Investigating Central Neurophysiologic Correlates of Non-Motor Symptoms of Parkinson's Disease
Phase: NA
Conditions: Parkinson Disease, Autonomic Dysfunction, Depression
Sponsor: University of North Carolina, Chapel Hill

Investigating Central Neurophysiologic Correlates of Non-Motor 
Symptoms of Parkinson’s Disease 
 
 
NCT number NCT05205772 
Document Date 12/03/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
Parkinson’s Disease TMS+EEG study – v1.0 5 Apr 2021 
ii 
INVESTIGATING CENTRAL NEUROPHYSIOLOGIC CORRELATES OF NON-MOTOR SYMPTOMS OF 
PARKINSON’S DISEASE 
 
Short Title: Parkinson’s disease TMS+EEG study 
 
 
Protocol Number: 23-0751 
Principal Investigator: Miriam Sklerov, MD MS 
Sponsor: N/A 
Funded by: N/A 
Version Number:  2.1.0 
3 December 2021 
 
 
Summary of Changes from Previous Version: N/A 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Justification 
for dose 
Allowing for fewer repetitions of stimulation 
trains 
This will improve tolerability and participant 
retention 

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Table of Contents 
STATEMENT OF COMPLIANCE ...................................................................................................................... 1 
1 
PROTOCOL SUMMARY ...................................................................................................................... 1 
1.1 
Synopsis ............................................................................................................................................. 1 
1.2 
Schema ............................................................................................................................................... 3 
1.3 
Schedule of Activities (SoA) ......................................................................................................... 4 
2 
INTRODUCTION ................................................................................................................................. 4 
2.1 
Study Rationale ................................................................................................................................ 4 
2.2 
Background ........................................................................................................................................ 5 
2.3 
Risk/Benefit Assessment ............................................................................................................... 6 
2.3.1 
Known Potential Risks ........................................................................................... 6 
2.3.2 
Known Potential Benefits ...................................................................................... 7 
3 
OBJECTIVES AND OUTCOME MEASURES .......................................................................................... 7 
4 
STUDY DESIGN .................................................................................................................................. 8 
4.1 
Overall Design ................................................................................................................................... 8 
4.2 
Scientific Rationale for Study Design ......................................................................................... 8 
4.3 
Justification for Dose ....................................................................................................................... 9 
4.4 
End of Study Definition ................................................................................................................... 9 
5 
STUDY POPULATION ....................................................................................................................... 10 
5.1 
Inclusion Criteria ............................................................................................................................. 13 
5.2 
Exclusion Criteria ........................................................................................................................... 14 
5.3 
Lifestyle Considerations ............................................................................................................... 14 
5.4 
Screen Failures ............................................................................................................................... 14 
5.5 
Strategies for Recruitment and Retention .............................................................................. 14 
6 
STUDY INTERVENTION .................................................................................................................... 15 
6.1 
Study Intervention(s) Administration ........................................................................................ 15 
6.1.1 
Study Intervention Description ........................................................................... 16 
6.1.2 
Dosing and Administration .................................................................................. 16 
6.2 
Measures to Minimize Bias: Randomization and Blinding ................................................ 14 
6.3 
Study Intervention Compliance .................................................................................................. 14 
6.4 
Concomitant Therapy .................................................................................................................... 14 
6.4.1 
Rescue Medicine ................................................................................................. 15 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL
 
15 
7.1 
Discontinuation of Study Intervention ...................................................................................... 15 
7.2 
Participant Discontinuation/Withdrawal from the Study ..................................................... 15 
7.3 
Lost to Follow-Up ........................................................................................................................... 16 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................................................... 16 
8.1 
Efficacy Assessments ................................................................................................................... 16 
8.2 
Safety and Other Assessments ................................................................................................. 18 
8.3 
Adverse Events and Serious Adverse Events ...................................................................... 18 
8.3.1 
Definition of Adverse Events (AE) ........................................................................ 19 
8.3.2 
Definition of Serious Adverse Events (SAE) ......................................................... 19 

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8.3.3 
Classification of an Adverse Event ....................................................................... 19 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 20 
8.3.5 
Adverse Event Reporting ..................................................................................... 20 
8.3.6 
Serious Adverse Event Reporting ........................................................................ 21 
8.3.7 
Reporting Events to Participants ......................................................................... 21 
8.3.8 
Events of Special Interest .................................................................................... 21 
8.3.9 
Reporting of Pregnancy ....................................................................................... 21 
8.4 
Unanticipated Problems ............................................................................................................... 21 
8.4.1 
Definition of Unanticipated Problems (UP) ......................................................... 21 
8.4.2 
Unanticipated Problem Reporting ....................................................................... 22 
8.4.3 
Reporting Unanticipated Problems to Participants ............................................. 22 
9 
STATISTICAL CONSIDERATIONS ....................................................................................................... 22 
9.1 
Statistical Hypotheses .................................................................................................................. 22 
9.2 
Sample Size Determination ........................................................................................................ 23 
9.3 
Populations for Analyses ............................................................................................................. 23 
9.4 
Statistical Analyses ........................................................................................................................ 23 
9.4.1 
General Approach ............................................................................................... 23 
9.4.2 
Analysis of the Primary Efficacy outcome measures ........................................... 24 
9.4.3 
Analysis of the Exploratory outcome measures .................................................. 24 
9.4.4 
Safety Analyses .................................................................................................... 24 
9.4.5 
Baseline Descriptive Statistics ............................................................................. 25 
9.4.6 
Planned Interim Analyses .................................................................................... 25 
9.4.7 
Sub-Group Analyses ............................................................................................ 25 
9.4.8 
Tabulation of Individual participant Data ............................................................ 25 
9.4.9 
Exploratory Analyses ........................................................................................... 25 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................................... 25 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ................................................ 25 
10.1.1 
Informed Consent Process .................................................................................. 25 
10.1.2 
Study Discontinuation and Closure ..................................................................... 26 
10.1.3 
Confidentiality and Privacy .................................................................................. 26 
10.1.4 
Future Use of Stored Specimens and Data .......................................................... 27 
10.1.5 
Key Roles and Study Governance ........................................................................ 27 
10.1.6 
Safety Oversight .................................................................................................. 27 
10.1.7 
Clinical Monitoring .............................................................................................. 28 
10.1.8 
Quality Assurance and Quality Control ............................................................... 28 
10.1.9 
Data Handling and Record Keeping ..................................................................... 28 
10.1.10 
Protocol Deviations ............................................................................................. 29 
10.1.11 
Publication and Data Sharing Policy .................................................................... 30 
10.1.12 
Conflict of Interest Policy .................................................................................... 30 
10.2 
Additional Considerations ............................................................................................................ 30 
10.3 
Abbreviations ................................................................................................................................... 31 
10.4 
Protocol Amendment History ...................................................................................................... 33 

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REFERENCES .................................................................................................................................... 34 
STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and  
clinical trial site staff who are responsible for the conduct, management, or oversight of NIH-
funded clinical trials have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Investigating Central Neurophysiologic Correlates of Non-motor 
Symptoms of Parkinson’s Disease 
Study Description: 
This is a randomized, single-blinded, triple crossover study with 3 one-day 
iTBS, separated by a wash-out period of 3 weeks1, sufficient for physiologic 
effects of one session of iTBS to return to baseline. Participants will 
undergo accelerated iTBS to 3 brain regions: medial prefrontal cortex 
(mPFC) (experimental site), dorsolateral prefrontal cortex (DLPFC) 
(alternative experimental site), or primary sensory cortex (S1) (control 
site). Participants will complete symptom questionnaires, neurologic 
examination and cognitive assessments, and orthostatic vital signs 
recording before and after each brain stimulation session. 
Objectives: 
 
 
 
Primary Objective:  Aim 1: To determine whether iTBS to the medial 
prefrontal cortex (mPFC) produces more robust changes in frontal 
midline theta (FMT) EEG power in people with Parkinson’s disease 
compared with stimulation at the dorsolateral prefrontal cortex 
(DLPFC) or the primary sensory cortex (S1). Aim 2: A. To evaluate FMT 
power correlations with burden of autonomic symptoms in Parkinson’s 

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disease. B. To evaluate FMT power correlations with burden of 
depression symptoms in Parkinson’s disease 
 
 
Exploratory Objectives:  
Aim 3: To evaluate the effect of iTBS on autonomic symptoms one day 
after, and 4 days after stimulation. Aim 4: To evaluate the effect of iTBS on 
depression symptoms one day after, and 4 days after stimulation. 
Aim 5: To create a database of EEG and TMS data in people with PD for the 
purpose of future research into novel neurostimulation therapies for PD 
NMS 
Outcome measures: 
Primary Outcome Measures: Aim 1: Degree of change of frontal midline 
theta power on EEG after brain stimulation. Aim 2: Degree of association 
between autonomic symptoms and frontal midline theta EEG power; 
Degree of association between depression symptoms and frontal midline 
theta EEG power. 
 
Exploratory Outcome measures: Aim 3: Change in SCOPA-AUT and OHQ 
from before to after iTBS; Aim 4: Change in BDI-II from before to after iTBS 
Study Population: 
Study population will be men and women of all demographic groups with 
Parkinson’s disease age 50-90 years who do not have a diagnosis of severe 
dementia who reside in North Carolina.  
Phase: 
N/A (pilot study) 
Description of 
Sites/Facilities Enrolling 
Participants: 
UNC Medical Center will be the only participating site.  
Description of Study 
Intervention: 
Participants will undergo three sessions of intermittent theta-burst 
stimulation (iTBS), an FDA-approved therapy for treatment of depression, 
while at rest. Stimulation will be delivered to the medial prefrontal cortex, 
dorsolateral prefrontal cortex, and the primary sensory cortex (one site 
per stimulation session). Electroencephalography will be collected 
immediately before and after stimulation, and questionnaires and clinical 
evaluations will be completed before and after stimulation sessions.  
Study Duration: 
Three years 
Participant Duration: 
The total number of contacts per subject, including in-person, telephone, 
email, and mailings will range from 4-15. Duration of each contact will 
range from 10 minutes – 2.5 hours. Total duration of an individual 
subject’s participation is expected to be 5-6 hours for informed consent, 
initial clinical evaluation and screening, questionnaires, and EEG/TMS visit.  
 
 
 
 
 
 

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1.2 
SCHEMA 
 
 
 
 
Day -21 to Day 
-1 
Screening 
Day 1 
Randomization 
Week 1 
Stimulation 
session #1 
Week 4 
Stimulation 
session #2 
Week 7 
Stimulation session 
#3, end of study 
4 in-clinic 
visits and 
9 telephone 
contacts 
DLPFC – mPFC – S1 
S1 – mPFC - DLPFC  
mPFC – S1 - DLPFC  
mPFC – DLPFC - S1 
DLPFC – S1-mPF
S1 – DLPFC - mPFC 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening 
Day -7 to -1 
Visit 1, Week 1 
Telephone visit, 
Week 1+1 day 
Telephone visit, 
Week 1+4 days 
Study Visit 2  
Week 4 
Telephone visit, 
Week 4+1 day 
Telephone visit, 
Week 4+4 days 
Study Visit 3 
Week 7 
Telephone visit, 
Week 7+1 day 
Telephone visit, 
Week 7+4 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
iTBS + EEG 
 
X 
 
 
X 
 
 
X 
 
 
Concomitant 
medication review 
X 
X 
 
 
X 
 
 
X 
 
 
MDS-UPDRS  
X 
X 
 
 
X 
 
 
X 
 
 
Montreal Cognitive 
Assessment 
X 
 
 
 
 
 
 
 
 
 
Orthostatic Vital 
signs 
X 
X 
 
 
X 
 
 
X 
 
 
Adverse event 
review and 
evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Freezing of Gait 
questionnaire 
X 
X 
 
 
X 
 
 
X 
 
 
Epworth Sleepiness 
Scale 
X 
 
 
 
 
 
 
 
 
 
REM sleep disorder 
questionnaire 
X 
 
 
 
 
 
 
 
 
 
OHQ and SCOPA-
AUT 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Beck Depression 
Inventory - II 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Case 
Report Forms (CRFs) X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Parkinson’s disease (PD) is the second most common neurodegenerative disease in the US. Autonomic 
dysfunction (AuD) and depression are common non-motor symptoms of PD which are strongly 
predictive of poor disease outcomes, and lack effective treatments. Non-invasive brain stimulation, such 
as transcranial magnetic stimulation (TMS), is a safe, effective, FDA-approved treatment for major 
depression disorder and psychotic disorders, and is undergoing study for treatment of motor symptoms 

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in PD. Intermittent theta-burst stimulation (iTBS) is a TMS paradigm that has been found to be as 
effective in fewer treatments than traditional TMS paradigms, and is FDA approved to treat major 
depression disorder. Few studies have investigated the use of any neurostimulation tool to treat non-
motor symptoms of PD. The overarching objective of this study is to determine the feasibility of using 
transcranial magnetic stimulation to treat AuD and depression in PD. Based on preliminary evidence 
implicating brain structures (the medial prefrontal cortex and the anterior cingulate gyrus) in both AuD 
and depression in PD, the central hypothesis in this study is that the medial prefrontal cortex is a major 
driver of AuD and depression in PD, and an effective brain stimulation target. 
2.2 
BACKGROUND  
Parkinson’s disease (PD) is a common, progressive neurodegenerative disease characterized by a 
combination of motor and non-motor symptoms that is made debilitating by both motor and non-motor 
symptoms. The prevalence of PD in North Carolina (NC) is about 400 cases per 100,000 among Medicare 
beneficiaries [1]. Non-motor symptoms (NMS) of PD are common and associated with significant 
morbidity and mortality2. Autonomic nervous system dysfunction, which causes symptoms such as 
orthostatic hypotension (OH), constipation and gastroparesis, urinary retention or incontinence, and 
sexual dysfunction, affects more than half of PD patients [2-4], and is strongly predictive of poorer quality 
of life and overall prognosis [5, 6]. Similarly, refractory depression in PD is a common and disabling NMS3. 
Unfortunately, both of these NMS have limited treatment options.  
Both invasive (Deep brain stimulation, DBS) and more recently non-invasive (transcranial magnetic 
stimulation, TMS) neurostimulation are used for the clinical and/or experimental treatment of motor 
symptoms but have yet to be thoroughly investigated in the context of NMS in PD. The development of 
brain stimulation treatments requires an understanding of structural and functional brain networks4–6. 
The feasibility of such rational design of brain stimulation is made possible with the growing 
understanding of brain network dysfunction in PD7,8 
The hypothalamus (HTH), anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), and insula play 
key roles in the central autonomic network (CAN), by modulating autonomic function9, and in the limbic 
network where they regulate emotion. Pathology is found in these areas in PD10. Functional and structural 
brain MRI studies in PD consistently implicate the CAN, including the mPFC, as a substrate in AuD11–14. 
Other key nodes of both autonomic and depression networks, such as the dorsolateral prefrontal cortex 
(DLPFC), remain spared by PD pathology10. MRI abnormalities in the ACC and mPFC in PD depression 
mirror findings in PD AuD15–19.  
 
Our group used resting state functional MRI (rs-fMRI) to study brain correlates of autonomic 
symptoms in PD11. In a publicly-available database of early PD, we found reductions in hypothalamic 
functional connectivity in PD with high burden of autonomic symptoms11. Our preliminary brain MRI data 
in people with PD points to central dysregulation in PD autonomic dysfunction, particularly implicating 
the HTH, ACC, and mPFC (Fig. 1, Appendix). Interestingly, these regions of the CAN are also important 
nodes of the limbic network, implicated in the regulation of mood and emotion20.  
Electroencephalography (EEG) provides high temporal resolution for the measurement of brain network 
dynamics and their modulation by non-invasive brain stimulation21–23. EEG correlates of autonomic 
function in the neurologically healthy localize to frontal midline areas and associate with theta oscillations 
(4-8 Hz)24–28. The majority of these studies are primarily focused on heart rate variability (HRV) responses, 

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thought to represent sympathetic and parasympathetic autonomic nervous system function, though this 
is agreed to be an indirect measure and remains controversial29. There are no studies investigating EEG 
correlates of AuD in PD to our knowledge. I hypothesize that altered frontal midline theta (FMT) 
oscillations are a marker of AuD and thus a target for non-invasive brain stimulation. 
TMS is a form of non-invasive neurostimulation used to modulate brain networks. TMS, effective when 
applied to the dorsolateral prefrontal cortex (DLPFC) or mPFC30, is FDA approved for the treatment of 
major depressive disorder (MDD). Theta-burst TMS (TBS) was recently developed for treatment of 
neurologic and psychiatric symptoms. TBS has equivalent if not longer-lasting effects compared with 
traditional repetitive TMS (rTMS)31,32. Continuous TBS is thought to have inhibitory effects while 
intermittent TBS (iTBS) has excitatory effects33. In MDD, iTBS is equivalent or more effective compared 
with rTMS and has recently been FDA approved34,35.   
Studies of effects of TMS on autonomic function exhibit mixed results36. Four studies, including only one 
study in PD, found that DLPFC stimulation has a positive effect on autonomic function or symptoms37–40. 
There has been one study investigating the effect of iTBS on autonomic function41. In this study, iTBS was 
applied to the DLPFC in subjects with MDD while concordant HRV was assessed. Intriguingly, this study 
reported significant heart rate decelerations in the iTBS groups compared to sham (placebo) stimulation, 
indicating autonomic nervous system engagement. Interestingly, there are no published reports of TMS 
targeted to CAN structures to probe autonomic function. Taken together, the literature suggests iTBS 
applied to CAN network nodes, particularly the mPFC which is implicated in PD pathology as well as 
depression and AuD, may improve AuD by restoring FMT oscillations and top-down control of the CAN. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Psychological risk 
Breach of confidentiality: While there is the potential for breach of confidentiality, all study personnel 
will minimize this risk to study subjects. All data will be de-identified before analysis, and any treatment 
outcome data will be treated with strict confidentiality. Electronic data will be stored on password-
protected servers within the UNC School of Medicine and any hard-copy data will be stored in locked 
cabinets in locked offices in the UNC Department of Neurology. 
Risk of embarrassment: There is a risk of distress or embarrassment for the participant if they have 
difficulty performing well on cognitive and physical tests. The research team will take extra care to 
perform these evaluations in a judgement-free manner, and provide appropriate encouragement to the 
participant, as is routinely done in a clinical setting. Additionally, we will request that the participant be 
alone in the examining room with the examiner, without care partner or other persons in the room, while 
performing these examinations, unless otherwise preferred by the participant, to help minimize this risk.  
Physical risk:  

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Risk of injury and discomfort: Transcranial magnetic stimulation (TMS) is FDA approved for treatment of 
many neuropsychiatric symptoms in the USA. TMS is not related to electroconvulsive therapy, which 
applies many orders of magnitude higher stimulation electrical current. The level of electrical stimulation 
produced by TMS is within the range of activity that is endogenous to the brain. Furthermore, the intensity 
of stimulation is calibrated to the sensitivity of the individual participant such that the level of stimulation 
is matched to the naturally occurring brain activity in that individual. In order to monitor side effects, 
participants will be asked to complete an adverse effects from stimulation questionnaire after each 
stimulation session. Research personnel supervising the stimulation sessions will also check with the 
participant periodically during the stimulation session to ensure the participant is comfortable. If any side 
effects occur that are rated by the participant as stronger than “moderate”, or the participant reports 
severe discomfort during stimulation, the stimulation session will be terminated immediately. 
 
There is a very low theoretical likelihood that stimulation of neuronal circuits can lead to epileptic 
discharges. To minimize this risk, we will exclude potential participants with personal history of epilepsy 
or risk factors for epilepsy. If abnormalities on EEG or a seizure is witnessed during the course of the study, 
a referral will be made to the UNC Department of Neurology for follow up, and/or the participant’s 
treating neurologist will be notified. In the unlikely event that a seizure with loss of consciousness is 
witnessed during the course of the study, the participant will be instructed not to operate a motor vehicle 
until cleared by the Department of Motor Vehicles (DMV). 
One of the scales that will be administered assess symptoms of depression (BDI-II questionnaire). Upon 
receiving this questionnaire, the research coordinator will check the scoring for this assessment. If the 
patient scored in the “severe” range (>28 points), the PI will be notified, and appropriate immediate 
referrals for care will be made per the patient’s preference. The participant’s treating neurologist or 
primary care physician will be immediately notified via a phone call. 911 will be called in the event that a 
participant is threatening to hurt themselves or others. 
 
Hearing loss is a potential risk of TMS. This is a rare and moderate to severe risk. To protect against hearing 
loss, ear plugs are worn by the participant and by the technical operator during stimulation sessions.  
 
There have been rare reports of mood episode switches in people with Bipolar disorder after iTBS (from 
depressed mood to mania or hypomania). This is a rare but potentially severe.  
 
Other potential risks associated with participation in this study include: 
- 
Scalp irritation irritation due to application of the electroencephalogram electrodes to the scalp. 
This is infrequent and mild. 
- 
Headache and dizziness are rare and mild 
- 
Muscle tightness and twitching during stimulation are very common and mild 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
The primary potential benefit for research subjects in this study is the benefit of adding to medical 
knowledge. There is a potential benefit for symptoms of depression as well. 
 

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3 
OBJECTIVES ANDOUTCOME MEASURES 
 
 
OBJECTIVES 
Outcome Measures 
Primary 
 
Aim 1: To determine whether iTBS 
to the medial prefrontal cortex 
(mPFC) produces more robust 
changes in frontal midline theta 
(FMT) EEG power in people with 
Parkinson’s disease compared with 
stimulation at the dorsolateral 
prefrontal cortex (DLPFC) or the 
primary sensory cortex (S1). Aim 2: 
A. To evaluate FMT power 
correlations with burden of 
autonomic symptoms at baseline 
before stimulation in Parkinson’s 
disease. B. To evaluate FMT power 
correlations with burden of 
depression symptoms at baseline 
before stimulation in Parkinson’s 
disease 
 
Aim 1: Degree of change of frontal 
midline theta power on EEG after 
brain stimulation. Aim 2: Degree of 
association between autonomic 
symptoms and frontal midline theta 
EEG power; Degree of association 
between depression symptoms and 
frontal midline theta EEG power. 
 
Exploratory 
 
Aim 3: To evaluate the effect of 
iTBS on autonomic symptoms one 
day after, and 4 days after 
stimulation. Aim 4:  To evaluate the 
effect of iTBS on depression 
symptoms one day after, and 4 
days after stimulation. 
Aim 5: To create a database of EEG 
and TMS data in people with PD for 
1. Change in SCOPA-AUT and OHQ 
from before to after iTBS; 2. Change 
in BDI-II from before to after iTBS 

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OBJECTIVES 
Outcome Measures 
the purpose of future research into 
novel neurostimulation therapies 
for PD NMS 
 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
This is a prospective, triple crossover (three stimulation sites which will be done at separate study visits), 
single-blinded study design. The difference in stimulation site precludes double-blinding as the study 
personnel will be aware of the difference in location while running the experiment.  
Aim 1: To determine whether iTBS to the medial prefrontal cortex (mPFC) produces more robust 
changes in frontal midline theta (FMT) EEG power in people with Parkinson’s disease compared with 
stimulation at the dorsolateral prefrontal cortex (DLPFC) or the primary sensory cortex (S1). 
Hypothesis:  
H0: Mean change in Frontal midline theta power on electroencephalogram after iTBS to the medial 
prefrontal cortex will be equal to FMT changes after dorsolateral prefrontal cortex stimulation and 
stimulation of S1. 
H1: Mean change in Frontal midline theta power on electroencephalogram after iTBS to the medial 
prefrontal cortex will be greater than FMT changes after dorsolateral prefrontal cortex stimulation and 
stimulation of S1. 
 
Aim 2A: To identify associations between symptoms of autonomic dysfunction at baseline before 
stimulation and frontal midline theta band frequency on electroencephalogram. 
H0: There is zero correlation between severity of autonomic dysfunction symptoms at baseline before 
stimulation with frontal midline theta power at baseline on electroencephalogram. 
H1: There is a negative correlation between severity of autonomic dysfunction symptoms at baseline 
before stimulation with frontal midline theta power at baseline on electroencephalogram. 
 
Aim 2B: To identify associations between symptoms of depression at baseline before stimulation and 
frontal midline theta band frequency on electroencephalogram. 
Hypothesis:  
H0: There is no correlation between severity of depression symptoms at baseline before stimulation with 
frontal midline theta power on electroencephalogram at baseline. 

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H1: There is negative correlation between depression symptoms at baseline before stimulation with 
frontal midline theta power on electroencephalogram at baseline. 
 
 
Exploratory objectives 
Aim 3: To evaluate the effect of iTBS on autonomic symptoms one day after, and 4 days after 
stimulation.  
Hypothesis:  
H0: Change in SCOPA-AUT and OHQ will be zero one day after stimulation and 4 days after stimulation 
compared to pre-stimulation. 
H1: Change in SCOPA-AUT and OHQ will be less than zero one day after stimulation and 4 days after 
stimulation. 
 
Aim 4: To evaluate the effect of iTBS on depression symptoms one day after, and 4 days after 
stimulation. 
Hypothesis:  
H0: Change in BDI-II will be zero one day after stimulation and 4 days after stimulation compared to pre-
stimulation. 
H1: Change in BDI-II will be less than zero one day after stimulation and 4 days after stimulation. 
 
 
Aim 5: To create a database of EEG and TMS data in people with PD for the purpose of future research 
into novel neurostimulation therapies for PD NMS. 
Hypothesis: We will maintain a de-identified database of EEG, clinical, and demographic data from 
people with PD undergoing iTBS. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The stimulation locations in the current study design were chosen due to prior data implicating the 
medial prefrontal cortex and dorsolateral prefrontal cortex in both autonomic and affective disorders. 
Primary sensory cortex was chosen as a control site due to it’s limited involvement in Parkinson’s 
disease pathology, autonomic function, and depression. We chose a control stimulation location rather 
than sham stimulation because participants will be able to feel the difference between real and sham 
stimulation in this crossover design. A triple crossover design was chosen to maximize study recruitment 
and minimize subject variability between stimulation arms.  
 
4.3 
JUSTIFICATION FOR DOSE 
Transcranial magnetic stimulation (TMS) is a safe, non-invasive tool routinely used in clinical care which 
applies magnetic fields to the brain using coils placed on the scalp. During the first stimulation session in 
the study, participants will receive a motor thresholding procedure in which electrodes are attached to 

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the first dorsal interosseous muscle of the right hand, or another muscle on the hand or arm that is 
accessible to be targeted by TMS to the motor cortex. The contralateral motor cortex will be targeted by 
single pulses of TMS with increased stimulator output until a motor evoked potential (MEP), defined as a 
near-instantaneous increase in muscle activity greater than 200 microvolts, is generated. Next, the 
intensity of single pulse TMS will be lowered until a MEP is generated on five out of 10 pulses. This is 
defined as the individual’s motor threshold. If MEP determination of motor threshold is not possible, the 
researcher will use visible twitches as a proxy for MEP. Participants will receive iTBS at 80% of their 
motor threshold.  
Subjects will undergo iTBS to the mPFC, left DLPFC, and left primary sensory area in a triple cross-over 
study design. I will use a MagVenture MagPro X100 TMS device with active cooling coil. Stimulation 
location will be determined using  established scalp coordinates for each stimulation location with the 
“10-20” international coordinate system 42–45. For the mPFC, stimulation will be done between the Fpz 
and Cz EEG electrode location. For left DLPFC, stimulation will be done at the F3 location using the Beam-
F3 technique46,47.  For the primary sensory cortex, stimulation will be done 1.5cm posterior to the motor 
hotspot and at vertex position used for intensity calibration. Accelerated iTBS will be performed in the 
reclined position to reduce symptoms of orthostatic hypotension, with subjects awake and at rest. 
Subjects will receive bursts of 3 pulses at 50 Hz repeated at 200-msec intervals (5Hz) for two seconds48,49. 
The two-second trains will be repeated 20 times every 10 seconds (3:30 total stimulation time), and 
followed by a rest period. This sequence may be repeated up to 4 times. Behavioral effects of stimulation 
last at least 36 hours after one stimulation session with this protocol1.  
A high-density EEG net (128 electrodes including electrooculography electrodes; MagStim EGI, Inc.) and 
two submental electromyography (EMG) electrodes will be applied. Continuous qEEG recording will be 
performed for 8 minutes while the participant is asked to keep their eyes open and focused on a 
crosshairs. Sampling rate during the continuous recording will be 1 kHz with Cz as the reference and a 
channel between Cz and Pz as ground, using an EGI system with SDK AmpServer Pro (Geodesic, Eugene, 
Oregon). Collecting EEG with TMS does not pose any additional risk over TMS on its own. EEG electrodes 
are placed on the scalp to record electrical brain activity. EEG does not involve brain stimulation and is 
used purely as a neuroimaging tool, posing minimal risk. 
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last scheduled procedure shown in the Schedule of Activities (SoA), Section 1.3. 
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. 
 
5 
STUDY POPULATION 
 
 
5.1 
INCLUSION CRITERIA 

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1. Men and women between 50 and 90 years of age, without a diagnosis of severe dementia 
2. Carry a diagnosis of idiopathic Parkinson’s disease based on the United Kingdom Parkinson’s 
Disease Society Brain Bank clinical diagnostic criteria 
3. Have had symptoms of Parkinson’s disease for at least 3 years 
4. Hospital’s study-specific informed consent must be obtained 
5. Must have capacity to provide informed consent in English 
6. For female participants, confirmation that they have not had a menstrual period in over 12 
months, or that they will use an effective form of contraception during the study 
 
5.2 
EXCLUSION CRITERIA 
1. Inability to provide informed consent. 
2. Severe dementia 
3. History of epilepsy or brain surgery  
4. Severe tremor or dyskinesia that would interfere with EEG as determined by the PI 
5. Parkinson’s patients with clinically significant medical or neurological conditions which may be an 
alternative cause of orthostatic hypotension, such as neuropathy, renal failure, heart failure, 
cardiac arrhythmias, severe diabetes, or spinal cord injuries 
6. We will exclude patients who are treated with medications which can significantly lower blood 
pressure or heart rate, such as antihypertensive medications, diuretics, and alpha-blocking 
medications 
7. Presence of other known central nervous system disease that may interfere with performance or 
interpretation of EEG or TMS 
8. Presence of any implanted metal devices including, but not limited to, pacemakers, deep brain 
stimulators, vagal nerve stimulators, bladder stimulators, or cochlear implants. 
5.3 
LIFESTYLE CONSIDERATIONS 
N/A 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
availability for study visits or a concomitant medication that is subsequently stopped may be 
rescreened. Rescreened participants should be assigned the same participant number as for the initial 
screening. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 

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Recruitment: Our sample for this study is 48 participants with Parkinson’s disease age 50-90 years (See 
Sample Size Calculation). To recruit 48 participants, we will need to pre-screen 400 potential participants, 
and screen 90 potential participants, according to our experience in recruiting people with Parkinson’s 
disease at our center. Participants will be recruited from among patients who are seen in neurology clinics 
at UNC for evaluation and treatment of idiopathic Parkinson’s disease. A member of the research team 
will review data available in Epic for eligibility and recruitment, and flag patients who may qualify for the 
study. The treating neurologist will also be asked to consider potential participants’ eligibility and ability 
to provide informed consent. Once potential participants have been identified, they will be asked in 
person, over telephone, and/or emailed by our research team to assess their interest in the study, and 
provide information about the research study. If the potential participant indicates they are interested, 
the study coordinator or research assistant will set up a time for the potential participant to have a 
screening research visit. 
Retention: Retention strategies will include incentive payment upon completion of all study arms. 
Additionally, the research staff will call the participant at least 2 days prior to each study visit to remind 
them of the upcoming visit.  
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INVESTIGATIONAL PRODUCT 
We will use the MagPro X100 system (MagVenture Inc., Alpharetta, GA, USA) for transcranial magnetic 
stimulation. The MagPro X100 is an advanced, high performance magnetic stimulator designed for 
research use. It is a high-quality product that allows a wide range of stimulation paramaters. This 
stimulator allows selection of different waveforms, current direction, stimulation rates. It is easily 
connectable to external equipment via programmable input and output triggers. The system operates via 
a built-in computer, and is controllable from an external device.  
6.1.1.1 SAFETY FEATURES 
In the USA, federal law regulates the sale of Medical Devices through the US Food and Drug Administration 
(FDA). Devices which are permitted to be marketed for their intended use must have either a 510(k) or 
PMA clearance. 
MagPro stimulators R20, R30, R30 with MagOption, X100, and X100 with MagOption are all FDA 510(k) 
cleared (k160280, K061645, K091940, and k150641). 
k150641: The intended use is treatment of Major Depressive Disorder in adult patients who have failed 
to receive satisfactory improvement from prior antidepressant medication in the current episode. 

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k160280, K061645, K091940: The intended use is for stimulation of peripheral nerves for diagnostic 
purposes. The use of devices for other than their FDA cleared intended use is considered as 
investigational. Such use is only permited if the Investigational Device Exemption (IDE) guidelines have 
been followed.  
All investigational devices must be labeled in accordance with the labeling provisions of the IDE regulation 
(§ 812.5) and must bear a label with this statement: “CAUTION Investigational Device. Limited by Federal 
(or United States) law to investigational use.” 
6.1.1.2 PREPARATION AND ADMINISTRATION OF STUDY INVESTIGATIONAL PRODUCT 
After participants have completed questionnaires and EEG, they will be comfortably seated. The 
researcher will be thoroughly trained in the safe use of TMS. All researchers administering TMS have 
written and digital documentation of training. Researchers will be present at all times during stimulation. 
To monitor side effects of stimulation, a questionnaire will be administered after each stimulation session.  
6.1.2 STUDY INTERVENTION DESCRIPTION 
 
Screening: Participants will be recruited from among patients who are seen in neurology clinics at UNC 
for evaluation and treatment of idiopathic Parkinson’s disease. A member of the research team will review 
data available in Epic for eligibility and recruitment, and flag patients who may qualify for the study. The 
treating neurologist will also be asked to consider potential participants’ eligibility. Once potential 
participants have been identified, they will be asked in person, over telephone, and/or emailed by our 
research team to assess their interest in the study, and provide information about the research study. If 
the potential participant indicates they are interested, the study coordinator or research assistant will set 
up a time for the potential participant to have a screening research visit. Screening visits may be scheduled 
in the UNC Neurology clinic, or at the Frohlich laboratory, depending on convenience for the participant. 
At the screening visit, the study team member conducting the visit will clearly state that agreement or 
refusal to participate will in no way influence the patient’s care. If the patient does not want to participate, 
this will be documented in the patient’s chart, and the patient will not be contacted in the future about 
this study. If the patient is interested in participating in the study, the study inclusion and exclusion criteria 
will be reviewed again with the patient at the study visit. The study will be explained in detail to the 
potential participant, all questions will be answered to the potential participant’s satisfaction, and the 
study coordinator, research assistant, PI, or co-I will obtain informed consent in person. 
 
Once consent is obtained, the participant will be assigned an anonymous research ID number. Only the 
study team members will have access to data linking the participant’s research data and any PHI. 
Demographic data will be obtained, including age, sex, concurrent medications, and disease duration. A 
trained research team member will administer a brief cognitive test (the Montreal Cognitive Assessment 
or MoCA)50, the Movement Disorders Society Unified Parkinson’s Rating Scale (MDS-UPDRS)51, and will 
obtain orthostatic vital signs. 
Stimulation study visits 
Clinical Evaluations: The SCOPA-AUT52, a validated questionnaire for autonomic symptoms in PD, and the 
Orthostatic Hypotension Questionnaire (OHQ)53, a validated questionnaire for symptoms of orthostatic 

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intolerance, will be administered before, and then by telephone one day after, and four days after each 
stimulation session. The Beck Depression inventory II (BDI-II)54, recommended for screening and 
assessment of depression severity in PD55, will be administered before, and then by telephone one day 
after, and four days after each stimulation. A trained research team member will administer the 
Movement Disorders Society Unified Parkinson Disease Rating Scale (MDS-UPDRS)51, a validated rating 
scale of PD symptom severity, at baseline. Participants will have orthostatic blood pressure measurement 
with a standard sphingomanometer cuff before and after each stimulation session. All evaluations will be 
done with subjects in the “on” medication state with regards to dopaminergic medication dosing. 
Quantitative EEG (qEEG) recordings will be done before and immediately after each stimulation session. 
EEG: A high-density EEG net (128 electrodes including electrooculography electrodes; MagStim EGI, Inc.) 
and two submental electromyography (EMG) electrodes will be applied. Continuous qEEG recording will 
be performed for 8 minutes while the participant is asked to keep their eyes open and focused on a 
crosshairs. Sampling rate during the continuous recording will be 1 kHz with Cz as the reference and a 
channel between Cz and Pz as ground, using an EGI system with SDK AmpServer Pro (Geodesic, Eugene, 
Oregon). Intermittent theta-burst stimulation: Subjects will undergo iTBS to the mPFC, left DLPFC, and left 
primary sensory area in a triple cross-over study design. I will use a MagVenture MagPro X100 TMS device 
with active cooling coil. Stimulation location will be determined using  established scalp coordinates for 
each stimulation location with the “10-20” international coordinate system 42–45. For the mPFC, 
stimulation will be done at the Fp1 EEG electrode location, which can be calculated as along the midline 
of the scalp and 10% of the distance from nasion to inion. For left DLPFC, stimulation will be done at the 
F3 location using the Beam-F3 technique46,47.  For the primary sensory cortex, stimulation will be done 
1.5cm posterior to the motor hotspot used for intensity calibration. Stimulation will be delivered at 80% 
active motor threshold. Accelerated iTBS will be performed in the reclined position to reduce symptoms 
of orthostatic hypotension, with subjects awake and at rest. Subjects will receive bursts of 3 pulses at 50 
Hz repeated at 200-msec intervals (5Hz) for two seconds48,49. The two-second trains will be repeated 20 
times every 10 seconds (4 minutes total stimulation time), and followed by a 20 minute rest period. This 
sequence will be repeated 4 times. Behavioral effects of stimulation last at least 36 hours after one 
stimulation session with this protocol1. TMS is FDA-approved for the treatment of symptoms of 
depression, and is a widely-used safe clinical tool. 
6.1.3 DOSING AND ADMINISTRATION 
During the first stimulation session in the study, participants will receive a motor thresholding procedure 
in which electrodes are attached to the first dorsal interosseous muscle of the right hand, or another 
muscle on the hand or arm that is accessible to be targeted by TMS to the motor cortex. The 
contralateral motor cortex will be targeted by single pulses of TMS with increased stimulator output 
until a motor evoked potential (MEP), defined as a near-instantaneous increase in muscle activity 
greater than 200 microvolts, is generated. Next, the intensity of single pulse TMS will be lowered until a 
MEP is generated on five out of 10 pulses. This is defined as the individual’s motor threshold. If MEP 
determination of motor threshold is not possible, the researcher will use visible twitches as a proxy for 
MEP. Participants will receive iTBS at 80% of their motor threshold.  
Subjects will undergo iTBS to the mPFC, left DLPFC, and left primary sensory area in a triple cross-over 
study design. I will use a MagVenture MagPro X100 TMS device with active cooling coil. Stimulation 

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location will be determined using  established scalp coordinates for each stimulation location with the 
“10-20” international coordinate system 42–45. For the mPFC, stimulation will be done at the Fp1 EEG 
electrode location, which can be calculated as along the midline of the scalp and 10% of the distance from 
nasion to inion. For left DLPFC, stimulation will be done at the F3 location using the Beam-F3 
technique46,47.  For the primary sensory cortex, stimulation will be done 1.5cm posterior to the motor 
hotspot used for intensity calibration. Accelerated iTBS will be performed in the reclined position to 
reduce symptoms of orthostatic hypotension, with subjects awake and at rest. Subjects will receive bursts 
of 3 pulses at 50 Hz repeated at 200-msec intervals (5Hz) for two seconds48,49. The two-second trains will 
be repeated 20 times every 10 seconds (4 minutes total stimulation time), and followed by a 20 minute 
rest period. This sequence will be repeated 4 times. Behavioral effects of stimulation last at least 36 hours 
after one stimulation session with this protocol1.  
A high-density EEG net (128 electrodes including electrooculography electrodes; MagStim EGI, Inc.) and 
two submental electromyography (EMG) electrodes will be applied. Continuous qEEG recording will be 
performed for 8 minutes while the participant is asked to keep their eyes open and focused on a 
crosshairs. Sampling rate during the continuous recording will be 1 kHz with Cz as the reference and a 
channel between Cz and Pz as ground, using an EGI system with SDK AmpServer Pro (Geodesic, Eugene, 
Oregon). Collecting EEG with TMS does not pose any additional risk over TMS on its own. EEG electrodes 
are placed on the scalp to record electrical brain activity. EEG does not involve brain stimulation and is 
used purely as a neuroimaging tool, posing minimal risk. 
 
6.2 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
To control for bias, we have decided on a prospective, controlled, triple crossover (three stimulation 
locations at separate study visits) study design. Participants will be blinded as to stimulation location, and 
each participant will experience stimulation at all locations. Each participant will have all rating scales 
performed by the same rater. Potential confounding factors, such as age, disease duration, cognitive 
function, and overall disease severity will be evaluated and controlled for, as indicated, in the final 
statistical models.  
Stimulation order will be randomized and counter-balanced. Participants are assigned a study ID number 
and randomized upon signing the informed consent form. Subject ID will be entered into the 
randomization algorithm by the research assistant. A randomization table will be generated by a 
computerized script that randomizes and counterbalances by ID, generating an Excel spreadsheet. We will 
perform complete counterbalancing, there are 6 potential sequences (mPFC-DLPFC-S1, mPFC-S1-DLPFC, 
DLPFC-mPFC-S1, DLPFC-S1-mPFC, S1-mPFC-DLPFC, S1-DLPFC-mPFC) and a plan for 48 participants. Every 
effort will be made to completely counterbalance our sample. Thus effects of stimulation order will be 
minimized. 
Treatment Assignment Procedures: Participants will receive stimulation to the medial prefrontal cortex, 
the dorsolateral prefrontal cortex, and the primary sensory cortex. The order of stimulation will be 
randomized and counterbalanced. Randomization will be performed using a script that generates a 

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spreadsheet. Randomization will be done after the screening visit is completed, before initiation of 
stimulation sessions. 
 
6.3 
STUDY INTERVENTION COMPLIANCE 
Compliance is determined by completion of all three stimulation sessions. 
6.4 
CONCOMITANT THERAPY 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications and supplements. Information 
about concomitant medications will be collected in pre-screening procedures, at the screening visit, and 
at each stimulation visit. Excluded medications include antihypertensive medications, diuretics, and 
alpha-blocking medications. 
 
6.4.1 RESCUE MEDICINE 
N/A 
   
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from stimulation does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the study protocol.  If a clinically significant finding is 
identified (including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
All remaining study questionnaires  
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 

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• 
There are factors that, in the opinion of the PI, would place the participant at increased physical 
or psychological risk, or preclude the participant’s compliance or completion of the study 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Case Report Form (CRF). Subjects who sign the informed consent form and are randomized but do 
not receive the study intervention may be replaced.  Subjects who sign the informed consent form, 
and are randomized and receive the study intervention, and subsequently withdraw, or are 
withdrawn or discontinued from the study, will not be replaced. 
 
Safety data will be collected on any participant that is discontinued due to an AE or SAE. Every effort 
will be made to complete protocol-specific follow up procedures if possible. If voluntary withdrawal 
occurs, the participant will be asked to continue scheduled evaluations and complete an end-of-
study evaluation. Medical and psychological follow up will be coordinated by the research team as 
described in this protocol. The researcher will make a note to file for all withdrawals.  
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled visits and is 
unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within two 
weeks and counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
8.1.1 SELF-COMPLETED QUESTIONNAIRES 
Participants will fill out the following questionnaires: 
• 
Scales for Outcomes in Parkinson’s – autonomic (SCOPA-AUT) – Autonomic self-completed 
symptom questionnaire, contains 21 questions plus 2 questions that are specific for men and 
2 specific for women; therefore ever participant will answer 23 questions52. Each item score 
range is 0-3 for severity of symptoms. Score range is 0-69 points, where higher points 

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indicates higher burden of symptoms. This will be completed prior to each stimulation session 
in person, and over telephone one day after and 4 days after stimulation 
• 
Orthostatic Hypotension Questionnaire (OHQ)53 - a validated questionnaire for symptoms of 
orthostatic intolerance, contains 10 questions. Each question is scored out of 10 possible 
points. Score range is 0-100, where higher points indicates higher burden of symptoms. This 
will be completed prior to each stimulation session in person, and over telephone one day 
after and 4 days after stimulation 
• 
Beck Depression inventory II (BDI-II)54 - recommended tool for screening and assessment of 
depression severity in PD55. Consists of 21 questions, each question ranges in score from 0-3 
points. Score range is 0-63, where higher points indicates higher burden of symptoms. This 
will be completed prior to each stimulation session in person, and over telephone one day 
after and 4 days after stimulation 
• 
MDS - Unified Parkinson’s disease Rating Scale (MDS-UPDRS) parts 1b and 2 – Validated 
clinical tool, it is a rating scale for disease severity in Parkinson’s disease. Part 1b is the Non-
Motor Aspects of Experiences of Daily Living, and consists of 7 questions, each worth 0-4 
points. Score range is 0-28 points. Part 2 is the patient ADL questionnaire and contains 13 
questions51, each worth 0-4 points. Score range is 0- 52 points, This will be completed at the 
screening visit only. 
• 
Freezing of Gait questionnaire– Assesses symptoms of freezing of gait in Parkinson disease. 
Continains 6 questions, each scored 0-456. Score range is 0-24, with higher score meaning 
higher burden of symptoms. This will be completed at the screening visit only 
• 
Epworth sleepiness scale – Assesses symptoms of fatigue and sleepiness. Contains 8 
questions, each scored 0-4.57 Score range is 0-24, with higher score meaning higher burden of 
symptoms. This will be completed at the screening visit only. 
• 
REM sleep disorder screening questionnaire – Screening questions about symptoms of REM 
sleep behavior disorder. This questionnaire contains 10 questions, one question has 4 parts58. 
Each question and question part is scored 0-1. Score range is 0-13, with higher score indicating 
higher burden of symptoms. This will be completed at the screening visit only 
8.1.2 OBJECTIVE EVALUATIONS 
Participants will undergo the following disease rating scales and cognitive examination evaluations prior 
to stimulation: 
• 
The MDS UPDRS part Ia - this is a questionnaire, administered by the investigator, and consists 
of 6 question, each scored 0-4 points. Score range is 0-24. It takes 10 minutes to administer51. 
This will be completed at the screening visit 
• 
MDS UPDRS part III – this is the neurological examination portion of the MDS UPDRS, and 
takes about 10 minutes to complete51. Each question is scored 0-4. Score range is 0-132, with 
higher score indicating higher burden of motor symptoms. This will be completed at the 
screening visit 
• 
The MDS UPDRS part IV – this is the dyskinesia rating portion. It consists of 6 questions, each 
scored from 0-4 points and takes 10 minutes to complete51. Score range is 0-24. This will be 
completed at the screening visit. 

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• 
MoCA – Montreal Cognitive Assessment. This is a neurocognitive screening tool, and takes 
about 15 minutes to administer50. The visiospatial/executive function portion consists of 
three questions with a score range of 0-5; the naming portion consists of three questions with 
a score range of 0-3; the attention portion consists of 4 questions with a score range of 0-6; 
the abstraction portion has 2 questions and has a score range of 0-2; The delayed recall is one 
question and is scored 0-5 points; and orientation is 6 questions with a score range of 0-6 
points. The total score range is 0-30, where lower score indicates higher burden of symptoms. 
This will be completed at the screening visit. 
• 
Participants will undergo EEG before and immediately after brain stimulation. A high-density 
EEG net (128 electrodes including electrooculography electrodes; MagStim EGI, Inc.) and two 
submental electromyography (EMG) electrodes will be applied. Continuous EEG recording will 
be performed for 8 minutes while the participant is asked to keep their eyes open and focused 
on a crosshairs. Sampling rate during the continuous recording will be 1 kHz with Cz as the 
reference and a channel between Cz and Pz as ground, using an EGI system with SDK 
AmpServer Pro (Geodesic, Eugene, Oregon). EEG frequency will be reported in Hz. The 
primary outcome measure, FMT power, will be reported in 𝜇. 
• 
iTBS: Subjects will undergo iTBS to the mPFC, left DLPFC, and left S1 in a triple cross-over study 
design. The MagVenture MagPro X100 TMS device with active cooling coil will be used. 
Stimulation location will be determined using  established scalp coordinates for each 
stimulation location with the “10-20” international coordinate system 42–45. For the mPFC, 
stimulation will be done at the Fp1 EEG electrode location, which can be calculated as along 
the midline of the scalp and 10% of the distance from nasion to inion. For left DLPFC, 
stimulation will be done at the F3 location using the Beam-F3 technique46,47.  For the primary 
sensory cortex, stimulation will be done at the motor hotspot used for intensity calibration. 
Stimulation will be delivered at 80% active motor threshold. Accelerated iTBS will be 
performed in the reclining position to reduce symptoms of orthostatic hypotension, with 
subjects awake and at rest. Subjects will receive bursts of 3 pulses at 50 Hz repeated at 200-
msec intervals (5Hz) for two seconds48,49. The two-second trains will be repeated 20 times 
every 10 seconds (4 minutes total stimulation time), and followed by a 20 minute rest period. 
This sequence will be repeated 4 times. Behavioral effects of stimulation last at least 36 hours 
after one stimulation session with this protocol1. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
Pre-screening for the study will involve review of the medical chart for the presence of exclusionary 
criteria, particularly medical conditions and medications, which may put the participant at risk during 
the study. These criteria will also be reviewed with the participant at the screening visit and at each 
stimulation session prior to stimulation. Screening will be performed within 21 days of initial study 
stimulation visit. 
 
Safety will be monitored throughout the study. A stimulation adverse effects questionnaire will be used 
based on common side effects experienced with TMS. This questionnaire will be administered at the end 
of each stimulation session. Additionally, participants will be continually asked about their comfort level 
during stimulation sessions. If a participant reports greater than moderate level of discomfort during 
stimulation, the stimulation will be immediately discontinued. 
 

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The PI will monitor the study for any adverse and serious adverse events. All serious adverse events will 
be reported to the IRB. Should there be a serious adverse event that occurs that increases the risks to the 
participants, the study will be stopped and an investigation will be conducted and a findings report 
generated before the study is resumed. At the time of enrollment, we will ensure we have an active and 
accurate phone number on file to contact the subject.  
 
Medical follow-up 
In the event that a subject is found during the course of the study to need medical or psychological follow-
up related to their study involvement, the following procedures will be followed to address their issues. 
 
Medical: For urgent issues, we will direct subjects to the nearest emergency room versus urgent care 
center for evaluation, based off of the described difficulties and symptoms. For nonurgent (subacute, 
chronic) issues related to neurologic condition, a follow-up appointment within our department will be 
scheduled for within 72 hours of the communication. If the issue is unrelated to their movement disorder 
but also nonurgent, we will communicate with the subject’s primary care physician and, when 
appropriate, disclose necessary information regarding the study protocol should it be relevant to the 
complaints at hand. 
Psychological: for urgent issues, we will direct subjects to the nearest crisis unit if necessary (including but 
not limited to suicidal ideations or intentions, severe and rapid depression/anxiety). For nonurgent 
(subacute/chronic) issues, will supply patient with local mental health care specialists near them as well 
as contact information for those within the university system to obtain the next available appointment. 
 
The burden of cost of all medical care for conditions which arise in the course of participation in the study 
will on the subject. In case symptoms occur outside of business hours, the subjects will be provided the 
telephone number of the hospital page operator and the operator will be asked to page the PI directly. 
For non-urgent issues, the subjects will be asked to call Dr. Sklerov’s office number or the research 
assistant’s phone number which are listed on the consent form of which the subject will receive a copy. 
For urgent or emergent issues, the subjects will be instructed to present to their nearest emergency room. 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 

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they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
 
8.3.3.3 EXPECTEDNESS  
 
The PI will be responsible for determining whether an adverse event (AE) is expected or unexpected.  An 
AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent with 
the risk information previously described for the study intervention. 
 

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8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT 
ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits, during study telephone calls, and interviews of a study participant 
presenting for medical care. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
Study personnel will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit.  Events will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
All AEs will be captured and recorded at each stimulation visit in person, and one day after, and four days 
after each stimulation visit over telephone. The AE report form will be completed by the researcher, and 
will include details about the stimulation, what is known about previous reported side effects, if the AE 
occurred in temporal relation to the stimulation, whether the AE improves or completely resolves once 
stimulation is ceased, whether the AE is worsening of a baseline symptom, and whether the AE is related 
to concurrent medication or medical condition. This form will be presented to the PI who will review and 
sign the form. Completed forms will be placed in the participant’s file in the study binder. AEs will also be 
documented in the AE log, which will also document the date, severity, relationship to treatment (as 
determined by the PI), actions taken, and outcome. Medical conditions and symptoms present prior to 
start of stimulation on the day of the visit will not be considered an AE. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
The study investigator shall complete an Unanticipated Adverse Device Effect Form and submit to the 
reviewing Institutional Review Board (IRB) as soon as possible, but in no event later than 10 working 
days after the investigator first learns of the effect.  The study team is responsible for conducting an 
evaluation of an unanticipated adverse device effect and shall report the results of such evaluation to 
the Food and Drug Administration (FDA) and the reviewing IRB within 10 working days after they first 

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receive notice of the effect. Thereafter, the sponsor shall submit such additional reports concerning the 
effect as FDA requests. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
N/A 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
N/A 
 
8.3.9 REPORTING OF PREGNANCY  
N/A 
 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
(UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
This definition could include an unanticipated adverse device effect, 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 application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects (21 CFR 812.3(s)). 
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the principal investigator (PI). The UP report will include the following information: 
 

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• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor within 10 days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB within 30 days of the investigator becoming aware of 
the problem.  
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO 
PARTICIPANTS  
N/A 
 
9 
STATISTICAL CONSIDERATIONS  
Statistical planning and analysis will be done by the PI Dr. Sklerov in collaboration with Dr. Flavio 
Frohlich and consultation with biostatistician Dr. Hongtu Zhu.  
 
 
9.1 
STATISTICAL HYPOTHESES 
 
Aim 1  
H0: Mean change in Frontal midline theta power on electroencephalogram after iTBS to the medial 
prefrontal cortex will be equal to FMT changes after dorsolateral prefrontal cortex stimulation and 
stimulation of S1. 
H1: Mean change in Frontal midline theta power on electroencephalogram after iTBS to the medial 
prefrontal cortex will be greater than FMT changes after dorsolateral prefrontal cortex stimulation and 
stimulation of S1. 
 
Primary Outcome Measure: The primary objective will test the degree of change in frontal midline theta 
(FMT) power (𝜇 )before and after iTBS at each stimulation location. The primary outcome measure will 
be FMT power. Aim 2a Hypothesis: 
H0: There is zero correlation between severity of autonomic dysfunction symptoms at baseline before 
stimulation with frontal midline theta power at baseline on electroencephalogram. 

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H1: There is a negative correlation between severity of autonomic dysfunction symptoms at baseline 
before stimulation with frontal midline theta power at baseline on electroencephalogram. 
 
 
Aim 2b Hypothesis:  
H0: There is no correlation between severity of depression symptoms at baseline before stimulation with 
frontal midline theta power on electroencephalogram at baseline. 
H1: There is negative correlation between depression symptoms at baseline before stimulation with 
frontal midline theta power on electroencephalogram at baseline. 
 
• 
Primary Outcome Measures: We will test associations between autonomic symptoms, depression 
symptoms, and FMT power at baseline before stimulation, where the FMT power (𝜇) will be the 
primary outcome measure.  
Exploratory objectives 
Aim 3 Hypothesis:  
H0: Change in SCOPA-AUT and OHQ will be zero one day after stimulation and 4 days after stimulation 
compared to pre-stimulation. 
H1: Change in SCOPA-AUT and OHQ will be less than zero one day after stimulation and 4 days after 
stimulation. 
 
• 
Primary Outcome Measures: Change in SCOPA-AUT and OHQ from before to one day and 4 days 
after stimulation 
 
Aim 4 Hypothesis:  
H0: Change in BDI-II will be zero one day after stimulation and 4 days after stimulation compared to pre-
stimulation. 
H1: Change in BDI-II will be less than zero one day after stimulation and 4 days after stimulation. 
 
• 
Primary Outcome Measure: Change in BDI-II before to one day and 4 days after stimulation 
Aim 5  is to maintain a de-identified database of EEG, clinical, and demographic data from people with 
PD undergoing iTBS. 
 
 

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9.2 
SAMPLE SIZE DETERMINATION 
Aim 1: There is no preliminary data for effect size estimation using the paradigm and patient population 
suggested in this study. The primary outcome measure in aim 1 is change in FTM.  
H0: Mean change in Frontal midline theta power on electroencephalogram after iTBS to the medial 
prefrontal cortex will be equal to FMT changes after dorsolateral prefrontal cortex stimulation and 
stimulation of S1. 
H1: Mean change in Frontal midline theta power on electroencephalogram after iTBS to the medial 
prefrontal cortex will be greater than FMT changes after dorsolateral prefrontal cortex stimulation and 
stimulation of S1. 
I expect a medium effect size of f2 ≥0.15. With significance level set at 𝛼 = 0.05, using linear multiple 
regression modeling in G*Power software, with 3 predictors, an N of 45 subjects yields power of 0.82 for 
this crossover design. In a published study examining theta power using EEG plus iTBS at the dorsolateral 
prefrontal cortex in healthy adults, they found significant changes in theta power after iTBS with an N of 
10 subjects59. Therefore we propose 48 subjects for this current study, which should sufficiently power 
our study for the primary outcome measures. 
Aim 2: Though there is no preliminary data for theta band power correlates of depression or autonomic 
symptoms in Parkinson’s disease, there are studies that have looked at EEG spectral power correlations 
of cognitive symptoms in PD. In one study that contained sufficient published data to calculate power, 
they found a correlation between EEG spectral power and executive dysfunction in PD with an OR of 0.130 
(95% CI [0.02-0.83])60. The primary outcome measure in Aim 2a and Aim 2b is FTM. I used G*Power 
software to calculate sample size for a linear regression model with a significance level set at 𝛼 = 0.05 and 
Power = 0.80, which yielded a necessary sample size of 22 subjects. 45 subjects yields a power of 0.98 
(95% confidence interval [0.24 – 0.99]). We will propose to recruit 48 subjects to ensure that our study is 
sufficiently powered. 
Aim 2a: 
H0: There is zero correlation between severity of autonomic dysfunction symptoms at baseline before 
stimulation with frontal midline theta power at baseline on electroencephalogram. 
H1: There is a negative correlation between severity of autonomic dysfunction symptoms at baseline 
before stimulation with frontal midline theta power at baseline on electroencephalogram. 
Aim 2b:  
H0: There is no correlation between severity of depression symptoms at baseline before stimulation with 
frontal midline theta power on electroencephalogram at baseline. 
H1: There is negative correlation between depression symptoms at baseline before stimulation with 
frontal midline theta power on electroencephalogram at baseline. 

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Exploratory objectives: There are no controlled studies using TMS or iTBS to treat autonomic symptoms. 
I used a meta-analysis of iTBS used to treat depression to estimate effect size61. They found a Hegdal g of 
1.0 (95% CI [0.3-1.7])for improvement in depression symptoms after iTBS. The primary outcome measure 
in Aim 3 is change in SCOPA-AUT and OHQ, and the primary outcome measure in Aim 4 is change in BDI-
II after stimulation. Using G*Power software to calculate sample size for a multiple linear regression with 
2 predictors, with 𝛼 = 0.05 and N=45, which yields a power of 0.95 (95% CI [0.26-1.00]). We propose to 
recruit 48 subjects. 
Aim 3: 
H0: Change in SCOPA-AUT and OHQ will be zero one day after stimulation and 4 days after stimulation 
compared to pre-stimulation. 
H1: Change in SCOPA-AUT and OHQ will be less than zero one day after stimulation and 4 days after 
stimulation. 
Aim 4: 
H0: Change in BDI-II will be zero one day after stimulation and 4 days after stimulation compared to pre-
stimulation. 
H1: Change in BDI-II will be less than zero one day after stimulation and 4 days after stimulation. 
Therefore, we propose 48 subjects for this current study which should anticipate adequate levels of power 
for hypothesis testing of parameters defined based on the primary outcome variables. To recruit 48 
participants, based on our recruitment for prior studies with similar patient population at UNC, we 
anticipate pre-screening 400 potential participants’ charts. We anticipate then screening 90 potential 
participants to find 48 participants who fulfill inclusion and exclusion criteria and who are interested in 
participating in the study, and are reasonably expected to be able to complete the study protocol. 
 
9.3 
POPULATIONS FOR ANALYSES 
We will use a modified Intention-to-Treat Analysis Dataset (e.g. participants who at least started the 
stimulation, whether or not they were able to complete the stimulation session, and/or sufficient 
follow-up outcome data). 
 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
 
All data are double entered by independent keyboard operators, compared to identify discrepancies, 
then reconciled with the data manager. All datasets are backed up daily. Linear mixed models with 
repeated measures across different regions or over time will be the primary analytic tool for testing 
our a priori hypotheses. To model correlation among repeated measures, we will primarily consider 
either random intercept or AR(1).  We will use the likelihood ratio test (or Wald test) statistic to test 

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the hypotheses.  We will appropriately handle missing data (e.g., missing responses and/or 
covariates) by using imputation or other methods.    To identify significant component terms in each 
of the models, we will examine the parameter estimates, 95% confidence intervals, and p-values of 
the component terms in an analysis of fixed effects for the final mixed models.  Before undertaking 
statistical modeling, we will perform descriptive analyses and examine the distributions of all 
measures. Appropriate transformations or nonparametric statistical tests will be considered if 
necessary. All statistical estimates of population parameters will be tabulated along with 
corresponding confidence intervals (CIs) and/or standard errors (SEs) to convey levels of precision / 
imprecision.   Following is a detailed plan for testing each hypothesis and the power assessment when 
feasible.  
 
Descriptive statistics: Categorical data (sex) will be presented as percentages. Continuous data (age, 
disease duration, scores on SCOPA-AUT, OHQ, BDI-II, MDS-UPDRS all parts, freezing of gait 
questionnaire, Epworth Sleepiness scale, REM sleep behavior disorder questionnaire, and MoCA,  will be 
presented as means with standard deviation and range. 
 
  
 
Primary analysis, Aim 1: To test the degree of change in the power of FMT before and after iTBS at 
each location, we will use linear mixed models with FMT being the dependent variable. We will 
primarily include stimulation location (mPFC, DLPFC, S1), time (before, after stimulation), and the 
interaction term Location*time in the model.    
Primary Analysis, Aim 2: 1. To test associations of autonomic symptoms in PD subjects with FMT, we 
will use linear regression modeling. The dependent variable will be FMT,  whereas primary covariates 
will be SCOPA-AUT, OHQ score, and magnitude of systolic blood pressure reduction during orthostatic 
blood pressure measurement. We will further use linear regression models to examine the 
associations between depression symptoms in PD subjects and FMT, using linear regression 
modeling. Exploratory Analyses: 1. We will use linear mixed modesl to examine the effect of iTBS on 
autonomic symptoms one day after, and 4 days after stimulation. SCOPA-AUT and OHQ will be the 
dependent variable in the ANOVA analysis. The factors will  be stimulation location (mPFC, DLPFC, S1) 
by time (before and after). 2. Similarly, we will use linear mixed models to evaluate the effect of iTBS 
on depression symptoms one day after, and 4 days after stimulation. BDI-II will be the dependent 
variable, whereas the  primary factors will be stimulation location (mPFC, DLPFC, S1) by time (before 
and after). In all statistical models, Some key confounding factors (age, disease duration) will be 
controlled in both linear mixed effects and regression models. Post-hoc analysis will be performed 
using Tukey’s method to control for multiple comparisons.  
 
9.4.2 ANALYSIS OF THE PRIMARY OUTCOMES 
 
See above 9.4.1 
 
9.4.3 ANALYSIS OF THE EXPLORATORY OUTCOMES 
 
See above 9.4.1 
 
9.4.4 SAFETY ANALYSES 

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Safety outcome will be the adverse effects questionnaire filled out at the end of each stimulation 
session (mean, median, and range), and the presence of AEs, SAEs, and UAEs which are deemed to be 
related to stimulation. AEs, SAEs, and UAEs reporting will be done at each stimulation visit, as well as 1 
day and 4 days after each visit over telephone. Each AE will be counted only once per participant. AEs 
will be reported as start date, stop date, severity, relationship to stimulation, expectedness, outcome, 
and duration. Adverse events leading to premature discontinuation from the study, and serious 
treatment-emergent AEs, will be presented in a table. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Baseline descriptive statistics reported will include age, sex, and disease disease duration, as well as 
scores on scales: MoCA, MDS-UPDRS sub-scores, SCOPA-AUT, OHQ, BDI-II, Epworth Sleepiness Scale, 
Freezing of Gait Questionnaire, REM sleep behavior disorder questionnaire, and orthostatic blood 
pressure reduction. 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
Interval safety assessments will be done quarterly, or more frequently if a SAE arises. During these 
assessments, all AEs and SAEs will be reviewed by the study team and advisors. Changes to the protocol 
will be considered if needed improve safety. All study data will be checked for completeness and quality 
in real-time by study personnel, and at least quarterly, to ensure sound data collection.  
 
9.4.7 SUB-GROUP ANALYSES 
 
Associations between the covariates of gender, age, and disease duration with the dependent and 
independent variables will be evaluated. Covariates will be accounted for in ANCOVA or linear 
regression models, respectively. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT 
DATA 
 
Individual participant data will not be listed. 
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 

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Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.   
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants and the IRB.  If the study is 
prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study 
participants and the Institutional Review Board (IRB) and will provide the reason(s) for the termination 
or suspension.  Study participants will be contacted, as applicable, and be informed of changes to study 
visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the IRB and/or Food and Drug Administration (FDA).] 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. Therefore, the study protocol, documentation, data, 

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and all other information generated will be held in strict confidence. No information concerning the 
study or the data will be released to any unauthorized third party without prior written approval of the 
PI.  
 
All research activities will be conducted in as private a setting as possible. 
This is a single site, investigator-initiated clinical trial, so there is no site monitoring plan in place. The 
latest version of the IRB approved protocol for this clinical trial will be followed. This responsibility is on 
the PI and researchers in the study. If there is a deviation from the protocol, the deviation from protocol 
log will be filled out, and deviations will be sent to the IRB every 8 weeks if necessary. 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB or Institutional policies. 
 
Electronic research data will be stored on password-protected servers within the UNC School of Medicine, 
and on the lab SharePoint, a HIPAA-secure cloud application approved by the UNC School of Medicine. 
Any hard-copy data will be stored in locked cabinets in locked offices in the UNC Department of Neurology. 
This data will be de-identified, and will not include the participant’s contact or identifying information. 
Rather, individual participants and their research data will be identified by a unique study identification 
number. The study data entry and study management systems will be secured and password protected. 
At the end of the study, all study databases will be de-identified. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored as described above. Permission to transmit data 
to researchers outside of the current study will be included in the informed consent.  
 
10.1.5 ETHICAL STANDARD 
The PI will ensure that study procedures are conducted in full conformity with the principles set forth in 
the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, 
as drafted by the US National Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal Regulations 25691 
(1997). 
 
 
10.1.6 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Miriam Sklerov, MD MS 
Assistant Professor of Neurology 
UNC School of Medicine  
170 Manning Drive 
CB#2059 
Chapel Hill, NC 27709 

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914-413-5308 
sklerovm@email.unc.edu 
 
Dr. Flavio Frohlich (Associate Professor, Department of Psychiatry, UNC School of Medicine) and Dr. 
David Rubinow (Professor, Chair Emeritus, Department of Psychiatry, UNC School of Medicine) will serve 
as senior advisors on this protocol. They will work with the PI to review AEs, SAEs, and UAEs, and to 
revise the study protocol or determine termination of the study as indicated. 
 
 
10.1.7 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of the PI, in conjunction with the advisors. The PI will review 
AEs in real time and make decisions regarding a participant’s continuation of the clinical trial. AEs will be 
assessed at each stimulation visit, as well as one day after and four days after each stimulation session 
over telephone. 
 
10.1.8 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
This is a single site, investigator-initiated clinical trial, so there is no site monitoring plan in place. The 
latest version of the IRB approved protocol for this clinical trial will be followed. This responsibility is on 
the PI and researchers in the study. If there is a deviation from the protocol, the deviation from protocol 
log will be filled out, and deviations will be sent to the IRB every 8 weeks if necessary. 
 
Informed consent forms and HIPAA forms will be reviewed regularly to ensure that they are filled out 
appropriately and consent form process was properly followed.  
 
Documentation of Adverse events (AE) and Serios Adverse Events (SAE) will be kept in the study binder 
for each participant, which is found in room 2135 of the UNC Physicians Office Building. It is the 
responsibility of the research staff to report all adverse events to the PI in a timely manner. All AEs and 
SAEs will be discussed with the PI.  
 
10.1.9 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The study personnel will perform quality management of study conduct and study data, documentation 
and completion at least on a quarterly basis for the duration of the study period. Any missing data or 
data anomalies will be reviewed with the PI for clarification/resolution. 
 

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The study will provide direct access to all trial related source data/documents, and reports for the 
purpose of inspection by local and regulatory authorities. 
 
10.1.10 
DATA HANDLING AND RECORD KEEPING  
 
10.1.10.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the study personnel under the supervision of the PI. The 
investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
All questionnaires will be in paper format and will be collected by the study coordinator in person at the 
study visit or via mail as described above. In order to maintain privacy and confidentiality regarding subject 
participation, there will be no more than one printed copy of a spreadsheet with subject ID numbers linked 
to their identifiers, which will only consist of name, medical record number, study ID number, age, and 
date of birth. This spreadsheet will be kept in the office of study personnel, within a locked cabinet with 
multiple layers of physical security to enter this office including necessary UNC employee badge access. 
An electronic copy of this form will be stored in a HIPAA compliant fashion, as detailed below. Once the 
study has ended, only codes shall remain, and the aforementioned spreadsheet shall be destroyed in a 
HIPAA-compliant fashion.  This will not directly affect any UNC medical records. 
 
Consent forms will be scanned and loaded into Epic, and a copy will be saved for our records on the UNC 
School of Medicine Neurology secure server, which is HIPAA compliant and password-secured. The 
original hard copy will be stored in a locked office, inside a locked office cabinet, located in the Physician’s 
office building. The participants will receive a copy of the signed consent form for their own personal 
records. 
 
All clinical data and logs of collected data will be recorded on paper forms and then transferred to 
computerized data forms. Paper forms will be stored in double-locked storage. All computerized records 
will be password protected and HIPAA compliant. Electronic study data will be stored as Excel 
spreadsheets and kept on School of Medicine (SOM) IT secure network, and on a cloud-based UNC SOM 
approved HIPAA-compliant server. Study data may also be stored in the UNC REDCap system. This is a 
secure, password-protected, HIPAA compliant web application developed by the NIH that is widely used 
in clinical research. A data dictionary will be created by the study coordinator and the PI. Data accuracy 
and completion will be monitored periodically by the PI using SAS software to look for missing data points 
and out of range values. Confidentiality will be maintained by storing all collected study information 
labeled with only the anonymous study identification numbers.  Electronic data will be stored using only 
study identification numbers in password protected databases and encrypted endpoints. The linked 
identified data will be stored separately from the deidentified research data on the SOM IT secure 
network. No individual identifying information will be included in any clinical reports or sample logs in this 
study.  
 
Stored data will include all data collected during the course of the study, and data obtained from the 
participants’ clinical chart including autonomic testing parameters, clinical scales, questionnaires, co-

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morbid medical conditions, date of PD diagnosis, age, concomitant medications, prior surgeries. The PI, 
co-Is, and research assistant will be in charge of data management. 
 
10.1.10.2 
STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 5 years have elapsed since the formal 
discontinuation of the study intervention, as recommended by the UNC School of Medicine.  
 
10.1.11 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol or International Conference on 
Harmonisation Good Clinical Practice (ICH GCP). The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the investigator to use continuous vigilance to identify and report deviations 
within 30 working days of identification of the protocol deviation, or within 30 working days of the 
scheduled protocol-required activity.  All deviations must be addressed in study source documents, 
reported to the IRB.  The investigator is responsible for knowing and adhering to the reviewing IRB 
requirements.  
 
10.1.12 
PUBLICATION AND DATA SHARING POLICY 
 
We plan submit the data obtained from this study for publication in a peer reviewed journal in a timely 
manner once recruitment and data analysis are complete.  
10.1.13 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership and institutional regulatory boards have established policies and procedures for all study 
group members to disclose all conflicts of interest and will establish a mechanism for the management 
of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
N/A 
 

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10.3 ABBREVIATIONS 
 
ACC 
Anterior Cingulate Cortex 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ANCOVA 
Analysis of Covariance 
AuD 
Autonomic dysfunction 
BDI-II 
Beck depression inventory - II 
CAN 
Central autonomic network 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
Cz 
Central midline sagittal plane electrode location on electroencephalography 
DBS 
Deep Brain Stimulation 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DLPFC 
Dorsolateral prefrontal cortex 
DMV 
Department of Motor Vehicles 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
EEG 
Electroencephalogram 
EMG 
Electromyogram 
F3 
Left frontal electrode location at position 3 on electroencephalography 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
FMT 
Frontal Midline Theta 
Fp1 
Left anterior pre-frontal electrode location on electroencephalography 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
HTH 
Hypothalamus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
iTBS 
Intermittent Theta-Burst Stimulation 
ITT 
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LSMEANS 
Least-squares Means 
MDD 
Major Depression Disorder 
MDS-UPDRS 
Movement Disorders Society Unified Parkinson’s Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEP 
Motor evoked potential 
MOCA 
Montreal Cognitive Assessment 
MOP 
Manual of Procedures 
mPFC 
Medial Prefrontal Cortex 
MRI 
Magnetic Resonance Imaging 
MSDS 
Material Safety Data Sheet 
NC 
North Carolina 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
NMS 
Non-motor symptoms 
OH 
Orthostatic Hypotension 
OHQ 
Orthostatic Hypotension Questionnaire 
OHRP 
Office for Human Research Protections 
PD 
Parkinson’s disease 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PPMI 
Parkinson’s Progression Markers Initiative 
QA 
Quality Assurance 
QC 
Quality Control 
qEEG 
Quantitative electroencephalogram 
REM 
Rapid eye movement 
rs-fMRI 
Resting State functional MRI 
S1 
Primary sensory cortex 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCOPA-AUT 
SCales for Outcomes in PArkinson’s - Autonomic 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TMS 
Transcranial Magnetic Stimuylation 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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