Received: 28 March 2021 Revised: 28 August 2021 Accepted: 29 August 2021

DOI: 10.1111/ejn.15439

RESEARCH REPORT

Disorganized resting-state functional connectivity between

the dorsal attention network and intrinsic networks in
Parkinson’s disease with freezing of gait

Qian Yu1 | Qun Li1 | Weidong Fang2 | Yuchan Wang1 | Yingcheng Zhu1 |
Juan Wang1 | Yalian Shen1 | Yu Han1 | Dezhi Zou1 | Oumei Cheng1

1
Department of Neurology, the First
Affiliated Hospital, Chongqing Medical
University, Chongqing, China
2
Department of Radiology, the First
Affiliated Hospital, Chongqing Medical
University, Chongqing, China
Correspondence
Oumei Cheng, Department of Neurology,
the First Affiliated Hospital, Chongqing
Medical University, Chongqing 400016,
China.
Email: chengoumei01@aliyun.com
Funding information
National Key Clinical Specialties
Construction Program of China; National
Natural Science Foundation of China,
Grant/Award Numbers: 81871002,
81471334, 81100981
Edited by: Yoland Smith
Abstract
Freezing of gait (FOG) is a common and complex manifestation of Parkinson’s
disease (PD) and is associated with impairment of attention. The purpose of
this study was to evaluate the functional network connectivity (FNc) changes
between the dorsal attention network (DAN) and the other seven intrinsic net-
works relevant to attention, visual–spatial, executive and motor functions in
PD with or without FOG. Forty-three idiopathic PD patients (21 with FOG
[FOG+] versus 22 without FOG [FOG ]) and 18 healthy controls (HC) were
recruited in this study. The data-driven independent component analysis
(ICA) method was used to extract and analyze the above-mentioned resting-
state networks (RSNs). Compared with FOG , FOG+ displayed decreased
positive connectivity between the DAN and medial visual network (mVN) and
sensory-motor network (SMN) and increased negative connectivity between
the DAN and default mode network (DMN). The within-network connectivity
in the SMN and visual networks were decreased, whereas the connectivity
within DMN was increased significantly in FOG+. Correlation analysis
showed that the clock drawing test (CDT) scores were positively correlated
with the functional connectivity of mVN (r = 0.573, p = 0.008) and lateral
visual network (lVN) (r = 0.510, p = 0.022), the Timed Up and Go Test (TUG)
duration were negatively correlated with the connectivity of SMN (r = 0.629,
p = 0.003), and the Frontal Assessment Battery (FAB) scores were negatively
correlated with the connectivity of DMN in FOG+. Functional connectivity
was changed in multiple intra-networks in patients with FOG. Inordinate

Abbreviations: CDT, clock drawing test; DAN, dorsal attention network; DMN, default mode network; DOT, digital ordering test; ECN, executive
control network; FAB, frontal assessment battery; FNc, functional network connectivity; FOG, freezing of gait; FOGQ, freezing of gait questionnaire;
FPN, frontal–parietal network; GM, gray matter; HAMA, Hamilton anxiety rating scale; HAMD, Hamilton depression rating scale; HC, healthy
controls; H-Y, Hoehn and Yahr Scale; ICA, independent component analysis; lVN, lateral visual network; MMSE, mini-mental scale examination;
MoCA, Montreal cognitive assessment; mVN, medial visual network; PD, Parkinson’s disease; RS-fMRI, resting-state functional magnetic resonance
imaging; RSNs, resting-state networks; SMA, supplementary motor area; SMN, sensory-motor network; TMT, trail making test; TUG, timed up and
go test; UPDRS, unified Parkinson’s disease rating scale; VAN, ventral attention network; WMN, working memory network.

Qun Li and Weidong Fang are co-first authors.

© 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd

Eur J Neurosci. 2021;1–13. wileyonlinelibrary.com/journal/ejn 1

2 YU ET AL.
inter-network connectivity between the DAN and other intrinsic networks
may partly contribute to the mechanism of freezing.
KEYWORDS
dorsal attention network, freezing of gait, Parkinson’s disease, resting-state functional
connectivity
1 | INTRODUCTION
Freezing of gait (FOG), which is defined as a transient
inability to generate forward gait, is a common symptom
in late-stage Parkinson’s disease (PD) (Nutt et al., 2011).
Due to the heterogeneity of FOG, its clear pathophysiology
has not been clarified (Ehgoetz Martens, Hall, et al., 2018).
Freezing occurs not only in the “off state” of PD patients
but also in the “on state.” Freezing is usually triggered by
specific events, such as walking through narrow channels,
turns and dual tasks. These phenomena indicate that FOG
is mediated not only by motor dysfunction but also by
non-motor deficits such as cognition. Previous studies
have found that compared with patients without FOG,
PD patients with FOG show worse cognitive ability
(Yao et al., 2017). Therefore, identifying the “weak link” in
the cognitive network may improve the pathophysiological
insight of FOG and enhance therapeutic strategies.
Resting-state functional magnetic resonance imaging
(RS-fMRI) has been used to detect the brain’s spontane-
ous neural activity in the resting state and recognize the
specific resting-state networks (RSNs) and their resting-
state functional connection (Biswal, 2012). Previous fMRI
studies have suggested that the connection changes of
the cognitive network (Canu et al., 2015; Tessitore
et al., 2012) and the decoupling between the basal ganglia
network and the cognitive control network (Shine
et al., 2013) are involved in FOG.
The integrated attention-control system plays a key
role in normal motor behavior (Rinne et al., 2018). The
main attention networks include the ventral attention net-
work (VAN) and the dorsal attention network (DAN). As
reported in previous studies, DAN was proposed to medi-
ate top-down allocation of attention, whereas VAN was
assumed to be involved in reacting to external stimuli and
triggering attention shift (Vossel et al., 2014). Patients are
prone to freeze when walking in complex circumstances,
indicating that their ability to allocate attention is
impaired. A strong white matter connection was found
between the DAN and the superior colliculus in a previous
study, and these connections play an important role in
saccades, head movements and attentional directional
change, thereby focusing on external stimulation and
ultimately activating the perception of objects in view
(Asplund et al., 2010; Bisley & Goldberg, 2010). Maidan
et al. (2019) found global efficiency of DAN was lower in
patients with FOG than patients without FOG, but no dif-
ferences were found in the VAN between the two groups.
They proposed that changes in the DAN may be associated
with a higher risk of FOG during complex walking condi-
tions. Instead, the VAN may be more involved in the pro-
cess of improving the gait of PD by external clues. Indeed,
FOG may not only be due to the functional impairment of
a signal network but also due to the failed communication
between different neural components. A number of studies
have demonstrated that abnormal functional connections
of the cognitive control network, sensorimotor network
and visual network play important roles in FOG (Canu
et al., 2015; Piramide et al., 2020; Tessitore et al., 2012;
Zhou et al., 2018).
Therefore, we hypothesize that the functional network
connectivity (FNc) changes between DAN and other RSNs
relevant to visuospatial, sensorimotor and executive func-
tion might be involved in FOG. In the current study, we
used RS-fMRI and ICA approach to examine the changes
of connectivity between the DAN and other intrinsic net-
works in patients with and without FOG. We chose medial
visual network (mVN), lateral visual network (lVN),
default mode network (DMN), left and right frontal–
parietal network (FPN), working memory network
(WMN) and SMN besides DAN, which are all thought to
be relevant to attention, visual–spatial, executive and
motor functions as the networks of interest (Smitha
et al., 2017). In order to explore the potential structural
changes under the abnormal functional connectivity, we
also measured the volume of gray matter (GM).
2 | MATERIALS AND METHODS
2.1 | Participants
Forty-three right-handed idiopathic PD patients and
18 healthy controls matched for age, gender and years of
education were recruited in this study. All patients met
the diagnostic criteria of the UK Parkinson’s Disease
Society Brain Bank criteria for idiopathic PD (Hughes
et al., 1992). Patients were excluded if they had (1) a
YU ET AL.
history of cerebrovascular disorders, traumatic brain
injury or other neurological diseases; (2) significant
merger disease, such as ophthalmopathy, oste-
oarthropathy or neuromuscular disorders that affect gait;
(3) severe cognitive dysfunction or dementia (Mini
Mental Scale Examination, MMSE < 24); and (4) contra-
indications for MRI testing. This study was approved by
the Ethics Committee of the First Affiliated Hospital,
Chongqing Medical University, China, in accordance
with the Declaration of Helsinki. Written informed con-
sent was obtained from all the participants.
2.2 | Neuropsychological assessment
The third part of the Unified Parkinson’s Disease Rating
Scale (UPDRS-III) (Antonini et al., 2013) and the Hoehn
and Yahr Scale (H-Y) (Hoehn & Yahr, 1967) were used to
evaluate motor symptoms and PD severity, whereas the
freezing of gait questionnaire (FOGQ) was used to assess
FOG severity (Nieuwboer et al., 2009). Patients who had a
score greater than or equal to 1 point on item 3 of the
FOGQ and an observed episode of freezing during motor
tests conducted by two experienced neurologists were cate-
gorized with FOG (FOG+) (n = 21). Patients who scored
less than 1 point and had no experience of episodic freez-
ing in the test were categorized without FOG (FOG )
(n = 22). To assess the type of FOG, patients were asked to
walk during their “ON state” and “OFF state.” All FOG
patients recruited in this study were considered as “OFF-
FOG” since they experienced frozen only during “OFF
state.” The MMSE (Folstein et al., 1975), Montreal Cogni-
tive Assessment (MoCA) (Nasreddine et al., 2005) and the
Frontal Assessment Battery (FAB) (Dubois et al., 2000)
were used for cognitive assessment, whereas the Hamilton
Depression Rating Scale (HAMD) and the Hamilton Anxi-
ety Rating Scale (HAMA) were used to exclude mood dis-
orders (Hamilton, 1959, 1967). In addition, the subjects
also performed Timed Up and Go Test (TUG), Trail
Making Test (TMT), adaptive digital ordering test (DOT)
and clock drawing test (CDT) to assess gait, executive,
attention and visual–spatial functions, respectively
(Ehrenstein et al., 1982; Podsiadlo & Richardson, 1991;
Shulman, 2000). All clinical assessments were performed
during an “OFF” state after at least 12 h of withdrawal
from anti-parkinsonian medications.
2.3 | Image acquisition
Functional and structural data were acquired with a GE
Signa HDxt 3.0 T scanner (General Electric Medical
Systems, Waukesha, WI) equipped with a standard
3
eight-channel head coil. Three-dimensional T1-weighted
images (repetition time [TR] = 8.3 ms, echo time [TE]
= 3.3 ms, flip angle = 15 , thickness/gap = 1.0/0 mm,
field of view [FOV] = 240  240 mm, matrix =
256  192), T2-FLAIR images (TR = 8000 ms,
TE = 126 ms, TI = 1500 ms, thickness/gap = 5.0/1.5 mm,
FOV = 240  240 mm, matrix = 256  192) and RS-fMRI
data (echo-planar image [EPI] 33 axial slices, thickness/
gap = 4.0/0 mm, in-plane resolution = 64  64 pixels,
TR = 2000 ms, TE = 40 ms, flip angle = 90 ,
FOV = 240  240 mm, time points = 240) were acquired.
During scanning, all subjects were instructed to remain
motionless with their eyes closed and not to fall asleep. In
order to keep the patients in a resting state, we also asked
them not to think about anything.
2.4 | Data processing
Data were processed and analyzed using DPARSF toolbox
version 2.2 (http://rfmri.org/DPARSF) with SPM8 soft-
ware package (http://www.fil.ion.ucl.ac.uk). Image
processing included the following steps: (1) removal of the
first 10 time points,(2) slice timing with the middle slice as
a reference, (3) spatial realigned, (4) spatial normalization
based on a standard brain space template (the Montreal
Neurological Institute template) and resampled to a voxel
size of 3  3  3 mm3, (5) cerebrospinal fluid signal and
white matter signal regression, (6) smooth (6 mm full
width at half maximum), (7) filter (0.01 < f < 0.1 Hz).
Friston 24-parameter model (six head motion parameters,
six head motion parameters one time point before and the
12 corresponding squared items) was further used to
reduced potential confounds of head motion. The instanta-
neous head motion of each subject was calculated based
on frame-wise displacement (FD) defined by Jenkinson
et al. (2002). Subjects with head motion (mean FD
Jenkinson) greater than 2 * SD above the group mean
motion were excluded from analysis (Yan et al., 2013). The
mean head motion + 2 * SD was 0.25 mm in this study.
2.5 | Identification of resting-state
networks
The preprocessed images were analyzed with MICA
(http://www.nitrc.org/projects/cogicat) using a subject
order-independent group ICA (SOI-GICA) approach. The
toolbox performed the analysis in three main steps: (1) con-
catenation of all the subjects’ resting-state fMRI data to
obtain a group total time course and to decompose the
dimensionality of the data, (2) application of the ICA
algorithm to obtain a stability index of each resting-state
4 YU ET AL.
network and (3) back-reconstruction of subject-specific
spatial maps and time courses with z-score conversions.
In the present study, eight components were identified as
resting-state networks of interest by careful visual inspec-
tion. To characterize each resting-state network of interest,
the individual spatial maps were used for a group-specific
one-sample t-test for the FOG+, FOG and HC groups
separately (p < 0.05), with AlphaSim correction and a clus-
ter threshold of >228 voxels (rmm = 5, FWHM = 6 mm)
(http://www.restfmri.net).
2.6 | Functional connectivity changes
between DAN and seven intrinsic
networks
Pearson’s correlation coefficients of the time courses of
each network of the individuals were calculated to obtain
the subject-wise correlation matrices. Then, a random-
effect one-sample t-test was performed to generate aver-
age functional connectivity matrices of every two net-
works for the FOG+, FOG and HC groups separately.
The significant group-level matrices for the three groups
were combined into one mask. In this mask, the func-
tional connectivity between DAN and the other seven
intrinsic networks of the three groups were compared
using a random-effects two-sample t-test with FDR multi-
ple comparison correction (p < 0.05).
2.7 | Functional connectivity changes of
eight brain networks of interest
The significantly different brain regions of the three
groups were integrated into one mask, and the analysis
of variance (ANOVA) of the internal connections of the
resting state networks among the three groups was car-
ried out in this mask, with age as a covariate (AlphaSim
corrected threshold of p < 0.05). The brain regions with
significant differences among the three groups were
extracted as a mask for two-sample post hoc t-tests
(corresponding to a corrected p < 0.05, as determined by
AlphaSim correction).
2.8 | Analysis of structural images
Voxel-based morphometry (VBM) was used to analyze
3D-T1 images, and the whole brain GM volume was
detected by SPM8 (Herman et al., 2014). The main steps
are as follows: (1) T1-weighted images were segmented
into GM, white matter (WM) and cerebrospinal fluid
(CSF); (2) spatially normalized to MNI space; (3) Gaussian
smoothing (FWHM 8 mm); (4) statistical analysis
(p < 0.05 with FDR correction).
2.9 | Statistical analysis
Statistical analysis was performed with SPSS version 19.0.
The chi-square test was used to compare categorical vari-
ables. For continuous variables, normality and homogene-
ity of variance were tested first. Two-sample t-test and one-
way ANOVA were used for comparison of the variables
with normal distribution and homogeneous variance. Non-
parametric tests were used to compare non-normally dis-
tributed continuous variables. Pearson correlation analysis
was used to evaluate the relationship between clinical vari-
ables and functional connectivity within and between net-
works. All statistical tests were two-tailed, and p values
<0.05 were considered statistically significant.
3 | RESULTS
3.1 | Clinical characteristics
Due to the head motion, two patients (one in FOG+, one
in FOG ) were excluded from the study. The
sociodemographic, clinical characteristics, motor and
neuropsychological assessment results are present in
Table 1. As expected, patients in the FOG+ group had a
longer TUG test duration than those in the FOG
groups. Furthermore, patients with FOG performed sig-
nificantly worse than patients without FOG in the
MoCA, FAB, TMT and CDT. There were no significant
differences in disease duration, UPDRS III, H&Y stage,
LEDD, HAMD and HAMA score between the FOG
group and the FOG+ group.
3.2 | Spatial maps of eight intrinsic brain
networks of interest
We identified all eight resting-state networks of
interest by visually inspecting the ICA-derived compo-
nents of the RS-fMRI data. Each RS network was ana-
tomically consistent with the previously published
“template” (Smith et al., 2009) (Figure 1).
3.3 | Functional connectivity changes
between DAN and other seven networks
The matrices in Figure 2 show the internetwork
functional connectivity of FOG+, FOG and the HC
YU ET AL. 5

TABLE 1 Demographic and clinical features of participants

Groups HC (N = 18) mean  SD FOG (N = 21) mean  SD FOG+ (N = 20) mean  SD p value
Age, years 61.3  6.7 60.2  7.9 64.5  6.2 0.066a
Gender F/M 10/8 13/8 11/9 0.444b
Disease duration, years NA 5.5  2.2 6.3  5.1 0.507c
UPDRS III NA 18.9  3.0 21.0  5.9 0.164c
H&Y stage NA 2.0  0.4 2.4  0.8 0.078c
L-Dopa dose (mg/d) NA 470.2  136.4 487.5  133.9 0.685c
TUG, s NA 10.8  0.8 12.7  1.4 0.000c*
FOGQ NA 4.0  2.1 14.1  5.9 0.000c*
MMSE 28.1  2.3 27.8  2.6 27.0  2.4 0.304a
MoCA 25.0  3.9 23.3  2.0 21.4  3.6 0.038a*
HAMA 2.9  3.0 4.4  4.9 4.5  3.1 0.592a
HAMD 6.1  5.0 6.8  5.7 4.2  3.1 0.193a
FAB NA 15.4  1.1 13.7  2.7 0.004c*
TMT NA 37.2  7.3 44.9  9.4 0.006c*
CDT NA 2.3  0.7 1.8  0.7 0.016c*
DOT NA 5.5  1.0 4.9  2.1 0.198c

Abbreviations: CDT, Clock Drawing Test; DOT, Digital Ordering Test; FAB, frontal assessment battery; FOG, freezing of gait; FOGQ, freezing of gait
questionnaire; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Depression Rating Scale; HC, healthy control; MMSE, mini-mental state exam;
MoCA, Montreal Cognitive Assessment; NA, not applicable; TMT, Trail Making Test; TUG, timed up and go test; UPDRS, Unified Parkinson’s Disease Rating
Scale.
a
Variance analysis.
b
Chi-square test.
c
Two independent sample t-test.
*Significant difference.

separately (※: p < 0.05, FDR corrected). Significant
negative connectivity was found between DAN and
DMN in the two patient groups. This negative connec-
tivity was not significant in HC. Furthermore, FOG+
showed increased negative connectivity between the
DAN and the DMN compared with FOG .
The inter-network connections between DAN and
mVN and SMN were lower in FOG+ than those in
FOG and HC. In addition, FOG+ had a lower inter-
network connection between mVN and SMN than
FOG (Table 2).
3.4 | Functional connectivity changes of
the eight interest brain networks among
groups
SMN but increased connectivity in the DMN (p < 0.01,
AlphaSim corrected; Figure 3b, Table 3).
3.5 | Correlation analysis
Correlation analysis showed that the CDT scores were
positively correlated with the functional connectivity of
the mVN (r = 0.573, p = 0.008) and lVN (r = 0.510,
p = 0.022), the TUG duration were negatively correlated
with the connectivity of SMN (r = 0.629, p = 0.003)
and the FAB scores were negatively correlated with the
connectivity of DMN (r = 0.622, p = 0.003) in
the patients with FOG (Figure 4). There was no signifi-
cant correlation between inter-network connectivity and
TUG test and cognitive scores.

Significant differences in within-network connectivity

were found in mVN, lVN, SMN and DMN among the 3.6 | VBM analysis
three groups (p < 0.01, AlphaSim corrected; Figure 3a,
Table 3). Compared with FOG and HC, patients with There were no statistically significant differences in GM
FOG displayed decreased connectivity in mVN, lVN and volume among groups.
6 YU ET AL.

F I G U R E 1 Eight resting-state networks of interest. Individual spatial maps were used in a group-specific one-sample t-test for the FOG
+, FOG and HC groups separately (p < 0.05) with AlphaSim correction and a cluster threshold of >228 voxels. DAN: dorsal attention
network; mVN: medial visual network; lVN: lateral visual network; DMN: default mode network; rFPN: right frontal parietal network;
lFPN: left frontal parietal network; SMN: sensory motor network; WMN: working memory network

F I G U R E 2 Inter-network functional connectivity of FOG+, FOG and the HC. Significant negative connectivity was found between
DAN and DMN in the two patient groups. This negative connectivity was not significant in the HC. In contrast, significant positive
connectivity was found between DAN and mVN, DAN and SMN, SMN and mVN in the HC, and this positive connectivity was decreased in
the patient groups. ※: Results were corrected for FDR at p < 0.05

4 | DISCUSSION connectivity between the DAN and DMN in PD patients

This study assessed the inter-network connectivity
between the DAN and other intrinsic networks in PD
with and without FOG. As the main findings, we
observed decreased positive connectivity between the
DAN and mVN and SMN and increased negative
with FOG. These findings indicate that the disorganized
connectivity between the DAN and other intrinsic net-
works may be involved in the FOG of PD.
The DAN mediates the top–down goal-directed atten-
tion allocation and plays an important role in the execu-
tion of attention required for gait (Ferrazzoli et al., 2017).
YU ET AL.
TABLE 2 Inter-network connectivity changes
z value (mean  SD)
FOG+ FOG
DAN-DMN 0.415  0.210 0.214  0.296
DAN-SMN 0.060  0.256 0.245  0.307
DAN-PVC 0.001  0.227 0.175  0.220
SMN-PVC 0.071  0.254 0.094  0.212
Note: A corrected threshold of p < 0.05 corrected by FDR. z value represent the connection strength between two networks; DAN-DMN: functional network
connectivity between DAN and DMN; DAN-SMN: functional network connectivity between DAN and SMN; DAN-PVC: functional network connectivity
between DAN and PVC; SMN-PVC: functional network connectivity between SMN and PVC. FOG+ vs. FOG : post-hoc two-sample t-test between FOG+ and
FOG .
The dorsolateral prefrontal cortex and posterior parietal
cortex are the important hubs of DAN, and they were
found to be activated during spatial attention transfer in
previous fMRI studies (Allan et al., 2019; Leh
et al., 2010). It has been suggested that DAN plays an
important role in visuospatial attention, involving in the
regulation of attention gathering, eye movement and
head rotation (Asplund et al., 2010; Cosman et al., 2015).
Although we did not detect any connectivity difference
within the DAN among the three groups, the functional
connectivity between the DAN and mVN in patients with
FOG was significantly lower than that in the other two
groups. This impaired connection may interfere with the
regulation of DAN in the process of visual–spatial atten-
tion conversion, resulting in the FOG of PD patients dur-
ing a complex walking situation. Moreover, we found a
decreased connectivity between the DAN and SMN in
patients with FOG, as compared with FOG and
HC. Tard et al. (2016) found that an attentional stimulus
can trigger event-related desynchronization before motor
preparation in patients without FOG, but in patients with
FOG, the coupling between attention and motor prepara-
tion was impaired. This finding is consistent with our
results and suggests that the impaired connectivity
between the DAN and the SMN may disturb the regula-
tion of cognitive strategies required for gait. To date, no
studies have reported changes in FNc between DAN and
SMN in patients with FOG in an active state. Whether
the reduced FNc we observed is a decoupling between
the SMN and the cognitive network or a reduction in
order to maintain homeostatic state requires further
research.
The DMN is active during rest and deactivates during
externally oriented (top–down) attention demanding cog-
nitive tasks (Hinz et al., 2019). Previous studies have
found that DMN is negatively correlated with other net-
works in the brain, such as the attention network
(Andrews-Hanna et al., 2010). In our study, we found
that the negative connection between DAN and DMN in
7
HC FOG+ vs. FOG p value
0.138  0.286 0.016
0.320  0.402 0.043
0.383  0.386 0.016
0.041  0.159 0.031
FOG+ was significantly stronger than that in FOG and
HC. It has been reported that the DAN is activated dur-
ing the spatial attention conversion, whereas the DMN is
deactivated (Asplund et al., 2010). A recent study investi-
gated alterations in FNc between the DMN and DAN in
mild cognitive impairment (MCI), Alzheimer’s disease
(AD) and healthy controls (HCs). An enhanced anti-
correlation between the DMN and DAN was found in
MCI compared with AD and HCs, which was proposed
to be a compensation for cognitive decline (Wang
et al., 2019). Although patients enrolled in our study had
no dementia (MMSE ≥ 24), patients with FOG had lower
FAB scores than FOG . Therefore, we speculate that the
enhanced negative connectivity between DAN and DMN
may be a compensatory response for cognitive decline in
PD. Of course, this is only a speculation and needs to be
further verified by longitudinal follow-up of these
patients.
In the present study, we also found the connectivity
between the SMN and mVN was decreased in patients
with FOG, as compared with the other two groups. As
the most important hub of the SMN, the supplementary
motor area (SMA) was revealed to be hypoactive in
patients with FOG in a previous study (Zhou
et al., 2018). Improvement of motor movements follow-
ing DBS of the subthalamic nucleus in PD with FOG
was correlated with the metabolic activities of the sup-
plementary motor area, and the modified FOG score by
DBS was correlated with the metabolic activities of
parietal, occipital, temporal sensory association cortices
(Lyoo et al., 2007), which are involved in the visual net-
work. Nackaerts et al. (2018) found that impaired writ-
ing amplitude in PD-FOG was associated with weaker
coupling in the visuomotor network. Unfortunately, we
did not find a correlation between the reduced FNc and
the FOG-related indicators. This might be attributed to
the fact that we only assessed the FOGQ and the TUG
duration to evaluate the FOG severity, rather than
using other quantitative gait analyses, such as stride
8 YU ET AL.

F I G U R E 3 (a) Intra-network functional connectivity differences among FOG+, FOG and HC. A comparison among the three groups
using ANOVA showed significant differences in the two visual-related networks (medial visual network and lateral visual network), the
sensory motor network and the default mode network. p < 0.01, AlphaSim corrected. (b) Intra-network functional connectivity changes
between FOG+ and FOG . The bilateral lingual gyrus, calcarine, cuneus of lVN, right precuneus of the mVN and the right middle frontal
gyrus, superior frontal gyrus, precentral gyrus, pre-motor and the supplementary motor cortex of the SMN showed significantly decreased
connectivity in FOG+ compared with FOG and HC. On the other hand, the DMN exhibited significantly increased connectivity in FOG+
compared with FOG and the HC in the left dorsolateral prefrontal cortex, bilateral middle frontal gyrus and the superior frontal gyrus
(p < 0.01, AlphaSim corrected)
YU ET AL. 9

TABLE 3 Significant differences between brain regions within the resting-state network

MNI coordinates
Resting-state F/T Size
network Cluster L/R value x Y z (voxels)
DMN Middle frontal gyrus, superior frontal gyrus, dorsolateral L 9.9609 30 27 36 66
prefrontal cortex
Middle frontal gyrus, superior frontal gyrus, dorsolateral R 11.7695 27 39 27 78
prefrontal cortex, anterior cingulate
SMN Middle frontal gyrus, superior frontal gyrus, precentral R 7.6928 30 9 57 27
gyrus, pre-motor cortex
mVN Calcarine, posterior cingulate, precuneus, lingual gyrus R 12.2489 15 66 15 76
lVN Lingual gyrus, cuneus, calcarine, middle occipital gyrus, L 20.7178 15 90 9 142
inferior occipital gyrus
Calcarine, lingual gyrus, cuneus R 12.3169 18 90 0 88
FOG+ > FOG
DMN Middle frontal gyrus, superior frontal gyrus, dorsolateral L 4.312 27 24 36 65
prefrontal cortex
Middle frontal gyrus, superior frontal gyrus, frontopolar R 4.3913 30 42 27 62
area
FOG+ < FOG
SMN Middle frontal gyrus, superior frontal gyrus, precentral R 3.938 30 9 57 17
gyrus, pre-motor and supplementary motor cortex
mVN Calcarine, posterior cingulate, precuneus, lingual gyrus R 4.7698 15 66 15 75
lVN Lingual gyrus, cuneus, calcarine, middle occipital gyrus, L 5.1016 9 87 6 125
inferior occipital gyrus
Calcarine, lingual gyrus, cuneus R 4.5896 18 90 0 80

Note: A corrected threshold of p < 0.05 corrected by AlphaSim; DMN: default mode network; SMN: sensory motor network; mVN: medial visual network; lVN:
lateral visual network; FOG+ > FOG : Compared with FOG , the functional connectivity of networks is increased in FOG+; FOG+ < FOG : Compared
with FOG , the functional connectivity of networks is decreased in FOG+.

length, stride velocity, turning duration, turning steps
and peak velocity.
Mi et al. (2017) found that the impaired gait perfor-
mances in FOG (first step range of motion, stride length
and turn steps) were correlated with the decreased ALFF
value in the bilateral sensorimotor regions and globus
pallidus, and the stride length during straight walking
was associated with abnormal activity within the tempo-
ral and occipital cortices. Similar findings were observed
in the within-network connectivity analysis. We found
significantly decreased connectivity within the mVN,
lVN and SMN in FOG+ compared with FOG and
HC. Furthermore, we observed that the CDT scores were
significantly correlated with the connectivity of the mVN
and lVN, and TUG duration was negatively correlated
with the connection of the SMN in patients with FOG.
Taken together, our study provides further evidence that
freezing of gait is associated with impaired visual net-
works and the sensorimotor network.
Patients with FOG displayed increased functional
connectivity within the DMN in our study. Correlation
analyses showed that the frontal executive function
(FAB scores) was negatively correlated with the func-
tional connectivity of the DMN. The DMN is known to
be associated with directing executive control processing
(Seeley et al., 2007). A recent functional near-infrared
spectroscopy (fNIRS) study found that higher BA10
(an important hub of DMN) activation during turning in
PD patients related to worse ambulation (Maidan
et al., 2017). Liang et al. (2020) found that MCI showed
higher functional connectivity of DMN than HCs. We
speculated that the increased connections within the
DMN may be a compensatory mechanism for cognition
decline in patients with FOG.
In a recent rs-fMRI study, Bharti et al. (2020) investi-
gated the within- and between-network functional con-
nectivity changes of 18 RSNs in PD with and without
FOG using ICA approach. They found that the FNc
between right FPN and executive control network (ECN)
was lower in PD-FOG than that in PD-nFOG and nega-
tively correlated with the FOGQ scores. We did not find
differences in functional connectivity of FPN and ECN
10
FIGURE 4 Correlation between intra-network functional connectivity and clinical variables in PD patients with FOG
between patients with and without FOG, which may be
due to the investigated subjects were different. Patients
recruited in their study were older and had a longer dis-
ease duration and higher depression scores than in our
study, whereas the reduced functional connectivity in the
frontal–parietal cognitive control network has been
found to be associated with increased depressive symp-
toms in a previous study (Schultz et al., 2019).
Recently, Song et al. (2021) reviewed 39 fMRI studies
(task-based fMRI and rs-fMRI) on PD with FOG. Several
hypotheses about the pathogenesis of PD-FOG were sum-
marized: impairment of cognitive control network,
abnormal activation and connection of sensorimotor
pathways, brainstem inhibition caused by the inhibitory
output of basal ganglia and cerebellar compensation. Our
results support the hypothesis that abnormal integration
of cognitive control networks and sensorimotor pathways
are involved in FOG.
Previous studies reported GM atrophy of cortical and
subcortical brain regions in patients with FOG (Jha
et al., 2015; Karachi et al., 2019). In our study, we found
no differences in the global brain GM volume among the
three groups. This result may be related to the fact that
our relatively small sample size may lead to a decrease in
statistical power and false-negative finding.
YU ET AL.
5 | LIMITATION
In the current study, some limitations should be con-
sidered. First, we only discussed the anterior DMN
and found abnormal increased functional connectivity
in the DMN of patients with FOG. The structure and
function of the DMN including anterior and posterior
DMN are very complex, so further research will be
required to explore the role of DMN in FOG. Second,
all FOG+ patients in the current study were “OFF-
FOG.” According to the different responses to dopami-
nergic drugs, FOG can be divided into dopamine-
responsive FOG (“OFF-FOG”), dopamine-induced FOG
(“ON-FOG”) and dopamine-ineffective FOG (“ONOFF-
FOG”) (Schaafsma et al., 2003). Different types of FOG
may have different pathological mechanisms (Factor
et al., 2014; Lucas McKay et al., 2019). In addition, we
did not assess patients’ FOG based on their FOG trig-
gers. Recent studies shown that FOG can be divided
into cognitive, sensory/perceptual and affective types,
based on the trigger factors (Ehgoetz Martens, Shine,
et al., 2018). Analysis of functional connections
changes in different subtypes of FOG may be helpful
to further reveal the mechanism of FOG. Third, we
only investigated changes in functional connectivity of
YU ET AL.
RSNs in patients with FOG, so further studies are
needed to confirm whether the functional connectivity
changes in resting state are consistent with the
real FOG.
6 | C ON C L U S I ON
This resting-state fMRI study revealed inordinate connec-
tivity between DAN and mVN, SMN and DMN. These
findings contribute to a further understanding of the neu-
ral network mechanisms of FOG in PD and provide evi-
dence for future improvements to cognitive training
therapy especially the attention training and the target
area of transcranial magnetic stimulation (TMS) therapy
of FOG.
ACK NO WLE DGE MEN TS
We would like to thank all the PD patients and healthy
controls who participated in our research. This research
was supported by the National Natural Science Founda-
tion of China (No. 81871002, 81471334, 81100981) and
the National Key Clinical Specialties Construction Pro-
gram of China.
CONFLICT OF INTEREST
We have no conflict of interest to report.
A U T H O R C ON T R I B U T I O N
Qian Yu MD: Manuscript Preparation, Research
project, Conceived and designed the experiments,
Imaging data processing. Qun Li MS: Manuscript
Preparation, Research project, Imaging data collection
and processing. Weidong Fang MD: Research project,
Imaging data collection and processing.
Yingcheng Zhu MS: Research project, Imaging data
processing.
Yuchan Wang MS: Research project. Juan Wang
MS: Research project.
Yalian Shen MS: Research project. Yu Han MD:
Research project.
Dezhi Zou MD: Research project. Oumei Cheng
MD: Corresponding author, Manuscript Preparation,
Research project PI.
P EE R R EV IE W
The peer review history for this article is available at
https://publons.com/publon/10.1111/ejn.15439.
DATA AVAILABILITY STATEMENT
The datasets used and/or analyzed during the current
study are available from the corresponding author on
reasonable request.
11
ORCID
Qian Yu https://orcid.org/0000-0003-4841-1557
Oumei Cheng https://orcid.org/0000-0002-1889-6541
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How to cite this article: Yu, Q., Li, Q., Fang, W.,
Wang, Y., Zhu, Y., Wang, J., Shen, Y., Han, Y.,
Zou, D., & Cheng, O. (2021). Disorganized
resting-state functional connectivity between the
dorsal attention network and intrinsic networks in
Parkinson’s disease with freezing of gait. European
Journal of Neuroscience, 1–13. https://doi.org/10.
1111/ejn.15439