Repetitive Transcranial Magnetic Stimulation in Spasmodic Dysphonia
Phase: NA
Conditions: Spasmodic Dysphonia, Laryngeal Dystonia
Sponsor: University of Minnesota

Repetitive Transcranial Magnetic Stimulation in 
Spasmodic Dysphonia 
Funding Sponsor: 
Minnesota’s Discovery, Research, and InnoVation 
Economy (MnDRIVE) and Department of Rehabilitation 
Medicine, Division of Physical Therapy, University of 
Minnesota 
Study Product: 
Magstim 
2002 
and 
Magstim 
Rapid2 
Magnetic 
Stimulators 
Protocol Identifiers: 
IDE Number: Trial 
Registration: Version / 
Date:
CTgov Number: 
 
Principal Investigator:
CTSI ID 25008 
None, non-significant risk 
IRB# 1609M94001 
8/2/2017 
NCT02957942
Mo Chen
CONFIDENTIAL 
This document is confidential and the property of the University of Minnesota. No part of it may be transmitted, 
reproduced, published, or used by other persons without prior written authorization from the study sponsor. 

1 
 
Statement of Compliance 
 
This document is a protocol for a human research study. This study will be conducted according 
to US and International standards of Good Clinical Practice, applicable government regulations 
and Institutional research policies and procedures.  
 
All individuals responsible for the design and conduct of this study have completed Human 
Subjects Protection Training and are qualified to be conducting this research prior to the 
enrollment of any subjects.   
 
 
 
 
 
As Principal Investigator, I agree to conduct this clinical study in accordance with the design and 
specific provisions of this protocol. Modifications to the study are acceptable only with an 
approved protocol amendment. I agree to obtain approval from the IRB and/or regulatory bodies 
of competent jurisdiction, for the protocol and informed consent before initiating the study, to 
obtain consent from subjects prior to their enrollment in the study, to collect and record data as 
required by this protocol and case report forms, to prepare adverse event and study reports as 
required by this protocol and to maintain study documentation for the period of time required. 
 
 
___________________________________  
 
________________ 
Mo Chen, PhD 
 
 
 
 
Date 
 
As a Sub-Investigator, I agree to conduct this clinical study in accordance with the design and 
specific provisions of this protocol. Modifications to the study are acceptable only with an 
approved protocol amendment. I agree to obtain approval from the IRB and/or regulatory bodies 
of competent jurisdiction, for the protocol and informed consent before initiating the study, to 
obtain consent from subjects prior to their enrollment in the study, to collect and record data as 
required by this protocol and case report forms, to prepare adverse event and study reports as 
required by this protocol and to maintain study documentation for the period of time required. 
 
 
___________________________________  
 
_________________  
Teresa Jacobson Kimberley, PT, PhD 
 
 
Date 
 
 
___________________________________  
 
_________________  
 
 
___________________________________  
 
_________________  
Rebekah Summers, BS 
 
 
 
 
 
Date 
 
 

2 
 
Version History 
 
Version # 
Approval Date 
Significant Changes from Previous Version 
Version 1 
12/13/2016 
Original Protocol Version 
Version 2 
2/13/2017 
Change in subject compensation 
Version 3 
8/2/2017 
Change in enrollment number and change PI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

3 
 
Table of Contents 
 
Statement of Compliance 
 
 
 
 
 
 
 
 
Version History 
 
 
 
 
 
 
 
 
 
Study Summary 
 
 
 
 
 
 
 
 
 
List of Abbreviations  
 
 
 
 
 
 
 
 
1. 
Study Contact Information 
 
 
 
 
 
 
 
1.1 
Sponsor Contact Information 
 
 
 
 
 
 
1.2 
Principal Investigator Contact Information (Coordinating Center) 
 
1.3 
Sub-Investigator Contact Information (Affiliate Sites)  
 
 
2. 
Introduction 
 
 
 
 
 
 
 
 
 
2.1 
Background and Rationale 
 
 
 
 
 
 
2.2 
Device Description 
 
 
 
 
 
 
 
2.3 
Device Accountability 
 
 
 
 
 
 
 
3. 
Study Objectives 
 
 
 
 
 
 
 
 
3.1 
Primary Objective 
 
 
 
 
 
 
 
3.2 
Secondary Objectives 
 
 
 
 
 
 
 
4. 
Study Design 
 
 
 
 
 
 
 
 
 
4.1 
Overview of Study Design 
 
 
 
 
 
 
4.2 
Anticipated Duration of the Clinical Investigation 
 
 
 
4.3 
Evaluation Criteria / Effectiveness 
 
 
 
 
 
4.3.1 Primary Endpoint  
 
 
 
 
 
 
4.3.2 Secondary Endpoints 
 
 
 
 
 
 
4.4 
Study Population  
 
 
 
 
 
 
 
4.4.1 Sample Size 
 
 
 
 
 
 
 
4.4.2 Subject Recruitment 
 
 
 
 
 
 
4.4.3 Subject Screening  
 
 
 
 
 
 
4.4.4 Prior and Concomitant Therapy 
 
 
 
 
 
4.4.5 Inclusion Criteria  
 
 
 
 
 
 
4.4.6 Exclusion Criteria  
 
 
 
 
 
 
4.4.7 Exit Criteria 
 
 
 
 
 
 
 
5. 
Study Procedures 
 
 
 
 
 
 
 
 
5.1 
Informed Consent 
 
 
 
 
 
 
 
5.1.1 Informed Consent  
 
 
 
 
 
 
5.1.2 Vulnerable Populations 
 
 
 
 
 
 
5.2 
Allocation Scheme 
 
 
 
 
 
 
 
5.3 
Clinical Procedures  
 
 
 
 
 
 
 
5.4 
Follow-Up Procedures and Therapy Transitions 
 
 
 
5.5 
Study Timetable / Schedule of Events 
 
 
 
 
 
5.6 
Study Protocol Compliance / Treatment Adherence 
 
 
 
5.7 
Deviations from the Clinical Protocol 
 
 
 
 
 
5.8 
Subject Withdrawal 
 
5.8.1  How to Withdraw Subjects 
5.8.2 Data Collection and Follow-up for Withdrawn Subjects  
 
 
 

4 
 
5.9 
Subject Compensation 
 
 
 
 
 
 
 
 
6. 
Data Collection and Analysis  
 
 
 
 
 
 
6.1 
Subject Populations for Analysis 
 
 
 
 
 
6.2 
Statistical Methods 
 
 
 
 
 
 
 
7. 
Safety and Adverse Events 
 
 
 
 
 
 
 
7.1 
Definitions 
 
 
 
 
 
 
 
 
7.2 
Safety Monitoring Plan  
 
 
 
 
 
 
7.2.1 Anticipated Risks / Risk Mitigation 
 
 
 
 
7.2.2 Medical Monitoring for Participant Safety 
 
 
 
7.2.3 Study Stopping Rules 
 
 
 
 
 
 
7.3 
Anticipated Adverse Events 
 
 
 
 
 
 
7.4 
Adverse Event Reporting 
 
 
 
 
 
 
7.4.1 Adverse Events 
 
 
 
 
 
 
 
7.4.2 Serious Adverse Events 
 
 
 
 
 
 
7.4.3 Unanticipated Adverse Device Effects 
7.4.4  UPIRTSO Events 
7.5 
Data Safety Monitoring Board  
 
 
 
 
 
8. 
Data Handling and Record Keeping 
 
 
 
 
 
 
8.1 
Confidentiality 
 
 
 
 
 
 
 
 
8.2 
Source Documents 
 
 
 
 
 
 
 
8.3 
Case Report Forms 
 
 
 
 
 
 
 
8.4 
Clinical Reports  
 
 
 
 
 
 
 
8.5 
Records Retention 
 
 
 
 
 
 
 
9. 
Study Monitoring, Auditing, and Inspecting  
 
 
 
 
9.1 
Study Monitoring Plan  
 
 
 
 
 
 
9.2 
Quality Assurance Procedures 
 
 
 
 
 
 
10. 
Ethical Considerations  
 
 
 
 
 
 
 
11. 
Study Finances  
 
 
 
 
 
 
 
 
12.1 Funding Source  
 
 
 
 
 
 
 
12.2 Conflicts of Interest 
 
 
 
 
 
 
 
12. 
Publications Plan 
 
 
 
 
 
 
 
 
13. 
References 
 
 
 
 
 
 
 
 
 
14. 
Appendices and Attachments  
 
 

5 
 
Study Summary 
 
Title 
Repetitive 
Transcranial 
Magnetic 
Stimulation 
in 
Spasmodic 
Dysphonia 
Short Title 
rTMS in Spasmodic Dysphonia 
Protocol Numbers 
CTSI 25008 
Study Sponsor 
Minnesota’s Discovery, Research and InnoVation Economy, Dept. 
Rehabilitation Medicine, Division of Physical Therapy  
Principal Investigator 
Mo Chen, PhD 
Study Design 
Pilot study: 2 groups, pre/post test design 
Study Duration 
24 months 
Study Center(s) 
CTSI 
Objectives 
The overall purpose of this study is to test whether brain excitability 
can be modulated in people with spasmodic dysphonia (a neurological 
disorder affecting the vocal folds) using repetitive transcranial 
magnetic stimulation (rTMS). More specifically, the study objectives 
include: (1) Determine safety and feasibility of the proposed protocol; 
(2): Determine amount of intracortical inhibition in the laryngeal 
motor cortex as measured in the thyroarytenoid muscle both within 
and between groups, before and after rTMS; (3) Explore changes in 
voice quality following rTMS. 
Number of Subjects 
Fifty participants will be enrolled. 
Main Inclusion / 
Exclusion Criteria 
Primary inclusion for spasmodic dysphonia: 
(1) 21-75 years of age 
(2) Diagnosis of adductor spasmodic dysphonia 
(3) Symptoms at worst severity if receiving regular botulinum 
injections 
 
Primary exclusion for participants with spasmodic dysphonia:  
(1) Other forms of dystonia 
(2) Vocal fold pathology or paralysis 
(3) Diagnosis of voice tremor 
(4) Laryngeal surgery  
(5) Laryngeal cancer or neurological condition other than dystonia  
(6) Contraindication to TMS 
(7) Medications with effect on CNS 
(8) Inability to complete tasks associated with study 
(9) Adult lacking ability to consent 
 
Primary inclusion for healthy participants (controls): 
(1) 21-75 years of age 
(2) Absence of vocal fold pathology 
 
Primary exclusion for healthy participants (controls): 
(1) Any health condition or disability that would interfere with 
participation 

6 
 
(2) Contraindications to TMS  
(3) Medications with effect on CNS  
(4) Adult lacking ability to consent 
 
Study Device 
Device: Magstim 2002 and Rapid2 Magnetic Stimulators and Magstim 
BiStim Module 
Manufacturer: Magstim Company LTD, Spring Gardens 
Carmarthenshire, Whales, UK SA34OHR 
US Distributor: Jali Medical, Inc. 
500 West Cummings Park, Suite 4950 
Woburn, MA 01801 
Duration 
of 
Device 
Exposure 
Each subject will receive a 20 minute session of low-frequency rTMS 
(1Hz, 1200 pulses). Single pulse TMS testing also will be applied for 
approximately 30 min before and after rTMS. 
Reference Therapy 
None 
Endpoints 
Corticospinal excitability and voice quality will be measured before 
and after rTMS application. Self-reported voice disability also will be 
assessed. 
Statistical Methods 
Corticospinal excitability and voice quality will be examined for 
effects of rTMS and group. 
 
 
 

7 
 
List of Abbreviations 
 
AdSD  
Adductor spasmodic dysphonia 
AE 
 
Adverse Event 
BTX  
Botulinum Toxin 
CFR 
 
Code of Federal Regulations 
CRF 
 
Case Report Form 
DSMB  
Data and Safety Monitoring Board 
DSMP  
Data and Safety Monitoring Plan 
EMG  
Electromyography 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICH 
 
International Conference on Harmonization 
IRB 
 
Institutional Review Board 
PHI 
 
Protected Health Information 
rTMS  
Repetitive Transcranial Magnetic Stimulation 
SAE 
 
Serious Adverse Event 
TMS  
Transcranial Magnetic Stimulation 
UADE  
Unanticipated Adverse Device Effect  
UPIRTSO 
Unanticipated Problems Involving Risk To Subjects or Others 
 
 
 

8 
 
1.0 
Study Contact Information 
 
1.1 
Principal Investigator Contact Information 
Mo Chen, PhD 
Manager, Non-invasive Neuromodulation Laboratory, MnDRIVE Brain Conditions 
University of Minnesota 
MMC 609, 420 Delaware St. SE. Minneapolis, MN, 55455 
Phone: 612-624-5220 
Campus location: Room 247, 717 Delaware St. SE. 
 
1.2 
Sub-Investigators Contact Information  
Teresa Jacobson Kimberley, PT, PhD 
Massachusetts General Hospital Institute of Health Professions 
Charlestown Navy Yard 
36 1st Ave. 
Boston, MA, 02129  
 
   
Email: tkimberley@mgh.harvard.edu 
 
 
Rebekah Summers, BS 
Graduate Research Assistant 
Department of Physical Rehabilitation 
MM 388, 420 Church St. SE 
Minneapolis, MN, 55455 
Office Phone: 612-626-0637 
Fax: 612-625-4274 
Email: schm2203@umn.edu 
 
1.3 
Key Study Personnel 
NA 
 

9 
 
2.0 
Introduction 
 
2.1 
Background and Rationale  
Focal dystonia is a neurological movement disorder characterized by excessive involuntary 
muscle contractions of any body part, severely impairing a person’s ability to function in 
their daily life. Often patients are misdiagnosed and receive years of unnecessary treatment.  
Adductor spasmodic dysphonia (AdSD) is the primary form of laryngeal dystonia and is 
characterized by excessive contraction of intrinsic muscles in the larynx, leading to 
intermittent hyper-adduction of the true vocal folds (‘vocal cords’) during speech (Aminoff 
et al., 1978). This results in severe difficulty in speaking, hindering effective 
communication and severely reducing quality of life.  
 
The cause of AdSD is unknown and there are no treatments that produce long-term 
benefits. Neuroimaging and neurophysiology studies have suggested that AdSD and other 
focal dystonias are associated with decreased inhibition and excessive plasticity in 
sensorimotor areas in the brain (Kimberley et al., 2009; Kimberley and Pickett, 2012; 
Kimberley et al., 2013; Kimberley et al., 2015a; Samargia et al., 2016). However, to our 
knowledge, no studies have investigated the effects of modulating excitability of the 
laryngeal motor cortex in healthy individuals or AdSD. This gap in the field is likely due to 
challenges in recording corticospinal excitability of intrinsic laryngeal muscles.  
 
Dr. Kimberley’s team has developed a transcranial magnetic stimulation (TMS) method to 
assess the cortical representation and excitability of the thyroarytenoid, a muscle affected in 
AdSD. Using this method, TMS data indicate differences in inhibition in people with 
AdSD vs. healthy controls. For this pilot project, we propose to further explore this 
excitability difference by investigating the effects of low-frequency inhibitory repetitive 
TMS (rTMS) applied to the laryngeal motor cortex of individuals with AdSD and healthy 
controls. Considering that rTMS at low frequencies (≤1 Hz) produces lasting inhibition in a 
process analogous to long-term depression, and that AdSD is associated with decreased 
cortical inhibition, the purpose of this pilot study is to determine safety, feasibility and 
response to 1Hz rTMS to the laryngeal motor cortex in individuals with AdSD and healthy 
people. 
 
2.2 
Device Description 
We will utilize two Magstim 2002 devices (US FDA #K060847) with a Bistim 70-mm 
figure-eight coil. rTMS will be delivered with air-film coils (real) and a Magstim Rapid2 
device (US FDA #K051864). For data acquisition, the electrode wires will be connected to 
a bipolar electromyography (EMG) pre-amplifier (Y03, Motion Lab Systems, Inc., LA, 
USA) with the gain of x300. The EMG signal will be passed through a band-pass filter with 
the cutoff frequencies of 15Hz and 2000Hz and then digitized by an analog-to-digital 
convertor (NI 9234, National Instruments Corporation, Austin, TX, USA) with a resolution 
of 24-bits at a sampling rate of 6400Hz. 
 
Both TMS devices are used for investigational purposes and labeled with the following 
statement: CAUTION – Investigational Device. Limited by Federal law to 
investigational use. 

10 
 
 
2.3 
Device Accountability 
The device is not supplied to the subject, and will not be in the subject’s possession at any 
time.  
 
3.0 
Study Objectives 
 
3.1 
Primary Objective 
The purpose of this project is to determine safety, feasibility and response to 1Hz rTMS to 
the laryngeal motor cortex in individuals with AdSD and healthy people. The following 
Aims will be tested: 
 
Aim 1: Determine safety and feasibility for the application of 1 Hz rTMS to the laryngeal 
motor cortex. 
Hypothesis: rTMS to laryngeal motor cortex will be safe and feasible as measured by no 
serious adverse events and 100% study completion by participants. 
 
Aim 2: Determine amount of intracortical inhibition in the laryngeal motor cortex as 
measured in the thyroarytenoid both within and between groups before and after rTMS. 
Hypotheses:  
• 
The AdSD group will demonstrate less inhibition in the laryngeal motor cortex at 
baseline.  
• 
rTMS will increase intracortical inhibition for the laryngeal motor cortex in both 
groups, but AdSD individuals will show greater changes. 
• 
There will be no difference between groups at posttest suggesting a normalizing of 
intracortical inhibition.  
 
Aim 3: Explore changes in voice quality following rTMS with a blinded assessment by a 
voice expert.  
Hypothesis: Clinical scores will show a trend toward improved voice quality in people with 
AdSD. 
 
4.0 
Study Design 
 
4.1 
Overview of Study Design 
This experiment is a pilot study involving within and between group comparisons: AdSD 
compared to healthy controls, before and after rTMS delivery. Participants will be asked to 
come to the University of Minnesota for 1 session. 
 
4.2 
Anticipated Duration of the Clinical Investigation 
The study’s duration is anticipated to require 24 months from enrollment to the final report 
to the IRB.  
 
If for any reason the study is terminated prior to the completion of subject participation, 
subjects would be withdrawn in accordance with Section 5.10. 
 

11 
 
4.3 
Evaluation Criteria/Effectiveness 
 
4.3.1 Primary Endpoint 
The primary clinical endpoint will be corticospinal excitability measured with TMS 
testing before and after application of low-frequency rTMS. 
 
4.3.2 Secondary Endpoints 
Secondary endpoints will include clinical voice measures collected before and after 
rTMS procedures with a blinded assessment by a voice expert (Cara Donohue, SLP, 
and Sharyl Samargia, CCC-SLP, PhD) (Zraick et al., 2011; Samargia et al., 2016). 
In addition, self-reported voice disability will be assessed prior to rTMS delivery. 
 
4.4 
Study Population 
 
4.4.1 Sample Size 
This is the first pilot study of this kind and, therefore, no data are available for 
sample size calculation. Data from this pilot study will be used for effect size 
calculations for future investigations. 
 
We plan to enroll 40 subjects (20 people with AdSD and 20 healthy controls). Due to 
the voluntary nature of our recruitment efforts, we expect a small number to dropout 
or fail screening qualifications. To ensure the needed number of enrollees, 50 
subjects have been requested to be recruited in our IRB application. 
 
Due to no direct benefit from participation, children will be excluded from this 
study. 
 
4.4.2 Subject Recruitment  
Healthy participants: Subjects will be recruited from the general public. University 
and local community advertisement will be made. Subjects will then self-identify if 
interested to learn more about the study. 
 
Spasmodic dysphonia participants: Subjects will be recruited from several sources: 
1. People with AdSD who have directly contacted Dr. Teresa Kimberley about 
research opportunities and patients that have participated in other studies from 
our team will be inquired if they are interested in this new pilot project. Study 
staff will contact only those who have given permission to be contacted about 
future studies. 
2. Dr. George Goding will ask his patient’s that have AdSD if they are interested in 
hearing more about a study they may qualify for and if so will give him/her a 
flyer or direct him/her to talk to other study staff to learn more.  
3. University and local community advertisement will be made. Postings also will 
be made on support group websites and organizations for dystonia. Subjects will 
then self-identify if interested to learn more about the study. 
 
 

12 
 
4.4.3 Subject Screening  
Subjects will be screened by co-investigators using a list of exclusion criteria in 
person, by email or by phone. Screening questions include all inclusion and 
exclusion criteria. The maximum allowable time between screening and participation 
will be limited to the duration of the study. Prior to the start of the session, an on-site 
screening form will also be completed to ensure appropriate qualification. Females 
who could potentially be pregnant will be offered a pregnancy test at the CTSI and, 
if positive, they will not be allowed to participate. If they refuse testing as they are 
certain there is no risk they are pregnant, they will sign a waiver to clarify and be 
allowed to participate. 
 
4.4.4 Prior and Concomitant Therapy 
The risk of seizures is acknowledged but we emphasize that because of standards set 
for rTMS (Rossi et al., 2009; Rossini et al., 2015) this risk has been very well 
contained. Particularly due to our low rate stimulation and exclusion criteria we have 
minimized risk to participants. Our rTMS parameters are well within these safety 
guidelines (Rossi et al., 2009; Rossini et al., 2015). However, we still recognize that 
this remote risk requires a rigorous safety plan. We will ask subjects if they have any 
other medical conditions and if they are taking any medications. Important 
medication information such as any pro-epileptic medications and any history of 
seizure will be collected to screen those at risk for a TMS-induced seizure. Subjects 
will also be screened for previous surgeries that might include metal, indwelling 
medical devices, etc. In the event of a seizure during rTMS, subjects may be given 
oxygen by nasal cannula and, if the seizure does not abate in the expected time 
frame, the on-call physician may administer lorazepam or a related medication to 
interrupt the seizure. In the event of a headache from rTMS treatment, subjects may 
be given acetaminophen. See Brain Plasticity Lab white paper on TMS safety 
(attached). 
 
Patients with AdSD who are currently receiving botulinum toxin injections will be 
asked about the duration between shots and scheduled to participate when their 
symptoms are reported to be the worst. This will typically be within 1 week of their 
regularly scheduled injections. 
 
4.4.5 Inclusion Criteria  
 
 
        
Subjects will be eligible to participate in the study if all of the following conditions 
exist: 
 
Primary inclusion for spasmodic dysphonia: 
(1) 21-75 years of age 
(2) Diagnosis of adductor spasmodic dysphonia (AdSD) 
(3) Symptoms at worst severity if receiving regular botulinum injections 
 
Primary inclusion for healthy participants (controls): 
(1) 21-75 years of age 
(2) Absence of vocal fold pathology 

13 
 
 
4.4.6 Exclusion Criteria 
Subjects will be excluded from participation in the study if any of the following 
conditions exist: 
 
Primary exclusion for participants with spasmodic dysphonia:  
(1) Other forms of dystonia 
(2) Vocal fold pathology or paralysis 
(3) Diagnosis of voice tremor 
(4) Laryngeal surgery  
(5) Laryngeal cancer or neurological condition other than dystonia  
(6) Contraindication to TMS* 
(7) Medications with effect on CNS 
(8) Inability to complete tasks associated with study 
(9) Adult lacking ability to consent 
 
Primary exclusion for healthy participants (controls): 
(1) Any health condition or disability that would interfere with participation 
(2) Contraindications to TMS*  
(3) Medications with effect on CNS  
(4) Adult lacking ability to consent 
 
*TMS contraindications: 
(1) The only absolute contraindication to TMS/rTMS is the presence of metallic 
hardware in close contact to the discharging coil (such as cochlear implants, deep 
brain stimulator, or medication pumps). In such instances there is a risk of 
inducing malfunctioning of the implanted devices. 
(2) Conditions classified as of increased or uncertain risk are listed below (Rossi et 
al., 2009; Rossini et al., 2015). Persons under those circumstances will be 
excluded from the study.  
a. Pregnancy 
b. Bipolar disorder 
c. Epilepsy or history of seizure episodes in the past two years 
d. Vascular, traumatic, tumoral, infectious, or metabolic lesion of the 
brain, even without history of seizure, and without anticonvulsant 
medication 
e. Use of medications that potentially lower seizure threshold 
f. Severe or recent heart disease 
(3) There is a small risk of fainting and hearing impairment with TMS/rTMS. For 
these reasons, the following precautions will be taken:  
a. Fainting: To avoid fainting, we will ask subjects to eat a full meal and 
drink extra decaffeinated fluids before study visits. We will also 
apply TMS and rTMS in a reclining chair.  
b. Hearing impairment: Participants will wear earplugs during the 
experiment to avoid hearing damage. 
 

14 
 
Additional information about risks and precautions for TMS/rTMS are included in 
the IRB protocol (Section 3). 
 
4.4.7 Exit/Discontinuation Criteria 
Subjects will exit the study if any of the following conditions exist: 
1. Subject voluntarily withdraws from the study. 
2. Subject death. 
3. Subject acquires any of the listed exclusion criteria. 
4. Subject completes the protocol. 
5. Subject’s wellbeing, in the opinion of the Investigator would be compromised 
by study continuation. 
6. Subject experiences an adverse event such as seizure. 
7. DSMB and/or IRB recommendation 
 
5.0 
Study Procedures 
 
5.1 
Informed Consent 
 
 
 
 
 
            
5.1.1 
Informed Consent  
All potential participants will receive a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about 
their participation in the study. Please see consent form for specific wording that is 
tailored for each participant category: spasmodic dysphonia or healthy participant. 
 
The consent form will be submitted with the protocol for review and will only be 
used once approval by the IRB for the study is given. The formal consent of a 
subject, using the IRB-approved consent form, will be obtained before that subject is 
submitted to any study procedure. This consent form will be signed by the subject 
and the investigator-designated research professional obtaining the consent. A copy 
of the IRB-approved consent form will be kept on-site and by the sponsor-
investigator. 
 
5.1.2 
Vulnerable Populations 
 
 
 
 
No vulnerable populations are included.  
 
5.2 
Allocation Scheme 
Individuals will be assigned to each group based on their diagnosis and symptoms. 
All subjects will be assigned to the same procedures. 
 
5.3 
Clinical Procedures 
Clinical assessment: Voice measures consisting of standard and published clinical 
scales will be collected for all participants to explore changes in voice quality 
(Zraick et al., 2011; Samargia et al., 2016). Voice quality will be measured by 
asking subjects to repeat 10 sentences with a high number of initial adductor 
phonemes, which often elicit symptoms in those with AdSD. These voice samples 
will be acquired digitally using a microphone. The frequency of voice breaks in the 

15 
 
recorded 10 sentences will be counted. These voice breaks will be the measure of 
disease severity. Other voice characteristics will be assessed using the Consensus 
Auditory-Perceptual Evaluation of Voice (CAPE-V) and the Voice Handicap Index 
(VHI). The CAPE-V is a reliable, valid clinical measure used by voice experts to 
assess voice quality. During a video recording, participants will be asked to repeat 6 
sentences and then describe their voice problems. Voice experts will use the 
recording to rate voice quality based on several criteria (loudness, pitch, strain, 
breathiness, roughness, overall severity and others). In the current study, the total 
score in this scale will be used to rate the voice quality of participants before and 
after rTMS. The VHI is a self-administered questionnaire with questions about how 
often a given voice-related problem affects the life of participants. It reliably 
measures the influence of the subjects’ voice disorder on their quality of life across 
three dimensions including: physical, functional and social. The total score for each 
participant will be measured before rTMS to assess how the voice disorder affects 
quality of life. 
 
TMS testing: TMS testing will be performed to measure the corticospinal 
excitability before and after rTMS. TMS testing will be completed according to 
established methods (Kimberley and Di Fabio, 2010; Samargia et al., 2014; 
Kimberley et al., 2015a; Kimberley et al., 2015b). Single and paired-pulse TMS 
testing will be delivered with a 70-mm figure-of-eight coil connected to a Magstim 
200 stimulator (Magstim Company, Dyfed, UK), positioned on the scalp area over 
the left primary motor cortex. The laryngeal motor cortex will be identified by 
measuring the motor evoked potentials (MEP) of the thyroarytenoid muscle. Cortical 
stimulation will be spatially tracked with a neuronavigation system (BrainSight, 
Rogue Research Inc. Quebec, Canada) to decrease variability of stimulus delivery.  
 
The TMS variables that will be measured in the study include single pulses that 
evoke a response in the muscle. The variable of interest is the amplitude of motor 
evoked potential (MEP) in response to different stimulation intensities and duration 
of silent period after the evoked response. Testing will include no more than 200 
pulses (rTMS delivery will involve 1200 pulses — see below). Overall, the testing 
procedures will take approximately 60 minutes (30 minutes before and 30 after 
rTMS). 
 
Fine-wire electrodes: All participants will undergo vocal muscle testing using fine-
wire EMG. With the subject seated in a supportive chair, fine-wire EMG electrodes 
will be inserted in the thyroarytenoid muscles (the “vocal cords”) by a trained 
physician, Dr. Goding. The skin on the throat will be numbed using a lidocaine 
cream and also an injection of a lidocaine (numbing) agent. Once the skin has been 
numbed, the electrode will be placed into the muscle. To place the electrode, two 
fine wires will be inserted using a small gauge needle (30MM, 27 guage) with the 
edges of the wire electrode hooked around the tip of the needle and connected to an 
EMG machine. The needle will be passed through the skin and into the larynx. When 
the vocal cord is entered, an increased EMG signal associated with speech is 
detected. The needle will then be removed, leaving only the flexible wires in place. 

16 
 
Once the needle is removed, participants will not feel the presence of the electrode. 
Participants will be able to breath, talk and move their head with the electrode in 
place. At the end of the testing for vocal muscles, the electrodes will be gently pulled 
out. This process is nearly unnoticeable due to the very small diameter of the wires. 
Procedures will be the same as previous study (IRB # 0608M91226. Study Title 
“Pathophysiology of Spasmodic dysphonia: a TMS study”). 
 
rTMS application: rTMS will be delivered to the left laryngeal motor cortex with a 
hand-held figure-of-eight coil positioned over the scalp and connected to a Rapid2 
magnetic stimulator (Magstim Company, Dyfed, UK). The protocol described below 
is FDA approved and has been used extensively by our lab without incident. The risk 
of seizure is minimized by using a low rate of stimulation and a sub-threshold level 
of intensity. 
 
All participants will receive low-frequency rTMS pulses. rTMS at a low frequency is 
known to be inhibitory to the neurons receiving the stimulation. rTMS will be 
delivered at 90% of the threshold which elicits MEPs in the thyroarytenoid muscle, 
as determined during TMS testing. Pulses will be delivered at a frequency of 1 Hz 
without interruption (total = 1200 pulses) which has been shown to alter cortical 
excitability and behavior (Gerschlager et al., 2001). rTMS delivery will take 20-30 
minutes. During the stimulation, the subject will only feel a slight tapping sensation 
on the head due to the repetitive discharging of the cutaneous nerves in the scalp. 
After stimulation, corticospinal excitability and voice quality will be measured. 
 
Because the purpose of this study is to collect preliminary data for feasibility and 
safety, sham rTMS will not be tested. 
 
5.4 
Follow-Up Procedures and Therapy Transitions 
There are no follow-up procedures or therapy transitions. Subjects receiving 
botulinum toxin will be allowed to continue with injections as they desire. 
 
 
5.5 
Study Timetable / Schedule of Events  
Pre-screening of all participants will be completed by phone, email or in person. 
Onsite testing will include answering to study questionnaires, voice quality 
assessments, completing TMS tests, and the rTMS protocol. Testing will occur prior 
to botulinum toxin injection for those patients with AdSD currently being treated 
with the toxin. Data will be collect when symptoms are at their worst according to 
the patient’s self-report. However, due to the demanding time commitment placed on 
participants, flexibility will be allowed to modify the schedule if needed. Botulinum 
toxin injections will be administered by each participant’s physician and the costs 
associated with injection will not be covered by the study. 
 
 

17 
 
 
Experiment schedule 
Pre-screening 
Study visit 
Review consent form Consent and HIPAA 
Medical history 
On-site screening 
Eligibility 
Report of symptoms 
 
Clinical assessment, voice quality and disability 
 
Corticospinal excitability (TMS pre-tests) 
 
20 min of rTMS 
 
Voice quality assessment 
 
Corticospinal excitability (TMS post-tests) 
 
Report of symptoms 
 
5.6 
Study Protocol Compliance / Treatment Adherence 
Subjects will be notified of the voluntary nature of participation. In the consent 
forms, subjects are made aware of the resources for those who wish to withdraw 
from the study. Criteria and procedures for withdrawing subjects are noncompliance 
and disqualification by previously outlined criteria, such as a developed neurological 
disease, implanted device, or pregnancy. See section 5.8 for more detail. Refer to 
section 5.8 for subject withdrawal and replacement.  
 
5.7 
Deviations from the Clinical Protocol 
When a deviation from the protocol is necessary for an individual subject, the 
investigator will complete a description of the deviation from the protocol and 
justification on the Protocol Deviation Form.  
 
5.8 
Subject Withdrawal 
 
5.8.1 How to Withdraw Subjects 
Subjects may be withdrawn from the study for the following reasons: 
o occurrence of intolerable pain or discomfort during testing 
o failure to attend scheduled testing or treatment sessions 
o subject consent withdrawal 
 
In the event of subject withdrawal, all collected data and personal information will 
be documented and kept private. If a subject is withdrawn from the study, they will 
keep their identifier code and an additional subject will be recruited to account for 
the needed subject sample. Withdrawn subjects will be documented and future 
participants will start at the beginning of the study. Additional subjects will be drawn 
from the same pool of candidates who expressed interest in the study. The same 
recruitment procedures and experimental procedures will be followed for all 
subjects.  
 
5.8.2 Data Collection and Follow Up for Withdrawn Subjects 
For withdrawn subjects, documentation will be made. If a subject withdraws before 
consenting to the study, screening information will be documented and reported. 

18 
 
Withdrawal will be determined from a volunteer’s personal decline on-site in which 
case no calls or letters will need to be used. 
 
5.9 
Subject Compensation 
Subjects will receive a $100 gift card to compensate for their participation in the 
study. 
 
6.0 
Data Collection and Analysis 
 
6.1 
Subject Population(s) for Analysis 
All subjects will have corticospinal excitability and voice quality measurements 
taken before and after rTMS. All subject data will be processed and analyzed to 
explore for the effects of rTMS. Self-reported voice disability will be measured 
before TMS testing in participants with AdSD. 
 
6.2 
Statistical Methods 
For both groups, changes from baseline will be explored for effects of rTMS in 
corticospinal excitability and voice quality. Since this is a pilot study and the sample 
size will likely not be adequate for differential statistics, data will be analyzed with 
descriptive statistics (measures of central tendency and variability) to look for trends 
related to rTMS effects and group. 
 
7.0 
Safety and Adverse Events 
 
7.1 
Definitions 
Adverse Event (AE) 
An adverse event (AE) is any symptom, sign, illness or experience that 
develops or worsens in severity during the course of the study. Intercurrent 
illnesses or injuries will be regarded as adverse events. Abnormal results of 
laboratory or diagnostic procedures are considered to be adverse events if the 
abnormality: 
• Results in study withdrawal 
• Is associated with a serious adverse event 
• Is associated with clinical signs or symptoms 
• Leads to additional treatment or to further diagnostic tests 
• Is considered by the Investigator to be of clinical significance. 
 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) is any adverse event that is: 
• Fatal 
• Life-threatening 
• Requires or prolongs a hospital stay 
• Results in persistent or significant disability or incapacity 
• A congenital anomaly or birth defect 
Important medical events are events that may not be immediately life-
threatening, but are clearly of major clinical significance and may be SAEs. 

19 
 
They may jeopardize the subject, and may require intervention to prevent one 
or the other serious outcomes noted above.  
 
Hospitalization  
Hospitalization shall include any initial admission (even if less than 24 hours) 
to a healthcare facility as a result of a precipitating clinical adverse effect; to 
include transfer within the hospital to an intensive care unit. Hospitalization or 
prolongation of hospitalization in the absence of a precipitating, clinical 
adverse effect (e.g., for a preexisting condition not associated with a new 
adverse effect or with a worsening of the preexisting condition; admission for a 
protocol-specified procedure) is not, in itself, a serious adverse effect. 
 
Unanticipated Adverse Device Effect (UADE) 
An unanticipated adverse device effect is any serious adverse effect on health 
or safety or any life-threatening problem or death caused by, or associated 
with, a device, if that effect problem, or death was not previously identified in 
nature, severity, or degree of incidence in the investigational plan, or any other 
unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects. 
 
Unanticipated Problems Involving Risk To Subjects or Others (UPIRTSO) 
An adverse event that in the opinion of the Principal Investigator is 
unexpected, related to the device, and serious. 
 
7.2 
Safety Monitoring Plan  
 
 
 
 
Plans to minimize risks to study participants: 
• 
All investigators and study staff have completed required training re: human 
subject protections. Study staff will comply with all related regulations and 
laws, included, but not limited to 45CFR parts 60 and 64, and HIPAA Privacy 
Regulations. 
• 
Subjects will be rigorously screened against inclusion/exclusion criteria to 
ensure that their participation is safe. 
• 
Research staff conducting clinical research procedures will be appropriately 
trained, licensed, credentialed and supervised 
• 
PI and study staff will monitor incidence of adverse events, feedback from 
subjects, observations from nurses, study staff, investigators and other safety 
indicators on a continuous basis.  
• 
To monitor symptoms or changes in health status due to TMS testing and rTMS 
delivery, participants will be asked to complete the form “Subject Report of 
Symptoms” before TMS testing, right after rTMS application, and at the end of 
the experiment so that the required actions are taken. 
• 
Study visits will be conducted at the CTSI Masonic Clinical Research Unit 
(MCRU) or Delaware Clinical Research Unit (DCRU) which are staffed with 
back-up personnel and have immediate access to Fairview’s emergency 
response personnel if needed.  

20 
 
• 
PI will ensure accuracy, completeness, clarity and timeliness of all study 
records. 
• 
Study data & information will be kept confidential and managed in accordance 
with requirements of HIPAA. All data will be stored in locked offices and not 
released without subject permission. 
• 
Subjects may discontinue participation at any time, for any reason. Any subject 
observed to have unacceptable responses to research procedures, or to be unable 
to safely tolerate participation in the study will be withdrawn. 
7.2.1 Anticipated Risks / Risk Mitigation 
1. Personal information: There is a small risk of loss of confidentiality. Subjects will 
be asked if they have any medical conditions and if they are taking any medications. 
This is important to know so that only those subjects who meet the inclusion and 
exclusion criteria are accepted into the study. A number of procedures are in place to 
protect participant confidentiality. Every participant enrolled in the study will 
receive a unique code number. All records and results will be labeled with this code 
number and the code will be shared only with the study investigators. Any 
information that is included in published manuscripts (e.g. demographic 
information) will not be linked to any other information that would identify who the 
subject was.  
 
2. TMS: Risks associated with TMS are rare but should be recognized and prevented 
with appropriate precautions. Serious adverse risks include the induction of a 
seizure. There have been reports of a seizure and induced mania from rTMS but 
none of these side effects have been reported with the type of rTMS that we are 
doing in this study. Mild adverse effects include fainting, headache, dental pain, and 
other changes in memory, mood, and hearing. The overall occurrence of a mild 
adverse event is 5% in sham and real TMS sessions combined (Maizey et al., 2013). 
Participants will be asked to complete the form “Subject Report of Symptoms” 
before TMS testing and at the end of the experiment so that the required actions are 
taken in case there are any changes to their health status. Participants will be 
instructed to contact study staff if they noticed any of the symptoms listed above 
after participation in the study. In addition, study staff may contact participants (via 
email or phone call) to follow-up on any issues or symptoms that occur during the 
experiment. People with a history of seizure within the last two years or a history of 
bipolar disorder will not be allowed to participate in this study. The tests may be 
discontinued without the participant’s consent if the study team observes any 
abnormal responses. TMS delivery may also interfere with implanted devices and, 
thus, TMS is not appropriate for persons with medical devices such as deep brain 
stimulators, pace makers and medication pumps. Currently, the effects of TMS on 
hormonal cycles and the unborn fetus are unknown. 
 
3. Needle (fine-wire) electrodes: Risks associated with the electrode placement are 
very rare and include vocal cord hemorrhage, hoarseness of voice, infection, or 
dysphagia (difficulty swallowing). Participants should not be on any blood thinner 
medication to avoid vocal cord hemorrhage. We will clean and prepare the skin 

21 
 
appropriately prior to using needle EMG to avoid infections. Subjects may 
experience localized minor discomfort in the area during the procedure and for 1-2 
days afterwards. 
 
7.2.2 Medical Monitoring for Participant Safety  
        
The Principal Investigator will oversee the safety of the study, including careful 
assessment and appropriate reporting of adverse events as outlined in Section 7.4. 
Dr. Goding, a University of Minnesota physician and ear nose and throat specialist, 
will be on-site during needle electrode placement and present for any necessary 
medical assistance. Medical monitoring will include a regular assessment of the 
number and type of serious adverse events.  
 
7.2.3 Study Stopping Rules 
If during a session, the subject should show any signs of disorientation or the 
presence of EMG activity that cannot be stopped by the subject, the session will be 
stopped for that subject. 
 
7.3 
Anticipated Adverse Events 
Risks associated with TMS are rare but should be recognized and prevented with 
appropriate precautions. Serious adverse risks include the induction of a seizure. 
Mild adverse effects include fainting, headache, dental pain, and other changes in 
memory, mood, and hearing. TMS delivery may also interfere with implanted 
devices. 
 
7.4 
Adverse Event Reporting 
All Adverse Events occurring during the study period must be recorded. The clinical 
course of each event will be followed until resolution, stabilization, or until it has 
been determined that study treatment or participation is not the cause.  
 
 
We will promptly review documented adverse effects and abnormal test findings to 
determine  
1) if the abnormal test finding should be classified as an adverse effect;  
2) if there is a reasonable possibility that the adverse effect was caused by the 
investigational device or, if applicable, other study treatment or diagnostic 
product(s); and  
3) if the adverse effect meets the criteria for a serious adverse effect. 
If our final determination of causality is “unknown and of questionable relationship 
to the investigational device or, if applicable, other study treatment or diagnostic 
product(s)”, the adverse effect will be classified as associated with the use of the 
investigational device or study treatment or diagnostic drug product(s) for reporting 
purposes. If our final determination of causality is “unknown but not related to the 
investigational device or, if applicable, other study treatment or diagnostic 
product(s)”, this determination and the rationale for the determination will be 
documented in the respective subject’s case history. 
 

22 
 
7.4.1 Adverse Events:  
All observed or volunteered adverse effects and abnormal test findings, regardless of 
treatment group, if applicable, or suspected causal relationship to the investigational 
device or, if applicable, other study treatment or diagnostic product(s) will be 
recorded in the subjects’ case histories. For all adverse effects, sufficient information 
will be pursued and/or obtained so as to permit: 
1) an adequate determination of the outcome of the effect (i.e., whether the 
effect should be classified as a serious adverse effect) and;  
2) an assessment of the casual relationship between the adverse effect and the 
investigational device or, if applicable, the other study treatment or diagnostic 
product(s).  
 
Adverse effects or abnormal test findings felt to be associated with the 
investigational device or, if applicable, other study treatment or diagnostic product(s) 
will be followed until the effect (or its sequelae) or the abnormal test finding 
resolves or stabilizes at a level acceptable to the Sponsor-Investigator. 
 
Adverse Events that do not qualify as Serious Adverse Events, or as Unanticipated 
Adverse Device Effects will be reported the IRB with the continuing review progress 
report. These events will be reported to FDA with the IDE Annual Report. 
 
7.4.2 Serious Adverse Events 
Principal investigation contact information for Serious Adverse Event Notification: 
Mo Chen, PhD 
612/624-5220 (Telephone) 
 
At the time of the initial report, the following information will be provided: 
- Study Identifier  
- Whether study treatment was discontinued 
- Study Center 
 
- Reason the event is classified as serious 
- Subject Number 
- Event Description 
- Date of Onset  
- Investigator assessment of association  
- Current Status  
between event and study device 
 
Serious Adverse Events that are at least possibly related must be reported to the IRB 
within 10 working days, and to FDA within 15 calendar days.  
 
7.4.3 Unanticipated Adverse Device Effects  
 
We will submit a completed Form FDA 3500 A to the FDA’s Center for Devices 
and Radiological Health for any observed or volunteered adverse effect that is 
determined to be an unanticipated adverse device effect. A copy of this completed 
form will be provided to all participating sub-investigators.  
 
The completed Form FDA 3500 A will be submitted to the FDA as soon as possible 
and, in no event, later than 10 working days after the Sponsor-Investigator first 
receives notice of the adverse effect. 

23 
 
If the results of our follow-up evaluation show that an adverse effect that was 
initially determined to not constitute an unanticipated adverse device effect does, in 
fact, meet the requirements for reporting; we will submit a completed Form FDA 
3500 A as soon as possible, but in no event later than 10 working days, after the 
determination was made. 
 
For each submitted Form FDA 3500 A, we will identify all previously submitted 
reports that that addressed a similar adverse effect experience and we will provide an 
analysis of the significance of newly reported adverse effect in light of the previous, 
similar report(s). 
 
We will report to the IRB any observed or volunteered adverse effect that is 
determined to meet all of the following criteria:  
1) associated with the investigational device or, if applicable, other study 
treatment or diagnostic product(s);  
2) a serious adverse effect; and  
3) an unexpected adverse effect.  
Applicable adverse effects will be reported to the IRB as soon as possible and, in no 
event, later than 10 calendar days following the Sponsor-Investigator’s receipt of the 
respective information.  
 
Adverse effects which are  
1) associated with the investigational drug or, if applicable, other study 
treatment or diagnostic product(s);  
2) fatal or life-threatening; and  
3) unexpected  
will be reported to the IRB within 24 hours of receipt of the respective information. 
 
If the Adverse Event is Serious, Unanticipated, Device Related, and determined by 
the Sponsor to present an unreasonable risk to subjects, the Sponsor must terminate 
the study within 5 working days of that determination. 
 
7.4.4 UPIRTSO Events 
We will submit a report of UPIRTSO events to the IRB within 10 working days of 
first learning of the event.  
  
7.5 
Data Safety Monitoring Board  
 
 
          
The study involves no greater than minimal risk which does not require a safety 
monitoring board. The CTSI will monitor data integrity. 
 
8.0 
Data Handling and Record Keeping 
 
8.1 
Confidentiality  
 
 
 
 
       
Information about study subjects will be kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). This study does not include the collection of PHI and hence will not 

24 
 
require subjects to sign any release of PHI. Subjects will be asked to give 
demographic information, the medications they are taking, and any other health 
related problems. 
 
8.2 
Source Documents 
Source Data are the clinical findings and observations, laboratory and test data, and 
other information contained in Source Documents. Source Documents are the 
original records (and certified copies of original records); including, but not limited 
to, hospital medical records, physician or office charts, physician or nursing notes, 
subject diaries or evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, x-rays, etc. When applicable, information recorded on 
the CRF shall match the Source Data recorded on the Source Documents.  
 
8.3 
Case Report Forms 
A Case Report Form will be completed for each subject enrolled into the clinical 
study. The investigator will review and approve each completed CRF; the 
investigator’s signature serving as attestation of the investigator’s responsibility for 
ensuring that all clinical and laboratory data entered on the CRF are complete, 
accurate and authentic.  
 
Subjects will be asked to give demographic information, the medications they are 
taking, and any other health related problems. This information will be protected by 
limiting the number of persons involved in data collection and analysis as well as 
maintaining identifiers within a locked cabinet in a secure lab. No information from 
this study will be documented in the subject's medical record. 
 
8.4 
Clinical Reports  
 
 
 
 
An annual progress report will be submitted to the IRB. The PI will submit a final 
report of the clinical study to the sponsor and reviewing IRB within 3 months of 
termination or completion of the clinical study or the Investigator’s part of the 
clinical study. This study does not involve other funding sources. 
 
 
 
 
8.5 
Records Retention 
 
 
 
 
 
We will retain the specified records and reports for 6 years. 
 
9.0 
Study Monitoring, Auditing, and Inspecting 
This study will be monitored according to FDA/GCP guidelines. The Investigator will 
allocate adequate time for such monitoring activities. The Investigator will also ensure that 
the monitor or other compliance or quality assurance reviewer is given access to all study-
related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), 
and has adequate space to conduct the monitoring visit. 
 
9.1 
Study Monitoring Plan  
 
 
 
 
Independent monitoring of the clinical study for clinical protocol will be conducted 
periodically (i.e., at a minimum of annually) by qualified staff of the University of 

25 
 
Minnesota’s Clinical and Translational Science Institute (CTSI). CTSI staff will 
monitor the data integrity of this study. 
 
9.2 
Auditing and Inspection 
 
 
 
    
We will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, government regulatory bodies, and University compliance and quality 
assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.). The investigator will ensure 
the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
We will accept inspection by government regulatory authorities and applicable 
University compliance and quality assurance offices. 
 
10.0 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice, applicable government regulations and Institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct. The decision of the IRB concerning the conduct of the study 
will be made in writing to the investigator and a copy of this decision will be provided to 
the sponsor before commencement of this study.  
 
11.0 Study Finances  
 
11.1 Funding Source 
This study is funded by departmental funds: Minnesota’s Discovery, Research and 
InnoVation Economy (MnDRIVE) and Department of Rehabilitation Medicine, 
Division of Physical Therapy, at University of Minnesota.  
Participant payment will be provided by the National Spasmodic Dysphonia 
Association (NSDA). 
 
11.2 Conflicts of Interest 
The PI and study staff do not have any conflicts of interest. Any investigator who has 
a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must refer to the 
Regents Policies on Individual Conflict of Interest Policy or Institutional Conflict of 
Interest Policy. These policies require University Faculty and staff to report external 
professional activities and business and significant financial interests related to his or 
her University activities by submitting a REPA (Report of External Professional 
Activities) at least once per year. Faculty and staff should also file a REPA when 
substantial changes in business or financial interests occur, when an activity that 
presents a potential conflict of interest is anticipated, or when submitting an 
application for research support or technology transfer, submitting research protocols 

26 
 
to the IRB, or receiving financial contributions. All University of Minnesota 
investigators will follow the University conflict of interest policy. 
 
12.0 Publications Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, 
nor any of the information provided by the sponsor for the purposes of performing the 
study, will be published or passed on to any third party without the consent of the study 
sponsor. Any investigator involved with this study is obligated to provide the sponsor with 
complete test results and all data derived from the study. 
 
13.0 References 
 
Aminoff MJ, Dedo HH, Izdebski K. Clinical aspects of spasmodic dysphonia. J Neurol 
Neurosurg Psychiatry. 1978; 41: 361-365. 
Gerschlager W, Siebner HR, Rothwell JC. Decreased corticospinal excitability after subthreshold 
1 Hz rTMS over lateral premotor cortex. Neurology. 2001; 57: 449-455. 
Kimberley TJ, Borich MR, Arora S, Siebner HR. Multiple sessions of low-frequency repetitive 
transcranial magnetic stimulation in focal hand dystonia: clinical and physiological 
effects. Restor Neurol Neurosci. 2013;  
Kimberley TJ, Borich MR, Prochaska KD, Mundfrom SL, Perkins AE, Poepping JM. 
Establishing the definition and inter-rater reliability of cortical silent period calculation in 
subjects with focal hand dystonia and healthy controls. Neurosci Lett. 2009; 464: 84-87. 
Kimberley TJ, Borich MR, Schmidt RL, Carey JR, Gillick B. Focal hand dystonia: 
individualized intervention with repeated application of repetitive transcranial magnetic 
stimulation. Arch Phys Med Rehabil. 2015a; 96: S122-128. 
Kimberley TJ, Di Fabio RP. Visualizing the effects of rTMS in a patient sample: small N vs. 
group level analysis. PLoS One. 2010; 5: e15155. 
Kimberley TJ, Pickett KA. Differential activation in the primary motor cortex during individual 
digit movement in focal hand dystonia vs. healthy. Restor Neurol Neurosci. 2012; 30: 
247-254. 
Kimberley TJ, Schmidt RL, Chen M, Dykstra DD, Buetefisch CM. Mixed effectiveness of rTMS 
and retraining in the treatment of focal hand dystonia. Front Hum Neurosci. 2015b; 9: 
385. 
Maizey L, Allen CP, Dervinis M, Verbruggen F, Varnava A, Kozlov M, et al. Comparative 
incidence rates of mild adverse effects to transcranial magnetic stimulation. Clin 
Neurophysiol. 2013; 124: 536-544. 
Rossi S, Hallett M, Rossini PM, Pascual-Leone A, Safety of TMSCG. Safety, ethical 
considerations, and application guidelines for the use of transcranial magnetic stimulation 
in clinical practice and research. Clin Neurophysiol. 2009; 120: 2008-2039. 
Rossini PM, Burke D, Chen R, Cohen LG, Daskalakis Z, Di Iorio R, et al. Non-invasive 
electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: 
Basic principles and procedures for routine clinical and research application. An updated 
report from an I.F.C.N. Committee. Clin Neurophysiol. 2015; 126: 1071-1107. 
Samargia S, Schmidt R, Kimberley TJ. Shortened cortical silent period in adductor spasmodic 
dysphonia: evidence for widespread cortical excitability. Neurosci Lett. 2014; 560: 12-
15. 

27 
 
Samargia S, Schmidt R, Kimberley TJ. Cortical Silent Period Reveals Differences Between 
Adductor Spasmodic Dysphonia and Muscle Tension Dysphonia. Neurorehabil Neural 
Repair. 2016; 30: 221-232. 
Zraick RI, Kempster GB, Connor NP, Thibeault S, Klaben BK, Bursac Z, et al. Establishing 
validity of the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V). Am J 
Speech Lang Pathol. 2011; 20: 14-22. 
 
14.0 Appendices and Attachments 
• Consent Form 
o Healthy: ConsentForm_Healthy 
o Spasmodic dysphonia: ConsentForm_SD 
 
• HIPAA form 
o HIPAA_0409_rTMS in SD 
 
• Recruitment and screening materials 
o Healthy: 
Recruitment 
flyer_Healthy; 
Phone 
Script_Healthy; 
Email 
Script_Healthy 
o Spasmodic dysphonia: Recruitment flyer_ SD; Phone Script_SD; Email 
Script_SD 
o All: Initial Screening.doc, On site TMS screening, CAPE_V, VHI 
 
• Experiment procedures: 
o Experiment checklist 
 
• Symptoms report 
o Subject Report of Symptoms 
 
• TMS guidelines 
o UMN Brain Plasticity Laboratory NIBS_White Paper  
o FDA guidelines_rTMS