Exercise and Parkinson's: Comparing Interventions and Exploring Neural Mechanisms
Phase: NA
Conditions: Parkinson Disease
Sponsor: Washington University School of Medicine

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
______________________________________________________________________________________ 
 
1 
EXERCISE AND PARKINSON’S: COMPARING 
INTERVENTIONS AND EXPLORING NEURAL 
MECHANISMS 
 
NCT01768832 
 
1R01NS077959-01A1 
 
LAST REVISED JULY 25, 2015 
 
LAST REVIEWED AND APPROVED BY IRB 
DECEMBER 1, 2017

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
______________________________________________________________________________________ 
 
2 
 
TABLE OF CONTENTS 
 
A 
INTRODUCTION ............................................................................................................................... 4 
A1 
STUDY ABSTRACT ......................................................................................................................... 4 
A2 
PRIMARY HYPOTHESIS ................................................................................................................... 4 
A3 
PURPOSE OF THE STUDY PROTOCOL .............................................................................................. 5 
B 
BACKGROUND .................................................................................................................................. 5 
B1 
PRIOR LITERATURE AND STUDIES .................................................................................................. 5 
B2 
RATIONALE FOR THIS STUDY ......................................................................................................... 8 
C 
STUDY OBJECTIVES........................................................................................................................ 8 
C1 
PRIMARY AIM ................................................................................................................................ 8 
C2 
SECONDARY AIM ........................................................................................................................... 9 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ........................................................... 9 
D 
INVESTIGATIONAL AGENT .......................................................................................................... 9 
D1 
PRECLINICAL DATA ................................................................ERROR! BOOKMARK NOT DEFINED. 
D2 
CLINICAL DATA TO DATE .......................................................ERROR! BOOKMARK NOT DEFINED. 
D3 
DOSE RATIONALE AND RISK/BENEFITS ..................................ERROR! BOOKMARK NOT DEFINED. 
E 
STUDY DESIGN ................................................................................................................................. 9 
E1 
OVERVIEW OR DESIGN SUMMARY ................................................................................................. 9 
E2 
SUBJECT SELECTION AND WITHDRAWAL......................................................................................10 
2.a 
Inclusion Criteria ....................................................................................................................10 
2.a 
Exclusion Criteria ....................................................................................................................10 
2.b 
Ethical Considerations ............................................................................................................10 
2.c 
Subject Recruitment Plans and Consent Process ....................................................................11 
2.d 
Randomization Method and Blinding ......................................................................................12 
2.e 
Risks and Benefits ....................................................................................................................12 
2.f 
Early Withdrawal of Subjects ..................................................................................................13 
2.g 
When and How to Withdraw Subjects ......................................................................................13 
2.h 
Data Collection and Follow-up for Withdrawn Subjects .........................................................13 
E3 
STUDY DRUG ................................................................................................................................13 
3.a 
Description ................................................................................ Error! Bookmark not defined. 
3.b 
Treatment Regimen .................................................................... Error! Bookmark not defined. 
3.c 
Method for Assigning Subjects to Treatment Groups ................ Error! Bookmark not defined. 
3.d 
Preparation and Administration of Study Drug ......................... Error! Bookmark not defined. 
3.e 
Subject Compliance Monitoring ................................................ Error! Bookmark not defined. 
3.f 
Prior and Concomitant Therapy ................................................ Error! Bookmark not defined. 
3.g 
Packaging .................................................................................. Error! Bookmark not defined. 
3.h 
Blinding of Study Drug .............................................................. Error! Bookmark not defined. 
3.i 
Receiving, Storage, Dispensing and Return .............................. Error! Bookmark not defined. 
F 
STUDY PROCEDURES ....................................................................................................................13 
F1 
SCREENING FOR ELIGIBILITY ........................................................................................................13 
F2 
SCHEDULE OF MEASUREMENTS ....................................................................................................14 
F3 
VISIT 1 ..........................................................................................................................................16 

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F4 
VISIT 2 ETC. ..................................................................................................................................18 
F5 
SAFETY AND ADVERSE EVENTS ....................................................................................................20 
5.a 
Safety and Compliance Monitoring .........................................................................................20 
5.b 
Medical Monitoring .................................................................................................................21 
i 
Investigator only ...................................................................................... Error! Bookmark not defined. 
ii 
Independent expert to monitor ................................................................. Error! Bookmark not defined. 
iii 
Institutional Data and Safety Monitoring Board ...................................... Error! Bookmark not defined. 
iv 
Independent Data and Safety Monitoring Board ...................................... Error! Bookmark not defined. 
5.c 
Definitions of Adverse Events ..................................................................................................21 
5.d 
Classification of Events ...........................................................................................................21 
i 
Relationship ............................................................................................. Error! Bookmark not defined. 
ii 
Severity .................................................................................................... Error! Bookmark not defined. 
iii 
Expectedness ........................................................................................... Error! Bookmark not defined. 
5.e 
Data Collection Procedures for Adverse Events ....................... Error! Bookmark not defined. 
5.f 
Reporting Procedures ..............................................................................................................22 
5.g 
Adverse Event Reporting Period ..............................................................................................22 
5.h 
Post-study Adverse Event ........................................................................................................22 
F6 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ....ERROR! BOOKMARK NOT DEFINED. 
G 
STATISTICAL PLAN ........................................................................................................................22 
G1 
SAMPLE SIZE DETERMINATION AND POWER .................................................................................23 
G2 
INTERIM MONITORING AND EARLY STOPPING ..............................................................................24 
G3 
ANALYSIS PLAN............................................................................................................................24 
G4 
STATISTICAL METHODS ................................................................................................................24 
G5 
MISSING OUTCOME DATA ............................................................................................................24 
G6 
UNBLINDING PROCEDURES .....................................................ERROR! BOOKMARK NOT DEFINED. 
H 
DATA HANDLING AND RECORD KEEPING .............................................................................24 
H1 
CONFIDENTIALITY AND SECURITY ................................................................................................24 
H2 
TRAINING......................................................................................................................................25 
H3 
CASE REPORT FORMS AND SOURCE DOCUMENTS .........................................................................25 
H4 
RECORDS RETENTION ...................................................................................................................25 
H5 
PERFORMANCE MONITORING .......................................................................................................25 
I 
STUDY MONITORING, AUDITING, AND INSPECTING ..........................................................25 
I1 
STUDY MONITORING PLAN ...............................................................................................................25 
I2 
AUDITING AND INSPECTING ..............................................................................................................25 
J 
STUDY ADMINISTRATION ...........................................................................................................26 
J1 
ORGANIZATION AND PARTICIPATING CENTERS ...........................ERROR! BOOKMARK NOT DEFINED. 
J2 
FUNDING SOURCE AND CONFLICTS OF INTEREST ..............................................................................26 
J3 
COMMITTEES ...............................................................................ERROR! BOOKMARK NOT DEFINED. 
J4 
SUBJECT STIPENDS OR PAYMENTS ....................................................................................................26 
J5 
STUDY TIMETABLE ...........................................................................................................................26 
K 
PUBLICATION PLAN ......................................................................................................................26 
L 
ATTACHMENTS ...............................................................................................................................26 
L1 
TABLES ...................................................................................ERROR! BOOKMARK NOT DEFINED. 
L2 
INFORMED CONSENT DOCUMENTS.................................................................................................26 
L3 
PATIENT EDUCATION BROCHURES...........................................ERROR! BOOKMARK NOT DEFINED. 
L4 
SPECIAL PROCEDURES PROTOCOLS .........................................ERROR! BOOKMARK NOT DEFINED. 
L5 
QUESTIONNAIRES OR SURVEYS .....................................................................................................26 
M 
REFERENCES ...................................................................................................................................27 
 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
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A Introduction 
 
A1 Study Abstract 
Parkinson disease (PD) is a progressive, neurodegenerative disorder that affects 
1-1.5 million people in the United States. Difficulty with walking has been recognized as 
one of the earliest signs marking onset of disability in people with PD [1]. Walking 
difficulties and other symptoms are not fully addressed by current treatment approaches 
[2, 3], making clear the need for additional approaches. Exercise is one such approach. 
Current literature supports use of exercise as an adjunct to traditional treatments for 
improving gait, balance, and quality of life [4]. The primary aims of the proposed work 
are to compare the effects of three community based exercise programs on locomotor 
function and to determine whether and how these interventions alter the function and 
connectivity of locomotor control networks in the brain. To this end, we will utilize task-
based functional magnetic resonance imaging (fMRI) and resting state functional 
connectivity (rs-fc) MRI to assess brain function and connectivity before and after the 
exercise interventions. 
 
One hundred twenty people with PD will be randomly assigned one of three 
community-based exercise groups: tango dancing, treadmill training or stretching 
(control). Tango has been chosen because evidence suggests tango may be superior to 
a more traditional exercise program for improving gait, balance and quality of life [5, 6]. 
Treadmill training has been chosen because studies suggest that it can improve gait and 
quality of life [7]. Stretching has been chosen for the control group because it is an 
intervention that does not directly target walking and will allow us to control for the social 
and attentional aspects of participating in group exercise. Each group will receive 3 
months of intervention, attending tri-weekly one-hour group classes. Each participant will 
be evaluated at three time points over 6 months. MRI and behavioral measures will be  
conducted with participants OFF medication, with behavioral measures also assessed 
ON medication. 
A2 Primary Hypothesis 
 
Hypothesis 1a: Both tango and treadmill training will improve forward walking 
performance, but only tango will improve backward walking performance. Walking 
performance in the stretching group will not change. 
 
Hypothesis 1b: Tango and treadmill training will similarly improve disease severity. 
Tango will result in larger improvements in balance and quality of life compared to 
treadmill training and stretching. 
 
Hypothesis 2a: Following tango, a differential BOLD signal increase will be observed in 
the premotor area, supplementary motor area, and putamen during both imagined 
forward walking and imagined backward walking; following treadmill training, BOLD 
signal will increase in the primary somatosensory cortex and cerebellum during imagined 
forward walking, but not during imagined backward walking. No BOLD signal changes 
will occur in the stretching group. 
 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
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Hypothesis 2b: BOLD signal changes will be directly related to changes in actual 
locomotor performance. 
 
Hypothesis 3a: Following tango, resting state functional connectivity of the premotor 
area, supplementary motor area, and putamen will increase; following treadmill training, 
resting state functional connectivity of the primary somatosensory cortex and cerebellum 
will increase. No changes will occur in the stretching group. 
 
Hypothesis 3b: Changes in resting state functional connectivity of the locomotor control 
network will be directly related to changes in actual locomotor performance. No changes 
will occur in the stretching group. 
A3 Purpose of the Study Protocol 
 
B Background 
 
B1 Prior Literature and Studies 
SIGNIFICANCE 
Parkinson disease (PD) is the second most common neurodegenerative disorder, 
affecting 1-1.5 million Americans. PD is characterized by numerous non-motor and 
motor symptoms including gait dysfunction. Gait dysfunction is of particular concern in 
PD as it is most often the first area of difficulty reported by people with PD and is thought 
to represent the leading edge of disability [1]. As such, the emergence of gait difficulty is 
considered a red flag and there is a clear need to develop interventions that can 
effectively address gait deficits such as reduced speed and reduced stride length [2, 3]. 
These gait difficulties have been noted in PD not only for forward walking, but also for 
backward walking, where gait speed and stride length are even more reduced relative to 
healthy controls [4, 5]. While pharmacological and surgical approaches to the 
management of PD can help to partially alleviate some gait problems, they do not 
completely address the issue, indicating a need for additional and complementary 
approaches to the treatment of gait in PD. Numerous studies have demonstrated the 
effectiveness of exercise as a complementary treatment for improving gait function in 
PD. Among the exercise approaches known to improve walking function, tango and 
treadmill training have recently emerged as two promising therapies for improving gait 
while also providing benefit with respect to disease severity and quality of life (for 
reviews see [6-8]). While these studies have been helpful in identifying possible 
intervention approaches for improvement of gait dysfunction, they have done little to 
elucidate the neural mechanisms by which the improvements are occurring and have not 
directly compared tango to treadmill training. 
 
One of the difficulties in understanding the role of exercise interventions in improved gait 
function for individuals with PD is that the underlying neural mechanisms responsible for 
gait-related disturbances in PD are not well understood. Our lack of understanding of the 
locomotor network may be due in part to the difficulty in collecting imaging data during 
locomotion. Because of the difficulty in accurately using brain imaging techniques to 
examine online locomotion, imagined walking has been used to gain a functional 
understanding of the neural correlates of gait in both healthy controls [9, 10] and 

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populations with neurological disorders [11, 12]. In healthy controls, la Fougère et al. [9] 
compared real walking using positron emission tomography to imagined walking during 
functional magnetic resonance imaging and concluded that while some differences were 
apparent in the final motor pathways, the two tasks resulted in activation of very similar 
locomotor networks. The advent of resting state functional connectivity, which assesses 
activity at rest and therefore eliminates the need to evoke real or imagined locomotor 
behaviors, presents another viable means of assessing locomotor networks using 
imaging. Rs-fcMRI, as its name implies, measures activity at rest and only requires that 
participants lie quietly in the scanner. Rs-fcMRI focuses on spontaneous fluctuations in 
the blood oxygen level dependent (BOLD) signal at rest. These spontaneous fluctuations 
are not random, but rather are correlated among functionally related regions. Previous 
rs-fcMRI results have shown correlations equal to those seen during task-based MRI 
[13, 14]. These spontaneous fluctuations show coherence across areas of the brain 
known to be not only functionally related, but also anatomically connected as  
demonstrated by studies combining rs-fcMRI with diffusion tensor imaging (a technique 
used to trace white matter tracts) [14]. Rs-fcMRI identifies related networks within the 
resting state BOLD data, providing insight regarding the neuronal activation patterns of 
different brain regions and reflecting the amount of functional communication between 
these regions [15]. Rs-fcMRI techniques have been used to successfully identify several 
networks, including the visual, auditory, default mode, and motor networks, among 
others [15, 16]. Rs-fcMRI methods have also been employed in groundbreaking studies 
examining connectivity in disease states such as Alzheimer disease, schizophrenia, 
depression, and several others yielding key advances in our understanding of these 
conditions (for review see [16]). Rs-fcMRI holds great promise as a potential biomarker 
for progression of disease, elucidating compensatory mechanisms associated with 
disease processes, informing targeting of neurosurgical treatments, and investigating 
new treatment strategies. Although used successfully in many other populations with 
neurological disorders, rs-fcMRI has been little utilized to date to study PD. We are 
excited about the possibility of utilizing rs-fcMRI to study individuals with PD. We will 
combine measures of imagined walking (Aim 2) with measures of resting state functional 
connectivity (Aim 3) to gain a fundamental understanding of the human locomotor 
control network in PD and how it is altered by exercise. Both the imagined and the 
resting state tasks have the benefit of not requiring any actual motor output from the 
participants, thus limiting the extent to which the effects of the disease on movement 
production might confound the data collection process. 
 
Tango and PD 
Over 50% of the general population does not achieve recommended daily levels of 
physical activity [17], and activity levels in those with PD may be lower than those of 
individuals without PD [18]. As such, development of exercise programs that are 
enjoyable and engaging, thus promoting regular participation, is critical. Dance may be a 
highly suitable intervention as it incorporates many features recommended as key 
components of exercise programs for those with PD [19] in a format that is engaging, 
motivating and social [20]. Evidence from our studies over the past five years supports 
the beneficial effects of tango on balance, quality of life, disease severity, and most 
importantly for the present proposal, locomotor performance. We have repeatedly 
demonstrated improvements in both forward and backward walking, with increases in 
gait velocity of approximately 0.1 m/s following tango [21-24]. This is not surprising, as 
the basic tango step for the leader is forward walking and for the follower is backward 
walking. In our classes, we have men and women dance both the leader and the 
follower roles equally to ensure that all participants get similar experiences 

Earhart, GM 
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moving in both directions. 
 
We have recently completed a 12-month tango intervention study which suggests that in 
addition to improved gait, participation in tango may convey several other substantial 
benefits including reduced disease severity and a slowed progression of disability over 
the long term [25]. Our earlier work also suggests that tango may be superior to some 
forms of traditional exercise for those with PD [21]. However, the traditional exercise 
program used for comparison to tango in our earlier work was modeled on community-
based classes offered in the St. Louis area that were considered the current standard of 
care. This traditional exercise program did not include many of the elements now 
recommended for a PD-specific exercise program. In the present application, we 
propose to compare tango to an intensity-matched treadmill training program designed 
to specifically target locomotor function in people with PD. 
 
Very few studies have examined the neural underpinnings of dance or the effects of 
tango dancing on brain activity. Brown et al. [26] utilized task-based fMRI to study brain 
activity during production of tango-like leg movements performed to music by healthy 
young subjects lying supine in the scanner. This study specifically implicated the 
putamen in the control of dance movements performed to a metered and predictable 
beat. This work informs our hypotheses (2a and 3a) that locomotion-related activity and 
connectivity of the putamen will increase following tango training in people with PD. To 
our knowledge, the only study to utilize neuroimaging before and after tango training is 
that of Sacco et al. [27], who also studied healthy young controls. Following one week of 
tango training, participants showed increased activation of the supplementary motor 
area (SMA) and premotor area (PMA) during imagined forward walking as compared to 
baseline. This study informs our hypotheses (2a and 3a) that locomotion-related activity 
and connectivity of the SMA and PMA will increase following tango training in people 
with PD. 
 
Treadmill Training in PD 
Over the past decade, there have been several studies examining the effects of treadmill 
training on gait in people with PD. These studies have consistently shown improvements 
in forward walking velocity following training, regardless of the training paradigm or 
training schedule used (for review see [7, 8]). These improvements are, similarly to 
tango, on the order of 0.1 m/s. Some have also noted improvements in balance [28] and 
quality of life [29] with treadmill training, though these aspects have been investigated on 
a very limited basis and are not addressed by most studies. Treadmill training has the 
advantage of being task specific, as walking is the focus of the intervention. We will 
utilize traditional forward walking treadmill training, though we recognize that multi-
directional treadmill training including backward and sideways walking has been utilized 
successfully in people with PD [30]. Multi-directional training is beyond the scope of this 
proposal, however, as we aim to determine the effects of traditional treadmill training. 
Very recent evidence suggests that low intensity treadmill training with more minutes per 
session may be superior to higher intensity training with fewer minutes per session [31, 
32]. As such, we have chosen to implement treadmill training at a speed matched to 
preferred overground walking speed in our proposal. We will utilize a low intensity 
treadmill training approach which will not only follow in line with the latest available 
evidence, but also allow us to keep the intensity of the treadmill training similar to that of 
the tango classes.  
 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
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To our knowledge, there are currently no studies that have utilized neuroimaging to 
examine the effects of treadmill training in PD. This represents a major gap in the 
literature and an obvious hole in our understanding of the mechanisms of action of 
treadmill training in PD. Aims 2 and 3 will address this critical knowledge gap. Despite 
the lack of literature in PD, there is currently a small body of literature describing 
changes in neural activity following treadmill training in other populations including those 
with stroke, spinal cord injury, and hemispherectomy [33-35]. These studies have noted 
increases in activity in the primary somatosensory cortex following treadmill training in 
people with spinal cord injuries [35] and strokes [33]. Furthermore, increases in  
cerebellar activity following treadmill training were seen preferentially in those 
participants with spinal cord injury for whom overground walking performance improved 
[35] to the point of being functional. These studies inform our hypotheses (2a and 3a) 
that activity and connectivity of the primary somatosensory cortex and cerebellum will 
increase following treadmill training in PD. 
 
Exercise and Imaging: A Multi-Faceted Approach 
The proposed direct comparison of tango to treadmill training is critical as it will put these 
two emerging forms of therapy head-to-head in order to determine their differential 
effects on actual locomotor performance (Aim 1), on brain activity during imagined 
walking (Aim 2), and on resting state functional connectivity of the locomotor control 
network (Aim 3) in people with PD. The combination of neuroimaging with exercise 
interventions is novel and will fill important gaps in our knowledge regarding basic 
locomotor control in PD and the mechanisms by which different exercises might convey 
benefit with respect to locomotor function. Previous neuroimaging work in different 
populations, as well as prior work in PD examining the effects of either tango or treadmill 
training on locomotion, sets the stage for this exciting work. Our use of different 
interventions along with two different neuroimaging techniques makes for a powerful and 
multi-faceted approach that will yield an extremely rich data set capable of addressing 
multiple gaps in our current knowledge. 
B2 Rationale for this Study 
Effective treatment of locomotor dysfunction in PD is essential, as gait difficulty is an 
early and major contributor to disability. The proposed study will provide important 
insights into the effects of different modes of exercise on locomotor function in PD, filling 
current knowledge gaps and guiding future design and delivery of optimal exercise 
interventions. This work is innovative because it: 1) uses a community-based exercise 
approach, 2) examines dance as a novel form of exercise and directly compares it to 
traditional treadmill training and stretching, 3) tests participants OFF medication to allow 
more accurate assessment of disease severity, and 4) utilizes two distinct neuroimaging 
approaches, in conjunction with interventions, to explore potential mechanisms of the 
effects of exercise on both brain function and brain connectivity. 
C Study Objectives 
 
C1 Primary Aim 
SPECIFIC AIM 1: To determine the effects of tango, treadmill training, and  
stretching (control) exercise on locomotor function and other aspects of PD. The 
primary variable for this aim is gait velocity. Additional gait variables of interest are stride 

Earhart, GM 
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9 
length, stride length variability, gait asymmetry, interlimb coordination, freezing of gait 
questionnaire scores, and six minute walk test distance. A secondary aim is to compare 
the effects of the different interventions on disease severity, balance, and quality of life. 
 
C2 Secondary Aim 
SPECIFIC AIM 2: To determine the effects of tango, treadmill training and stretching on 
brain activity assessed by task-based fMRI blood oxygen level  dependent (BOLD) 
signal during imagined walking. 
 
SPECIFIC AIM 3: To determine the effects of tango, treadmill training and stretching on 
resting state functional connectivity of the locomotor control network assessed by rs-fc 
MRI. 
 
C3 Rationale for the Selection of Outcome Measures 
To our knowledge, there are currently no studies that have utilized neuroimaging to 
examine the effects of treadmill training in PD. This represents a major gap in the 
literature and an obvious hole in our understanding of the mechanisms of action of 
treadmill training in PD. Despite the lack of literature in PD, there is currently a small 
body of literature describing changes in neural activity following treadmill training in other 
populations including those with stroke, spinal cord injury, and hemispherectomy [33-35]. 
These studies have noted increases in activity in the primary somatosensory cortex 
following treadmill training in people with spinal cord injuries [35] and strokes [33]. 
Furthermore, increases in cerebellar activity following treadmill training were seen 
preferentially in those participants with spinal cord injury for whom overground walking 
performance improved [35] to the point of being functional. These studies inform our 
hypotheses (2a and 3a) that activity and connectivity of the primary somatosensory 
cortex and cerebellum will increase following treadmill training in PD. 
 
D Investigational Agent  
 
None 
E Study Design  
 
E1 Overview and Design Summary 
This study will directly compare tango dancing and treadmill training, to each other and 
to a control group that participates in a stretching program to determine their effects on 
gait and function in people with PD. One hundred twenty people with PD will be 
randomly assigned one of three community-based exercise groups: tango dancing, 
treadmill training or stretching (control). Each group will receive 3 months of intervention, 
attending one-hour group classes. Each participant will be evaluated at three time points 
over 6 months. MRI and behavioral measures will be conducted with participants OFF 
medication, with behavioral measures also assessed ON medication. We will utilize 

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10
brain imaging techniques to examine how participation in these exercise programs 
modifies brain function. The information gained will inform the development of optimal 
exercise interventions, and perhaps other treatment approaches, designed to specifically 
target walking problems in PD. 
 
Screening phone call - 15-20 minutes  - on medicaion 
Pre-Intervention Evaluation - 4.5 hours - off medication 
3 exercise sessions per week for 12 weeks - 1 hour each - on medicaion 
Post Intervention Evaluation Visit - 4 hours - off medication 
Follow-Up Evaluation - 12 weeks after conclusion of exercise class - 2 hours (no fMRI) - 
off medication 
E2 Subject Selection and Withdrawal  
 
2.a 
Inclusion Criteria  
1) at least grade 3/5 strength and normal joint ranges of motion in both legs 
2) vision corrected to 20/40 or better  
3) able to walk independently for 10 feet with or without an assistive device  
4) normal gross somatosensory function in the feet (2-point discrimination, vibration, joint 
kinesthesia, and light touch)  
5) no history of vestibular disease 
6) no evidence of dementia (MMSE ≥ 26, and AD8 ≤ 2 [36, 37]). 
 
PD diagnostic criteria include those used for clinically defined “definite PD”, as 
previously described by Racette et al. [38] based upon established criteria [39-41]. Each 
participant must have had clear benefit from levodopa and meet the above inclusionary 
and exclusionary criteria. All participants will complete the Kinesthetic and Visual 
Imagery Questionnaire (KVIQ-20)[42] with an additional four question imagined gait task 
assessment. This test is used to assess ability to imagine motor tasks and has been 
previously used in PD [43]. Participants with a mean KVIQ-20+gait subsection score 
more than one standard deviation below the mean of an age-matched healthy cohort 
(Earhart lab, pilot data) will be excluded from the study. We anticipate that individuals in 
Hoehn and Yahr stages of I-III will participate. Informed consent will be obtained from 
each participant. 
2.a 
Exclusion Criteria  
1) Serious medical problem (aside from PD)  
2) Use of neuroleptic or other dopamine-blocking drug  
3) Use of drug that might affect balance, like a benzodiazepine  
4) Evidence of abnormality on brain imaging (previously done for clinical evaluations-not 
part of this research)  
5) History or evidence of other neurological deficit, such as previous stroke or muscle 
disease  
6) History or evidence of orthopedic, muscular, or psychological problem.  
 
 
In addition to the above state inclusion and exclusion criteria, all subjects will complete 
the MRI Procedure Screening Form with no contra-indications for MR participation. 

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Indication of any of the following will require follow-up with Dr. Perlmutter and will most 
likely result in exclusion from the study.  
1) Pregnancy  
2) Aneurysm clip(s)  
3) Cardiac pacemaker  
4) Implanted cardioverter defibrillator (ICD)  
5) Electronic implant or device  
6) Magnetically-activated implant or device  
7) Neurostimulation system  
8) Spinal cord stimulator  
9) Internal electrodes or wires  
10) Bone growth/bone fusion stimulator  
11) Cochlear, otologic, or other ear implant  
12) Insulin or other infusion pump  
13) Implanted drug infusion device  
14) Any type of prosthesis (eye, penile, etc.)  
15) Heart valve prosthesis  
16) Eyelid spring or wire  
17) Artificial or prosthetic limb  
18) Metallic stent, filter, or coil  
19) Shunt (spinal or intraventricular)  
20) Vascular access port and/or catheter  
21) Radiation seeds or implants  
22) Swan-Ganz or thermodilution catheter  
23) Medication patch (Nicotine, Nitroglycerine)  
24) Any metallic fragment or foreign body  
25) Wire mesh implant  
26) Tissue expander (e.g., breast)  
27) Surgical staples, clips, or metallic sutures  
28) Joint replacement (hip, knee, etc.)  
29) Bone/joint pin, screw, nail, wire, plate, etc.  
30) IUD, diaphragm, or pessary  
31) Dentures or partial plates  
32) Tattoo or permanent makeup  
33) Body piercing jewelry  
34) Hearing aid (Remove before entering MR system room)  
35) Other implant _______________________  
36) Breathing problem or motion disorder  
37) Claustrophobia Ethical Considerations  
 
2.b 
Subject Recruitment Plans and Consent Process 
 
The principal investigator and research team will identify potential participants from the 
Washington University School of Medicine’s Movement Disorders Center's database of 
more than 2200 people with idiopathic PD, from the Volunteers for Health database or 
via the movement disorders webpage 
(http://neuro.wustl.edu/patientcare/clinicalservices/movementdisorders/movementdisord
ersclinicals). Individual's identified as meeting the study criteria will be initially 
approached either by letter or a phone call. If interest is expressed by the individual a 

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12
phone interview will be conducted to explain the study and identify individuals that meet 
the inclusion criteria. Any individual qualifying for inclusion based on the information 
supplied during the phone interview, will be invited to participate in the study. Informed 
consent will be obtained from each subject by a member of the study team prior to 
starting the experiment. All study team members have enrolled and consented both PD 
patients as well as control participants in the past. 
 
During the consent process, it will be emphasized that participation in this or any other 
study in our lab is done on a voluntary basis only. The investigator completing the 
consent procedure will verbally state and make reference to the written statement about 
withdrawing from the study at any time. 
 
A copy of the consent form will be provided to all participants. 
2.c 
Randomization Method and Blinding 
Participants will be assessed during the week prior to starting the intervention (pre-
intervention), the week following completion of the intervention (postintervention), 
and three months after completing the intervention (follow-up) (Figure 1). At the 
preintervention visit participants will be notified as to whether they were randomized to 
the tango, treadmill or stretching group. Randomization sequences will be generated a 
priori by an independent statistician. Prior to commencing exercise all participants will 
undergo a physical examination and will be required to complete an on medication 
screening graded exercise test per previously established protocols [44-46] in order to 
determine whether or not they can exercise safely. All groups will receive 12 weeks of 
exercise, meeting 3 times per week for one hour each session. The exercise groups will 
thus participate in 180 minutes of exercise per week, meeting the CDC guidelines for 
physical activity[17]. All groups will exercise in community-based group settings to 
ensure that participants have similar experiences with respect to social interactions 
associated with participating in a group exercise class. Participants will be assigned to 
groups using a process of stratified blocked randomization. Self-selected forward gait 
velocity measured at baseline will be used to stratify participants into three categories: 
<1.1 m/s, 1.1-1.3 m/s, and >1.3 m/s. These strata have been chosen based upon our 
preliminary data from 60 individuals tested OFF medication. The average velocity for this 
group was 1.2 +/- 0.1 m/s (mean +/- SD). Thus the middle stratum includes individuals 
within one SD of the mean and the upper and lower strata include individuals more than 
one SD above or below the mean, respectively. Each stratum will be randomized to the 
3 groups using a block size of 10 to ensure that there is no temporal bias and guarantee 
that the number of participants at each level of walking performance who enter each 
study arm is the same. 
2.d 
Risks and Benefits 
There are no identifiable legal, social, or psychological risks associated with participation 
in the proposed studies. The identifiable risks are minimal and we are aware of no 
alternative procedures that can provide the same information.  
 
The potential risks to subjects are: a) effects of withholding overnight medication, b) loss 
of confidentiality, c) stumbling during locomotion, d) falling into the safety harness during 
testing on the treadmill, e) mechanical injury involving moving apparatus, f)Skin irritation 
from surface electrode preparation or rubbing of the electrodes on your skin during data 
collection may occur. g) fatigue associated with long periods of exercise and MRI 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
______________________________________________________________________________________ 
 
13
scanning, h) dizziness after the MRI, i)claustrophobic reaction to being in the MRI tube 
and j) effects of the loud noise generated by the MR scanning sequence. 
 
We do not yet know the full extent to which exercise may benefit people with Parkinson 
disease. Recent evidence suggests that the benefits may include improvements in 
physical function as well as quality of life. This study will allow us to determine what the 
benefits may be and if different types of exercise have different benefits. 
 
This project will be the first to directly compare tango to treadmill training and will explore 
the neurophysiologic changes in brain function and connectivity following these two 
different forms of exercise. The information gained will provide critical insights regarding 
the relative merits of the two exercise approaches for improving function in people with 
PD and add to our understanding of the potential mechanisms by which these 
interventions convey their respective benefits. If the three interventions both impart 
improvements in function and do so through very different effects on the brain, as 
hypothesized, this would suggest that both interventions are beneficial and that a 
combination of exercise might be more effective than either intervention alone as 
different aspects of locomotor control may be targeted. This could lead to future studies 
comparing different combination approaches to exercise rather than single mode 
exercise programs. Future work could examine the effects of different doses of exercise 
or different exercise intensities, the effects of long-term participation in exercise, and the 
retention of benefits through inclusion of follow-up evaluations. The imaging techniques 
proposed herein will also lay the groundwork to allow us to answer many other questions 
regarding locomotor control mechanisms in PD. The potential implications of this work 
are vast and the proposed study will set the stage for much future research. 
2.e 
Early Withdrawal of Subjects  
Based upon our previous intervention studies, we anticipate an attrition rate of 
approximately 15-20% due to dropouts or failure to complete the required minimum of 
85% of classes. 
2.f 
When and How to Withdraw Subjects  
Individuals may withdraw at any time during the duration of the study 
2.g 
Data Collection and Follow-up for Withdrawn Subjects  
No follow-up will be completed for withdrawn subjects 
 
E3 Study Drug  
None 
F Study Procedures  
 
F1 Screening for Eligibility 
Possible participants will be screened via a phone interview. The screening process will 
identify if the individual meets the inclusion criteria stated above and does not meet any 
of the exclusion critera. 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
______________________________________________________________________________________ 
 
14
F2 Schedule of Measurements 
Time requirements: 
Screening phone call - 15-20 minutes  - on medicaion 
Pre-Intervention Evaluation - 4.5 hours - off medication 
3 exercise sessions per week for 12 weeks - 1 hour each - on medicaion 
Post Intervention Evaluation Visit - 4 hours - off medication 
Follow-Up Evaluation - 12 weeks after conclusion of exercise class - 2 hours (no fMRI) - 
off medication 
 
Screening phone call 
Following the consent process we will complete an MRI screening form. If the individual 
is not excluded from completing an MRI scanning session we will continue with the 
screening process.  
 
In addition, all eligible participants must be able to perform the imagined gait tasks in the 
MRI at or above a previously determined threshold. All participants will complete the 
Kinesthetic and Visual Imagery Questionnaire (KVIQ-20) (Malouin, et al, 2007) with an 
additional four question “imagined” gait task assessment (Pickett, Peterson & Earhart, 
2012). The KVIQ-20 is used to assess vividness of mental imagery during motor tasks 
and has been previously used with PD patients (Heremans, et al, 2011). Participants 
with a mean KVIQ-20 + gait subsection score more than one standard deviation below 
the mean of an age matched healthy cohort (data recently collected in Dr. Earhart’s lab) 
will be excluded from the study. 
 
Any individual who is accepted for the study based on the above will be given a packet 
of questionnaires to complete at home and continue on following the procedure below. 
This portion will be completed with a researcher who is blinded to the individual's group 
assignment. The specific questionnaires that will be included in the packet are as 
follows: 
Epworth Sleepiness Scale 
Non-Motor Symptom Questionnaire 
Stages of Readiness to Exercise Questionnaire 
Fall History Questionnaire 
Footedness/Handedness Questionnaire 
Community Healthy Activities Model Program for Seniors (CHAMPS) Physical Activity 
Questionnaire for Older Adults 
Activities Balance Confidence (ABC) Scale 
Geriatric Depression Scale (GDS) 
Prospective & Retrospective Memory Questionnaire (PRMQ) 
 
Visit 1 (pre-test): 
Prior to commencing any exercise all participants will undergo a physical examination 
and will be required to complete an on medication screening graded exercise test per 
previously established protocols (Schenkman, M., et al., 2008; Christiansen, C.L., et al., 
2009; Katzel, L.I., et al., 2001) in order to determine whether or not they can exercise. 
 
A single 90 minute fMRI session will be completed first. During this session, participants 
will have 2 structural scans: a T1-weighted (T1W) sagittal, magnetization prepared rapid 
acquisition with gradient echo (MP-RAGE, TR=2400 ms, TI=1000 ms, TE=3.16 ms, 
FA=15°, 1.0 mm3 voxels, 8:09 min) and a T2-weighted (T2W) fast spin echo (TR=3200 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
______________________________________________________________________________________ 
 
15
ms, TE=455 ms, 1.0 mm3 voxels, 4:43 min). Two functional connectivity scans will be 
acquired via BOLD sensitized fMRI (TR=2200 s, TR=25 ms, 4.0 mm3 voxels, 7-min runs 
of 194 frames). During these scans, participants will remain still and keep their eyes 
closed. Participants will be visual monitored via an eye tracking device during data 
acquitions and will be given an emergency indicator which can be pressed at any time to 
stop the scans. During the imagined walking component 9 minutes of eco-planar 
imaging data will be acquired (TR=2200ms, TE=2.5ms, 4 mm3 voxels) will be acquired 
while the participant views the cue or null condition on a mirror mounted to the head coil. 
 
All individuals will then complete the following battery of questionnaires and 
assessments(approximately 90 minutes): 
Montreal Cognitive Assessment 
Wechsler Test of Adult Reading (WTAR) 
Spatial Delayed Response Task (SDR) 
Nback Working Memory Test (Nback) 
Trail Making Test 
Stroop Test 
Go-No-Go (GNG) 
Verbal Fluency 
RMswitch task 
Frontal Systems Behavior Scale (FrSBe) 
 
All individuals will complete the clinical assessments listed below as well as gait and 
balance testing consisting of the following (approximately 1 hour): 
RMswitch task 
Go-No-Go (GNG) 
Spatial Delayed Response Task (SDR) 
Nback Working Memory Test (Nback) 
Mini Mental Status Exam (MMSE) 
The New Freezing of Gait Questionnaire (nFOG_Q) 
Mini BESTest 
The Smell Threshold Kit 
Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) 
Five times sit to stand (5xSTS) - 6 minute walk (6MWT) - 9 Hole Peg Test (9HPT) 
PDQ-39 
Forward preferred speed, forward fast, backward, tandem and dual task walking on a 
GAITRite computerized walkway system. 
Spatiotemporal gait assessment will be completed simultaneously with the GaitRITE 
assessment. 
 
Exercise training begins: 
 
Each Participant will be assigned to a group (treadmill training, tango dance training or 
stretching) using a process of stratified blocked randomization and notified of their group 
assignment following their initial visit. This is necessary as walking speed must first be 
assessed prior to group assignment.  
 
Within one week of the initial visit, the training sessions will begin. All groups will receive 
12 weeks of exercise, meeting 3 times per week for one hour each session. The 
exercise groups will thus participate in 180 minutes of exercise per week, meeting the 
CDC guidelines for physical activity. All groups will exercise in community-based group 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
______________________________________________________________________________________ 
 
16
settings to ensure that participants have similar experiences with respect to social 
interactions associated with participating in a group exercise class 
 
The individual groups will complete 1 hour of training following the protocol listed below: 
 
Tango Training: Tango classes will be modeled on those of our previous studies, and will 
include a brief warm up and a cool down, with 45 minutes of the hour devoted to tango 
specifically as described previously in our lab. Participants will dance both leading and 
following roles and will change partners frequently in order to ensure that everyone 
spends time moving forward and backward and gets experience dancing with many 
different partners. Partners will be individuals without PD and will include spouses and 
caregivers of those with PD as well as healthy  volunteers. 
 
Treadmill Training: The treadmill training group will have the same warm up and cool 
down period as the tango group with 45 minutes of the hour devoted to walking on the 
treadmill. Participants will walk on the treadmill at their own self-selected comfortable 
pace. Overground walking speed will be reassessed every 2 weeks and treadmill speed 
adjusted as needed to ensure that it continues to match overground walking speed. This 
model of treadmill training was chosen for two reasons: 1) to be of comparable intensity 
to the tango class where the basic dance step is walking done at preferred pace and 2) 
because recent evidence suggests that training at preferred speed for longer durations is 
more effective in enhancing gait than training at higher intensity for shorter blocks of 
time. The periodic reassessment of overground preferred speed and subsequent 
adjustment of treadmill speed will help to ensure that the treadmill training is also 
progressive in nature and in that way mirrors the progressive nature of the tango classes 
as much as possible. 
 
Stretching Group: The stretching class will also have the same warm up and cool down 
as the other groups, with 45 minutes devoted to stretching and flexibility exercises taken 
from the Be Active and Fitness Counts programs.  
 
 
 
Post-Intervention Evaluation (4 hours): 
This assessment will be completed off medication and will exactly mirror the pre-
intervention assessment with the following exceptions: 
No KVIQ/GIQ 
No physical examination and medical screening. 
No consent documents and payment forms. 
 
Follow-Up Evaluation - 12 weeks after exercise classes have ended (2 hours): 
This assessment will be completed off medication and will NOT include an MRI session. 
All other components completed in the post-intervention evaluation will be repeated. 
F3 Forms to be completed prior to first visit 
Following the phone screening session, all individuals who are accepted for the study 
will be sent the following assessments and questionnaires in the mail 
 
Epworth Sleepiness Scale 
Non-Motor Symptom Questionnaire 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
______________________________________________________________________________________ 
 
17
Stages of Readiness to Exercise Questionnaire 
Fall History Questionnaire 
Footedness/Handedness Questionnaire 
Community Healthy Activities Model Program for Seniors (CHAMPS) Physical Activity 
Questionnaire for Older Adults 
Activities Balance Confidence (ABC) Scale 
Geriatric Depression Scale (GDS) 
Prospective & Retrospective Memory Questionnaire (PRMQ) 
 
F4 Visit 1 - Pre-Intervention Evaluation 
Prior to commencing any exercise all participants will undergo a physical examination 
and will be required to complete an on medication screening graded exercise test per 
previously established protocols (Schenkman, M., et al., 2008; Christiansen, C.L., et al., 
2009; Katzel, L.I., et al., 2001) in order to determine whether or not they can exercise. 
 
A single 90 minute fMRI session will be completed first. During this session, participants 
will have 2 structural scans: a T1-weighted (T1W) sagittal, magnetization prepared rapid 
acquisition with gradient echo (MP-RAGE, TR=2400 ms, TI=1000 ms, TE=3.16 ms, 
FA=15°, 1.0 mm3 voxels, 8:09 min) and a T2-weighted (T2W) fast spin echo (TR=3200 
ms, TE=455 ms, 1.0 mm3 voxels, 4:43 min). Two functional connectivity scans will be 
acquired via BOLD sensitized fMRI (TR=2200 s, TR=25 ms, 4.0 mm3 voxels, 7-min runs 
of 194 frames). During these scans, participants will remain still and keep their eyes 
closed. Participants will be visual monitored via an eye tracking device during data 
acquitions and will be given an emergency indicator which can be pressed at any time to 
stop the scans. During the imagined walking component 9 minutes of eco-planar 
imaging data will be acquired (TR=2200ms, TE=2.5ms, 4 mm3 voxels) will be acquired 
while the participant views the cue or null condition on a mirror mounted to the head coil. 
 
All individuals will then complete the following battery of questionnaires and 
assessments(approximately 90 minutes): 
Montreal Cognitive Assessment 
Wechsler Test of Adult Reading (WTAR) 
Spatial Delayed Response Task (SDR) 
Nback Working Memory Test (Nback) 
Trail Making Test 
Stroop Test 
Go-No-Go (GNG) 
Verbal Fluency 
RMswitch task 
Frontal Systems Behavior Scale (FrSBe) 
 
All individuals will complete the clinical assessments listed below as well as gait and 
balance testing consisting of the following (approximately 1 hour): 
RMswitch task 
Go-No-Go (GNG) 
Spatial Delayed Response Task (SDR) 
Nback Working Memory Test (Nback) 
Mini Mental Status Exam (MMSE) 
The New Freezing of Gait Questionnaire (nFOG_Q) 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
______________________________________________________________________________________ 
 
18
Mini BESTest 
The Smell Threshold Kit 
Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) 
Five times sit to stand (5xSTS) - 6 minute walk (6MWT) - 9 Hole Peg Test (9HPT) 
PDQ-39 
Forward preferred speed, forward fast, backward, tandem and dual task walking on a 
GAITRite computerized walkway system. 
Spatiotemporal gait assessment will be completed simultaneously with the GaitRITE 
assessment. 
 
F5 Intervention  
Each Participant will be assigned to a group (treadmill training, tango dance training or 
stretching) using a process of stratified blocked randomization and notified of their group 
assignment following their initial visit. This is necessary as walking speed must first be 
assessed prior to group assignment.  
 
Within one week of the initial visit, the training sessions will begin. All groups will receive 
12 weeks of exercise, meeting 3 times per week for one hour each session. The 
exercise groups will thus participate in 180 minutes of exercise per week, meeting the 
CDC guidelines for physical activity. All groups will exercise in community-based group 
settings to ensure that participants have similar experiences with respect to social 
interactions associated with participating in a group exercise class 
 
The individual groups will complete 1 hour of training following the protocol listed below: 
 
Tango Training: Tango classes will be modeled on those of our previous studies, and will 
include a brief warm up and a cool down, with 45 minutes of the hour devoted to tango 
specifically as described previously in our lab. Participants will dance both leading and 
following roles and will change partners frequently in order to ensure that everyone 
spends time moving forward and backward and gets experience dancing with many 
different partners. Partners will be individuals without PD and will include spouses and 
caregivers of those with PD as well as healthy  volunteers. 
 
Treadmill Training: The treadmill training group will have the same warm up and cool 
down period as the tango group with 45 minutes of the hour devoted to walking on the 
treadmill. Participants will walk on the treadmill at their own self-selected comfortable 
pace. Overground walking speed will be reassessed every 2 weeks and treadmill speed 
adjusted as needed to ensure that it continues to match overground walking speed. This 
model of treadmill training was chosen for two reasons: 1) to be of comparable intensity 
to the tango class where the basic dance step is walking done at preferred pace and 2) 
because recent evidence suggests that training at preferred speed for longer durations is 
more effective in enhancing gait than training at higher intensity for shorter blocks of 
time. The periodic reassessment of overground preferred speed and subsequent 
adjustment of treadmill speed will help to ensure that the treadmill training is also 
progressive in nature and in that way mirrors the progressive nature of the tango classes 
as much as possible. 
 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
______________________________________________________________________________________ 
 
19
Stretching Group: The stretching class will also have the same warm up and cool down 
as the other groups, with 45 minutes devoted to stretching and flexibility exercises taken 
from the Be Active and Fitness Counts programs. 
 
F6 Visit 2 – Post-Intervention Evaluation 
 
A single 90 minute fMRI session will be completed first. During this session, participants 
will have 2 structural scans: a T1-weighted (T1W) sagittal, magnetization prepared rapid 
acquisition with gradient echo (MP-RAGE, TR=2400 ms, TI=1000 ms, TE=3.16 ms, 
FA=15°, 1.0 mm3 voxels, 8:09 min) and a T2-weighted (T2W) fast spin echo (TR=3200 
ms, TE=455 ms, 1.0 mm3 voxels, 4:43 min). Two functional connectivity scans will be 
acquired via BOLD sensitized fMRI (TR=2200 s, TR=25 ms, 4.0 mm3 voxels, 7-min runs 
of 194 frames). During these scans, participants will remain still and keep their eyes 
closed. Participants will be visual monitored via an eye tracking device during data 
acquitions and will be given an emergency indicator which can be pressed at any time to 
stop the scans. During the imagined walking component 9 minutes of eco-planar 
imaging data will be acquired (TR=2200ms, TE=2.5ms, 4 mm3 voxels) will be acquired 
while the participant views the cue or null condition on a mirror mounted to the head coil. 
 
All individuals will then complete the following battery of questionnaires and 
assessments(approximately 90 minutes): 
Montreal Cognitive Assessment 
Wechsler Test of Adult Reading (WTAR) 
Spatial Delayed Response Task (SDR) 
Nback Working Memory Test (Nback) 
Trail Making Test 
Stroop Test 
Go-No-Go (GNG) 
Verbal Fluency 
RMswitch task 
Frontal Systems Behavior Scale (FrSBe) 
 
All individuals will complete the clinical assessments listed below as well as gait and 
balance testing consisting of the following (approximately 1 hour): 
RMswitch task 
Go-No-Go (GNG) 
Spatial Delayed Response Task (SDR) 
Nback Working Memory Test (Nback) 
Mini Mental Status Exam (MMSE) 
The New Freezing of Gait Questionnaire (nFOG_Q) 
Mini BESTest 
The Smell Threshold Kit 
Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) 
Five times sit to stand (5xSTS) - 6 minute walk (6MWT) - 9 Hole Peg Test (9HPT) 
PDQ-39 
Forward preferred speed, forward fast, backward, tandem and dual task walking on a 
GAITRite computerized walkway system. 
Spatiotemporal gait assessment will be completed simultaneously with the GaitRITE 
assessment. 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
______________________________________________________________________________________ 
 
20
 
F7 Visit 3 – Follow-up  
 
A follow-up visit will be scheduled for 12 weeks after the final exercise class has been 
completed. 
 
All individuals will complete the following battery of questionnaires and assessments 
(approximately 90 minutes): 
Montreal Cognitive Assessment 
Wechsler Test of Adult Reading (WTAR) 
Spatial Delayed Response Task (SDR) 
Nback Working Memory Test (Nback) 
Trail Making Test 
Stroop Test 
Go-No-Go (GNG) 
Verbal Fluency 
RMswitch task 
Frontal Systems Behavior Scale (FrSBe) 
 
All individuals will complete the clinical assessments listed below as well as gait and 
balance testing consisting of the following (approximately 1 hour): 
RMswitch task 
Go-No-Go (GNG) 
Spatial Delayed Response Task (SDR) 
Nback Working Memory Test (Nback) 
Mini Mental Status Exam (MMSE) 
The New Freezing of Gait Questionnaire (nFOG_Q) 
Mini BESTest 
The Smell Threshold Kit 
Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) 
Five times sit to stand (5xSTS) - 6 minute walk (6MWT) - 9 Hole Peg Test (9HPT) 
PDQ-39 
Forward preferred speed, forward fast, backward, tandem and dual task walking on a 
GAITRite computerized walkway system. 
Spatiotemporal gait assessment will be completed simultaneously with the GaitRITE 
assessment. 
 
 
F8 Safety and Adverse Events  
 
8.a 
Safety and Compliance Monitoring 
 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
______________________________________________________________________________________ 
 
21
8.b 
Medical Monitoring  
Effects of medication withdrawal will be monitored via patient report and if the effects are 
too severe, participation in the study will be terminated prior to the second day of "off 
medication" testing. 
8.c 
Definitions of Adverse Events 
An adverse event is any patient reported  
8.d 
Classification of Events 
We do not anticipate any adverse events; however, the following procedures will be 
followed to minimize the risk. 
 
a) Temporary Worsening of Parkinson's symptoms. A temporary worsening of 
Parkinson's disease symptoms may result from not taking anti-Parkinson's medication 
for study evaluations. Once the individual resumes taking their medication, symptoms 
should return to their typical levels. Effects of medication withdrawal will be monitored 
and if the effects are too severe, participation in the study will be terminated prior to the 
second day of "off medication" testing . 
 
b) Loss of confidentiality. Loss of confidentiality is highly unlikely. To safeguard against 
this, we will comply with all HIPAA regulations. Data will not be identified by subject 
name. All data will be coded, and code sheets will be stored in locked files. 
 
c) Stumbling during locomotion. Subjects will be closely attended by a physical therapist 
during walking. Walking will be performed in a large, open space and the therapist will 
be prepared to assist subjects who may stumble. It is therefore unlikely that subjects will 
experience falls during testing or will be injured as the result of a fall. 
 
d) Falling into safety harness. During testing on the treadmill, subjects will wear a 
modified parachute harness connected to an overhead beam that is rated to support 
heavy loads. A subject who falls will be supported fully by the harness and is therefore 
unlikely to be injured. Subjects will also be able to hold the support guides which will 
help them to stabilize balance during treadmill testing. In addition, the treadmill will be 
equipped with redundant safety features to prevent subject injury and allow immediate 
cessation of treadmill movement at the touch of a button. 
 
e) Mechanical injury involving moving apparatus. The treadmill is equipped with a safety 
switch that, when pressed, will immediately stop treadmill movement. The treadmill is 
also equipped with a break that can be applied at any time. Treadmill design is such that 
accelerations and decelerations are not abrupt, but are smooth, non-jarring transitions. 
Furthermore, it will be laboratory policy that: 1) the PI or another lab member will always 
be the first test subject for any new protocol and 2) on the day of an experiment, the 
exact protocols to be used will first be run without a subject to ensure proper system 
function. 
 
f)Skin irritation may be prevented by notifying investigators of any potential allergens due 
to adhesive or alcohol (i.e. skin preparation). 
 
g) Fatigue. The proposed study involves one-hour exercise training sessions. Rest 
breaks will be provided as frequently as needed but you still are likely to be tired 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
______________________________________________________________________________________ 
 
22
afterwards. Some of the proposed studies involve stretching, stepping or walking for 
periods of time up to 60 minutes and this may result in fatigue for some subjects. Rest 
breaks will be provided as frequently as possible and no subjects with history or 
indication of orthostatic hypotension will be admitted to the studies. Fatigue during the 
MRI may also occur. We will maintain contact with the participant through out the 
session to monitor them. Additionally we can remove the individual from the scanner if 
they report being too sleepy to continue. 
 
h) Dizziness. At the completion of the test, when the subject may be a little dizzy, 
investigators will walk very near the subject to the outer room and make sure the subject 
is not dizzy before he/she is dismissed. 
 
i) Claustrophobia. All individuals will be screened for previous claustrophobic 
experiences prior to participation. During the scanning sequence all participants will 
have an emergency squeeze bulb in their hand that, when squeezed, will notify the 
researchers of their distress. We will immediately remove the individual from the scanner 
at this time. 
 
j) Loud noise. While inside the magnet, subjects will be able to communicate with the 
investigators through an intercom. To help protect the participant's hearing two levels of 
hearing protection will be worn by all participants. Ear plugs will be inserted into the ear 
and outer headphones will be placed over your ears. Also, they will be given an alarm 
device to press if the intercom system should be ineffective because of the loud noises. 
This alarm will create a definite signal to the investigators that the subject wishes to 
communicate or exit. If a test is in progress, the test will be stopped and investigators will 
either speak to the subject using the intercom or enter the room and take the patient out 
of the magnet. 
 
The risks associated with these studies are minimal. Participant safety will be 
continuously monitored by the PI during experimental sessions and participants will be 
advised of how to contact the PI if they have any concerns that arise outside of these 
sessions.  
8.e 
Reporting Procedures 
Any adverse events will be reported to the local IRB immediately and will trigger an 
immediate review, like the annual review described previously, to determine what 
changes need to be made and whether the study should continue or conclude. 
8.f 
Adverse Event Reporting Period 
Patients will be followed for 12 weeks following their final exercise session. Adverse 
events will be documented throughout this period. 
8.g 
Post-study Adverse Event 
Any advent reported to the investigators following the conclusion of the study will be 
documented and reviewed. 
G Statistical Plan  
 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
______________________________________________________________________________________ 
 
23
G1  Sample Size Determination and Power 
Using PASS software (NCSS, LLC, Kaysville, UT), we have powered each aim based 
upon preliminary data. Our primary variable of interest in Aim 1 is gait velocity. Average 
forward gait velocity +/- SD was 1.2 +/-  0.1 m/s and average backward gait velocity was 
0.6 +/- 0.1 in a sample of 60 individuals with PD (H&Y = 2.4 +/- 0.2) tested OFF 
medication in our laboratory over the past year for a different study. The study has been 
powered to be able to detect differences of 1 SD, or 0.1 m/s, which is equivalent to an 
effect size of 0.4. Changes of 0.1m/s or more in gait velocity have been reported 
previously following both tango [22-24] and treadmill training [8, 29, 61, 62]. With an 
effect size of 0.4, 27 participants per group will provide 89% power to detect differences 
between or within groups using two-tailed tests at a significance level of 0.05. Based 
upon additional preliminary data from our lab, we have determined that this sample size 
is also more than sufficient to adequately power our secondary variables in Aim 1 (MDS-
UPDRS-III, mini-BESTest, PDQ-39).  
 
Aims 2 and 3 have been powered based upon preliminary data from our lab and sources 
in the literature. For Aim 2, our preliminary data from controls before and after a single 
session of treadmill training indicate an effect size of 0.91 for change in beta weights 
using the cerebellum as an exemplar region (pre = -0.094 +/- 0.111, post = 0.418 +/- 
0.116, Figure 9) during imagined forward walking. We recognize that responses in those 
with PD may be less pronounced than in controls and as such have used a very 
conservative effect size of 0.45, half the size of the effect observe in controls, for our 
power calculation. Our preliminary data from people with PD (n=8) imagining forward 
walking indicate a beta weight of -0.075 +/- 0.097, which is comparable to the value 
obtained from young controls at baseline. Utilizing the data from the sample with PD and 
an estimated effect size of 0.45, 18 subjects per groups will provide 80% power to detect 
differences between groups and 88% power to detect within group differences. 
Significant findings of differential BOLD signal changes have been localized in PD 
populations during similar imagined walking MRI paradigms with a total of 12 PD 
participants per group [59], further supporting that our proposed sample size is likely 
adequate. For Aim 3, utilizing rs-fcMRI (Figures 7,8) to determine correlations between 
regions in the locomotor control network, we have powered the study to enable detection 
of differences in correlation coefficients of 0.1 (mean correlation = 1.0, SD = 0.1, p = 
0.05, effect size = 0.44, per data from Wu et al. 2009 and our own preliminary data). We 
will have 80% power to detect between group differences and 88% power to detect 
within group differences with 18 subjects per group.  
 
Based upon our previous intervention studies [23], we anticipate an attrition rate of 
approximately 15-20% due to dropouts or failure to complete the required minimum of 
85% of classes. We also expect MRI related complications due to head motion in 
roughly 30% of tested individuals. This estimate is based upon our preliminary data from 
individuals with PD (Fig. 4, 5) where we lost 24% of scans due to head motion greater 
than 2mm of translation or rotation during a scan. As such, we will recruit 40 subjects per 
group to account for attrition and data loss due to head motion and still obtain the 
needed final sample sizes for each aim. For Aim 1 dropouts will be handled utilizing 
intent to treat analyses with the last observation carried forward. Dropouts will be 
excluded from analyses in Aims 2 and 3 as full imaging data are needed from two time 
points. 

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24
G2  Interim Monitoring and Early Stopping 
The protocol will also be evaluated and the risk to benefit ratio assessed twice annually. 
G3  Analysis Plan and Statistical Methods 
For Aim 1, we will employ a repeated measures ANOVA with group (tango, treadmill, 
and stretching) and time (pre-intervention, post-intervention, and follow-up) as factors to 
determine whether and how these interventions impact gait velocity, our primary variable 
for Aim 1. Similar analyses will also be performed for secondary variables of interest, 
including the MDS-UPDRS-III, mini-BESTest, and PDQ-39. As a secondary analysis for 
gait velocity, MDS-UPDRS-III, and mini-BESTest, we will determine percent difference 
between OFF and ON medication values at pre-intervention and post-intervention time 
points and compare these difference values using RM ANOVAS with group and time as 
factors. (If prescribed medications change over the course of the study then levodopa 
equivalent daily dose will be included as a covariate in these analyses.) This will allow us 
to determine if response to medications was different before vs. after intervention and 
whether this effect differed between groups. Analyses will be conducted using NCSS 
software (NCSS, LLC, Kaysville, UT). All imaging analyses will be conducted using Brain 
Voyager (Brain Innovation, Maastricht, The Netherlands) and custom written Matlab 
(MathWorks, Natick, MA) software. For Aim 2, we will apply random effects general 
linear model analysis using forward and backward imagined tasks as individual 
contrasts. A false discovery rate (FDR) correction will be used to compensate for 
multiple comparisons. BOLD signal changes within the previously specified regions of 
interest will be compared for pre- and post-intervention conditions. Additionally, the three 
groups will be compared to each other in the post-intervention condition using RFX 
ANCOVA. For Aim 3, we will use an independent component analysis (ICA) to examine 
the strength of the correlation coefficients for anatomical regions identified as part of the 
locomotor control network. The strength of these correlations before vs. after 
intervention will be compared via two-tailed RM ANOVAs with group and time as factors. 
Finally, we will correlate BOLD signal changes during the imagined walking tasks (Aim 
2) and changes in connectivity (Aim 3) with changes in motor performance. 
 
G4  Missing Outcome Data 
 
For Aim 1 dropouts will be handled utilizing intent to treat analyses with the last 
observation carried forward. Dropouts will be excluded from analyses in Aims 2 and 3 as 
full imaging data are needed from two time points. 
 
H Data Handling and Record Keeping  
 
H1 Confidentiality and Security 
All data and data monitoring will be kept strictly confidential according to HIPAA 
regulations. Results will be coded and the code sheets will be stored in locked files. 

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25
H2 Training  
All investigators involved with this study will complete safety training, HIPPAA 
requirements and will undergo yearly training by the PI in data handling and 
safeguarding. 
H3 Case Report Forms and Source Documents 
Any adverse events will be reported to the local IRB immediately and will 
trigger an immediate review to determine what changes need to be made and whether 
the study should 
H4 continue or conclude.Records Retention 
Data will not be identified by participant name. All data will be coded, and code sheets 
will be stored in locked files behind a locked door. Records will be stored for a minimum 
of seven years. 
H5 Performance Monitoring  
Participant safety will be continuously monitored by the PI and participants will be 
advised of how to contact Dr. Earhart if they have any concerns that arise outside of 
these sessions. Data quality will also be assessed on an ongoing basis, as data will be 
processed immediately after each experimental session. In addition, Dr. Earhart and Dr. 
Perlmutter will conduct a twice yearly review of data to ensure that the studies are 
progressing in a timely manner. The protocol will also be evaluated and the risk to 
benefit ratio assessed twice annually. All data and data monitoring will be kept strictly 
confidential according to HIPAA regulations. Results will be coded and the code sheets 
will be stored in locked files. 
 
I Study Monitoring, Auditing, and Inspecting  
 
I1 
Study Monitoring Plan & Auditing and Inspecting  
The risks associated with these studies are minimal, as detailed in the Human Subjects 
Research section of the application. Participant safety will be continuously monitored by 
the PI and participants will be advised of how to contact Dr. Earhart if they have any 
concerns that arise outside of these sessions. Data quality will also be assessed on an 
ongoing basis, as data will be processed immediately after each experimental session. 
In addition, Dr. Earhart and Dr. Perlmutter will conduct a twice yearly review of data to 
ensure that the studies are progressing in a timely manner. The protocol will also be 
evaluated and the risk to benefit ratio assessed twice annually. Any adverse events will 
be reported to the local IRB immediately and will trigger an immediate review to 
determine what changes need to be made and whether the study should continue or 
conclude. All data and data monitoring will be kept strictly confidential according to 
HIPAA regulations. Results will be coded and the code sheets will be stored in locked 
files. 

Earhart, GM 
                                                                    Revised July 25, 2015 
 
 
 
 
______________________________________________________________________________________ 
 
26
J Study Administration 
 
J1 Funding Source and Conflicts of Interest 
DHHS, National Institutes of Health 
 
 
J2 Subject Stipends or Payments  
All participants will be paid $75 for each completed MRI session and $50 for the follow-
up evaluation The maximum possible compensation amount equals $200.  
 
Individuals able to begin an MRI session but who withdraw during the session will be 
compensated $25 for their time. 
J3  Study Timetable 
 
 
 
 
 
 
 
 
 
 
K Publication Plan  
 
Preparation and submission of manuscripts is projected to occur in the fifth year of the 
study. 
 
L  Attachments (attached to HRPO document) 
 
L1  Informed consent documents 
One consent document version for all participants. 
 
L2  Questionnaires or surveys 
 
Epworth Sleepiness Scale  
Non-Motor Symptom Questionnaire  
Stages of Readiness to Exercise Questionnaire  
Fall History Questionnaire  
Table 2. Project Timeline 
Year 1 
Year2 
Year3 
Year4 
Year5 
Standardize  Protocol train Personnel 
X 
Recruit Participants 
X 
X 
Evaluate Participants 
X 
X 
X 
X 
Deliver Exercise Interventions 
X 
X 
X 
Data Entry/Verification 
X 
X 
X 
X 
Analyze Data 
X 
X 
Prepare & Submit Manuscripts 
X 

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                                                                    Revised July 25, 2015 
 
 
 
 
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27
The New Freezing of Gait Questionnaire (nFOG_Q)  
Mini Mental Status Exam (MMSE)  
Five times sit to stand (5xSTS) - 6 minute walk (6MWT) - 9 Hole Peg Test (9HPT)  
PDQ-39  
Footedness/Handedness Questionnaire  
Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS)  
Kinesthetic and Visual Imagery Questionnaire (KVIQ) & Gait Imagery Questionnaire 
(GIQ)  
Community Healthy Activities Model Program for Seniors (CHAMPS) Physical Activity 
Questionnaire for Older Adults  
Activities Balance Confidence (ABC) Scale  
Mini BESTest  
Montreal Cognitive Assessment  
Wechsler Test of Adult Reading (WTAR)  
Trail Making Test  
Stroop Test  
Verbal Fluency  
Geriatric Depression Scale (GDS)  
Frontal Systems Behavior Scale (FrSBe)  
Prospective & Retrospective Memory Questionnaire (PRMQ) 
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