† These authors contributed equally.
Academic Editor: Graham Pawelec
Background: Adolescent and young adult cancer patients (AYACPs)
experience a high incidence of psychological distress. However, the effect of
psychological distress on the functional connectivity between the hemispheres in
AYACPs remains unknown. Voxel-mirrored homotopy connectivity detection is an
effective way to explore the effects of psychological distress on functional
connectivity throughout the brain in AYACPs. Methods: Twenty-four AYACPs
underwent structural magnetic resonance imaging. Results:
Voxel-mirrored homotopy connectivity in the psychological distress group was
significantly lower in the superior parietal gyrus, middle frontal gyrus (orbital
part), superior frontal gyrus (dorsolateral), superior occipital gyrus,
precuneus, lingual gyrus, calcarine fissure and surrounding cortex than in the
non-psychological distress group, while in the inferior temporal gyrus and middle
frontal gyrus (orbital part), voxel-mirrored homotopy connectivity was
significantly higher (p
Patients diagnosed with cancer between 15–39 years old are defined as adolescent and young adult cancer patients (AYACPs) [1]. More than 1 million new diagnoses of cancer in adolescents and young adults occur annually worldwide [2]. The overall 5-year survival rate for AYACPs has exceeded 80% with the development of cancer screening and medical technology [3]. AYACPs have more opportunities to confront physical, medical and financial challenges during the diagnosis and treatment of cancer [4, 5]. Adolescence and young adulthood are important transitional phases of life with many essential developmental changes. During this time, being diagnosed with cancer may cause unique developmental challenges at this particularly vulnerable point for them [6]. The prevalence and severity of psychological distress (PD) are higher and more common among AYACPs [7, 8]. They suffer from all kinds of psychological problems, including psychological distress, anxiety and depression [5, 9]. Neuroimaging studies have also suggested that poorer psychosocial outcomes are manifestations of brain network disruptions [10, 11]. Although clinical scales are available to measure mental status, AYACPs may not report these due to cancer shame [12]; moreover, the scales are subjective and cannot objectively reflect the psychological state of patients. Psychological distress affects the progression, prognosis and treatment outcome of cancer [13]. Objective and accurate early identification of psychological distress in AYACPs is beneficial to cancer treatment. Functional changes in brain regions and neural circuits in patients with psychological distress can be provided by neuroimaging studies that provide insight and explore the neuropathology of physiological disorders in AYACPs.
Resting-state functional magnetic resonance imaging (fMRI) has shown abnormal activity or functional connectivity in many brain regions, including the frontal lobe (dorsolateral prefrontal cortex, DLPFC; ventrolateral prefrontal cortex, VLPFC; ventromedial prefrontal cortex, VMPFC), limbic system (anterior cingulate cortex, ACC; amygdala; hippocampus), thalamic striatum (thalamus; globus pallidus; nucleus accumbens; putamen; caudate nucleus) and insula among youth or elderly healthy or depressive subjects [14, 15, 16, 17]. Raichle et al. [18] analyzed the oxygen extraction fraction (OEF), cortical blood flow (CBF) and BOLD signals from positron emission imaging (PET) and fMRI data in normal adult human. Based on the signal characteristics in the active state of the resting-state fMRI, the concept of a default mode network (DMN) was obtained. This network mainly includes the posterior cingulate cortex/precuneus (PCC/PCUN), medial prefrontal cortex (MPFC), bilateral angular cortex and lateral temporal gyrus, temporal cortex, and hippocampus [19]. These structures or systems are mainly involved in emotional processing, cognitive control, self-instruction, emotional cognition and reward processing, especially in the process of nonadaptive rumination in the face of negative emotional stimulation [20].
Patients with PD present abnormal network activity, functional connectivity or network attributes in multiple cortices or subcortical areas, such as amplitude of low-frequency fluctuations (ALFF) in the cerebellum and striatum and disruptions in local homogeneity (ReHo), voxel-mirrored homotopy connectivity (VMHC), functional connectivity and small-world network attributes in the prefrontal lobe, orbitofrontal gyrus, anterior cuneiform lobe, insula, and limbic system brain areas (such as the ACC, amygdala and hippocampus) [21, 22]. VMHC is a kind of resting state functional magnetic resonance imaging (rs-fMRI) method developed in recent years that analyzes the synchronous activity between the two hemispheres. Homotopy refers to the highly similar endogenous spontaneous activities of neurons of the same origin in the left and right hemispheres. This is one of the important features of the internal functional framework of the brain. Reflections in the mode of information communication between the two hemispheres of the brain is very important for the brain information integration function. Homotopy is also a potential mechanism of human cognitive and behavioral coherence [23]. It has been gradually applied to the research of many central nervous system diseases and mental disorders [23, 24].
Compared with the healthy population, patients with PD have decreased brain activity in the limbic system and increased activity in the frontal-temporal cortex [25, 26, 27]. Abnormal activity in these brain regions is involved in top-down (high-level emotional cognitive processing) and bottom-up (coding perceptual information resulting in emotional stimulation) regulatory abnormalities in the prefrontal subcortical loop [28]. These abnormal brain activities are presented in multiple mental disorders, such as depression [29], bipolar disorder [27], anxiety, posttraumatic stress disorder [30] and borderline personality disorder [31]. These disruptions may be different across the above-mentioned diseases in various forms and degrees of emotional regulation abnormalities. However, the differences involve the cognitive control network, the participation of the reward loop and the emotional volatility (such as bipolar disorder) [32].
The theoretical framework of this study is research domain criterion (RDoC), a brain-centered research strategy, developed by National Institute of Mental Health (NIH) (2021). RDoC is a study framework for understanding mental disorders. It incorporates various levels of knowledge (from genomics and circuitry to behavior and self-report) to investigate the fundamental functional dimensions that span the full range of human behavior from normal to abnormal. The aim of this research strategy is to establish a classification system for mental disorders based on brain mechanisms. According to the idea of RDoC, a brain-centered, neuroimaging-based mind-brain association research framework was developed. This research framework emphasizes the use of brain functional networks as the starting point for establishing research hypotheses and inferring the psychological and behavioral characteristics associated with a particular brain functional network.
Fan et al. [33] experienced that linking the course of depression to changes in brain function can help understand the neural structure of major depression in adults. Another previous study also showed that the correlation between cognitive performance and homotopy in health adults [34]. However, the effect of PD on the functional connectivity between the hemispheres in AYACPs remains unknown. This study attempted to explore changes in homotopy of resting-state functional connectivity between hemispheres among AYACPs with PD by identifying focal lesions in VMHC and distinguishing patients with and without PD based on these regions.
This study is a cross-sectional design. Participants were enrolled and data were collected between March 2018 and August 2019 in the hospital. Twenty-four AYACPs were included. The inclusion criteria required that participants (1) were aged 15–39 years; (2) had a primary diagnosis of cancer (cervical, ovarian, uterine, lung or nasopharyngeal carcinoma) within the previous 3 months; (3) knew their disease diagnosis; (4) had strong right-handedness according to the Edinburgh Hands Survey [35]; and (5) were native Chinese speakers. Participants were excluded if they (1) had reported a history of central nervous system injuries, such as brain damage or congenital dementia; (2) had physical diseases that could have damaged cognitive function, such as cerebral hemorrhage, chronic pain, severe vision or hearing impairment, or limb disorders; and (3) had any contraindications for fMRI scanning, such as strong magnetic objects in the body or claustrophobia.
Eligible participants were screened by the Distress Thermometer (DT) before 8:00
AM, which was before the daily rounds (approximately 8:30 AM) to minimize the
effects of treatment or the patients’ routine on their psychological condition.
The DT is recommended by the National Comprehensive Cancer Network for cancer
patients. Cancer patients’ psychological distress was measured by an 11-point
numerical simulation thermometer (0 = no distress, 10 = extreme distress) [36].
According to current guidelines, a score of 4 or more is considered to be
associated with clinical psychological distress [37]. The participants were
divided into two groups: the PD group with a DT score
The HADS was developed by Zigmond & Snaith [38]. Screening patient anxiety and
depression, widely used in cancer patients in hospitals with mental disorders
[39, 40]. The HADS comprised 14 items in total using a 4-point Likert scoring
system (not at all = 0, almost all the time = 3). Of these items, 7 items were
used to assess anxiety (HADS-A), and 7 items were used to assess depression
(HADS-D). A higher score indicated more severe anxiety or depression. The total
score of the subscale can range from 0 to 21: 0–7 = negative; 8–10 = light;
11–14 = moderate; 15–21 = severe. The Cronbach’s
The International Cognition and Cancer Task Force (ICCTF) has proposed that a
high-resolution T1-weighted anatomical MRI scan and rs-fMRI should be contained
in a minimal set of MRI sequences to evaluate functional brain networks [42]. In
the hospital, the brain rs-fMRI data were gathered on a Philips
3 T scanner (Ingenia, Philips Healthcare, Best, NL) applying a head coil of
8-channel SENSE. The participants were instructed to close their eyes and relax
throughout rs-fMRI data acquisition. A gradient echo-planar imaging (EPI)
sequence was used to obtain blood-oxygen-level-dependent (BOLD) fMRI data. The
EPI sequence parameters were as follows: repetition time/echo time (TR/TE) =
2000/30 msec, thickness = 4 mm, field of view (FOV) = 224
Rs-fMRI images are preprocessed through the graph theory network analysis toolbox of image connectives (GRETNA) [43]. In this study, imaging data processing was mainly based on the MATLAB platform (MATLAB R2015b, The MathWorks, Inc., Natick, Mass). Data Processing Assistant for Resting-state fMRI (DPARSF 2.3) was used to preprocess the functional images [44, 45]. The graphical user interface (GUI) of Statistical Parameter Mapping (SPM12) was used to integrate and visualize the necessary steps of fMRI data.
Before preprocessing, each volume’s first ten time points of fMRI data were
removed to avoid instability in the initial magnetic field. The remaining rs-fMRI
images were processed in sequence as follows: (1) the 35th plane was used as the
reference plane to carry out slice timing to control the time difference across
different scanning plane images at the same time point, and a spatial correction
to control the head motion effect of different time points of image acquisition
was carried out. Participants with head motion exceeding a maximum displacement
of 1.5 mm or 1.5-degree angular motion in any direction were excluded from the
study. (2) T1 images were registered to functional images and then reoriented.
(3) For spatial normalization, T1-weighted anatomical images were divided into
white matter, gray matter and cerebrospinal fluid and then passed through 12
parametric nonlinear affine transformations that standardized the images of each
subject into the Montreal Neurological Institute (MNI) space. The above
transformation parameters were applied to the functional images, and then the
functional images were resampled to 3
To calculate the VMHC between symmetrical voxels across hemispheres of the brain, the preprocessed functional image was converted into symmetrical space using the following procedures: (1) averaging standardized gray matter images of all subjects to generate the average image; (2) averaging the above-average image with bilateral mirror templates to create a group-specific symmetrical template; and (3) registering each standardized gray matter image to the generated symmetrical template and then transforming the functional image based on a nonlinearity strategy. VMHC at the individual level was calculated from the symmetrical unilateral gray matter hemispheric template. Pearson correlation analysis was conducted between each voxel and its corresponding voxel in the mirror-symmetric hemispheres of each subject. Then, the Fisher z transform was applied to the calculated correlation coefficients to obtain the standardized distribution data. Finally, the VMHC values used for statistical analysis were generated. The above steps were carried out in DPARSF 2.3 software. VMHC was calculated based on bilateral symmetrical brain regions, so the coordinates of peak points of corresponding brain regions on the left and right also correspond to each other.
All statistical analyses were performed by SPSS software for Windows
(version 24.0, IBM Corp., Armonk, NY, USA). Descriptive statistics, ANOVAs,
independent samples t-tests, Kruskal-Wallis tests, and
The regional differences in VMHC were determined by analysis of covariance. In
the unilateral hemisphere of the symmetrical template, AlphaSim analysis
determined by Monte Carlo simulation was used to correct the VMHC results for
multiple comparisons. The AlphaSim program is part of a standard neuroimaging
toolbox of the Analysis of Functional NeuroImages (AFNI) (Linux, Ubuntu 18.04,
NIH, USA) (http://afni.nimh.nih.gov) and is
one of the methods for multiple comparison correction combining voxel intensity
and cluster extent. In AlphaSim, Monte Carlo permutation simulations were applied
to estimate the null distribution [46]. Specifically, the algorithm generates an
estimate of the overall significance level achieved for various combinations of
probability thresholds and cluster size thresholds by iteration of the process of
random image generation, Gaussian filtering, thresholding, image masking, and
tabulation of cluster size frequencies. However, the algorithm of AlphaSim is
different from the abovementioned [47]. We thought that it does provide the
appropriate cluster-level threshold to achieve the desired false-positive rate.
Moreover, AlphaSim has been widely used in the published literature about
psychological distress [48, 49]. The threshold was set as p
After obtaining the time series in the brain areas that were different, the
relationship between VMHC and patient psychological characteristics was examined
by bivariate Pearson’s or Spearman correlation analysis. Area under the curve
(AUC) analysis of receiver operating characteristic (ROC) curves was used to
determine the best thresholds to distinguish PD from NPD and was characterized as
follows: 0.9–1.0 = excellent; 0.8–0.9 = very good, 0.7–0.8 = good; 0.6–0.7 =
weak; And 0.5–0.6 = poor [50]. For the ROC analysis of multi-index combinations,
the binary logistic regression method was used to calculate the prediction value
of the joint index. Values of p
Fifteen participants with PD and nine participants with NPD were recruited. There was no significant difference between the two groups in the demographic characters. Table 1 summarizes their demographics and clinical characteristics.
Variables | N (Percentages, %)/Mean |
Z | p | ||
PD (N = 15) | NPD (N = 9) | ||||
Gender (M/F) | 5/10 | 3/6 | –0.533 | 0.594 | |
Age (years) | 31.87 |
29.33 |
–1.351 | 0.177 | |
Education | –0.573 | 0.567 | |||
Junior high school or below | 6 (40) | 3 (33) | |||
High school | 5 (33) | 4 (44) | |||
Diploma | 4 (27) | 2 (23) | |||
Cancer type | –0.310 | 0.757 | |||
Cervical cancer | 9 (60) | 5 (56) | |||
Ovarian cancer | 2 (13) | 1 (11) | |||
Tongue cancer | 1 (7) | / | |||
Lung cancer | 2 (13) | 2 (22) | |||
Nasopharyngeal cancer | 1 (7) | 1 (11) | |||
Cancer stage | –0.156 | 0.876 | |||
Stage I–IIa | 13 (87) | 8 (89) | |||
Stage IIb–IIIa | 2 (13) | 1 (11) | |||
Treatment type | –0.876 | 0.381 | |||
Surgery | 9 (60) | 7 (78) | |||
Surgery + Chemotherapy | 6 (40) | 2 (22) | |||
Note: NPD, Non-Psychological distress; PD, Psychological distress. |
The results showed 16 regional changes between PD and NPD. Compared with the PD
group, the NPD group had considerably declined VMHC values in the middle frontal
gyrus (orbital part) and bilateral inferior temporal gyrus, but significantly
increased values in the superior parietal gyrus, middle frontal gyrus (orbital
part), superior frontal gyrus (dorsolateral) (SFGdor), superior occipital gyrus,
precuneus, lingual gyrus, calcarine fissure and surrounding cortex (Table 2 and
Fig. 1). As shown in Table 3, PD and NPD groups were significantly different in
anxiety and depression (p
Brain area with VMHC
difference between PD and NPD.* Note: The VMHC of PD was lower
in superior parietal gyrus, middle frontal gyrus, superior frontal gyrus,
dorsolateral, superior occipital gyrus, precuneus, lingual gyrus, calcarine
fissure and surrounding cortex than that of NPD, while the VMHC value of PD in
inferior temporal gyrus and middle frontal gyrus (orbital part) was higher. The
figure in the lower left corner represents the z coordinate value of the
coordinate system of Montreal Institute of Neurology, and the icon on the right
represents the T value (p
Region | Number of voxels | Peak MNI coordinate | T | |||
X | Y | Z | ||||
PD |
||||||
ITG.R | 9 | 45 | –66 | –27 | –4.4788 | |
ITG.L | 7 | –45 | –66 | –27 | –4.4788 | |
ORBsupmed.R | 46 | 27 | 45 | –21 | –4.3893 | |
ORBsupmed.L | 24 | –33 | 45 | –12 | –3.8578 | |
PD |
||||||
CAL.R | 54 | 24 | –21 | 9 | 5.572 | |
CAL.L | 36 | –24 | –21 | 9 | 5.572 | |
LING.R | 28 | 6 | –78 | –3 | 5.1997 | |
LING.L | 27 | –6 | –78 | –3 | 5.1997 | |
MFG.R | 127 | 42 | 12 | 42 | 4.1998 | |
FGdor.L | 222 | –42 | 12 | 42 | 4.1998 | |
SOG.R | 24 | 15 | –99 | 21 | 4.4679 | |
SOG.L | 27 | –15 | –99 | 21 | 4.4679 | |
PCUN.R | 67 | 15 | –57 | 51 | 4.2652 | |
PCUN.L | 69 | –15 | –57 | 51 | 4.2652 | |
SPG.L | 22 | –18 | –72 | 60 | 3.1435 | |
SPG.R | 32 | 18 | –72 | 63 | 3.2036 | |
Note: 1 voxel = 3 |
Region | PD | NPD | t | p* |
HADS | 16.867 ± 3.021 | 8.333 ± 4.062 | 5.890 | |
HADS-A | 8.933 ± 2.502 | 4.444 ± 2.404 | 4.870 | |
HADS-D | 7.933 ± 1.981 | 3.889 ± 2.083 | 4.747 | |
Note: HADS, Hospital anxiety and
depression scale; HADS-A, Hospital anxiety and depression scale-Anxiety; HADS-D,
Hospital anxiety and depression scale-Depression; NPD, Non- Psychological
distress; PD, Psychological distress. * p |
Region | HADS-D | |
r | p* | |
SFGdor.L | –0.563 | 0.029 |
SPG.L | –0.576 | 0.025 |
SPG.R | –0.522 | 0.046 |
Note: HADS-D, Hospital anxiety and
depression scale-Depression; L, Left; R, Right; SFGdor, Superior frontal gyrus,
dorsolateral; SPG, Superior parietal gyrus. * p |
ROC curve analysis demonstrated that four regions of VMHC changes could identify patients with PD. They were the left SFGdor (AUC = 0.681, p = 0.014, sensitivity = 0.444, specificity = 0.40; see Fig. 2A), left calcarine fissure and surrounding cortex (AUC = 0.614, p = 0.036, sensitivity = 0.867, specificity = 0.222; see Fig. 2B), right postcentral gyrus (PoCG) (AUC = 0.651, p = 0.022, sensitivity = 0.800, specificity = 0.444; see Fig. 2C) and left precuneus (AUC = 0.629, p = 0.029, sensitivity = 0.800, specificity = 0.333; see Fig. 2D). The combined ROC analysis showed that the combined index had a better discrimination effect and more balanced sensitivity and specificity in predicting PD patients when the VMHC characteristics of these four regions were integrated and collected (AUC = 0.704, p = 0.027, sensitivity = 0.733, specificity = 0.667; Fig. 2E).
ROC analysis of VMHC in the altered regions as a potential means to differentiate between PD and NPD. (A) The ROC curve of VMCH in SFGdor.L, AUC = 0.681, p = 0.014, sensitivity = 0.444, specificity = 0.40; (B) The ROC curve of VMCH in CAL.L, AUC = 0.614, p = 0.036, sensitivity = 0.867, specificity= 0.222; (C) The ROC curve of VMCH in PoCG.R, AUC = 0.651, p = 0.022, sensitivity = 0.800, specificity = 0.444; (D) The ROC curve of VMCH inPCUN.L, AUC = 0.629, p = 0.029, sensitivity = 0.800, specificity = 0.333; (E) The ROC curve of combined VMCH values, AUC = 0.704, p = 0.027, sensitivity = 0.733, specificity = 0.667, which had a better discrimination effect and more balanced sensitivity and specificity in predicting PD patients.
The current study found that an increased in the middle frontal gyrus (orbital part) and inferior temporal gyrus of VMHC values among AYACPs with PD compared to those without PD in VMHC. The middle frontal gyrus (orbital part) is a part brain area of the frontal limbic loop, which is mainly involved in the processing of conditioned emotion [51] and the rumination process [52]. These loops ensure the formation of normal emotions by coordinating emotions and external stimulation [53]. The increase in VMHC in the orbital part of the middle frontal gyrus (orbital part) may promote the generation of depressive symptoms by mediating the rumination process associated with poor emotional regulation and nonadaptive thinking [26]. In addition, graph theory research has also found that the right middle frontal gyrus (orbital part), which significantly presented lower homotopy in our study, relative to the emotion-related region [54]. Abnormal VMHC in these areas may be a compensatory effect for the readjustment to emotional dysfunction.
We discovered 16 regions of functional connectivity between the two hemispheres that changed among AYACPs with PD. Compared with cancer patients in other age groups, AYACPs with PD presented different focally disrupted sites [17, 55]. Compared to healthy controls, depressed adolescents showed reduced resting-state functional connectivity in the dorsolateral prefrontal cortex (DLPFC) and the ventromedial prefrontal cortex (VMPFC) [56]. Similarly, VMHC in the PD group was significantly lower in the superior frontal gyrus than in the NPD group in this study, suggesting that adolescent depression may be characterized by dysfunction of frontolimbic circuits underpinning emotional regulation. Moreover, the abnormal range of information exchange between hemispheres in the AYACPs with PD was larger than that in normal people with PD of the same age [57]. The unique pattern of VMHC changes between the PD and NPD groups suggests that abnormal information exchange between hemispheres may be the neural basis of psychological distress in AYACPs. These changes provide a new perspective to recognize and understand the heterogeneity of neurological changes among different populations.
We also found that the decrease in VMHC in the left DLPFC and bilateral superior parietal gyrus was significantly negatively correlated with the severity of depression in the PD group. When emotional impulses are produced in the marginal center, emotional expression is restricted by the prefrontal cortex. The two sides of the prefrontal cortex seem to be responsible for controlling different emotional responses. The right side regulates depression-related emotions, and the left side regulates relatively positive emotions. Normann et al. [58] hypothesized that one aspect of the pathogenesis of depressive disorder is hypofunction of the left brain and hyperactivity of the right brain. Effectively stimulating the excitability of the left superior frontal gyrus (dorsolateral) can relieve patients’ depression [59].
The results revealed the possibility of distinguishing NPD and PD based on some of the differences in VMHC. ROC analyses showed that the changes in VMHC in the SFGdor, CAL, PoCG and PCUN can objectively and effectively identify cancer patients with PD. When the VMHC changes in the four regions were integrated, a more optimized discrimination ability was revealed. This demonstrated that the synergism of multiple brain regions may be involved in the compensation of neurological changes caused by PD, and the change in functional coordination between hemispheres may not only be related to early response to psychological distress but also may affect PD by mobilizing the reserve in brain function activity in these regions. Additionally, as questionnaires have been criticized for their subjectivity, being easily affected by the environment and limited by participants’ conditions, this result identified an objective psychological testing method that can be applied in further understanding AYACPs’ psychological distress.
The strengths of this study include applying objective indicators to the study of psychological distress in AYACPs. However, the current study has a few limitations that need to be addressed. First, we did not establish a group of healthy controls, that is, there was an absence of normal people without PD. We cannot identify whether the severity of the emotional disorder is related to the functional imbalance in particular brain regions. Second, this study was conducted with AYA patients receiving treatments, and VMHC changes cannot eliminate the disease effects. Moreover, the small sample size may have decreased the authority to notice functional differences. We targeted on AYACPs, which was scarcely investigated the correlation between their psychological distress and functional connectivity before. Our study could serve as a preliminary investigation of this important but overlooked correlation among AYACPs.
The characteristic differences in the mirrored homotopic connectivity between the PD group and NPD group will support us in understanding the neural mechanisms of PD. VMHC detection is an effective method to explore the potential neural mechanisms of mental disorders in AYACPs and optimize the treatment of mental disorders. Meanwhile, VMHC abnormalities in the SFGdor, calcarine fissure and surrounding cortex, PoCG and PCUN regions are correlate with psychological distress for AYACPs, which may contribute to promoting the realization of objective psychological testing.
JX the primary author, led the work conception and design of the study. LL and YL the corresponding authors, analysis, interpretation of data and drafting the article. LW, PX, JL and JZ organized the survey, revised the paper and provided constructive suggestion. LL, YL and XL analyzed data and revised it critically for important content. ASKC revised the paper critically for important intellectual content.
All procedures performed in the trial were in accordance with the ethical standards of the Third Xiangya Hospital, Central South University IRB. This study was approved by the ethics committee of The Third Xiangya Hospital of Central South University (No. 2018-S039). All participants have signed the informed consent form.
We would like thanks to Wisdom Accumulation and Talent Cultivation Project, National Natural Science Foundation of China and Fundamental Research Funds for the Central Universities of Central South University fund project for their finical supports. And grateful to all participants for their voluntary participation and all the members of our research team.
Paper supported by the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University (NO. YX202006); The National Natural Science Foundation of China (NO. 82073409); Fundamental Research Funds for the Central Universities of Central South University (No. 2020zzts841).
The authors declare no conflict of interest.