International Urology and Nephrology

https://doi.org/10.1007/s11255-020-02614-8

UROLOGY - ORIGINAL PAPER

Regional brain atrophy in overactive bladder syndrome: a voxel based

morphometry study
Long Zuo1 · Yang Zhou1 · Shuangkun Wang1   · Biao Wang2 · Hua Gu1 · Jingnan Chen3

Received: 10 June 2020 / Accepted: 13 August 2020

© Springer Nature B.V. 2020

Abstract
Objectives  To investigate whether patients with overactive bladder syndrome (OAB) have brain volume changes using
voxel-based morphometry (VBM) and correlations with clinical tests.
Methods  With institutional review board approval and after obtaining written informed consent, structural magnetic reso-
nance imaging data were prospectively acquired in 28 patients and 28 control subjects. OAB symptoms were assessed
using the OAB symptom score (OABSS) scale. The gray matter volume (GMV) of each voxel was compared between the
two groups while controlling for the effects of age, sex, and education level. Correlation analysis was performed to identify
correlations between abnormal GMV regions and OABSS scores in patients. Multiple comparisons were corrected using
a false discovery rate (FDR) method.
Results  Patients with OAB exhibited a GMV reduction in the right cerebellum, bilateral hippocampus, left insula, right
superior temporal gyrus, left anterior cingulate gyrus, bilateral caudate nucleus and right middle frontal gyrus. Furthermore,
there was a significant negative correlation between the local GMV of the right cerebellar hemisphere and OABSS score.
Conclusions  Patients with OAB have abnormal GMV in brain regions localized within the brain-bladder control network. It
deepens our understanding of the structural changes in the brain area of the network. The patterns of structural reorganization
in patients with OAB may provide useful information in the neuropathological mechanisms of the OAB.

Keywords  Overactive bladder syndrome · Brain-bladder control network · Voxel-based morphometry · Gray matter
volume · Structural reorganization

Introduction prevalent and costly condition that greatly impairs living

Overactive bladder syndrome (OAB) is defined as a symp-
tom complex including urgency, with or without urge incon-
tinence, but usually with frequency and nocturia. OAB is a
Electronic supplementary material  The online version of this
article (https​://doi.org/10.1007/s1125​5-020-02614​-8) contains
supplementary material, which is available to authorized users.
* Shuangkun Wang
shuangkunwang@126.com
1
Department of Radiology, Beijing Chao‑Yang Hospital,
Capital Medical University, 8 Gongren Tiyuchang Nanlu,
Chaoyang District, Beijing 100020, China
2
Department of Urology, Beijing Chao‑Yang Hospital, Capital
Medical University, Beijing, China
3
School of Economics and Management, Beihang University,
Beijing, China
quality of patients worldwide [1].
In order to explore the etiology of OAB, researchers
propose many hypotheses. Using blood oxygenation-level
dependent (BOLD) imaging from functional magnetic reso-
nance imaging (fMRI), emerging research on central patho-
physiologic mechanisms attracts more and more attention.
The fMRI has revealed the pathophysiological model of
brain-bladder control network (BBCN) in OAB, in which
areas such as prefrontal lobe, cingulate gyrus, thalamus,
basal ganglia and insular lobe are important, according to a
large number of existing studies [2]. A broad consensus has
been reached that the BBCN of OAB may provide new tar-
gets for therapeutic intervention. However, at present, there
are few studies on the structure of the model.
Clearly, structural abnormalities in the BBCN might
underlie the functional abnormalities detected on brain
fMRI. The voxel-based morphometry (VBM) of high-reso-
lution T1-weighted imaging is the most common method for

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Vol.:(0123456789)

depicting subtle structural properties of brain tissues, which
enables the assessment of differences in the local volume
at voxel level [3]. Compared with the traditional region of
interest (ROI) measurement, the VBM can detect the dam-
age of occult brain structure, thus improving the statistical
validity of morphological analysis. As a consequence, the
VBM approach facilitates the accurate analysis of the mor-
phological changes of gray matter (GM).
However, the microstructure changes of gray matter in the
brain of patients with OAB are not clear. At present, there
are few studies based on voxel morphological analysis of
OAB patients. We presume that the BBCN has the structural
abnormality of GM in OAB patients. Thus, the data-driven
VBM method is applied to analyze the morphology of whole
brain GM in OAB patients in order to further explore the
pathophysiological mechanism of the disease.
Methods
Participants
The experimental protocol was approved by the Committee
for Human Research at ***Hospital [disclosure of hospital
name/other identifier during review process (2015-ke-21)]
and written informed consent was obtained from all par-
ticipants. Twenty-eight subjects with OAB and 28 healthy
control participants were included in this study.
According to the 2002 ICS (International Continence
Society) definition, the OAB patients must complain of uri-
nary urgency, with or without urge incontinence, usually
with frequency and nocturia, in the absence of infection
or other identifiable causes. The inclusion criteria were as
follows: (1) age ≥ 18 years old, (2) clinical diagnosed with
OAB, and (3) willing to participate in the experimental pro-
tocol and capable of understanding the study procedures.
The exclusion criteria were the following: (1) a postvoid
residual volume ≥ 150 mL and/or pelvic organ prolapse, (2)
urinary tract infections within the last month of the survey,
(3) history of urinary system surgery, (4) urethral obstruc-
tion (e.g. benign prostate hyperplasia), and (5) newonset or
chronic neurological diseases (such as stroke, spinal cord
damage, Parkinson’s disease, and multiple sclerosis).
Healthy controls must have no prior diagnosis of OAB
or interstitial cystitis/bladder pain syndrome, no significant
lower urinary tract symptoms (American Urological Asso-
ciation symptom index < 7), no bladder or pelvic pain, and
no evidence of urinary infection.
OAB or incontinence symptoms were assessed using a
version of the OAB symptom score (OABSS). OAB was
divided into 3 groups according to the following score
ranges: mild, a total score ≤ 5; moderate, a total score of
6–11; severe, a total score ≥ 12. To assess the cognitive
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International Urology and Nephrology
function of OAB patients in this study, we used the Mini-
Mental State Examination as an objective test. Depression
symptoms were assessed using the Self-Rating Depression
Scale (SDS). Anxiety symptoms were assessed using the
Self-Rating Anxiety Scale (SAS).
OAB symptom score (OABSS) is a self-administered
questionnaire of OAB symptoms including four aspects:
daytime frequency, nighttime frequency, urgency, and
urgency incontinence [4]. OABSS has advantages over other
OAB scales, gaining popular acceptance.
Self-Rating Depression scale (SDS) consists of 20 items,
each of which consists of seven grades, including two items
of psychiatric-emotional symptoms, eight items of physi-
cal disorders, two items of psychomotor disorders and eight
items of depressive mental disorders [5]. Self-rating anxi-
ety scale (SAS) contains 20 items that reflect the subjective
feelings of anxiety, and each item is divided into four grades
according to the frequency of symptoms [6].
Mini Mental State Assessment scale (MMSE) is the most
widely used neuropsychological scale for screening cogni-
tive function in the world. It focuses on the orientation of
time and place, calculation, memory, language ability, visual
space and application function [7]. MMSE is characterized
by short testing time and good sensitivity.
MR imaging data acquisition
All subjects emptied their bladders before undergoing
MRI. Three-dimensional sagittal T1-weighted images
were acquired with a Magnetom Prisma Tim MR imager
(Siemens, Erlangen, Germany) at the Magnetic Reso-
nance Center of ***Hospital (disclosure of hospital
name/other identifier during review process). The imag-
ing parameters were as follows: repetition time/echo
time = 1900 ms/2.52 ms; flip angle = 9°; slices = 176; field
of view = 256 mm × 256 mm; data matrix = 256 × 256; in-
plane resolution = 1 mm × 1 mm.
VBM processing
The VBM analysis was performed using VBM8 tool-box
(https:​ //dbm.neuro.​ uni-jena.de/vbm) with default parameters
running in the SPM8 (statistical parametric mapping, https​
://www.fil.ion.ucl.ac.uk/spm) software. The main steps are
as follows: firstly, the MRI data is transformed from medical
digital imaging and communication (Digital Imaging and
Communications in Medicine, DICOM) format to neuro-
imaging information technology processing scheme (Neu-
roimaging Informatics Technology Initiative, NIFTI) format
using MICRON software. The 3D-T1WI structural images
of the whole brain were corrected and segmented into gray
matter, white matter and cerebrospinal fluid. Then, the aff-
ine transformation of the gray matter image is registered to
International Urology and Nephrology

the standard brain of the Montreal Institute of Neurology
(Montreal Neurological Institute, MNI), and the DARTEL
(Diffeomorphic Anatomical Registration Exponentiated Lie)
algorithm is used to create a specific template to study the
organization. Subsequently, the original gray matter image
space is registered with the newly generated template and
further standardized to the MNI space (1.5 mm isotropic
voxel). The corresponding deformation of the gray matter
image is modulated by Jacobian determinant to correct the
volume change. Finally, the gray matter image modulated by
6 mm half-height and full-width isotropic Gaussian kernel
is used to smooth the gray matter image.
Statistical analysis of VBM
All fMRI data were checked by the Lilliefors goodness-of-fit
test for normality. To compare the voxel-wise group differ-
ences of GMV in the OAB and control groups, two-sample
t tests was applied with age, sex, gender, and years of educa-
tion as covariates. A cluster-level false discovery rate was
used to correct for multiple comparisons across voxels, with
a significant p value of a significant threshold. The results
were overlaid on the MNI brain template.
Statistical analysis of clinical data
Wilcoxon’s rank-sum test and Spearman’s rank correlation
were applied to data with non-normal distributions; other-
wise, Student’s t test and partial correlation were performed.
The Pearson correlation analysis was performed to study
the relationship between OABSS and neuropsychological
scores (i.e. SAS and SDS scores). To further analyze the
relationship between VBM with clinical data, the partial cor-
relation analysis was performed to study the relationship
between GMV and clinical data (i.e. duration of OAB symp-
toms, MMSE, OABSS, SAS and SDS scores) after moving
the effects of age, sex, and education level. The statistical
procedures were carried out in Statistical Product and Ser-
vice Solutions (SPSS) version 16 (SPSS Inc., Chicago, IL,
USA). Due to multiple testing, p values were corrected by
the FDR method, and the suggested p values are adjusted
p values.
Results
Group demographics and neuropsychological tests
conducted
No significant differences in gender, age, or education level
were found between patients and control subjects (p > 0.05).
The overactive bladder symptom score (OABSS) was used to
define and classify OAB as mild (n = 4), moderate (n = 18),
or severe (n = 6). All subjects had normal scores of MMSE,
while SAS and SDS scores were significantly higher in OAB
patients than controls. The Pearson correlation analysis dem-
onstrated that no significant correlation between OABSS and
SDS in patients with OAB (p > 0.05) or between OABSS
and SAS in patients with OAB (p > 0.05). Table 1 shows
demographic and clinical data of patients with OAB and
healthy control subjects.
VBM analysis and correlation of GMV with OABSS
scores
Compared with healthy controls, OAB patients showed
decreased gray volume in the following brain areas: right
cerebellum, bilateral hippocampus, left insula, right supe-
rior temporal gyrus, left anterior cingulate gyrus, bilateral
caudate nucleus and right middle frontal gyrus (Fig. 1 and
Table 2).
As shown in Fig. 2, a negative correlation was found
between GMV and OABSS scores in the right cerebellum
(r = − 0.6895, p = 0.0001, FDR corrected). No significant

Table 1  Demographic and OAB (n = 28) Control Group (n = 28) p value

clinical data of patients with
OAB and healthy control Sex (female/male) 25/3 26/2 NA
subjects
Age (years) 43.89 ± 13.27 50.12 ± 12.11 0.0720
Handedness (right/left) 28/0 28/0 NA
Levels of education (years) 12.65 ± 3.05 14.02 ± 2.37 0.0590
MMSE 28.92 ± 2.21 29.23 ± 1.78 0.5656
Duration of OAB symptoms
 < 1 year 14 NA
 > 1 year 10
 Don’t know 4
OABSS 8.58 ± 2.79 NA NA
SAS 46.03 ± 2.37 39.48 ± 1.30 0.0001
SDS 54.51 ± 2.40 43.15 ± 1.50 0.0001

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Fig. 1  Regions showing intergroup differences in GMV between
OAB patients and healthy controls. Compared to the healthy controls,
the OAB subjects showed decreased GMV in the right cerebellum,
bilateral hippocampus, left insula, right superior temporal gyrus, left
association was found between the GMV and other clinical
data in OAB patients (p > 0.05).
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International Urology and Nephrology
anterior cingulate gyrus, bilateral caudate nucleus and right middle
frontal gyrus. GMV gray matter volume, OAB left orbital frontal cor-
tex
Discussion
In our study, VBM was applied to quantitatively analyzes the
characteristics of gray matter in OAB patients, improving
the accuracy and repeatability of measurement. Compared
with the traditional manual ROI measurement, VBM is com-
pleted automatically requiring no manual intervention. The
International Urology and Nephrology

Table 2  Voxel-based GMV Areas BA L/R Volume(mm3) MNI(peak) t value

Analysis of covariance shows
brain regions and coordinates X Y Z
with significant differences
between the OAB and control Cerebellum R 945 36 – 68 – 40 – 8.0546
groups Hippocampus 20 R 999 20 – 8 – 14 – 5.1472
Hippocampus 20 L 711 – 28 – 22 – 16 – 6.4093
Insula 48 L 2736 – 36 14 – 12 – 6.1540
Superior Temporal Gyrus 48 R 414 46 0 – 10 – 6.5841
Anterior Cingulate Gyrus 32 L 1962 – 4 28 24 – 6.9257
Caudate nucleus 25 L 1008 – 12 26 6 – 6.2307
Caudate nucleus 25 R 1296 12 8 18 – 6.0451
Middle Frontal Gyrus 45 R 1539 46 30 34 – 7.0841

Fig. 2  The correlation between

significantly abnormal GMV
and clinical data. OABSS scores
negatively correlate with GMV
values for the right cerebellum
(r = − 0.5243, P = 0.0060).
GMV gray matter volume,
OABSS overactive bladder
symptom score

result revealed that patients with overactive bladder syn-
drome (OAB) have GM atrophy of regions in brain. Specifi-
cally, many atrophy GM regions are located in the BBCN,
such as insula, anterior cingulate, caudate nucleus and mid-
dle frontal gyrus. The correlation analysis further illustrated
that the severity of OAB symptoms and the atrophy of the
GM could be mutually affected.
It is generally thought that voluntary control of micturi-
tion requires four main steps: (1) conscious bladder sensa-
tion; (2) comprehensive evaluation of environmental, emo-
tional, and social aspects to ensure that urination is safe,
appropriate, and comfortable; (3) release of spinal urination
reflex; (4) full sensorimotor function to relax external ure-
thral sphincter (EUS) and pelvis muscles. Cerebellar func-
tion is an important part of sensorimotor control by cer-
ebellar circuits gaining the control of movement through
trial and error [8]. Even though not listed in the BBCN
mentioned above, many experimental and clinical evidence
supported that the cerebellum is one of the most important
regions that contribute to urinary dysfunction. HUANG
et al. reported that the cerebellar fastigial nucleus produced
a presser response under electrical stimulation with or with-
out bladder contraction in male cats [9]. A fMRI study from
Michels et al. showed that micturition itself was associated

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with significant activity only present in the cerebellum. Fur-
thermore, activity in the cerebellum was observed during
interruption of actual micturition [10]. Clinically, patients
with cerebellar stroke have shown urinary dysfunction and
the cerebellum is involved in the modulation of the micturi-
tion reflex [11]. Our present results reveal the underlying
structural abnormality of cerebellum in OAB patients cor-
responding to the previous experimental and clinical studies.
Furthermore, we find the correlation between the severity
of OAB symptoms and the atrophy of the GM in the right
cerebellum. Loss of the cerebellum’s inhibition might have
led to the OAB. The above studies suggest that the cerebel-
lum may play an inhibitory role in the micturition reflex.
The limbic system of the brain deals with three key func-
tions: emotions, memories and stimulation. This system is
composed of several parts, among which the anterior cin-
gulate gyrus, insula and hippocampus will be discussed
because their abnormal GM atrophy in our study. Accord-
ing to the mentioned four cognitive processes of micturition,
the limbic system forms the effect of emotions on voiding,
involving in interoception, social judgment and emotional/
motivational processing. Similar to all other movements,
micturition is the result of activation of the motor system in
the central nervous system. Thus, micturition is regulated
by both the voluntary and emotional motor systems. The
anterior cingulate cortex (ACC) connects to both the “emo-
tional” limbic system and the “cognitive” prefrontal cortex
[12]. In addition, Arienzo et al. pointed out that there was a
somatotopic sensory organization of human ACC and SMA
in young male subjects by fMRI recordings [13]. So the
ACC is postulated to participate in the sensation of bladder
fullness and micturition control, including pelvic floor con-
tractions. We are the first to reveal the underlying structure
abnormality of the ACC in OAB patients. Many fMRI stud-
ies have shown that the activity in insula during urine storage
[14]. In heathy subjects with normal micturition function,
its activation obviously increased when the bladder filling
up. The signal from the insula can be transmitted to ACC
where the subjective sensation on how much the bladder is
filled is interpreted. Although co-activation of the insula and
ACC to generate the emotional responses to bladder filling
and desire to void observed in almost all fMRI studies, the
feeling of urgency may be mediated by ACC actually [15].
Komesu et al. using task-state fMRI studied OAB patients
showed increased brain activation in the limbic system, spe-
cifically the insula and the ACC, associated with urgency
sensations [16]. Tai et al. visualized the brain switching cir-
cuits controlling reflex micturition in anesthetized rats by
fMRI [17]. They found a complex brain network regulating
micturition switch on the brain stem and micturition was
associated with hippocampus which was activated during
micturition and was not activated during storage. Hippocam-
pal activation during micturition was identified in human
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International Urology and Nephrology
by fMRI studies also [18]. Our results show that there are
systematic atrophy in many parts of the limbic system, sug-
gesting that the microstructural changes of the limbic system
may be an important pathogenic factor in patients with OAB.
The caudate nucleus is tightly connected with limbic sys-
tem. The caudate nucleus, a part of the basal ganglia that
subserve executive function, is supposed to be responsi-
ble for stereotyped and repetitive behaviors. Tatsuya et al.
applied electrical stimulation to the caudate nucleus educed
inhibition of the spontaneous bladder contraction on the
model of spontaneous isovolumetric bladder contractions
in adult male cats [19]. A recent study suggests that cau-
date BOLD signal may reflect inhibition [20]. According
to a lock design experiment in 12 healthy subjects, Zhang
et al. posed the assumption that a complex visceral sensory-
motor circuit is evoked during the inhibitory control of the
micturition reflex, which comprised of the caudate nucleus
as a combined activating region [21]. Combined with our
findings, it can be speculated that the atrophy of the caudate
nucleus weakens its activity of inhibiting voiding behavior.
During voiding process, the activation of frontotempo-
ral cortical has been reported. Many neurological diseases
affecting frontotemporal cortical, such as stroke, Parkinson
disease, and dementia, show various urinary symptoms,
including urinary incontinence, urgency, hesitancy, and
urinary retention [22]. These can further help us identify
important frontotemporal cortical regions for micturition.
Urinary symptoms including urgency, frequency, and incon-
tinence occur in frontotemporal dementia, but are typically
considered a late feature [23]. It has been reported that sev-
eral patients with temporal lobe epilepsy experience uri-
nary urge at the beginning of seizures [24]. Corresponding
to previous studies, our study found gray matter atrophy in
the right superior temporal gyrus and right middle frontal
gyrus, which may be the structural basis of frontotemporal
lobe dysfunction in patients with urinary urgency previously
found by fMRI.
Our study achieved some meaningful findings, but
some limitations indeed exist. Firstly, as participants were
recruited from only one single center, they may not be rep-
resentative of the OAB population as a whole. Secondly,
we will continue to expand the sample size to compare the
GMV of OAB patients with different levels of severity and
duration of OAB symptoms. Finally, future longitudinal
studies should be performed to further clarify the causal
relationship between GMV loss and OAB.
Conclusion
This study demonstrated predominantly decreased gray mat-
ter volume of BBCN in patients with OAB, in which the
right cerebellum atrophy was associated with the severity
International Urology and Nephrology
of OAB symptoms. It would be helpful to understand the
underlying morphological changes of the BBCN. Our study
provides a novel perspective on the neuropathological mech-
anisms of the OAB.
Funding  This study was supported by grants from the National Nature
Science Foundation of China (No. Grant nos. 81541129, 81301016,
KZ73100001) and the Beihang University Research Fund Program
under Project ZG216S1871.
Compliance with ethical standards  Urodyn 27(6):466–474
Conflicts of interest  None of the contributing authors have any conflict
of interest, including specific financial interests or relationships and
affiliations relevant to the subject matter or materials discussed in the
manuscript.
Informed consent  All patients have provided informed consent.
Research involving human participants  This study was approved by
the Committee for Human Research in Beijing Chaoyang Hospital and
followed by all regulations (Grant nos. 2015-ke-21).
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