Nocturnal enuresis is characterized by unintentional urination during the night on more than two occasions per month, causing distress for both the affected child and their caregivers. In recent years, there has been growing interest in exploring its underlying mechanisms from a neuroscientific perspective. The purpose of our study is to elucidate the neurostructural correlates of nocturnal enuresis in pediatric patients. By understanding the neurocorrelations of nocturnal enuresis, we aim to contribute to a better understanding of its pathomechanism, ultimately improving treatment strategies and acceptance of this condition.

For this purpose, we utilized data from the Adolescent Brain Cognitive Development (ABCD) study, which is the largest longitudinal study of neurodevelopment and child health in the United States. The study population closely represents the demographics of the general U.S. population. We retrieved tabulated imaging, socioeconomic, and clinical information at baseline from the fourth public ABCD data release. We excluded individuals with incomplete clinical or socioeconomic information, presence of encopresis, obstipation, daytime incontinence, severe brain conditions, a history of parental drug use, mental health issues, drug use during pregnancy, and a history of parental mental health issues.
In the following sections, we compare four groups: individuals with a current history of nocturnal enuresis, individuals with a former history of nocturnal enuresis, individuals who have ever experienced nocturnal enuresis, and a control group who have never experienced nocturnal enuresis.
In multivariate linear regression models, we examined the association of different neuroimaging metrics with the presence versus absence of nocturnal enuresis. In the first model, we assessed the association of each neuroimaging variable with the presence of nocturnal enuresis, correcting for handedness. Similarly, we tested the association of neuroimaging variables with a positive history of nocturnal enuresis but no current symptoms. Subsequently, we compared neuroimaging metrics between individuals currently experiencing nocturnal enuresis and those with a history of nocturnal enuresis but no present symptoms to identify differences between individuals who wet the bed and those who have stopped wetting the bed.

In our final analysis, we grouped individuals with current symptoms and those with past symptoms of nocturnal enuresis together to compare their brain structure and functional connectivity.
The neuroimaging metrics included the averaged fractional anisotropy (FA), neurite density (ND), mean diffusivity (MD), radial diffusivity (RD), fiber tractography (FT), and axial diffusivity (AD) of 35 white matter tracts, as well as thickness and surface areas of 68 cortical regions, and the inter- and intra-network correlations of 13 predefined functional groups and 21 subcortical regions. To correct for multiple comparisons, we applied the false discovery rate to generate adjusted p-values. All analyses were performed using R software (version 4.2.2).

Subjects' Ascertainment
After excluding individuals with incomplete imaging, clinical, or socioeconomic information, severe brain conditions, a history of parental drug use, mental health issues, drug use during pregnancy, and a history of parental mental health issues, a total of 3,472 participants were included in our analysis: 2,076 in the control group, 225 with current nocturnal enuresis, 2,301 who have ever experienced nocturnal enuresis, and 1,171 with a history of nocturnal enuresis but no current symptoms.
Control vs. Case
Children with nocturnal enuresis exhibited increased cortical volume compared to those without, particularly in the precuneus and subcortical regions. The presence of nocturnal was associated with higher cortical volume in the right (adjusted p value=0.0223) and left precuneus areas (adjusted p value=0.0223), right rostral middle frontal cortex (adjusted p value=0.0216), left and right thalamus (adjusted p value=0.006), cerebellum (adjusted p value=0.0108), putamen (adjusted p value=0.023), and pallidum (adjusted p value=0.048). No differences in sulcal depths and cortical thickness remained significant after FDR correction.

Control vs. Prior Wetters
A positive history of nocturnal enuresis without current symptoms was associated with increased cortical area and volume (Figure 2), most prominently in the frontal cortex and subcortical regions. Changes were observed in the superior frontal cortex (adjusted p value=0.0106), rostral middle frontal cortex (adjusted p value=0.002), pars orbitalis (adjusted p value=0.001), medial orbitalis cortex (adjusted p value=0.001), caudal middle frontal cortex (adjusted p value=0.0239), rostral anterior cingulate (adjusted p value=0.023), and insula (adjusted p value=0.005) regions. Similar to our comparison between the control and case groups, involvement of the thalamus (adjusted p value=0.0175), cerebellum (adjusted p value=0.001), putamen (adjusted p value=0.001), pallidum (adjusted p value=0.001), brain stem (adjusted p value=0.0001), and ventral diencephalon (adjusted p value=0.0001) was evident. Additionally, the hippocampus (adjusted p value=0.018), amygdala (adjusted p value=0.012), and accumbens area (adjusted p value=0.028) appeared to be involved. Notably, mean diffusivity, a parameter for white matter integrity, was decreased in the hippocampus. No differences in sulcal depths and cortical thickness remained significant after FDR correction.

Case vs. Prior Wetters
In this analysis, no metrics appeared to differ from each other, suggesting that there is no difference in the brain between current and former bedwetters.

Patients Who Ever Wet vs. Control
Children who had ever experienced nocturnal enuresis exhibited a significant increase in cortical area and volume in the frontal cortex and subcortical area, similar to the results of the previous analysis comparing the case group with the control and prior wetter groups. Additionally, a decrease in cortical volume was observed in the pars triangularis (adjusted p value=0.039), lateral/medial orbitofrontal cortex (adjusted p value=0.013), and paracentral cortex (adjusted p value=0.036), emphasizing the importance of the frontal cortex in the context of continence. In this group, an increase in the default network with the cingulo-opercular network was also observed.

Through our strict exclusion and inclusion criteria, we were able to identify a homogeneous group, enabling us to pinpoint neurostructural and functional correlates of nocturnal enuresis. Upon examining the results from the different group comparisons, the precuneus appears to be relevant to the occurrence of current nocturnal enuresis, and subcortical regions like the thalamus also seem to play a role in nocturnal enuresis.
Our findings also suggest that neurostructural differences persist even after patients have stopped wetting the bed. Significant results were observed when comparing current bedwetters with former bedwetters, and similar results were found when comparing the current bedwetter group with the prior bedwetter group, indicating that the changes in the brain might be permanent even without the symptoms.

Nocturnal enuresis appears to be associated with cortical thickening in the subcortical and frontal cortex areas. This suggests the involvement of memory, learning, and emotion in the pathomechanism of nocturnal enuresis. The involvement of subcortical regions, which play a pivotal role in cognitive, affective, and social functions, indicates significant brain changes that appear to be present even when symptoms are not evident. However, it also seems correlated with reduced white matter integrity in the hippocampus. These results might be evidence of a delay in the maturation or evolution of these areas. We need to continue monitoring the patients several years down the road to ascertain if this change is permanent. Our findings suggest that the role of the central nervous system in the context of nocturnal enuresis is more substantial than previously thought.

Continence 12S (2024) 101367
DOI: 10.1016/j.cont.2024.101367