupled phase
oscillators [60–63].
Pair-wise phase lags. Even though the spatio-temporal structure of the connectome is far
more complex than networks with bi-modal δ time-delays, results in Fig 10 still show in- (A,
D) and anti-phase (B) clusterings between the brain hemispheres for realistic frequencies and
different levels of synchronization. An intermittent state of in and anti-phase epochs is also
often observed, panel (C), as seen by the mean-field parameters shown on the bottom. If the
frequency is such that μhτexti is in the right hemisphere, then the latter regimes occurs for
most of the cases with low coherence. High coherence almost exclusively leads to slowing
down that pushes Ohτexti in the first quadrant and therefore in-phase synchronization. Never-
theless such levels of coherence are not expected to occur in a healthy brain, and these regimes
are biologically implausible, Fig 10(A) and 10(D).
The good match of the simulated brain dynamics with the theoretical predictions for net-
works with much simpler structure, is not only limited to the regimes of synchronization. As
predicted, in all examples in Fig 10 stronger nodes in each hemisphere generally lag in phase,
since O < μ. This occurs for in- and anti-phase synchronization, but also during the intermit-
tent regime. The division between the latter two is often fuzzy, since the intervals of anti-phase
synchronization rarely last longer than several seconds, before being interrupted with in-phase
epochs.
Anti-phase regime is assumed when the hemispheric complex order parameters are at a dis-
tance larger than π/2, and in-phase otherwise, allowing comparison with the analytical results.
They capture the dynamics fairly well, even for a distance not much larger than π/2 as shown
in Fig 10(C). A better approach would be intermittent intervals to be analyzed separately, since
the frequency of synchronization might differ during each interval, and averaging it can lead
to wrong values for the phases. Moreover, even if varying frequencies of synchronization are
properly detected, averaging of the relative phases over different regimes, Fig 10(B) and 10(C),
makes them to be distributed at distances smaller than π, which might be mistaken for an
actual stationary clustering, rather than a mix of 0 and π clusterings. This is shown in Fig 11,

Fig 10. Simulated dynamics over a healthy human connectome. In-phase (A, D) anti-phase (B) and intermittent synchronization (C). Top left plot of each panel are
relative phases for the synchronized and two unsynchronized oscillators (black) closest to the limits, and ±(O − μ)t (dashed). Top middle are scatter plots of nodes
averaged phases versus their in-strengths. Nodes of left/right hemisphere are up/down pointing triangles, black line is a theoretical prediction, blue is the linear fit. Top
right are the PDF of in-strengths color-coded with nodes’s phases. Middle left are phases of the synchronized oscillators (color-coded with in-strength) and their PDF;
and middle right is their geometric representation and complex order parameters (black arrows). Bottom left and right are evolutions of order parameter and mean field
frequencies, for whole brain (blue) and for each hemisphere (red and magenta). Order parameters for uncoupled case are green for whole brain and cyan for one
hemisphere. Parameters: N = 68 oscillators, noise intensity D = 2. Coupling strengths (A, B) K = 0.8, (C) K = 1.1, (D) K = 1.6, natural frequency (A) f = 10Hz and (B–D)
f = 20Hz.
where PLV and the instantaneous and time-averaged phase lags are shown for an intra and an
inter hemispheric links.
The left panel of Fig 11 shows an intrahemispheric link between in-phase brain regions,
and the right depicts an interhemispheric link with epochs of in- and anti-phase locking. Since

Fig 11. Evolution and statistics of PLV and phase lags for one (A) intra and (B) inter-hemispheric link. (a, b, f, g) Phase lag, Δθ, (black), and angle of
the cPLV, ϕ, (red and magenta for significant PLV, blue otherwise). (c, h) PLV (blue) and its mean value (black), and two levels of significance (magenta
and red). (d, e, i, j) Estimated PDF (magenta line and dashed red) and histograms of phase lags, and their means (red and magenta arrows). Parameters:
f = 20Hz, D = 2, (A) K = 1.1, (B) K = 1.16.
K26 > K30 the phase difference Δϕ30,26 2 [0, π/2) and results are very similar for the both signif-
icant levels, despite their large difference. The region 41 is stronger connected than the 14, so it
is expected that during in-phase intervals Δϕ14,41 2 (−π/2, 0], and Δθ14,41 2 (π/2, π] for anti-
phase, c.f. with Fig 8(n) and 8(o). Consequently, distributed peaks appear for the histograms of
phase lags in the bottom plots of Fig 11(B), but their mean is in (−π/2, −π] leading to possible
wrong conclusion about the synchronization of these nodes.
Whole brain phase lags statistics. Whole brain phase statistics are characterized by the
mean and the standard deviation of the PLVs, and the correspondent phase-lags for each pair
of brain regions. These are shown in Fig 12, where 1–standard deviation is plotted to keep the
colors/coherence consistency across the images. In the upper row, the regions are arranged
according to Desikan-Kiliany atlas [55], with the left hemisphere first, while in the lower row,
nodes of each hemisphere are ordered increasingly according to their strength.
Strengths of the tracts are reflected in PLV (first column in Fig 12), where the links with
stronger direct connection show higher functional connectivity. The negative bias of the track-
ing techniques towards interhemispheric connections is also manifested. Consequently fewer
external links have significant coherence, especially for the higher surrogates criterion, when

Fig 12. Statistics of PLV and phases for 68 brain regions. Nodes are as given by Desikan Kiliany parcelation (top) and ordered within hemispheres by the in-strength
(bottom). For each link the mean and 1–standard deviation are shown, while white are links with no periods of significant coherence. Parameters: K = 1.18, f = 20Hz,
D = 2.
only the strongest links survive. Phase lags within hemispheres, especially for stronger links,
are around 0, revealing the in-phase synchronization. Between hemispheres, the phase lags are
less informative, due to the intermittent in- and anti-phase synchronization, also seen in Fig
11(B) for the same regime. Still, many inter-hemispheric links have phases around ±π or closer
to ±π/2. The latter is often hallmark of intermittent in and anti-phase regimes, as discussed for
the results of Fig 11(B). The intermittency is also manifested by increased variance of the
phases, visible for the inter-hemispheric links. This is much less manifested in the coherence,
which stays stable during different regimes, as was also indicated by the hemispheric order
parameters in Fig 10. The large variation of the overall order parameter observed there, is only
due to the bursts of anti-phase ordering when it gets close to 0, whereas the coherence within
each hemisphere is quite stable.
The impact of the chosen significant coherence, and the difference between instantaneous
and averaged phases for the phase statistics of each link is illustrated in Fig 13 for anti-phase
regime. Higher significance level causes only slightly larger variance for the phase lags, panel
(A), but as seen in Fig 11, it can substantially reduce the number of accounted links, especially
between hemispheres, illustrated through one such a link in panel (C). It is due to the latter
mechanism that the overall distribution of the mean lags is less uniform for higher surrogates,
panel (B). On contrary, time-averaging stronger decreases the variance for the links, because it
diminishes the network and stochastic heterogeneities, but it does not affect the means of the
phase lags for particular links, as can be also seen for the link in Fig 13(C) or in Fig 11(B).
The overall statistics for the distinctive phase regimes in the brain are illustrated in Fig 14.
Phase lags and PLVs are depicted for a same subject, for various frequencies and coupling
strengths, with noise proportional to the frequency to account for the frequency dependent
decrease of the coherence [47]. Time-averaged coherence is shown in the first column, in addi-
tion to the mean of the PLVs of each time-window. The former speaks about the overall regime
of synchronization, whilst the latter depends on the length of windows compared to the fre-
quency and is more affected by the noise. The mean PLV alone is hence not informative, but
needs to be compared with a significance level. Mean phase lags for times of significant

Fig 13. Statistics of PLV metrics for two significance levels. (A) Standard deviation of phase lags. (B) Histogram of mean phase lags for all the links, calculated over
periods of significance. (C) Evolutions of PLV (top) and phase lags (middle), and their histograms (bottom) for both levels of significance (magenta and red in all plots)
for one inter-hemispheric link. Parameters: K = 0.55, f = 20Hz, D = 4.
coherence are shown in the third and fourth column for two different surrogate procedures.
They produce largest difference for anti-phase regime (second row), which requires low coher-
ence that is even smaller between hemispheres due to fewer tracts. For very low synchroniza-
tion, as shown on the bottom, they are identical and therefore only one is shown, while for
high overall coherence (second and third row), higher significance level discards the tails in
phase lags’ distribution (last column), which mainly represent links between weaker nodes,
thus making the distribution sharper.
Possible paths for transition between different regimes of synchronization are also shown
in Fig 14. For low frequencies, in-phase synchronization occurs (first row), which becomes
intermittent/anti-phase for increased frequency (second row), at similar level of overall coher-
ence. By increasing the coupling and henceforth the level of coherence, the brain switches to
in-phase regime (third row) that can again switch to anti-phase by further increasing the fre-
quency, but only at very low overall coherence (bottom row). Also note that the overall low
coherence at the bottom row leads to spatially homogeneous values for the mean PLVs, as
compared to the cases with much higher coupling and global partial coherence shown in the
second and third row. Low coupling renders all links to be around a same level of coherence,
without strongly coherent and incoherent links like in the middle rows, and as a result, for
every pair of regions exists at least one time-window with statistically significant PLV. Hence-
forth the absence of links with no significant PLV.
Spatial distribution of phase-lags in Fig 14 is in agreement with the theoretical predictions.
Besides being 0 centered for strong nodes within the same hemisphere regardless of the syn-
chronization regime, lags around 0 and ±π appear between the hemispheres, resembling in-
and anti-phase regimes. In addition, weak regions lead the stronger, and for anti-phase hemi-
spheres π is added. Hence, the inverted distribution of green and blue shades for the intra and
inter-hemispheric links in the phase lags matrices, with darker shades corresponding to ±π/4
for internal links, and lighter for external with the values around π ± π/4.

Fig 14. PLV and phase lags during different regimes of brain dynamics. (left to right) Coherence over the whole time-series, mean PLV, mean phase lags ϕ for low
and high coherence (they are identical for the bottom row), and histograms and PDF of the mean phase lags of coherent links. White are the links with no significant
PLV. Nodes in all matrices are sorted by their in-strength. The level of the noise is D = 0.2f.
Frequency dependent spatial distribution of phase lags is illustrated in Fig 15 for intra and
inter-hemispheric brain subnetworks, for two frequencies and a same global coupling. The
subnetworks consist of the 10 strongest brain regions in each hemisphere based on the sum of
their outgoing links. Strength of the nodes is reflected in their size, whilst links are color-coded
with their phase lags taken from the upper triangle of the matrices. As predicted, strong coher-
ence is observed during in-phase synchronization at f = 6Hz, which together with similar
strengths of the nodes, renders almost zero phase lags for all the links, internal and external.
During anti-phase regime observed at 20Hz, the links within the hemispheres have lags distrib-
uted around 0, but much wider than before, whilst those between them are distributed around
±π. The coherence decreases for increasing frequencies, and together with the earlier discussed

Fig 15. Intra- and inter- hemispheric subnetworks of the 10 strongest nodes. In- and anti-phase synchronization.
Parameters: K = 0.5, D = 0.5.
non-stationarity, these cause far higher variability of phases, than during in-phase synchroni-
zation. Hence the appearance of dark shades of green and blue for in-phase, and light for anti-
phase synchronization.
Discussion
In this study we analyze the mechanisms by which the spatio-temporal features of the connec-
tome impose the architecture of phase lags between distant brain regions. A general relation-
ship is provided for how organization of time-delays drives the hemispheres to in or anti phase
coherence, whereas the topology dictates the sign of the phase lags. Both aspects of connec-
tome also determine the overall coherence, which restricts the regimes of phase organization
that can be observed. The presented qualitative findings are relevant for phases in frequency
decomposed neural activity.
Model set-up
Phase lags are analyzed when only pair-wise interactions are explicitly considered, and for net-
work connectivity. The former approach is justified if interactions are too weak, and can be
represented on average as a stochastic influence to the inherent dynamics at each region. This
leads to mean value of the phase differences at 0 or ±π, depending on whether the delay is long
enough to change the sign of the interaction.
Despite its simplicity that allows analytical tractability, the phenomenological oscillatory
model resembles the non-stationary oscillations of the neural activity, which is characterized
by transient synchronization. To better understand the underlying organization that regulates
the large-scale brain dynamics, and henceforth the phase relationships between network
nodes, we analyze synchronization for networks with bimodal delays as a first approximation
of the connectome. Theoretical insights are validated numerically for more realistic frequency
and couplings heterogeneities, and compared with in-silico brain dynamics, while examining
the methodological limitations.
Phase lags during these epochs of coherence depend on the delays, which are constant, and
on coupling strength and frequency mismatch. The latter can be different across the time-
series, but the statistics of the narrow frequency content is generally expected to be similar
across the regions. Consequently, the natural frequencies are modeled as stochastic with equal
means.
Frequency depression, and in- and anti-phase synchronization

Accounting for the network dynamics is a more complex approach that is more realistic, espe-
cially when the overall coherence is not insignificant. The brain network model predicts that

the distribution of the phase lags will always have a peak at 0, with an additional peak at ±π
appearing for anti-phase synchronization.
Of crucial importance here is whether the frequency increases or decreases during synchro-
nization. For lowest frequencies of electro-physiological brain signals, delays cause relative
phases within the first quadrant, so the frequency is depressed regardless of the topology of the
delays, whilst the phase locking is in-phase. Hence stronger nodes on average phase lag behind
the weaker, for any arrangements of the natural frequencies. For higher frequencies, theoreti-
cal and numerical results show that for ordered networks both directions of the frequency shift
are possible. However, in-silico brain dynamics exclusively shows frequency depression, so
for equal stochastic frequencies better connected brain nodes phase-lag behind the weaker,
whereas for anti-phase regime the π distance should be also accounted.
The frequency depression due to delayed interactions has wider importance than the 1:1
synchronization that is discussed here. Slowing down in an anatomically constrained dynam-
ical system with noise has been shown to induce the whole-brain FC [64], by utilizing power
to phase interactions. The latter are one of the mechanisms for cross-frequency coupling [65],
which besides the well-known beta-theta interactions in the hippocampus [66], are also shown
to occur for cortical signals [67].
The effects of signal mixing and spread due to volume conduction cause artificial synchrony
between nearby sources that are alleviated with inverse source reconstruction techniques [68].
Nevertheless, linear mixing of signals from multiple sources can still lead to wrong coherence
and phase synchrony estimates and this is commonly eliminated with interaction metrics that
detect exclusively lagged interactions [28, 69]. This comes at the cost of an inability to detect
true zero-phase lag interactions, which as we show, may be instead neurophysiologically
meaningful and due to the coupling structure, as also suggested by other studies [33]. Includ-
ing the actual zero-phase lagged interactions would henceforth potentially have an important
impact on whole brain data analyses of M/EEG data, as it has been found that indices of Func-
tional Connectivity sensitive to zero lag such as PLV tend to be more reliable within groups
and across sessions [70, 71].
Ordered versus complex networks

Although the general theoretical findings for the ordered networks still hold for the simulated
dynamics over the connectome, the main contributor to their disparity is the complex spatio-
temporal structure of the connectome. This is firstly reflected in the distribution of time-
delays, which is neither exactly bi-modal δ, nor fully structured or random. Secondly, the
weights of the links are not homogeneous for the nodes, as assumed by our approximation,
but differ by several orders of magnitude. For the latter, combining other network measures,
such as centrality or clustering coefficient [72], could potentially increase the predictability of
the analysis. The remaining open issues of our brain network model are conceptual and are a
common concern for most of the studies based on the connectomics. These are questions
about the meaning of the weights and utilization of links, but also about the actual propagation
velocity along tracts, which is shown to depend on large number of quantities [73].
Methodological limitations
The level of significant coherence does not impact the overall architecture of phase lags,
although when it is lower it mostly increases the variance of the results by flattening the distri-
bution. However, the stricter level of significance can fail to capture phase-locking, especially
between the hemispheres where the coherence is lower due to reduced wiring.

Increased variance of the phases can also indicate an alteration between different stable
states. This often causes intermittent in- and anti- phase synchronization, when several peaks
appear in the distribution of pair-wise phase lags. We showed that averaging of these non-sta-
tionary dynamics leads to improper description of phase relationships and can be avoided by
differentiating of the separate regimes during the analysis. However, identification of time-
dependent dynamics is a major challenge in analysis of biological signals [74].
Inherent variability of the frequencies or coupling strengths [48, 75] is another source of
non-stationarity for which we demonstrated that the observed phase-lags depend on the over-
all statistics of the averaged parameters. Nevertheless, dividing the time-series to different
epochs for more precise identification of phase lags for different regimes is also possible in
cases when the non-autonomous forcing can be recovered [74], as well as quantification of the
non-autonomicity [76].
Besides the notion of synchronization, functional brain connectivity can be also described
by directed information flows [77], or effective connectivity [78, 79]. Bayesian frameworks [80,
81], although limited to instantaneous interactions, offer another approach for studying the
connectivity between neural systems, by inferring coupling functions [82] that are spatially
and frequency specific [42, 43].
Supporting information
S1 Files. Data and scripts. The folder contains the data used in this work together with the
Matlab codes (scripts and functions) necessary to perform the simulations and the analysis. Data
and codes are also available at https://gitlab.thevirtualbrain.org/spase.petkoski/plos_PLSNS.
(ZIP)
Acknowledgments
We are thankful to Marmaduke Woodman for providing us with the connectome from the
HCP database, and to Katarzyna Petkoska for post-processing the figures.
Author Contributions
Conceptualization: Spase Petkoski, J. Matias Palva, Viktor K. Jirsa.
Data curation: Spase Petkoski.
Formal analysis: Spase Petkoski.
Investigation: Spase Petkoski.
Methodology: Spase Petkoski, J. Matias Palva, Viktor K. Jirsa.
Project administration: Spase Petkoski, J. Matias Palva, Viktor K. Jirsa.
Resources: Viktor K. Jirsa.
Software: Spase Petkoski.
Supervision: Viktor K. Jirsa.
Validation: Spase Petkoski.
Visualization: Spase Petkoski.
Writing – original draft: Spase Petkoski, J. Matias Palva, Viktor K. Jirsa.
Writing – review & editing: Spase Petkoski, J. Matias Palva, Viktor K. Jirsa.

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Phase-Lags in Large Scale Brain Synchronization: Methodological Considerations and In-Silico Analysis

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RESEARCH ARTICLE

Phase-lags in large scale brain

* spase.petkoski@univ-amu.fr (SP); viktor.jirsa@univ-amu.fr (VKJ)

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Academy of Finland (Grant No. 253130), http://

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Numerical analysis and statistics

y_ 1;2 ðtÞ ¼ o1;2 K sin½y1;2 ðtÞ y2;1 ðt tÞ: ð4Þ

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frequency O, preserving a constant phase shift ϕ1,2 = θ1 − θ2, which becomes

where O is described by a transcendental function and the critical coupling reads

y_ 1;2 ðtÞ ¼ o1;2 þ 1;2 sin o

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_ i ¼ oi O Ki r sinði þ O~t Þ cosð ODtÞ; ð16Þ

where we have introduced ~t ¼ t1 þt

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From here the frequency of steady synchronization is given as

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xi ðtÞ ¼ xI ðtÞ þ xII ðtÞ ¼ ½zint ðt t1 Þ þ zext ðt t2 Þ=2; ð24Þ

RI;II ¼ r I;II ¼ r; FI;II ¼ Oðt t1 Þ þ c1;2 ; ð25Þ

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only on the interval (0, π), yielding

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z_ I;II ¼ ðim gÞz I;II K=4½ðz I;II 2

This allows evaluating increase/decrease of phases ϕi as function of the nodes strength Ki in Eq

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Connectome based modeling (numerical results)

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Frequency depression, and in- and anti-phase synchronization

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Ordered versus complex networks

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24. Petkoski S, Iatsenko D, Basnarkov L, Stefanovska A. Mean-field and mean-ensemble frequencies of a

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y_ 1;2 ðtÞ ¼ o1;2 K sin½y1;2 ðtÞ y2;1 ðt tÞ: ð4Þ

y_ 1;2 ðtÞ ¼ o1;2 þ 1;2 sin o

_ i ¼ oi O Ki r sinði þ O~t Þ cosð ODtÞ; ð16Þ

xi ðtÞ ¼ xI ðtÞ þ xII ðtÞ ¼ ½zint ðt t1 Þ þ zext ðt t2 Þ=2; ð24Þ