Pudendal Nerve Mapping Towards Improved Neuromodulation for Urinary Retention
Phase: NA
Conditions: Urinary Retention, Underactive Bladder
Sponsor: University of Michigan

 
Pudendal Nerve Mapping Towards Improved 
NeuromodulaƟon for Urinary RetenƟon 
 
NCT04236596 
 
Date of IRB Approval: February 4, 2022 

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Pudendal Nerve Mapping Study 
 
 
Pudendal nerve mapping towards improved neuromodulation for urinary retention 
 
 
University of Michigan IRBMED 
Protocol HUM00165005 
 
NIH Award OT2OD028191 
 
 

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Table of Contents 
1. Study Summary ...................................................................................................................................... 4 
1.1 Background and Significance ........................................................................................................ 4 
1.2 Objective ........................................................................................................................................... 6 
1.3 Specific Aims .................................................................................................................................... 7 
1.4 Primary Outcomes ........................................................................................................................... 7 
1.5 Secondary Outcomes ..................................................................................................................... 7 
1.6 Investigative team ............................................................................................................................ 7 
2. Research Procedures ........................................................................................................................... 8 
2.1 Pre-study surveys ............................................................................................................................ 8 
2.2 Visit 1: Pre-implant imaging (Aim 1) ............................................................................................. 8 
2.3 Bladder diaries ................................................................................................................................. 9 
2.4 Visit 2: Stage-1 implant electrophysiology (Aim 2) ..................................................................... 9 
2.5 Visit 3: Computed Tomography (Aim 3) ..................................................................................... 10 
2.6 Patient-specific computational model (involves no direct patient interaction) (Aim 3) ........ 11 
2.7 Visit 4: Stimulation during cystometrogram (Aim 4) ................................................................. 11 
2.8 Final surveys .................................................................................................................................. 13 
2.9 Patient timeline............................................................................................................................... 13 
3. Study Statistics and Data Analysis Plan .......................................................................................... 13 
3.1 Sample size .................................................................................................................................... 13 
3.2 Data Analysis plan ......................................................................................................................... 14 
3.2.1 Selectivity Index ...................................................................................................................... 14 
3.2.2 Bladder excitation ................................................................................................................... 14 
3.2.3 Leak Point Pressure ............................................................................................................... 15 
4. Study Recruitment ............................................................................................................................... 15 
5. Study Population .................................................................................................................................. 15 
5.1 Inclusion Criteria ............................................................................................................................ 16 
5.2 Exclusion Criteria ........................................................................................................................... 16 
6. Study Sites ............................................................................................................................................ 16 
7. Informed Consent ................................................................................................................................ 17 
8. Waiver of Informed Consent .............................................................................................................. 17 
9. Confidentiality of Data ......................................................................................................................... 17 
10. Data Safety and Monitoring ............................................................................................................. 17 

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10.1 Data Safety and Monitoring Plan .............................................................................................. 17 
10.2 Severity ......................................................................................................................................... 18 
10.3 Serious Adverse Event ............................................................................................................... 18 
10.4 Termination of Subjects .............................................................................................................. 18 
10.4.1 Subject Decision ................................................................................................................... 18 
10.4.2 Investigator Decision ........................................................................................................... 19 
11. Protection of human subjects .......................................................................................................... 19 
11.1 Potential benefits of this research ............................................................................................. 19 
11.1.1 Potential benefits to society ................................................................................................ 19 
11.1.2 Potential benefits to participants ........................................................................................ 19 
11.2 Risks to Human subjects ............................................................................................................ 19 
11.2.1 Potential Risks and Protection against risks .................................................................... 20 
11.2.2 Identifying information ......................................................................................................... 20 
11.2.3 Magnetic resonance imaging ............................................................................................. 20 
11.2.4 Computed tomography ........................................................................................................ 20 
11.2.5 Clinical catheters .................................................................................................................. 20 
11.2.6 Electrical stimulation ............................................................................................................ 21 
11.2.7 Reasonableness of risks ..................................................................................................... 21 
12. Research Costs ................................................................................................................................. 21 
13. Investigational Drug ........................................................................................................................... 21 
14. Investigational Device ....................................................................................................................... 21 
15. Marketed Drugs/Device .................................................................................................................... 21 
16. Additional Requirements .................................................................................................................. 22 
16.1 Biosafety ....................................................................................................................................... 22 
16.2 Point of care testing .................................................................................................................... 22 
16.3 Tissue procurement .................................................................................................................... 22 
16.4 Clinical research unit ................................................................................................................... 22 
16.5 Nurse or student nurse research .............................................................................................. 22 
16.6 Pregnant women and newborns ............................................................................................... 22 
References ................................................................................................................................................ 22 
 
 
 
 

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1. Study Summary 
1.1 Background and Significance 
In general, primary bladder complaints include an inability to maintain urine in the bladder or a 
constant feeling of needing to empty (incontinence and overactive bladder (OAB)) and an 
inability to effectively empty the bladder (underactivity, voiding dysfunction). A significantly 
greater focus in healthcare management and bladder study has been placed on problems with 
maintaining urine in the bladder, likely due to discomfort with and social stigmas of incontinence. 
However, underactivity affects a similarly high percentage of the population and can lead to 
significant conditions including urinary tract infections [1] and urinary retention-driven 
incontinence and OAB, impacting quality of life [2]. Underactive bladder is a symptom often 
indicating detrusor (bladder muscle) underactivity (DUA) and results in prolonged urination and 
urinary retention [2]. These effects may also be due to bladder outlet obstruction (BOO), such 
as for an enlarged prostate, making DUA and BOO challenging to differentiate [3]. The specific 
prevalence of DUA is not known as a wide range has been reported, including 9-28% of men 
under 50, up to 48% of older men [2], [3], and 12-45% of older women [3]. DUA is common for 
cases of damage to or problems with the nervous system, including Parkinson disease, multiple 
sclerosis, and peripheral neuropathies like Guillain-Barré syndrome [2], [3]. Other factors with 
an unclear relationship to DUA include reduced mobility, colorectal dysfunction, various 
medications, and menopause in women [2]. DUA affects tens of millions of Americans, and is 
expected to increase in prevalence as the population ages. 
Overall management of DUA is generally not successful, due to insufficient efficacy and/or poor 
tolerability of treatments [2]. Patients with moderate to severe cases will often use intermittent 
catheterization to empty their bladders. While this is a standard approach that has low infection 
rates with proper training, it is generally not well received by patients, some of whom are not 
always capable of catheterizing themselves and are candidates for indwelling catheters [2]. 
There are pharmacological therapies that help with detrusor contractions, such as 
parasympathomimetics, however evidence for their efficacy is limited and side effects such as 
cramping and visual effects limit their clinical utility [2]. Sacral nerve stimulation, as discussed 
further below, is used for non-BOO retention and has yielded the best efficacy to date [4]. It is 
thought to induce sphincter or pelvic floor relaxation rather than increased bladder contractility 
[2] and does not provide on-demand control. Electrical stimulation of ventral roots has been 
used to empty the bladder in spinal cord injured patients [5], however it requires an invasive 
surgery for electrode placement, limiting its utility in other groups. 
Many animal studies have demonstrated bladder excitation in response to electrical stimulation 
of pudendal nerve fibers [6]–[9]. Initial studies focused on the use of cuff electrodes to stimulate 
the entire pudendal nerve. Stimulation frequencies within 20-33 Hz are generally micturition-
selective while lower frequencies like 3-10 Hz activate the continence circuit, though there can 
be variation within and across experiments which may depend on nerve activation efficacy. 
Studies have obtained selective activation of micturition through several means, including 
stimulating within the urethra [10], [11] or on distal pudendal branches originating from proximal 
or distal regions of the urethra [12], [13]. Penetrating electrodes within the pudendal nerve [14] 
or spinal roots [15] have been used to selectively activate micturition-driving neurons. Most of 
these studies have focused on exciting the bladder. Only a few have reported clinically-relevant 
bladder emptying [12]. A primary factor in this limited output is the effect of anesthesia, which 
can depress synaptic transmission in spinal circuits and/or maintain sphincter closure or urethral 

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tone, depending on the agent used [16]. In general, these studies are performed in rats and 
cats, although other species like mice, pigs and non-human primates have been used 
occasionally. Each of these animals has similar lower urinary tract physiology and primary 
neural control through pudendal, pelvic, and hypogastric nerves [17] and are accepted as 
models for human anatomy and physiology. 
In contrast to animal studies, clinical exploration of pudendal neuromodulation for voiding has 
been limited. Thanks to the pudendal-driven micturition circuit originating within the urethra, 
stimulation with catheter-mounted electrodes has been performed in several pilot clinical 
studies, though the effects are marginal or only explored in a limited fashion [18]–[20]. This 
catheter stimulation approach is an in-clinic tool that is not feasible for at-home use by patients, 
though it allows for patient screening. One study has shown that it is possible to elicit bladder-
excitation responses with an electrode inserted percutaneously near the pudendal nerve, 
however the effects were again marginal due in part to the limited opportunity to explore 
stimulation paradigms and a lack of nerve-electrode visualization [21]. A recent modeling study 
suggested that it is possible to selectively activate different fascicles with a multi-contact cuff 
placed on the pudendal nerve [22]. While cadaver dissections suggested the surgical feasibility 
of cuff electrode placement to accomplish this selective stimulation [23], the invasive nature of 
the cuff electrode placement surgery has prevented validation of this computational model.   
Sacral neuromodulation (SNM) is a standard clinical treatment. FDA approval was granted for 
the Medtronic Interstim implantable neurostimulator over 20 years ago [4], and over 200,000 
people worldwide have been implanted. The Interstim system consists of an implantable pulse 
generator (IPG) and a stimulation lead. The lead consists of helical-coiled, insulated wires that 
terminate in four ring electrodes near the tip. The Interstim lead has barbs, or tines, along the 
distal end to provide anchoring and limit migration. For an initial evaluation phase (“stage 1 
implant”), the stimulation lead is placed through the third sacral foramen, generally using 
fluoroscopy, and externalized percutaneously to a stimulator worn on the waist [24]. During 
implant, anal bellows and/or patient sensations are typically used to determine relative nerve 
activation for different stimulation amplitudes and electrode combinations. If the patient has had 
sufficient improvement in symptoms (generally > 50%) after a 2- or 3-week observation period, 
the IPG is implanted in the lower back and connected to the stimulation lead, leaving a fully-
implanted system (“stage 2 implant”). Externally, a programmer can communicate with the IPG 
to monitor or modulate stimulation. Stimulation can be delivered bipolar between any pair of the 
four electrodes or monopolar between one electrode and the IPG.  
Since 2005, a few clinicians worldwide have started placing the Interstim lead at the pudendal 
nerve [21], [25], [26]. This is often done in patients who failed traditional SNM or who have 
concurrent pelvic symptoms [27]. The clinical steps for this pudendal nerve implant procedure 
follows the steps for SNM, in an off-label use, with fluroscopy and external anal sphincter (EAS) 
electromyogram (EMG) used to determine the proximity of the lead to the pudendal nerve [28], 
[29]. Patients at the University of Michigan health system who receive the Interstim at the 
pudendal nerve offer an opportunity to develop a new computational model of pudendal nerve 
electrical stimulation. Development of this model and validation of our ability to model the nerve 
and stimulation lead and will suggest whether it is possible to selectively stimulate the nerve 
such as to drive bladder excitation and voiding. Thus the goal of this study is to gather imaging 
data about the location of the nerve and stimulation lead, to create a computational model of the 

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nerve-lead, and then to validate that model with patients receiving a IPG and lead that target 
their pudendal nerve as part of their normal clinical care. This study is not studying or 
establishing the efficacy of the Interstim system at the pudendal nerve. We will collect indicators 
of patient symptoms at the start and end of study participation to determine whether any factors 
relate to our ability to model and stimulate the nerve. 
Figure 1 shows our overall study design, with example figures of our anticipated study 
progression as implemented for another neuromodulation approach by our team [30]. Further 
details on each step are given in Section 2 below. This NIH-funded project is part of the NIH 
SPARC (Stimulating Peripheral Activity to Relieve Conditions) program. A primary objective of 
the SPARC program is to enhance knowledge of anatomical and functional neural innervation of 
autonomic organs towards improved neuromodulation therapies. This project aligns perfectly 
with this objective, as we will use imaging and electrophysiology techniques to map a key nerve 
innervating pelvic organs in a relevant clinical population.  
Stimulation of the pudendal nerve is also a promising minimally invasive solution for the 
mitigation of stress urinary incontinence (SUI). SUI is a form of incontinence in which undesired 
urination occurs in association with physical exertion. SUI profoundly affects quality of life [31] 
and is prevalent in approximately 13% of women aged 19-44 years and 22% of women aged 
45-64 years [32]. There are a number of therapies and treatments for SUI [33], including 
conservative measures and minimally invasive options with varying and limited efficacy [34]. 
Pudendal nerve stimulation may help maintain urethral closure during events that cause SUI, 
such as coughs, however it has not been studied directly in patients. As described below, in this 
study we will also perform nerve stimulation during the final test visit when patients simulate 
conditions that cause SUI, such as with a cough. This study will examine whether nerve 
stimulation increases urethra pressures during these events. This study is not testing the 
efficacy of pudendal nerve stimulation against SUI but may provide preliminary support for a 
future study to examine it further. 
1.2 Objective 
The goal of this study is to map the pudendal nerve with imaging and electrophysiology, by 
gathering additional data from patients receiving an implanted neurostimulator as part of their 
 
Figure 1. Overall study design. At top, the standard progression of experimental steps for each study 
participant are shown. At bottom, corresponding images for planned steps are shown, from Dr. 
Lempka’s previous study performing patient-specific modeling of deep brain stimulation [1]. 

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normal clinical care, and to examine the response of the bladder and urethra to different 
pudendal nerve stimulation frequencies. 
1.3 Specific Aims 
The aims of this study are to: 
• 
Specific Aim 1: Use pre-implant magnetic neurography to identify and map the path of the 
pudendal nerve bilaterally.  
• 
Specific Aim 2: Examine activation of pudendal nerve paths during unilateral stage-1 
implant with pelvic floor catheters and electromyogram sensors. 
• 
Specific Aim 3: Create a patient-specific model of the implanted electrode and pudendal 
nerve and predict stimulation-driven nerve responses. 
• 
Specific Aim 4: Evaluate ability of model-derived stimulation paradigms to activate 
pudendal-nerve controlling bladder pathways during a cystometrogram. 
• 
Specific Aim 5: Determine the change in urethral leak point pressure (ULPP) with pudendal 
nerve stimulation. 
1.4 Primary Outcomes 
The primary outcome measure in this study are evoked bladder contractions of at least 20 
centimeters of water (cmH2O) during the stage-4 test in at least 50% of participants. 
1.5 Secondary Outcomes 
The secondary outcome measures in this study will be 1) selectivity indices for selective 
stimulation of pudendal nerve branches for both patient stimulation and simulated model 
stimulation and 2) selectivity index for selective stimulation of pudendal nerve branches for 
simulated model stimulation. The SI calculation may be modified in some patients, as 
necessary, for factors such as the presence of a short urethra that only allows for a single 
intraurethral pressure measure (female urethras < male urethras) and/or the placement of EMG 
in the perineal floor between yields one or more additional sensors. 3) Measurement of effect of 
pudendal nerve stimulation on urethral leak point pressure (ULPP) using stimulation targeted for 
the external urethral sphincter. 
1.6 Investigative team 
Tim Bruns, PhD, is an Associate Professor of Biomedical Engineering. He leads a research 
group that develops interfaces with the peripheral nervous system to restore function while 
focusing on autonomic organs like the bladder. He has over ten years of experience in studying 
neuromodulation for bladder control, including preclinical feline studies at the pudendal nerve 
and dorsal root ganglia and pilot clinical studies investigating intraurethral and genital nerve 
stimulation. At the University of Michigan, he was PI on a clinical study investigating skin-
surface neuromodulation for female sexual dysfunction, which was recently completed 
(HUM00101713).  
Priyanka Gupta, MD, is an Assistant Professor of Urology. She has extensive training in the 
use of neuromodulation for bladder conditions. In her clinical practice she regularly uses sacral 
neuromodulation, posterior tibial nerve stimulation, and pudendal neuromodulation to improve 
the bladder symptoms of her patients.  
Gaurang Shah, MD, is a Professor of Radiology, Director of Clinical Functional MRI Service 
within the Neuroradiology Division, and Director of Medical Student Education within 
Neuroradiology. He has a record of clinical expertise and research projects in a range of 

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advanced imaging techniques, including neurography to identify and track peripheral nerves as 
well as fMRI, resting stage fMRI, diffusion tensor imaging (DTI), and tractography. 
Scott Lempka, PhD, is an Assistant Professor of Biomedical Engineering and Anesthesiology. 
He has more than a decade of experience in modeling nerve stimulation for a variety of clinical 
applications, including deep brain stimulation and spinal cord stimulation. In these applications, 
he has implemented a patient-specific modeling approach towards improving neuromodulation 
efficacy. He also has expertise in clinical neuromodulation studies that combine clinical testing 
with patient-specific computational models. 
2. Research Procedures 
We will conduct the proposed study in accordance with the requirements of the University of 
Michigan Medical School Institutional Review Board (IRBMED). All study visits will be conducted 
at University of Michigan Health System locations.  
2.1 Pre-study surveys 
Once enrolled in the study, participants will complete surveys to assess their pre-implant pelvic 
organ function. The participants will five complete clinically validated surveys on: 
1 
Bladder health: American Urological Association Symptom Index (AUASI) also called 
International Prostate Symptom Score (IPSS) [35], [36] 
2 
Bladder health: Michigan Incontinence Symptom Index (M-ISI) [37] 
3 
Sexual function: Female Sexual Function Index short form (FSFI-6) for women [38] 
and the International Index of Erectile Function (IEEF-5) also called Sexual Health 
Inventory for Men (SHIM) for men [39], [40] 
4 
Bowel function: Colorectal-Anal Distress Inventory 8 (CRAD-8) [41] 
5 
Pelvic pain: Female GenitoUrinary Pain Index (FGUPI) for women and Male 
GenitoUrinary Pain Index (MGUPI) for men [42].  
Additionally, some participants (i.e., recruited patients who are in urinary retention with 
detrusor underactivity and have failed bladder outlet surgery, S3 neuromodulation or PTNS 
trial as identified by Dr. Gupta) will complete two additional clinically validated surveys as 
well as a three-question catheterization survey. 
6 
Quality of Life: Short Form 12-Item version 2 (SF-12v2) quality of life survey [43] 
7 
Sexual Health: Sexual Quality of Life Questionnaire-Female (SQOL-F) for women [44] 
and the Sexual Quality of Life Questionnaire-Male (SQOL-M) for men [45] 
The AUASI and M-ISI surveys are already part of the normal clinical care for these patients and 
the F/MGUPI are sometimes also given already. Participants will also complete a questionnaire 
on demographics. All of these surveys are loaded in section 29 of the IRB protocol. Surveys will 
be completed over the phone, or on paper either in person and/or mailed to participants before 
study visits, and/or online, through RedCAP or a similar, clinically-approved interface.  
2.2 Visit 1: Pre-implant imaging (Aim 1) 
Once a patient is consented for study participation, an imaging session will be scheduled as part 
of the research study. Pre-menopausal women will undergo a urine pregnancy test prior to 
imaging session. A research staff member (i.e. study investigator/coordinator/research staff) will 
administer the test by providing participants with a specimen cup. Participants will then provide 
a urine sample, a research staff member will read the results by placing a dip stick inside the 

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specimen cup. This test will be covered by research funds and not billed to the patient. We will 
use magnetic resonance neurography (MRN) to identify the nerve path and surrounding tissue 
(Figure 2), as it is a structural MRI technique that allows for the identification and 
characterization of fine structures like peripheral nerves [46], [47]. We may also perform 
diffusion tensor imaging (DTI), which is a specialized imaging technique used with MR 
neurography and provides more specific structural information about peripheral nerves such as. 
DTI can indicate the myelinated fiber density and differentiate between motor and sensory-
dominated fascicles in peripheral nerves [48]. This imaging session will be performed at the 
main University of Michigan hospital, Department of Radiology, or at another University of 
Michigan Health System location with MRI facilities. The MRN and DTI will be reviewed for 
planning the stage-1 implant. This imaging session is not part of the patient's normal clinical 
care, but the procedures performed are often used during other patients' care. Some enrolled 
patients may have a previously implanted, non-MRI compatible Interstim neurostimulator at the 
sacral nerve or pudendal nerve that is no longer providing therapeutic benefit and is being 
removed during the stage-1 surgery of this study. These patients will undergo the MRI at a later 
point in the study as is convenient for them, after the new MRI-compatible neurostimulator is 
placed in the stage-1 surgery. 
2.3 Bladder diaries 
Prior to each of the stage-1 and stage-2 procedures, patients complete a bladder diary for three 
days as part of their normal clinical care. They bring this diary with them to the clinic on 
procedure days (included as Medtronic Daily Diary in section 44.1). Observations in these 
diaries will be added to the research data set for each participant. After the stage-1 implant 
procedure, one or more representatives of Medtronic regularly touch base with the patient to 
see whether they are responding to the stimulation. This is normal clinical practice. In these 
conversations, the Medtronic representatives use a Patient Management Worksheet. Data 
collected in these worksheets (e.g. bladder urgency score, daily voids, bladder retention) will 
also be collected for this study. 
2.4 Visit 2: Stage-1 implant electrophysiology (Aim 2) 
Participants will undergo normal surgical steps during the standard stage-1 implant of their 
 
Figure 2. Preliminary, unoptimized pudendal nerve MR neurography and nerve reconstruction from a 
male volunteer under a different IRB protocol. At left, approximate axial locations for three scans are 
shown on a diagram of the pelvis. The fat saturation (Fat Sat) T2 scan, shown at location 2 here, 
clearly visualizes the pudendal nerve bilaterally in Alcock's canal. In the Fat Sat images, the pudendal 
nerve can be segmented and copied on to higher-definition proton density (PD) images. Here PD 
images at locations 1 and 3 are shown, with 3 showing separation of pudendal branches. At right, the 
imaged nerve path is reconstructed for a series of 3-mm interval scans. 

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neurostimulator lead at the pudendal nerve, as part of their normal clinical care. This is the first 
stage of a full implant system, in which the stimulation lead is inserted and connected to an 
external stimulator. If a patient responds positively to this stage-1 implant, then a following 
stage-2 surgery will be performed as part of their normal clinical care to implant the pulse 
generator (described below). These surgical procedures are typically done at the main 
University of Michigan hospital but may be performed at another UMHS facility as scheduling 
requires. Dr. Gupta regularly performs these procedures as part of her clinical practice. Prior to 
the stage-1 and stage-2 surgeries, pre-menopausal women will undergo a urine pregnancy test. 
This is part of their normal clinical care as pregnancy is also an exclusion for clinical care. Once 
the patient is prepared for surgery, the clinical team will place up to 3 standard clinical catheters 
in the urethra, positioned with the pressure-sensing ports in the distal urethra, proximal urethra, 
and/or bladder (See Figure 3). The primary catheter will be a standard clinical-use Covidien 
Manoscan manometry catheter, to provide high-resolution urethra pressure data, as has been 
done previously [50], [51]. Other catheters will only be used to infuse some fluid into the bladder 
(2 catheters in total) or if the manometry catheter is unavailable (up to 3 catheters in total). A 
standard clinical abdominal catheter may also be placed in the rectum. The standard external 
anal sphincter electromyogram needles will be placed on either side of the anus for normal 
clinical monitoring. A pair of standard clinical electromyogram needles may also be placed in the 
perineal region. These catheters and electromyogram sensors will be recorded from 
continuously during the implant procedure. The sensors cannot transmit energy to the patient. 
During the surgical placement of the neurostimulator lead, if a location is identified that may be 
the final position then a pre-planned, structured set of stimulation parameters will be applied 
through each lead contact. We will vary the amplitude and pulse width of the applied stimulation 
pulses through the stimulation lead, staying within the programmed capabilities of the medical 
device. The total duration of these structured stimulation tests will last for up to fifteen minutes. 
This time duration is within the normal variance of the surgical procedure itself, and will not 
significantly affect the surgical duration or affect the care of the patient. The total impact on the 
surgical procedure, including placement of catheters and electromyogram sensors and 
stimulation testing, will not last longer than 30 minutes.  
2.5 Visit 3: Computed Tomography (Aim 3) 
As part of their normal clinical care, patients undergo a stage-2 surgery procedure to implant the 
pulse generator of the implantable neurostimulator. Patients undergo the stage-2 procedure if 
they have responded positively to the stage-1 procedure, as determined by Dr. Gupta. Most 
patients undergoing the stage-1 procedure proceed to the stage-2 surgery, 2-3 weeks after the 
stage-1 implant. If a study participant does not respond to the stage-1 implanted stimulation 
lead and they are not having a stage-2 surgery, then they will be removed from the study. 
On the same day that participants receive the implanted stimulator in the stage-2 outpatient 
surgery they will undergo a computed tomography (CT) scan of the pelvis as part of the 
research study.  Again, prior to the CT scan, pre-menopausal women will undergo a urine 
pregnancy test to detect pregnancy. This test will be similar to visit 1, a research staff member 
(e.g. study investigator/coordinator/research staff) will administer the test and obtain the results. 
This test will be covered by the research study. This CT scan will be performed during the same 
clinical visit as for the stage-2 procedure. If allowed by scheduling and patient preference, the 
CT scan will be prior to the stage-2 implant, to allow the patient to leave the hospital once they 
are ready after the implant. Otherwise, the CT scan will be after the stage-2 implant when the 
patient is ready. This CT scan will be of the pelvis, to determine the final location of the 

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implanted stimulation electrode, with respect to landmarks like the participant's ischial spine. 
This CT scan is not part of the patient's normal clinical care for the Interstim implantation, but is 
the same procedure as used during other patients' care. 
2.6 Patient-specific computational model (involves no direct patient interaction) (Aim 3)  
As part of the research study, the pudendal nerve for each patient will be identified and 
segmented from the MRN images with Materialise Mimics Innovation Suite (Figure 2). We will 
co-register the three-dimensional surfaces from MRN, DTI, and CT images to create a patient-
specific computational model, as has been done for other types of implant table 
neurostimulators [30], [52]. A software program (Comsol Multiphysics) will be used to estimate 
voltage fields generated by the neurostimulator electrode stimulation. These estimates will be 
validated using stage-1 recordings. The computational model will be used to predict electrode 
stimulation parameters for recruiting different parts of the pudendal nerve using the NEURON 
computational software. Computational modeling of implanted stimulator activation of nerves 
has been done previously by our research team [53].The computational model produced with 
the Mimics Innovation Suite will not be used to diagnose or be used as a diagnostic procedure. 
These software programs will be used to determine our ability to model the nerve and electrode. 
2.7 Visit 4: Stimulation during cystometrogram (Aim 4) 
As part of their normal clinical care, patients visit the clinic about 4-5 weeks after their stage-2 
surgery. After their clinic visit, patients will undergo an experimental cystometrogram (bladder 
filling) in a urodynamics suite as part of this research study. This test will occur at the University 
of Michigan main hospital or a local UMHS clinic, as determined by Dr. Gupta's clinical 
schedule, in a urology cystometry suite. Prior to the test, pre-menopausal women will undergo a 
urine pregnancy test to detect pregnancy. This test will be covered by the research study and 
clinical staff will obtain the results.  
Patients will be situated for a normal cystometrogram, in a reclining position, as shown in Figure 
3 Top (from [54]) or in an upright sitting position. It is standard clinical practice to offer patients 
an antibiotic right before a cystometrogram. The antibiotic pill will be provided by and 
administered by the clinical staff. Clinical staff will insert standard urodynamic catheters into the 
urethra, bladder, and bowel (or vagina), and standard urodynamic EMG surface electrodes 
around the external anal sphincter and maybe perineal region, similar to the stage-1 procedure. 
Standard EMG surface electrodes may also be placed on the abdomen and/or lower back to 
record abdominal muscle activity. The primary urethra catheters will be a standard clinical-use 
Covidien Manoscan manometry catheter, to provide high-resolution urethra pressure data [50], 
[51], and a standard urodynamics catheter for infusing fluid into the bladder (2 urethra catheters 
in total). If the manometry catheter is unavailable one or two standard urodynamics catheters 
may be used to measure urethra pressures.  Warm saline will be used to fill the bladder (~30-50 
mL/min) through the bladder catheter until the participant just perceives filling. This is a standard 
clinical step in cystometrogram, using a standard clinical urodynamics instrument. Normal 
cystometrograms continue infusion until voiding (Figure 3 Bottom, from [54]), however stopping 
at this not-full state will allow for the assessment of stimulation effects on the bladder. 
Stimulation paradigms identified by the patient-specific model will be applied through the 
implanted neurostimulator until stimulation-driven voiding occurs or the participant expresses a 
very strong desire to void. At that point, the patient will be allowed to void and/or residual saline 
will be removed from the bladder via the bladder catheter. Approximately half of patients 
normally do not void around the catheter during a cystometrogram. For any participant like this, 

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they will have the catheters removed and will empty their bladder on to a void scale or into a 
toilet. This sequence will be repeated up to three times.  
At two or more time points within a cystometrogram, the urethral leak point pressure (ULPP) will 
be measured during 
Valsalva and/or forceful 
coughing. This will occur 
after infusing saline into 
the bladder to in 
intermediate volume(s) 
below the sensation of 
fullness and then pausing. 
Urethral leakage may not 
be observed; however, 
urethral pressures will be 
recorded and compared to 
pressures during pudendal 
nerve stimulation. If 
leakage is observed, an 
equal amount of saline 
may then be reinfused. 
Pudendal nerve 
stimulation will be turned 
on to a stimulation 
paradigm for maximum 
urethral sphincter 
activation at a comfortable 
level, for a maximum of a 
60-second pulse train 
while the ULPP 
measurement is repeated 
using Valsalva and/or 
forceful coughing. The 
saline infusion will then be 
resumed until the 
participant perceives 
fullness and then will be 
stopped. Leak point 
pressure will again be 
assessed without and then 
with pudendal nerve 
stimulation as before. 
Each assessment of leak 
point pressure may be 
performed with stimulation 
on and then repeated with 
stimulation off, or with 
 
 
Figure 3. Top: Standard cystometrogram (CMG) setup, with a pump to 
infuse saline, bladder and rectal pressure catheters and sensors, and 
a flowmeter for voiding. From [45]. Our study will add one or more 
urethra catheters, abdominal, anal sphincter and/or perineal EMG, 
and will not use fluoroscopy. Bottom: Standard CMG outputs, with in-
bladder pressure (Pves; blue), abdominal (rectal) pressure (Pabd; 
red), bladder muscle pressure (Pdet=Pbes-Pabd; green), EMG, urine 
flow (black), and volume (infused, voided). From [45].  

Version 7.January 12, 2022 
14 
The target population size (N=40) was selected based on Dr. Gupta's clinical practice and direct 
input from the funding agency (NIH SPARC). We seek to have 20 patients complete all parts of 
this study and yield data. Due to patient heterogeneity (e.g. prior surgical procedures that limit 
effects of neural stimulation; implanted hip replacements that obscure MRI data) and drop-outs 
among enrolled patients, we anticipate that approximately half of enrolled participants will 
complete all study steps and yield usable data. This study size is within the range of sample 
sizes used in prior pelvic floor / pudendal nerve anatomy mapping studies with cadavers (N=7 
[23], 13 [55], 28 [56], 43 [57]). To our knowledge, no studies have performed pudendal mapping 
with MR imaging data. Additionally, this sample size is comparable to prior human subject 
studies stimulating the pudendal nerve or its branches (N=10 pudendal implant after sacral 
implant [58], N=12 cutaneous genital nerve [59], N=21 percutaneous genital nerve [60], N=30 
pudendal versus sacral implant [26]). 
3.2 Data Analysis plan 
The primary outcome measures in this study, towards being able to model electrical stimulation 
of the pudendal nerve will be evoked bladder contractions of at least 20 centimeters of water 
(cmH2O) during the stage-4 test in at least 50% of participants. A second outcome measure will 
be identification of ULPP with and without stimulation. Results of the patient surveys 
(demographics, pelvic organ function surveys as defined above) and voiding diaries will be 
compared to our ability to selectively model and stimulate the pudendal nerve and cause 
bladder excitation and ULPP measures with stimulation to determine if there are any trends or 
relationships to participant characteristics.  
3.2.1 Selectivity Index 
For a given stimulation electrode location during the visit 2 stage-1 electrophysiology, a 
Selectivity Index (SI) will be calculated for each catheter or electromyogram sensor recording 
from distal pudendal nerve branches. This includes sensors in the proximal urethra (proximal 
perineal branch - PPB), distal urethra (distal perineal branch - DPB), and anal EMG (ischeal 
rectal nerve - IRN).  
𝑆𝑆𝑆𝑆𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑋𝑋=
𝑋𝑋
𝑃𝑃𝑃𝑃𝑃𝑃+ 𝐷𝐷𝐷𝐷𝐷𝐷+ 𝐼𝐼𝐼𝐼𝐼𝐼 
For the model-based or theoretical SI, PPB, DPB, and IRN represent the percentage of model 
axons activated within the proximal perineal, distal perineal, and inferior rectal nerves, 
respectively. For experimental SI, PPB and DPB are the maximal intraurethral pressures 
measured at proximal and distal sphincter locations. IRN is the maximum, normalized rectal 
nerve response. This SI will be used to determine whether any stimulation electrode 
combinations have selective recruitment of any individual pudendal nerve branches (SI > 0.67, 
for example). The SI calculation may be modified in some patients, as necessary, for factors 
such as the presence of a short urethra that only allows for a single intraurethral pressure 
measure (female urethras < male urethras) and/or the placement of EMG in the perineal floor 
between yields one or more additional sensors. During visit 4 experimental cystometrogram 
testing, experimental Selectivity Indexes will also be calculated as described above. 
3.2.2 Bladder excitation 
The primary metric of successful bladder excitation will be a target evoked bladder contraction 
of at least 20 cmH2O during the visit 4 cystometrogram in at least 50% of participants. 
Additionally, any stimulation-driven or participant-driven voiding efficiency will be calculated as 

Version 7.January 12, 2022 
15 
[volume voided] / [volume voided + residual measured still in bladder]. 
3.2.3 Leak Point Pressure 
The ULPP will be determined as the maximum urethra pressure during any Valsalva and 
forceful coughing events from the urethra catheter sensors. The ULPP during pudendal nerve 
stimulation will be compared to the ULPP without stimulation at each volume level tested. 
 
4. Study Recruitment 
Dr. Gupta will recruit patients in her clinical practice that fail conservative treatments for relevant 
bladder symptoms and are being considered for a pudendal nerve implant. Generally, these 
patients are very willing to help, as they have failed a series of prior conservative treatments 
and they know the pudendal implant is an off-label use. We will augment this recruitment by 
asking other U-M Urology clinicians to refer patients of theirs who may be candidates. 
Additionally, we will recruit patients from Dr. Gupta’s practice and other Urology clinicians who 
have failed treatment with an implanted Interstim neurostimulator at the sacral nerve. Either Dr. 
Gupta will perform the subject recruitment or she will introduce the patient to the study 
coordinator, who will then discuss the study with the patient and perform recruitment. Patient 
information will not be shared outside of direct clinical conversations or inquiries by the study 
coordinator.  
As has been reported previously, patients who fail the traditional sacral nerve Interstim implant 
often respond positively to pudendal nerve implants [26], [61]. Dr. Gupta will recruit sacral-nerve 
implanted patients who did not achieve clinical success to have a replacement implant at the 
pudendal nerve. Failed-sacral patients will be broadly recruited across clinicians within the 
Neurourology and Pelvic Reconstructive Surgery section at the University of Michigan Health 
System, which includes six Urologists who regularly see these types of patients and implant 
Interstim devices. Any patients not initially under Dr. Gupta’s care who are interested in this 
study will be referred to her for subsequent care for receiving the IPG as well as any 
participation in this study. Additionally, we will also look for patients with urinary retention with 
detrusor underactivity and have failed bladder outlet surgery, S3 neuromodulation or a PTNS 
trial. These patients will be identified and referred to the study by Dr. Gupta and her clinic.  
Aside from the first study visit – MR imaging – all other study participation parts will be linked to 
standard visits as part of clinical care. This plan will help retain subjects as they will not have 
excessive visits in addition to their normal clinical visits. Also, our study coordinator will maintain 
regular contact with each participant, reminding them of appointments. As we cannot fully 
control the timing of participants, due to the random nature of patients seeking assistance, we 
will have plans in place to stagger and/or delay surgeries for participants based on study 
progression as long as no significant impacts on clinical care are anticipated. 
5. Study Population 
We will recruit 40 participants for this study. We expect that 80% of participants will be women 
(N=32) and 20% men (N=8), as there is about a ~4:1 rate of Interstim implantation in women 
versus men [62]. Within that, we anticipate 32 Caucasian (26 women; 6 men) of which two 
women will be Hispanic, 2 African American (women), and 6 Asian American (4 women; 2 men). 
We will not decline any participants based on their group membership. Within the University of 
Michigan local Ann Arbor area, the demographics are 73% Caucasian, 14% Asian American, 

Version 7.January 12, 2022 
16 
8% African American, and 5% from other groups, which we rounded off to 15% Asian American, 
5% African American, and 80% Caucasian. We will target to have at least eight patients as 
being clinically diagnosed with detrusor underactivity (DUA), which is one of the approved 
indications for Interstim use. Dr. Gupta has previously implanted DUA patients with Interstim at 
the pudendal nerve, and inclusion of a few of these patients within the study will allow us to test 
our ability to model and stimulate their pudendal nerve along with non-DUA patients. 
 
5.1 Inclusion Criteria 
• 
Clinically referred as having bladder problems that have not responded to conservative 
treatment. Normal clinical care includes referral to implant of Medtronic Interstim 
neurostimulator at the pudendal nerve. Fully eligible to receive an Interstim implant. 
• 
Adult (18 or older), capable of providing own informed consent and communicating clearly 
with research team 
• 
Capable of speaking, reading, and understanding English, as all study questionnaires are 
standardized assessments only available in English 
• 
Capable of attending all experimental sessions (Visit 1: pre-stage-1 imaging, Visit 2: stage-1 
surgery, Visit 3: CT after stage-2 surgery, Visit 3: cystometrogram test) 
5.2 Exclusion Criteria 
• 
Implanted materials that prohibit magnetic imaging.  
• 
Any medical problems that prevent an individual from laying flat in an MRI or CT scanner, 
are are claustrophobic. 
• 
Areflexive or atonic bladder. 
• 
Pregnant or planning to become pregnant. If a woman of child-bearing potential wishes to 
participate in this study, they will be pre-screened with a test to detect pregnancy. 
• 
Diagnosed neurogenic bladder, pudendal nerve damage, lower motor dysfunction, or other 
conditions that would affect the neural circuits involved in micturition.   
• 
Unwilling to allow de-identified data to be stored for future use or shared with other 
researchers. 
6. Study Sites 
All research activities will be performed at University of Michigan Health System locations, also 
known as Michigan Medicine. All participants will be normal patients at Michigan Medicine. The 
MRI, and CT will be performed at the main hospital in Ann Arbor, or at another Michigan 
Medicine location with appropriate facilities. The stage-1 and stage-2 implant surgeries as well 
as the final visit testing will be performed at the main Ann Arbor Michigan Medicine hospital or 
another Michigan Medicine location, as scheduling permits. These sites are normal clinical 
sites for studies of this nature. Dr. Gupta has full clinical privileges at these locations, and sees 
patients across these locations. All members of the research team hold primary appoints within 
the University of Michigan Medical School. Data analysis and computational model development 
will occur at the research labs of Dr. Bruns and Dr. Lempka, which are in the University of 
Michigan North Campus Research Complex (NCRC), which is primarily filled with Michigan 
Medicine research institutes, research labs, and core facilities. NCRC is a short drive or bus ride 
from the main Michigan Medicine hospital and not far from other Michigan Medicine sites such 
as in Livonia. Drs. Bruns and Lempka regularly visit the main hospital for meetings with the 
study team and other clinical collaborators. 

Version 7.January 12, 2022 
17 
7. Informed Consent 
Full, written consent will be obtained by Dr. Gupta while the patient is in clinic or by the study 
coordinator. In the instance consent is obtained by the study coordinator, the research team will 
adopt an optional electronic informed consent procedure using SignNow. This option will be our 
preferred method for obtaining consent. Once Dr. Gupta identifies an eligible participant, if 
consent is not obtained while the patient is in clinic, Dr. Gupta will notify the study coordinator 
who will reach out to the participant over the telephone to discuss the study and obtain consent 
with the patient over the phone using SignNow. The consent form will be read to the participant 
and time will be allowed for questions or if the patient would like to read/review the consent form 
on their own.  
In the instance a potential participant does not have access to the internet or is not internet 
inclined, research staff will revert back to using the standard procedures for obtaining consent 
on paper during the MRI visit. 
8. Waiver of Informed Consent 
We are not seeking a waiver of informed consent. 
9. Confidentiality of Data 
Proper, standard procedures will be followed to protect participant identities. Patient information 
will be saved on a secure server and password protected. Experimental data will have coded 
references to each participant, and will be stored separately on a secure M-Box folder. The 
code key will be kept with the patient information. The study coordinator will have access to the 
patient information and code key. The study coordinator's office will have a locked door. Paper 
research records will be stored in a locked cabinet in the study coordinator's office. No patient-
identifying information will be shared outside the research team. 
10. Data Safety and Monitoring 
10.1 Data Safety and Monitoring Plan 
A full Data and Safety Monitoring Board will not be used for this study as it is a small study. 
Once data collection has begun, Drs. Bruns and Gupta will discuss project progression, 
participant safety, and overall data on a monthly basis via phone, email correspondence, or an 
in-person meeting. Additionally, a Medical Monitor within the Urology department will be 
identified to provide an outside council on any clinical issues that arise. Adverse Events (AEs) 
will be reported promptly to the IRB and to the Medical Monitor. If multiple patients experience 
adverse events related to research procedures, then the Medical Monitor will be consulted to 
discuss whether the study should be stopped or reassessed. If there is any evidence of a 
pattern of unanticipated AEs (regardless of causality), or Serious Adverse Events (SAEs), then 
the Medical Monitor will immediately review the data. 
All research personnel involved in any way in this project will have completed training in the 
protection of human research participants per guidelines issued by the U.S. Department of 
Health and Human Services, Office for Human Research Protection. The protocol will undergo 
review and approval by the IRBMED and other necessary regulatory and oversight entities prior 
to implementation.  
We will ask the subjects who consent to participate in the MRI procedures to sign a safety 
screening form (see attached MRI Safety Screening form) and heed safety guidelines regarding 

Version 7.January 12, 2022 
18 
appropriate clothing (removal of metal fasteners, jewelry, and any other metal objects that can 
be safely removed).  
10.2 Severity 
Drs. Gupta and Bruns will grade any Adverse Event signs and symptoms as mild, moderate, 
severe, or life threatening according to the following definitions in Table 1. 
Table 1. Adverse events severity scale. 
Grade 
Definition 
0 
None: 
No adverse event 
1 
Mild: 
Causing no limitation of usual activity with no treatment needed 
2 
Moderate: 
Causing some limitations of usual activities and resolved with 
treatment 
3 
Severe: 
Causing inability to carry out usual activities and requiring 
professional medical attention 
4 
Life Threatening: 
Patient was at immediate risk of death from the event  
5 
Fatal: 
Causing death 
 
10.3 Serious Adverse Event 
Serious Adverse Events (SAEs) will be identified as any adverse event (AE) that: 
• 
Is fatal; 
• 
Is life threatening, meaning the patient was, in the view of the investigator, at  
• 
immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction 
that, had it occurred in a more serious form or progressed, might have caused death; 
• 
Causes a persistent or significant disability or incapacity; 
• 
Requires or prolongs inpatient hospitalization. Inpatient hospitalization will be considered a 
hospitalization if is longer than 24 hours or requires an intervention to treat emergent 
symptomatology (non-diagnostic); 
• 
Is a congenital anomaly or birth defect; 
Other important medical events may be considered SAEs when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes as listed in this definition. We will report all SAEs to 
the IRBMED, including death, due to any cause which occurs during this study and until 30 days 
after the last participation in the study, whether or not expected and regardless of causality.   
10.4 Termination of Subjects 
10.4.1 Subject Decision 
Subject participation is strictly voluntary and the research strictly knowledge driven; therefore, a 
subject may withdraw from further participation in the study without penalty or harm. Any 
reason(s) the subject may give for terminating his or her participation will be kept confidential. 

Version 7.January 12, 2022 
19 
We will store the study documents according to the procedures outlined in the Confidentiality of 
Data section of this protocol (Section 9). We will require no further information of the subject and 
the subject will be compensated for their completed study visits prior to termination. 
10.4.2 Investigator Decision 
Study personnel (principal investigator, co-investigators, and study coordinator) will be 
authorized to release a subject from further study participation according to the following 
guidelines: 
• 
The researcher believes that it is not in the subject’s best interest to stay in the study. 
• 
Subject becomes ineligible to participate. 
• 
Subject’s condition changes such that he or she needs treatment that is not allowed while 
taking part in the study. 
• 
Subject does not follow instructions from the researchers. 
• 
The study is suspended or canceled. 
Upon termination of a subject, the investigators will ensure the subject is dismissed with any 
study documents to which he or she is entitled, as well as guidance for resuming medications 
safely. Subjects will be compensated for their completed study visits prior to termination. 
Investigators will require no further obligation or participation from a terminated subject. 
11. Protection of human subjects 
11.1 Potential benefits of this research  
11.1.1 Potential benefits to society 
Bladder dysfunction affects a large percentage of the population, well over 10%, leading to 
significant healthcare impacts. The knowledge gained here will provide key insights into function 
of a primary nerve in the bladder system, potentially leading to improvements in future 
technologies, and will also investigate the potential for directly controlling the bladder with 
pudendal stimulation. Direct pudendal stimulation for bladder voiding has been repeatedly 
studied in animal studies but only limited studies in humans. These patients provide an ideal 
opportunity to explore whether this preclinically validated approach has clinical merit, benefiting 
future candidates for this implant. Additionally, the use of magnetic resonance and ultrasound 
imaging technology to identify and map the nerve may help inform the healthcare treatment of 
future patients. These patients also provide an opportunity to assess whether pudendal nerve 
stimulation may offer the potential to treat stress urinary incontinence through improvements in 
urethral leak point pressure. 
11.1.2 Potential benefits to participants  
We do not expect patients to benefit directly from this study beyond the clinical care they will 
already receive. The use of MR imaging before the procedure and ultrasound and catheter 
sensors during the implant may help improve nerve targeting with the implant, thereby reducing 
surgery duration and improving outcomes, although we are not seeking to optimize the implant 
procedure and will not be testing the use of these standard clinical techniques against control 
surgeries without them. 
11.2 Risks to Human subjects 
Potential risks include release of identifying information, discomfort during imaging, physical 
harm from Magnetic Resonance Imaging if an individual has an implanted medical device that is 

Version 7.January 12, 2022 
20 
not accounted for, exposure to radiation during computed tomography scan, infection, and 
shock or burn due to electrical stimulation. 
11.2.1 Potential Risks and Protection against risks 
Participants will already be receiving the neurostimulator implant as part of their clinical care 
and thus all risks inherent to it are separate from what this study will add. 
11.2.2 Identifying information 
The primary risk of participation in this experimental study is the release of identifying 
information. The potential harm is release of research data leads to temporary embarrassment 
over the need of the patient to require treatment for bladder problems. The likelihood of this risk 
is Rare. Proper, standard procedures will be followed to protect participant identities. Patient 
information will be saved on a secure server and password protected. Experimental data will 
have coded references to each participant, and will be stored separately on a secure Box folder. 
The code key will be kept with the patient information. The study coordinator will have access to 
the patient information and code key. 
11.2.3 Magnetic resonance imaging 
The magnetic resonance imaging sequences (MRN, DTI) are not expected to add risks to 
patients. Some patients may not tolerate imaging scans, which could have a temporary 
psychosocial impact on a participant. The likelihood of this risk is Rare. As is standard in clinical 
MRI studies, these participants will be offered a dose of anxiolytic medication. If participants are 
unable to complete scans they will be removed from the study. If removed from the study, 
participants will still receive their normal clinical care for the implanted neurostimulator. MRI 
could cause significant physical harm if an individual has an implanted metal device that is not 
properly accounted for. The likelihood of this risk is Rare. All research subjects undergo a safety 
screening prior to imaging for contraindications to MRI such as metal foreign bodies and 
implanted devices (see section 44.1 for MRI safety screening form).  Subjects will be changed 
into hospital attire and given ear plugs and or headphones for hearing protection during imaging 
using a Philips 3.0T Ingenia MR scanner. The 16 channel anterior coil and 12 channel posterior 
coil combination is used to image the pelvis. The imaging will last about one hour and will not 
require a contrast injection. These imaging techniques are diagnostic tools often used as part of 
standard clinical practice. 
11.2.4 Computed tomography 
As the computed tomography (CT) scan uses radiation, it has a higher risk than magnetic 
resonance imaging. Excess radiation exposure can increase the risk of cancer. The amount of 
added radiation for this study is like being exposed to as much as 2 to 4 years’ worth of 
everyday exposure from the sun and other environmental radiation (3 mSv per year). The risk of 
cancer due to this added exposure is very small compared to the natural risk of cancer and still 
rare overall for participants due to the CT itself. As with MRI, CT scans are a common 
diagnostic tool as part of normal clinical care. 
11.2.5 Clinical catheters 
The standard urodynamic urethra and rectal catheters and manometry catheter added during 
the visit 2 stage-1 implant and the visit 4 cystometrogram testing have a risk of temporary 
infection (e.g. urinary tract infection), similar to any foreign object being placed in the body, even 
if temporarily. The likelihood of this Risk is Infrequent. Standard sterilization and handling 
techniques will be used to mitigate against the risk of urinary tract infections or other infections 

Version 7.January 12, 2022 
21 
due to placement of catheters during testing. It is also standard clinical practice for patients to 
be offered an antibiotic medication before the testing begins to mitigate against any risk of 
infection. Patients will be on standard post-operative medications for their neurostimulator 
implant, which provide relevant coverage for catheter infection risk as well. 
11.2.6 Electrical stimulation 
During the visit 2 and visit 4 testing of stimulation from the implanted stimulator, the electrical 
current may be tested over a range of amplitudes and pulse widths, providing a range of total 
charge delivered to the participant. Side effects related to higher currents, such as muscle 
contractions or discomfort, may occur, but are known to be reversible by either reducing the 
amplitude of the stimulation or stopping the stimulation entirely. Whenever using electricity to 
stimulate tissue, there is also the possibility of a shock hazard, including an electrical burn. 
However, only electrical stimulators approved by the United States Food and Drug 
Administration will be used in this study and all stimulation parameters will be within the limits of 
the stimulator. Therefore, the risk of tissue damage or electrical shock during the electrical 
stimulation is minimal. 
11.2.7 Reasonableness of risks 
The risks of study participation are minimal beyond risks that patients will already be undergoing 
as part of their normal clinical care prior to and including the implant of the neurostimulator. 
Release of personal information, risks of MR and CT imaging, and risks of infections due to 
catheter placement are all overlapping in scope and occurrence with activities that happen 
during normal clinical care of these patients. With these subject's participation, we anticipate 
greatly increasing the knowledge of a critical nerve's anatomy and ability of a 3rd line treatment 
(implantable neurostimulator) to interact with it. This study may lead to improved future 
treatments that will improve upon the treatment that patients like these are able to receive.  
12. Research Costs 
All research-specific costs will be covered by NIH award OT2OD028191 and 
 
, under direction of study investigators Tim Bruns and Priyanka Gupta. Study 
participants will not be billed for any research study procedures that are not part of their 
standard clinical care, including the visit 1 imaging, visit 2 additional clinical catheters, visit 3 CT 
imaging, and visit 4 cystometrogram. All normal clinical care procedures involved in the 
Interstim implantation at the pudendal nerve will be billed to the patient or their insurance 
provider following standard procedures. 
13. Investigational Drug 
There is no involvement of any investigational drug in this study. 
14. Investigational Device 
There is no involvement of any investigational device in this study. 
15. Marketed Drugs/Device 
The Medtronic Interstim implantable neurostimulator has no restrictions on its availability. It is 
commonly used at Michigan Medicine and worldwide for regulatory-approved implantation at a 
sacral nerve or at the off-label pudendal nerve location to be used in this study. We have 
discussed this project with the University of Michigan MICHR IND/IDE Investigator Assistance 
Program (MIAP), which provides comprehensive regulatory support to U-M investigators 

Version 7.January 12, 2022 
22 
involved in regulated clinical research. MIAP's assessment was that we are not testing the 
safety or efficacy of the device (Interstim) and do not have a control arm to our study. We are 
testing our ability to map the nerve. Thus the MIAP assessment was that there is not a 
requirement for an Investigational Device Exemption (IDE). The U-M IRB consults with MIAP 
when determining final IDE requirements. In the unlikely event that the IRB reverses this no-IDE 
assessment we will promptly work with MIAP to receive an IDE from the FDA. 
16. Additional Requirements 
16.1 Biosafety 
This research does not involve the use of infectious agents, recombinant DNA, or gene transfer. 
16.2 Point of care testing 
This research does not involve laboratory testing of the patient. 
16.3 Tissue procurement 
This research does not involve use of redundant/residual biological specimens. 
16.4 Clinical research unit 
This research does not involve the use of the Michigan Clinical Research Unit (MCRU). 
16.5 Nurse or student nurse research 
No one participating in this research study is a nurse or student nurse. 
16.6 Pregnant women and newborns 
This research does not involve laboring women and/or newborns. 
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