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Received: 30 April 2021    Revised: 8 August 2021    Accepted: 25 September 2021

DOI: 10.1002/jnr.24979

RESEARCH ARTICLE

Functional and structural alterations in the pain-­related circuit

in major depressive disorder induced by electroconvulsive
therapy

Ting Zhang1,2,3 | Qiangqiang Hou1,2,3 | Tongjian Bai1,2,3  | Gongjun Ji1,2,3 |

Huaming Lv1,2,3 | Wen Xie4 | Shengchun Jin4 | Jinying Yang5 | Bensheng Qiu5 |
Yanghua Tian1,2,3,6  | Kai Wang1,2,3,6,7

1
Department of Neurology, The First
Affiliated Hospital of Anhui Medical Abstract
University, Hefei, China Approximately two-­thirds of major depressive disorder (MDD) patients have pain,
2
Anhui Province Key Laboratory of
which exacerbates the severity of depression. Electroconvulsive therapy (ECT) is
Cognition and Neuropsychiatric Disorders,
Hefei, China an efficacious treatment that can alleviate depressive symptoms; however, treat-
3
Collaborative Innovation Center of ment for pain and the underlying neural substrate is elusive. We enrolled 34 patients
Neuropsychiatric Disorders and Mental
Health, Hefei, China
with MDD and 33 matched healthy controls to complete clinical assessments and
4
Anhui Mental Health Center, Hefei, China neuroimaging scans. MDD patients underwent second assessments and scans after
5
Center for Biomedical Engineering, ECT. We defined a pain-­related network with a published meta-­analysis and calcu-
University of Science and Technology of
lated topological patterns to reveal topologic alterations induced by ECT. Using the
China, Hefei, China
6
Institute of Artificial Intelligence, Hefei amplitude of low-­frequency fluctuations (ALFFs), we probed local function aberra-
Comprehensive National Science Center, tions of pain-­related circuits in MDD patients. Subsequently, we applied gray matter
Hefei, China
7 volume (GMV) to reveal structural alterations of ECT relieving pain. The relation-
School of Mental Health and Psychological
Sciences, Anhui Medical University, Hefei, ships between functional and structural aberrations and pain were determined. ECT
China
significantly alleviated pain. The neural mechanism based on pain-­related circuits
Correspondence indicated that ECT weakened the circuit function (ALFF: left amygdala and right sup-
Yanghua Tian and Kai Wang, Department
plementary motor area), while augmenting the structure (GMV: bilateral amygdala/
of Neurology, The First Affiliated Hospital
of Anhui Medical University, Hefei, Anhui, insula/hippocampus and anterior cingulate cortex). The topologic patterns became
China.
less efficient after ECT. Correlation analysis between the change in pain and GMV
Email: ayfytyh@126.com (Y. T.) and
wangkai1964@126.com (K. W.) had negative results in bilateral amygdala/insula/hippocampus. Similarity, there was
a positive correlation between a change in ALFF in the left amygdala and improved
Funding information
The Natural Science Foundation of clinical symptoms. ECT improved pain by decreasing brain local function and global
China (31970979, 91432301, 31571149,
network patterns, while increasing structure in pain-­related circuits. Functional and
81171273, and 91232717 to K.W.;
81671354, 32071054, and 91732303 to Y.T.; structural alterations were associated with improvement in pain.
and 82001429 to T.B.) and the Science Fund
for Distinguished Young Scholars of Anhui KEYWORDS
Province (1808085J23 to Y.T.)
major depressive disorder, pain, topologic patterns

Edited by Junie Warrington and Jeremy Hogeveen. Reviewed by Christopher Abbott and
Wei Liao.

Ting Zhang, Qiangqiang Hou, and Tongjian Bai should be considered joint first author.

J Neurosci Res. 2022;100:477–489. wileyonlinelibrary.com/journal/jnr© 2021 Wiley Periodicals LLC.     477 |

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478       ZHANG et al.
1 |  I NTRO D U C TI O N
Major depressive disorder (MDD) has been recently reported to be
the third leading cause of years lived with disability, while chronic
pain is also a leading cause (GBD 2017 Disease and Injury Incidence
and Prevalence Collaborators, 2018). Epidemiological evidence
has suggested that approximately two-­thirds of depressed pa-
tients present with pain (Bair et  al.,  2003; Robinson et  al.,  2009).
Pain frequently exacerbates depressive symptoms and correlates
with treatment-­resistant depression (Bair et  al.,  2003; Greenberg
et al., 2003). Therefore, comorbid pain in patients with MDD is asso-
ciated with worse outcomes and more burdensome healthcare costs
than MDD alone (Dhanju et  al.,  2019). Electroconvulsive therapy
(ECT) is an efficacious treatment that can alleviate depressive symp-
toms, while there are contradictory results for pain.  Several stud-
ies have reported that ECT increase the pain threshold and relieve
chronic, severe pain (Leong et  al.,  2015; Schreiber et  al.,  2003). In
contrast, another study reported that there is no difference in pain
threshold during and after ECT (Gormsen et al., 2004). Thus, the ef-
ficacy of ECT in relieving pain should be further determined.
As a common physical symptom, pain refers to subjective sen-
sory and emotional experiences to real or imagined physical injuries
(Vaccarino et al., 2009). Generally, the transmission of noxious stim-
uli from peripheral receptors to the cerebral cortex involves multiple
central ascending pathways. First, nociceptive signals originating
from the periphery are detected by primary afferent nociceptive
neurons and transmitted to the neurons of the dorsal horn of the
spinal cord. Then, nociceptive signals are projected to the brain, in-
cluding the periaqueductal gray (PAG), amygdala, hippocampus, and
thalamus. From there, neurons project to the cortical areas, includ-
ing somatosensory cortices, anterior cingulate cortex, and insula to
modulate pain processing (Urien & Wang,  2019). Abnormalities in
pain-­related circuits lead to pain paresthesia. Evidence from animal
experiments indicated that enhanced inhibition of the amygdala
pathway induces pain in depression (Zhu et  al.,  2019). In contrast,
patients with chronic pain exhibit altered brain function and struc-
ture (Saab, 2012). Neuroimaging data reveal decreased gray matter
volume and changed intrinsic activity in hippocampus in migraine
patients, which is related to headache frequency and the number of
migraine attacks (Liu, Chou, et al., 2018). Current research has impli-
cated the limbic brain in pain processing. In addition to amygdala and
hippocampus, limbic regions contain the anterior cingulate cortex
(ACC) and insula. The ACC is responsible for the emotional aspects
of pain (Meda et al., 2019; Rainville et al., 1997). Antidepressants al-
leviated mood and pain symptom via decreasing the activity of ACC
(Mayberg et al., 2002). The insula is also implicated in pain, includ-
ing the sensory-­discriminative and affective-­motivational aspects of
pain (Lu et al., 2016). In addition, the medial prefrontal cortex plays
a top-­down control role in pain processing (Urien & Wang,  2019).
The above-­mentioned regions can be commonly activated by painful
stimuli, which are defined as pain-­related circuit. The literature sug-
gests that pain-­related circuit is pivotal for probing the mechanism
underlying pain.
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Significance
Pain symptom is a common complaint in depressive
populations, which exacerbates depressive severity.
Electroconvulsive therapy (ECT) can alleviate depressive
symptoms; however, treatment for pain and the underlying
neural substrate is elusive. Therefore, this study explored
the effect of ECT on pain symptom. Meanwhile, we probe
the neural substrates behind this using multimodal func-
tional magnetic resonance imaging. We found striking ef-
ficacy of ECT on pain symptoms. Structural and functional
plasticity of pain-­related circuit may contribute to the ef-
ficacy. Network analysis found less effective pain-­related
network caused by ECT.
With the development of functional magnetic resonance im-
aging, exploring the brain mechanism with neuroimaging data is
widely used. Various imaging analysis approaches have emerged.
Graph theoretical analysis is a popular method with which to reveal
the topologic patterns of a specific network (Wang et  al.,  2015).
Recent research on irritable bowel syndrome showed that the
characteristic path length is associated with psychological scores
(Kano et  al.,  2020). Individuals with lower back pain present aber-
rant small-­world parameters compared with controls (Liu, Zhang,
et al., 2018). Similarly, other resting state functional analyses, such
as the amplitude of low-­frequency fluctuation (ALFF), have been ad-
opted to reflect brain intrinsic activity of participants at rest (Zang
et  al.,  2007). A previous study reported that patients with chronic
lower back pain have increased ALFF in the ACC and supplemen-
tary motor cortex (SMA). The ascending ALFF in the insula, amyg-
dala, and hippocampus was associated with pain severity (B. Zhang
et  al.,  2019). Additionally, voxel-­based morphometry (VBM) is a
practical structural analysis method which provides a comprehen-
sive assessment of anatomic structure throughout the entire brain
(Luders et al., 2004). Gray matter volume (GMV) is a common indica-
tor to represent the volume of a specific gray matter area. Bhatt et al.
(2019) reported that patients with irritable bowel syndrome showed
smaller GMV in the prefrontal cortex and anterior mid-­cingulate.
According to prior evidence, we hypothesized that ECT can re-
lieve pain in patients with MDD. With respect to the related neu-
ral substrates, we speculated that ECT regulates the functional,
structural plasticity, and topological patterns of pain-­related circuit.
Thus, we first compared the difference in pain between pre-­ and
post-­ECT data. Then, we probed the local intrinsic neuron activity
of pain-­related circuit using ALFF, as well as the structural plasticity
using GMV in patients with MDD at baseline compared with post-­
ECT. In addition, using graph theoretical analysis, we explored the
topologic patterns change of pain-­related networks before and after
ECT. Finally, we revealed the relationship between changes in pain
and functional, structural, and topological alterations.

ZHANG et al.
2 | M E TH O DS
2.1 | Participants
MDD group: We recruited 34 patients with a professional diagnosis
of MDD and pain symptom from the Inpatient Department of Anhui
Mental Health Center. The diagnosis was confirmed by two psy-
chiatrists in a structured interview according to the Diagnostic and
Statistical Manual of Mental Disorders-­IV (DSM-­IV) criteria. Patients
with central nervous system disease, recent trauma, severe physical
disease, other psychiatric disorders, and substance abuse were ex-
cluded. Besides, we eliminated patients who underwent ECT within
3 months, patients in whom ECT and MRI were contraindicated, and
patients with head motion that exceeded >3 mm or >3°. The eligible
patients presented with treatment resistance or urgent suicidal idea-
tions and were scheduled for ECT.
Healthy control (HC) group: Thirty-­three HCs matched for age,
sex, and educational level were recruited via advertising. The exclu-
sion criteria were similar to the MDD group other than physical pain
and a history of depression.
This study was in accord with the tenets of the Declaration
of Helsinki and approved by the Anhui Medical University Ethics
Committee. All participants signed informed consent before
enrollment.
2.2 | Measures
2.2.1 | Experiment design and clinical assessment
All eligible patients were assessed with the 17-­item Hamilton
Depression Rating Scale (HDRS) (Williams,  1988) and the 15-­item
somatic symptom severity scale of the Patient Health Questionnaire
(PHQ-­15) (Kroenke et  al.,  2002) and scanned with fMRI, including
resting-­state fMRI and 3D T1, before the first ECT session and 72–­
96  hr after the last session. HCs had one clinical assessment and
scan.
Pain scores
PHQ-­15 is a measurement with good reliability and validity to evalu-
ate the severity of somatic symptoms. PHQ-­15 contains 15 items,
each scored from 0 (not bothered at all) to 2 (bothered a lot). Among
the 15 items, five focus on pain symptoms, including abdominal pain,
back pain, joint or limb pain, headaches, and chest pain. Therefore,
pain scores ranged from 0 to 10 (Werumeus Buning et al., 2016).
2.2.2 | ECT procedures
Patients signed informed consent and were instructed to fast
for at least 8  hr before ECT. As our prior studies described (Bai
et al., 2017; Zhang et al., 2020), a modified bi-­frontal ECT protocol
using the Thymatron System IV Integrated ECT System (Somatics,
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      479
Lake Bluff, IL, USA) was used. Patients underwent 6 to 12 sessions
of ECT according to their therapeutic response. Considering that
low-­frequency treatment acquires longer course and causes se-
vere cognitive impairments (Charlson et  al.,  2012), we used three
daily sessions first followed by more sessions applied every other
day during weekdays. Based on their age, we set the initial energy.
For example, for those over 50 years old, the initial percent energy
dial setting was to their age (e.g., 51% for a 51-­year-­old patient); for
those under 50 years, the initial percent energy dial was set as their
age minus five (e.g., 30% for a 35-­year-­old patient). If seizure activ-
ity cannot be triggered, the percent energy should be upregulated
until striking a therapeutically satisfactory seizure. During each ECT
session, patients were under anesthesia with propofol (1.4  mg/kg)
in addition to adjuvant drugs with succinylcholine (0.5 mg/kg) and
atropine (0.5 mg).
2.2.3 | Neuroimaging data acquisition
We collected imaging data using a 3.0  T MRI scanner (Discovery
GE750w; GE Healthcare, Buckinghamshire, UK) at the University
of Science and Technology of China (Hefei, Anhui Province).
Participants were required to remain still and close their eyes with-
out thinking during scanning.
The functional images were acquired using 217 echo-­planar
imaging volumes with the following parameters: TR  =  2,400  ms;
TE  =  30  ms; flip angle  =  90°; matrix size  = 64 ×  64; field of
view = 192 × 192 mm2; slice thickness = 3 mm; and 46 slices (voxel
size  = 3 × 3 × 3 mm3). We also collected a 3D T1-­weighted ana-
tomic image with 188 slices in the sagittal orientation using the fol-
lowing parameters: TR  =  8.16  ms; TE  =  3.18  ms; flip angle  = 12°;
field of view = 256 × 256 mm2; slice thickness = 1 mm; and voxel
size = 1 × 1 × 1 mm3.
2.2.4 | Functional MRI preprocessing
We preprocessed functional images using the Data Processing
Assistant for Resting-­State Functional MR Imaging toolkit (DPARSF),
which was based on Statistical Parametric Mapping software (SPM8;
http://www.fil.ion.ucl.ac.uk/spm) and the Resting State Functional
MR Imaging Toolkit (Chao-­Gan & Yu-­Feng, 2010; Song et al., 2011).
The steps were as follows: deleting the first five volumes; slice tim-
ing correction; realigning; co-­registering to respective 3D T1 ­images;
regressing out 24 Friston motion parameters, white matter high
and cerebrospinal fluid signals; spatial normalizing based on the
unified segmentation of structural images; spatial smoothing with
a 6-­mm Gaussian kernel full-­width at half-­maximum (FWHM); and
detrending.
ALFF analysis
ALFF is an important imaging measurement to examine local brain
activities since it is strongly associated with the blood oxygen level
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480       ZHANG et al.
dependent (BOLD) signal time courses across different regions
(Zang et al., 2007). The ALFF was calculated using the DPARSF soft-
ware. A fast Fourier transform (FFT) was used to convert the filtered
time series to the frequency domain. Then, we calculated the square
root of the power to obtain amplitude values. ALFF was the sum of
the amplitude values, which was calculated in the 0.01–­0.1 Hz low-­
frequency power range. Subsequently, the ALFF was normalized by
the mean within-­brain ALFF value for each participant to reduce the
global effects of variability across participants.
2.2.5 | Structural MRI processing
We preprocessed 3D T1-­weighted anatomical images using the voxel-­
based morphometry toolbox (VBM8) (http://dbm.neuro.uni-­jena.
de/vbm.html) in Statistical Parametric Mapping software (SPM8)
(http://www.fil.ion.ucl.ac.uk/spm). The preprocessing procedure
was shown as follows: segmenting each structural image into gray
matter, white matter, and cerebrospinal fluid using a fully automated
algorithm within SPM8; transforming to the Montreal Neurological
Institute (MNI) space applying diffeomorphic anatomic registration
through exponentiated Lie algebra (DARTEL) normalization; and
smoothing the normalized gray matter images (FWHM  =  6  mm).
Then we acquired GMV which refers to the volumetric ratio of gray
matter after correcting the partial volume effects of the voxel unit
(Hutton et al., 2009).
2.2.6 | Definition of pain-­related network
Painful signal transmission requires different levels of neuron coop-
eration from the periphery-­to-­the center. In this study we focused
on the pain-­related network in the brain. As previously mentioned,
the pain-­related network involved the PAG, thalamus, prefrontal
cortex, ACC, insula, amygdala, and hippocampus. We identified
the pain-­related circuit mask using a term-­based meta-­analysis tool
based on a map derived for “pain” from 516 PubMed publications
(http://neuro​synth.org) (Yarkoni et al., 2011). This meta-­analysis map
underwent false discovery rate (FDR) correction, with an expected
FDR of 0.01. The pain-­related circuit mask is presented in Figure 1.
We applied the pain-­related network mask to automated anatomic
labeling (AAL-­90) and reconstructed a pain-­related network with 35
nodes (Figure 2).
Construction of the pain-­related functional network
We constructed a pain-­related functional network using the Graph
Theoretical Network Analysis toolbox (GRETNA) (http://www.nitrc.
org/proje​c ts/gretn​a/). First, we correlated the time series between
each pair of predefined nodes and obtained Pearson's correlation
coefficients. Notably, we only retained positive correlations while
converting negative correlations to zero. Then, we generated brain
functional connectivity matrices [N × N (N = 35 was the number of
nodes, according to the pre-­defined pain-­related network)] for each
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participant. Network edges were defined using a sparsity threshold-
ing method ranging from 0.12 to 0.4 in 0.01 increments. Individual
functional connectivity matrices were transformed to a binary for-
mat. If the correlation coefficient was greater than a given threshold,
we set the attribute value to one, otherwise the attribute value was
0. In addition, we made a supplementary analysis to explore absolute
network of functional connectivity.
Network properties
We computed the following five global network properties using
GRETNA: global efficiency (Eglob); local efficiency (Eloc); shortest
path length (Lp); clustering coefficient (Cp); and small worldness (σ).
These network measures have been elaborated in the existing litera-
ture, including the algorithm and usage (Rubinov & Sporns, 2010).
The Lp of a network refers to the average of all shortest paths
between any pair of nodes in the network. The Cp of a node is the
possibility of the neighbor nodes interacting with each other. The
Cp of a network refers to the average Cp of all nodes in the network.
To calculate small-­world parameters related to Cp and Lp, we com-
pared the network with a random network. A small-­world parame-
ter has a similar Cp and Lp which are designated γ = Cpreal/Cprand and
λ = Lpreal/Lprand, respectively. These two parameters can be synthe-
sized as a scalar quantitative index. Specifically, small worldness
(σ = γ/λ) is generally >1. Eglob is the average inverse of the shortest
path length and indicates the efficiency of information transmission
between nodes in the network. The Eloc of a node is the Eglob of the
sub-­network composed of its neighbor nodes. The Eloc of a network
is the average Eloc of all nodes in the network. The range of sparsity
threshold varies from 0.12 to 0.40 with steps of 0.01. Then, we cal-
culated the area under the curve to represent the property values.
2.3 | Statistical analysis
Two-­sample t tests and chi-­squared tests were applied to compare
the differences in demographic data (age, educational level, and sex
ratio) between the MDD group and HCs using SPSS23.0. To probe
the functional and structural plasticity of the pain-­related circuit fol-
lowed by ECT, we compared the differences in ALFF and GMV be-
tween pre-­and post-­ECT within the pain-­related mask with drug load
(Redlich et  al.,  2016) as a covariate using SPM8 parametric paired
t tests. The statistical maps were corrected with a cluster-­level
family-­wise error (FWE) method and the significance of the voxel
level was set at a p < 0.001. The cluster level was set at a p < 0.05
(two-­t ailed), cluster threshold was set to >17 in ALFF analysis and
>389 in GMV analysis, respectively. For the region with aberrant
function and structure, we extracted and compared ALFF and GMV
values from pre-­ and post-­ECT, and HCs. Then, we focused on the
modulating effect of ECT on the global properties of the pain-­
related network. Paired t tests were used to compare the difference
in global network parameters between pre-­ and post-­ECT using
GRETNA. In addition, we compared the global network properties
with the HCs. To demonstrate the relationship between altered

ZHANG et al.
F I G U R E 1   Pain-­related network mask based on a meta-­analysis (http://neuro​synth.org). ACC, the anterior cingulate cortex; Hipp.L, the
left hippocampus; Hipp.R, the right hippocampus; INS.L, the left insula; INS.R, the right insula; PAG, the periaqueductal gray
ALFF, GMV, and global network properties and changes in clinical
symptoms, we calculated the improvement rate of the clinical score
(HDRS, PHQ-­15, and pain score) change and performed correlation
analysis. To improve the standards correlation analysis, we identi-
fied outliers by bootstrapping the Mahalanobis distance Ds for each
observation from the bivariate mean and excluded all points with an
average Ds of 6 or greater (Schwarzkopf et al., 2012). The improve-
ment rate equals (post-­ECT minus pre-­ECT)/pre-­ECT. To disentangle
pain symptoms from depression, we performed a partial correla-
tional analysis between the improvement rate of pain symptoms and
changed neuroimaging phenotypes (ALFF, GMV, and global network
properties) while controlling HDRS score. The significant threshold
was set at 0.05 (two-­t ailed) with no corrections.
3 | R E S U LT S
3.1 | Demographics and clinical characteristics
Thirty-­four MDD patients and 33 HCs were enrolled in the final
analysis. There were no differences in age (t  =  1.714, df  =  65,
p = 0.091), sex ratio (χ2 = 1.089, df = 1, p = 0.340), or educational
level (t = −1.753, df = 65, p = 0.084) between the two groups. There
were significant inter-­group differences in the HDRS, PHQ-­15,
and pain scores (t = 26.267, df = 65, p < 0.001; z = 6.157, df = 65,
p < 0.001; z = 6.564, df = 65, p < 0.001, respectively). The demo-
graphic and clinical features are summarized in Table 1. After ECT,
patients with MDD had lower HDRS, PHQ-­15, and pain scores than
before ECT (t  =  −15.620, df  =  33, p  < 0.001; z  =  −4.871, df  =  33,
p < 0.001; z = −5.025, df = 33, p < 0.001, respectively; Figure 3).
3.2 | Functional alterations in the pain-­
related circuit
The ALFF was decreased after ECT in two brain regions: left amyg-
dala and right supplementary motor area (SMA; Figure 4). Compared
|
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      481
to HCs, patients with MDD had a significantly lower ALFF in the
left amygdala and the right SMA (t = −2.519, p = 0.015; t = −3.682,
p < 0.001, respectively) after ECT (Table 2).
3.3 | Structural alterations in the pain-­related circuit
The GMV was increased after ECT in three main regions: ACC; left
amygdala/insula/hippocampus; and right amygdala/insula/hip-
pocampus (Figure  5; Table 2). Compared to HCs, there were no
­intergroup GMV differences in these regions.
3.4 | Pain-­related network properties
Patients with MDD had a significantly decreased Eglob (t = −2.790,
p = 0.009) and small-­world property (sigma, t = −2.6, p = 0.014), but
exhibited longer relative Lp (lambda, t = 2.761, p = 0.009) after ECT
(Figure  2). Other global network properties (Eloc, gamma) showed
no alterations pre-­ and post-­ECT. Compared to HCs, there were no
intergroup global parameter differences in MDD patients. Similar
results in absolute network were found in Supporting Information
(Figure S1).
3.5 | Correlation analysis
Partial correlation suggested that there was a moderate, negative
partial correlation between the GMV change of the left amyg-
dala/insula/hippocampus and the right amygdala/insula/hip-
pocampus and the percentage of pain score change (r  =  −0.440,
df = 30, p = 0.012; r = −0.446, df = 30, p = 0.011, respectively).
Consistently, zero-­order correlations showed that there was a sta-
tistically significant, moderate, negative correlation between the
GMV change of the left amygdala/insula/hippocampus and the
right amygdala/insula/hippocampus and the percentage of pain
score change (r = −0.472, df = 31, p = 0.006; r = −0.422, df = 31,
 | 482      

F I G U R E 2   Pain-­related network construction and the regulatory effect of electroconvulsive therapy (ECT) on the global network properties. In the upper left corner, the pain-­related
network was constructed by correlation analysis between 35 nodes. Inset maps (with mean and SE) show significant between-­group differences in the area under the curve in network
efficiency (Eloc and Eg) and small worldness (sigma, lambda, and gamma). Error bar maps indicate the SE of global properties across sparsities. Eg, global efficiency; Eloc, local efficiency
ZHANG et al.

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ZHANG et al.       483

TA B L E 1   Demographic and clinical features of the participants

Patients Controls p

Sample size (n) 34 33

Age (y)† 40.53 (13.44) 35.27 (11.56) 0.091
Sex (m/f) 4/30 7/26 0.340
Education level (y) 10.71 (4.65) 12.58 (4.05) 0.084
HDRS 24.68 (4.66) 1.82 (1.83) <0.001
(range of possible scores) (0–­52) (0–­52)
PHQ -­15 10.65 (4.50) 2.76 (2.97) <0.001
Pain score‡ 2.5 (1.75,6.25) 0 (0,0) <0.001
Age of onset (years) 34.62 (11.58) N/A
Duration (months) 68.26 (86.13) N/A
First episode (yes/no) 16/18 N/A
Psychiatric symptoms (yes/no)§ 5/29 N/A
SSRIs 28 N/A
SNRIs 19 N/A
SARIs 2 N/A
NaSSA 9 N/A
Antipsychotics 25

Note: Age, educational level, HDRS score, PHQ-­15 score, and pain symptom score were compared between groups by an independent samples t test
or Wilcoxon test, and gender ratios were compared by a Chi-­square test.
Abbreviations: HDRS, Hamilton Depression Rating Scale; NaSSA, norepinephrine and specific serotonergic antidepressants; PHQ-­15, 15-­item
somatic symptom severity scale of the Patient Health Questionnaire; SARIs, serotonin antagonist and reuptake inhibitors; SNRIs, serotonin–­
norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors.
†
Data are presented as the mean (standard deviation).
‡
Data are presented as the median (interquartile range).
§
Psychiatric symptoms: Depressed patients with delusions or auditory hallucinations.

p  =  0.014, respectively), indicating that age had very little influ-
ence in controlling for the relationship between the improvement
rate of pain and HDRS.
Zero-­order correlations identified a moderate positive correla-
tion between the ALFF change of the left amygdala and the per-
centage HDRS and PHQ-­15 changes (r = 0.358, df = 31, p = 0.041;
r = 0.424, df = 31, p = 0.014, respectively). However, Partial correla-
tion suggested that there was no statistically significant relationship
between changed ALFF in the left amygdala and the improvement
rate of PHQ-­15 after controlling HDRS (r = 0.292, df = 30, p = 0.105).
There was no significant correlation between global network prop-
erties and clinical symptoms.
4 | D I S CU S S I O N
In present study we showed that ECT significantly decreased pain
in MDD patients. Based on the pain-­related circuit, our results in-
dicated that ECT induced increased structure, but decreased func-
tion of the pain-­related circuit. In addition, ECT enabled global
network parameters to become less effective. Furthermore, our
findings suggested that the structural and functional plasticity of
the pain-­related circuit followed by ECT was associated with pain
alleviation.
Converging evidence has indicated that the amygdala is a vital
brain region involved in regulating emotions, somatic responses, and
pain processing (Davis & Whalen,  2001; Leaver et  al.,  2018; Urien
& Wang, 2019). Prior studies have reported aberrant activity of the
amygdala in MDD related to depressive symptoms (Qiu et al., 2018).
Zu et al. (2019) reported that decreased functional connectivity be-
tween the amygdala and insula is correlated with somatic symptoms
in depressed patients. In addition, the amygdala is a key hub for
transmitting pain signals in an animal model of comorbid pain and de-
pression (Zhu et al., 2019). Therefore, we speculated that ECT mod-
ulates amygdala function to relieve pain. As expected, ECT induced
amygdala hypoactivation, which was related to an improvement in
depression, somatic symptoms, and pain complaints. In agreement
with previous reports, ECT decreased amygdala activity to negative
stimuli, whereas increased GMV of amygdala was associated with
improved clinical responses (Joshi et al., 2016; Redlich et al., 2017).
In addition, the amygdala was involved in the neural circuit of neuro-
pathic pain. Opioids inhibit glutamate release from the amygdala and
modulate pain processing in animals (Kissiwaa et al., 2020). Hence,
decreased activity in the amygdala induced by ECT was implicated
in ameliorating pain.
Furthermore, other limbic regions, including the insula, hippo-
campus, and ACC displayed volumetric increases followed by ECT.
As a critical node of the pain-­related circuit, the insula has been
10974547, 2022, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jnr.24979 by University Of Illinois, Wiley Online Library on [03/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ZHANG et al.

F I G U R E 4   Regulatory effect of electroconvulsive therapy (ECT) on pain-­related network function. ECT decreased the low-­frequency
amplitude fluctuation of the left amygdala and right supplementary motor area
F I G U R E 3   The effect of electroconvulsive therapy on clinical symptoms
| 484      
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10974547, 2022, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jnr.24979 by University Of Illinois, Wiley Online Library on [03/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ZHANG et al.       485

TA B L E 2   Regions showing significant differences between pre-­and post-­ECT patients with depression

Brain regions (ECT–­post minus ECT–­pre) Voxel size MNI coordinate (x, y, z) Statistic (t value)

ALFF
L. amygdala 17 −18, −6, −18 −7.558
R. SMA 24 9, 9, 60 −5.181
GMV
B. ACC 389 −1.5, 19.5, 30 4.589
L. amygdala/insula/hippocampus 4,312 −15, −7.5, −18 8.650
R. amygdala/insula/hippocampus 5,199 31.5, −6, −22.5 7.936

Note: All statistical maps were corrected with the cluster-­wised family-­wise error correction with a two-­t ailed significance of voxel (p < 0.001) and
cluster (p < 0.05).
Abbreviations: ACC, anterior cingulate cortex; ALFF, amplitude of low-­frequency fluctuations; B, the bilateral; ECT, electroconvulsive therapy; GMV,
gray matter volume; L, left; MNI, Montreal Neurological Institute; R, right; SMA, supplementary motor area.

F I G U R E 5   Regulatory effect of electroconvulsive therapy (ECT) on the pain-­related network structure. ECT increased the gray matter
volume of the left amygdala/insula/hippocampus, right amygdala/insula/hippocampus, and anterior cingulate cortex

reported to signal pain intensity and expectations of painful stimuli
in healthy populations (Fazeli & Büchel,  2018). Structural neuro-
imaging studies have suggested that ECT facilitates an increase in
the insular GMV bilaterally (Xu et  al.,  2019). Indeed, our results
indicated that an increase in the insular GMV following ECT was
related to decreased pain. The hippocampus is another cardinal re-
gion implicated in pain processing (Vachon-­Presseau et al., 2016).
Indeed, it has been reported that decreased hippocampal GMV in
migraine patients is related to headache frequency and the num-
ber of attacks (Liu, Chou, et al., 2018). Electroconvulsive seizures
induce angiogenesis in the hippocampus of animals (Hellsten
et  al.,  2005; Newton et  al.,  2006). Human imaging data have
demonstrated that neuroplastic changes are responsible for the
volumetric increase in the hippocampus (Nuninga et  al.,  2020).
Similarly, the current study showed an increase in the hippocampal
GMV that was correlated with decreased pain. In addition, we ob-
served an increase in the ACC volume. The ACC is a relevant region
for emotional regulation and can be activated in acute and chronic
pain (Bliss et al., 2016). ACC lesions weaken subjective emotional
experiences to nociceptive stimulus (Barthas et  al.,  2015). A sys-
tematic review of neuroimaging studies suggested that abnormal
ACC structure was regarded as a biomarker of treatment response
(Enneking et al., 2020); however, there was no significant relation-
ship between changed GMV in the ACC and decreased pain. A
relatively crude measurement of pain may have accounted for the
negative result.
 |
486       ZHANG et al.
In addition, our results showed that ECT weakened the intrin-
sic activity of right SMA. It has been reported that patients with
phantom limbic pain have increased functional connectivity in the
SMA network that is positively correlated with pain scores (Zheng
et al., 2020). In addition, the SMA has been linked to the regulation
of emotions (Wager et  al.,  2008). A randomized control study re-
ported that alterations in SMA metabolism are responsible for an
antidepressant effect (Chen et  al.,  2018). The current study also
showed that ECT reduced the neural activity of the SMA.
At the global network level, ECT enables lower pain-­related
network global properties. It is acknowledged that “small-­world”
is an optimized pattern to produce high value at a low energy cost
(Bullmore & Sporns,  2012). In this study we investigated the to-
pological patterns of the pain-­related network using resting-­state
fMRI. MDD patients showed a small-­world property (sigma  > 1
and lambda  ≈  1) that changed following ECT (sigma was reduced
and lambda was increased). Lambda is the path length of a real
network relative to a random network. The decrease in sigma (the
ratio of gamma and lambda) observed in MDD patients after ECT
was primarily a result of an alteration in lambda because gamma
was unchanged. This pattern of pain-­related network functional re-
configuration can be summarized as a shift to lower integrative ca-
pacity with high additional expense of metabolic connection costs.
Thus, pain-­related functional networks become less optimal after
ECT treatment. Prior research has reported that ECT can reorga-
nize the brain network topology in depressed patients and make the
brain network topology more segregated and less integrated (Sinha
et al., 2019). In agreement with this finding, our results indicated that
global efficiency was downregulated by ECT, although we did not
demonstrate a relationship between a change in topologic param-
eters and improved clinical symptoms. The limited sample size and
heterogeneous network definition method may provide possible ex-
planations for this observation.
We found that there were overlaps between functional and
structural alterations in amygdala. ECT enables to increase the GMV
of amygdala but decrease the ALFF of the amygdala, meanwhile,
reduce the efficiency of pain-­related network (including amygdala).
Convergent evidence has indicated that amygdala played a cru-
cial role in emotional and pain processing (Urien & Wang,  2019).
Acknowledgedly, amygdala was a core region of limbic system.
Prior studies have reported lower volume in pain-­related meso-
limbic system while stronger activity in patients with chronic pain
(Yang et  al.,  2020). Pain intensity was associated with the activity
of amygdala which can be weaken by oral morphine to relieve pain
(Younger et  al.,  2011). Wang J. and colleagues have observed that
ECT enables to reorganize emotion regulation network and modu-
late the neural plasticity of amygdala (Wang et al., 2017, 2018, 2020;
Xu et al., 2020). Similarly, we speculated that altered structure and
function of amygdala might be a potential substrate of ECT alleviat-
ing pain.
There were several limitations that warrant discussion. First,
the sample size was relatively small, therefore the results should
10974547, 2022, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jnr.24979 by University Of Illinois, Wiley Online Library on [03/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
be validated with a larger sample. In addition, the node of the pain-­
related network definition method depends on the ALL-­90 template,
which was relatively course to more granular parcellations methods
such as FreeSurfer. Future work should apply a more elaborate com-
puting method (e.g., FreeSurfer) to reduce the effect of anatomic
heterogeneity and inter-­subject variability. Additionally, this study
identified marginal correlations possibly due to relatively rough
measurement of pain symptom. Therefore, we need more accurate
quantitative measurements in the future. Besides, static ALFF can-
not reflect temporal variability, future work would pay close atten-
tion to more novel method, such as dynamic ALFF (Li et  al.,  2019;
Yang et al., 2021).
In conclusion, the current study investigated the intrinsic activ-
ity, structure, and topological pattern alterations of the pain-­related
circuit induced by ECT. We found that ECT reduced left amygdala
and right SMA activity. Specifically, the functional changes in the
left amygdala correlated with the improvement of clinical symp-
tom. Moreover, ECT increased the GMV of the bilateral amygdala/
insula/hippocampus and ACC. The GMV alterations in the amyg-
dala/insula/hippocampus were associated with alleviation of pain.
ECT ­decreased the global efficiency and small-­worldness parameter,
while increasing the path length. This study probed the neural sub-
strates of ECT reducing pain and guided targeted neuromodulation
of specific brain regions for therapeutic purposes.
D EC L A R AT I O N O F T R A N S PA R E N C Y
The authors, reviewers and editors affirm that in accordance to the
policies set by the Journal of Neuroscience Research, this manuscript
presents an accurate and transparent account of the study being re-
ported and that all critical details describing the methods and results
are present.
AC K N OW L E D G M E N T S
We thank the Anhui Mental Health Center and the University of
Science and Technology of China for support.
C O N FL I C T O F I N T E R E S T
The authors declare no conflict of interest.
AU T H O R C O N T R I B U T I O N S
All authors had full access to all the data in the study and take re-
sponsibility for the integrity of the data and the accuracy of the data
analysis. Conceptualization, T.Z., T.B., and K.W.; Methodology, Y.T.
and G.J.; Investigation, T.Z. and H.L.; Formal Analysis, T.Z. and Q.H.;
Resources, J.Y. and B.Q.; Validation, W.X. and S.J.; Writing –­Original
Draft, T.Z.; Writing –­Review and Editing, T.B.; Visualization, G.J.;
Supervision, Y.T.; Project Administration, K.W.; Funding Acquisition,
T.B., Y.T., and K.W.
PEER REVIEW
The peer review history for this article is available at https://publo​
ns.com/publo​n/10.1002/jnr.24979.
 |

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ZHANG et al.       487

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