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Effect of sacral-root stimulation on the motor cortex in patients with idiopathic overactive bladder syndrome
Neurophysiologie Clinique/Clinical Neurophysiology (2008) 38, 39—43 Disponible en ligne sur www.sciencedirect.com
journal homepage: http://france.elsevier.com/direct/neucli
ORIGINAL ARTICLE/ARTICLE ORIGINAL
Effect of sacral-root stimulation on the motor cortex in patients with idiopathic overactive bladder syndrome Effet de la stimulation de la racine sacrée sur le cortex moteur chez les patients présentant une hyperactivité vésicale idiopathique K.K. Liao a,c, J.T. Chen a,c,f, K.L. Lai a,c, C.Y. Liu a,c, C.Y. Lin a,c,e, Y.Y. Lin a,c, B. KJ. Yu b,d, Z.A. Wu a,c,∗ a
Department of Neurology, Taipei Veterans General Hospital, 201, Section II, Shih-Pai Road, 11217 Taipei, Taiwan Department of Obstetrics and Gynecology, Kaohsuing Veterans General Hospital, Kaohsuing, Taiwan c Department of Neurology, National Yang Ming Medical University School of Medicine, Taipei, Taiwan d Department of Obstetrics and Gynecology, National Yang Ming Medical University School of Medicine, Taipei, Taiwan e Institute of Physiology, National Yang Ming Medical University School of Medicine, Taipei, Taiwan f Department of Neurology, Cathay General Hospital, Taipei, Taiwan b
Received 26 May 2007; accepted 9 September 2007 Available online 11 October 2007
KEYWORDS Brain reorganization; Plasticity; Overactive bladder; Sacral neuromodulation; Sacral-root stimulation; Transcranial magnetic stimulation
∗
Summary Aims of the study. — It is presumed that idiopathic overactive bladder syndrome (OBS) is due to visceral hypersensitivity. Sacral-root stimulation can restore the bladder function, but its mechanism remains uncertain. It is well-known that long-term peripheral stimulation can induce brain plasticity. Hence, we investigated whether brain reorganization occurred along with clinical improvement after sacral-root stimulation. Material and methods. — Because toe flexion is the index for monitoring wire placement, we used the flexor hallucis brevis (FHB) as the target muscle. Transcranial magnetic stimulation (TMS) was applied to study motor cortex excitability and the brain mapping of the muscle. Results. — Six patients with idiopathic OBS were included in the study. All demonstrated clinical improvement after sacral-root stimulation. Motor cortex excitability and the area of representation for the flexor hallucis brevis muscle increased for at least 30 min after sacral-root stimulation had terminated.
Corresponding author. E-mail address: [email protected] (Z.A. Wu).
0987-7053/$ — see front matter © 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.neucli.2007.09.004
40
K.K. Liao et al. Conclusion. — Our results showed that cerebral activities changed after sacral-root stimulation. The improvement in urinary urgency and urgency perception was probably due in part to brain reorganization. © 2007 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Réorganisation cérébrale ; Plasticité ; Neuromodulation sacrée ; L’hyperactivité vésicale ; Stimulation de la racine sacrée ; Stimulation magnétique transcrânienne
Résumé Objectif de la recherche. — On suppose que le syndrome d’hyperactivité vésicale idiopathique (idiopathic overactive bladder syndrome IOBS) est dû à une hypersensibilité viscérale. La stimulation de la racine sacrée peut restaurer la fonction vésicale, mais son mécanisme demeure incertain. Il est bien connu que la stimulation périphérique à long terme peut induire une plasticité cérébrale. Nous avons dès lors examiné, si l’amélioration clinique consécutive à une stimulation de la racine sacrée était ou non associée à une réorganisation cérébrale. Matériel et méthodes. — La flexion de l’orteil étant utilisée comme indice de l’emplacement de l’électrode, nous avons choisi de réaliser les enregistrements au niveau du fléchisseur du gros orteil. Nous avons utilisé la stimulation magnétique transcrânienne pour étudier l’excitabilité du cortex moteur et la cartographie cérébrale du muscle. Résultats. — Six patients présentant une OBS idiopathique ont été inclus dans l’étude. Tous les sujets présentaient une amélioration clinique après stimulation de la racine sacrée. L’excitabilité du cortex moteur et la zone de représentation du muscle fléchisseur de l’hallux a augmenté durant au moins 30 minutes après la fin de la stimulation de la racine sacrée. Conclusions. — Nos résultats montrent que les activités cérébrales se modifient après stimulation de la racine sacrée. Les améliorations de l’impériosité et de la perception de l’impériosité sont probablement dues en partie à une réorganisation cérébrale. © 2007 Elsevier Masson SAS. All rights reserved.
Introduction Sacral neuromodulation is a therapeutic procedure consisting of sacral-root stimulation of S2—4. This has been applied for the treatment of pelvic floor disorders, such as overactive bladder syndrome (OBS). Though the mechanism of sacral neuromodulation is uncertain, it has been hypothesized that sacral neuromodulation stimulates the somatic afferent axons in the spinal roots, which in turn modulate the voiding and continence reflex pathways [6]. The action is postulated to involve not only the arc of sacral reflex, but also supraspinal influences [3]. It is presumed that idiopathic OBS is due to visceral hypersensitivity. Sacral-root stimulation may have a deafferentation effect and reverse urinary perception. Removal of sensory input can induce changes in cortical motor representation [2,4,13]. If sacral neuromodulation can drive a dynamic change of the brain and produce functionally relevant changes in bladder control, the technique of transcranial magnetic stimulation (TMS) might help assess cortical plasticity after sacral neuromodulation. Hence, we applied TMS to study the effect of sacral neuromodulation on the brain.
Materials and methods Subjects We included six female patients (age: 33—68 y/o; mean: 45.3 ± 12.7 y/o). All had urinary frequency (more than 20 times a day), urgency perception, and nocturia, as evidenced in the voiding diary. Besides, the normal urine routine, a neurological investigation showed intact sacralroot functions (S2—S4), such as normal anal sphincter tone
and normal sensory function of the sacral area. Based upon the standardization of the International Continence Society [1], idiopathic OBS was diagnosed after local pathology or metabolic factors had been excluded. None of the subjects had any surgical intervention in the pelvis and all patients were right-footed. The protocol was approved by the Human Ethics Committee and the subjects gave their informed consents before entering the study. The following assessments were done before and after sacral neuromodulation.
Sacral-root stimulation A test stimulating wire (30571SC; Medtronic, Minneapolis, Minnesota, USA) was inserted into the left or right S2—4 foramen for a week. To be sure the stimulating wire was in the correct position, we observed the muscle contraction of the toe flexor. Otherwise, the patient was questioned about typical pulling sensations in the rectum and vagina. If acceptable, the stimulating wire was then connected to an external stimulating control box (3625; Medtronic). The patient was given instructions regarding adjustment of the stimulator amplitude during the stimulation period. A visual analogue scale (VAS 0—10; 0: absolute perfect results; 10: no improvement) and an urgency scale (0—3; 0: normal, 1: mild, 2: moderate, 3: severe) were recorded by the patients to compare the effect of sacral neuromodulation after test stimulation. Moreover, all patients completed a seven-day bladder diary that included the number of voiding events per day, the number of nocturia events and the number of pads used.
Surface recordings Because the motor evoked potentials (MEP) of the sphincter muscles were more variable than those of the flexor hallucis
Effect of sacral root stimulation on the motor cortex Table 1
41
Clinical profiles of patients with overactive bladder.
Patient (before/after SN)
1 B/A
2 B/A
3 B/A
4 B/A
5 B/A
6 B/A
Mean B/A
Sex Age Daytime frequency Nocturia Urgency scale (0—3) Pads a day VAS (0—10)
F 68 27/16 8/4 3/2 6/3 10/5
F 52 32/20 8/5 3/1 6/4 10/7
F 33 28/11 7/2 3/1 4/1 10/3
F 41 25/8 5/1 3/0 3/0 10/2
F 38 30/9 6/2 3/1 3/1 10/2
F 40 26/10 10/3 3/1 4/1 10/3
45.3 28.0/12.3* 7.3/2.8* 3/1* 4.2/1.7* 10/3.7*
SN: sacral neuromodulation; urgency scale: 0, normal and 3, severe; VAS: visual analogue scale: 0, normal and 10 the worst condition. * P value < 0.05.
brevis (FHB) muscles, the FHB was taken as the target muscle in the study. The EMG signals of the FHB muscles were recorded with bipolar surface electrodes. A ground electrode was placed at the ankle. The EMG signals were filtered by the EMG machine (Neuropack M1, Nihon Kohden, Japan) using a bandwidth of 20 Hz—1 kHz. We measured the onset latency and the peak-to-peak amplitude of the FHB response.
TMS For the TMS study, the subject sat comfortably in a chair. The subjects wore a tightly fitting swimming cap. The scalp grid, 12 × 9 cm was marked on the cap and comprised 70 stimulation points with rows 2 cm apart, anteroposteriorly and 1 cm apart, mediolaterally over one hemisphere. The center of the cap (0,0) was aligned at the intersection of the interaural and inion—nasion lines (vertex). The protocol included motor threshold, maximal MEP amplitudes, and brain mapping with active stimulation sites. All were done before the test stimulation and 30 min after the seven-day test stimulation. Motor threshold was measured to assess cortical excitability. The figure-of-eight coil was held over the scalp and oriented 90 degrees perpendicular and tangential to the sagittal midline, so that the induced current flow was per-
Table 2
pendicular to the estimated alignment of the central sulcus [10]. The motor threshold for the FHB muscle was determined with the subjects in a relaxed state. In the beginning, the coil was discharged at 100% of stimulator output, to determine the site on the grid that produced the greatest toe muscle response. The coil was then discharged over this point with a lower intensity in 5% decrements, until the EMG responses had amplitudes of 50—100 V with five out of 10 consecutive stimuli. Mapping was used to measure the size of the mean motor output area at 120% threshold intensity [9] and was defined as the number of scalp positions, whose stimulation evoked MEPs larger than 50 V in at least one out of four trials. The best MEP was selected for analysis. The coil was moved systemically over the skull in steps of 1 cm to identify all scalp positions, whose stimulation produced an EMG response. The intensity used in the first session was applied for the post-treatment session [8]. Four stimuli were applied to each position [5].
Inion magnetic stimulation and H:M ratio We further investigated whether sacral-root stimulation and magnetic stimulation (MS) also modulated other levels of the nervous system. Inion magnetic stimulation was done for the
Electrophysiological study of subjects before and after sacral neuromodulation.
Patient (before/after)
1 B/A
2 B/A
3 B/A
4 B/A
5 B/A
6 B/A
Mean B/A
Transcranial MS Threshold Amp. (mV) Amp. ratio Latency (ms) Map area
75/75 2.5/3.4 1/1.36 37.2/38.3 11/14
80/80 3.2/3.9 1/1.22 37.4/38.0 9/15
65/70 3.6/4.5 1/1.25 36.5/36.2 14/19
70/65 2.8/4.1 1/1.46 37.5/36.2 15/23
70/65 3.0/4.0 1/1.33 39.8/39.2 13/21
65/60 3.8/4.5 1/1.18 36.4/35.9 17/22
70.8/69.1 3.2/4.1* 1/1.3* 37.5/37.3 13.2/19.0*
Inion MS Amp. (mV) Amp. ratio
0.56/0.54 1/0.96
0.48/0.51 1/1.06
0.72/0.69 1/0.96
0.65/0.66 1/1.02
0.58/0.61 1/1.05
0.68/0.64 1/0.94
0.61/0.61 1/1
H reflex H/M (%)
2.3/2.1
1.9/1.8
2.7/2.5
1.8/2.0
2.6/2.2
1.9/2.4
2.2/2.2
B/A: before/after; MS: magnetic stimulation. Map area: number of sites to evoke motor response. * P value < 0.05.
42
K.K. Liao et al.
assessment of brainstem excitability with a double cone coil placed over the inion, or below it on the median line [12], and the soleus H:M ratio was used for spinal excitability.
Statistical analysis The Wilcoxon signed-ranks test was used to compare the data before and after sacral-root stimulation. A P value less than 0.05 was considered significant.
Results All the subjects had clinical improvement after test stimulation (Table 1). Improvement was noted in daily frequency (before: 28.0 ± 2.6; after 12.3 ± 4.7; P = 0.0313; four of six subjects; improvement ≥50%), nocturia (before: 7.3 ± 1.8; after: 2.8 ± 1.5; P = 0.0313; five of six subjects; improvement ≥50%), urgency (before: 3.0 ± 0.0; after: 1 ± 0.6; P = 0.0313; five of six subjects; improvement ≥50%), pad consumption (before: 4.2 ± 1.5; after 1.7 ± 1.5: P = 0.0313; five of six subjects; improvement ≥50%), and subjective assessment with VAS (before 10.0 ± 0.0; after 3.7 ± 2.0; P = 0.0313; five of six subjects; improvement ≥50%) (Table 1). None of the subjects had a complication during the sacral-root stimulation protocol.
TMS The FHB responses to TMS were increased in the amplitudes (before 3.2 ± 0.5 mV; after 4.1 ± 0.4 mV; P = 0.0313) after sacral-root stimulation (Table 2; Fig. 1). The number of active sites also increased (before 13.2 ± 2.9; after 19.0 ± 3.7; P = 0.0313) after sacral-root stimulation. The changes were not significant in threshold (before 70.8 ± 5.8%; after 69.1 ± 7.4%, P = 0.625) and latency (before: 37.4 ± 1.2 ms; after: 37.3 ± 1.4 ms, P = 0.7188).
Inion magnetic stimulation and soleus H:M ratio The soleus H:M ratio (before 2.2 ± 0.4; after: 2.2 ± 0.3; P = 0.875) and FHB response to inion magnetic stimulation (before 0.61 ± 0.09 mV; after: 0.61 ± 0.07 mV; P = 0.8125) did not change after sacral-root stimulation.
Discussion Our results showed that sustained sacral-root stimulation may reorganize the human brain and its ability to excite the motor cortex. The results indicate that sacral-root stimulation modulates not only the spinal arc of micturition, but also the supraspinal area. It is well-known that the brain urinary center has a role in the sensory perception of bladder fullness and voiding motor control, and also clear that the brain urinary center is beyond the motor cortex and incorporates a number of other cerebral areas. Imaging studies have shown that there is a complex connection among the pons (pontine micturition center, PMC), periaqueductal gray (PAG), thalamus, insula, anterior cingulate gyrus and prefrontal cortices [7]. The PMC and the PAG are thought to have a role in the supras-
Figure 1 Brain mapping was studied in a patient (No 2) with idiopathic overactive bladder syndrome with transcranial magnetic stimulation. Each column represents the amplitude of motor evoked potential (MEP) at the stimulation site. It showed that MEP amplitudes and area of representation for the flexor hallucis brevis muscle increased after sacral neuromodulation. Otherwise, there was a slight tendency towards a lateralization of the center of gravity of the MEP maps after sacral neuromodulation. (A): before sacral neuromodulation; (B): after sacral neuromodulation. X-axial: from medial (Cz) to lateral (A1); Yaxial: from frontal to parietal along the saggital sulcus; Z-axial: MEP amplitude. The unit of amplitude is V.
pinal control of continence and micturition; the insula, anterior cingulate gyrus, and prefrontal regions in the modulation of this control, and cognition of bladder sensations and the insula and anterior cingulate in the modulation of the autonomic function. Hence, reorganization of the motor cortex is possibly an indirect index of the dynamic
Effect of sacral root stimulation on the motor cortex change of the brain urinary center after sacral-root stimulation. It is hypothesized that sacral-root stimulation counteracts the sensitive visceral afferents and restores the bladder perception of volume and the ability to void [6]. Therefore, it is inferred that sacral-root stimulation has a deafferentation effect on the overactive bladder. TMS studies prove that deafferentation may produce brain reorganization [2]. Muscles proximal to the deafferented level usually have larger amplitudes of motor evoked potentials to TMS and have a larger cortical representation [2]. This may well account for our results, because FHB muscles are usually innervated by the S1 or S2 root, that is, proximal to the S3 deafferented level. In a study of deafferentation, the site of amplitude change is inferred at the motor cortex, because transcranial stimulation and inion stimulation do not produce a similar effect [2]. This is also supported by the result that the FHB response to inion magnetic stimulation and the soleus H:M ratios were not changed after sacral-root stimulation, indicating that the motor neuron excitability of the brainstem and spinal cord remained unchanged. In a study of fecal incontinence, sacral-root stimulation may have decreased the cortical representation and motor cortex excitability of the anal sphincter muscles, which are usually innervated by S3 [11]. If this is true, it seems that sacral-root stimulation decreases anal sphincter muscle responses, but increases its neighbor muscle responses, that is, foot muscle responses. This suggests that the cortical representation of foot muscles increases at the expense of the representation of the anal sphincter muscles. Our results showed that sustained sacral-root stimulation may alter cerebral activities, along with the clinical improvement. The improvement in urinary urgency and urgency perception is probably in part due to brain reorganization.
Acknowledgement We thank Mr. Jim Ascencio for the English editing and Miss Tzu-Jen Tsou for French abstract.
43
References [1] Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardization of terminology of lower urinary tract function: report from the standardization subcommittee of the International Continence Society. Am J Obstet Gynecol 2002;187:116—26. [2] Brasil-Neto JP, Valls-Sole J, Pascual-Leone A, Cammarota A, Amassian VE, Cracco R, et al. Rapid modulation of human motor cortical motor outputs following ischemic nerve block. Brain 1993;116:511—25. [3] Braun PM, Baezner H, Seif C, Boehler G, Bross S, Eschenfelder CC, et al. Alterations of cortical electrical activity in patients with sacral neuromodulator. Eur Urol 2002;41:562—6. [4] Cohen LG, Brasil-Neto JP, Pascual-Leone A, Hallett M. Plasticity of cortical motor output organization following deafferentation, cerebral lesions and skill acquisition. Adv Neurol 1993;63:187—200. [5] Cohen LG, Hallett M. Noninvasive mapping of human motor cortex. Neurology 1988;38:378—83. [6] Fowler CJ. The perspective of a neurologist on treatmentrelated research in fecal and urinary incontinence. Gastroenterology 2004;126:S172—4. [7] Kavia RB, Dasgupta R, Fowler CJ. Functional imaging and the central control of the bladder. J Comp Neurol 2005;493:27—32. [8] Koski L, Mernar TJ, Dobkin BH. Immediate and long-term changes in corticomotor output in response to rehabilitation: correlation with functional improvements in chronic stroke. Neurorehabil Neural Repair 2004;18:230—49. [9] Liepert J, Bauder H, Wolfgang HR, Miltner WH, Taub E, Weiller C. Treatment induced cortical reorganization after stroke in humans. Stroke 2000;31:1210—6. [10] Rosler KM, Hess CW, Heckmann R, Ludin HP. Significance of shape and size of the stimulating coil in magnetic stimulation of the human motor cortex. Neurosci Lett 1989;100:347—52. [11] Sheldon R, Kiff ES, Clarke A, Harris ML, Hamdy S. Sacral nerve stimulation reduces corticospinal excitability in patients with faecal incontinence. Br J Surg 2005;92:1423—31. [12] Ugawa Y, Uesaka Y, Terao Y, Hanajima R, Kanazawa I. Magnetic stimulation of corticospinal pathways at the foramen magnum level in humans. Ann Neurol 1994 Oct;36:618—24. [13] Ziemann U, Corwell B, Cohen LG. Modulation of plasticity in human motor cortex after forearm ischemic nerve block. J Neurosci 1998;18:1115—23.
journal homepage: http://france.elsevier.com/direct/neucli
ORIGINAL ARTICLE/ARTICLE ORIGINAL
Effect of sacral-root stimulation on the motor cortex in patients with idiopathic overactive bladder syndrome Effet de la stimulation de la racine sacrée sur le cortex moteur chez les patients présentant une hyperactivité vésicale idiopathique K.K. Liao a,c, J.T. Chen a,c,f, K.L. Lai a,c, C.Y. Liu a,c, C.Y. Lin a,c,e, Y.Y. Lin a,c, B. KJ. Yu b,d, Z.A. Wu a,c,∗ a
Department of Neurology, Taipei Veterans General Hospital, 201, Section II, Shih-Pai Road, 11217 Taipei, Taiwan Department of Obstetrics and Gynecology, Kaohsuing Veterans General Hospital, Kaohsuing, Taiwan c Department of Neurology, National Yang Ming Medical University School of Medicine, Taipei, Taiwan d Department of Obstetrics and Gynecology, National Yang Ming Medical University School of Medicine, Taipei, Taiwan e Institute of Physiology, National Yang Ming Medical University School of Medicine, Taipei, Taiwan f Department of Neurology, Cathay General Hospital, Taipei, Taiwan b
Received 26 May 2007; accepted 9 September 2007 Available online 11 October 2007
KEYWORDS Brain reorganization; Plasticity; Overactive bladder; Sacral neuromodulation; Sacral-root stimulation; Transcranial magnetic stimulation
∗
Summary Aims of the study. — It is presumed that idiopathic overactive bladder syndrome (OBS) is due to visceral hypersensitivity. Sacral-root stimulation can restore the bladder function, but its mechanism remains uncertain. It is well-known that long-term peripheral stimulation can induce brain plasticity. Hence, we investigated whether brain reorganization occurred along with clinical improvement after sacral-root stimulation. Material and methods. — Because toe flexion is the index for monitoring wire placement, we used the flexor hallucis brevis (FHB) as the target muscle. Transcranial magnetic stimulation (TMS) was applied to study motor cortex excitability and the brain mapping of the muscle. Results. — Six patients with idiopathic OBS were included in the study. All demonstrated clinical improvement after sacral-root stimulation. Motor cortex excitability and the area of representation for the flexor hallucis brevis muscle increased for at least 30 min after sacral-root stimulation had terminated.
Corresponding author. E-mail address: [email protected] (Z.A. Wu).
0987-7053/$ — see front matter © 2007 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.neucli.2007.09.004
40
K.K. Liao et al. Conclusion. — Our results showed that cerebral activities changed after sacral-root stimulation. The improvement in urinary urgency and urgency perception was probably due in part to brain reorganization. © 2007 Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Réorganisation cérébrale ; Plasticité ; Neuromodulation sacrée ; L’hyperactivité vésicale ; Stimulation de la racine sacrée ; Stimulation magnétique transcrânienne
Résumé Objectif de la recherche. — On suppose que le syndrome d’hyperactivité vésicale idiopathique (idiopathic overactive bladder syndrome IOBS) est dû à une hypersensibilité viscérale. La stimulation de la racine sacrée peut restaurer la fonction vésicale, mais son mécanisme demeure incertain. Il est bien connu que la stimulation périphérique à long terme peut induire une plasticité cérébrale. Nous avons dès lors examiné, si l’amélioration clinique consécutive à une stimulation de la racine sacrée était ou non associée à une réorganisation cérébrale. Matériel et méthodes. — La flexion de l’orteil étant utilisée comme indice de l’emplacement de l’électrode, nous avons choisi de réaliser les enregistrements au niveau du fléchisseur du gros orteil. Nous avons utilisé la stimulation magnétique transcrânienne pour étudier l’excitabilité du cortex moteur et la cartographie cérébrale du muscle. Résultats. — Six patients présentant une OBS idiopathique ont été inclus dans l’étude. Tous les sujets présentaient une amélioration clinique après stimulation de la racine sacrée. L’excitabilité du cortex moteur et la zone de représentation du muscle fléchisseur de l’hallux a augmenté durant au moins 30 minutes après la fin de la stimulation de la racine sacrée. Conclusions. — Nos résultats montrent que les activités cérébrales se modifient après stimulation de la racine sacrée. Les améliorations de l’impériosité et de la perception de l’impériosité sont probablement dues en partie à une réorganisation cérébrale. © 2007 Elsevier Masson SAS. All rights reserved.
Introduction Sacral neuromodulation is a therapeutic procedure consisting of sacral-root stimulation of S2—4. This has been applied for the treatment of pelvic floor disorders, such as overactive bladder syndrome (OBS). Though the mechanism of sacral neuromodulation is uncertain, it has been hypothesized that sacral neuromodulation stimulates the somatic afferent axons in the spinal roots, which in turn modulate the voiding and continence reflex pathways [6]. The action is postulated to involve not only the arc of sacral reflex, but also supraspinal influences [3]. It is presumed that idiopathic OBS is due to visceral hypersensitivity. Sacral-root stimulation may have a deafferentation effect and reverse urinary perception. Removal of sensory input can induce changes in cortical motor representation [2,4,13]. If sacral neuromodulation can drive a dynamic change of the brain and produce functionally relevant changes in bladder control, the technique of transcranial magnetic stimulation (TMS) might help assess cortical plasticity after sacral neuromodulation. Hence, we applied TMS to study the effect of sacral neuromodulation on the brain.
Materials and methods Subjects We included six female patients (age: 33—68 y/o; mean: 45.3 ± 12.7 y/o). All had urinary frequency (more than 20 times a day), urgency perception, and nocturia, as evidenced in the voiding diary. Besides, the normal urine routine, a neurological investigation showed intact sacralroot functions (S2—S4), such as normal anal sphincter tone
and normal sensory function of the sacral area. Based upon the standardization of the International Continence Society [1], idiopathic OBS was diagnosed after local pathology or metabolic factors had been excluded. None of the subjects had any surgical intervention in the pelvis and all patients were right-footed. The protocol was approved by the Human Ethics Committee and the subjects gave their informed consents before entering the study. The following assessments were done before and after sacral neuromodulation.
Sacral-root stimulation A test stimulating wire (30571SC; Medtronic, Minneapolis, Minnesota, USA) was inserted into the left or right S2—4 foramen for a week. To be sure the stimulating wire was in the correct position, we observed the muscle contraction of the toe flexor. Otherwise, the patient was questioned about typical pulling sensations in the rectum and vagina. If acceptable, the stimulating wire was then connected to an external stimulating control box (3625; Medtronic). The patient was given instructions regarding adjustment of the stimulator amplitude during the stimulation period. A visual analogue scale (VAS 0—10; 0: absolute perfect results; 10: no improvement) and an urgency scale (0—3; 0: normal, 1: mild, 2: moderate, 3: severe) were recorded by the patients to compare the effect of sacral neuromodulation after test stimulation. Moreover, all patients completed a seven-day bladder diary that included the number of voiding events per day, the number of nocturia events and the number of pads used.
Surface recordings Because the motor evoked potentials (MEP) of the sphincter muscles were more variable than those of the flexor hallucis
Effect of sacral root stimulation on the motor cortex Table 1
41
Clinical profiles of patients with overactive bladder.
Patient (before/after SN)
1 B/A
2 B/A
3 B/A
4 B/A
5 B/A
6 B/A
Mean B/A
Sex Age Daytime frequency Nocturia Urgency scale (0—3) Pads a day VAS (0—10)
F 68 27/16 8/4 3/2 6/3 10/5
F 52 32/20 8/5 3/1 6/4 10/7
F 33 28/11 7/2 3/1 4/1 10/3
F 41 25/8 5/1 3/0 3/0 10/2
F 38 30/9 6/2 3/1 3/1 10/2
F 40 26/10 10/3 3/1 4/1 10/3
45.3 28.0/12.3* 7.3/2.8* 3/1* 4.2/1.7* 10/3.7*
SN: sacral neuromodulation; urgency scale: 0, normal and 3, severe; VAS: visual analogue scale: 0, normal and 10 the worst condition. * P value < 0.05.
brevis (FHB) muscles, the FHB was taken as the target muscle in the study. The EMG signals of the FHB muscles were recorded with bipolar surface electrodes. A ground electrode was placed at the ankle. The EMG signals were filtered by the EMG machine (Neuropack M1, Nihon Kohden, Japan) using a bandwidth of 20 Hz—1 kHz. We measured the onset latency and the peak-to-peak amplitude of the FHB response.
TMS For the TMS study, the subject sat comfortably in a chair. The subjects wore a tightly fitting swimming cap. The scalp grid, 12 × 9 cm was marked on the cap and comprised 70 stimulation points with rows 2 cm apart, anteroposteriorly and 1 cm apart, mediolaterally over one hemisphere. The center of the cap (0,0) was aligned at the intersection of the interaural and inion—nasion lines (vertex). The protocol included motor threshold, maximal MEP amplitudes, and brain mapping with active stimulation sites. All were done before the test stimulation and 30 min after the seven-day test stimulation. Motor threshold was measured to assess cortical excitability. The figure-of-eight coil was held over the scalp and oriented 90 degrees perpendicular and tangential to the sagittal midline, so that the induced current flow was per-
Table 2
pendicular to the estimated alignment of the central sulcus [10]. The motor threshold for the FHB muscle was determined with the subjects in a relaxed state. In the beginning, the coil was discharged at 100% of stimulator output, to determine the site on the grid that produced the greatest toe muscle response. The coil was then discharged over this point with a lower intensity in 5% decrements, until the EMG responses had amplitudes of 50—100 V with five out of 10 consecutive stimuli. Mapping was used to measure the size of the mean motor output area at 120% threshold intensity [9] and was defined as the number of scalp positions, whose stimulation evoked MEPs larger than 50 V in at least one out of four trials. The best MEP was selected for analysis. The coil was moved systemically over the skull in steps of 1 cm to identify all scalp positions, whose stimulation produced an EMG response. The intensity used in the first session was applied for the post-treatment session [8]. Four stimuli were applied to each position [5].
Inion magnetic stimulation and H:M ratio We further investigated whether sacral-root stimulation and magnetic stimulation (MS) also modulated other levels of the nervous system. Inion magnetic stimulation was done for the
Electrophysiological study of subjects before and after sacral neuromodulation.
Patient (before/after)
1 B/A
2 B/A
3 B/A
4 B/A
5 B/A
6 B/A
Mean B/A
Transcranial MS Threshold Amp. (mV) Amp. ratio Latency (ms) Map area
75/75 2.5/3.4 1/1.36 37.2/38.3 11/14
80/80 3.2/3.9 1/1.22 37.4/38.0 9/15
65/70 3.6/4.5 1/1.25 36.5/36.2 14/19
70/65 2.8/4.1 1/1.46 37.5/36.2 15/23
70/65 3.0/4.0 1/1.33 39.8/39.2 13/21
65/60 3.8/4.5 1/1.18 36.4/35.9 17/22
70.8/69.1 3.2/4.1* 1/1.3* 37.5/37.3 13.2/19.0*
Inion MS Amp. (mV) Amp. ratio
0.56/0.54 1/0.96
0.48/0.51 1/1.06
0.72/0.69 1/0.96
0.65/0.66 1/1.02
0.58/0.61 1/1.05
0.68/0.64 1/0.94
0.61/0.61 1/1
H reflex H/M (%)
2.3/2.1
1.9/1.8
2.7/2.5
1.8/2.0
2.6/2.2
1.9/2.4
2.2/2.2
B/A: before/after; MS: magnetic stimulation. Map area: number of sites to evoke motor response. * P value < 0.05.
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K.K. Liao et al.
assessment of brainstem excitability with a double cone coil placed over the inion, or below it on the median line [12], and the soleus H:M ratio was used for spinal excitability.
Statistical analysis The Wilcoxon signed-ranks test was used to compare the data before and after sacral-root stimulation. A P value less than 0.05 was considered significant.
Results All the subjects had clinical improvement after test stimulation (Table 1). Improvement was noted in daily frequency (before: 28.0 ± 2.6; after 12.3 ± 4.7; P = 0.0313; four of six subjects; improvement ≥50%), nocturia (before: 7.3 ± 1.8; after: 2.8 ± 1.5; P = 0.0313; five of six subjects; improvement ≥50%), urgency (before: 3.0 ± 0.0; after: 1 ± 0.6; P = 0.0313; five of six subjects; improvement ≥50%), pad consumption (before: 4.2 ± 1.5; after 1.7 ± 1.5: P = 0.0313; five of six subjects; improvement ≥50%), and subjective assessment with VAS (before 10.0 ± 0.0; after 3.7 ± 2.0; P = 0.0313; five of six subjects; improvement ≥50%) (Table 1). None of the subjects had a complication during the sacral-root stimulation protocol.
TMS The FHB responses to TMS were increased in the amplitudes (before 3.2 ± 0.5 mV; after 4.1 ± 0.4 mV; P = 0.0313) after sacral-root stimulation (Table 2; Fig. 1). The number of active sites also increased (before 13.2 ± 2.9; after 19.0 ± 3.7; P = 0.0313) after sacral-root stimulation. The changes were not significant in threshold (before 70.8 ± 5.8%; after 69.1 ± 7.4%, P = 0.625) and latency (before: 37.4 ± 1.2 ms; after: 37.3 ± 1.4 ms, P = 0.7188).
Inion magnetic stimulation and soleus H:M ratio The soleus H:M ratio (before 2.2 ± 0.4; after: 2.2 ± 0.3; P = 0.875) and FHB response to inion magnetic stimulation (before 0.61 ± 0.09 mV; after: 0.61 ± 0.07 mV; P = 0.8125) did not change after sacral-root stimulation.
Discussion Our results showed that sustained sacral-root stimulation may reorganize the human brain and its ability to excite the motor cortex. The results indicate that sacral-root stimulation modulates not only the spinal arc of micturition, but also the supraspinal area. It is well-known that the brain urinary center has a role in the sensory perception of bladder fullness and voiding motor control, and also clear that the brain urinary center is beyond the motor cortex and incorporates a number of other cerebral areas. Imaging studies have shown that there is a complex connection among the pons (pontine micturition center, PMC), periaqueductal gray (PAG), thalamus, insula, anterior cingulate gyrus and prefrontal cortices [7]. The PMC and the PAG are thought to have a role in the supras-
Figure 1 Brain mapping was studied in a patient (No 2) with idiopathic overactive bladder syndrome with transcranial magnetic stimulation. Each column represents the amplitude of motor evoked potential (MEP) at the stimulation site. It showed that MEP amplitudes and area of representation for the flexor hallucis brevis muscle increased after sacral neuromodulation. Otherwise, there was a slight tendency towards a lateralization of the center of gravity of the MEP maps after sacral neuromodulation. (A): before sacral neuromodulation; (B): after sacral neuromodulation. X-axial: from medial (Cz) to lateral (A1); Yaxial: from frontal to parietal along the saggital sulcus; Z-axial: MEP amplitude. The unit of amplitude is V.
pinal control of continence and micturition; the insula, anterior cingulate gyrus, and prefrontal regions in the modulation of this control, and cognition of bladder sensations and the insula and anterior cingulate in the modulation of the autonomic function. Hence, reorganization of the motor cortex is possibly an indirect index of the dynamic
Effect of sacral root stimulation on the motor cortex change of the brain urinary center after sacral-root stimulation. It is hypothesized that sacral-root stimulation counteracts the sensitive visceral afferents and restores the bladder perception of volume and the ability to void [6]. Therefore, it is inferred that sacral-root stimulation has a deafferentation effect on the overactive bladder. TMS studies prove that deafferentation may produce brain reorganization [2]. Muscles proximal to the deafferented level usually have larger amplitudes of motor evoked potentials to TMS and have a larger cortical representation [2]. This may well account for our results, because FHB muscles are usually innervated by the S1 or S2 root, that is, proximal to the S3 deafferented level. In a study of deafferentation, the site of amplitude change is inferred at the motor cortex, because transcranial stimulation and inion stimulation do not produce a similar effect [2]. This is also supported by the result that the FHB response to inion magnetic stimulation and the soleus H:M ratios were not changed after sacral-root stimulation, indicating that the motor neuron excitability of the brainstem and spinal cord remained unchanged. In a study of fecal incontinence, sacral-root stimulation may have decreased the cortical representation and motor cortex excitability of the anal sphincter muscles, which are usually innervated by S3 [11]. If this is true, it seems that sacral-root stimulation decreases anal sphincter muscle responses, but increases its neighbor muscle responses, that is, foot muscle responses. This suggests that the cortical representation of foot muscles increases at the expense of the representation of the anal sphincter muscles. Our results showed that sustained sacral-root stimulation may alter cerebral activities, along with the clinical improvement. The improvement in urinary urgency and urgency perception is probably in part due to brain reorganization.
Acknowledgement We thank Mr. Jim Ascencio for the English editing and Miss Tzu-Jen Tsou for French abstract.
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