Progress in Neuropsychopharmacology & Biological Psychiatry xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Progress in Neuropsychopharmacology
& Biological Psychiatry
journal homepage: www.elsevier.com/locate/pnp

Common and distinct brain networks underlying panic and social anxiety
disorders
Yong-Ku Kim, Ho-Kyoung Yoon⁎
Department of Psychiatry, College of Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea

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

Keywords: Although panic disorder (PD) and phobic disorders are independent anxiety disorders with distinct sets of di-
Functional connectivity agnostic criteria, there is a high level of overlap between them in terms of pathogenesis and neural under-
Panic disorder pinnings. Functional connectivity research using resting-state functional magnetic resonance imaging (rsfMRI)
Resting state shows great potential in identifying the similarities and differences between PD and phobias. Understanding
Social anxiety disorder
common and distinct networks between PD and phobic disorders is critical for identifying both specific and
general neural characteristics of these disorders. We review recent rsfMRI studies and explore the clinical re-
levance of resting-state functional connectivity (rsFC) in PD and phobias. Although findings differ between
studies, there are some meaningful, consistent findings. Social anxiety disorder (SAD) and PD share common
default mode network alterations. Alterations within the sensorimotor network are observed primarily in PD.
Increased connectivity in the salience network is consistently reported in SAD. This review supports hypotheses
that PD and phobic disorders share common rsFC abnormalities and that the different clinical phenotypes be-
tween the disorders come from distinct brain functional network alterations.

1. Introduction Currently, agoraphobia is unlinked with PD in the Diagnostic and

Phobic disorder or phobia is the most common form of anxiety
disorder, and is characterized by persistent, marked, and unreasonable
fears of an object or situation. People with a phobia avoid specific si-
tuations or objects that induce these types of fears. One of the most
famous types of phobia is social anxiety disorder (SAD), also called
social phobia, which involves an excessive fear of embarrassment in
social situations and avoidance of such situations. Panic disorder (PD)
involves repeated and spontaneous panic attacks. A panic attack is an
extreme form of fear, and is characterized by physical sensations, such
as a racing heart, shortness of breath, and chest pain that lasts for a
short period of time. Agoraphobia is characterized by a fear of being
alone or a fear of being in public places together with avoidance of such
situations. The relationship between PD and agoraphobia is particularly
complicated. Traditionally, agoraphobia has been viewed as a compli-
cation of panic symptoms and has tended to be co-diagnosed with PD.
Statistical Manual of Mental Disorders 5 (2013). However, high co-
morbidity and the conceptual overlap still pose obstacles to the diag-
nostic distinction between PD and agoraphobia (Asmundson et al.,
2014). While obsessive-compulsive disorder and post-traumatic stress
disorder have been split into discrete disorder categories, PD and
phobic disorders remain together in the chapter on anxiety disorders.
Although PD and phobic disorders are independent anxiety disorders
with distinct sets of diagnostic criteria, there is a high level of overlap
between them in terms of pathogenesis and neural underpinnings.
Epidemiological and translational studies have shown similarities and
differences across these disorders. For example, one epidemiological
study found high comorbidity among anxiety disorders including PD,
SAD, specific phobia (SP), and agoraphobia (Kessler et al., 2005). A
twin study reported that PD, agoraphobia, and SP strongly co-ag-
gregated within families, and that common genetic factors explained a
moderate to high proportion of variance in these disorders without the

Abbreviations: AI, anterior insular cortex; ACC, anterior cingulate cortex; BOLD, blood-oxygen-level-dependent; CEN, central executive network; dACC, dorsal anterior cingulate cortex;
dlPFC, dorsolateral prefrontal cortex; DMN, default mode network; dmPFC, dorsomedial prefrontal cortex; DTI, diffusion tensor imaging; EEG, electroencephalography; FC, functional
connectivity; fMRI, functional magnetic resonance imaging; ICA, independent component analysis; mOFC, medial orbitofrontal cortex; mPFC, medial prefrontal cortex; MTL, middle
temporal lobe; PCC, post cingulate cortex; OFC, orbitofrontal cortex; PD, panic disorder; pgACC, perigenual anterior cingulate cortex; rACC, rostral anterior cingulate cortex; ROI, region
of interest; ReHo, regional homogeneity; rsFC, resting-state functional connectivity; rsfMRI, resting-state functional magnetic resonance imaging; SAD, social anxiety disorder; SMN,
sensorimotor network; SN, salience network; SP, specific phobia; SPECT, single-photon emission computed tomography; VMHC, Voxel-mirrored homotopic connectivity; vmPFC, ven-
tromedial prefrontal cortex
⁎
Corresponding author at: Department of Psychiatry, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan-si, Gyeonggi-do 15355, Republic of Korea.
E-mail address: hkhkgogo@korea.edu (H.-K. Yoon).

http://dx.doi.org/10.1016/j.pnpbp.2017.06.017
Received 17 February 2017; Received in revised form 14 May 2017; Accepted 18 June 2017
0278-5846/ © 2017 Published by Elsevier Inc.

Please cite this article as: Kim, Y.-K., Progress in Neuropsychopharmacology & Biological Psychiatry (2017),
http://dx.doi.org/10.1016/j.pnpbp.2017.06.017
Y.-K. Kim, H.-K. Yoon
influence of a common environment (Mosing et al., 2009). On the other
hand, many linkage and candidate gene studies, as well as a PD
genome-wide association study and other phobic disorders have pro-
duced inconclusive results to date (Shimada-Sugimoto et al., 2015).
Understanding similarities and differences between PD and phobic
disorders is critical for identifying both specific and general neural
characteristics of these disorders.
Resting-state functional MRI (rsfMRI) has been developed for ana-
lyzing large-scale connectivity in brain networks. Resting-state func-
tional connectivity (rsFC) measures the temporal correlation of spon-
taneous blood-oxygen-level-dependent (BOLD) signals between
spatially remote brain regions during times without the performance of
an explicit task. Several resting-state networks have been identified and
investigated. The default mode network (DMN), one of the canonical
resting-state brain networks, is the most studied network (Smith et al.,
2009). The DMN, a set of temporally correlated brain regions, is most
active during rest and is deactivated during the performance of cogni-
tively demanding goal-directed tasks. This network includes the medial
prefrontal cortex (mPFC), the posterior cingulate cortex (PCC)/pre-
cuneus, the ventral/perigenual anterior cingulate cortex (pgACC), and
the inferior parietal cortex. In addition to the DMN, many other major
canonical resting-state networks are frequently identified in existing
literature (Barkhof et al., 2014). These networks include the salience
network (SN: dorsal anterior cingulate cortex (dACC) and anterior in-
sular cortex (AI) circuitry), the central executive network (CEN: the
dorsolateral prefrontal cortex (dlPFC) and parietal cortex), the dorsal
attention network (DAN: intraparietal sulcus, precentral and superior
frontal gyrus), the sensorimotor network (SMN: primary sensorimotor
cortex, supplementary motor area and secondary somatosensory
cortex), the visual network (Striate cortex, occipital pole, and lateral
visual areas), and the auditory network (Superior temporal gyrus).
This rsfMRI analysis-based method has several specific features for
investigating functional alterations of brain networks in psychiatric
disorders (Woodward and Cascio, 2015). First, reliable and re-
producible results can be obtained through this relatively standard
method. Second, because this method does not depend on explicit task
performance, it can be evaluated in populations incapable of per-
forming task-based functional MR imaging, such as pediatric subjects
and patients with reduced consciousness. Moreover, in comparison to
the modular representations of traditional fMRI, functional connectivity
provides a broader network representation of the functional archi-
tecture of the brain. Proper connection and harmonious interaction
between brain areas are crucial for optimal brain functioning. There-
fore, this technique may offer a new understanding of the functional
integration of brain regions involved in the symptomatology of anxiety
and other psychiatric disorders (Peterson et al., 2014).
Several different approaches can be used in rsfMRI analysis. There
are two widely used rsFC analysis methods, namely, seed-based ap-
proaches and independent component analysis (ICA) (Fox and Raichle,
2007; van den Heuvel and Hulshoff Pol, 2010). In seed-based ap-
proaches, according to an a priori hypothesis, individual seed voxels are
extracted from a predefined brain region and are correlated with the
time courses of other voxels in selected seeds of the brain. In contrast,
ICA is a multivariate, data-driven method that decomposes fMRI time-
series data throughout the brain into linear mixtures of spatially in-
dependent and temporally coherent components.
Our comprehensive literature review focuses on PD and SAD be-
cause there are, to our knowledge, no resting-state studies in patient
samples with SP as a primary diagnosis. Based on a literature review,
we elaborate on the common and distinct network alterations between
the disorders, explore the clinical relevance of rsFC alterations, and
discuss future considerations regarding the usefulness of rsfMRI for
biomarkers of psychiatric disorders.
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Progress in Neuropsychopharmacology & Biological Psychiatry xxx (xxxx) xxx–xxx
2. Panic disorder
Until recently, the majority of work on brain function in PD has
focused on cognitive task-related or conditioned stimuli-related brain
activity. There is growing evidence, however, for resting-state networks
in PD.
Two studies on PD have demonstrated alterations of DMN. The work
of Shin et al. (2013) reported that rsFC between the pgACC and the
precuneus was increased in patients with PD compared to control
subjects. The research also observed that GABA concentration of the
pgACC was correlated with functional connectivity between the pgACC
and the precuneus. Using voxel-mirrored homotopic connectivity
(VMHC) analysis, another rsfMRI study also reported an aberrant rsFC
within the DMN (Lai and Wu, 2014). Therein, investigators found de-
creased inter-hemispheric connectivity of bilateral PCC and the pre-
cuneus in PD. The mPFC (including the pgACC) has been associated
with cognitive processes, such as mental representation, theory-of-
mind, and/or narrative processing (Frith and Frith, 2007; Hartwright
et al., 2014; Mano et al., 2009). The pgACC plays a role in monitoring
and appraising the external environment and mutually interacting with
various regions of the brain to regulate stressor-related autonomic re-
actions. (Gianaros and Sheu, 2009; Ryan et al., 2011). Though the PCC/
precuneus is not directly connected to the visceral autonomic system, it
is involved in a wide spectrum of attentional processes including self-
monitoring, remembering the past, thinking about the future, and as-
sessing the environment (Wagner et al., 2005). The PCC is also im-
plicated in somatosensory processing, evaluation of sensory events,
spatial orientation, and memory and memory retrieval (Olson and
Musil, 1992).
Several studies examining resting-state connectivity in PD reported
consistent changes in the SMN. The work of Pannekoek et al. (2013a)
examined rsFC using seed regions of interest (ROI) in bilateral amyg-
dala, bilateral dACC, and bilateral PCC. The research found increased
rsFC between the right amygdala and bilateral precuneus in patients
with PD compared to healthy control subjects. Altered dACC rsFC with
frontal, parietal, and occipital areas was also found. Notably, the left
dACC demonstrated increased positive connectivity with the post-
central gyrus, known as the somatosensory cortex, with the function of
integrating and interpreting most of the sensory information from the
body (Northoff et al., 2006). A whole-brain analysis study using a novel
functional connectivity metric revealed increased FC between the tha-
lamus and postcentral gyrus in PD patients (Cui et al., 2016). Altered
connectivity between the post/precentral gyrus and the thalamus was
found to be positively related to the scores on the Spielberger State-
Trait Anxiety Inventory and the Body Perception Questionnaire. The
postcentral and precentral gyrus are known to be engaged in inter-
oception processing (Critchley et al., 2004; Inoue et al., 2013). Re-
cently, a whole-brain functional connectome study using the new
method of network-based statistics revealed limbic-motor-sensory re-
gion connectivity alteration in certain subjects (Lai and Wu, 2016). In
that study, the precentral gyrus was one of the central hubs for altered
functional connectivity network in PD. The findings of that study
seemed to make the original “fear network model” more comprehensive
in terms of our understanding of the sensory-related symptoms of PD.
These sensorimotor region-centered results are quite distinct from the
findings of functional connectome alterations in other anxiety dis-
orders, such as posttraumatic stress disorder.
To summarize, although contemporary rsfMRI studies on PD are still
scarce, emerging evidence consistently suggests that abnormalities of
the DMN in PD appear prominent within emotion regulatory networks.
Functional connectivity in the DMN has been linked to core processes of
human cognition, such as the integration of cognitive and emotional
processing, mentalizing, autobiographical memory retrieval, and en-
visioning the future (Buckner et al., 2008; Greicius et al., 2003). Hy-
perconnectivity has also been suggested in SMN. This hy-
perconnectivity of SMN may cause abnormally high interoceptive
Y.-K. Kim, H.-K. Yoon Progress in Neuropsychopharmacology & Biological Psychiatry xxx (xxxx) xxx–xxx

Table 1
Resting-state fMRI studies of panic disorder.

Study Sample Brain regions and/or networks Main finding

analysed

Pannekoek et al. 11 PD Seed: bilateral amygdala, bilateral PD patients showed increased rsFC between the right amygdala and the bilateral precuneus. The
(2013a) 11 HC dACC, and bilateral PCC dACC demonstrated altered connectivity with frontal, parietal and occipital areas in PD
Shin et al. (2013) 11 PD Seed: pgACC PD patients showed increased FC between pgACC and precuneus compared to controls. The
11 HC functional connectivity between the pgACC and the precuneus negatively correlated with the GABA
concentration of the pgACC
Lai and Wu (2014) 30 PD Whole brain analysis: VMHC analysis The controls had significantly higher VMHC values than PD patients in the PCC and precuneus. The
21 HC VMHC value in the posterior cingulate cortex was also negatively correlated with panic severity
Cui et al. (2016) 18 PD Whole brain analysis The greater FC between somatosensory cortex and thalamus in PD; the increased FC between
21 GAD hippocampus/parahippocampus and fusiform gyrus in GAD
22 HC
Lai and Wu (2016) 53 PD Whole brain analysis: network-based PD patients had significant functional alterations in limbic, sensory, and motor regions. The central
54 HC statistics method hubs were the left parahippocampal gyrus and left precentral gyrus

dACC, dorsal anterior cingulate cortex; FC, functional connectivity; HC, healthy controls; PCC, post cingulate cortex; OFC, orbitofrontal cortex; PD, panic disorder; pgACC, perigenual
anterior cingulate cortex; rsFC, resting-state functional connectivity; GAD, generalized anxiety disorder; VMHC, voxel-mirrored homotopic connectivity.

sensitivity and somatosensory stimulus processing, which underlie the Therefore, the further research is necessary to understand the meaning
typical somatic symptoms of PD. Table 1 shows fMRI studies of resting of the measured values from new analysis methods, and care must be
state networks in PD. taken in interpreting the results. Inter-study differences in sample size,
the sociodemographic and clinical characteristics of the participants,
such as the various medication status and the incompatible illness
3. Social anxiety disorder
duration may also be other reasons for the discrepant results.
Studies investigating whole-brain in SAD have provided relatively
To date, most studies investigating emotional processing using
consistent results. An ICA study of rsfMRI found selective alterations of
fearful social cues showed altered brain responses in limbic and para-
resting-state networks in SAD patients (Liao et al., 2010a). SAD patients
limbic brain areas. Therefore, up until this point, many investigations
showed decreased FC in the SMN and visual network, increased in the
on SAD have focused on resting-state limbic or SN connectivity (Sripada
self-referential network, and both increased and decreased FC in the
et al., 2012).
DAN, CEN, DMN and SN. An rsfMRI study using a regional homogeneity
Because the amygdala plays significant roles in emotion process,
(ReHo) analysis showed decreased coherence in the bilateral angular
many studies use the amygdala as a seed ROI to analyze rsFC of SAD
gyri, the left mPFC and the right ACC in SAD (Qiu et al., 2011). A
patients. The work of Liao et al. (2010b) reported increased bidirec-
whole-brain analysis using a graph-theory method found decreased
tional influences between the amygdala and visual regions and between
connectivity in the bilateral precuneus in SAD patients (Liu et al.,
the medial orbitofrontal cortex (mOFC) and amygdala in SAD patients.
2015b). According to the findings of that research, the rsFC in the
Decreased effective connectivity from the bilateral inferior temporal
precuneus had a negative correlation with illness duration. In fact, the
gyri to the bilateral amygdalae is also reported in their study. A study
precuneus is a critical hub of DMN, and plays a significant role in self-
by Hahn et al. (2011) investigated the rsFC in patients with SAD. Their
related mental processing (Cavanna and Trimble, 2006). Interestingly,
research revealed a reduced rsFC between the left amygdala and the
a study by Liu et al. (2015a), using multivariate pattern analysis, ex-
mOFC as well as the PCC/precuneus in the patient group. The work of
plored the potential for rsFC to distinguish SAD patients from normal
Prater et al. (2013) reported decreased rsFC between the amygdala and
controls. The consensus functional connections used to distinguish SAD
pgACC in patients with SAD. The work of Dodhia et al. (2014) reported
were largely located within or across the DMN, SN, SMN, visual net-
reduced rsFC from the left and right amygdala to the mPFC/pgACC in
work, and cerebellar regions. Among these regions, the region with the
generalized SAD patients. The authors of that research found that
highest weight in SAD diagnosis was the right mOFC. Previous research
oxytocin enhanced the reduced amygdala-frontal connectivity in SAD.
proposed the potential of the rsFC as a complementary tool for SAD in
A recent treatment study showed increased connectivity of the left
clinical diagnosis.
amygdala with the dorsomedial prefrontal cortex (dmPFC) and the right
To summarize, the most consistent findings in SAD are abnormal-
dACC normalized after CBT in SAD patients (Yuan et al., 2016). They
ities in amygdala-frontal, SN, and DMN connectivity. Other intrinsic
also found that the changes of the connectivity between the left
neural networks have been identified (e.g., CEN), but insufficient lit-
amygdala and the dACC positively correlated with anxiety symptoms in
erature exists to implicate these neural networks in SAD. Thus, they are
patients. A recent study using bilateral amygdalae, dACC, and PCC as
not reviewed here. Table 2 shows fMRI studies of resting state networks
the seed ROIs also showed increased negative right amygdala con-
in SAD.
nectivity and increased positive bilateral dACC connectivity
(Pannekoek et al., 2013b). Increased connectivity in the dACC may be
due to limbic hyperactivity because the dACC of the SN is directly in- 4. Medial temporal lobe subsystem disruption in DMN: a common
volved in conflict monitoring and anticipation (Botvinick et al., 2001; neural-network
Brown and Braver, 2005). The seed-based approach studies using
amygdala as a seed region suggest alterations within the amygdala- Alterations in DMN were consistently observed in brain networks of
frontal FC network in SAD. The discrepancy in results between these patients with both PD and SAD (Fig. 1). A large number of studies have
studies (e.g. increased and decreased amygdala-mOFC connectivity) now connected particular patterns of resting connectivity between
could be ascribed to differences in analysis methods. Liao et al. (2010b) DMN and the psychopathologies of other psychiatric disorders in-
employed Granger causality analysis (GCA) which estimates directed cluding ADHD, depression, and schizophrenia (Greicius et al., 2003).
influences between brain systems using the temporal dynamics in the The DMN is an interconnected set of brain regions showing higher in-
fMRI data. The definition of effective connectivity in GCA is different trinsic activity at rest (Raichle and Snyder, 2007). DMN activity de-
from the concept of functional connectivity value of the approaches creases when task performance requires an increase in activity of other
using correlations with, or between a priori defined regions of interest. specific regions. On the other hand, it is supposed that this default

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Y.-K. Kim, H.-K. Yoon Progress in Neuropsychopharmacology & Biological Psychiatry xxx (xxxx) xxx–xxx

Table 2
Resting-state fMRI studies of social anxiety disorder.

Study Sample Brain regions and/or networks Main finding

analysed

Liao et al. (2010b) 22 SAD Seed: bilateral amygdala Decreased effective connectivity from ITG to amygdala in SAD patients compared to controls.
21 HC Increased connectivity between the mOFC and amygdala and between the visual regions and
amygdala in SAD patients
Hahn et al. (2011) 7 SAD Seed: bilateral amygdala Reduced rsFC between left amygdala and mOFC as well as PCC/precuneus in SAD patients
1 PD compared to HC
2 SAD + PD
27 HC
Prater et al. (2013) 20 SAD Seed: bilateral amygdala SAD patients showed decreased connectivity between amygdala and pgACC
17 HC
Dodhia et al. (2014) 18 SAD Seed: bilateral amygdala FC from left and right amygdala to mPFC/pgACC is reduced in SAD. Oxytocin normalized the
18 HC reduced amygdala-mPFC/pgACC connectivity in SAD
Yuan et al. (2016) 15 SAD Seed: bilateral amygdala SAD Patients showed higher connectivity of left amygdala with dmPFC and dACC compared to
19 HC controls. Increased amygdala-dACC connectivity normalized after CBT
Liao et al. (2010a) 20 SAD Eight resting-state networks identified FC was significantly different in DAN, CEN, DMN and core network; decreased FC was found in
20 HC and investigated the somato-motor network and visual network; increased FC was found in the self-referential
network in SAD patients
Pannekoek et al. 12 SAD Seed: bilateral amygdala, dACC, PCC Increased negative right amygdala connectivity with the left middle temporal gyrus, left
(2013b) 12 HC supramarginal gyrus and left lateral occipital cortex in SAD. Increased positive bilateral dACC
connectivity with the left precuneus and left lateral occipital cortex in SAD. No group
differences in connectivity were found for PCC/precuneus seeds.
Qiu et al. (2011) 20 SAD Whole brain analysis: regional SAD patients showed decreased coherence in the bilateral angular gyrus, right ACC and the left
20 HC homogeneity method mPFC within the DMN and in the right dlPFC and right inferior parietal gyrus within the CEN
Liu et al. (2015a) 20 SAD Whole brain analysis: multivariate The right mOFC was the region with the highest weight in SAD diagnosis
20 HC pattern analysis method
Liu et al. (2015b) 20 SAD Whole brain analysis: graph theory SAD patients showed decreased FC in the bilateral precuneus and increased FC in the right
20 HC method fusiform gyrus. A negative correlation was observed between the FC value in the precuneus and
the illness duration

ACC, anterior cingulate cortex; CEN, central executive network; dACC, dorsal anterior cingulate cortex; dlPFC, dorsolateral prefrontal cortex; DMN, default mode network; dmPFC,
dorsomedial prefrontal cortex; FC, functional connectivity; HC, healthy controls; ITG, inferior temporal gyrus; mOFC, medial orbitofrontal cortex; mPFC, medial prefrontal cortex; PCC,
post cingulate cortex; PD, panic disorder; ReHo, regional homogeneity; rsFC, resting-state functional connectivity; SAD, social anxiety disorder.

system of the human brain might be continuously busy with tasks such
as monitoring and evaluating the present and the relevant future by
extracting analogies from autobiographical information (Bar, 2009).
The work of Andrews-Hanna et al. (2010) suggested that the DMN
consisted of two subsystems that interact with a common core system.
The first subsystem included the dmPFC, the temporoparietal junction,
the lateral temporal cortex, and the temporal pole, and it was selec-
tively activated during instances in which a person was thinking about
the thoughts and emotional states of others. The second subsystem,
called the medial temporal lobe (MTL) subsystem, included the ventral
medial prefrontal cortex (vmPFC), the posterior inferior parietal lobule,
the retrosplenial cortex, the parahippocampal cortex, and the hippo-
campal formation. The MTL subsystem is implicated in auto-
biographical memory and future simulations. These two subsystems
interact with a midline common core system consisting of the anterior
medial prefrontal cortex and the PCC, which is typically activated
during the processing of information regarding the self. The MTL and
the dmPFC subsystems interact and communicate with the midline core
system to facilitate the constitution of mental representations of
personally significant life events.
Perceiving and inferring the emotional status of others is one of the
most important factors in phobia. A recent review on the DMN and
social understanding of others by Li et al. (2014) proposed the crucial
role of the MTL subsystem in emotion perception processes. It has been
postulated that the DMN makes sensory inputs meaningful as “situated
conceptualizations” for distinct emotions because the DMN recon-
stitutes past experiences for use in the present (Lindquist et al., 2012).
The vmPFC, as part of the DMN, is understood to receive reinforcement
expectancy information through stimulus-reinforcement learning pro-
cesses (Blair, 2007; Li et al., 2014). Therefore, vmPFC might play a
pivotal role in the anticipatory processes of SAD and PD with agor-
aphobia. Agoraphobia is characterized by a phobic anxiety in situations
where escape can be difficult or embarrassing, and is highly comorbid
with PD. Because most previous imaging studies lack information on
the coincidence of agoraphobia, there is very little evidence for the
neural networks specific to agoraphobia (Wittmann et al., 2014). The
neural substrate underpinnings of panic disorder with comorbid agor-
aphobia might be quite different from those underlying panic disorder

Fig. 1. Medial and lateral view of the altered brain net-

works consistently observed in resting-state fMRI studies of
in panic disorder (PD) and social anxiety disorder (SAD).
Green areas represent the overlap altered network between
PD and SAD (default mode network: ventromedial pre-
frontal cortex, perigenual anterior cingulate cortex, and
precuneus/posterior cingulate cortex). Red areas represent
the regions of increased connectivity only in SAD (salience
network: dorsal anterior cingulate cortex, anterior insula,
and amygdala). Blue areas represent the regions of in-
creased connectivity only in PD (sensorimotor network:
precentral and postcentral gyrus). (For interpretation of
the references to colour in this figure legend, the reader is
referred to the web version of this article.)
Medial view Lateral view

4
Y.-K. Kim, H.-K. Yoon
without phobic avoidance. Thus, this vmPFC alteration could be asso-
ciated with agoraphobia rather than with the panic attack itself (Na
et al., 2013). Although to date there is no existing research on resting-
state connectivity in SP, it should be noted that consistent results have
been reported regarding the role of the cingulate cortex, the prefrontal,
and the orbitofrontal cortices in SP neuroimaging studies. Taken to-
gether, these findings provide a basis for the hypothesis that alterations
in the MTL subsystem are a hallmark of at least some common forms of
PD and phobias.
5. DMN and serotonin
Alterations in DMN might be due to dysfunction in various neuro-
transmitter systems, and the serotonergic system is assumed to be a key
system for these alterations. Impaired serotonin (5-HT) synthesis in the
central nervous system had been observed in molecular investigations
on the pathogenesis of anxiety disorders (Kotting et al., 2013; Lee and
Meltzer, 2001). There was a large amount of evidence for a genetic
predisposition to PD and SAD (Gottschalk and Domschke, 2016; Yoon
et al., 2008). Recent evidence also suggested a relationship between
inflammatory and immunological parameters, serotonin levels, and
panic symptoms (Kim and Kim, 2016; Zepf and Stewart, 2016). Several
5-HT receptor subtypes showed considerable spatial overlap with the
DMN (Saulin et al., 2012). The influence of 5-HT on the DMN was the
subject of various previous studies. The core DMN regions are in-
nervated by serotonergic neurons from the midbrain raphe nuclei
(Michelsen et al., 2007). The work of Hahn et al. (2012) proposed a key
role for serotonin 1-A receptors in DMN modulation. A rsfMRI study
reported acute tryptophan depletion-induced mood changes and DMN
connectivity alterations in certain subjects (Kunisato et al., 2011). A
pharmacological fMRI study showed that escitalopram, which is a ser-
otonin reuptake inhibitor intended to treat generalized anxiety dis-
order, decreased DMN regional pairwise connectivity. A recent fMRI
study demonstrated that platelet maximal 5-HT uptake velocity pre-
dicted global DMN activation (Scharinger et al., 2014). This finding
suggested a pivotal role for neuronal 5-HT reuptake in DMN regulation.
In addition, it has been shown that selective serotonin reuptake in-
hibitors and serotonin-norepinephrine reuptake inhibitors modulated
DMN connectivity (van de Ven et al., 2013; van Wingen et al., 2014).
Along with the serotonin, endogenous opioids play a pivotal role in
PD and anxiety disorders (Graeff, 2017). Endogenous opioids deficit
results in heightened sensitivity to suffocation and separation anxiety in
panic patients. Experimental results indicate that serotonin interacts
synergistically with endogenous opioids in the dorsal periaqueductal
gray through 5-HT1A and μ-opioid receptors to inhibit proximal de-
fense and, supposedly, panic attacks (Roncon et al., 2013). Further
study regarding endogenous opioids and resting state brain con-
nectivity can shed lights on the role of opioids in anxiety disorders.
6. Sensorimotor network and panic attacks
Panic attacks consist of the rapid onset of intense anxiety, with
prominent somatic symptoms, such as chest tightness, palpitations,
abdominal discomfort, and dizziness. Neural correlates of panic attacks
on a state level might be distinct from those of trait anxiety, such as
anticipatory anxiety. Sensory-related regions are connected with limbic
areas to manage one's oversensitivity to an unknown fear. Inadequate
control due to dysfunction of these areas may cause abnormally high
interoceptive sensitivity and somatosensory stimulus processing, which
may eventually lead to panic attacks. Alterations of the precentral gyrus
(a motor region) associated with anxiety and PD have been mentioned
in several early studies. In a previous study, a pentagastrin challenge
test (anticipated to provoke the symptoms of a panic attack) demon-
strated hypoactivity of the precentral gyrus (Boshuisen et al., 2002). A
single-photon emission computed tomography (SPECT) study also de-
monstrated that cognitive behavioral therapy was associated with
5
Progress in Neuropsychopharmacology & Biological Psychiatry xxx (xxxx) xxx–xxx
increased regional cerebral blood flow in the precentral as well as the
postcentral gyrus (Seo et al., 2014). A structural study showed residual
gray matter deficits in the precentral gyrus (even following remission)
under antidepressant treatment (Lai and Wu, 2013). These findings
suggested that precentral alteration might be a trait marker and un-
derlying pathophysiology in PD. Two recent studies using whole-brain
rsFC analysis also supported this hypothesis regarding the significance
of network alterations (Cui et al., 2016; Lai and Wu, 2016). Motor area
responses in PD might have negative feedback for persistently high
interoceptive sensitivity. Therefore, an aberrant sensory-motor area
network might be a marker of vulnerability for panic attacks, as op-
posed to the PD itself (Fig. 1).
7. Salience network and amygdala-frontal connectivity in social
anxiety disorder
Besides DMN alterations, SN connectivity and amygdala-frontal al-
terations are also consistently reported in SAD (Fig. 1). The SN is
generally comprised of core regions including the bilateral AI and the
dACC, and is readily identified using ICA analysis of rsfMRI data (Seeley
et al., 2007). Apart from these core regions, other limbic areas in-
cluding the amygdala, ventral striatum, dorsomedial thalamus, hy-
pothalamus and ventral tegmental area extending toward the temporal
pole are also often reported as part of this network. The SN plays an
important role in saliency detection and amplification, as well as in
enhancing access to resources once a salient event has been detected.
The SN also plays a pivotal role in switching between externally-or-
iented and internally-oriented brain networks (Sridharan et al., 2008).
This set of regions is important for detecting errors, response selection,
and conflict monitoring (Botvinick et al., 2004). People with high trait
anxiety and anxiety disorders general show a similar pattern of SN
dysfunction (Sylvester et al., 2012). Subjects with high trait anxiety
may make more errors in trials involving response conflict relative to
healthy controls in tasks that use non-emotional stimuli (Basten et al.,
2011). Among the core regions of the SN, the dACC is implicated in the
affective processing of negative information in SAD patients (Amir
et al., 2005). This area also has been associated with self-focused at-
tention (Lemogne et al., 2012). Therefore, we hypothesize that in-
creased connectivity in the SN is necessary for balancing and resolving
limbic hyperactivity. Alternatively, increased connectivity in the dACC
may be due to repeated and sustained higher vigilance and alertness in
SAD patients.
Abnormal functional connectivity involving the amygdala and a
lower part of the PFC known as the orbitofrontal area has also been
consistently observed in SAD. The orbitofrontal cortex (OFC) plays a
crucial role in the modulation of fear via the amygdala (Rosenkranz and
Grace, 2002). Studies investigating emotional processing using pictorial
or conditioned stimuli showed increased amygdala reactivity in anxiety
disorder patients (Hariri et al., 2002; Monk et al., 2008). This amygdala
hyperactivity has been suggested to be inversely related to orbitofrontal
reactivity during the suppression of negative emotions (Phan et al.,
2005). White matter deficits of the OFC–amygdala connection were
shown in SAD patients (Phan et al., 2006). However, alterations of the
OFC might not be specific to SAD considering similar findings in other
psychiatric disorders (Jackowski et al., 2012). Structural and functional
OFC abnormalities have been reported in PD as well (Bystritsky et al.,
2001; Na et al., 2013). Reduced regional cerebral blood flow (rCBF) has
been observed in the right OFC during unexpected panic attacks in a
panic provocation study (Kent et al., 2005). Therefore, alterations of
amygdala-frontal connectivity seem to be a common pathomechanism
of phobic disorders, rather than a special characteristic that appears
only in SAD. Additional rsfMRI research is needed to understand the
role of amygdala-OFC connectivity in anxiety disorders.
Y.-K. Kim, H.-K. Yoon
8. Future directions and conclusion
This review summarized the current status of research that utilized
rsfMRI to examine alterations in rsFC in brain networks of patients with
PD and SAD. Although there are concerns about the small sample size of
relevant populations within the existing literature, together with an
insufficient amount of literature to draw inferences from and replicate
these network alterations, emerging studies have yielded some con-
sistent findings. Research on resting-state brain activity using fMRI
holds great promise as a method to elucidate the neurobiological un-
derpinnings of psychiatric disorders. Because rsfMRI is easy to acquire
and does not depend on cognitive tasks, reliable and stable results can
be obtained with this approach. Moreover, the method is well suited for
pediatric and cognitively impaired subjects for whom the performance
of task-based functional MR imaging is difficult. Accordingly, rsfMRI
has become a common technique in clinical research studies and stands
to play a vital role in the development of novel imaging biomarkers.
However, our understanding of the functional and clinical relevance of
aberrant patterns of functional connectivity remains poorly defined.
Furthermore, it is unclear how to interpret altered RSNs as a function of
disease, recovery, and treatment. Studies based on rsfMRI will be more
meaningful with increased understanding of the underlying neurophy-
siological correlates. Recent investigations, therefore, have begun to
combine rsfMRI with other imaging techniques (e.g., diffusion tensor
imaging (DTI)) or electrophysiological methods (e.g., electro-
encephalography (EEG) or magnetoencephalography (MEG)). The work
of Kirino et al. (2016) conducted a simultaneous EEG and rsfMRI re-
cording study to evaluate FC within and outside the DMN in schizo-
phrenia patients. The work of Sui et al. (2011) proposed a multimodal
canonical correlation analysis and joint ICA model to fuse fMRI and DTI
data for classification of schizophrenia and bipolar disorders. It would
be useful to combine rsfMRI and DTI methods to investigate both
functional and structural connectivity. Emerging imaging-genetics ap-
proaches using rsfMRI techniques also stand to be a great complement
to existing efforts to reveal the pathogenesis of psychiatric disorders at
neuronal and genetic levels. The work of Yang et al. (2010) demon-
strated a hybrid machine learning method to combine fMRI and ge-
netics data for automatic recognition of schizophrenia patients relative
to healthy controls. More work is needed to determine whether
rsfMRI—either alone or in combination with other measures of brain
connectivity (e.g. structural connectivity)—meets biomarker standards
for diagnosis.
Although rsfMRI has the advantage of obtaining stable and reliable
results, there are still discrepancies in findings across studies, and even
within the existing studies. These discrepancies may be due to diag-
nostic complexity and methodological differences. It remains unclear
how to interpret altered functional connectivity in resting states in PD
and SAD, and its involvement in their symptomatology is complex. The
phenomenological complexity of categorical approaches of the diag-
nostic system results in substantial overlap between psychiatric dis-
orders (Insel et al., 2010). Transdiagnostic dimensional approaches
(e.g., using measures of trait anxiety) or subphenotype determination of
discrete psychiatric disorders will help to identify underlying neural
pathomechanisms that are potentially unique. Multicenter studies with
larger samples are needed to better clarify the role and the nature of
functional connectivity alterations in psychiatric disorders. Further-
more, several different approaches have been used in rsfMRI analysis.
The most common methods are seed-based and ICA approaches. Seed-
based approaches are relatively simple and are more suitable for re-
search on resting fMRI data in adults because the ROIs are well defined
by many investigators. ICA can be used to spatially identify distinct
resting-state brain networks. Compared to seed-based methods, ICA has
the advantage of requiring few a priori assumptions. A multi-approach
analysis, integrating large-scale network connectivity analyses and
more localized connectivity methods, should be encouraged with the
aim of establishing a comprehensive view of resting-state functional
6
Progress in Neuropsychopharmacology & Biological Psychiatry xxx (xxxx) xxx–xxx
connectivity. This type of approach might facilitate increased re-
producibility in findings. Graph-based analysis also provides a distinct
alternative to seed-based analyses and ICA (Fair et al., 2009; Salvador
et al., 2005; van den Heuvel et al., 2008).
This article reviewed recent studies on brain connectivity using
rsfMRI methods in patients with PD and SAD. The reviewed studies
suggest that PD and SAD have both common and distinct neural net-
works. Common alterations involve aberrant connectivity in the DMN.
Among DMN systems, the MTL subsystem is closely related to the
common psychopathology of PD and phobias. In contrast, PD is more
closely linked to interoceptive pathways involving the sensorimotor
cortex. Salience network connectivity is more prominent in SAD.
Identifying these common and distinctive aspects of resting-state brain
connectivity helps to assemble phenotypically heterogeneous phobic
disorders into more meaningful subgroups. This work, in turn, will
elucidate underlying mechanisms and biomarkers of existing and novel
therapeutic interventions.
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