Neurophysiologie Clinique/Clinical Neurophysiology (2015) 45, 151—158
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ORIGINAL ARTICLE/ARTICLE ORIGINAL
Transcranial magnetic stimulation identifies cortical excitability changes in monosymptomatic nocturnal enuresis La stimulation magnétique transcrânienne identifie des modifications d’excitabilité corticale dans l’énurésie nocturne E.M. Khedr a,∗, N. Abo-Elfetoh a, K.A. Elbeh a, A.A. Baky a, R.M. Gamal b, D. El Hammady b, F. Korashy a a b
Department of neuropsychiatry, Assiut university hospital, Assiut, Egypt Rheumatology and rehabilitation department, faculty of medicine, Assiut University, Assiut, Egypt
Received 28 November 2014; accepted 15 February 2015 Available online 22 April 2015
KEYWORDS Nocturnal enuresis; Cortical excitability; Resting and active motor threshold; Cortical silent period; Transcallosal inhibition
∗
Summary Objectives. — A limited number of electroencephalography (EEG) studies in nocturnal enuresis (NE) have reported cortical dysmaturity. The aim of the present study was to test this notion by examining cortical excitability in subjects with nocturnal enuresis (NE) using transcranial magnetic stimulation (TMS). Material and methods. — We investigated 41 patients with NE meeting the DSM-IV diagnostic criteria for NE, and 18 age- and sex-matched controls. Each subject was assessed clinically regarding frequency, duration of enuresis and Health Survey Measurement. Neurophysiological measures included resting and active motor thresholds (RMT, AMT), motor evoked potentials (MEP) of upper and lower limbs, cortical silent period duration (CSP) and transcallosal inhibition (TCI), in the upper limbs. Results. — Patients had a significantly lower Health Survey Measurement score for both physical and mental health components compared to the control group. RMT and AMT of both upper and lower limbs as well as the duration of the CSP and TCI were significantly reduced compared with the control group. There was significant positive correlation between RMT, AMT and Health Survey Measurement scores, especially Social Functioning.
Corresponding author. Department of neurology, faculty of medicine, Assiut university hospital, 71111 Assiut, Egypt. E-mail address: [email protected] (E.M. Khedr).
http://dx.doi.org/10.1016/j.neucli.2015.02.001 0987-7053/© 2015 Elsevier Masson SAS. All rights reserved.
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E.M. Khedr et al. Conclusion. — Patients with nocturnal enuresis are characterized by pathologically increased excitability and reduced inhibitory processing in the motor cortex, which could contribute to the pathogenesis of nocturnal enuresis. © 2015 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Énurésie nocturne ; Excitabilité corticale ; Seuil moteur au repos et sous activation ; Période de silence corticale ; Inhibition transcalleuse
Résumé But de l’étude. — Quelques études EEG ont fait état d’une dysmaturité corticale chez les patients atteints d’énurésie nocturne (EN). Notre étude vise à évaluer cette hypothèse en mesurant, au moyen de la stimulation magnétique transcrânienne (SMT) l’excitabilité corticale de patients présentant une EN. Matériel et méthodes. — Notre étude a porté sur 41 patients remplissant les critères DSM-IV d’EN et sur 18 contrôles appariés par le sexe et l’âge. Chaque patient a été évalué cliniquement : fréquence et durée de l’énurésie, Health Survey Measurement (HSM). Sur le plan neurophysiologique, nous avons mesuré les seuils moteurs au repos (SMR) et sous activation volontaire (SMA), les potentiels évoqués moteurs (PEM) des membres supérieurs et inférieurs, la durée de la période de silence corticale (PSC) et l’inhibition transcalleuse (ITC) au niveau des membres supérieurs. Résultats. — Par rapport aux contrôles, les patients présentaient un score HSM significativement inférieur aussi bien pour la santé physique que mentale. Les SMR et SMA des membres supérieurs et inférieurs, la durée de la PSC et l’ITC étaient également significativement inférieurs chez les patients par rapport aux contrôles. Une corrélation significative fut trouvée entre les SMR et SMA, d’une part, le score HSM, d’autre part, en particulier le fonctionnement social. Conclusion. — Les patients présentant une EN présentent une augmentation pathologique d’excitabilité du cortex moteur et une diminution des processus d’inhibition de celui-ci, qui peuvent contribuer à la pathogenèse de l’EN. © 2015 Elsevier Masson SAS. Tous droits réservés.
Introduction Nocturnal enuresis (NE) or bedwetting is defined as the involuntary voiding of urine in bed beyond the age at which bladder control is normally expected [10]. Bedwetting is a widespread and distressing condition that can have a deep impact on a child or young person’s behavior, emotional wellbeing and social life. It is also very stressful for the parents or carers [4]. Monosymptomatic nocturnal enuresis (MNE) describes bedwetting in children with no daytime urinary symptoms to suggest underlying voiding dysfunction. The etiology of NE is not fully understood. It seems to be multifactorial and several explanations have been put forward to explain this phenomenon, including genetic influences, difficulties in waking, decreased night-time secretion of antidiuretic hormone, and stress and psychological factors [8,13]. A possible explanation is that this is related to a deficiency of inhibitory signal processing in the brainstem that accounts for the inability to inhibit detrusor activity and micturition during sleep [5,14]. Based on functional and structural abnormalities in some brain areas, it has been recently proposed that enuresis represents delayed functional maturation of the central nervous system (CNS) in this multifactorial model [21]. Indeed, Lei et al. [12] found microstructural abnormalities in the thalamus, the medial frontal gyrus, the anterior cingulate cortex (ACC) and the insula of the children with primary MNE using diffusion tensor imaging. A limited number of electroencephalographic (EEG) studies have also been performed to clarify the relationship between nocturnal enuresis and selective cortical dysmaturity [9,15,20]. In a child with primary MNE, Toros
et al. [19] reported an increased hyperventilation (HV) response, which is commonly considered to be a sign of brain damage, dysfunction or instability of the cerebral cortex as a result of delayed maturation [9,11]. We therefore speculate that the structure of the brain is likely to be abnormal in MNE patients. However, the exact cerebral areas involved in the pathogenesis of MNE remain unclear. Therefore, as a further step towards understanding this condition we evaluated changes in motor cortical excitability of children with MNE using transcranial magnetic stimulation.
Materials and methods Subjects This study was conducted in the Neuropsychiatry department, Assiut University Hospital from May 2013 to May 2014. All subjects were diagnosed as patients with primary monosymptomatic nocturnal enuresis according to the Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV) [1]: repeated urination into bed or clothes, occurring twice per week for at least three consecutive months in a child of at least 5 years of age and not due to either a drug side effect or a medical condition. All patients had been taking the tricyclic antidepressant drug Imipramine (25 mg once/day) for at least 3 months without satisfactory results. The study included two groups. The experimental group consisted of 41 nocturnal enuresis patients (28 females), with a mean age of 13.8 ± 3.7 years (range 8—22 years), and control group of 18 age-matched healthy volunteers
Cortical excitability in nocturnal enuresis (13 females) with a mean age of 14.2 ± 3.5 years (range 9—21 years). Each subject underwent neurological examination as well as a generic health survey, the SF-36v2 Health Survey [16], to compare the disease (enuresis) burden across populations. This survey includes 36 questions to measure functional health and well-being from the patient’s point of view. This is a practical, reliable and valid measure of physical and mental health that can be completed in five to ten minutes. The SF-36v2 provides scores for each of the eight health domains as well as psychometrically based Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. None of the patients suffered from any other clinically relevant disorder. They continued their normal drug treatment throughout the study. All female patients and control subjects were tested outside the period of menstruation.
Neurophysiological Investigations F waves were elicited by stimulation of the posterior tibial nerve. 10 stimuli were given, and the average latency value was determined to confirm that lumbosacral root function was normal. Motor cortical excitability was evaluated by measuring the resting and active motor thresholds (RMT and AMT, respectively), motor evoked potentials (MEP), cortical silent period (CSP), and transcallosal inhibition (TCI) of the abductor digiti minimi muscle (ADM). RMT, AMT and MEPs in the gastrocnemius muscle were also assessed in each subject. Participants sat in a comfortable chair. Electromyographic (EMG) recordings from the ADM of both hands were acquired with silver-silver chloride 9 surface electrodes, using a muscle belly-tendon set-up with a 3 cm diameter circular ground electrode placed on the wrist. A Nihon Kohden Machine model 9400 (Tokyo — Japan) was used to collect the signals. EMG parameters included a bandpass of 20—1000 Hz as a recording time window of 200 ms. TMS was performed with a 90 mm figure of eight coil connected to Magstim super rapid magnetic stimulator (Magstim limited company — UK).
Determination of motor thresholds Thresholds were determined after localization of the motor hot spot for the ADM and calf muscle in each hemisphere. Relaxation and EMG signals were monitored and recorded for 20 ms prior to stimulation. The RMT was defined as the minimal intensity that could elicit motor evoked potentials of 50 V peak-to-peak amplitude in five out of 10 consecutive trials. The AMT was determined in the same way while subjects made a mild contraction of about 10% of maximum contraction and was defined as the minimal intensity that could elicit an MEP larger than 200 V in five out of 10 consecutive trials. Both the RMT and the AMT were expressed as a percentage of the maximal stimulator output (equal to 100%).
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MEPs at 130% of the resting motor threshold Stimuli at 130% of the RMT were applied at the hot spot of ADM and calf muscle of each hemisphere in subjects at rest. Peak-to-peak amplitudes and onset latency (from the onset of stimulus to the MEP) were measured and averaged over five consecutive responses.
Contralateral cortical silent period (CSP) The duration of the CSP was determined for the left hemisphere during isometric 50% maximum voluntary contraction of the contralateral ADM. The participants were asked to perform 50% of the maximum voluntary abduction of the thumb as judged by audio-visual feedback. Voluntary contraction started 5 seconds before TMS. Stimuli were delivered not closer than one every 15 seconds to avoid fatigue. Ten magnetic stimuli were applied at an intensity of 130% of the RMT. The EMG traces were rectified and averaged. The duration of the CSP (ms) was determined visually from the end of the MEP to the recurrence of at least 50% of EMG background activity.
Transcallosal inhibition (TCI) TCI was assessed in the same way as CSP, except that the subject contracted the right ADM muscle and an intensity of 150% of the RMT was used during stimulation of the right hemisphere. The onset and offset of the TCI were defined as the points where the EMG trace fell persistently below and where it returned persistently above the base line. The TCI duration is calculated as the time of offset of TCI minus the onset.
Ethical approval The study was approved by the Institutional Ethical Committee of Assiut University Hospital. Prior to the investigation, patients and healthy subjects gave their informed consent according to the declaration of Helsinki.
Statistical analysis The SPSS version 16 package was used in this study. Nonparametric Mann-Whitney U tests were used to compare demographic and clinical data between the patients and the control group. One-way ANOVA was used to compare patients and healthy subjects in different neurophysiological parameters. P values of < 0.05 were considered significant. Correlations between frequency of enuresis and neurophysiological parameters using non-parametric Spearman Correlation were measured.
Results There were no significant differences between patients and controls in age, sex distribution, order of birth and level of education. However the patients had significantly lower
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Table 1
Demographic and clinical data of patients and control.
Data
Nocturnal enuretic patients n = 41
Control n = 18
P values
Age Sex male/female Order of birth
13.76 ± 3.38 13/28 2.03 ± 1.3
14.28 ± 3.75 5/13 2.2 ± 1.1
0.616 0.952 0.566
Educational status Primary school Prep school Secondary school
14 17 10
7 7 4
0.089
Frequency of enuresis/week
7.1 ± 3.4
0
0.00
Health Survey Measurement Model (SF-36v2) Physical health
Quality of life 60.36 ± 18.1 87.44 ± 18.2 85.49 ± 28.4 77.26 ± 26.7 72.36 ± 39.5
75.56 ± 10.7 88.1 ± 9.1 84.72 ± 12.54 89.1 ± 13.3 84.36 ± 7.9
0.0001 0.863 0.886 0.028 0.033
Mental health Role-emotional (RE) Social functioning (SF) Vitality (VT) Mental health (MH) Component mental health summation (CMHS)
72.36 ± 39.5 47.41 ± 21.96 59.27 ± 12 50.27 ± 16.5 57.14 ± 15.2
98.17 ± 7.8 84 ± 12.7 70.83 ± 13.1 68.2 ± 10.8 80.3 ± 7.8
0.0001 0.0001 0.003 0.0001 0.0001
Health transition (HT)
80.6 ± 20.8
91.67 ± 14.85
0.026
General health (GH) Physical functioning (PF) Role—physical (RP) Bodily pain (BP) Component of Physical health summation (CPHS)
scores in the Health Survey Measures of both physical [general health (GH), bodily pain (BP), Component of Physical health Summation (CPHS)] and mental health components [Role-Emotional (RE), social functioning (SF), vitality (VT), mental health (MH), and component mental health summation (CMHS)], as detailed in Table 1.
F wave latency The F wave latency of right and left gastrocnemius muscle was normal in both groups with no evidence of lumbosacral root affection.
Motor thresholds The resting and active motor thresholds of right ADM (RMT, AMT) were significantly reduced (P = 0.002, and P = 0.001 respectively) in the patients (42.5 ± 6.3 and 27.7 ± 6.6) compared with controls (48.4 ± 6, and 36.8 ± 7.4). Similar differences were seen in the resting and active motor threshold of right gastrocnemius muscle in individuals with NE (68.4 ± 7.3 and 52.1 ± 6.9 respectively) compared with controls (74.7 ± 4.5 and 61.9 ± 4.9; with P = 0.002 and P = 0.0001 for resting and active motor threshold respectively) (see Table 2, Fig. 1a and b). These findings are consistent with the notion of hyperexcitability of the motor cortex in patients with NE.
Motor evoked potentials There was a significant reduction in MEP latencies of the right gastrocnemius muscle in patients vs. controls 30.0 ± 3.5 (patients) vs. 32.5 ± 3.1 ms (controls); P = 0.013 but no significant difference in ADM (20.0 ± 2.9 vs. 20.6 ± 1.1ms; P = 0.27). There were also no significant differences in MEP amplitude in either ADM or gastrocnemius muscles (793 ± 690 (patients) vs. 840 ± 470 V (controls) for ADM and 135 ± 130 vs. 100 ± 60 V for gastrocnemius with P = 0.7 and P = 0.2 respectively) (Table 2, Fig. 2 a and b).
Cortical silent period (CSP) and transcallosal inhibition (TCI) The duration of the CSP was shorter in the patient group compared with controls (100.3 ± 23.2 (patients) vs. 124.7 ± 15.9 ms (controls); P = 0.0001) consistent with reduced inhibition in the motor cortex. TCI duration was significantly reduced in patients compared with the control subjects (20.1 ± 2.7 vs. 21.7 ± 3 ms; P = 0.040) with a tendency towards earlier onset in NE patients (35.5 ± 4.0 vs. 37.9 + 4.6 ms; P = 0.074) (Table 2 and Fig. 3a and b). There were significant positive correlations between RMT and AMT of ADM with SF (r = 0.47, P = 0.0001 and r = 0.58, P = 0.0001 respectively) and also RMT, AMT of gastrocnemius muscle with SF (r = 0.35, P = 0.006 and r = 0.54; P = 0.0001 respectively). A significant positive correlation was recorded
Cortical excitability in nocturnal enuresis
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Table 2 Cortical excitability measurements of right abductor digiti minimi (ADM) and gastrocnemius muscles among patients and control groups. Data recorded from abductor digiti minimi (ADM) and gastrocnemius muscles
Nocturnal enuretic patients n = 41
P value
Abductor digiti minimi (ADM) Resting motor threshold Active motor threshold Cortical latency of 130% MEP Amplitude of 130% MEP Cortical silent period latency Cortical silent period amplitude Transcallosal inhibition duration Transcallosal inhibition onset latency
43.5 28.6 20.0 0.793.0 100.3 1.3 20.1 35.5
± ± ± ± ± ± ± ±
6.6 7 2.9 0.690 23.3 1.1 2.7 4.0
48.4 36.8 20.6 0.840 124.7 1.8 21.74 37.9
± ± ± ± ± ± ± ±
6 5.4 1.1 0.470 15.9 1.6 3 4.6
0.009 0.0001 0.27 0.27 0.0001 0.292 0.040 0.07
Gastrocnemius muscle Resting motor threshold Active motor threshold Cortical latency of 130% MEP Amplitude of 130% MEP
69.1 52.9 30.0 0.135.0
± ± ± ±
7.1 8.8 3.5 0.130
74.7 61.9 32.5 0.100
± ± ± ±
4.5 4.9 3.1 0.060
0.001 0.000 0.013 0.27
Control n = 18
Figure 1 Resting and active motor threshold (RMT, AMT) of abductor digiti minimi and gastrocnemius muscles. RMT and AMT of ADM were significantly reduced in the nocturnal enuresis (NE) patients compared with controls with P = 0.002, and P = 0.001 respectively. Similarly such differences were recorded for resting and active motor threshold of right gastrocnemius muscle with P = 0.002 and P = 0.0001 for resting and active motor threshold respectively.
between AMT of gastrocnemius and CMHS (r = 0.33, P = 0.01). Significant positive correlations between CSP duration with CMHS (r = 0.35 and 0.007) on one hand and with general health score (GH) (r = 0.29, P = 0.02) on the other hand were also observed (Fig. 4).
Discussion PNE can cause significant psychosocial stress and anxiety. Patients can experience perplexity, humiliation, social isolation and fear of detection by others. These children are frequently aware of the social and emotional consequences of their condition. In the present study the significant effect of enuresis on quality of life (SF-36v2) was recorded with
lower scores of SF-36v2 than controls for both physical and mental components. Results from experiments using positron emission tomography (PET) scanning suggest that voluntary motor pathways involved in pelvic floor control originate from the most medial part of the primary motor cortex [3]. In the present study we examined motor cortical excitability using TMS in order to understand more about the role of motor cortex in the pathogenesis of MNE. Our data show that in comparison with healthy control subjects, patients with MNE have reduced RMT, AMT, as well as reduced CSP duration in both ADM and gastrocnemius muscle. They also had a slightly shorter MEP onset latency in the gastrocnemius muscle. These findings are consistent with the notion of increased
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Figure 2 Motor evoked potential latencies in ms and amplitude of abductor digiti minimi and gastrocnemius muscles uV. Significant reduction of MEPs latencies of right gastrocnemius muscle were recorded in patients vs. control group with P = 0.013, while no significant difference of MEPs latencies of ADM were recorded in patients vs. control group (P = 0.27). Moreover, no significant differences in MEP amplitudes recorded from right ADM or gastrocnemius muscle between studied groups were demonstrated.
excitability of the corticospinal output and a reduction in excitability of cortical inhibitory mechanisms. The lower motor thresholds are consistent with increased excitability of the corticospinal tract. If this hyperexcitability extends to other cortical regions it could be related to anxiety and psychosocial stress. The significant positive correlation between RMT, AMT with SF-36v2 (especially SF) recorded in this study, supports this hypothesis. Anxiety and stress are characterized by cognitive arousal and changes in bodily sensation due to enhanced autonomic activity, which may reflect a central increase in cortical excitability in different regions of the brain. In fact, an
association between relative EEG right frontal hyperactivity and the state or trait measures of anxiety has been shown [5,6,17]. Increased frequencies of a high-level HV response in resting-state EEG recordings together with anxiety suggest that delayed cortical maturity and comorbid psychiatric disorders might be important factors in the pathogenesis of nocturnal enuresis [19]. As all patients were taking tricyclic antidepressant drugs (imipramine 25 mg at night) throughout the study, it is possible that these might influence cortical excitability. In rodents, imipramine has been associated with enhanced LTP and with changes in serotoninergic and cholinergic
Figure 3 Cortical silent period duration (trace a) and transcallosal inhibition duration and onset latency in ms (trace b). Significant shortening of CSP duration and TCI duration were found in the patient group compared with controls (P = 0.0001, 0.040 respectively). A tendency towards earlier onset of TCI in NE patients compared with control group was shown (P = 0.074).
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Figure 4 Correlation between resting motor threshold of abductor digiti minimi and gastrocnemius muscle and social functioning (SF). Significant positive correlations were shown between RMT of ADM and gastrocnemius with SF (P = 0.0001 for each).
transmission [2,7,18]. However, little is known about the actions of imipramine in human brain, and there are no reports of it causing changes in thresholds or cortical inhibition. Other drugs that act on 5-HT and cholinergic systems do not affect either thresholds or CSP/TCI [23]. The CSP describes a suppression of EMG activity during a voluntary contraction of the target muscle and depends, at least in part, on inhibitory mechanisms at the level of the motor cortex, probably mediated by gamma-aminobutyric acid (GABA)-B receptors [22]. Thus a shorter CSP in subjects with MNE suggests that there is reduced excitability in GABA-B mediated inhibitory mechanisms in motor cortex. The reduced duration of TCI, which is also thought to be mediated by GABAergic mechanisms, would be compatible with this idea. It is therefore possible that a deficiency of inhibitory signal processing in the motor cortex may reduce its ability to inhibit brainstem control of detrusor activity and micturition during sleep. This could be aggravated by hyperexcitability of motor cortex output leading to bedwetting. Future studies that combine neuroimaging techniques with transcranial cortex stimulation may provide new insights in understanding the pathophysiology of NE aiming for developing novel approaches for more effective treatments.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements The authors would like to thank Professor Dr. John Rothwell for his valuable comments and revision of this manuscript.
References [1] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th Ed. Washington, DC: Amerian Psychiatric Association; 1994. [2] Birnstiel S, Haas HL. Acute effects of antidepressant drugs on long-term potentiation (LTP) in rat hippocampal slices. Naunyn Schmiedebergs Arch Pharmacol 1991;344(1):79—83. [3] Blok BFM, Sturms LM, Holstege G. A PET study on cortical and subcorticalcontrol of pelvic floor musculature in women. J Comp Neurol 1997;389:535—44. [4] Butler RJ, Heron J. The prevalence of infrequent bedwetting and nocturnal enuresis in childhood. A large British cohort. Scand J Urol Nephrol 2008;42(3):257—64. [5] Crost NW, Pauls CA, Wacker J. Defensiveness and anxiety predict frontal EEG asymmetry only in specific situational contexts. Biol Psychol 2008;78:43—52. [6] Davidson RJ, Marshall JR, Tomarken AJ, Henriques JB. While a phobic waits: regional brain electrical and autonomic activity in social phobics during anticipation of public speaking. Biol Psychiatry 2000;47:85—95. [7] Dazzi L, Vacca G, Ladu S, Pisu MG, Serra M, Biggio G. Long-term treatment with antidepressant drugs reduces the sensitivity of cortical cholinergic neurons to the activating actions of stress and the anxiogenic drug FG 7142. Neuropharmacology 2001;41(2):229—37. [8] Djurhuus JC, Rittig S. Current trends, diagnosis, and treatment of enuresis. Eur Urol 1998;33(Suppl. 3):30—3. [9] Hallioglu O, Ozge A, Comelekoglu U, Topaloglu AK, Kanik A, et al. Evaluation of cerebral maturation by visual and quantitative analysis of resting electroencephalography in children with primary nocturnal enuresis. J Child Neurol 2001;16: 714—8. [10] Hjalmas K. Nocturnal enuresis: basic facts and new horizons. Eur Urol 1998;33(Suppl. 3):53—7. [11] Kaada B, Retvedt A. Enuresis and hyperventilation response in the EEG. Dev Med Child Neurol 1981;23:591—9. [12] Lei D, Ma J, Shen X, Du X, Shen G, Liu W, et al. Changes in the brain microstructure of children with primary monosymptomatic nocturnal enuresis: a diffusion tensor imaging study. PLoS One 2012;7(2):e3102—3.
158 [13] Norgaard JP, Djurhuus JC, Watanabe H, Stenberg A, Lettgen B. Experience and current status of research into the pathophysiology of nocturnal enuresis. Br J Urol 1997;79:825—35. [14] Ornitz EM, Russell AT, Hanna G, Gabikian P, Gehricke JG, Song D, et al. Prepulse inhibition of startle and the neurobiology of primary nocturnal enuresis. Biol Psychiatry 1999;45:1455—66. [15] Salmon MA, Taylor DC, Lee D. On the EEG in enuresis. In: Kolvin I, MacKeith RC, Meadow SR, editors. Bladder control and enuresis. London: Heinemann; 1973. [16] Stewart AL, Ware JE. Measuring functioning and well-being: the medical outcomes study approach. Durham NC: Duke University Press; 1992. [17] Sutton SK, Davidson RJ. Prefrontal brain asymmetry: a biological substrate of the behavioral approach and inhibition systems. Psychol Sci 1997;8:204—10. [18] Tokarski K, Bijak M. Antidepressant-induced adaptive changes in the effects of 5-HT, 5-HT1A and 5-HT4 agonists on the population spike recorded in hippocampal CA1 cells do not involve
E.M. Khedr et al.
[19]
[20]
[21]
[22] [23]
presynaptic effects on excitatory synaptic transmission. Pol J Pharmacol 1996;48(6):565—73. 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(6):471—6. von Gontard A, Benden B, Mauer-Mucke K, Lehmkuhl G. Somatic correlates of functional enuresis. Eur Child Adolesc Psychiatry 1999;8:117—25. von Gontard A, Schmelzer D, Seifen S, Pukrop R. Central nervous system involvement in nocturnal enuresis: evidence of general neuromotor delay and specific brainstem dysfunction. J Urol 2002;166:2448—51. Ziemann U. TMS and drugs. Clin Neurophysiol 2004;115: 1717—29. Ziemann U. Pharmaco-transcranial magnetic stimulation studies of motor excitability. Handb Clin Neurol 2013;116:387—97, http://dx.doi.org/10.1016/B978-0-444-53497-2.00032-2.
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ORIGINAL ARTICLE/ARTICLE ORIGINAL
Transcranial magnetic stimulation identifies cortical excitability changes in monosymptomatic nocturnal enuresis La stimulation magnétique transcrânienne identifie des modifications d’excitabilité corticale dans l’énurésie nocturne E.M. Khedr a,∗, N. Abo-Elfetoh a, K.A. Elbeh a, A.A. Baky a, R.M. Gamal b, D. El Hammady b, F. Korashy a a b
Department of neuropsychiatry, Assiut university hospital, Assiut, Egypt Rheumatology and rehabilitation department, faculty of medicine, Assiut University, Assiut, Egypt
Received 28 November 2014; accepted 15 February 2015 Available online 22 April 2015
KEYWORDS Nocturnal enuresis; Cortical excitability; Resting and active motor threshold; Cortical silent period; Transcallosal inhibition
∗
Summary Objectives. — A limited number of electroencephalography (EEG) studies in nocturnal enuresis (NE) have reported cortical dysmaturity. The aim of the present study was to test this notion by examining cortical excitability in subjects with nocturnal enuresis (NE) using transcranial magnetic stimulation (TMS). Material and methods. — We investigated 41 patients with NE meeting the DSM-IV diagnostic criteria for NE, and 18 age- and sex-matched controls. Each subject was assessed clinically regarding frequency, duration of enuresis and Health Survey Measurement. Neurophysiological measures included resting and active motor thresholds (RMT, AMT), motor evoked potentials (MEP) of upper and lower limbs, cortical silent period duration (CSP) and transcallosal inhibition (TCI), in the upper limbs. Results. — Patients had a significantly lower Health Survey Measurement score for both physical and mental health components compared to the control group. RMT and AMT of both upper and lower limbs as well as the duration of the CSP and TCI were significantly reduced compared with the control group. There was significant positive correlation between RMT, AMT and Health Survey Measurement scores, especially Social Functioning.
Corresponding author. Department of neurology, faculty of medicine, Assiut university hospital, 71111 Assiut, Egypt. E-mail address: [email protected] (E.M. Khedr).
http://dx.doi.org/10.1016/j.neucli.2015.02.001 0987-7053/© 2015 Elsevier Masson SAS. All rights reserved.
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E.M. Khedr et al. Conclusion. — Patients with nocturnal enuresis are characterized by pathologically increased excitability and reduced inhibitory processing in the motor cortex, which could contribute to the pathogenesis of nocturnal enuresis. © 2015 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Énurésie nocturne ; Excitabilité corticale ; Seuil moteur au repos et sous activation ; Période de silence corticale ; Inhibition transcalleuse
Résumé But de l’étude. — Quelques études EEG ont fait état d’une dysmaturité corticale chez les patients atteints d’énurésie nocturne (EN). Notre étude vise à évaluer cette hypothèse en mesurant, au moyen de la stimulation magnétique transcrânienne (SMT) l’excitabilité corticale de patients présentant une EN. Matériel et méthodes. — Notre étude a porté sur 41 patients remplissant les critères DSM-IV d’EN et sur 18 contrôles appariés par le sexe et l’âge. Chaque patient a été évalué cliniquement : fréquence et durée de l’énurésie, Health Survey Measurement (HSM). Sur le plan neurophysiologique, nous avons mesuré les seuils moteurs au repos (SMR) et sous activation volontaire (SMA), les potentiels évoqués moteurs (PEM) des membres supérieurs et inférieurs, la durée de la période de silence corticale (PSC) et l’inhibition transcalleuse (ITC) au niveau des membres supérieurs. Résultats. — Par rapport aux contrôles, les patients présentaient un score HSM significativement inférieur aussi bien pour la santé physique que mentale. Les SMR et SMA des membres supérieurs et inférieurs, la durée de la PSC et l’ITC étaient également significativement inférieurs chez les patients par rapport aux contrôles. Une corrélation significative fut trouvée entre les SMR et SMA, d’une part, le score HSM, d’autre part, en particulier le fonctionnement social. Conclusion. — Les patients présentant une EN présentent une augmentation pathologique d’excitabilité du cortex moteur et une diminution des processus d’inhibition de celui-ci, qui peuvent contribuer à la pathogenèse de l’EN. © 2015 Elsevier Masson SAS. Tous droits réservés.
Introduction Nocturnal enuresis (NE) or bedwetting is defined as the involuntary voiding of urine in bed beyond the age at which bladder control is normally expected [10]. Bedwetting is a widespread and distressing condition that can have a deep impact on a child or young person’s behavior, emotional wellbeing and social life. It is also very stressful for the parents or carers [4]. Monosymptomatic nocturnal enuresis (MNE) describes bedwetting in children with no daytime urinary symptoms to suggest underlying voiding dysfunction. The etiology of NE is not fully understood. It seems to be multifactorial and several explanations have been put forward to explain this phenomenon, including genetic influences, difficulties in waking, decreased night-time secretion of antidiuretic hormone, and stress and psychological factors [8,13]. A possible explanation is that this is related to a deficiency of inhibitory signal processing in the brainstem that accounts for the inability to inhibit detrusor activity and micturition during sleep [5,14]. Based on functional and structural abnormalities in some brain areas, it has been recently proposed that enuresis represents delayed functional maturation of the central nervous system (CNS) in this multifactorial model [21]. Indeed, Lei et al. [12] found microstructural abnormalities in the thalamus, the medial frontal gyrus, the anterior cingulate cortex (ACC) and the insula of the children with primary MNE using diffusion tensor imaging. A limited number of electroencephalographic (EEG) studies have also been performed to clarify the relationship between nocturnal enuresis and selective cortical dysmaturity [9,15,20]. In a child with primary MNE, Toros
et al. [19] reported an increased hyperventilation (HV) response, which is commonly considered to be a sign of brain damage, dysfunction or instability of the cerebral cortex as a result of delayed maturation [9,11]. We therefore speculate that the structure of the brain is likely to be abnormal in MNE patients. However, the exact cerebral areas involved in the pathogenesis of MNE remain unclear. Therefore, as a further step towards understanding this condition we evaluated changes in motor cortical excitability of children with MNE using transcranial magnetic stimulation.
Materials and methods Subjects This study was conducted in the Neuropsychiatry department, Assiut University Hospital from May 2013 to May 2014. All subjects were diagnosed as patients with primary monosymptomatic nocturnal enuresis according to the Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV) [1]: repeated urination into bed or clothes, occurring twice per week for at least three consecutive months in a child of at least 5 years of age and not due to either a drug side effect or a medical condition. All patients had been taking the tricyclic antidepressant drug Imipramine (25 mg once/day) for at least 3 months without satisfactory results. The study included two groups. The experimental group consisted of 41 nocturnal enuresis patients (28 females), with a mean age of 13.8 ± 3.7 years (range 8—22 years), and control group of 18 age-matched healthy volunteers
Cortical excitability in nocturnal enuresis (13 females) with a mean age of 14.2 ± 3.5 years (range 9—21 years). Each subject underwent neurological examination as well as a generic health survey, the SF-36v2 Health Survey [16], to compare the disease (enuresis) burden across populations. This survey includes 36 questions to measure functional health and well-being from the patient’s point of view. This is a practical, reliable and valid measure of physical and mental health that can be completed in five to ten minutes. The SF-36v2 provides scores for each of the eight health domains as well as psychometrically based Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. None of the patients suffered from any other clinically relevant disorder. They continued their normal drug treatment throughout the study. All female patients and control subjects were tested outside the period of menstruation.
Neurophysiological Investigations F waves were elicited by stimulation of the posterior tibial nerve. 10 stimuli were given, and the average latency value was determined to confirm that lumbosacral root function was normal. Motor cortical excitability was evaluated by measuring the resting and active motor thresholds (RMT and AMT, respectively), motor evoked potentials (MEP), cortical silent period (CSP), and transcallosal inhibition (TCI) of the abductor digiti minimi muscle (ADM). RMT, AMT and MEPs in the gastrocnemius muscle were also assessed in each subject. Participants sat in a comfortable chair. Electromyographic (EMG) recordings from the ADM of both hands were acquired with silver-silver chloride 9 surface electrodes, using a muscle belly-tendon set-up with a 3 cm diameter circular ground electrode placed on the wrist. A Nihon Kohden Machine model 9400 (Tokyo — Japan) was used to collect the signals. EMG parameters included a bandpass of 20—1000 Hz as a recording time window of 200 ms. TMS was performed with a 90 mm figure of eight coil connected to Magstim super rapid magnetic stimulator (Magstim limited company — UK).
Determination of motor thresholds Thresholds were determined after localization of the motor hot spot for the ADM and calf muscle in each hemisphere. Relaxation and EMG signals were monitored and recorded for 20 ms prior to stimulation. The RMT was defined as the minimal intensity that could elicit motor evoked potentials of 50 V peak-to-peak amplitude in five out of 10 consecutive trials. The AMT was determined in the same way while subjects made a mild contraction of about 10% of maximum contraction and was defined as the minimal intensity that could elicit an MEP larger than 200 V in five out of 10 consecutive trials. Both the RMT and the AMT were expressed as a percentage of the maximal stimulator output (equal to 100%).
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MEPs at 130% of the resting motor threshold Stimuli at 130% of the RMT were applied at the hot spot of ADM and calf muscle of each hemisphere in subjects at rest. Peak-to-peak amplitudes and onset latency (from the onset of stimulus to the MEP) were measured and averaged over five consecutive responses.
Contralateral cortical silent period (CSP) The duration of the CSP was determined for the left hemisphere during isometric 50% maximum voluntary contraction of the contralateral ADM. The participants were asked to perform 50% of the maximum voluntary abduction of the thumb as judged by audio-visual feedback. Voluntary contraction started 5 seconds before TMS. Stimuli were delivered not closer than one every 15 seconds to avoid fatigue. Ten magnetic stimuli were applied at an intensity of 130% of the RMT. The EMG traces were rectified and averaged. The duration of the CSP (ms) was determined visually from the end of the MEP to the recurrence of at least 50% of EMG background activity.
Transcallosal inhibition (TCI) TCI was assessed in the same way as CSP, except that the subject contracted the right ADM muscle and an intensity of 150% of the RMT was used during stimulation of the right hemisphere. The onset and offset of the TCI were defined as the points where the EMG trace fell persistently below and where it returned persistently above the base line. The TCI duration is calculated as the time of offset of TCI minus the onset.
Ethical approval The study was approved by the Institutional Ethical Committee of Assiut University Hospital. Prior to the investigation, patients and healthy subjects gave their informed consent according to the declaration of Helsinki.
Statistical analysis The SPSS version 16 package was used in this study. Nonparametric Mann-Whitney U tests were used to compare demographic and clinical data between the patients and the control group. One-way ANOVA was used to compare patients and healthy subjects in different neurophysiological parameters. P values of < 0.05 were considered significant. Correlations between frequency of enuresis and neurophysiological parameters using non-parametric Spearman Correlation were measured.
Results There were no significant differences between patients and controls in age, sex distribution, order of birth and level of education. However the patients had significantly lower
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Table 1
Demographic and clinical data of patients and control.
Data
Nocturnal enuretic patients n = 41
Control n = 18
P values
Age Sex male/female Order of birth
13.76 ± 3.38 13/28 2.03 ± 1.3
14.28 ± 3.75 5/13 2.2 ± 1.1
0.616 0.952 0.566
Educational status Primary school Prep school Secondary school
14 17 10
7 7 4
0.089
Frequency of enuresis/week
7.1 ± 3.4
0
0.00
Health Survey Measurement Model (SF-36v2) Physical health
Quality of life 60.36 ± 18.1 87.44 ± 18.2 85.49 ± 28.4 77.26 ± 26.7 72.36 ± 39.5
75.56 ± 10.7 88.1 ± 9.1 84.72 ± 12.54 89.1 ± 13.3 84.36 ± 7.9
0.0001 0.863 0.886 0.028 0.033
Mental health Role-emotional (RE) Social functioning (SF) Vitality (VT) Mental health (MH) Component mental health summation (CMHS)
72.36 ± 39.5 47.41 ± 21.96 59.27 ± 12 50.27 ± 16.5 57.14 ± 15.2
98.17 ± 7.8 84 ± 12.7 70.83 ± 13.1 68.2 ± 10.8 80.3 ± 7.8
0.0001 0.0001 0.003 0.0001 0.0001
Health transition (HT)
80.6 ± 20.8
91.67 ± 14.85
0.026
General health (GH) Physical functioning (PF) Role—physical (RP) Bodily pain (BP) Component of Physical health summation (CPHS)
scores in the Health Survey Measures of both physical [general health (GH), bodily pain (BP), Component of Physical health Summation (CPHS)] and mental health components [Role-Emotional (RE), social functioning (SF), vitality (VT), mental health (MH), and component mental health summation (CMHS)], as detailed in Table 1.
F wave latency The F wave latency of right and left gastrocnemius muscle was normal in both groups with no evidence of lumbosacral root affection.
Motor thresholds The resting and active motor thresholds of right ADM (RMT, AMT) were significantly reduced (P = 0.002, and P = 0.001 respectively) in the patients (42.5 ± 6.3 and 27.7 ± 6.6) compared with controls (48.4 ± 6, and 36.8 ± 7.4). Similar differences were seen in the resting and active motor threshold of right gastrocnemius muscle in individuals with NE (68.4 ± 7.3 and 52.1 ± 6.9 respectively) compared with controls (74.7 ± 4.5 and 61.9 ± 4.9; with P = 0.002 and P = 0.0001 for resting and active motor threshold respectively) (see Table 2, Fig. 1a and b). These findings are consistent with the notion of hyperexcitability of the motor cortex in patients with NE.
Motor evoked potentials There was a significant reduction in MEP latencies of the right gastrocnemius muscle in patients vs. controls 30.0 ± 3.5 (patients) vs. 32.5 ± 3.1 ms (controls); P = 0.013 but no significant difference in ADM (20.0 ± 2.9 vs. 20.6 ± 1.1ms; P = 0.27). There were also no significant differences in MEP amplitude in either ADM or gastrocnemius muscles (793 ± 690 (patients) vs. 840 ± 470 V (controls) for ADM and 135 ± 130 vs. 100 ± 60 V for gastrocnemius with P = 0.7 and P = 0.2 respectively) (Table 2, Fig. 2 a and b).
Cortical silent period (CSP) and transcallosal inhibition (TCI) The duration of the CSP was shorter in the patient group compared with controls (100.3 ± 23.2 (patients) vs. 124.7 ± 15.9 ms (controls); P = 0.0001) consistent with reduced inhibition in the motor cortex. TCI duration was significantly reduced in patients compared with the control subjects (20.1 ± 2.7 vs. 21.7 ± 3 ms; P = 0.040) with a tendency towards earlier onset in NE patients (35.5 ± 4.0 vs. 37.9 + 4.6 ms; P = 0.074) (Table 2 and Fig. 3a and b). There were significant positive correlations between RMT and AMT of ADM with SF (r = 0.47, P = 0.0001 and r = 0.58, P = 0.0001 respectively) and also RMT, AMT of gastrocnemius muscle with SF (r = 0.35, P = 0.006 and r = 0.54; P = 0.0001 respectively). A significant positive correlation was recorded
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Table 2 Cortical excitability measurements of right abductor digiti minimi (ADM) and gastrocnemius muscles among patients and control groups. Data recorded from abductor digiti minimi (ADM) and gastrocnemius muscles
Nocturnal enuretic patients n = 41
P value
Abductor digiti minimi (ADM) Resting motor threshold Active motor threshold Cortical latency of 130% MEP Amplitude of 130% MEP Cortical silent period latency Cortical silent period amplitude Transcallosal inhibition duration Transcallosal inhibition onset latency
43.5 28.6 20.0 0.793.0 100.3 1.3 20.1 35.5
± ± ± ± ± ± ± ±
6.6 7 2.9 0.690 23.3 1.1 2.7 4.0
48.4 36.8 20.6 0.840 124.7 1.8 21.74 37.9
± ± ± ± ± ± ± ±
6 5.4 1.1 0.470 15.9 1.6 3 4.6
0.009 0.0001 0.27 0.27 0.0001 0.292 0.040 0.07
Gastrocnemius muscle Resting motor threshold Active motor threshold Cortical latency of 130% MEP Amplitude of 130% MEP
69.1 52.9 30.0 0.135.0
± ± ± ±
7.1 8.8 3.5 0.130
74.7 61.9 32.5 0.100
± ± ± ±
4.5 4.9 3.1 0.060
0.001 0.000 0.013 0.27
Control n = 18
Figure 1 Resting and active motor threshold (RMT, AMT) of abductor digiti minimi and gastrocnemius muscles. RMT and AMT of ADM were significantly reduced in the nocturnal enuresis (NE) patients compared with controls with P = 0.002, and P = 0.001 respectively. Similarly such differences were recorded for resting and active motor threshold of right gastrocnemius muscle with P = 0.002 and P = 0.0001 for resting and active motor threshold respectively.
between AMT of gastrocnemius and CMHS (r = 0.33, P = 0.01). Significant positive correlations between CSP duration with CMHS (r = 0.35 and 0.007) on one hand and with general health score (GH) (r = 0.29, P = 0.02) on the other hand were also observed (Fig. 4).
Discussion PNE can cause significant psychosocial stress and anxiety. Patients can experience perplexity, humiliation, social isolation and fear of detection by others. These children are frequently aware of the social and emotional consequences of their condition. In the present study the significant effect of enuresis on quality of life (SF-36v2) was recorded with
lower scores of SF-36v2 than controls for both physical and mental components. Results from experiments using positron emission tomography (PET) scanning suggest that voluntary motor pathways involved in pelvic floor control originate from the most medial part of the primary motor cortex [3]. In the present study we examined motor cortical excitability using TMS in order to understand more about the role of motor cortex in the pathogenesis of MNE. Our data show that in comparison with healthy control subjects, patients with MNE have reduced RMT, AMT, as well as reduced CSP duration in both ADM and gastrocnemius muscle. They also had a slightly shorter MEP onset latency in the gastrocnemius muscle. These findings are consistent with the notion of increased
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Figure 2 Motor evoked potential latencies in ms and amplitude of abductor digiti minimi and gastrocnemius muscles uV. Significant reduction of MEPs latencies of right gastrocnemius muscle were recorded in patients vs. control group with P = 0.013, while no significant difference of MEPs latencies of ADM were recorded in patients vs. control group (P = 0.27). Moreover, no significant differences in MEP amplitudes recorded from right ADM or gastrocnemius muscle between studied groups were demonstrated.
excitability of the corticospinal output and a reduction in excitability of cortical inhibitory mechanisms. The lower motor thresholds are consistent with increased excitability of the corticospinal tract. If this hyperexcitability extends to other cortical regions it could be related to anxiety and psychosocial stress. The significant positive correlation between RMT, AMT with SF-36v2 (especially SF) recorded in this study, supports this hypothesis. Anxiety and stress are characterized by cognitive arousal and changes in bodily sensation due to enhanced autonomic activity, which may reflect a central increase in cortical excitability in different regions of the brain. In fact, an
association between relative EEG right frontal hyperactivity and the state or trait measures of anxiety has been shown [5,6,17]. Increased frequencies of a high-level HV response in resting-state EEG recordings together with anxiety suggest that delayed cortical maturity and comorbid psychiatric disorders might be important factors in the pathogenesis of nocturnal enuresis [19]. As all patients were taking tricyclic antidepressant drugs (imipramine 25 mg at night) throughout the study, it is possible that these might influence cortical excitability. In rodents, imipramine has been associated with enhanced LTP and with changes in serotoninergic and cholinergic
Figure 3 Cortical silent period duration (trace a) and transcallosal inhibition duration and onset latency in ms (trace b). Significant shortening of CSP duration and TCI duration were found in the patient group compared with controls (P = 0.0001, 0.040 respectively). A tendency towards earlier onset of TCI in NE patients compared with control group was shown (P = 0.074).
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Figure 4 Correlation between resting motor threshold of abductor digiti minimi and gastrocnemius muscle and social functioning (SF). Significant positive correlations were shown between RMT of ADM and gastrocnemius with SF (P = 0.0001 for each).
transmission [2,7,18]. However, little is known about the actions of imipramine in human brain, and there are no reports of it causing changes in thresholds or cortical inhibition. Other drugs that act on 5-HT and cholinergic systems do not affect either thresholds or CSP/TCI [23]. The CSP describes a suppression of EMG activity during a voluntary contraction of the target muscle and depends, at least in part, on inhibitory mechanisms at the level of the motor cortex, probably mediated by gamma-aminobutyric acid (GABA)-B receptors [22]. Thus a shorter CSP in subjects with MNE suggests that there is reduced excitability in GABA-B mediated inhibitory mechanisms in motor cortex. The reduced duration of TCI, which is also thought to be mediated by GABAergic mechanisms, would be compatible with this idea. It is therefore possible that a deficiency of inhibitory signal processing in the motor cortex may reduce its ability to inhibit brainstem control of detrusor activity and micturition during sleep. This could be aggravated by hyperexcitability of motor cortex output leading to bedwetting. Future studies that combine neuroimaging techniques with transcranial cortex stimulation may provide new insights in understanding the pathophysiology of NE aiming for developing novel approaches for more effective treatments.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements The authors would like to thank Professor Dr. John Rothwell for his valuable comments and revision of this manuscript.
References [1] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th Ed. Washington, DC: Amerian Psychiatric Association; 1994. [2] Birnstiel S, Haas HL. Acute effects of antidepressant drugs on long-term potentiation (LTP) in rat hippocampal slices. Naunyn Schmiedebergs Arch Pharmacol 1991;344(1):79—83. [3] Blok BFM, Sturms LM, Holstege G. A PET study on cortical and subcorticalcontrol of pelvic floor musculature in women. J Comp Neurol 1997;389:535—44. [4] Butler RJ, Heron J. The prevalence of infrequent bedwetting and nocturnal enuresis in childhood. A large British cohort. Scand J Urol Nephrol 2008;42(3):257—64. [5] Crost NW, Pauls CA, Wacker J. Defensiveness and anxiety predict frontal EEG asymmetry only in specific situational contexts. Biol Psychol 2008;78:43—52. [6] Davidson RJ, Marshall JR, Tomarken AJ, Henriques JB. While a phobic waits: regional brain electrical and autonomic activity in social phobics during anticipation of public speaking. Biol Psychiatry 2000;47:85—95. [7] Dazzi L, Vacca G, Ladu S, Pisu MG, Serra M, Biggio G. Long-term treatment with antidepressant drugs reduces the sensitivity of cortical cholinergic neurons to the activating actions of stress and the anxiogenic drug FG 7142. Neuropharmacology 2001;41(2):229—37. [8] Djurhuus JC, Rittig S. Current trends, diagnosis, and treatment of enuresis. Eur Urol 1998;33(Suppl. 3):30—3. [9] Hallioglu O, Ozge A, Comelekoglu U, Topaloglu AK, Kanik A, et al. Evaluation of cerebral maturation by visual and quantitative analysis of resting electroencephalography in children with primary nocturnal enuresis. J Child Neurol 2001;16: 714—8. [10] Hjalmas K. Nocturnal enuresis: basic facts and new horizons. Eur Urol 1998;33(Suppl. 3):53—7. [11] Kaada B, Retvedt A. Enuresis and hyperventilation response in the EEG. Dev Med Child Neurol 1981;23:591—9. [12] Lei D, Ma J, Shen X, Du X, Shen G, Liu W, et al. Changes in the brain microstructure of children with primary monosymptomatic nocturnal enuresis: a diffusion tensor imaging study. PLoS One 2012;7(2):e3102—3.
158 [13] Norgaard JP, Djurhuus JC, Watanabe H, Stenberg A, Lettgen B. Experience and current status of research into the pathophysiology of nocturnal enuresis. Br J Urol 1997;79:825—35. [14] Ornitz EM, Russell AT, Hanna G, Gabikian P, Gehricke JG, Song D, et al. Prepulse inhibition of startle and the neurobiology of primary nocturnal enuresis. Biol Psychiatry 1999;45:1455—66. [15] Salmon MA, Taylor DC, Lee D. On the EEG in enuresis. In: Kolvin I, MacKeith RC, Meadow SR, editors. Bladder control and enuresis. London: Heinemann; 1973. [16] Stewart AL, Ware JE. Measuring functioning and well-being: the medical outcomes study approach. Durham NC: Duke University Press; 1992. [17] Sutton SK, Davidson RJ. Prefrontal brain asymmetry: a biological substrate of the behavioral approach and inhibition systems. Psychol Sci 1997;8:204—10. [18] Tokarski K, Bijak M. Antidepressant-induced adaptive changes in the effects of 5-HT, 5-HT1A and 5-HT4 agonists on the population spike recorded in hippocampal CA1 cells do not involve
E.M. Khedr et al.
[19]
[20]
[21]
[22] [23]
presynaptic effects on excitatory synaptic transmission. Pol J Pharmacol 1996;48(6):565—73. 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(6):471—6. von Gontard A, Benden B, Mauer-Mucke K, Lehmkuhl G. Somatic correlates of functional enuresis. Eur Child Adolesc Psychiatry 1999;8:117—25. von Gontard A, Schmelzer D, Seifen S, Pukrop R. Central nervous system involvement in nocturnal enuresis: evidence of general neuromotor delay and specific brainstem dysfunction. J Urol 2002;166:2448—51. Ziemann U. TMS and drugs. Clin Neurophysiol 2004;115: 1717—29. Ziemann U. Pharmaco-transcranial magnetic stimulation studies of motor excitability. Handb Clin Neurol 2013;116:387—97, http://dx.doi.org/10.1016/B978-0-444-53497-2.00032-2.
