Effect of Peripheral Neuromodulation on Vaginal Blood Flow
Phase: NA
Conditions: Female Sexual Dysfunction, Spinal Cord Injuries
Sponsor: University of Michigan

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Study Title: Effect of peripheral neuromodulation on vaginal blood flow 
PI: Tim Bruns, PhD 
Study ID: HUM00148746 
NCT#: NCT04384172 
Protocol Version IRB Approval Date: 5/7/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Effect of peripheral neuromodulation on vaginal blood flow 
 
 
 
University of Michigan IRBMED 
Protocol HUM00148746 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
1.1 Background and Significance ......................................................................................................... 5 
1.2 Objective ............................................................................................................................................ 6 
1.3 Specific Aims ..................................................................................................................................... 6 
1.4 Primary Outcomes............................................................................................................................ 6 
1.5 Secondary Outcomes ...................................................................................................................... 6 
1.6 Investigative team ............................................................................................................................ 6 
2. Research Procedures .......................................................................................................................... 7 
2.1 Pre-study surveys ............................................................................................................................. 7 
2.2 Study visits 1 & 2 .............................................................................................................................. 7 
2.3 Pelvic function daily diaries ............................................................................................................. 8 
2.4 Patient timeline ................................................................................................................................. 9 
3. Study Statistics and Data Analysis Plan ........................................................................................ 9 
3.1 Sample size ....................................................................................................................................... 9 
3.2 Data Analysis plan............................................................................................................................ 9 
4. Study Recruitment ............................................................................................................................. 10 
5. Study Population ................................................................................................................................ 10 
5.1 Inclusion Criteria ............................................................................................................................. 10 
5.2 Exclusion Criteria............................................................................................................................ 11 
6. Study Sites ........................................................................................................................................... 12 
7. Informed Consent ............................................................................................................................... 12 
8. Waiver of Informed Consent............................................................................................................ 13 
9. Confidentiality of Data ...................................................................................................................... 13 
10. Data Safety and Monitoring ........................................................................................................... 13 
10.1 Data Safety and Monitoring Board ............................................................................................ 14 
10.2 Severity .......................................................................................................................................... 14 
10.3 Serious Adverse Event ................................................................................................................ 14 
10.4 Termination of Subjects .............................................................................................................. 14 
10.4.1 Subject Decision ................................................................................................................... 14 
10.4.2 Investigator Decision ............................................................................................................ 15 
11. Protection of human subjects ...................................................................................................... 15 
11.1 Potential benefits of this research ............................................................................................. 15 
11.1.1 Potential benefits to society ................................................................................................ 15 

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11.1.2 Potential benefits to participants ........................................................................................ 15 
11.2 Risks to Human subjects ............................................................................................................ 15 
11.2.1 Potential Risks and Protection against risks .................................................................... 15 
11.2.2 Identifying information .......................................................................................................... 15 
11.2.3 Electrical stimulation ............................................................................................................. 16 
11.2.5 Intravaginal sensor ............................................................................................................... 16 
11.2.6 History of trauma ................................................................................................................... 16 
11.2.7 Spinal cord injured participants .......................................................................................... 16 
11.2.8 Reasonableness of risks...................................................................................................... 17 
12. Research Costs ................................................................................................................................ 17 
13. Investigational Drug ........................................................................................................................ 17 
14. Investigational Device ..................................................................................................................... 17 
15. Marketed Drugs/Device .................................................................................................................. 17 
15.1 Device ............................................................................................................................................ 17 
15.2 PMA Number ................................................................................................................................ 17 
15.3 Purpose of the device .................................................................................................................. 17 
15.4 Frequency and total duration of use for an individual subject............................................... 17 
15.5 FDA classification of device........................................................................................................ 17 
15.6 How research use departs from the FDA-approved indication ............................................. 18 
15.7 Purpose of evaluation .................................................................................................................. 18 
15.8 Risk designation for device ......................................................................................................... 18 
15.9 Justify risk level and evaluate safety risk ................................................................................. 18 
15.10 Procedures for controlling device ............................................................................................ 18 
16. Additional Requirements ............................................................................................................... 18 
16.1 Biosafety ........................................................................................................................................ 18 
16.2 Point of care testing ..................................................................................................................... 18 
16.3 Tissue procurement ..................................................................................................................... 18 
16.4 Clinical research unit ................................................................................................................... 18 
16.5 Nurse or student nurse research ............................................................................................... 19 
16.6 Pregnant women and newborns ................................................................................................ 19 
REFERENCES .......................................................................................................................................... 19 
 
 
 

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1. Study Summary 
 
1.1 Background and Significance 
Female sexual health is an important determinant in quality of life, contributing to both increased 
meaning in life and general well-being [1]. Unfortunately, approximately 41% of women suffer 
from female sexual dysfunction (FSD) [2]. There are several domains that contribute to sexual 
dysfunction. Difficulty with genital arousal can arise from low activity in the nerves or blood 
vessels of the genitals. Problems with low sexual interest can stem from hyperactivity in the 
brain. Some women suffer from FSD due to neurological conditions such as spinal cord injury 
(SCI). After injury, neural connections between central sexual function neural circuits (e.g. 
desire) and peripheral sexual functions (e.g. genital arousal) are interrupted. Although not a 
factor in mortality, sexual function remains a critical component of quality of life after SCI and is 
frequently reported as a high priority for restoration [3], [4].  
 
A challenge in studying sexual function in women is the complexity of sexual arousal, which 
includes both cognitive desire and genital arousal components [5]. Overall female sexual 
function is not well understood, which contributes to the lack of good treatment options for 
dysfunction, regardless of type. Pharmaceuticals such as sildenafil (viagra) have occasionally 
been reported to improve genital arousal [6] but results are inconsistent and frequently present 
with mild to moderate side-effects [7]. There is a need for an effective treatment for women who 
have genital arousal deficiencies without concurrent side-effects. The ultimate goal of this 
research is to provide improvement in genital sexual arousal for women FSD due to either 
neurogenic (i.e. SCI) or non-neurogenic causes. 
 
One treatment avenue is the use of electrical stimulation on targeted nervous system pathways. 
Sacral neuromodulation (SNM) and percutaneous tibial nerve stimulation (PTNS) are common 
third-line treatments for irregularities in pelvic organ function, such as bladder incontinence, and 
have been used for decades [8]. Some patients undergoing SNM or PTNS to improve bladder 
function have also reported an improvement in their sexual health as an additional benefit [9]. 
This is not entirely unexpected, as organs of the pelvic floor share common nerve pathways and 
spinal circuits [10]. For example, the sacral root targeted by SNM gives rise to the pudendal 
nerve, of which a distal branch is the genital nerve. Each has been a target for electrical 
stimulation to treat bladder problems and may also be a treatment option for FSD. This neuro-
functional overlap gives reason to believe that the nerves that innervate the organs associated 
with genital arousal and that have been previously targeted in bladder neuromodulatory studies 
are a viable treatment option for women with genital arousal deficiencies. 
 
In order to explore the potential for electrical stimulation to modulate genital arousal, our lab has 
started a research focus of examining peripheral nerve stimulation to address female sexual 
dysfunction, targeting pudendal and tibial nerve pathways [11]–[14]. In animal studies we have 
shown that tibial and genital nerve stimulation can lead to increases in vaginal blood flow [11], 
[12], which is an indicator of sexual arousal [15]. A human subjects study from our group 
(HUM00101713) focused on non-neurogenic subjects with FSD and showed that stimulating the 
posterior tibial and dorsal genital nerves repeatedly across twelve weekly sessions are feasible 
approaches for improving sexual function based on improvements in clinically validated surveys 
[13]. The mechanisms that underlie this clinical effect, such as whether the applied nerve 
stimulation increases vaginal blood flow in women, are still largely unknown. This study aims to 
address this gap, to study the short-term effect of stimulation on vaginal blood flow. The 
inclusion of healthy women and non-neurogenic women with FSD will also provide information 
about the underlying neural circuitry, based on whether either stimulation approach has better 

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efficacy in spinal intact or damaged participants. While genital nerve stimulation is generally 
successful at improving bladder function in individuals with SCI, tibial nerve stimulation has had 
mixed results. These findings by other researchers suggest potential outcomes for our different 
study groups.  
 
1.2 Objective 
The overall purpose of this research is to improve sexual function in women with sexual 
dysfunction. The goal of this study is to see if either of two nerve stimulation interventions cause 
a short-term change in vaginal blood flow. The effect of this intervention will be compared 
between women who have neurogenic (spinal cord injury) or non-neurogenic dysfunction and 
healthy women, to reveal mechanisms underlying neural control over vaginal blood flow. 
 
1.3 Specific Aims 
The aims of this study are to: 
• 
Aim 1: Compare the effect of skin-surface genital nerve stimulation and tibial nerve 
stimulation on vaginal blood flow in women with spinal cord injury caused neurogenic 
sexual dysfunction. 
• 
Aim 2: Compare the effect of skin-surface genital nerve stimulation and tibial nerve 
stimulation on vaginal blood flow in women with non-neurogenic female sexual 
dysfunction. 
• 
Aim 3: Compare the effect of skin-surface genital nerve stimulation and tibial nerve 
stimulation on vaginal blood flow in neurologically-intact women without sexual 
dysfunction. 
1.4 Primary Outcomes 
The primary outcome measure in this study is the maximum change in VPA from the average 
baseline value for each stimulation location across each stimulation participant group. To 
determine if participant type, stimulation location, and stimulation interval (i.e. timing within 
stimulation duration) has an effect on VPA, an ANOVA will be performed.  
1.5 Secondary Outcomes 
The secondary outcome measures will be the change in heart rate, blood pressure, and 
subjective arousal from baseline for each stimulation location and participant group. 
1.6 Investigative team 
Dr. Tim Bruns is an Associate Professor in the Biomedical Engineering Department. He leads a 
research lab that develops interfaces with the peripheral nervous system to restore function. He 
is an expert on the use of electrical stimulation to activate spinal circuits to control pelvic organs. 
During his doctoral and postdoctoral training, Dr. Bruns participated in human subjects research 
studies with spinal cord injured subjects and individuals undergoing spine surgery to examine 
nerve stimulation approaches to control bladder function and develop new nerve electrodes. At 
Michigan, Dr. Bruns was PI on HUM00101713, which studied the use of skin-surface electrical 
stimulation to improve sexual function in women with sexual dysfunction. 
 
Dr. Priyanka Gupta is a Urologic Surgeon specializing in the diagnosis and management of 
voiding dysfunction and pelvic floor disorders. She completed a fellowship in Female Pelvic 
Medicine and Reconstructive Surgery at Beaumont Health in Royal Oak, Michigan. During her 
fellowship she gained additional expertise in the surgical management of pelvic organ prolapse, 
urinary incontinence, and the use of neuromodulation and robotic technology. Dr. Gupta’s 
clinical practice includes both the surgical and non-operative management of pelvic organ 
prolapse, incontinence, pelvic pain, voiding dysfunction, and pelvic floor disorders. Dr. Gupta’s 

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research interests include outcomes of pelvic organ prolapse treatments and neuromodulation, 
and surgical education in the developing world. 
 
Dr. Gianna Rodriguez is an Associate Professor of Physical Medicine and Rehabilitation. Her 
clinical practice primarily revolves around evaluation and management of men and women with 
spinal cord injuries (SCI) and disorders. Dr. Rodriguez has a particular interest in pelvic organ 
function, studying bladder and bowel care management practices by patients in this community 
and has a strong history of working with urologists at the University of Michigan. 
 
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 
Prior to the first visit, participants will complete five clinically validated surveys: 
1 
The American Urological Association Symptom Index (AUASI) bladder symptom index 
[16] 
2 
The Female Sexual Function Index (FSFI) [17] 
3 
Fecal Incontinence Severity Index (FISI) [18] 
4 
Patient Assessment of Constipation-Symptoms (PAC-SYM) [19] 
5 
The short-form (SF-36) quality of life survey [20], [21] 
 
Surveys will be completed over the phone or online in REDCap, a standard clinical tool for 
survey data collection [22]. Each survey is included in section 29.1.  
 
2.2 Study visits 1 & 2 
The same steps will be followed for all three Aims. Participants will have two study visits. The 
interval between visits will be at least one month but not more than five months.  
On each study day, subjects will complete a urine pregnancy test. Next, subjects will recline in a 
comfortable position on an elevated table, with pillows and blankets provided if desired. An 
MCRU staff member will be available to provide assistance, if needed, in addition to one or 
more clinical research team members. A vaginal plethysmography transducer (Biopac TSD204) 
will be inserted about 3 inches into the patient’s vagina by a clinical staff member. Additionally, 
the transducer measures vaginal pulse amplitude (VPA), 
the standard clinical technique for assessing genital 
sexual arousal in women [5], [23]–[25]. No energy is 
transmitted from the TSD204 to the participant. A heart 
rate monitor (e.g. electrocardiogram or pulse oximetry) 
and blood pressure monitor will be placed on the 
participant's arm, hand, or chest (as is appropriate per 
monitor) to monitor off-target autonomic responses. 
 
On the first study day, one of the two stimulation 
approaches will be randomly selected and prepared. For 
dorsal genital nerve stimulation, two circular 1.25-inch 
diameter transcutaneous electrical stimulation (TENS) 
electrodes (ValuTrode Fabric CF3200 or equivalent) will 
be placed on either lateral side of the clitoris (Figure 1). 
For tibial nerve stimulation, the two electrodes will be 
 
Figure 1. Electrode locations (red 
dots) for genital nerve stimulation, 
on either side of the clitoris. 

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placed just above the medial malleolus and 
the ipsilateral calcaneus on one leg (Figure 2). 
The placement of TENS device will be 
performed clinical study team members, 
specifically Dr. Priyanka Gupta, Alyssa 
Gracely, Gianna Rodriguez, or Giulia Lane. 
Each clinical study team member is a 
practicing MD physician trained in the use of 
neuromodulation including technology such as 
this. The conductivity of the electrodes may be 
tested with an impedance meter (Digitimer 
D175), which is connected to an electrode set 
and uses very low, imperceptible current 
levels. If the meter indicates poor conductivity, 
the electrodes may be repositioned. Prior to starting stimulation with a TENS device (Empi 
Select, or similar), the stimulation amplitude will be determined. The current will be increased 
until the participant expresses discomfort and then reduced to a comfortable level, or a 
maximum level of 60 mA is reached. During stimulation, the set stimulation amplitude will be 
applied at a frequency of 20 Hz, which is standard for PTNS and the frequency we used in our 
previous human subjects’ study (HUM00101713). Participants will have a 5-minute baseline 
VPA recording period followed by 20 minutes of electrical stimulation through the electrode pair. 
A 5-minute recovery period will end the VPA recording.  
Prior to placement of the VPA probe and following the 5-minute baseline recording, 20-minute 
stimulation session, and 5-minute recovery period 
participants will be asked to verbally report their 
agreement with the statement, “I feel sexually aroused 
(e.g. sexually excited, turned on) right now,” according 
to a 5-point Likert scale: (1) strongly disagree, (2) 
disagree, (3) neutral, (4) agree, and (5) strongly agree. 
At the end of each session participants will be asked 
their general opinions of that stimulation session, 
whether it seemed to elicit any genital arousal 
responses such as lubrication, warmth, tingling, or any 
sensations they would characterize as pleasurable, 
and whether they would consider further use of it. 
At the second study day, stimulation using the same 
steps will be performed at the other location.  
 
2.3 Pelvic function daily diaries 
To look for off-target or carry-over stimulation effects, 
participants will be asked to complete a daily bladder, 
bowel, and sexual function diary from two days before 
until two days after a session, to provide objective 
measures across several parameters (e.g. 
incontinence episodes, regularity). The full diary is in 
section 44.1. Figure 3 shows the daily questions. 
Surveys will be completed in REDCap or over the 
phone. 
 
Figure 2. Electrode locations (white circles) 
for tibial nerve stimulation near the ankle. 
Figure 3. Pelvic function daily diary 
questions 

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2.4 Patient timeline 
Research Activity timetable summary: 
1. Consent 
2. Pre-session surveys 
3. Study visit 1:  
Days 1 & 2: At-home diary 
Day 3: Test session and diary  
Days 4 & 5: At-home diary 
4. Interval of one to five months 
5. Study visit 2:  
Days 1 & 2: At-home diary.  
Day 3: Test session and diary  
Days 4 & 5: At-home diary 
 
Figure 4 provides a visual summary of the timeline for each study participant. 
 
3. Study Statistics and Data Analysis Plan 
 
3.1 Sample size 
The target population size (N=40) is based on intended recruitment of 40 women; 10 normal 
women (e.g. without SCI nor FSD), 10 non-SCI women with FSD, and 20 women with SCI. 
Efforts will be made to recruit equal numbers between AIS A SCI and AIS B-C SCI participants, 
but it may be challenging to get exactly 10 in each SCI group. The AIS A SCI and AIS B-C SCI 
is based on the International Standards for Neurological Classification of Spinal Cord Injury. AIS 
A SCI refers to complete, no sensory or motor function SCI, while AIS B-C SCI refers to 
incomplete SCI (e.g. sensory but not motor function is preserved). This is a pilot study with no 
comparable studies for identifying an effect size and performing a power analysis. If we 
determine that a larger population size is needed for any participant groups, based on 
preliminary data analyses, then the target group size will be increased. 
 
3.2 Data Analysis plan 
VPA will undergo optimization, filtration, and a spectral analysis as in [11], [12], [15]. The 
change in VPA from the average baseline value will be determine for each stimulation at four-
 
Figure 4. Timeline summary for each participant. 

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minute intervals, during which stimulation is paused for ten seconds. Although VPA will be 
recorded continuously, the genital nerve stimulation may cause a motion artifact and so equal 
pauses in stimuli will be used in each interval for both stimulation approaches. We may 
eliminate this pause if data analysis indicates that there are no artifacts or that filtration and 
spectral analysis eliminates artifacts. Similar calculations may be done for the heart rate and 
blood pressure. An ANOVA will be performed to determine whether participant type, stimulation 
location, and stimulation interval (i.e. timing within stimulation duration) has an effect on VPA. 
Wilcoxon signed rank tests will be used to test for differences within the groups. Similarly, 
changes in cardiovascular parameters will be assessed, to see if general autonomic responses 
are triggered with either stimulation location or patient group. We will also look for correlations 
between the pre-session survey scores (e.g. FSFI total score), patient demographics (e.g. age, 
BMI), and changes in items (e.g. decrease in incontinence events) with the maximal VPA 
responses with a regression analysis. 
 
4. Study Recruitment 
This study addresses a potentially sensitive topic. During the recruitment and consenting 
processes, all study activities will be carefully explained with particular attention to matters of 
privacy and confidentiality. Many women with spinal cord injury (SCI) have had negative 
healthcare experiences with respect to reproductive health. Alternatively, grateful patients can 
feel compelled to participate out of a sense of loyalty. As such, for recruitment and consenting 
processes, we will emphasize that participation is entirely voluntary, and refusal or withdrawal 
will have no effect on any care they receive.  
 
SCI participants will primarily be recruited through direct interactions with clinicians on the study 
team, Drs. Rodriguez and Gupta, in their clinical practice. We will also seek referrals from 
clinical colleagues who work with SCI women. Additionally, colleagues of Dr. Gupta and Dr. 
Rodriguez may distribute or post the study flyer in their urogynecology or SCI clinics. Women 
with female sexual dysfunction (FSD) may also be recruited from urogynecology or sexual 
health clinics run by a member of the study team or a colleague. If this occurs, these colleagues 
will have a general understanding of the study and will refer any patient questions to study 
investigators or the study coordinator. We will place flyers in relevant Physical Medicine & 
Rehabilitation, Urology, and Obstetrics & Gynecology clinics. We will also advertise the study on 
an online University of Michigan health research portal (umhealthresearch.org). Additionally, we 
will place flyers at several clinics outside of the UM healthcare system in Southeast Michigan, 
specifically, Detroit Medical Center/Wayne State, PM& R/Novi Rehab Institute of Michigan) and 
John D. Dingell VA Medical Center. Furthermore, this study will recruit via social media 
platforms (Facebook and Instagram). The study will be advertised via these social media 
platforms and direct interested people to the umhealthresearch.org website. 
 
 
Non-SCI participants will be primarily recruited through the online health portal and we will place 
flyers in Obstetrics & Gynecology clinics, particularly Dr. Gupta's clinics.   
 
5. Study Population 
 
5.1 Inclusion Criteria 
• 
All participants will need internet access to complete the initial surveys and the diaries. 
 
Non-dysfunction participants  
Inclusion criteria: 

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• 
Adult (over 18 years old) cis-gender female 
• 
Neurologically stable 
• 
Sexually active at least once per month 
• 
Able to understand consent and communicate effectively with research team 
 
Non-SCI dysfunction participants 
Inclusion criteria: 
• 
Adult (over 18 years old) cis-gender female 
• 
Neurologically stable 
• 
Sexually active at least once per month 
• 
Sexual dysfunction, per short-form FSFI score below 19 
• 
Lubrication difficulties, per short-form FSFI lubrication subdomain score below or equal 
to 3  
• 
Able to understand consent and communicate effectively with research team 
 
Spinal cord injured participants 
Inclusion criteria: 
• 
Adult (over 18 years old) cis-gender women 
• 
Clinically diagnosed spinal cord injury (AIS A-C) at level within T6-S1 at least six months 
prior 
• 
Nominally sexually active, but at minimum interest in sexual pleasure even if fully self-
induced 
• 
Sexual dysfunction, per short-form FSFI score below 19 
• 
Able to understand consent and communicate effectively with research team 
 
5.2 Exclusion Criteria 
Non-dysfunction participants  
Exclusion criteria: 
• 
Male 
• 
Pregnancy or planning to become pregnant during study period 
• 
Sexual dysfunction, per short-form FSFI score below 19 
• 
Lubrication difficulties, per short-form FSFI lubrication subdomain score below or equal 
to 4 
• 
Clinically diagnosed bladder dysfunction, pelvic pain, or other pelvic organ symptoms 
• 
Suspected or diagnosed epilepsy 
• 
Previous pelvic surgery 
• 
Active sepsis or active pressure sores in the pelvic region 
• 
Experience with electrical stimulation for bladder or sexual problems 
• 
Recent use of TENS on pelvis, back, or legs 
• 
Implanted pacemaker, defibrillator, spinal cord stimulator, or other nerve stimulator 
• 
Currently taking any experimental drug 
• 
Currently has or tested positive in the last 14 days for COVID-19 or is symptomatic for 
COVID-19. 
 
Non-SCI dysfunction participants  
Exclusion criteria: 

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• 
Male 
• 
Pregnancy or planning to become pregnant during study period 
• 
Clinically diagnosed bladder dysfunction, pelvic pain, or other pelvic organ symptoms 
• 
Suspected or diagnosed epilepsy 
• 
Previous pelvic surgery 
• 
Active sepsis or active pressure sores in the pelvic region 
• 
Experience with electrical stimulation for bladder or sexual problems 
• 
Recent use of TENS on pelvis, back, or legs 
• 
Implanted pacemaker, defibrillator, spinal cord stimulator, or other nerve stimulator 
• 
Currently taking any experimental drug 
• 
Currently has or tested positive in the last 14 days for COVID-19 or is symptomatic for 
COVID-19. 
 
 
Spinal cord injured participants 
Exclusion criteria: 
• 
Male 
• 
Spinal cord injury at or above T6 level (C1-T5) 
• 
Spinal cord injury at or below S1 level 
• 
Reported change in motor or sensory function in the last month 
• 
Diagnosed lower motor neuron syndrome or dysfunction  
• 
Suspected or diagnosed epilepsy 
• 
Lower leg spasticity 
• 
Pregnancy or planning to become pregnant during study period 
• 
Previous pelvic surgery 
• 
Active sepsis or active pressure sores in the pelvic region 
• 
Experience with electrical stimulation for bladder or sexual problems 
• 
Recent use of TENS on pelvis, back, or legs 
• 
Implanted pacemaker, defibrillator, spinal cord stimulator, or other nerve stimulator 
• 
Currently taking any experimental drug 
• 
Currently has or tested positive in the last 14 days for COVID-19 or is symptomatic for 
COVID-19. 
 
 
6. Study Sites  
All research activities will be performed at University of Michigan Health System locations, also 
known as Michigan Medicine. The two electoral stimulation sessions will be performed at MCRU 
sites at Domino’s Farms or the Cardiovascular Center in Ann Arbor. These sites are normal 
clinical sites for studies of this nature. All clinical team members have full clinical privileges at 
both locations and see patients at both locations. All members of the research team hold 
primary appoints within the University of Michigan Medical School.  
 
7. Informed Consent 
We will explain the study verbally and in writing, and we will provide the informed consent form 
to the participant for review before signing. We will inform participants that the purpose of the 
study is to learn if electrical stimulation of certain peripheral nerves can affect vaginal blood 

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flow. We will also explain to each participant that there will be no expected benefit to them by 
participating in this research study. However, it is possible (although not anticipated) that during 
the stimulation session participants may experience short-term improvement in sexual function. 
Additionally, we will also explain that the knowledge gained from this research may be beneficial 
for others, society, and/or science. 
 
The research team will adopt an optional electronic informed consent procedure using SignNow. 
This option will be our preferred method for obtaining consent. Once an interested participant is 
identified, the study coordinator who will reach out to the participant over the telephone to 
discuss the study and either obtain consent or schedule a time call the participant after they 
have had a time to review the consent form. In the instance a potential participant does not have 
access to the internet or is not inclined to use the internet, research staff will revert back to 
using the standard procedure for obtaining consent on paper during the first study visit. We will 
recruit all potential and eligible subjects who can speak, read, and understand English. 
 
8. Waiver of Informed Consent  
 
We are seeking a waiver of informed consent as there are a set of surveys that get completed at 
the very beginning of the study and daily diaries for the two days prior to the first study visit. 
Subjects will be able to complete their surveys and diaries at home and at their leisure. We 
prefer that they are completed before the test session in order to ensure that their answers 
won’t be affected by the treatment and so that the time spent by the participant at that session is 
not too long. In order to do this expeditiously, it would be simplest to send them the surveys and 
diaries if they agree to take part during their initial recruitment call. This means, though, that a 
participant could be completing surveys and diaries before formally signing the consent form if 
they are not being recruited during a visit at a clinic with a study team member or if they are not 
doing electronic consent. 
 
9. Confidentiality of Data 
 
Proper, standard procedures will be followed to protect participant identities. Each subject will 
be assigned an identification number. Only this number will be used to identify subjects in any 
individual tabulation. The surveys that the patients are required to fill out as part of the study will 
also only use this identification number as the piece of identifying information. These surveys 
will only be administered and collected by the study coordinator or other research team staff. 
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. 
 
Only group data is expected to be published. If individual subject data is published, then no 
identifying information will be included. Study files will also be maintained in a secured location. 
Access to computerized data will be restricted to IRB approved study personnel and password 
authorization will be enforced. Data collection will be limited to the study investigators and 
research staff. All study personnel who have access to the data will be educated regarding the 
need to protect confidentiality and the procedure to be followed to ensure such protection. All 
staff will also be required to sign a standard medical record confidentiality agreement. 
 
10. Data Safety and Monitoring 

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10.1 Data Safety and Monitoring Board 
All research personnel involved in this study will have completed training in the protection of 
human research participants. 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. 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 the data. 
 
10.2 Severity 
The investigator 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 
Mild: 
Causing no limitation of usual activity 
Moderate: 
Causing some limitations of usual activities 
Severe: 
Causing inability to carry out usual activities 
Life Threatening: 
Patient was at immediate risk of death from the event  
 
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 
Participation is strictly voluntary, and the research is 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. 
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. 

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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 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 
This study will provide new knowledge about the effect of peripheral nerve stimulation on 
vaginal blood flow for women with intact and damaged spinal cords. These findings may lead to 
new methods of treating female sexual arousal disorder for women with and without SCI. 
 
11.1.2 Potential benefits to participants  
We do not expect participants to benefit directly from this study. It is possible the stimulation 
session may give participants short-term improvement in sexual function. Others may benefit 
from the knowledge gained from this study. Researchers may use the knowledge gained in this 
study to design treatments for sexual dysfunction. 
 
11.2 Risks to Human subjects 
Potential risks include release of identifying information, physical discomfort or pain during 
stimulation, skin irritation from gel and alcohol pad prior to electrode placement, women with 
SCI could have an increase in blood pressure (autonomic dysreflexia), infection from 
intravaginal sensors, and women with a history of trauma may feel triggered by the research 
intervention. 
 
11.2.1 Potential Risks and Protection against risks 
See sections 11.2.2 through 11.2.7 for a complete list of potential risks and protections against 
each risk. 
 
11.2.2 Identifying information 
A risk to participating in the study is an increased risk of loss of privacy. Participants personal 
information will be protected per HIPAA guidelines. Only the study coordinator will keep the 
necessary PHI (name, address) to recruit and schedule the participant session. Otherwise all 
references to each participant will be coded. Thus, only one person beyond each participant’s 
normal clinical team (for UMHS patients) will have access to their PHI. If individual subject data 
is published, then no identifying information will be included. Study files will be maintained in a 

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secure location. Access to computerized data will be restricted to IRB-approved study personnel 
and will be password protected. Data collection will be limited to the study investigators and 
study staff. All study personnel who have access to the data will be educated regarding the 
need to protect confidentiality and the procedures to follow to ensure such protection. The 
likelihood of this risk is rare. 
 
11.2.3 Electrical stimulation 
Electrical stimulation can result in pain at site of stimulation. We will keep stimulation current 
levels at or below the perception threshold, which is normally below the pain threshold. Subjects 
will be able to report any discomfort or pain associated with the stimulation and current levels 
will be decreased until the discomfort is no longer observed. The likelihood of this risk is rare to 
infrequent. 
 
11.2.4 Skin irritation 
Participants skin may be cleaned with a mild abrasive gel and an alcohol pad prior to the 
placement of electrodes. If this procedure causes discomfort and/or skin irritation, it will be 
stopped and not performed in the second visit. We anticipate the likelihood of this risk to be 
rare. 
 
11.2.5 Intravaginal sensor 
The intravaginal sensor could cause an infection if it is not properly sterilized or improper sterile 
technique is used. Vaginal sensors will be properly sterilized between each session and 
placement of the sensor will be performed by a clinical staff who is trained in sterile procedures 
such as clean intermittent catheterization. If the sensor shows any signs of damage due to 
reuse or repeated sterilizations, then it will be replaced. We will have back-up sensors on hand 
throughout the study. The sensor is specifically designed to be human use only and reused. As 
sensor placement will be guided by clinical staff who are trained in sterile methods including the 
standard clean intermittent (urethra) catheterization procedure, we expect that the likelihood of 
this risk is rare to infrequent. 
 
11.2.6 History of trauma 
Subjects with a history of trauma may feel triggered by the research intervention. To reduce the 
risk of trauma triggering, patients will be fully informed about the treatment regimen and that 
their participation is voluntary. If psychological trauma occurs, patients will be referred to our 
sexual health therapists for treatment. The likelihood of this risk is rare to infrequent. 
 
11.2.7 Spinal cord injured participants 
In spinal cord injured participants, electrical stimulation of nerves can lead to autonomic 
dysreflexia responses such as increased blood pressure that could have serious consequences 
to the subject. Risk of autonomic dysreflexia, or syndrome in which there is a sudden onset of 
excessively high blood pressure is generally limited to patients with injuries at the cervical and 
upper-thoracic levels. Thus, we are only recruiting spinal cord injured participants who have 
injuries within levels T6 to S1 (lower sacral levels excluded to avoid subjects with damage to 
pelvic spinal circuits). Additionally, we will have cardiovascular monitors (heart rate, blood 
pressure) that will be watched for any abnormal increases. The MCRU staff member and clinical 
research team member(s) present will be aware of these parameters, and will respond as 
needed by terminating stimulation, helping the subject to relax, and seeking further medical care 
if needed. Prior to the session we will ask spinal cord injured participants to try to empty their 
bladder, or if they have done it recently, to help further reduce the likelihood of autonomic 
dysreflexia. The likelihood of this risk is rare to infrequent. 
 

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11.2.8 Reasonableness of risks 
The risks of participation in the study are minimal, and if there is pain caused by the stimulation 
it can be stopped by reducing the stimulation amplitude or stopping stimulation completely. 
Autonomic dysreflexia risk will be limited based on our subject recruitment, cardiovascular vitals 
will be tracked, and clinical team members will be prepared to respond if necessary. 
Psychological discomfort can be reduced with psychological support. Infection can be treated 
with antibiotics. Study team members are fully trained on protection of human private 
information, and thus the odds of privacy loss occurring are minimally greater than the 
participant already faces while getting their normal clinical treatment. The study will provide new 
human data that has never been addressed before. This presents a significant scientific benefit 
that may lead to new treatment for a patient population that is significantly underserved. 
 
12. Research Costs 
 
All research-specific costs will be covered by research accounts overseen by the research 
team. Study participants will not be billed for any research study procedures. Participants will be 
reimbursed for each study visit and travel expenses. 
 
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 
 
15.1 Device 
Transcutaneous electrical nerve stimulator (Empi Select TENS) 
 
15.2 PMA Number 
K061650 
 
15.3 Purpose of the device 
The Empi TENS unit is used to apply electrical stimulation to the skin, to provide relief for pain 
through electrodes that accompany the unit. We will use the unit and accompanying electrodes 
to apply stimulation over cutaneous nerves that may modulate vaginal blood flow - the posterior 
tibial nerve and the dorsal genital nerve. The selection of stimulation parameters will be similar 
to normal use of the device for pain. 
 
15.4 Frequency and total duration of use for an individual subject 
The TENS device will be used once per subject, for 20 minutes of total stimulation during the 
test session. 
 
15.5 FDA classification of device 
Class 2 

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15.6 How research use departs from the FDA-approved indication 
The Empi SELECT Transcutaneous Electrical Nerve Stimulator Device is used for the 
symptomatic relief and management of chronic, intractable pain and relief of pain associated 
with arthritis. It is also used as an adjunctive treatment for post-surgical and post-trauma acute 
pain. The purpose of using the device in this study is to evaluate whether or genital nerve or 
tibial nerve stimulation will modulate autonomic neural circuits and vaginal blood flow. 
 
15.7 Purpose of evaluation 
Our goal is to determine support for a possible new indication for use of the device. 
 
15.8 Risk designation for device 
Non-significant risk 
 
15.9 Justify risk level and evaluate safety risk 
The device is not an implant. The device does not sustain human life or present a potential for 
serious health risk. The device does not have a substantial importance in diagnosing, curing, 
mitigating, or treating disease. The device is used in one short-term skin-surface stimulation 
sessions. The device applies electrical stimulation through electrodes placed on the skin. It is 
battery-powered, and thus does not have a ground-fault risk. As noted elsewhere in the 
protocol, stimulation could lead to pain or discomfort below the electrodes. This is not expected 
to be significant pain. If observed, stimulation will be reduced or terminated such that the 
discomfort ceases. Each electrode placement will be performed be study personnel familiar with 
proper use of the device. 
 
15.10 Procedures for controlling device 
The PI (Dr. Bruns) will have ultimate responsibility for receiving, labeling, storing, and 
dispensing the device. Once the study begins, study personnel will coordinate storage and use 
of the device, with oversight by Dr. Bruns. The PI or co-I Dr. Gupta will be present for initial use 
of the device, verifying that it will be done in a manner consistent with the protocol. Any use of 
the device, in a session that either does not attend, will include study team personnel that have 
been previously overseen by Dr. Bruns or co-I Dr. Gupta. Dr. Gupta has clinical experience with 
the device. After such a session, a report will be sent to Dr. Bruns verifying appropriate device 
usage. At the end of the study the device will be retained by the PI (Dr. Bruns) in their office for 
potential use in a future study. 
 
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 

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This research will involve the use of the Michigan Clinical Research Unit (MCRU) Clinical 
Support Services includes space and support of clinical personnel for each visit. MCRU has 
been consulted during the planning of this study, and a budget estimate was obtained. 
 
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 pregnant women and/or newborns. 
 
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