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Table of Contents    
Year : 2018  |  Volume : 66  |  Issue : 5  |  Page : 1365-1366

Brain networking in primary monosymptomatic nocturnal enuresis: News from Brain-Bladder-Control matrix

1 Department of Pediatric Nephrology, Kasturba Medical College, Manipal Acadmey of Higher Education, Manipal, Karnataka, India
2 Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Web Publication17-Sep-2018

Correspondence Address:
Dr. Narayan Prasad
Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.241399

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How to cite this article:
Rangaswamy D, Prasad N. Brain networking in primary monosymptomatic nocturnal enuresis: News from Brain-Bladder-Control matrix. Neurol India 2018;66:1365-6

How to cite this URL:
Rangaswamy D, Prasad N. Brain networking in primary monosymptomatic nocturnal enuresis: News from Brain-Bladder-Control matrix. Neurol India [serial online] 2018 [cited 2019 Feb 16];66:1365-6. Available from:

The International Children's Continence Society defines primary monosymptomatic nocturnal enuresis (PMNE) as episodes of urinary incontinence without additional lower urinary tract symptoms during sleep in children ≥5 years of age who have previously been dry for less than 6 months.[1] It can occur in up to 20% of children and is known to cause significant psychosocial stress and lowered self-esteem in them.[2] An observation that most cases resolve spontaneously with increasing age, supports the theory that a maturation delay in the areas of brain involved in bladder control play a role in PMNE.[3] Nocturnal polyuria, detrusor overactivity, disturbed sleep and the underlying genetic constitution are other factors that are associated with and contribute towards PMNE.

A complex synchronization between the autonomic and somatic nervous systems at various centres in the spinal cord, brainstem especially the midbrain and cerebral cortex permits a coordinated function of urinary storage and micturition. The delayed cortical maturity in PMNE and the associated psychiatric problems were noted in 2003 by Toros et al., who demonstrated an increased frequency of high-level hyperventilation response in resting-state electroencephalogram recordings.[4] Supporting the theory of maturational delay in central nervous system, Iscan et al., in 2002, showed a longer P300 latency; and Freitag et al., in 2006, showed increased I–III and I–V inter-peak latencies on event-related brain potentials and brainstem auditory evoked potentials, respectively, among children with PMNE.[5],[6]

With techniques in magnetic resonance imaging (MRI) evolving, structural MRI, functional MRI and diffusion MRI have taken over as the preferred investigative tool for research on bladder control, urgency and incontinence. Functional MRI (fMRI) detects blood oxygen level–dependent (BOLD) variation in the MRI signals associated with changes in neuronal activity of the brain during rest or the performance of a task. fMRI is safe, non-invasive, and repeatable, resulting in its widespread use for various indications and potential newer applications that are emerging on a daily basis.[7] Using event-related fMRI in children with PMNE, Yu et al., demonstrated deficits in working memory, and Lei et al., reported an altered forebrain activation during the conduction of a response inhibition task.[8],[9] A resting-state fMRI during no obvious task performance can assess white matter integrity in children, as demonstrated by Gordon et al.[10] Resting-state fMRI examines low-frequency oscillations (0.01–0.1 Hz) associated with spontaneous brain activity.[11] Lei et al., using resting-state fMRI data, compared regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) values among 16 children with PMNE and 16 healthy controls. The ALFF analysis detected fluctuations in spontaneous, low-frequency oscillations, while ReHo reflected the temporal homogeneity of regional BOLD signals regardless of their intensities. Children with PMNE exhibited significant differences in ALFF or ReHo in the left inferior frontal gyrus, medial frontal gyrus and left midbrain. They concluded that a delay in maturation across several areas in the central nervous system involved in the micturition control network impairs a child's ability related to decision making with regard to voiding.[12]

Jiang et al., in their study using resting-state fMRI, investigated the intensity of functional connectivity among the nodes in the brain network and between the two hemispheres of the brain by comparing degree centrality (DC) and voxel-mirrored homotopic connectivity (VMHC) respectively, amongst children with PMNE and in normal controls.[13] While evaluating network theory in the brain, it has been determined that there are a few nodes involved in network structures that play a crucial role and are said to be central. Central nodes are identified using centrality metrics, with the ‘degree’, the ‘betweenness' between the nodes, and the ‘Eigenvector centrality' being the most popular. The ‘degree' identifies the most connected nodes, whereas ‘betweenness centrality' identifies the nodes located on the most travelled paths. The ‘Eigenvector centrality' considers nodes connected to other highly central (high degree) nodes. The DC makes the brain network more complete by establishing a quicker connection type.[14] As VMHC quantifies functional connectivity of every voxel and compares the strength of the connectivity between the left hemispheric brain areas to the mirrored right hemispheric areas, Jiang et al., justified its use in evaluating children with PMNE who exhibit dysplasia in brain regions related to urination control.[13] To gauge the emotional and behavioural problems associated in children with PMNE, the authors have also used a self-scoring perceived health competence scale, comprising six sections and eighty items in total.

When compared to healthy controls, Jiang et al., demonstrated four areas in the brain with a poor networking among the nodes in children with PMNE, using the DC component of resting-state fMRI. The four areas were the posterior cerebellar lobe, anterior cingulate cortex (ACC), medial frontal gyrus, and superior left temporal gyrus. Additionally, in children with PMNE, the VHMC values were lower in the cerebellar lobe and the ACC. Their overall scores on the self-concept scale were also lower compared to that of healthy controls. They also suggested that the poor connectivity across different areas of the brain could explain the pathogenesis of PMNE and their associated behavioural changes. Lack of connectivity from the cerebellar nodes impaired vasopressin secretion from the hypothalamus; lack of connection in the ACC caused obstacles in sending out signals to the cerebrum in time; diminished attention and control occurred due to deficits in the medial frontal gyrus; and, impaired memory occurred due to the involvement of the temporal lobe. All these factors contributed to the resultant nocturnal enuresis and associated attention deficits among them.

In their experiments using resting-state fMRI analysed by Resting-State fMRI Data Analysis Toolkit (REST) software, Yu et al., also implicated aberrant brain connections that resulted in impaired intelligence in children with primary nocturnal enuresis. The cerebello-thalamo-frontal pathway involving the left and right dorsolateral prefrontal cortex, thalamus and cerebellar hemisphere, were the predominant sites of altered functional connectivity. They suggested that cerebellum with its strong functional connections was involved in working memory control and execution. This would possibly explain the phenomena of attention deficits associated with PMNE and the co-existing aberrant cerebellar connections. They also suggested that an altered thalamic connectivity may impair the ability to wake up during sleep in response to the need to void.[2] Unlike Jiang et al.,[13] who demonstrated low values of DC and VHMC across different areas in brain, Yu et al.,[8] identified increased connectivity between the right ACC and the left cerebellum (crus I), and in the right inferior frontal gyrus among children with PMNE. This could possibly be due to a neural reorganization to compensate for the deficient regions, required during manipulation and memory maintenance.

It would be interesting to see whether or not the functionality of the involved area observed in the study by Jiang et al.,[13] improves once the children affected with NE become continent with age.

  References Top

Nevéus T, von Gontard A, Hoebeke P, Hjälmås K, Bauer S, Bower W, et al. The standardization of terminology of lower urinary tract function in children and adolescents: Report from the Standardisation Committee of the International Children's Continence Society. J Urol 2006; 176:314-24.  Back to cited text no. 1
Yu B, Sun H, Ma H, Peng M, Kong F, Meng F, et al. Aberrant whole-brain functional connectivity and intelligence structure in children with primary nocturnal enuresis. PloS one 2013;8:e51924.  Back to cited text no. 2
Klackenberg G. Nocturnal enuresis in a longitudinal perspective: A primary problem of maturity and/or a secondary environmental reaction?. Acta Paediatrica 1981;70:453-7.  Back to cited text no. 3
Toros F, Ozge A, Bozlu M, Cayan S. Hyperventilation response in the electroencephalogram and psychiatric problems in children with primary monosymptomatic nocturnal enuresis. Scand J Urol Nephrol 2003;37:471-6.  Back to cited text no. 4
Iscan A, Ozkul Y, Unal D, Soran M, Kati M, Bozlar S, et al. Abnormalities in event-related potential and brainstem auditory evoked response in children with nocturnal enuresis. Brain Dev 2002;24:681-7.  Back to cited text no. 5
Freitag CM, Rohling D, Seifen S, Pukrop R, von Gontard A. Neurophysiology of nocturnal enuresis: Evoked potentials and prepulse inhibition of the startle reflex. Dev Med Child Neurol 2006;48:278-84.  Back to cited text no. 6
Gore JC. Principles and practice of functional MRI of the human brain. J clin Invest 2003;112:4-9.  Back to cited text no. 7
Yu B, Guo Q, Fan G, Ma H, Wang L, Liu N. Evaluation of working memory impairment in children with primary nocturnal enuresis: Evidence from event-related functional magnetic resonance imaging. J Pediatr Child Health 2011;47:429-35.  Back to cited text no. 8
Lei D, Ma J, Du X, Shen G, Tian M, Li G. Altered brain activation during response inhibition in children with primary nocturnal enuresis: An fMRI study. Hum Brain Mapp 2012;33:2913-9.  Back to cited text no. 9
Gordon EM, Lee PS, Maisog JM, Foss-Feig J, Billington ME, Vanmeter J, et al. Strength of default mode resting-state connectivity relates to white matter integrity in children. Dev Sci 2011;14:738-51.  Back to cited text no. 10
Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med 1995;34:537-41.  Back to cited text no. 11
Lei D, Ma J, Du X, Shen G, Tian M, Li G. Spontaneous brain activity changes in children with primary monosymptomatic nocturnal enuresis: A resting-state fMRI study. Neurourol Urodyn 2012;31:99-104.  Back to cited text no. 12
Jiang K, Ding L, Li H, Shen H, Zheng A, Zhao F, et al. Degree centrality and voxel-mirrored homotopic connectivity in children with nocturnal enuresis: A functional MRI study. Neurol India 2018;66:1359-64.  Back to cited text no. 13
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Joyce KE, Laurienti PJ, Burdette JH, Hayasaka S. A new measure of centrality for brain networks. PLoS One 2010;5:e12200.  Back to cited text no. 14


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