Brain network study of attentional cognitive impairment in children with bronchial asthma

Bronchial asthma often causes cognitive impairment, especially attentional deficit, which has a serious impact on children's learning. This study aims to provide objective indicators for the evaluation of attention in asthma children. Thirty‐one asthmatic and typically developing children (TDC) were tested by resting‐state functional magnetic resonance imaging (rs‐fMRI). Brain network‐based methods of degree centricity and voxel‐mirrored homotopic connectivity (VMHC) methods were used in the study. Compared with the TDC group, asthmatic children had lower DC values in the right superior frontal gyrus (after FDR correction, P < 0.05). Meanwhile, VMHC values of bilateral superior frontal gyrus and bilateral superior parietal lobule in asthmatic children were lower than those in TDC group (after FDR correction, P < 0.05). There was significant correlation between the correct percentage of CPT and DC value in right superior frontal gyrus, VMHC value in right superior frontal gyrus, and right superior parietal lobule. In this study, impaired superior frontal gyrus and parietal lobe function are associated with attentional deficit in asthmatic children, and these brain regions are key brain regions in attention‐related networks.


| INTRODUCTION
Bronchial asthma is a complex multifactorial disease characterized by chronic airway inflammation, reversible airway obstruction, inflammatory exudation, and airway hyperresponsiveness (Busse, 2010). By the end of 2014, the number of asthma patients worldwide has increased to 334 million (Prajapati & Kothari, 2018) and is expected to increase to 400 million by 2025 (Masoli et al., 2004), making asthma a serious public health problem. In asthma attacks, bronchial smooth muscle contraction and airway swelling cause airflow restriction, leading to insufficient oxygen intake in vital organs. The brain is most sensitive to hypoxia, and long-term hypoxia will affect brain function and cause cognitive impairment (Brannan & Lougheed, 2012). In a variety of cognitive functions, attention is the basis of other cognitive functions, as any advanced cognitive function requires attention participation (Cooper et al., 2016). Attention deficit Lin Zhu and Jing Zhao contributed to the work equally and should be regarded as co-first authors.
Jianxin Xiong and Kaihua Jiang contributed to the work equally and should be regarded as co-corresponding authors.
is the important cause of school-age children's learning difficulties and academic performance decline. However, the current clinical assessment methods for attention mainly rely on behavioral tasks and assessment scales, which are subjective to a certain extent, so it is very necessary to find an objective and accurate evaluation index in clinical diagnosis and treatment.
Previous studies have confirmed that children with bronchial asthma have obvious cognitive impairment of attention. Guo et al. established a chronic asthma model in adolescent mice and found that the impairment of attention and memory function in adolescent mice was related to chronic intermittent hypoxia caused by asthma through a controlled study, suggesting that asthma may cause cognitive impairment in children (Guo et al., 2013). Bender et al. used drugs to control nocturnal asthma attacks to conduct therapeutic experimental studies and found that patients with nocturnal asthma attacks might have impaired daytime cognitive functions, which were mainly reflected in higher neurocognitive functions such as attention (Bender & Annett, 1999). These studies confirmed the existence of attentional cognitive impairment in bronchial asthma but did not further find the brain mechanism, which limited the clinical application of asthma treatment.
As an emerging imaging technology, resting-state functional magnetic resonance imaging (rs-fMRI) has the advantages of non-invasive, non-radioactive and high spatial resolution, and has been widely used in basic and clinical studies (Bédard et al., 2015;Li et al., 2016). At present, there are few studies on attentional impairment of bronchial asthma by fMRI. Zhang et al. conducted a comparative study of 39 asthma patients and 60 healthy controls and found that the regional homogeneity of bilateral occipital lobe and bilateral sensorimotor area of asthma patients significantly enhanced, and asthma patients had enhanced regional homogeneity in bilateral occipital lobe, left paracentral lobule, and right sensorimotor area after group cognitive behavioral therapy intervention, which indicated the cognitive level of attention improved (Zhang et al., 2017). Wang et al. found that decreased gray matter volume of right superior temporal gyrus in asthmatic patients was associated with attention deficit (Wang et al., 2014). These studies suggested that attentional cognitive impairment was associated with functional abnormalities in multiple brain regions. In order to study the brain mechanism of attentional cognitive impairment, it is necessary to combine the functional connectivity of brain regions. Therefore, this study adopted the two algorithms of degree centrality (DC) (Wu et al., 2020) and voxel-mirrored homotopic connectivity (VMHC) (Jia et al., 2020) based on functional connectivity to analyze and explore which brain regions were related to asthma attention impairment. DC reflects the role of the node in information transmission in brain functional network and VMHC analyzes the collaborative activities between two symmetrical hemispheres. The two algorithms can calculate the whole brain's characteristics of functional connectivity, which previous studied cannot achieve.
This study will combine rs-fMRI and attentional behavior analysis, study the characteristics of center brain regions and homotopic connectivity between the two hemispheres, explore the correlation between abnormal brain function connection and clinical symptoms, and look for reliable clinical objective indicators for attention. The results of this study would provide a better way for the early assessment of asthma children's attention deficit.

| Participants
The asthma group included 31 children aged (8.98 ± 1.52 years, 17 boys and 14 girls) who were diagnosed by specialist from Changzhou Children's Hospital of Nantong University during January 2020 to September 2021. The diagnostic criteria were according to the guidelines for diagnosis and prevention of bronchial asthma in children (2016 edition) (Respiratory Group, Pediatrics Society of Chinese Medical Association and Editorial Committee of Chinese Journal of Pediatrics, 2016). All children met the following criteria: (1) Recurrent wheezing, coughing, shortness of breath, and chest tightness are mostly related to contact with allergens, cold air, physical and chemical irritation, respiratory tract infection, exercise, and hyperventilation (such as laughter and crying) and often occur or worsen at night and/or early morning.
(2) When the attack occurs, scattered or diffuse asthma can be heard in both lungs, mainly in expiratory phase, and prolonged in expiratory phase. (3) The above symptoms and signs are effective with anti-asthma treatment, or relieved by themselves. (4) Wheezing, coughing, shortness of breath, and chest tightness caused by other diseases is excluded. These children were treated with standardized therapy for at least 2 months and were in clinical remission.
The TDC group included 31 children (8.31 ± 1.39 years, 16 boys and 15 girls) from an ordinary school in Changzhou. And all the asthma and TDC children should also meet the following criteria: (1) IQ > 80 measured by the Wechsler Intelligence Scale for Children 4th edition-Chinese version (Yang et al., 2013); (2) righthandedness; (3) older than 5-year-old; (4) having no medical history related to neural and mental diseases; (5) excluding children with attention deficit hyperactivity disorder (ADHD) based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), which is the most important standard in clinic. The study was approved by the ethics committee of Changzhou Children's Hospital of Nantong University (2020-008). Each parent gave informed consent and agreed to participate in the study.

| Image acquisition
A Siemens 1.5-Tesla Magnetom Avanto scanner was applied in the study. All the children were asked to close eyes, keep calm, and awake. The echo-planar imaging sequence of fMRI used the following parameters:

| Data analysis
The first 10 time points of fMRI data were discarded to avoid the signal changes before the steady state of the children and the MRI machine. Then the data were preprocessed using the Data Processing Assistant for Resting-State fMRI Advanced Edition (DPARSFA) V4.3 software package (Yan et al., 2016). The preprocessing of the data analysis included the following procedures: (1) Slice timing correction; (2) head motion correction; (3) spatial normalization to a standard template (Montreal Neurological Institute, MNI) and resampling (3 Â 3 Â 3 mm 3 ); (4) the linear trend, head motion parameter measured by Friston-24 model, white matter (WM), and cerebrospinal fluid (CSF) signals were further regressed out as nuisance covariates; (5) DC and VMHC calculation; (6) spatial smoothing with a Gaussian kernel of 6 mm full width at half maximum (Jiang et al., 2021).

| Continue performance test (CPT)
CPT is a Go/Nogo task to test children's attentional behavior. The stimulus content includes the Arabic numeral 0-9. We make the number 1 as the cue, the 9 after 1 as the Go stimulus, the other numbers after 1 as the Nogo stimulus, and the other numbers after not-1 as the distraction stimulus. The stimulus consists of 400 numbers, among which the sequence of numbers 1 to 9 is 20%, the sequence of numbers 1 to notÀ9 is 20%, the sequence of numbers not-1 to 9 is 20%, and the probability of other numbers appearing randomly. Children were asked to respond to the "9" button that appeared immediately after "1" and not to press any other number. The stimulus lasted 200 ms with a stimulus interval of 1300 ms. The stimulus appeared in the center of the monochrome CRT display. The US E-Prime software was used to control the presentation of stimuli and automatically record behavioral results (Ding & Pang, 2021). The correct number of CPT is seemed as abnormal when it is less than 36 of 40.

| Statistical analysis
The comparison of CPT between two groups used the measure of two-sample t test by the software of SPSS 22.0. In the fMRI study, participants with head motion > 3 mm of translation or 3 of rotation in any direction were discarded and all the participants were eligible. Two-sample t test was performed as a measure of comparing the resting-state DC and VMHC between the two groups by DPARSFA. The t test results were corrected by FDR multiple comparison (P < 0.05, cluster size ≥10). And the results of two-sample t tests were overlaid on the Ch2 template (Jiang et al., 2021). The Pearson correlation between the correct percentage of CPT and DC and VMHC value was done also by SPSS 22.0.

| The comparison of attention behavior
The correct number of continuous performance test (CPT) in the asthma group was significantly lower than the TDC group (34.62 ± 2.73 vs. 36.76 ± 2.40, P = 0.001, t = À3.57; Figure 1). The percentage of the total number F I G U R E 1 Comparison of CPT behavior between asthma and TDC group. Note: "A" stands for the comparison of the reaction time of CPT between asthma and TDC group while "B" stands for the comparison of the correct number. of targets in the asthma group was also lower than the TDC group (0.87 ± 0.07 vs. 0.92 ± 0.06, P = 0.001, t = À3.57). And the reaction time in the asthma group was significantly longer than the TDC group (479.73 ± 76.86 vs. 428.58 ± 71.27, P = 0.004, t = 2.97; Figure 1).

| The comparison of DC and VMHC value between asthma and TDC group
Compared with TDC group, asthma children exhibited lower DC value in the right superior frontal gyrus (after FDR correction, P < 0.05; Table 1 and Figure 2). F I G U R E 2 Comparison of DC values between asthma and TDC group. Note: The blue areas showed the brain region where the DC value of asthma group was lower than that of the TDC group.
Compared with TDC group, asthma children exhibited lower VMHC value in bilateral superior frontal gyrus and bilateral superior parietal lobule (after FDR correction, P < 0.05; Table 1 and Figure 3).

| The correlation between the correct percentage of the total number of CPT and DC and VMHC value
There was significant correlation between the correct percentage of CPT and DC value in right superior frontal gyrus (r = 0.419, P = 0.001), VMHC value in right superior frontal gyrus (r = 0.270, P = 0.034), and VMHC value in right superior parietal lobule (r = 0.256, P = 0.045).

| DISCUSSION
DC and VMHC are two commonly used indexes to study brain networks. DC reflects the centrality of the brain region in the whole brain. The higher the degree of centrality, the more connections it has with other brain regions, and the more important it is in the whole brain (Hu et al., 2018). VMHC reflects the connection strength of homotopic brain regions in the whole brain. The more coincident the bilateral homotopic regions are, the higher the values of VMHC are (Dong et al., 2019). In this study, we used these two indexes to study the brain network in asthma children, in order to find the early indicators for the assessment of attentional cognitive impairment.
This study found that the correct number of CPT in asthma children was significantly lower than normal children, and the reaction time in asthma children was significantly longer than normal children. The CPT result was consistent with previous studies (Fluegge & Fluegge, 2018;Irani et al., 2017). In order to further research the brain mechanisms of asthma's attentional impairment, the brain network analysis methods of fMRI were used in the study.
This study found that the DC value of right superior frontal gyrus in asthma children was lower than that in normal children, and the VMHC value between left and F I G U R E 3 Comparison of VMHC values between asthma and normal group. Note: The blue areas showed the brain regions where the VMHC values of asthma group were lower than those of TDC group. right superior frontal gyrus was lower than that in normal children. The superior frontal gyrus, located in the upper prefrontal lobe, has long been considered as a complex cellular area (Petrides & Pandya, 1999). The superior frontal gyrus has been reported to be involved in many cognitive and motor control tasks, especially the posterior superior frontal gyrus which contains the supplementary motor area and is mainly involved in motor tasks (Fiori et al., 2016;Martino et al., 2011). The lateral part of superior frontal gyrus is mainly involved in executive task and attentional task in working memory (du Boisgueheneuc et al., 2006;Tang et al., 2020). The medial part of the superior frontal gyrus, which is activated during cognition-related tasks, is part of the default mode network (DMN) (Mak et al., 2017;Yan et al., 2019). Studies have found that DMN is involved in the regulation of attention and cognitive behavior. When performing attention-related tasks, DMN brain regions are activated. DMN activity antagonizes dorsal attention network, which also reflects the influence of DMN on attentional cognition. When the human brain is completing a specific task, more attention is used to concentrate on the task, and the functional activity of DMN decreases. In the resting state, attention is more used to observe the external environment, and the functional activity of DMN is significantly increased (Gao et al., 2019;Kucyi et al., 2020). In this study, the DC value of the right superior frontal gyrus and the VMHC value between the bilateral superior frontal gyrus of asthma children were both lower than normal children, and the DC and VMHC value were positively related to the accuracy of CPT, which also reflected the effect of this DMN brain region on attentional cognition. In asthma children, the functional connection between the right superior frontal gyrus and other brain regions was decreased, as well as the VMHC between the two sides of the superior frontal gyrus was decreased, which weakened the effect of the superior frontal gyrus on attentional cognition, leading to the impairment of attentional cognition in asthma children.
The VMHC value of bilateral superior parietal lobule of asthma children was lower than normal children. The superior parietal lobule is an important node of the dorsal attention network, which has similar functions with the intraparietal suleus, the core brain region of the dorsal attention network, receiving visual information input and participating in the regulation of spatial orientation. Specifically, the intrapietal sulcus is mainly involved in the endogenous attention shift caused by the change of target features but unchanged spatial position, while the superior parietal lobule is mainly related to the exogenous attention shift caused by the target spatial movement (Allan et al., 2019;Molenberghs et al., 2007;Spadone et al., 2021). The dorsal attention network, also known as the visuospatial attention network, is responsible for the management of spatial attention and visual movement, and participates in the top-down (endogenous) goal-oriented attention orientation (Majerus et al., 2018). The dorsal attention network is involved in attentional switching and spatial attention control during the adjustment of visual attention function (Menon, 2011). Therefore, as an important component of the dorsal attention network, the superior parietal lobule is directly related to attentional cognition. In this study, the VMHC value of bilateral superior parietal lobule in asthma was lower than normal children, and the VMHC value was positively related to the accuracy of CPT, also confirmed that the attentional impairment in asthma children was associated with the functional impairment of the superior parietal lobule. The functional connection between the two homotopy brain regions was weakened, which impaired the function of the superior parietal lobule to regulate attention and could not accurately complete the exogenous attention transfer, leading to the decrease of the attention level of asthma children.

| CONCLUSIONS
In conclusion, this study found that the attentional behavior of asthma children was lower than that of normal children, and the impaired functions of superior frontal gyrus and superior parietal lobule were related to the attention deficit of asthma children. This study explored the possible mechanism of attention deficit in asthma children and found that the attention deficit was related to the damage of the key nodes of DMN and the dorsal attention network. This study will provide objective indicators for the evaluation of attention in asthma children. However, the sample size of the study was relatively small, and we did not determine the number of participants to recruit in each group. We will further enlarge the sample size and make the study more reliable.

ACKNOWLEDGMENT
The authors thank the imaging department of Wujin People's Hospital for data collection.

CONFLICTS OF INTEREST
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

ETHICS STATEMENT
All human studies were approved by the Ethical Committee of Changzhou Children's Hospital of Nantong University in Jiangsu Province, China (Approval Number: 2020-008), and written informed consents were obtained from the custodians of each participant before samples collecting. All methods were performed in accordance with the relevant guidelines and regulations (e.g., Declaration of Helsinki).

AUTHOR CONTRIBUTIONS
Kaihua Jiang and Lin Zhu designed the study, conducted the analysis, and drafted the initial manuscript; Ye He, Congyin Qin, and Jianfeng Wu were involved in the acquisition of the data; Yuya Yang, Qiuling Shangguan, and Yi Chen contributed to the conduct of the study; Jianxin Xiong and Jing Zhao designed the study, reviewed and revised the manuscript. All authors reviewed the manuscript and approved the final version.

DATA AVAILABILITY STATEMENT
The datasets generated and/or analyzed during the current study are not publicly available due the data files were too large (more than 7G) for upload. But they are available from the corresponding author on reasonable request.