International Journal of Psychophysiology 157 (2020) 61–69

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International Journal of Psychophysiology

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

Dysregulated brain salience within a triple network model in high trait

anxiety individuals: A pilot EEG functional connectivity study
Chiara Massullo a, Giuseppe Alessio Carbone a, Benedetto Farina a, Angelo Panno a,
Cristina Capriotti a, Marta Giacchini a, Sérgio Machado b, c, d, Henning Budde c, e,
Eric Murillo-Rodríguez c, f, Claudio Imperatori a, c, *
a
Cognitive and Clinical Psychology Laboratory, Department of Human Science, European University of Rome, Italy
b
Laboratory of Physical Activity Neuroscience, Physical Activity Sciences Postgraduate Program, Salgado de Oliveira University, Rio de Janeiro, Brazil
c
Intercontinental Neuroscience Research Group, Yucatán, Mexico
d
Neurodiveristy Institute, Laboratory of Physical Activity Neuroscience, Queimados, Rio de Janeiro, Brazil
e
Faculty of Human Sciences, Medical School Hamburg, Hamburg, Germany
f
Laboratorio de Neurociencias Moleculares e Integrativas Escuela de Medicina, División Ciencias de la Salud, Universidad Anáhuac Mayab Mérida, Yucatán, Mexico

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

Keywords: Although previous studies have reported the association between large-scale brain networks alterations and
Trait anxiety pathological anxiety, abnormalities in the dynamic interaction among the triple network model in anxiety dis­
Triple network orders and, especially, in trait anxiety is still poorly explored. Thus, the main aim of the current study was to
eLORETA
investigate triple network functional dynamics in subjects with high trait anxiety during resting state (RS)
EEG
through electroencephalography (EEG) connectivity.
Salience network
Twenty-three individuals with high-trait-anxiety (HTA) and forty-five participants with low-trait-anxiety
(LTA) were enrolled. EEG analyses were conducted by means of the exact Low-Resolution Electromagnetic To­
mography software (eLORETA). Compared to LTA participants, HTA subjects showed a decrease of alpha con­
nectivity within the salience network (SN), between the dorsal anterior cingulate cortex (dACC) and both left and
right anterior insula (AI). Furthermore, SN functional connectivity strength was negatively correlated with
higher trait anxiety, even when controlling for potential confounding variables (e.g., depressive and obsessive-
compulsive symptoms).
Taken together, our results point out a specific functional connectivity pattern in HTA individuals, which
consists in a dysfunctional communication within the SN, specifically in the AI-dACC pathway. This functional
pattern could underline, at rest, saliency detection and brain correlates of altereted emotion regulation and
cognitive control processes typically involved in anxiety.

1. Introduction modifications), cognitive (e.g., attentional biases) and behavioral al­

Trait anxiety is considered a stable personality feature characterized
by core aspects, such as worry, difficult relaxation and frequent over­
estimation of potential threat in uncertain daily life situations; indeed
individuals with high-trait-anxiety (HTA) show protracted hyperarous­
al, hypervigilance and apprehension (Spielberger and Sydeman, 1994;
Sylvers et al., 2011; Weger and Sandi, 2018). High levels of trait anxiety
are considered a vulnerability factor for psychopathology due to several
aspects including biological (e.g., hypothalamus-pituitary-adrenal axis
terations (e.g., less risk-taking) (Panno et al., 2018; Sandi and Richter-
Levin, 2009; Weger and Sandi, 2018). More specifically, HTA is
considered a vulnerability indicator for anxiety disorders (Indovina
et al., 2011; Kim and Whalen, 2009), which shares with such disorders
several neurophysiological alterations in circuits linked to saliency,
threat detection and cognitive control processes (Kara and Polo, 2014;
Sylvester et al., 2012; Williams, 2016).
This aspect is particularly worrying considering the high prevalence
of anxiety symptoms in non-clinical samples (Remes et al., 2016). For

* Corresponding author at: Cognitive and Clinical Psychology Laboratory, Department of Human Science, European University of Rome, Via degli Aldobrandeschi
190, 00163 Roma, Italy.
E-mail address: claudio.imperatori@unier.it (C. Imperatori).

https://doi.org/10.1016/j.ijpsycho.2020.09.002
Received 29 June 2020; Received in revised form 12 August 2020; Accepted 6 September 2020
Available online 22 September 2020
0167-8760/© 2020 Elsevier B.V. All rights reserved.
C. Massullo et al.
example, higher than normal trait anxiety levels are relatively frequent
among university students, with a prevalence ranging between 11.5%
and 56% across published studies (Chandavarkar et al., 2007; Haghighi
and Gerber, 2019; Macauley et al., 2018; Ozen et al., 2010).
Psychopathological alterations and psychiatric disorders are
increasingly acknowledged to be associated with brain connectivity
dysregulations and network neuroscience supplies a theoretical frame­
work to understand these alterations (Bassett et al., 2018). Indeed, the
study of large-scale brain networks provides a robust model to investi­
gate dysfunctional processes (e.g., cognitive and affective) in psychiatric
diseases, and brain networks alterations are shown to have a central role
in several disorders including anxiety disorders (Menon, 2019; Menon,
2011). According to this dynamic and integrated view of the mind-brain
functioning (Turk-Browne, 2013), high levels of trait anxiety and anxi­
ety disorders seems to be related to several functional and structural
neural networks alterations, particularly in the Central Executive
Network (CEN), Salience Network (SN) and Default Mode Network
(DMN) (Sylvester et al., 2012; Williams, 2016).
Composed by lateral and midline cortical areas including the medial
prefrontal cortex (mPFC), posterior cingulate cortex/precuneus (PCC/
PCUN), the DMN is active during task-free conditions and it is strictly
linked to mind wandering, self-referred mental activity, autobiograph­
ical memory and mentalization about self and others (Andrews-Hanna,
2012; Raichle et al., 2001). Differently, the CEN is a task-positive
network supporting higher order cognitive functions, such as atten­
tional control and working memory, and including both dorsal and pa­
rietal brain regions [i.e., the dorsolateral prefrontal cortex (DLPFC), and
the posterior parietal cortex (PPC)] (Cole and Schneider, 2007; Niendam
et al., 2012). Lastly, the SN deals with identifying relevant stimuli (i.e.,
internal or external) in order to better elaborate them and execute a
greater cognitive control (Seeley et al., 2007). The main nodes of this
network are the dorsal anterior cingulate cortex (dACC) and the bilateral
anterior insula (AI) (Menon, 2011; Menon and Uddin, 2010), which is
known to be a central hub for information integration (Kurth et al.,
2010).
As concerns trait anxiety, neuroimaging studies detected several
functional alterations in these networks or in several core regions of
them. For example, individuals with high-trait-anxiety showed a
disruption of the DMN during Resting State (RS) (Imperatori et al.,
2019a; Modi et al., 2015; Zidda et al., 2018) suggesting a possible failure
of coordination of this network. Similarly, a reduced involvement of
frontal regions (e.g., DLPFC) has been observed to be associated with
dysfunctional regulation of attentional control in these subjects (Bishop,
2009). Furthermore, a functional Magnetic Resonance Imaging (fMRI)
study (Geng et al., 2016), comparing HTA to low trait anxiety (LTA)
adolescents, showed weaker functional connectivity within the SN and
between the SN and other brain regions, which are part of different
functional systems including the DMN and the executive control one.
According to the “triple network” perspective (Menon, 2011; Menon
and Uddin, 2010), the DMN, the SN and the CEN dynamically operate in
order to activate higher order cognitive functions and regulate behavior
and affects. Functional connectivity abnormalities among these three
networks have been reported in several pathological conditions, such as
depression and obsessive-compulsive disorder (Menon, 2019). Although
previous studies reported the association between large-scale networks
alterations and pathological anxiety (Sylvester et al., 2012; Williams,
2016), little is known about abnormalities in the dynamic interactions
among the triple network model in anxiety disorders and, especially, in
trait anxiety. Dysfunctional communication among DMN, CEN and SN is
considered one of the most reasonable explanations of psychopathology
across multiple psychiatric disorders (Menon, 2019; Menon, 2011).
Furthermore, as observed by Modi et al. (2015), the knowledge about RS
functional brain networks alterations associated with HTA levels may be
critical in understanding the neurobiology of clinical anxiety. Therefore,
the main aim of the current study was to investigate triple network
functional dynamics in subjects with HTA during RS through
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International Journal of Psychophysiology 157 (2020) 61–69
electroencephalography (EEG). Compared to fMRI, which offers
spatially relevant data in terms of functional interactions among brain
structures, the EEG provides significant information about how neural
systems interact in different frequency bands with each other (Neuner
et al., 2014; Thatcher et al., 2014; Whitton et al., 2018), revealing
valuable evidence under a clinical and neurophysiological point of view.
Moreover, the sustainability of EEG in detecting large-scale brain net­
works has been documented (Liu et al., 2018), even with low number of
recording electrodes.
Lastly, a further purpose of the present research was to explore the
association between triple network functional connectivity and trait
anxiety controlling for potential related confounding variables such as
depressive and obsessive-compulsive symptoms (Goodwin, 2015) as
well as alcohol problems (Adan et al., 2017; Stewart and Zeitlin, 1995).
According with previous brain networks studies in trait anxiety (Geng
et al., 2016; Imperatori et al., 2019a; Modi et al., 2015), we hypothe­
sized that, compared to LTA individuals, those with HTA would be
characterized by a decreased functional connectivity among the triple
network.
2. Methods
2.1. Participants
The enrollment procedure lasted from October 2019 to January
2020. Study participants were recruited by posts spread around the
university. One hundred and one subjects voluntarily accepted to
participate in the study, provided the written informed consent, and
were further screened. Inclusion criteria were: right handedness, neither
negative history nor actual presence of neurological or psychiatric dis­
orders, negative psychoactive substances assumption in the past two
weeks before the EEG recording. After eligibility screening, 71 partici­
pants were finally enrolled in the study. Three subjects (3.1%) did not
have usable EEG data and were consequently excluded from the anal­
ysis. Therefore, the final sample consisted of 68 participants (28 men
and 40 women, mean age: 22.09 ± 3.24 years, range: 18–34), in line
with similar other studies on this topic (Aftanas and Pavlov, 2005;
Aftanas et al., 2003; Geng et al., 2016; Imperatori et al., 2019a; Modi
et al., 2015; Savostyanov et al., 2009; Takacs et al., 2015). Furthermore,
a previous study (Geng et al., 2016) investigating the association be­
tween trait anxiety and RS inter-network functional connectivity
observed among several relations a minimum effect size of r = 0.336.
This effect size is also in line with a recent meta-analysis on EEG brain
connectivity in autism (Mehdizadefar et al., 2019) reporting, on a total
of 26 effect sizes, an average Cohen’s d of 0.722 (i.e., r = 0.340). Thus,
according to G*Power 3.1 software (Faul et al., 2009), the current
sample size and an effect size equal to r = 0.336 (i.e., the minimum effect
size observed by Geng et al., 2016) would provide a statistical power of
0.80. The research project was developed according to the Helsinki
declaration standards and was approved by the European University’s
ethics review board.
2.2. Questionnaires
All participants were administered the Italian versions of the
following self-report questionnaires: the trait version of the State–Trait
Inventory for Cognitive and Somatic Anxiety (STICSA; Carlucci et al.,
2018), the Teate Depression Inventory (TDI; Balsamo and Saggino,
2013), the Obsessive-Compulsive Inventory Revised (OCI-R; Sica et al.,
2009), and a questionnaire to detect problematic alcohol use, namely
the CAGE (Agabio et al., 2007). A checklist with dichotomous items
(Imperatori et al., 2019a; Imperatori et al., 2019b) was also adminis­
tered to assess inclusion criteria as well as socio-demographic data
(including tobacco use in the last sixth months).
The STICSA (Ree et al., 2000) is a 21 item self-report on a 4-point
Likert scale with total scores ranging from 21 to 84 (higher scores
C. Massullo et al. International Journal of Psychophysiology 157 (2020) 61–69

indicate higher anxiety symptoms severity). This inventory has been Table 1
developed in order to assess both state (i.e., present) and trait (i.e., Cortical location of the 31 electrodes.
general) anxiety investigating somatic and cognitive anxiety symptoms Scalp electrodes Cortical structure Montreal Neurological Institute
(with 11 and 10 items, respectively). Compared to other trait-anxiety coordinates
questionnaires (e.g., the State-Trait Anxiety Inventory), the STICSA is x y z
considered a more suitable measure of anxiety symptomatology with a
Fp1 Superior frontal gyrus 25 65 − 5
better convergent and discriminant validity (Grös et al., 2007). In the
−
F3 Middle frontal gyrus − 40 45 30
present study, a cut-off of 43 has been used to constitute HTA and LTA F7 Inferior frontal gyrus − 50 40 − 10
groups. This cut-off has more empirical support and predictive utility AF3 Superior frontal gyrus − 25 60 20
and it is recommended for use in research settings (Van Dam et al., FC1 Superior frontal gyrus − 20 15 65
Fp2 Superior frontal gyrus 25 65 − 5
2013). Furthermore it is also widely used in the investigation on trait
FC5 Inferior frontal gyrus − 60 15 20
anxiety (Fekete et al., 2016; Van Dam et al., 2012; Van Dam et al., 2014; F4 Middle frontal gyrus 40 45 30
Waechter and Stolz, 2015; Xu et al., 2017). The Cronbach’s α in our F8 Inferior frontal gyrus 50 40 − 10
sample was of 0.86 for the STICSA total score. AF4 Middle frontal gyrus 30 60 15
The TDI is an instrument developed in order to assess major FC2 Middle frontal gyrus 30 10 65
FC6 Inferior frontal gyrus 60 15 20
depression and it is composed by 21 self-reported items (Balsamo and C3 Postcentral gyrus − 50 − 20 60
Saggino, 2013) rated on 5 point Likert Scale. The total TDI scores extend CP1 Postcentral gyrus − 30 − 45 70
from 0 to 84 in which as the total score increases, the severity of the CP5 Supramarginal gyrus − 65 − 45 30
depressive symptoms increases too. This test has shown good psycho­ C4 Postcentral gyrus 55 − 20 55
CP2 Postcentral gyrus 30 − 45 70
metric properties (Balsamo et al., 2014) and, in our sample, the Cron­
CP6 Supramarginal gyrus 65 − 50 30
bach’s α was of 0.88. P3 Inferior parietal lobule − 40 − 70 45
The OCI-R is a reliable self-report questionnaire constituted by 18 PO3 Cuneus − 30 − 90 30
items with six subscales (i.e., checking, washing, obsessing, ordering, P4 Inferior parietal lobule 45 − 70 45
mental neutralizing, and hoarding) assessing the different dimensions of PO4 Precuneus 35 − 85 35
O1 Middle occipital gyrus 20 − 100 10
obsessive-compulsive related symptomatology (Foa et al., 2002). The
−
O2 Middle occipital gyrus 20 − 100 5
Italian version of this questionnaire has shown good psychometric T3 Middle temporal gyrus − 65 − 15 − 15
properties (Sica et al., 2009). In our sample the internal consistency was T5 Inferior temporal gyrus − 60 − 65 − 10
satisfactory (i.e., Cronbach’s α = 0.90). T4 Middle temporal gyrus 70 − 20 − 10
T6 Middle occipital gyrus 55 − 70 0
The CAGE is a short screening tool developed to assess problematic
Fz Superior frontal gyrus 5 45 50
alcohol use composed by 4 dichotomous (1 = yes; 0 = no) items (Agabio Cz Superior frontal gyrus 5 − 10 70
et al., 2007; Ewing, 1984; Mayfield et al., 1974). Total score ranges go Pz Precuneus − 5 − 65 65
from 0 to 4 with higher scores reflecting more severe problematic pat­
terns of alcohol use. The CAGE has shown satisfactory psychometric
properties (e.g., high test-retest reliability; Dhalla and Kopec, 2007) and MathWorks, Inc.). More specifically, offline artifacts rejection (i.e.,
the Cronbach’s α in our sample was 0.82. cardiac pulses, muscular or movement activities) were performed visu­
ally on the raw EEG trace by posing a marker at the onset of the artifact
2.3. EEG recordings and connectivity analysis signal and a further marker at the end of the artifact (Imperatori et al.,
2013). Artifacts rejection was performed by two independent trained
EEG recording sessions were held in the European University of researchers using the EEGplot function and rejection. In case of
Rome’s Cognitive and Clinical Psychology Laboratory. All recordings disagreement, a senior researcher resolved any discrepancies. Succes­
(lasting at least 5 min) were performed in eye-closed RS condition (i.e., sively, the artifact segments (i.e., the EEG signal interval included be­
people were sitting on a comfortable armchair in an isolated from noise tween the two markers) were deleted. Once performed artifact rejection
and semi-darkened room and they were instructed to keep awake). procedure, for each participant it has been obtained at least 180 s of EEG
Participants were given the following instructions: “now please make recording, not necessarily consecutive. EEG traces were then segmented
yourself comfortable and close your eyes for a few minutes until I tell you to in 2 s epochs and analyzed using a widely validate software, namely the
open them again”. Participants were also informed about the possibility exact Low-Resolution Electromagnetic Tomography (eLORETA). This
to stop the procedure in case of need. software is suitable to localize distributed electrical activity in the scalp
In order to avoid any interfering effect on EEG trace, participants in a three-dimensional way (Pascual-Marqui et al., 2011). Furthermore,
refrained from consume caffeine, tea and/or alcohol, as well as smoking, several studies showed a satisfactory localization agreement with other
in the 4 h previous the EEG recording collection (Dimpfel et al., 1993; neuro-imaging techniques (De Ridder et al., 2011; Horacek et al., 2007;
Kahkonen et al., 2003). Huang et al., 2018; Kirino, 2017; Muller et al., 2005; Pizzagalli et al.,
For EEG recordings it was used a cap with 31 channels placed ac­ 2004; Zumsteg et al., 2005). Satisfactory localization agreement for
cording to the 10/20 system (see Table 1 for the specific location of the paralimbic or limbic brain areas, including insula, was also documented
electrodes). Furthermore, both electrocardiogram and electro- with low number (i.e., <30) of electrodes (Mulert et al., 2004).
oculogram were recorded. EEG was acquired using Micromed System Another benefit of the LORETA method is that both EEG signal
Plus digital EEGraph (Micromed© S.p.A., Mogliano Veneto, TV, Italy). reconstruction and analyses are independent of the reference used
EEG data were recorded with a right-mastoid reference and re- during the recordings, which can be arbitrary (Lamm et al., 2005; Lubar
referenced offline to the algebraic average of the left and right mas­ et al., 2003; Pascual-Marqui et al., 2011).
toid. Impedances were kept below 5 kΩ before starting EEG recording According to the aims of the current study, eLORETA software is able
and checked again at the end of EEG session for each participant. to evaluate modifications in the neuronal synchronization at changing
Particularly, impedances of the right and left mastoid reference elec­ time intervals and frequencies (Thatcher et al., 2014), so it is considered
trodes were checked to be identical. For EEG it was used a 256 Hz suitable in investigating brain connectivity and network activity (Neu­
sampling frequency and recordings were offline filtered 1–100 Hz (with ner et al., 2014; Thatcher et al., 2014; Whitton et al., 2018). Further­
values corresponding respectively with high and low frequency pass more, due to its good temporal resolution (Canuet et al., 2011; Whitton
band filters). Signal processing (i.e., filtering and artifact rejection et al., 2018), EEG has the benefit to provide ecological information to
procedure) was performed using EEGlab toolbox for MATLAB (The both clinicians and researchers (Todder et al., 2012; Toppi et al., 2016).

63
C. Massullo et al.
According to previous studies (Imperatori et al., 2020; Li et al.,
2018), in order to perform the connectivity analysis within the triple
network, totally 9 Regions of Interest (ROIs) have been defined. Of
these, 4 ROIs belonged to the CEN (i.e., bilateral DLPFC and bilateral
parietal cortex), 2 ROIs to the DMN (i.e., mPFC and PCC) and 3 ROIs to
the SN (i.e., dACC and bilateral AI). All these ROIs have been reported in
Fig. 1. In order to obtain functional connectivity data, it was used the
lagged phase synchronization (LPS) (Pascual-Marqui, 2007; Pascual-
Marqui et al., 2011), which allows to estimate how similar are two time
series (i.e., the synchrony of two signals) by taking into account the
phases of analyzed signal, independent from power (Bowyer, 2016).
This procedure is widely used in neurophysiological studies (e.g., Hata
et al., 2016; Imperatori et al., 2017; Olbrich et al., 2014) because it
minimizes the artifacts, such as volume-conduction related ones, by
removing the instantaneous zero-lag contribution (Hata et al., 2016).
LPS values range from 0 to 1 corresponding to the absence and to the
maximum synchronization, respectively (Olbrich et al., 2014; Pascual-
Marqui, 2007). Furthermore, as recommended (Canuet et al., 2011;
Pascual-Marqui et al., 2011), in order to perform the source recon­
struction, the “single nearest voxel” option (i.e., each ROI consisting of a
single voxel, the closest to each seed) has been selected. Both this pro­
cedure and the LPS between all the defined ROIs have been computed by
the eLORETA software (Pascual-Marqui et al., 2011). In the current
study, the following five frequency bands were considered for all EEG
analysis: delta (1–4 Hz); theta (4.5–7.5 Hz); alpha (8–13 Hz); beta
(13.5–30 Hz); gamma (30.5–60 Hz).
2.4. Statistical analysis
EEG triple network connectivity analysis was performed by
comparing HTA vs LTA individuals by means of eLORETA software. For
sensitivity analyses, a power spectrum analysis was also performed (see
Supplementary material). EEG connectivity data were analyzed using
the statistic non parametric mapping available in the eLORETA soft­
ware. This statistics is based on Fisher’s permutation and applies the
nonparametric randomization procedure in order to perform the
correction of significance for multiple testing (Nichols and Holmes,
2002). Specifically, this method uses 5000 data randomizations to
define the critical probability threshold of T-values corresponding to
statistically p-values (p < 0.05 and p < 0.01) corrected for multiple
comparisons across all ROIs and all considered frequencies (Hata et al.,
2019; Kitaura et al., 2017). The eLORETA software also provides effect
size thresholds for t-statistics corresponding to Cohen’s d values (Cohen,
1988): small = 0.2, medium = 0.5, large = 0.8. Furthermore, in order to
provide other useful statistics [i.e., degrees of freedom and confidence
intervals (CI)] raw connectivity values from significant ROIs were also
manually exported and analyzed using independent t-tests.
Differences between groups were analyzed with Chi-squared (χ2) test
(for dichotomous variables) and Kolmogorov-Smirnov Z test (for
dimensional measures). Finally, in order to measure trait anxiety also as
a continuous variable, the association between STICSA scores and only
statistically significant EEG connectivity data observed in the between-
group comparison was evaluated through Spearman’s rho correlation
coefficients with age, sex, tobacco use, TDI, OCI-R and CAGE total score
as covariates (i.e., standardized residual). IBM SPSS Statistics for Win­
dows, version 18.0 (Chicago, USA), has been used for the statistical
analyses.
3. Results
3.1. Study participants
According to STICSA cut-off (Van Dam et al., 2013), 23 and 45
participants were included in the HTA group (i.e., STICSA total score ≥
43) and LTA group (i.e., STICSA total score < 43), respectively. No
significant differences in clinical and demographical variables have
64
International Journal of Psychophysiology 157 (2020) 61–69
been detected between groups (all details are reported in Table 2) except
for depression (TDI total score, Z = 1.17; p = 0.004). As concerning
neurophysiological data, for all subjects, suitable RS EEG recordings
have been acquired. By visually assessing EEG traces, no significant al­
terations of background rhythm frequency, such as sleepiness or focal
abnormalities, have been detected. The average time analyzed was of
281.83 ± 35.39 s and 270.09 ± 30.46 s, respectively for HTA and LTA
participants (Z = 0.93, p = 0.356).
3.2. Functional connectivity results
As concerning functional connectivity results, in the comparison
between HTA and LTA individuals, the eLORETA software provided
significance thresholds (T) corrected for multiple comparisons corre­
sponding to T = ±3.78 and T = ±4.24 respectively for p < 0.05 and p <
0.01. Effect size for T-thresholds was 1.63, 4.06, and 6.50, correspond­
ing, respectively to small, medium and large effect size. Groups signif­
icantly differ in alpha frequency band functional connectivity (Fig. 2
Panel A). More in particular, compared to LTA individuals, HTA in­
dividuals group shows a decreased alpha connectivity between the dACC
and left AI (T = − 3.93; p = 0.032), and between the dACC and right AI
(T = − 3.85; p = 0.040). The independent t-tests, performed on raw
values, confirmed the significant differences between groups (i.e., HTA
vs LTA) for both the dACC-left AI [0.06 ± 0.04 vs 0.11 ± 0.06; t(64,40) =
− 3.98; p < 0.001; 95% CI (− 0.072, − 0.024); d = 0.92] and dACC-right
AI [0.07 ± 0.04 vs 0.12 ± 0.07; t(65,43) = − 3.69; p < 0.001; 95% CI
(− 0.076, − 0.023); d = 0.81] connectivity data.
No significant differences were observed in the other frequency
bands. The most evident modification of EEG connectivity observed in
the delta band was noticed between the right AI and the mPFC (T = 1.92;
p = 0.981). The most prominent modification of EEG connectivity
observed in the theta band was reported between the right DLPFC and
the right PPC (T = − 1.69; p = 0.999). The most relevant modification of
EEG connectivity observed in the beta band was detected between the
dACC and the mPFC (T = 1.32; p = 0.999). Lastly, the most evident
modification of EEG connectivity observed in the gamma band was
noticed between bilateral PPC (T = − 1.88, p = 0.987).
After controlling for age, sex, tobacco and alcohol use, depressive
and obsessive-compulsive symptoms, the strength of alpha connectivity
between the dACC and both left and right AI was negatively and
significantly correlated with the STICSA total score (rho = − 0.34, p =
0.004 and rho = − 0.26, p = 0.034; Fig. 2 Panel B) as well as with somatic
dimension (rho = − 0.32, p = 0.008 and rho = − 0.24, p = 0.049). The
strength of alpha connectivity between the dACC and left AI was also
negatively and significantly correlated with anxiety cognitive symptoms
(rho = − 0.29, p = 0.016). Detailed partial correlations are reported in
Table 3.
4. Discussion
The main goal of the current study was to investigate RS-EEG triple
network functional connectivity pattern in individuals with HTA.
Compared to individuals with LTA, those with high levels showed a
decrease of alpha functional connectivity between the dACC and both
the right and left AI (i.e., the main hubs of SN; Kurth et al., 2010; Menon,
2011; Menon and Uddin, 2010). More interestingly, the strength of these
EEG patterns were negatively correlated with STICSA total score, espe­
cially with the somatic dimension, even when controlling for potential
confounding variables (i.e., sex, age, tobacco use, problematic alcohol
use, obsessive-compulsive and depressive related symptoms) which are
known to be associated with trait anxiety (e.g., Comeau et al., 2001;
Donner and Lowry, 2013; Weger and Sandi, 2018). Our data do not
reveal any significant difference between groups, neither with the hubs
of the DMN, nor with those of the CEN, suggesting that individuals with
HTA could be characterized by a specific dysfunctional communication
within the SN during RS.
 C. Massullo et al.
65

International Journal of Psychophysiology 157 (2020) 61–69

Fig. 1. Triple network eLORETA ROIs and Montreal Neurological Institute coordinates (axial, sagittal, and coronal view). Abbreviations: dACC = dorsal Anterior Cingulate Cortex; DLPFC = Dorsolateral Prefrontal
Cortex; mPFC = medial Prefrontal Cortex; PCC = Posterior Cingulate Cortex; PPC = Posterior Parietal Cortex.
C. Massullo et al. International Journal of Psychophysiology 157 (2020) 61–69

Table 2 switching between the DMN and CEN (Menon, 2011; Menon and Uddin,
Clinical and demographical data of the sample. 2010; Sridharan et al., 2008), thus disengaging RS related brain circuits
Variables HTA LTA Test p= and activating higher order cognitive functions that include attentional
N = 23 N = 45 processes (Sridharan et al., 2008).
Age – M ± SD 22.30 ± 21.98 ± Z= 0.288 Intriguingly, in the current study, we observed a decrease of EEG
2.70 3.51 0.98 connectivity in the alpha frequency band in individuals with HTA.
Females – N (%) 12 (52.2%) 28 (62.2%) χ2 = 0.426 Previous RS EEG studies showed that both trait anxiety (Aftanas and
0.63 Pavlov, 2005; Knyazev et al., 2004; Pavlenko et al., 2009; Putman,
Tobacco use (in the last 6 7 (30.4%) 12 (26.7%) χ2 = 0.743
months) – N (%) 0.11
2011) and anxiety disorders (Gordeev, 2008; Kara and Polo, 2014;
CAGE total score – M ± SD 0.39 ± 0.94 0.16 ± 0.64 Z= 0.994 Newson and Thiagarajan, 2018) are related with several psychophysi­
0.42 ological alterations, such as the decrease of alpha activity alone or in
OCI-R total score – M ± SD 19.57 ± 15.93 ± Z= 0.621 association with a significant increase in beta activity. At network level,
13.29 11.80 0.75
combined EEG and fMRI studies in healthy subjects showed that during
TDI total score – M ± SD 39.04 ± 28.69 ± Z= 0.004
11.14 10.70 1.77 RS condition alpha oscillations are positively associated with the ac­
STICSA total score – M ± SD 49.43 ± 33.36 ± Z= <0.001 tivity of the SN and CEN in order to sustain cognitive control and
6.32 5.49 3.90 maintain alertness (Sadaghiani and Kleinschmidt, 2016). Accordingly,
STICSA somatic subscale – M 22.30 ± 15.31 ± Z= <0.001 although the functional meaning of EEG alpha frequency is still unclear,
± SD 4.10 2.44 2.96
STICSA cognitive subscale – 27.13 ± 18.04 ± Z= <0.001
it has been proposed that the synchronization in the alpha frequency
M ± SD 4.61 4.70 2.69 plays a relevant role in the top-down control of cortical activation
improving behavioral performance (Klimesch, 2012; Klimesch et al.,
Abbreviations: HTA = high-trait anxiety; LTA = low-trait anxiety; M = mean,
2007). Therefore, according to Geng et al. (2016), the decrease of alpha
SD = standard deviation; N = number; CAGE = questionnaire to detect prob­
lematic alcohol use; OCI-R = Obsessive Compulsive Inventory Revised; TDI =
connectivity, within the SN hubs observed in the HTA group, might
Teate Depression Inventory; STICSA = State-Trait Inventory for Cognitive and reflect the top-down cognitive control deficit of the SN in anxiety. The
Somatic Anxiety, χ2 = Chi-squared test, Z = Kolmogorov-Smirnov Z test. dysregulation in this circuit has been hypothesized to play a central role
in the pathology of anxiety due to its involvement in anxiety related
Our results seem to be in accordance with previous data reporting SN
alterations in both anxiety disorders (Kim and Yoon, 2018; Sylvester Table 3
et al., 2012; Williams, 2016) and HTA (Geng et al., 2016; Markett et al., Spearman’s rho correlations (standardized residual) among significant ROIs
2016). The SN and particularly the AI-dACC pathway seem to be connectivity values and trait anxiety controlling for age, sex, tobacco use, TDI,
involved in homeostatic and cognitive, as well as emotional, salience OCI-R and CAGE total score.
detection processes (Menon and Uddin, 2010; Seeley et al., 2007). As Alpha EEG connectivity
previously suggested (Paulus, 2007; Sridharan et al., 2008), the alter­ dACC-left AI dACC-right AI
ation of the AI-dACC pathway and its underlying processes represent a
STICSA total score − 0.34** − 0.26*
core feature of several psychopathologies including anxiety disorders.
STICSA somatic subscale − 0.32** − 0.24*
More specifically, while the AI signals potential salient stimuli in in­ STICSA cognitive subscale − 0.29* − 0.20
ternal or external environment, the dACC mainly deals with cognitive
Abbreviations: TDI = Teate Depression Inventory; OCI-R = Obsessive Compul­
and autonomic control by modulating the response in associative, motor
sive Inventory Revised; CAGE = CAGE questionnaire to detect problematic
and sensory related brain regions (Critchley et al., 2003; Menon and
alcohol use; STICSA = State-Trait Inventory for Cognitive and Somatic Anxiety;
Uddin, 2010). Therefore, the AI-dACC pathway is critical in detecting dACC = dorsal Anterior Cingulate Cortex; AI = Anterior Insula; EEG =
relevant information in the environment and in implementing the electroencephalography.
cognitive control (Sridharan et al., 2008). Furthermore, in a triple *
p < 0.05.
network perspective, the AI is considered to have a crucial role in **
p < 0.01.

Fig. 2. Panel A: Results of the eLORETA between comparisons in alpha frequency band. Compared to low-trait-anxiety participants, those with high-trait-anxiety
showed a decrease of alpha connectivity (blue line) between the dorsal anterior cingulate cortex (dACC) and bilateral Anterior Insula (AI). Panel B: Scatterplot
of the correlation between STICSA total score and EEG connectivity between dACC and both left and right AI values adjusted (i.e., standardized residual) for the effect
of potentially competing factors (i.e., sex, age, tobacco use, problematic alcohol use, depressive and obsessive-compulsive symptoms). (For interpretation of the
references to color in this figure legend, the reader is referred to the web version of this article.)

66
C. Massullo et al.
symptoms such as altered saliency detection and cognitive control pro­
cesses (Menon, 2011, Geng et al., 2016). Furthermore, our results seems
to be consistent with previous EEG studies reporting the association
between the drop of cortical alpha connectivity with both anxiety
(Hinrichs and Machleidt, 1992; Knyazev et al., 2016) and a specific trait
alteration in emotional processing (i.e., alexithymia; Houtveen et al.,
1997; Imperatori et al., 2016). Notwithstanding these data, future lon­
gitudinal studies are needed to clarify the causal direction between the
altered brain connectivity patterns and anxiety symptoms. Furthermore,
it cannot be excluded that this association is mediated by other vari­
ables, which may alter the integration within the SN, producing, in turn,
anxiety symptoms.
Although these results may be interesting, some limitations should
be considered. Firstly, as previously observed, this is a cross-sectional
report; thus, causal relationships between investigated variables
cannot be established. Secondly, although participants underwent
screening questions in order to identify past and/or current psychiatric
disorders, a full structured clinical interview has not been performed.
Third, we did not evaluate the variation of state anxiety, which make our
interpretation specific to trait anxiety and to the RS condition (i.e., eyes
closed). Lastly, while the eLORETA software is a reliable tool to inves­
tigate brain connectivity characterized by satisfactory localization
agreement for paralimbic/limbic (e.g., insula) structures (Mulert et al.,
2004), it has an intrinsic limit in space resolution, particularly in the
identification of deep subcortical sources (e.g., the amygdala), which are
involved in the pathophysiology of anxiety (Sylvester et al., 2012; Wil­
liams, 2016). Similarly, although 31 electrodes might be suitable in
order to detect large-scale brain networks, it is known that spatial res­
olution of EEG sources increases with the number of electrodes, and
therefore high-density recordings are more reliable in the esteem of EEG
source analysis (Liu et al., 2018). Therefore, further longitudinal reports
using a test-retest paradigm (Tian et al., 2016) with larger samples and
combining multimodal neuroimaging data (i.e., high-density EEG/
fMRI), during both task-based and task-free conditions, should be
implemented in order to better understand the neural dynamics un­
derlying trait anxiety. These future studies should confirm or reject the
present data, that, consequently, must be considered only as
preliminary.
In conclusion, even considering these limitations and to the best of
our knowledge, our study might be considered the first to examine the
RS-EEG triple network synergistic interactions in HTA individuals that
use a well validated tool to detect and localize electro-cortical activity (i.
e., the eLORETA). Taken together, our results suggest a specific func­
tional connectivity pattern, characterizing individuals with HTA, which
consists in a dysfunctional communication within the SN, and more
specifically in the AI-dACC pathway. This functional pattern might un­
derline brain correlates of altered at rest saliency detection, emotion
regulation and cognitive control processes, which are typical of anxiety,
and could be a potential target of auto-neuromodulation techniques,
such as neurofeedback training (Wang et al., 2013), in individuals with
HTA.
Declaration of competing interest
The authors declare that they have no conflict of interest.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.ijpsycho.2020.09.002.
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