The Cognitive Characteristics of PNE Children with Different Genders: A Resting-State fMRI Study
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.333504
Source of Support: None, Conflict of Interest: None
Keywords: ALFF, children, gender, PNE, rs-fMRI
Primary nocturnal enuresis (PNE) refers to the unconscious micturition behavior of children beyond five years old who cannot wake up at night to control micturition. The incidence rate of children reaches 6–10%, and some children's symptoms can last to adulthood., The incidence of psychological diseases in enuresis children is about four times higher than that in normal children, mainly manifested as attention deficit, anxiety, and obsessive compulsive disorder., At present, there are few studies on the cognitive function of PNE, and the cognitions between different genders of PNE is even rarer. There have been some studies on attention impairment of PNE children using scale. Researchers found that PNE showed more obvious attention impairment than normal children through the comparative analysis of the fifth edition of the diagnostic statistical manual of mental disorders and the children's behavior checklist. However, scale analysis is not enough to explain the mechanism of cognitive dysfunctions.,
Nowadays, functional magnetic resonance imaging (fMRI), as a new technique that has the advantage of being noninvasive, with the children not being exposed to radiation, and the images have a high spatia l resolution. fMRI has been widely used in research related to cognitive understanding and in eliciting neural mechanisms responsible for clinical diseases. The resting state (rs-) fMRI is characterized by high repeatability, which can shorten the examination time and improve patient compliance, and has good clinical application value.,
There have been some studies using fMRI on the research of PNE. Lei et al. used the method of amplitude of low frequency fluctuation (ALFF) in the study of PNE and found that the brain area with reduced ALFF value in enuresis compared with normal children was located in the left inferior frontal gyrus (extended to the medial frontal gyrus), while ALFF value in PNE was higher than normal children in the posterior cingulate gyrus, middle temporal gyrus, and left midbrain. Lei's study has found the basic functional imaging features of PNE, but the differences of different genders are not yet clear.
In this study, the characteristics of fMRI of children with enuresis of different genders are compared, and the results of attention behavior are analyzed. The aim of this study is to explore the brain mechanism of cognitive differences by comparing ALFF value and attention cognitive behavior in PNE and normal children of different genders.
The PNE group included 32 children aged (8.61 ± 1.93 years, 15 boys and 17 girls) who were diagnosed by urologists during January 2016 to April 2019. The diagnostic criteria were according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V). All children must meet the following criteria: 1) older than 5-year-old; 2) right-handedness; 3) no contraindication for MRI; 4) IQ >80 measured by the Wechsler Intelligence Scale for Chinese Children-Revised; 5) bed-wetting at least twice a week and lasting for more than 6 months; 6) having no symptoms, signs, and medical history related to neural and mental system; 7) having no urinary system disease; 8) being able to control urination in the daytime but not after falling asleep.
The control group included 35 children (8.72 ± 1.63 years, 16 boys and 19 girls) from an ordinary school. The inclusion criteria were the same as 1-4 of the PNE group. Informed consent was obtained from the parent of each child, and all the participants agreed to take part in the study.
The images were acquired using the Siemens 1.5-Tesla Magnetom Avanto scanner. Children were asked to lie supine with heads fixed by a belt and foam pads for minimizing head motion. During fMRI scanning, children were instructed to close their eyes and remain as still as possible in a calm and awake status. fMRI data were acquired using an echo-planar imaging (EPI) sequence with the following parameters: 18 axial slices, repetition time (TR) =2000 ms, echo time (TE) =40 ms, flip angle = 90°, thickness/gap = 6.0/1.2 mm, field of view (FOV) =240 × 240 mm, matrix = 64 × 64, 180 volumes (6 min). High-resolution T1-weighted three-dimensional (3D) images were acquired sagittally, covering the entire brain using the following parameters: TR = 414 ms, TE = 11 ms, flip angle = 90°, in-plane resolution = 256 × 256, FOV = 240 mm × 240 mm and thickness/gap = 5.0/1.5 mm.
The first 10 volumes of fMRI data were discarded to avoid transient signal changes before the magnetization reached a steady-state and to allow the participants to get used to the scanning noises. Then the data were preprocessed using the Data Processing Assistant for Resting-State fMRI Advanced Edition (DPARSFA) V4.3 software package. DPARSFA is a widely used rs-fMRI analytic tool which is based on the Statistical Parametric Mapping (SPM8). The preprocessing included the following procedures: 1) slice timing correction; 2) head motion correction; 3) spatial normalization to a standard template (Montreal Neurological Institute; MNI) and re-sampling (3 × 3 × 3 mm3); 4) removal of linear trend; 5) spatial smoothing with a Gaussian kernel of 6 mm full width at half maximum. 6) ALFF calculation of the whole brain. ALFF calculation was performed after preprocessing. ALFF is the amplitude of low frequency fluctuations of the blood oxygen level dependent (BOLD) signal of every single voxel.
Continue performance test (CPT) is an indicative Go/Nogo task. The stimulus content is the Arabic numeral 0–9, 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 (0, 2, 3, 4, 5, 6, 7, 8) as the distraction stimulus. The stimulus consists of 400 numbers, among which the sequence of numbers 1–9 is 20%, the sequence of numbers 1-not-9 (the number after 1 is not 9) is 20%, the sequence of numbers not-1 to 9 (the number after not-1 is 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 was 200 ms with a stimulus interval of 1,300 ms. The stimulus appears in the center of the CRT display, black and white. Use the e-prime software to control the presentation of stimuli and automatically record behavioral results.
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 the resting-state ALFF and CPT difference between the two groups. The correlation between the CPT behavior and the degree centrality of all enuresis and normal children were analyzed. The results of two-sample t-test of ALFF were superimposed on the Ch2 template for viewing. A threshold value of P < 0.05 was set, and only regions with no less than 228 voxels were considered statistically significant.
Comparison of ALFF between PNE and normal children
There were no obviously different brain regions of ALFF between normal boys and girls. The brain regions which had obvious differences of ALFF between PNE boys and girls were right middle frontal gyrus, left inferior parietal lobule, and right posterior cerbellar lobe. And the group of PNE boys were higher than PNE girls on all the three regions (P < 0.05), [Figure 1] and [Table 1].
Comparison of CPT behavior between PNE and normal children
Amplitude of low frequency fluctuation is a data-driven analysis method to study the changes of blood oxygenation level dependent (BOLD) signal in the resting state of brain, which is a method to analyze the amplitude of the local characteristics of BOLD signal activity. ALFF is considered to be able to directly reflect the spontaneous activity of neurons, avoid the influence of error under the hypothesis driven algorithm, and directly reflect the brain region with abnormal activity., The CPT behavior results of this study showed that the reaction time of PNE and normal boys was lower than that of girls, but there was no significant difference in the correct number. This is consistent with different personality traits of male and female school-age children, with boys showing more “impulsive” characteristics. Meanwhile, the accuracy of attention behaviors of the two groups is similar. fMRI showed no significant differences in ALFF between normal boys and girls, suggesting that the results of brain functional imaging of different genders in normal children were basically the same. So does fMRI differ by gender in children with PNE?
The research found that brain regions which had obvious differences of ALFF between PNE boys and girls were right middle frontal gyrus, left inferior parietal lobule, and right posterior cerbellar lobe. Right middle frontal gyrus and left inferior parietal lobule are both components of default mode network (DMN). DMN is the most important part of resting state network which participates in introverted thinking related to “ego,” monitoring the external environment and spontaneous thinking. The brain activity of DMN is stronger in the resting state and becomes significantly weakened while carrying out goal-directed tasks. Disruption of DMN may lead to dysfunction, leading to neuropsychiatric disorders. The prefrontal cortex plays a key role in complex cognitive functions such as attention regulation, learning, memory, thinking, and reasoning. The middle frontal gyrus and the superior frontal gyrus constitute the dorsolateral prefrontal cortex, which is an important node in the cognitive control network and participates in the functions of higher cognitive regulation, working memory, and decision-making. Inferior parietal lobule is an important part of the attention network, which is mainly involved in the attention of visual space and individual perception and action. The left inferior parietal lobule is a part of the Wernicke region and plays an important role in semantic understanding. According to Moulton et al., the left inferior parietal lobule is involved in visual search, spatial attention, and working memory in motor language. In this study, the ALFF value of the left inferior parietal lobule in children with PNE decreased, indicating that the function of the left inferior parietal lobule was lower, and it coordinated with some areas of the right middle frontal gyrus to cause the decline of the attention and executive function of PNE girl.
ALFF was also higher in boys with PNE in the right posterior cerbellar lobe than in girls. Yu et al. took event-related fMRI based on n-back paradigm and found that children with PNE existed working memory deficit and was related to dysfunction of cerebellum. Yu et al. also used this technique to analyze the white matter fiber bundles of PNE children, and found that the FA value of cerebellum was significantly lower than that of the control group, which indicated that the abnormal white matter fiber development might affect the function of the “frontal lobe—thalamus—cerebellum” neural circuit. This study took fractional ALFF method and found that the symptom of enuresis and working memory dysfunction in children with PNE were associated with cerebellum damage in the early stage. Therefore, enuresis itself has been proved to have cerebellar functional impairment. The cerebellum is involved in cognitive processes such as working memory, spatial processing, and time perception processing. The connection between the cerebellum and the cerebellum has an impact on cognitive functions, and different parts are involved in different cognitive functions., In this study, the ALFF value of the right posterior cerbellar lobe in PNE girls was lower than that in boys, indicating that the cerebellar damage in PNE girls was more severe, resulting in impaired working memory function associated with it.
In this study, both fMRI and CPT behavior were compared between different genders of PNE and normal children. This study found that girls with PNE performed more obvious damages on attention, executive function, and working memory than boys which might be related to the fact that girls were more likely to suffer from confidence impairment due to enuresis leading to cognitive dysfunctions. However, there are still many shortcomings: 1. Magnetic resonance data were collected on Siemens 1.5T machine. Currently, the international mainstream is inclined to 3.0T MRI. Our research group is also transforming to Siemens 3.0T MRI and is in the process of data collection; 2. After the gender grouping of PNE and normal group, the sample size of each group is less than 20, which needs to be further increased to improve the data reliability; 3. Further research can be combined with the behavior scale for analysis. This study found that girls with PNE performed more obvious damages on attention, executive function and working memory than boys which might be related to the fact that girls were more likely to suffer from confidence impairment due to enuresis leading to cognitive dysfunctions.
We would like to thank all the participants and researchers in this study. This work was supported by the Science and Technology Project of Jiangsu Province (BL2014037).
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3]