Supraspinal Mechanisms Involved in Voiding Dysfunction.
Phase: NA
Conditions: Neurogenic Bladder, Multiple Sclerosis, Voiding Dysfunction
Sponsor: The Methodist Hospital Research Institute

 
Brain Targets in Patients with 
Bladder Emptying Difficulties 
 
 
NCT03574610 
 
Document Date: January 24, 2020 

R e s e ar c h Str at e g y: S u pr a s pi n al T ar g et s i n N e ur o g e ni c V oi di n g D y sf u n cti o n  
  
1.  SI G NI FI C A N C E  
  
V oi di n g d y sf u n cti o n ( V D) i s a m or bi d a n d c o stl y ur ol o gi c al c o n diti o n c h ar a ct eri z e d b y i nt er mitt e nt, fl u ct u ati n g, or 
a b s e nt fl o w of uri n e. 1  V D m a y l e a d t o i n c o m pl et e bl a d d er e m pt yi n g or uri n ar y r et e nti o n, uri n ar y tr a ct i nf e cti o n s, 
s e p si s, bl a d d er or ki d n e y st o n e s, a n d p er m a n e nt r e n al f ail ur e a n d c a n b e pr e s e nt i n p ati e nt s wit h or wit h o ut 
n e ur ol o gi c di s or d er s. 2    
  C urr e ntl y  t h e  o nl y  a v ail a bl e  t h er a pi e s  f or  V D  i n cl u d e  i n d w elli n g  bl a d d er  c at h et er s  or  i nt er mitt e nt  
s elf c at h et eri z ati o n s.    
C at h et eri z ati o n i s a b ur d e n, i n g e n er al, a n d e v e n m or e s o i n n e ur o p at hi c p ati e nt s, i n w h o m l o w er e xtr e mit y 
s p a s m s, c o m pr o mi s e d h a n d d e xt erit y, or vi s u al di st ur b a n c e s, m a y b e pr e s e nt. T h e c o st a n d m or bi d si d e eff e ct s 
( h e m at uri a,  p ai n,  tr a u m a,  stri ct ur e s,  a n d  i nf e cti o n s),  a s s o ci at e d  wit h  c at h et eri z ati o n s,  ur g e  u s  t o  l o o k  i nt o  
alt er n at e t h er a p e uti c t ar g et s f or V D, p o s si bl y b e y o n d t h e bl a d d er, s u c h a s t h e br ai n ( w h ere bl a d d er a n 
ur et hr al c o ntr ol c e nt er s ar e l o c at e d).   
  
T h e h u m a n l o w er uri n ar y tr a ct h a s t w o f u n cti o n s: st or a g e a n d v oi di n g. T hi s st u d y will c o n c e ntr at e o n s u pr a s pi n al 
( br ai n)  ar e a s  c o ntr olli n g  t h e  d eli c at e  a n d  c o m pl e x  n e ur al  cir c ul at or y  (t h e  “ s wit c h”)  fro m  st or a g e  of  uri n e  t o  
i niti ati o n of v oi di n g. N or m al v ol u nt ar y v oi di n g i s c o ntr oll e d b y s u pr a p o nti n e c e nt er s i n t h e br ai n, all o wi n g t h e 
p o nti n e mi ct uriti o n c e nt er t o tri g g er ( s wit c h o n) t h e v oi di n g r efl e x. V D o c c ur s if t h e d etr u s or m u s cl e c a n n ot 
m ai nt ai n  e ff e cti v e  c o ntr a cti o n s  ( e. g.,  d etr u s or  u n d er a cti vit y ),  if  t h e  ur et hr a  f ail s  t o  r el a x  a n d  l o w er  ur et hr al  
r e si st a n c e, or if t h er e i s f ail ur e i n s y n c hr o ni zi n g t h e s e a cti o n s l e a di n g t o d etr u s or s p hi n ct er d y s s y n er gi a ( D S D) 
i n s u b s et of n e ur o p at hi c p ati e nt s.3, 4  A l m o st all p ati e nt s wit h D S D ar e d e p e n d e nt o n c at h et eri z ati o n a n d ar e 
at m u c h hi g h er ri s k f or a ut o n o mi c d y sr efl e xi a, r e c urr e nt uri n ar y tr a ct i nf e cti o n s, a n d r e n al i n s uffi ci e n c y. 2    
  
A ni m al m o d el s h a v e c o n v e nti o n all y b e e n u s e d t o st u d y n e ur al c o ntr ol of t h e  bl a d d er. H o w e v er, a ni m al s diff er 
fr o m  h u m a n s  i n  n u m er o u s  w a y s  ( e. g.  s o ci al  b e h a vi or).  Criti c al  di sti n cti o n s  e xi st  b et w e e n  v ol u nt ar y  v oi di n g  
( h u m a n s)  a n d m or e i n sti n cti v e  bl a d d er  e m pt yi n g  ( a ni m al s),  w h e n  all t h e s o ci al,  e m oti o n al,  a n d m e c h a ni c al 
crit eri a f or v oi di n g ar e c o n si d er e d. T h e c o n s ci o u s h u m a n i nt e nti o n t o v oi d, or n ot t o v oi d, hi g hli g ht s t h e 
n e e d f or h u m a n  r e s e ar c h, r at h er t h a n e x cl u si v e r eli a n c e o n a ni m al d at a, i n br ai n c o ntr ol o v er bl a d d er.   
  
Wit h t h e e v ol uti o n of n e ur oi m a gi n g t o ol s a n d r e s o ur c e s, s u c h a s f u n cti o n al m a g n eti c r e s o n a n c e i m a gi n g (f M RI), 
w e h a v e b e g u n t o g ai n a d diti o n al i n si g ht i nt o br ai n c o ntr ol o v er bl a d d er f u n cti o n i n h e alt h y  i n di vi d u al s. Y et, o ur 
u n d er st a n di n g of s u pr a s pi n al c e nt er s a n d t h eir r ol e i n i niti ati n g or m o d ul ati n g  v oi di n g c o nti n u e s t o b e 
r u di m e nt ar y i n p ati e nt s wit h n e ur o g e ni c ( e. g. M ulti pl e S cl er o si s [ M S] or Str o k e) or n o n n e ur o g e ni c v oi di n g 
d y sf u n cti o n ( e. g. u n d er a cti v e bl a d d er or F o wl er’ s s y n dr o m e).   
  
• 
T h e o v er all o bj e cti v e  of m y pr o p o s e d st u d y i s t o c h ar a ct eri z e  a n d m o d ul at e  s p e cifi c s u pr a s pi n al r e gi o n s 
d uri n g t h e “ s wit c h o v er” of uri n e st or a g e t o v oi di n g i n M S p ati e nt s wit h V D t o i m pr o v e v oi di n g.   
  
• 
S u pr a s pi n al i n v ol v e m e nt i n V D i n h u m a n s ( e s p e ci all y i n n e ur o p at hi c p ati e nt s) h a v e n ot b e e n i n v e sti g at e d, 
a n d o ur pr o p o s e d st u d y will b e t h e s e mi n al r e s e ar c h i n t h e fi el d.  
  
• 
T h e fi n di n g s fr o m m y pr o p o s e d st u d y m a y l a y t h e f o u n d ati o n t o st u d y ot h er eti ol o gi e s of V D s u c h a s 
U n d er a cti v e Bl a d d er or d etr u s or u n d er a cti vit y, str o k e, or P ar ki n s o n’ s di s e a s e, all of si g nifi c a nt i nt er e st t o 
N ati o n al I n stit ut e of Di a b et e s a n d Di g e sti v e a n d Ki d n e y Di s e a s e s.   
  
2.  I N N O V A TI O N  
  
I n v e sti g ati o n of br ai n c o ntr ol o v er t h e bl a d d er i n h e alt h y  i n di vi d u al s t hr o u g h t h e u s e of f u n cti o n al n e ur oi m a gi n g 
s h o w s t h at t h e i niti al aff er e nt s e n s or y i n p ut c o m e s fr o m t h e bl a d d er d uri n g “ bl a d d er f ull n e s s or t h e str o n g d e sir e 
t o v oi d”. N e xt, t h e f or e br ai n d et er mi n e s t h e p er s o n’ s s o ci al cir c u m st a n c e s a n d w h et h er t o pr o c e e d wit h v oi di n g 

or not. Once it is socially acceptable to void, centers in the brain and spinal cord coordinate and initiate urethral 
sphincter/pelvic floor relaxation, followed by a sustained detrusor contraction.5 Specifically, the pontine 
micturition center (PMC) signals the bladder to begin the voiding phase when the sensations from the bladder 
are transmitted to the periaqueductal gray (PAG) and higher brain centers.5-7 Previous positron emission 
topography studies in healthy individuals have demonstrated activation of the right dorsomedial pontine 
tegmentum, PAG, hypothalamus, and the right inferior frontal gyrus at the time of voiding.8,9 Neuroimaging may 
augment the diagnosis of VD and aid in therapeutic planning in certain etiologies of VD.10-12   
  
• 
Combining urodynamic studies (UDS) with functional magnetic resonance imaging (fMRI) is technically 
challenging, but necessary, in order to elucidate simultaneous brain-bladder activities. We have 
established and refined our simultaneous platform in healthy individuals and neuropathic patients.  
  
• 
Despite the challenges, our fMRI/UDS platform evaluates the entire bladder cycle, including the voiding 
phase. This is the strength and novelty of our protocol as, in contrast to other neuroimaging studies, 
individuals in our study void or attempt to void while in the MRI scanner during the UDS.  
  
• 
In this proposal, we have taken the next step to move beyond the exploratory phase of identifying 
supraspinal targets involved in VD, into targeted cortical stimulation of these regions (another testament 
to the novelty of our project).  
  
• 
Our investigative brain targets will also include areas of urethral activity, which is innovative and not 
traditionally studied.  
Our fMRI/UDS platform: UDS provides valuable information on bladder pressures and urethral sphincter function 
especially in patients with neurogenic VD.13-15 Over the past four years, we have established a concurrent 
fMRI/UDS platform in healthy controls16 and in MS patients17,18 and evaluated the entire bladder cycle in realtime 
in over fifty individuals, specifically when patients void or attempt to void in the fMRI scanner while UDS is being 
performed. Our platform outperforms other neuroimaging studies, wherein voiding is not studied.   
 
Figure 1. A. Our concurrent UDS and fMRI set up where MRI-compatible bladder and rectal catheters are passed 
through a small opening in the wall between the control room and the scanner room (Philips Ingenia 3.0T full body 
scanner with a standard 12-channel head coil). B. Our combined fMRI and UDS testing protocol.  
  
Transcranial Magnetic Stimulation (TMS) and Transcranial Rotating Permanent Magnet Stimulator (TRPMS):  
Currently, the only neuromodulation modalities available for bladder target the peripheral nerves, including the  
Sacral Neuromodulator, the Posterior Tibial Nerve Stimulator, and the intradetrusor injection of neurotoxin 
OnabotulinumtoxinA. Further, they mainly target the storage phase (urinary urgency and incontinence). As part 
of my K12 proposal I have focused on identifying supraspinal changes following onabotulinumtoxinA 
injection in the bladder using our fMRI/UDS platform in MS patients.19 While others have evaluated the 
brain changes following sacral neuromodulator use for overactive bladder patients.20,21   
  
( A )   
( B )  

• 
However, to date, there has been no central (brain) neuromodulation for bladder and specifically 
for the voiding phase. It has become prudent to look beyond the bladder in managing neurogenic 
bladder VD and fMRI/UDS identified supraspinal regions and our proposal offer some hope for potential 
therapeutic targets.   
  
TMS is a non-invasive centrally acting electromagnetic neuromodulator that is held over the scalp and delivers 
a rapidly pulsed magnetic field to the cortex to activate neurons, within a limited area, without requiring 
anesthesia or causing any significant side effects. TMS and repetitive TMS (rTMS) are substantially safe and 
are widely used for brain mapping and/or to modulate cortical excitability.22,23 Two small studies have 
demonstrated the feasibility and efficacy of rTMS in patients with MS (n=10), and Parkinson’s disease (n=8) with 
bladder symptoms. Their findings suggest that TMS improves both the storage and voiding phase, and reduces 
postvoid residuals of the urine, while appropriately increasing the detrusor pressure at the time of voiding.24,25 
Interestingly, in three MS patients with DSD, following rTMS, the abnormally high detrusor pressures at the time 
of voiding were decreased to a more appropriate level, possibly implying the restoration of synergistic voiding 
with coordinated relaxation of urethral sphincter and the pelvic floor.24 In a more recent study, fifty-eight children 
(ages from 6 to 14) with nocturnal enuresis were randomly assigned to receive anticholinergic medication 
(oxybutynin), TMS, or placebo TMS. Authors reported improvements in bladder capacity, voiding scores, and 
enuresis events, seven months following TMS use.26   
  
Limitations of TMS and Innovation in our proposal: Commercialized TMS devices use large coils that restrict 
their portability and can only be applied to one location of the 
cortex. However, brain control during voiding appears to 
be dependent on multiple regions and their connectivity 
including the urethral regions, requiring a transcranial 
modulator that could safely stimulate/inhibit multiple 
areas at the same time. The neurophysiology and 
neuromodulation laboratory at our institution has developed 
a non-invasive, portable, and multifocal brain magnetic 
modulator, called27,28 Transcranial Rotating Permanent 
Magnet Stimulator (TRPMS).  
  
• 
TRPMS uses small, high field strength permanent 
magnets rapidly spun by miniature electric motors. It is 
therefore wearable and portable, and capable of multifocal stimulation.27 TRPMS will selectively induce, 
modulate, or suppress neuronal activity, and also modulate the strengths of the functional 
connections between two or more cerebral cortical areas when they are stimulated  
simultaneously, depending on the strength, frequency and pattern of stimulation.29   
Figure 2. TRPMS cap with microstimulators placed on sites corresponding to left primary motor, right lateral premotor, 
and right supplementary motor cortex. The smartphone image shows the Android app used to operate the device.  
The current prototype operates on a 9 – 12 V battery and can be triggered by a smartphone or tablet app, thereby 
allowing it to be potentially used for stimulation treatment at home in the future.   
Flexibility of TRPMS applications: Earlier studies involving repeated stimulation of the left inferior frontal gyrus 
pars triangularis (IFG) has shown that TRPMS stimulation of this part of Broca’s area during encoding of words 
facilitates word memory. In contrast, chronic repeated stimulation of this area at rest in the absence of word 
memorization disrupts it.30 A preliminary open label study done in one chronic ischemic stroke (CIS) patient prior 
to the start of an ongoing randomized double blind sham treatment-controlled trial, has revealed the following 
restorative changes: after 2 two-week sessions of treatment, movement-related fMRI showed increasing levels 

of neural activation of the stimulated intact cortex surrounding the lesion. Marked quantitative improvements 
were seen in grip strength, lower extremity motor function, and sensation measures on the affected side, as well 
as gait speed. These changes persisted at the 3-month follow-up time point after two other two-week treatment 
sessions.31 Other unpublished studies in healthy adults have shown modulatory effects on perception of body 
ownership, numerical ability, motor skill learning and functional connectivity of cortical areas.29   
• 
Therapeutic effects of multifocal TRPMS are currently being studied in pilot clinical trials on 
developmental stuttering, CIS, and type 1 myotonic dystrophy at our institution.32   
Safety profile of TRPMS: Repeated cerebral cortical stimulation with this device is well tolerated with no reported 
serious adverse events in more than 200 adult human subjects, including patients with chronic ischemic stroke, 
amyotrophic lateral sclerosis, type 1 myotonic dystrophy, and developmental stuttering in our institution. 
Electroencephalic recordings in 45 subjects have demonstrated that repeated TRPMS stimulation does not 
induce seizures or epileptiform changes.   
• 
TRPMS has been determined to be a Non-Significant Risk device by the Food and Drug 
Administration. Please see attachments under appendix for this proposal.  
Regions of Interest (ROI) from the literature: Earlier neuroimaging studies have identified brain regions directly 
involved in initiating or continuing voiding in healthy individuals. These regions include: Precentral Gyrus, 
Supplementary Motor Area, Dorsolateral Prefrontal Lobe, Inferior Frontal Gyrus (IFG), Cingulate Gyrus, Insula, 
Hypothalamus, PAG, and Pons (PMC).8,9,16,33 Although, PAG and PMC are the more apparent regions involved 
in initiation of voiding and could serve as potential targets for intervention, they are deep and inaccessible with 
our current technological modalities. Besides, these regions are responsible for other core vital functions such 
as regulating circulation and breathing wherein modulation would not be safe.   
• 
On the other hand, we propose that if we shift our focus to modulate areas of the brain that are 
more cortically accessible and amendable to modulation, such as areas responsible for urethral 
sphincter relaxation, we may indirectly improve voiding. Table 1 summarizes the currently available 
cortical brain regions involved in voiding as potential ROIs in healthy, MS and non-neurogenic VD.  
  
MNI  
BA  
HA  
Area  
Neuroimaging  
Task  
Reference  
Healthy   
52, 24, 12  
45/44   Right  IFG  
PET  
Voiding  
Blok 19988  
63, 18, 18  
44/45  Right  IFG  
fMRI  
Initiation of voiding  
Mehnert 201534  
40, 35, 6  
46  
Right  IFG  
fMRI  
Initiation of voiding  
Khavari 201416  
8, -8, 62  
6  
Right  Medial frontal gyrus  
fMRI  
PF contraction  
Zhang 200535  
6, -18, 57  
3, -18, 57  
6  
Right  Medial frontal gyrus  
PET  
PF contraction  
Kuhtz-buschbeck 
200536  
2, 2, 62  
6  
Right  Superior frontal gyrus  
fMRI  
PF contraction  
Kuhtz-buschbeck 
201137  
48, 4, 10  
6  
Right  IFG  
PET  
Voiding (urethral)  
Nour 200038  
-44, 1, 28  
6  
Left  
Precentral gyrus  
fMRI  
Initiation of voiding  
Khavari 201416  
2, -32, 66  
4  
Right  Superiomedial precentral  PET  
Voiding  
Blok/Holstege 19978,9  
-6, -26, 74  4  
Left  
Superiomedial precentral  PET  
Voiding  
Blok/Holstege 19978,9  
Non-neurogenic voiding dysfunction   
54, -4, 6  
6  
Right  Precentral  
fMRI  
Urethra   
Fowler 201039  
Neurogenic voiding dysfunction (MS)   
-39, 34, 5  
45  
Left  
IFG  
fMRI  
Initiation of voiding  
Khavari 201717  
38, 33, 6  
45   
Right  IFG  
fMRI  
Voiding  
Khavari 201717  

Table 1: MNI: Montreal Neurological Institute coordinates; BA: Brodmann Areas; HA: Hemisphere; PF: Pelvic Floor  
  
In a small group of women with urinary retention, due to urethral sphincter dysfunction, peripheral nerve 
neuromodulation modified the activity of the right postcentral gyrus, precentral/temporal, and inferior temporal 
regions.10,39 fMRI studies report that medial prefrontal cortex and supplementary motor areas are the main 
cortical regions involved in pelvic floor contraction36,37,40, and could be used to phenotype responders versus 
non-responders to biofeedback assisted pelvic floor physical therapy in overactive bladder patients.41   
• 
Aims 1 and 2 of this proposal characterize specific brain regions that are activated during voiding in MS 
and these regions will be added to the current data (table 1) to individualize the targets used in aim 
3 for multi-site transcranial modulation.   
  
3. APPROACH  
Preliminary Data over the past four years   
Healthy Controls (HC): Our established fMRI/UDS 
platform demonstrated activation of brain regions of 
cerebellum, thalamus, caudate, lentiform nucleus, 
supplementary motor area, postcentral gyrus, left 
superior frontal gyrus, anterior and posterior cingulate 
gyrus and insula, as well as other brain structures 
such as the pons at the time of “initiation of voiding” 
in 
HC, figure 3.16 We also have established an algorithm 
for 
visualization and evaluation of neuroimaging data 
with 
a three-dimensional augmented reality (AR) device in HC 
during 
repetitive 
voiding.42 
The 
network 
under 
investigation was found to consist of two large sub-
networks, one in the frontal lobe and one that connected 
sensory regions with deeper brain structures, including the PMC. This data will serve as our HC for this proposal.  
  
MS patients: We have evaluated twenty-seven MS 
patients with neurogenic  
lower  urinary 
 tract dysfunction using  
our  
established 
 fMRI/UDS platform.16 Our analyses described, for the 
first time, brain regions activated at initiation of 
voiding in female  
MS patients (Figure 4).17    
  
Figure 3. Average fMRI activation maps with concurrent 
UDS tracings. Asterisk denote “initiation of voiding” in 
the event-related analysis of the fMRI data in HC.  
Figure 4. BOLD signals at initiation of voiding. A, HCs B, 
MS showing higher signals in regions with warmer 
colors. C, subtraction image between MS and HCs.  

MS patients with DSD: Our data on a subgroup analysis of MS patients with 
DSD (n=4), showed statistically significant greater activation in the right 
middle frontal gyrus, right medial frontal gyrus, right cingulate gyrus, right 
caudate nucleus, and brainstem at “initiation of voiding”.17   
  
Changes in brain following intradetrusor injection of OnabotulinumtoxinA  
(IDBTX-A): fMRI/UDS results from our recent study examining the impact of 
IDBTX-A in MS with urinary urgency (N=12) demonstrated that activation 
increased in specific brain regions associated with the sensation and 
process of urinary urgency six weeks post therapy (Figure 5). This is the 
first study of its kind to evaluate the possible sensory effects of IDBTX-A in 
humans. These preliminary results have been submitted to the 2018 
national Urology and Neurourology meeting.   
Figure 5. A. subtraction BOLD activation maps of post minus pre IDBTX-A for the  
ROIs in sagittal (1 and 2) and horizontal (w and 4) images. 1) Right Cingulate 2) 
Pons 3) Insula 4) Right Prefrontal Cortex; B. ROI coordinates using MNI and RPI 
coordinates, and the p values.  
OBJECTIVES/ SPECIFIC AIMS/ HYPOTHESES  
A priori selected grey matter Regions of Interest for aim 1: Based on our preliminary data and the 
summary of literature outlined in table 1, we propose the following a priori selected ROIs for the cortical and 
deep grey matter and nuclei for aim 1: Inferior frontal and precental gyrus, thalamus, PAG, and pons.  A 
priori selected white matter tracts (WMT) for aim 2: Since MS lesions affect the white matter mainly, it is 
prudent to evaluate the WMT involved in bladder function in this patient population. Two WMTs are particularly 
important in proper function of the bladder: Anterior thalamic radiation (ATR) and Superior longitudinal 
fasciculus (SLF)43,44.   
Clinical and UDS data will be used to categorize female MS patients with stable disease into two groups. The 
standardization of terminology by the International Continence Society does not provide clear definition for 
VD,45,46 however we propose the following based on expert opinion. Group 1: MS patients with VD (patients who 
perform self-catheterization or have a postvoid residual of urine ≥ 20%Maximum Cystometric Capacity); and 
Group 2: MS patients without VD (patients who void spontaneously and their postvoid residual of urine < 40%% 
Maximum Cystometric Capacity). Patients in Group 1 will be further subdivided into patients with DSD (Group  
1a) versus without DSD (Group 1b). DSD is defined as increased EMG activity ≥ 20% during detrusor contraction 
(voiding) in the absence of valsalva maneuvers on UDS.47,48  
We hypothesize that female MS patients with VD have a distinct pattern of brain activation and connectivity at  
“initiation of voiding” and targeted cortical modulation may be feasible and lead to improved voiding.   
  
Specific Aim 1: Activation patterns of the grey matter ROIs are different among female MS subjects with VD, 
specifically those with DSD. We will determine the distinct activation patterns by:   
a) Assessing Blood Oxygen Level Dependent (BOLD) signal and functional connectivity (FC) patterns in the 
ROI’s at “initiation of voiding” in Groups 1a, 1b, and 2.  
b) Comparing BOLD signals and FC patterns in Group 1 versus 2, and specifically Group 1a versus 1b.  
  
Specific Aim 2: Damage to preselected WMT in female MS patients provides an independent predictive 
measure for VD. We will use diffusion tensor imaging and our established algorithm of measurement42 to:  
a) Measure fractional anisotropy (FA) and mean diffusivity (MD) of the ATR and SLF in Groups 1a, 1b, and 2.   
b) Assess whether damage to SLF or ATR are associated with voiding dysfunction in our patient population.  
  
Specific Aim 3: Targeted cortical stimulation in Group 1 causes changes in ROI (identified during specific aim1) 
that better recapitulate the activation patterns in group 2 or HCs by:   
a) Assessing BOLD and FC activation in the ROIs following individualized TRPMS in patients in Group 1.  
b) Evaluating voiding improvement via UDS and validated questionnaires following TRPMS.  

c) Identifying baseline clinical/UDS or neuroimaging factors that could predict response to TRPMS.  
d) Evaluating EMG changes in the pelvic floor following TRPMS. 
  
EXPERIMENTAL PLAN AND FEASIBILITY  
We have completed and recently published a well-powered study, on twenty-seven female MS patients, that 
evaluated brain response to bladder filling during the bladder storage phase.17 Aims 1 and 2 are retrospective 
analysis of the voiding phase from our extensive and meticulously collected neuroimaging raw data available to 
us from our prior completed cohort. Aim 3 is a small, pilot feasibility study (n=8).  
Study duration: Based on our experience, we anticipate that one year will allow appropriate time for data analysis 
for Aims 1 and 2. An additional (concurrent) 1-2 years will allow for appropriate patient recruitment, performance 
of the protocols, and data evaluation for Aim 3.   
  
Endpoints    
Primary Endpoint  
a) BOLD signal intensity and FC pattern in a priori selected ROIs at “initiation of voiding” in MS patients.  
b) BOLD and FC pattern changes following TRPMS.   
Secondary Endpoints  
a) FA and MD of ATR and SLF white matter tracts in Groups 1 and 2.  
b) Clinical scores: UDS parameters, urinary symptom scores, surveys at baseline and following TRPMS.   
c) BOLD signal characteristics and FC patterns in ROIs in patients with versus without DSD.   
  
Selection and Recruitment of the Subject  
Inclusions: Adult female patients with clinically stable MS [Expanded Disability Status Score (EDSS) ≤6.5], with 
bladder symptoms ≥3 months, will be screened. Patients will be considered to have VD if they have an increased 
Postvoid Residual (≥ 20%   Maximum Cystometric Capacity) or abnormally slow and /or incomplete micturation 
based on abnormally slow urine flow rates. Patients who perform self-catheterization will be included in the VD 
category as well.   
 Patients with active UTI can be treated and subsequently screened for the trial. 
Regarding patients with DSD: Appropriately placed and traced perineal surface electrodes used for EMG 
recordings can be used to determine presence or absence of DSD.50 There is no clear cutoff or consensus for 
the amount of EMG activity change during the voiding phase. We will use increased EMG activity by 20% during 
detrusor contraction (voiding), in the absence of valsalva maneuvers, to determine DSD.51   
  
Exclusions: Men, anatomical bladder outlet obstruction (anti-incontinence procedures, urethral strictures, or 
advanced pelvic organ prolapse). Severe debilitating MS, history of seizures, pregnancy or planning to become 
pregnant, contraindications to MRI, history of augmentation cystoplasty, presence of other neurological disorders 
besides MS.  
  
Relevant biological variables (sex): At this point, males are excluded from our evaluation to avoid potential 
confounding factors by common bladder outlet pathologies secondary to benign or malignant prostatic pathology, 
primary bladder neck obstruction, and urethral strictures (all common in men). In addition posture during urination 
(lying flat in the scanner versus sitting or standing) appears to affect voiding and this difference is more noticeable 
in males versus females, especially when bladder symptoms are present.52-54 Due to these differences between 
sexes and the possibility of them being confounding factors at this point we are excluding males.   
  
Subject recruitment: Our Neurourology Clinic where I serve as the clinical director, has three fulltime fellowship 
trained urologists and is a referral center in Houston. My mentor and chairman Dr. Boone is a nationally 
recognized clinician in this field. Eligible patients for our study will be screened and recruited from our clinic.   
  
Description of interventions  
Subject Evaluations: Each patient will undergo a detailed history and physical examination with the following 
assessments: Demographic Form, American Urological Association Symptom Score (AUASS), Neurogenic 

Bladder Symptom Score (NBSS)55, MRI Safety Screening Questionnaire, Hospital Anxiety and Depression 
Scale56, and Expanded Disability Status Scale57. AUASS and NBSS both include questions regarding the voiding 
phase and are validated in neurogenic patients. Postvoid residual urine, urinalysis, urine culture, and pregnancy 
(if applicable) will be assessed prior to the MRI scan. A clinical UDS will be performed within 10 years prior to 
the neuroimaging scan. Consent will be signed during the first visit.  High density Eelectromyography (EMG) will 
be performed at the beginning of the first and the last sessions of TRPMS  treatment however this is an optional 
testing and patients can refuse to participate in the EMG testing Patients from Group 1 who participate in the 
TRPMS will undergo a repeat fMRI scanning following the completion of the therapy. In addition their symptoms 
will be assessed with repeat UDS and validated questionnaires.   
After their post TRPMS Intervention Fmri visit, subjects will return to the clinic to complete 4 months (+/- 1 month) 
and 12 months (+/-1 month) follow up visits. At these follow-up visits, they will completing validated 
questionnaires, uroflow testing and PVR scan. 
  
Simultaneous UDS/fMRI: Double lumen 7 French MRI-compatible catheters are placed in the bladder and 
rectum. Either 3T or 7 T full body MRI scanner with standard 12 channel head coil is used. Instructions to 
communicate using right hand signals representing “strong desire to void” and “voiding” are given. In order to 
keep our noise-to-signal ratio low, all stimulators including any extra visual stimuli and the UDS machine are 
removed from the MRI room. Filling and voiding cycles are repeated up to 4 times in each patient. If the patient 
is unable to void, then the bladder will be drained passively.   
  
Transcranial Rotating Permanent Magnet Stimulator (Aim 3 only): We will use the data obtained in Aim 1 to 
further identify superficial cortical targets for intervention in each patient with voiding dysfunction and we will 
construct an individualized therapeutic cap to deliver repeated 100 – 500 ms stimuli at 0.02 Hz for 40 min each 
week day for 2 weeks (based on our preliminary TRPMS data in other neurological disorders)27,29. As discussed 
in the Innovation section of this proposal, TRPMS is safe, precisely programmable, inexpensive, and can 
modulate multiple areas of the brain at the same time, making it an ideal modality for our proposal.   
  
Data Collection and Statistical Analysis  
Three-dimensional structural images are obtained from a T1-weighted sequence; (sagittal direction, 0.7 in-plane 
resolution) as well as functional images collected with simultaneous UDS (axial echo-planar, TR = 3,000ms, 
4.0mm slice thickness, 3.38mm in-plane resolution). AFNI software will be used for analysis. Structural and 
functional images will be registered and motion-corrected. Patients with rapid motion (> 4.5mm) will be excluded 
from analysis. Voxel activation will be identified at “initiation of voiding” which is signaled by patient’s right hand. 
Significant differentially-activated voxels will be identified under the generalized linear model. Group level 
analysis will be performed by transforming data into Talairach space, and significantly activated/deactivated 
voxels will be identified using a Student’s T-test or a non-parametric test if indicated. We will use SPSS (v19.0) 
to perform statistical analysis of clinical data (i.e. demographic, UDS data). FC analysis will be performed using 
CONN, a functional connectivity toolbox for MATLAB58, Version 15a, which utilizes the statistical parametric 
mapping MATLAB toolbox. fMRI images acquired during the voiding task together with their corresponding 
anatomical datasets will be processed using the default- Montreal Neurological Institute (MNI) preprocessing 
option to enable group analysis in MNI space. A region-based connectivity analysis will be performed for each 
patient group based on ROIs. FC will be quantified by T-values for a p-value < 0.05 (two-sided, FDR-corrected). 
Diffusion Tensor Imaging (DTI) images will be acquired (32 directions, one B0 image) using the standard MRI 
pulse sequence available on the Siemens 3Tesla or 7 Tesla MRI scanner. The software packages TackVis 
(version 0.6.0.1) and the Diffusion Toolkit (version 0.6.3, trackvis.org) will be used to calculate and extract 
selected white matter tracts of interest. This software also enables calculating FA and MD values for the 
segmented WMTs.  
  
Power Analysis: fMRI studies suggest that approximately 12 subjects are required to achieve 80% power at the 
single voxel level for typical activations, while accounting for intra-and inter-subject variability.59 Most fMRI 
studies, evaluating bladder function have included 8-12 subjects.60 For this proposed study, we account for 10% 
exclusions due to movement artifact and anticipate 13 patients for groups 1 and 2, with total of N=26. 

(Recruitment and scanning is already completed for Aims 1 and 2, data analysis is pending funding). Aim 3 is a 
small pilot feasibility study and we propose N=8.   
   
Limitations of the study and alternative strategies: The primary strength of this study is the simultaneous 
neuroimaging and UDS platform which includes the voiding or attempt to void phase. However, limitations do 
exist: voiding dysfunction is heterogeneous and dynamic and variations within studies may exist. Our patient 
population represents only a subset of a larger and more complex group and may have inter and intra-subject 
variability. Although patients with MS are generally accustomed to UDS and MRIs, combined UDS/fMRI may 
create anxiety and non-physiologic state. Furthermore, voiding supine may pose a challenge to many individuals 
who can void spontaneously while seated. The repetition of the filling and voiding task four times is an attempt 
to provide a high enough level of signal to evaluate the fMRI data. This provides a rich dataset that can be 
analyzed to infer information about the brain at initiation of voiding. Additionally, by preselecting our ROIs and 
WMTs we increase our specificity; however we may miss other important brain centers/pathways.  
  
Direct comparisons between the current TRPMS prototype that we plan to use and a commercially used 
conventional TMS coil show that the maximum voltage induced in an inductor by the former (12 - 30 V/m) is  
about 6% of the maximum machine output of the latter (200 - 500 V/m). Although this lower voltage has added 
advantages of portability, multi-site stimulation capability, and significantly lower side effects such as heat, 
seizure activity, or headaches, it may raise a concern of not being strong enough to have an effect in our 
patients. Alternatively we may add to the stimulated targets or consider selecting only one region and use the 
commercially available TMS for our next trial.  
  
TRANSITION PLAN AND FUTURE DIRECTIONS  
Etiology of voiding dysfunction (neurogenic and non-neurogenic) remains unknown. Currently, we are not aware 
of any study that has evaluated supraspinal centers involved in voiding in MS patients with VD. This project 
seeks to improve our ability to understand brain control of the bladder, suggest new diagnostic methods, and 
provide a crucial step in improving the treatment for the morbid and intractable condition of VD. Following the 
completion of this proposal we would be able to:  
  
• 
Apply our findings to patients with non-neurogenic voiding dysfunction, such as patients with Fowler’s 
syndrome, where the data concerning the etiology and effective treatments are scarce.61 Concerning 
etiology, some investigators believe this is a result of learned behavior in response to pain or injury, such 
as UTI or trauma. Others theorize that the dyssynergic sphincter exists, and is due to habitual contraction 
of the pelvic floor (external sphincter) that results in reflexive abnormal muscle contractions. The use of 
our unique fMRI/UDS platform to target the voiding phase, and the results from this study, will provide an 
excellent preliminary data to evaluate patients with non-neurogenic voiding dysfunction.    
• 
Apply our findings to patients with Underactive Bladder (UAB) or detrusor underactivity. The National 
Institute on Aging and the National Institute of Diabetes and Digestive and Kidney Diseases have invited 
applications to investigate the etiology and consequences of UAB in older persons to identify better 
diagnosis, evaluation, and treatment options. We believe the results of our proposed study could lay  
the foundation to study supraspinal control in UAB, and potentially create avenues for 
translational clinical trials.  
• 
Evaluate effects of individualized TRPMS as a potential therapy for VD in neurogenic or non-neurogenic 
patients. This new understanding of the cortical regions of the brain related to voiding and how they can 
be modulated might shift clinical attention from the bladder to more cerebral control, possibly creating 
further avenues for intervention. Data obtained in this study will provide the scientific rationale for 
subsequent multicenter, efficacy-based clinical trials and could potentially transform VD.   
  
ETHICAL CONSIDERATIONS AND RESOURCE SHARING PLAN  
A similar version of this trial is already approved by our Institutional Review Board and is ongoing as part of my 
K12 (KURe Program). All subjects will be properly counseled and consented before enrolling in this study. Our 
informed consent states that participation is completely voluntary and patients can withdraw at any point and this 
will not affect their relationship with the physician and their treatment course. All staff members involved in the 
collection of data and handling of patients will have proper privileges and training by our Research Institute and 

MRI Core. Before proceeding with fMRI testing, patients will be asked to remove all clothing and items containing 
metal. All materials used during the fMRI/UDS scans are MRI compatible. Pregnancy tests and urinalysis will 
exclude patients who are pregnant or have a UTI. No minor or vulnerable individuals will be recruited for the 
study. If an adverse effect occurs, the principal investigator and appropriate authorities will be informed and 
proper actions will be taken based on Good Clinical Practice.   
  
Our research sharing plan includes:  
• 
All data and resources developed within the scope of this proposal will be made available to the scientific 
community. This includes publications (through PubMed Central and/or publication in open-access 
journals) and raw data if applicable. Our trial will be registered at http://clinicaltrials.gov/.  
• 
Houston Methodist Hospital and Research Institute are committed to the open and timely dissemination 
of research outcomes. We recognize that promising new methods, technologies, and scientific insights 
may arise during the course of our research. We are aware of and agree to abide by the principles for 
sharing research resources as recommended by National Institute of Health (NIH). We will follow NIH 
recommendations on Rigor and Reproducibility.  
• 
The data generated in this grant will be presented at national and international conferences, including 
NIH-sponsored meetings and specifically American Urology Association, Society of Urodynamics, 
Female Pelvic Medicine and Urogenital reconstruction, and International Continence Society. In addition, 
over the past three years I have presented my work at the annual Urology Program Directors’ meeting 
by NIDDK and I will continue to do so.  
• 
The data and results will be published in a timely fashion. All final peer-reviewed manuscripts that arise 
from this proposal will be submitted to the digital archive PubMed Central. The format or presentation 
of final research data shall be determined at the time such data is generated and in accordance with 
generally accepted scientific standards. Final progress reports will include information detailing the steps 
towards implementation of additional data-sharing plans. These manuscripts will be deposited into NIH 
Manuscript Submission system as required by the public access policies of NIH funding.  
• 
Any unique research resources generated from this project, as available, will be freely distributed upon 
request to qualified academic investigators for non-commercial research through Methodist’s Material 
Transfer Agreement  
• 
BBRAIN working group is an international working group focusing on Brain-Bladder connection and 
includes experts in the field such as Derek Griffiths, Bertil Blok, and Ulrich Mehnert. BBRAIN meets 
annually and my results have been presented and will continue to be presented within this focused 
research group. BBRAIN is considering creating a secure international platform for future collaborative 
and multicenter data analysis studies of which I will be a part.