nature publishing group Articles Clinical Investigation Task positive and default mode networks during a working memory in children with primary monosymptomatic nocturnal enuresis and healthy controls Kaihua Zhang1, Jun Ma2, Du Lei1,3, Mengxing Wang1, Jilei Zhang1 and Xiaoxia Du1 BACKGROUND: Nocturnal enuresis is a common develop- event-related brain potentials indicated that maturational mental disorder in children, and primary monosymptomatic delays in central nervous system development are indicators nocturnal enuresis (PMNE) is the dominant subtype. of PMNE pathogenesis (5–8). Primary nocturnal enuresis chil- METHODS: This study investigated brain functional abnor- dren show a higher prevalence of all sleep disturbances (9). malities that are specifically related to working memory in Furthermore, the prevalence of fine motor coordination and children with PMNE using function magnetic resonance imag- visuomotor integration were abnormal in prepubertal children ing (fMRI) in combination with an n-back task. Twenty children with PMNE. These studies suggested that PMNE should not be with PMNE and 20 healthy children, group-matched for age considered as a voiding disorder alone (10). and sex, participated in this experiment. Magnetic resonance imaging (MRI) techniques, such as RESULTS: Several brain regions exhibited reduced activation structural MRI, functional MRI (fMRI), and diffusion MRI, during the n-back task in children with PMNE, including the provide efficient, feasible and noninvasive methods to inves- right precentral gyrus and the right inferior parietal lobule tigate the biological mechanisms of incontinence. Several extending to the postcentral gyrus. Children with PMNE exhib- studies reported alterations in brain functions in patients with ited decreased cerebral activation in the task-positive network, urgency and urge incontinence using fMRI (11,12). We per- increased task-related cerebral deactivation during a working formed a series of MRI experiments to investigate functional memory task, and longer response times. and structural abnormalities that are associated with PMNE. CONCLUSION: Patients exhibited different brain response Our previous studies identified microstructural abnormalities patterns to different levels of working memory and tended to in the thalamus, medial frontal gyrus, anterior cingulate cor- compensate by greater default mode network deactivation tex, and insular cortex of children with PMNE using diffusion to sustain normal working memory function. Our results sug- MRI (13) and neurochemical abnormalities in the prefrontal gest that children with PMNE have potential working memory cortex (PFC) and pons of children with PMNE using proton dysfunction. magnetic resonance spectroscopy (14). We also reported that the nature of local intrinsic activity changed in the PFC dur- ing resting states in children with PMNE (15). Furthermore, octurnal enuresis is a common developmental disorder we demonstrated that functional brain networks in PMNE Nthat affects 15–20% of 5-y-old children (1). This disorder patients were characterized by a significantly lower clustering can persist into adolescence, and it negatively affects the self- coefficient and global and local efficiencies, and a higher -char image and performance of these children (2). Primary mono- acteristic path length using graph theory-based network anal- symptomatic nocturnal enuresis (PMNE) is diagnosed when a ysis (unpublished data). These findings suggest that children child exhibits enuresis without additional lower urinary tract with PMNE have brain network alterations that affect global symptoms with the exclusion of nocturia or a history of bladder communication and integration. These studies demonstrated dysfunction without a period of established urinary continence that children with PMNE exhibit structural, functional (under for more than 6 mo (3). Several factors are associated with and resting states), and neurochemical abnormalities in the brain, contribute to nocturnal enuresis, including heredity, polyuria, which suggest that children with PMNE have potential cog- detrusor overactivity, sleep, and central nervous system mecha- nitive problems. In fact, forebrain activation in children with nisms (4). Previous studies using electroencephalograms and PMNE was altered during a response inhibition task (16). The first two authors contributed equally to this work. 1Department of Physics, Shanghai Key Laboratory of Magnetic Resonance, East China Normal University, Shanghai, China; 2Department of Developmental and Behavioral ­Pediatrics of Shanghai Children’s Medical Center, XinHua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Children’s Environmental Health, Shanghai, China; 3Department of Radiology, MR Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China. Correspondence: Xiaoxia Du ([email protected]) Received 23 October 2014; accepted 12 March 2015; advance online publication 15 July 2015. doi:10.1038/pr.2015.120 422 Pediatric ReseArcH Volume 78 | Number 4 | October 2015 Copyright © 2015 International Pediatric Research Foundation, Inc. Working memory in nocturnal enuresis Articles Previous research suggests that the PFC is important for 1100 bladder control (11,12). We demonstrated previously that the PFC was abnormal in children with PMNE (13–16). The PFC 900 is responsible for executive functions, such as mediating con- * * flicting thoughts, making choices, predicting future events, 700 and governing social control (17). The dorsolateral and ventro- lateral PFC play important roles in working memory (18). One Response time (ms) 500 previous study utilized event-related fMRI in PMNE subjects and identified a dysfunction in the left cerebella of PMNE chil- 300 dren. However, this study did not investigate PFC abnormali- Mean RT 0-back RT 1-back RT 2-back RT ties during n-back working memory (19). The fMRI-testing paradigm in this previous study was a type of visual working 100 memory task-categorical n-back paradigm of moderate dif- ficulty without differentiation degrees. It is not clear whether impairments during different difficult n-back tasks exist in 90 children with PMNE. Working memory is an important cognitive function in Accuracy (%) humans that refers to the ability to transiently store and 80 manipulate information “held online” in the service of com- plex cognition for further behavioral guidance (20). Working 70 memory primarily involves a bilateral parieto-frontal net- Mean CR 0-back CR 1-back CR 2-back CR work in the performance of classical n-back tasks (18). We Figure 1. Working memory task performance in children with PMNE hypothesized that children with PMNE have potential dys- and controls. The solid line represents HC, and the dashed line represents function during working memory, and they use different PMNE. CR, average percentage of correct responses; HC, healthy children; cognitive strategies during working memory compared to RT, average response times. *P < 0.05 children with PMNE compared with healthy children. This study investigated working memory in healthy children. children with PMNE and healthy children using the classic n-back task with three levels of difficulty (0-back, 1-back, and The control group exhibited significant activation in the right 2-back) and fMRI. medial frontal gyrus, bilateral middle, inferior and superior frontal gyri, bilateral inferior parietal lobules extending to the RESULTS superior parietal lobule, the right middle temporal gyrus, bilat- Task Performance eral caudate, and bilateral cerebellum posterior lobes in “2-back” Children with PMNE exhibited slight better performance minus “0-back” contrast (Table 1 and Figure 2). The PMNE accuracy (during 1-back and 2-back) compared with control group also exhibited similar frontal-occipital activation, includ- children, but no significant differences in the overall or indi- ing bilateral middle and inferior frontal gyri, bilateral inferior vidual n-back task means. For example, the average percent- parietal lobules extending to the superior parietal lobule, and ages of correct responses were 85.3 ± 7.3% for children with bilateral cerebellum posterior lobes (Table 1 and Figure 2). PMNE, and 82.9 ± 7.1% for the control children. The PMNE There were no significant differences between groups. group exhibited a longer response times (RT) during the The control group exhibited significant activation in the left n-back task, and the average RT and 1-back RT were signifi- medial frontal gyrus, bilateral middle, inferior and superior cantly longer in PMNE children. The average RT was longer frontal gyri, bilateral inferior parietal lobules extending to the in PMNE children (P < 0.05): 671.6 ± 114 ms in children with precuneus and superior parietal lobule, the right middle tem- PMNE, and 588.9 ± 68.9 ms in control children. The 1-back RT poral gyrus, and the right cerebellum posterior lobe in “2-back” was also longer in PMNE children (P < 0.05): 687.8 ± 132.7 ms minus “1-back” contrast (Table 2 and Figure 3). The PMNE in children with PMNE, and 582.3 ± 76.4 ms in control chil- group exhibited similar but weaker activation in the right dren. Additional details are shown in Figure 1. medial frontal gyrus, bilateral middle and inferior frontal gyri, bilateral inferior parietal lobules, and the right superior pari- Functional MRI Data etal lobule (Table 2 and Figure 3).The PMNE group exhibited Task-positive networks across multiple cognitive domains. significantly