978284 ANP ANZJP ArticlesTan et al.

Research

Australian & New Zealand Journal of Psychiatry

Decreased integration of the 2021, Vol. 55(6) 577­–587

https://doi.org/10.1177/0004867420978284
DOI: 10.1177/0004867420978284

frontoparietal network during a © The Royal Australian and

New Zealand College of Psychiatrists 2020

working memory task in major Article reuse guidelines:

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depressive disorder

Editor’s Choice
Wenjian Tan1,2, Zhening Liu1,2, Chang Xi1,2, Mengjie Deng1,2,
Yicheng Long1,2, Lena Palaniyappan3,4,5 and Jie Yang1,2

Abstract
Background: Working memory deficits are a common feature in major depressive disorder and are associated with
poor functional outcomes. Intact working memory performance requires the recruitment of large-scale brain networks.
However, it is unknown how the disrupted recruitment of distributed regions belonging to these large-scale networks
at the whole-brain level brings about working memory impairment seen in major depressive disorder.
Methods: We used graph theory to examine the functional connectomic metrics (local and global efficiency) at the
whole-brain and large-scale network levels in 38 patients with major depressive disorder and 41 healthy controls during
a working memory task. Altered connectomic metrics were studied in a moderation model relating to clinical symptoms
and working memory accuracy in patients, and a machine learning method was employed to assess whether these met-
rics carry enough illness-specific information to discriminate patients from controls.
Results: Global efficiency of the frontoparietal network was reduced in major depressive disorder (false discovery
rate corrected, p = 0.014); this reduction predicted worse working memory performance in patients with less severe
illness burden indexed by Brief Psychiatric Rating Scale (β =–0.43, p = 0.035, t =–2.2, 95% confidence interval = [–0.043,–
0.002]). We achieved a classification accuracy and area under the curve of 73.42% and 0.734, respectively, to dis-
criminate patients from controls based on connectomic metrics, and the global efficiency of the frontoparietal network
contributed most to the diagnostic classification.
Conclusions: We report a putative mechanistic link between the global efficiency of the frontoparietal network and
impaired n-back performance in major depressive disorder. This relationship is more pronounced at lower levels of
symptom burden, indicating the possibility of multiple pathways to cognitive deficits in severe major depressive disorder.

Keywords
Major depressive disorder, functional connectome, global efficiency, frontoparietal, working memory

Introduction 1
 epartment of Psychiatry, The Second Xiangya Hospital of Central
D
South University, Changsha, China
Major depressive disorder (MDD), characterized by low 2
National Clinical Research Center for Mental Disorders, The Second
self-esteem, loss of interest in normally enjoyable activi- Xiangya Hospital of Central South University, Changsha, China
3
Department of Psychiatry, University of Western Ontario, London,
ties and low energy, is the second largest cause of disabil-
ON, Canada
ity worldwide. In addition to mood changes, notable 4
Robarts Research Institute, University of Western Ontario, London,
neurocognitive impairments also occur in patients with ON, Canada
MDD (Ahern and Semkovska, 2017), affecting a large 5
Lawson Health Research Institute, London, ON, Canada
number of cognitive domains including processing speed,
Corresponding author:
learning and memory. Neurocognitive impairments predict Jie Yang, Department of Psychiatry, The Second Xiangya Hospital of
poor response to treatment (Roiser et al., 2011), and ‘cog- Central South University, Changsha 410011, Hunan, China.
nitive remission’ is increasingly discussed as a therapeutic Email: yang0826@csu.edu.cn

Australian & New Zealand Journal of Psychiatry, 55(6)

578
target to improve functioning and prevent relapses in MDD
(Bortolato et al., 2016).
Of the various neurocognitive deficits, working memory
(WM) deficits, the failure to represent, maintain and update
information in a short term (Baddeley, 1992), have been
observed both in acute depression and in a proportion of
patients after remission from psychopathological symp-
toms (Reppermund et al., 2009). Patients with MDD exhibit
delayed reaction time accompanied by reduced accuracy of
WM performance when compared with healthy controls
(HCs) (Rose and Ebmeier, 2006). Such WM deficits sig-
nificantly correlate with the number of hospitalizations and
the longitudinal course of the depressive illness (Harvey
et al., 2004).
Previous studies investigating the neurobiological
mechanism of impaired WM in MDD implicate extensive
brain regions. Patients with MDD display abnormal pre-
frontal, parietal, temporal, occipital and subcortical activa-
tion during WM tasks (Wang et al., 2015; Yuksel et al.,
2018). This pattern indicates an aberration in the co-activa-
tions of diverse regions, related to aberrant pattern of large-
scale information-processing networks that underwrite task
performance. For example, the failure to suppress the
default-mode network (DMN) (Bartova et al., 2015) and
the hypoconnectivity of the frontoparietal network (FPN)
has been observed in patients with MDD during WM pro-
cessing (Vasic et al., 2009). As a flexible hub of cognitive
control (Zanto and Gazzaley, 2013), FPN plays a crucial
role in the top-down modulation of attention preparation
and orientation during WM processing (Wallis et al., 2015),
and the integrity of its microstructural connectivity seems
to predict WM performance (Burzynska et al., 2011).
Relevant to this work, mounting evidence suggests a prom-
inent role for both cingulo-opercular (Huang et al., 2020)
and FPN abnormalities in the WM deficits of MDD (Vasic
et al., 2009; Yuksel et al., 2018).
Many previous studies that explored the neuroimaging
correlates of the WM deficits in MDD have failed to study
task-related disruptions that occur at a more systemically
organized connectomic level. Nevertheless, the functional
connectome topology has been acknowledged to be critical
for understanding clinical symptoms (Gong and He, 2015),
on one hand, and cognitive impairment (Sheffield et al.,
2017), on the other, as system-level disruptions are more
sensitive markers of emergent functions such as cognition
and behavior (Bullmore and Sporns, 2012). We have previ-
ously employed graph theory and reported a mechanistic
link between connectome topology and impaired n-back
performance in schizophrenia and bipolar disorder (Yang
et al., 2020a, 2020b), and further found the moderating
effect of connectome properties on the relationship between
clinical symptoms and WM performance. In fact, irrespec-
tive of the diagnosis, the severity of certain psychiatric
symptoms such as lack of motivation, apathy and anhedo-
nia (negative symptoms as determined by Brief Psychiatric
Australian & New Zealand Journal of Psychiatry, 55(6)
ANZJP Articles
Rating Scale [BPRS]) relates to cognitive dysfunction (Zhu
et al., 2019). In other words, lack of effort may occur in the
presence of high symptom severity, affecting WM perfor-
mance, while in the presence of low symptom burden, an
extensive connectomic disruption may be required to pro-
duce the same degree of WM deficits. We tested the hypoth-
esis that the relationship between clinical symptom burden
and WM performance in MDD is moderated by task-related
connectome properties.
The human brain appears to possess a high efficiency for
information transfer to adapt to a complicated and change-
able environment (Bullmore and Sporns, 2012). We assess
whether putative measures of this information transfer effi-
ciency are altered in patients with MDD during WM pro-
cessing. In network science, ‘local efficiency’ and ‘global
efficiency’ are the most intuitive network properties to
measure the information transfer efficiency. Local effi-
ciency denotes the mean local efficiency of information
transfer in the immediate neighborhood of each node or the
fault tolerance of a network in terms of local information
processing (Latora and Marchiori, 2001), and global effi-
ciency denotes the overall capacity for parallel information
transfer and integrated processing (Bullmore and Sporns,
2012). The associations between global and local efficiency
with cognition have been highlighted in previous studies
(Sheffield et al., 2015), and it has been reported that patients
with MDD showed altered global and local efficiency of
the whole-brain and large-scale networks in both resting-
state studies (Meng et al., 2014; Wang et al., 2017) and
when performing tasks involving emotion processing (Park
et al., 2014). However, it is unclear whether the functional
connectomic metrics are aberrant when performing a WM
task in patients with MDD.
This study aimed to investigate the functional connec-
tome of patients with MDD during WM performance. To
this end, we constructed weighted networks from 2-back
WM functional magnetic resonance imaging (fMRI) data.
Given our prior observation of bipolar depression and the
prior reports from other groups using resting-state fMRI
studies (Meng et al., 2014; Wang et al., 2017), we expected
reduced global but increased local efficiency in MDD. This
pattern would indicate a reduced connectome-level integra-
tion but an increased network-level segregation affecting
task performance. Given the critical role of frontoparietal
and cingulo-opercular networks in the n-back task, we also
hypothesized that the changes in connectomic properties
will specifically involve these networks. We also explored
whether clinical symptoms were associated with WM per-
formance and whether this relationship will be influenced
by altered global and local efficiency of brain networks.
Finally, we employed a Support Vector Machine (SVM)
approach to test whether the topological metrics from WM
fMRI data carry sufficient illness-specific information to
discriminate the patterns observed in a patient with MDD
from that of controls.
Tan et al. 579

Table 1. Demographic, neuropsychological and behavioral data.

Patients with MDD HCs t/χ2 p

(n = 38) (n = 41)
Age (years) 27.3 ± 6.4 25.5 ± 4.6 1.4 0.17

Gender (M/F) 24/14 20/22 1.94 0.16

Education (years) 12.8 ± 3.2 14.7 ± 2.5 −2.85 0.006*

Illness duration (months) 45.17 ± 67.68 N/A N/A N/A

Treat duration (days) 24.49 ± 59.70 N/A N/A N/A

HAMD 20.46 ± 4.46 N/A N/A N/A

HAMA 16.22 ± 8.03 N/A N/A N/A

BPRS 29.30 ± 6.12 N/A N/A N/A

WAIS_information 17.7 ± 6 21.3 ± 5.1 −2.75 0.007*

WAIS_digit_Sym 74 ± 18.2 91.1 ± 15.1 −4.4 < 0.001*

Target_ACC_2back (%) 65.6 ± 21.8 75.9 ± 17.4 −2.2 0.032*

Target_ACC_0back (%) 88.6 ± 15.2 91 ± 17.7 −0.54 0.59

Target_RTC_2back (ms) 705.34 ± 200.9 673.59 ± 145.78 0.76 0.45

Target_RTC_0back (ms) 517.03 ± 102.04 500.96 ± 107.39 0.64 0.52

MDD, major depressive disorder; HC, healthy control; n, number; HAMD, 17-item Hamilton Depression Rating Scale; HAMA, Hamilton Anxiety
Rating Scale; BPRS, Brief Psychiatric Rating Scale; WAIS_information, information subscale of Wechsler Adult Intelligence Scale–Chinese Revised;
WAIS_digit_Sym, digit symbol subscale of Wechsler Adult Intelligence Scale–Chinese Revised; N/A, not available. Target_ACC_2back, mean
accuracy rate of the target under the 2-back load; Target_ACC_0back, mean accuracy rate of the target under the 0-back load; Target_RTC_2back,
mean response time of the target under the 2-back load; Target_RTC_0back, mean response time of the target under the 0-back load.
*p<0.05.

Methods and materials
Participants
All study procedures were approved by the medical ethics
committee of the Second Xiangya Hospital, Central South
University. Before obtaining consent, the capacity to pro-
vide informed consent of all potential participants was
ascertained by two licensed psychiatrists. All participants
were right-handed native Chinese speakers and they were
provided written informed consent for the protocols
approved by the Department of Psychiatry, the Second
Xiangya Hospital of Central South University, China. All
study procedures were conducted in strict accordance with
the Declaration of Helsinki.
The study cohort comprised 48 patients with MDD and
48 HCs matched for age and gender. Patients were confirmed
to meet the DSM-IV (Diagnostic and Statistical Manual of
Mental Disorders, 4th edition) criteria for MDD (First et al.,
1995). Diagnostic procedures include medical history infor-
mation collected from patients and their families, as well as
careful medical, neurological and psychiatric examinations
performed by a clinical psychiatrist. Clinical symptoms were
assessed with the 17-item Hamilton Depression Rating Scale
(HAMD) (Hamilton, 1960), Hamilton Anxiety Rating Scale
(HAMA) (Hamilton, 1959), and the BPRS (John and Overall,
1962) for patients with MDD. Details are presented in Table 1.
Patients with MDD were excluded if they met the following
criteria: (1) aged less than 18 years or greater than 45 years;
(2) previous electroconvulsive therapy and any other con-
traindications to magnetic resonance imaging (MRI); (3) his-
tory of alcohol or substance abuse except nicotine; (4)
chronic neurological disorders or debilitating physical ill-
ness; and (5) benzodiazepine treatment, if any, stopped less
than 24 hours before scanning.
HCs were recruited using the Structured Clinical
Interview for DSM-IV Axis I Disorders, Research Version,
Non-patient Edition (SCID-I/NP). The inclusion and exclu-
sion criteria for HCs were the same as those for patients
except that they did not meet the Diagnostic and Statistical
Manual of Mental Disorders, 5th edition (DSM-5) criteria
for any mental disorders, and their first-degree relatives
had no history of any psychiatric disorders.
All subjects were assessed for cognitive functions with
information and digit symbol subscales of Wechsler Adult

Australian & New Zealand Journal of Psychiatry, 55(6)

580
Intelligence Scale–Chinese Revised (WAIS-CR) (Gong,
1983) to measure verbal comprehension and processing
speed, respectively. Details are presented in Table 1.
MRI data acquisition and preprocessing
All imaging scans were performed on a Philips Achieva 3T
scanner with an 8-channel head coil using gradient-recalled
echo-planar imaging (EPI) pulse sequence. The parameters
are as follows: repetition time (TR) = 2000 ms, echo time
(TE) = 30 ms, flip angle = 90°, field of view (FOV) = 240×
240 mm2, matrix = 64 × 64, slices = 36, slice thickness =
4 mm, gap = 0 mm, and total volumes = 250.
Data preprocessing was carried out using the DPABI
toolbox (Yan et al., 2016). We discarded the first two
images to adjust for magnetic saturation delay, and the
remaining 248 volumes were obtained for further analyses.
The preprocessing procedure includes the following steps:
slice timing correction, head motion realignment, spatial
normalization with the brain template of Montreal
Neurologic Institute (MNI) and smoothing (full width at
half maximum [FWHM] = 8 mm). Nuisance covariates
including 12 head motion parameters, white matter, ventri-
cle signals and temporal derivatives were regressed out.
The global signal was not removed as recent studies have
shown illness-related variance in global signals (Yang
et al., 2014). Displaced volumes (framewise displacement
>0.5 mm) were interpolated by nearest-neighbor interpola-
tion (Power et al., 2012). The exclusion criteria for sample
selection included the following: (1) head motions larger
than a 2.5-mm translation or 2.5° rotation in any direction,
and (2) fMRI data failed to normalize to MNI space, which
is visually inspected by an experienced data analyst. After
quality control, a total of 38 patients with MDD and 41 HCs
were included in the final analysis. We did not detect any
difference in the total number of displaced volumes that
were interpolated in two groups: patients group, mean
(SD) = 17 (21.3); HCs, mean (SD) = 11.6 (13.2); p = 0.18.
Network construction
The WM paradigm adopted in this study comprised ‘0-back’
and ‘2-back’ load conditions: the ‘0-back’ condition, in
which participants pressed a button each time when they
saw the letter ‘x’, and the ‘2-back’ condition, in which par-
ticipants pressed a button when the letter presented was
identical to what they saw two letters prior. Each letter was
displayed for 500 ms with an interstimulus interval of
1500 ms. Each block comprised 20 stimuli containing seven
targets and was preceded by an instruction shown for 2 sec-
onds. During resting periods, subjects were instructed to
fixate on a cross in the center of the screen for 20 seconds.
Stimulation blocks and resting periods alternated within the
experiment with a total of four 2-back and four 0-back
blocks. Each block contains 20 volumes, and therefore, the
Australian & New Zealand Journal of Psychiatry, 55(6)
ANZJP Articles
2-back and 0-back conditions consist of 80 volumes,
respectively. A detailed description of this paradigm is
given in Supplemental S1.
In the construction process of functional connection
matrix, we only concatenated the 80 fMRI volumes
obtained under the four blocks of 2-back performance (He
et al., 2012) in line with our prior works (Yang et al., 2020a,
2020b), for the 0-back is not considered to be a real WM
task. The mean time series was extracted from each of the
264 nodes using 6 mm spheres defined by the Power atlas
(Power et al., 2011). A 264 × 264 symmetric matrix was
generated for each participant by computing the Pearson’s
correlation coefficients between the time series for each
pair of regions of interest (ROIs). The resultant matrix was
converted to normally distributed scores using the Fisher z
transformation, and the variance due to the linear effects of
age, gender and education years was removed to derive the
corrected symmetric matrix. Global and local efficiency
were calculated on a series of weighted adjacency matrices
with different densities, ranging from top 10% to 50% of all
connections, with 2% increments, using scripts from the
Brain Connectivity Toolbox (www.brain-connectivity-tool-
box.net/).
We further parcellated the 264 nodes of the whole brain
into 14 large-scale networks, including ‘auditory’, ‘visual’,
‘cingulo-opercular’, ‘default mode’, ‘dorsal attention’,
‘frontoparietal’, ‘salience network’, ‘sensory/somatomotor
hand’, ‘subcortical network’, ‘ventral attention’, ‘sensory/
somatomotor mouth’, ‘cerebellar’, ‘uncertain’ and ‘mem-
ory retrieval’ (Power et al., 2011). The nodes of each large-
scale networks were isolated, and their global and local
efficiency were separately calculated on a series of weighted
adjacency matrices with different densities. The density
range was the same as that used in the whole-brain analysis
(i.e. 0.1:0.02:0.5). A series of weighted adjacency matrices
corresponding to each network were reconstructed by the
nodes only belonging to that network. Four large-scale net-
works, ‘sensory/somatomotor mouth’, ‘cerebellar’, ‘uncer-
tain’ and ‘memory retrieval’ network, had insufficient
number of nodes to meaningfully calculate sub-graph prop-
erties and thus were excluded from further analysis.
Statistical analysis
Analyses were conducted using SPSS statistical software,
version 22. Group-related differences in demographics, clin-
ical characteristics, WM performances and network proper-
ties were analyzed using a two-sample t-test and χ2 tests. As
network properties were calculated across densities, we first
used functional data analysis (FDA) (Bassett et al., 2012) to
synthesize values across densities. In the FDA, each network
metric curve is treated as a function (y = f (x)), and the sum of
differences in y-values is calculated across densities. It
should be noted that statistical maps of network metrics cal-
culated on all large-scale networks were generated after
Tan et al.
multiple-comparison analysis correction (false discovery
rate [FDR] corrected using the Benjamini–Hochberg method
with p < 0.05).
Exploratory analysis
Moderation analysis. We conducted linear regression analy-
ses to test the association of clinical symptoms, WM per-
formance and network properties. In the linear regression
model, we defined the accuracy of 2-back as the dependent
variable; clinical symptoms including HAMD, HAMA and
BPRS as the predictor; and altered network properties as
the moderator variable.
Machine learning. We extracted all calculated network
properties, including global and local efficiency of the
whole brain and all large-scale networks (a total of 22 fea-
tures) for the subsequent pattern recognition. We used
Least Absolute Shrinkage and Selection Operator (LASSO)
as the feature selection algorithm and then used the Akaike
information criterion (AIC) to find the best fitting model.
Notably, the feature selection procedure was performed
only on the training dataset. Features with non-zero regres-
sion coefficients of the best fitting model were retrieved for
the subsequent classification using the SVM toolkit libsvm
(www.csie.ntu.edu.tw/~cjlin/libsvm/). The kernel function
of the SVM was set as the sigmoid type, cost c = 10, and
other all related parameters were set as default to trade off
learning and extensibility (g = 1/number of all features and
coef = 0). We used the Leave-One-Out Cross-Validation to
evaluate the general performance. The average prediction
accuracy, area under the curve (AUC), true positive rate for
MDD and true positive rate for HCs were calculated to
evaluate the performance. The absolute values of the
regression coefficient of the best fitting model in each
round were summed to evaluate the discriminating ability
of the corresponding features for classification.
Results
Participant characteristics and
WM performance
The demographic and clinical variables are presented in
Table 1. No significant group differences were detected in
age and gender. The patients group was undereducated in
comparison with HCs: patients group, mean (SD) = 12.8
(3.2); HCs, mean (SD) = 14.7 (2.5); p = 0.006. The perfor-
mance of the patients group was worse than that of the HCs
in terms of the WAIS-CR information—patients group,
mean (SD) = 17.7 (6); HCs, mean (SD) = 21.3 (5.1);
p = 0.007; WAIS-CR digit symbol—patients group, mean
(SD) = 74 (18.2); HCs, mean (SD) = 91.1 (15.1); p < 0.001;
and accuracy of 2-back—patients group, mean (SD) = 65.6
(21.8); HCs, mean (SD) = 75.9 (17.4); p = 0.032.
581
Network properties
At the whole-brain level, there were no significant differ-
ences in global efficiency—patients group, mean
(SD) = 0.558 (0.021); HCs, mean (SD) = 0.565 (0.012);
p = 0.065—and local efficiency—patients group, mean
(SD) = 0.757 (0.015); HCs, mean (SD) = 0.756 (0.013);
p = 0.61—between patients with MDD and HCs (see Figure 1
and Table 2).
At the large-scale network level, patients with MDD
showed significant decreased global efficiency in the FPN
under 2-back—patients group, mean (SD) = 0.51 (0.037);
HCs, mean (SD) = 0.53 (0.029); p = 0.0007; p-corrected =
0.014—in comparison with HCs. We did not detect any
group difference in other large-scale networks after FDR
correction (for detailed information about network metrics
of all large-scale networks, see Figure 2 and Table 2) for
global efficiency. None of the examined networks (includ-
ing FPN) had significant changes in local efficiency when
compared with HCs.
Furthermore, examination of the 0-back control condi-
tion revealed that topological changes attributable to simple
attention and motor function during the WM task are rela-
tively small and insignificant (more information in
Supplemental S2 and Table S1).
Exploratory analysis
Moderation analysis. We further assessed whether the
altered global efficiency of the FPN can moderate the
impact of clinical symptoms on WM performance or not.
As shown in Figure 3, the global efficiency of FPN moder-
ated the relationship between BPRS and WM performance
(β =–0.43, p = 0.035, t =–2.2, 95% confidence interval [CI]
= [–0.043, –0.002]). The subscale scores of the BPRS are
presented in Supplemental Table S2. We did not find simi-
lar effect for HAMD and HAMA scores.
Machine learning. We achieved classification results with
average accuracy, AUC, true positive rate for MDD and
true positive rate for HCs of 73.42%, 0.734, 73.7% and
73.2%, respectively. We found that the global efficiency of
the FPN contributed most to the diagnostic classification.
The receiver operating characteristics and the contribution
ratio of each feature in the diagnostic classification are dis-
played in Figure 3 and Supplemental Table S3.
Discussion
To our knowledge, this is the first study to measure the
topology properties of the whole-brain and large-scale net-
works in patients with MDD during WM performance. We
report two key observations. First, compared with HCs,
there is a diminished global efficiency of the FPN in
patients with MDD. Second, in the presence of less severe
Australian & New Zealand Journal of Psychiatry, 55(6)
582
Figure 1. Global and local efficiency of the whole-brain functional connectome calculated on Power atlas in all groups.
The range of densities is 0.1:0.02:0.5.
illness burden as indexed by BPRS, a decrease in global
efficiency of the FPN is associated with decreased WM
accuracy. The results from SVM analysis also indicate that
the interplay between various levels of topological param-
eters carries sufficient illness-specific information relevant
to MDD, and the global efficiency of the FPN contributed
most to the diagnostic classification. Nevertheless, with the
modest classification accuracy, we urge caution in using the
reported connectomic pattern to predict depression at a
single-subject level.
This study denotes a diminished global efficiency of the
FPN in patients with MDD, but no whole-brain topology
alteration was observed. Prior studies have suggested that
WM deficits are common to affective and psychotic ill-
nesses (Lewandowski et al., 2014), and we have reported
altered whole-brain topology in schizophrenia and bipolar
depression during WM processing in our prior work (Yang
et al., 2020a, 2020b). The absence of the whole-brain con-
nectomic deficits in MDD during task performance may
underlie the smaller effect sizes of WM impairments in
MDD compared with the other two mental disorders.
Partially consistent with this study, our prior work has also
reported that the nodes located in FPN showed altered
nodal network metrics in schizophrenia (Yang et al.,
2020b). Combined evidence from the current and our pre-
vious research may suggest that the neurobiological mecha-
nism related to WM impairment across affective and
psychotic illnesses has some overlap at the global level,
with bipolar illness and schizophrenia showing increased
Australian & New Zealand Journal of Psychiatry, 55(6)
ANZJP Articles
local efficiency (segregation) at the whole-brain level,
though in MDD subjects the topological changes were
restricted to FPN.
In addition to our findings, empirical evidence from
resting-state neuroimaging research has highlighted FPN
dysfunction involved in the pathophysiological mecha-
nisms of MDD. A meta-analysis has denoted that MDD was
characterized by hypoconnectivity within the FPN (Kaiser
et al., 2015), and a prior study extended this notion and sug-
gested that the graded disruptions of FPN connectivity
were associated with the presence of affective and psy-
chotic illnesses (Baker et al., 2019). As the flexible hub of
cognitive control (Zanto and Gazzaley, 2013), FPN plays a
crucial role in WM processing, and its microstructure con-
nections can predict the WM performance (Burzynska
et al., 2011). Neural components that composed the FPN,
such as dorsolateral prefrontal cortex (DLPFC), parietal
cortex and anterior cingulate cortex (ACC), have shown
their WM-related abnormal activation (Fitzgerald et al.,
2008; Harvey et al., 2005; Matsuo et al., 2007), and the
hypoconnectivity within the FPN has also been observed in
MDD during WM processing (Vasic et al., 2009). This
study adds to this literature by revealing significantly
reduced global efficiency of FPN in MDD during WM
performance.
There is a theory suggesting that transient, flexible coor-
dination across distal brain regions and networks (i.e. net-
work integration) is necessary for complex cognition (Fries,
2005). Consistent with this theory, previous studies have
Tan et al. 583

Table 2. Topology properties of functional connectome under the 2-back condition.

Measures Patients with MDD HCs p-value p-corrected t

Whole brain
Global efficiency 0.558 (0.021) 0.565 (0.012) 0.065 0.24 −1.87
Local efficiency 0.757 (0.015) 0.756 (0.013) 0.61 0.75 0.5

AN
Global efficiency 0.46 (0.046) 0.48 (0.036) 0.025 0.2 −2.29
Local efficiency 0.55 (0.06) 0.55 (0.054) 0.8 0.85 −0.25

CON
Global efficiency 0.47 (0.045) 0.49 (0.034) 0.21 0.46 −1.27
Local efficiency 0.57 (0.06) 0.59 (0.07) 0.22 0.46 −1.24

DMN
Global efficiency 0.56 (0.03) 0.57 (0.027) 0.11 0.35 −1.6
Local efficiency 0.75 (0.036) 0.75 (0.032) 0.24 0.46 −1.2

DAN
Global efficiency 0.45 (0.041) 0.47 (0.036) 0.06 0.24 −1.9
Local efficiency 0.53 (0.048) 0.5 (0.07) 0.054 0.24 1.96

FPN
Global efficiency 0.51 (0.037) 0.53 (0.029) 0.0007 0.015* −3.54*
Local efficiency 0.66 (0.049) 0.67 (0.035) 0.14 0.39 −1.5

SN
Global efficiency 0.5 (0.034) 0.5 (0.038) 0.58 0.75 0.55
Local efficiency 0.61 (0.047) 0.62 (0.044) 0.85 0.85 −0.19

SSHN
Global efficiency 0.53 (0.038) 0.54 (0.03) 0.31 0.52 −1.03
Local efficiency 0.71 (0.037) 0.71 (0.032) 0.47 0.73 −0.73

SBN
Global efficiency 0.47 (0.034) 0.48 (0.03) 0.027 0.2 −2.26
Local efficiency 0.54 (0.055) 0.54 (0.048) 0.84 0.85 0.2

VAN
Global efficiency 0.43 (0.04) 0.43 (0.04) 0.6 0.75 −0.5
Local efficiency 0.43 (0.08) 0.42 (0.07) 0.5 0.73 0.67

VN
Global efficiency 0.53 (0.027) 0.53 (0.03) 0.7 0.81 0.39
Local efficiency 0.69 (0.028) 0.68 (0.03) 0.25 0.46 1.2

MDD, major depressive disorder; HC, healthy control; AN, auditory network; CON, cingulo-opercular network; DMN, default-mode network;
DAN, dorsal attention network; FPN, frontoparietal network; SN, salience network; SSHN, sensory somatomotor hand network; SBN, subcortical
network; VAN, ventral attention network; VN, visual network.
*p-corrected<0.05.

revealed that integration across distinct regions is critical
for the higher order cognitive functions, such as WM
(Cohen and D’Esposito, 2016), whereas the increased seg-
regation appears critical for motor execution (Cohen and
D’Esposito, 2016). Healthy individuals showed increased
integration during WM processing (Cohen and D’Esposito,
2016) and increased integration associated with better
behavioral performance. Furthermore, previous associa-
tions have been found between FPN efficiency and cogni-
tion (Sheffield et al., 2015). The decreased global efficiency

Australian & New Zealand Journal of Psychiatry, 55(6)

584
Figure 2. Global and local efficiency of large-scale networks calculated on Power atlas in all groups. The range of densities is
0.1:0.02:0.5, and symbol ‘*’ represents p-corrected <0.05.
AN, auditory network; CON, cingulo-opercular network; DMN, default-mode network; DAN, dorsal attention network; FPN, frontoparietal
network; SN, salience network; SSHN, sensory somatomotor hand network; SCN, subcortical network; VAN, ventral attention network; VN, visual
network.
observed in patients with MDD may indicate that a portion
of distal connections are broken down, which may follow
with previous studies documenting the hypoconnectivity of
distal regions (e.g. the inferior parietal cortex and superior
prefrontal areas) of the FPN network in patients with MDD
during WM performance (Vasic et al., 2009). This hypoc-
onnectivity may arise due to failure of co-activation of dis-
tal regions. WM-related abnormal activation of the neural
components within FPN has a considerable heterogeneous
pattern (Wang et al., 2015); in other words, frontal hyperac-
tivation may relate to parietal hypoactivation. Therefore,
these constellations may form a chain of evidence that
highlights WM-related aberrant activation, connectivity
and altered connectomic properties of the FPN in the MDD.
The global efficiency of FPN moderated the relationship
between BPRS and WM performance. In the presence of
lower BPRS scores, we observed an association between
decreased global efficiency of the FPN and decreased WM
accuracy. We did not see the same effect with HAMD
scores, indicating that the distinct features such as psy-
chotic symptoms captured by BPRS may mediate this rela-
tionship. This observation speaks to two important
mechanistic inferences. First, if global efficiency is consid-
ered the physiological index of effortful integration under-
writing WM accuracy, then patients with lower symptom
burden (i.e. non-psychotic MDD) could increase WM accu-
racy to near-normal levels by making more physiological
effort. On the contrary, this may not be possible in those
who are more severely unwell, especially with psychotic
Australian & New Zealand Journal of Psychiatry, 55(6)
ANZJP Articles
symptom burden. Second, when there are more severe
symptoms, especially of psychotic nature, multiple net-
works in addition to FPN may operate to affect cognition in
MDD.
Brain stimulation tools, including repetitive transcranial
magnetic stimulation (rTMS) and transcranial direct cur-
rent stimulation (tDCS), have documented their effect on
brain network regulation and can interfere with WM per-
formance (Lee and D’Esposito, 2012; Sandrini et al., 2012).
Selection of target location is also a knotty issue in brain
stimulation treatment; our findings suggest that the FPN is
a promising candidate network target. However, it must be
noted that the FPN covers extensive regions of the brain;
choosing a single node such as the DLPFC may bring about
the desired changes in all cases. Connectivity-guided target
selection within FPN may help personalize non-invasive
approaches for cognitive remission in MDD (Iwabuchi
et al., 2019).
This study has several limitations. First, the total num-
ber of included subjects was relatively small, which might
limit the general applicability of our findings. Further
research with larger sample size is needed to probe the rela-
tionship between WM performance and network proper-
ties. Second, although the n-back paradigm strongly recruits
WM, the version used in our study did not contain different
WM loads for us to examine the distinctive reorganization
of brain networks in patients with MDD and HCs with load
increased. Future investigations using more sophisticated
paradigm are needed to parse the network structure of
Tan et al. 585

Figure 3. Exploratory analysis results. (A) The moderating model of the FPN global efficiency on the relation of BPRS and
WM performance. (B) The receiver operating characteristics of the machine learning analysis. (C) The contribution ratio of all
features to the diagnostic classification. There were seven features that did not involve in the diagnostic clarification as their
contribution ratio was zero: GE of the CON, GE of the DMN, GE of the DAN, LE of the FPN; LE of the SSHN, GE of the VAN
and GE of the VN.

FPN_GE: global efficiency of the frontoparietal network; WBN, whole-brain network; AN, auditory network; CON, cingulo-opercular network;
DMN, default-mode network; DAN, dorsal attention network; FPN, frontoparietal network; SN, salience network; SSHN, sensory somatomotor
hand network; SCN, subcortical network; VAN, ventral attention network; VN, visual network; LE, local efficiency; GE, global efficiency.

patients with MDD under different WM loads. Third, the
education level was not matched between patients with
MDD and HCs. Nevertheless, we have treated education
years as a covariance factor to exclude its effect, and all
network properties were generated on the corrected sym-
metric matrix.
In this study, we report the decreased integration of the
FPN in patients with MDD during WM, and the findings of
our moderation model revealed that in the presence of less
illness burden, increases in integration may be a viable pre-
cognition option. In this sense, the treatment strategies
toward WM deficits should be precisely designed on the
current clinical symptom status of patients with MDD. For
patients with less illness burden, cognitive strategies that
increase global efficiency may be a feasible precognitive
option. Brain stimulation tools that affect global efficiency
need to be evaluated for precognitive benefits in MDD with
less illness burden. Encouraging preliminary results have
been achieved in this regard (Oliveira et al., 2013).
Author Contributions
W.T. drafted the article. Z.L. helped with the conception and
design, and revised the article. C.X., M.D. and Y.L. helped with
acquisition of data. L.P. interpreted the results and drafted and
revised the article. J.Y. analyzed the data and drafted and revised
the article.
Data Availability Statement
The data that support the findings of this study are available on
request from the corresponding author. The data are not publicly
available due to privacy or ethical restrictions.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship and/or publication of this
article: L.P. reports personal fees from Otsuka Canada, SPMM
Course Limited, UK, Canadian Psychiatric Association; book
royalties from Oxford University Press; and investigator-initiated
educational grants from Janssen Canada, Sunovion and Otsuka

Australian & New Zealand Journal of Psychiatry, 55(6)

586
Canada outside the submitted work. All authors report no biomed-
ical financial interests or potential conflicts of interest.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship and/or publication of this article: This
work was supported by the China Precision Medicine Initiative
(2016YFC0906300 to Z.L.), the National Natural Science
Foundation of China (81561168021 to Z.L.) and the Fundamental
Research Funds for the Central Universities of Central South
University (2019zzts813 to W.T.). L.P. acknowledges the support
of Tanna Schulich endowment.
ORCID iDs
Lena Palaniyappan https://orcid.org/0000-0003-1640-7182
Jie Yang https://orcid.org/0000-0001-7561-9076
Supplemental Material
Supplemental material for this article is available online.
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