Optimizing Motor Training in Parkinson Disease Through Neural Mechanisms (NEURODEGEN)
Phase: NA
Conditions: Parkinson Disease
Sponsor: VA Office of Research and Development

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1. TITLE:  Optimizing Motor Training in Parkinson Disease through Neural Mechanisms
Running Head: Optimizing Motor training in PD through Neural Mechanisms
Principal Investigator: Madeleine E. Hackney, Ph.D.
June 14, 2016
2. Abstract: 
Persons with Parkinson’s disease (PD) have impaired mobility, which adversely affects their quality of 
life. The effectiveness of adapted tango dance, in which participants both lead (internally guide: IG) 
and follow (externally guide: EG) movement has been demonstrated (Hackney & Earhart 2009, 
2010). To improve outcomes in those with PD, the underlying neural mechanisms for both motor 
impairments and improvement must be investigated. IG and EG movements have distinct neural 
patterns. Individuals with PD have trouble with IG movement but this problem is helped by strategies 
employed while “leading”. During “following”, participants with PD can exploit multiple external cues, 
which facilitate movement in PD, because EG tasks bypass the basal ganglia (Freedland et al., 
2002). 
Using a randomized controlled trial design, we will begin with an functional Magnetic Resonance 
Imaging (fMRI) investigation. We will examine neural correlates of a clinically-used foot-tapping task, 
during IG and EG conditions in older persons with and without PD. Then, we will assess the relative 
effectiveness of IG versus EG training used in an adapted tango class, compared to a behavioral 
control (health education) for improved mobility and foot tapping. Participants with PD will be 
assessed for disease severity, and will receive tests of outcome measures while “OFF” and "ON" 
medications, 1 week before training, and 1 week and 1 month after training. Participants must attend 
20 lessons of IG or EG adapted tango in 12 weeks, taught by an experienced instructor. In an fMRI 
scanner, we will assess participants for improved foot tapping after training and investigate changes 
in activation in specific neural circuits in conjunction with training effects upon mobility.
Our long-term goal is to optimize motor training for persons with PD by understanding lower limb 
motor circuitry in PD as well as neural changes in circuitry through which training is effective.
3. Introduction and Background/Significance
Impairments in Parkinson’s Disease: PD affects 1 million Americans and has formidable personal and 
socioeconomic costs (>$34 billion/year) that are increasing.10 PD cases are expected to double by 
2030.11 PD impacts the VHA health care system with 1.65% prevalence, compared to ~1% in the 
general population and 50% of these people use VHA as their only source of health care. Persons 
with PD report 3-4 points lower on the Short-Form 36 physical and mental health-related quality of life 
(QOL) than those with diabetes, heart disease, and stroke.12 Because of impaired gait, balance and 
mobility, people with PD often experience falls which leads to withdrawal from activities, low self-
esteem and poor mood.13 In one study, 70% of PD patients fell within one year and 50% had a repeat 
fall the next year.14 Multiple motor symptoms, including postural instability, gait impairment, turning 
difficulty and dual-tasking problems rob patients of QOL.1 Turning, gait initiation, and walking through 
doorways or other tight spaces can trigger freezing, i.e., a stoppage during gait 15, which affects 53% 
of patients who have had PD 5 years and more.16 Adverse changes to gait while dual-tasking are 
greater in those with PD than those without.17 18 Shorter stride length, and slower gait speed while 
performing a cognitive dual task may result from an underlying cognitive impairment, which is 
common in PD.19 A co-morbidity of mild cognitive impairment is associated with greater falls risk in 

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older people with PD.20 Spatial cognition, 21 set-switching, 22 23 executive function and attention 24 are 
impaired in those with PD, which may affect their mobility. However, exercise programs may improve 
cognition, 25 reduce rates of “near falling”,26 and fall incidence 27 in persons with PD.
Treatment of PD Mobility Impairment: Pharmacology and surgery do not fully address the needs of 
those with PD.2 Effective motor rehabilitation is necessary28, and should be safe, participant-friendly, 
promote high adherence and have demonstrated efficacy in improving disease severity, mobility and 
QOL. Traditional exercise programs often suffer from high attrition rates because of high patient task 
demand and lack of social interaction.29 Ideally, exercise activities should engage and sustain 
interest, because 60% of all Americans older than 65 do not achieve recommended daily amounts of 
physical activity.30 Activity levels in individuals with PD are even further reduced.31 
Several mobility programs are effective (e.g., movement strategies, dance, tandem biking, tai 
chi) for people with PD 8 32-35. Better mechanistic understanding of beneficial exercise effects could 
improve the design of targeted motor rehabilitation interventions for particular symptoms (e.g., 
freezing, bradykinesia, and various disease stages of PD). This information would be of great clinical 
significance to veterans and others with motor impairment of all etiologies, as well as due to PD.
In the last five years, the PI has published a series of studies of training in adapted Argentine-
tango (adapted tango) dance showing gains in mobility and balance, maintained one month later in 
individuals with PD (Hoehn & Yahr stages II-IV).3-5 36-38 Participant-friendly, adapted tango had low 
attrition (15%) demonstrating patient acceptance and feasibility with a diverse patient population. In 
classes, participants alternated between two motor training approaches: a) leading, consisting of 
internally guiding (IG) movement plans, and b) following, consisting of responding to external 
guidance (EG). While feasibility and promising outcomes have been demonstrated, previous studies 
were not designed to make inferences about the causal mechanisms of this intervention. Of interest 
now is what leading and following, in isolation, contribute to the observed benefits, because evidence 
shows IG and EG tasks activate distinct neural pathways, which may impact training effects. 
Internally and Externally Guided Movement Strategies: Qualities of effective rehabilitative programs 
are found in both IG and EG training within the context of adapted tango. For example, training for 
postural instability is most effective if dynamic balance practice and continual adjustment to 
environmental demands are incorporated.39 Specifically for individuals with PD, having complex 
movements broken down into simpler elements by the teacher, done in any dance pedagogy, may 
facilitate motor performance.8 Synchronizing movement to rhythm, inherent to dance, may enhance 
movement speed.40 A partner may enhance balance as even light touch contact can augment 
postural control.41 Nevertheless, there are key differences between IG and EG training that may affect 
training gains in mobility, as well as the neural circuitry that drives IG and EG movement.
Leading, which uses internally guided cognitive and motor skill, is thought to involve employing 
a “movement strategy” that demands increased focus on movement plans and mentally rehearsing 
and/or preparing for movement. Leaders must determine precise spatiotemporal movement 
parameters of a dance sequence. As such, leading may pose a challenge for individuals with PD, 
given that they have deficient executive control, specifically in cognitive processes involved in 
planning and executing complex, goal-directed behavior.42 However, movement strategies involving 
strong cognitive involvement and planning are associated with mobility improvements.8 For example, 
focusing on critical movement aspects (e.g., longer steps, quicker movements) helps individuals with 
PD to achieve nearly normal speed and amplitude.15 Thus, IG training may be helpful for PD patients.
The observed improved function gained via adapted tango in individuals with PD may also be 
due to the multiple external cues used in this training. Abundant evidence demonstrates benefits of 
rehabilitative exercise that exploits external cueing and specifically targets neural systems that 

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support balance 35 43. When following (EG training), participants focus on external cues, which may 
access CTC circuitry and bypass the basal ganglia.9 External cuing has improved movement initiation 
44 45. Other research showed that people with PD have faster reaction times when externally cued 
compared to self-initiated movement.46 Importantly, during EG partnered movement, such as that 
engaged during following in adapted tango, the participant is not required to plan precise 
spatiotemporal parameters of movement (e.g., direction, length of step, timing, and amount of 
rotation). From moment to moment the follower receives movement guidance from the leader via 
tactile and, to a lesser extent, visual cues. Because followers are not devoting attentional resources 
to planning movement, potentially they can attend more to their postural control. 
Because of the benefits of both IG and EG training, we will investigate the relative 
effectiveness of IG (leading) and EG (following) training, within the context of adapted tango, for 
improved mobility and functional performance in comparison to a behavioral control (health 
education), in Aim 2. We postulate that mobility gains will be greater in those who participate in IG 
training if selecting and planning movements is fundamental to gains. However, if training with 
concentrated external cueing is most effective, we expect to see greater mobility improvements in 
those who participate in EG training. 
Neural Mechanisms of Mobility Training: IG and EG training may impact the neural circuitry that 
drives IG and EG movement. However, little is known about the neural mechanisms underlying motor 
and cognitive improvements as a result of rehabilitative training in individuals with PD. A study 
utilizing positron emission tomography (PET) showed improved vocal intensity after training in the 
Lee Silverman Voice Training (LSVT®) LOUD program for speech improvement. These motor 
improvements were correlated with modification in motor, auditory, and prefrontal areas but there was 
no effect on the basal ganglia.47 However, in healthy participants, increased activity in the putamen 
was noted using PET when tango movements were performed to a metered beat.48 In a related 
finding, after a week of tango lessons, healthy individuals exhibited increased activity of 
supplementary motor (SMA) and premotor cortices during imagined walking.49 
Underlying mechanistic commonalities may exist amongst a variety of therapies that effectively 
target symptoms of individuals with PD.50 In the case of deep brain stimulation, stimulating the 
subthalamic nucleus is thought to suppress abnormal downstream network activity produced by the 
malfunctioning basal ganglia.51 If the mechanism of improvement resulting from motor training is 
similar, there may be a reduction in abnormal neural activity along the STC (putamen, ventral 
anterolateral thalamus, rostral SMA and primary motor cortex). Alternatively, with effective treatment, 
there may be enhanced compensatory capabilities within the CTC (cerebellum, ventral posterolateral 
thalamus, lateral premotor cortex and somatosensory cortex).52 Another possibility could be 
increased activity in the basal ganglia, which has been demonstrated to be hypoactive in drug-naïve 
individuals in early stages of PD.53
Neural Mechanisms of Internally and Externally Guided Movement in PD: Knowledge about neural 
changes that may occur after repeated and targeted training with IG and EG tasks will allow us to 
develop better rehabilitation training strategies for those with PD.  In healthy individuals performing 
EG finger-tapping tasks, the CTC circuit is primarily recruited, while during IG tasks the STC circuit is 
primarily recruited. 6 54 55 Given that there is dysfunction of the basal ganglia, which is involved in the 
STC circuit, people with PD have difficulty internally generating movement 7 56.  PD may influence 
STC and CTC circuits on a task-specific basis. For example, during EG movements, people with PD 
activate the CTC network in a way that is very similar to controls; however, in PD patients, both the 
CTC and STC are activated during IG tasks.6 In keeping with the idea of increased compensatory 
activity/connectivity of cerebellar circuits during IG tasks, striato-cortical and striato-cerebellar 
connections are weaker in individuals with PD than in controls, while cortico-cerebellar connections 

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are strengthened.57 As a compensatory response, those with PD tend to recruit the CTC circuit to 
perform IG tasks increasingly with time.55 
Studies investigating IG and EG movement typically have examined finger-tapping tasks.6 55 
Studies that clarify mechanisms of lower limb control are rare. There are differences in the brain 
functional anatomy between hand and foot movements.58 Therefore, to understand the mechanisms 
underlying impairments and training effects in whole-body balance and mobility tasks, lower limb 
neural activity must be investigated within the context of IG and EG tasks in individuals with and 
without PD. Thus we will employ foot-tapping, a task that is used in clinical practice to assess lower 
limb motor control, and also a task that has been adapted to functional neuroimaging. In Aim 1, we 
will investigate and identify neural correlates of performing a foot-tapping task in participants with PD, 
compared to age-matched controls. This will allow us to examine the neural circuitry involved in lower 
limb motor control in persons with PD. Keele et al. (1985)59 demonstrated that finger-tapping, 
forefoot-tapping and heel-tapping are highly correlated, suggesting a common underlying mechanism. 
Therefore, in keeping with studies employing finger-tapping, we hypothesize that IG and EG lower 
limb control will be associated with activation of the STC and CTC circuits, respectively, in healthy 
controls. But, those with PD will activate both the STC and CTC circuits during IG tasks, and only the 
CTC circuit during the EG task. Information gained from the achievement of Aim 1 will further the 
knowledge base of the pathophysiology of lower limb control in those with PD. 
We will use the information gained in Aim 1 about circuits involved in IG and EG movement to 
evaluate the effects of targeted training upon those same circuits in a clinical intervention we will test 
in Aim 2. Importantly, Aim 2 proposes to verify if functional improvement noted on foot-tapping and 
other mobility measures after IG and EG training is related to changes in the activity of IG and EG 
neural networks. We will also investigate the resting state functional connectivity (RSfc) of these 
circuits before and after training, because neural networks are best defined in terms of the structure 
of temporal interactions between regions.60 The resting state represents the intrinsic blood oxygen 
level dependent (BOLD) fluctuations of neural areas. Studying connectivity during resting state 
provides information related to hemodynamic consequences of slow variations in transient neuronal 
dynamics.61 These intrinsic fluctuations have a huge metabolic load, are likely functionally relevant 
and might be used as a marker of network dysfunction. 62 Persons with PD have altered RSfc in 
motor areas.56 63 Examining RSfc of circuits before and after targeted motor training may provide 
information about the pathophysiology of the disease and its training response.  Information gained 
from Aim 2 will provide bases for recommendations of specific motor strategies within a PD 
rehabilitative program. 
Significance
In 2003, the Under Secretary for Health, Department of VA, Dr. Roswell, stated that veterans aged 75 
and older would increase from 4 to 4.5 million and those over 85 would triple to 1.3 million. The 
prevalence of PD increases to 4% in the oldest age groups.64 Veterans with PD have relatively heavy 
disease burden and nearly 80% will be using VHA as their only source of health care.12 Clearly, more 
veterans with PD will need effective and enjoyable rehabilitative modalities that encourage social 
interaction.65 Group exercise programs effectively rehabilitate motor impairments, are social in nature 
and are likely to improve QOL in veterans and others with PD.66 
Through our series of adapted tango studies, which included veterans from WWII, Korea and 
Vietnam, we showed evidence for improved mobility, balance and QOL in those with PD. Now we aim 
to increase our knowledge about the pathophysiology of task-specific mobility impairments, specific 
types of motor training effects and associated changes in brain activity. With information about the 
relative effectiveness of leading and following in tango training we will know: 1) if there is evidence 
that either leading or following movement is superior, 2) preliminary evidence related to the effects of 
each training on executive function, procedural learning and spatial cognition, and 3) neural 

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structures and pathways that are accessed by each form of training. Another novel aspect is that we 
will evaluate neural activity of lower limb movements during EG and IG tasks, which is not well 
understood, nor has it previously been investigated in those with PD. 
This work will contribute to generalized motor theories that will impact care and create more 
efficient motor rehabilitation in these concrete ways: 1) This project is designed to discover general 
principles related to improving movement, e.g., if the IG group improves more than EG, we will 
assume such principles extend beyond tango and we would suggest that incorporating planning and 
initiating movement in mobility intervention may provide greater therapeutic effects. However, if EG 
improves more than IG, we would suggest cueing during training is essential for benefits. 2) Dance 
programs for older adults and individuals with PD are growing popular. Clinicians may use positive 
results from this study to suggest dance as a beneficial avenue for therapy. 3) Increased knowledge 
about the effects of specific types of motor training on neural circuitry will lead to greater specificity of 
treatment for individual patients with particular stages of disease and primary symptoms. Also, we will 
seek to partner with an organization, e.g., the National Parkinson Foundation to develop DVDs and 
manuals, presenting the training program fundamentals, graded to complexity from which clinicians 
can 
extract 
information 
relevant 
to 
their 
practice 
and 
incorporate 
as 
appropriate 
(http://www.parkinson.org/Improving-Care/Education.) Providing mechanistic basis for successful 
rehabilitative protocols involving exercise will lend greater support for clinical and community use, and 
may lead to insurance company support.  Demonstrating mechanisms of neural circuitry will provide 
evidence that training may be effective in ways similar to that of pharmacology and surgical devices, 
e.g., DBS. This project aims to provide enjoyable treatment while investigating neural mechanisms, 
upon which future clinical recommendations can be made. Clearly this novel work has potential to 
impact care and QOL of individuals with PD.
4. Objectives
Statement of Hypotheses and Specific Aims:  
In the VHA health care system, Parkinson’s disease (PD) presents a high illness burden as a result of 
compromised mobility and quality of life (QOL).1 Pharmacological agents and surgical options that 
alleviate impairments do not fully address needs of those with PD. 2 Motor rehabilitation is effective 
and lacks the side effects of pharmacology and surgery, but the underlying neural basis for motor 
improvements is largely unknown. To design better treatments for patients with PD that will improve 
motor function and QOL, we seek to understand the relationship between improved motor function 
and neural changes. Over the last 5 years, the PI has tested the efficacy of PD-adapted tango, which 
improved mobility and QOL in adults with PD after training. Adapted tango is a novel, patient-friendly 
method of motor rehabilitation in which participants learn to alternate leading (internally guided: IG) 
and following (externally guided: EG) partnered movement 3-5. IG and EG motor tasks are likely 
mediated by striato-thalamo-cortical (STC) and cerebello-thalamo-cortical (CTC) circuitry, 
respectively in healthy controls.6 Because PD causes dysfunction in the basal ganglia, patients have 
difficulty with IG tasks. 7 However, this impairment can be remediated by motor rehabilitation that 
uses skills similar to those used when “leading” in tango, in which participants engage cognitively in 
planning and selecting movements.8 Conversely, abundant evidence shows that external cues, such 
as those used for “following” during tango, facilitate movement in PD, presumably because EG tasks 
access CTC circuitry and bypass the basal ganglia.9 During “following”, participants with PD can 
exploit multiple external cues, which may aid rehabilitative effects. In individuals with PD, we aim to 
improve our understanding of lower limb motor control and the circuitry involved (Aim 1), 
determine the relative effectiveness of targeted IG and EG training, and explore neural 
mechanisms of mobility improvement through adapted tango (Aim 2). To accomplish this goal, 

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first we will use fMRI to investigate neural correlates of lower limb control with a foot-tapping task 
under IG and EG conditions in veterans with and without PD (Aim 1). Imaging studies have previously 
employed foot-tapping, which is used clinically to assess lower limb control. To achieve Aim 2, we will 
1) evaluate the relative effectiveness of practicing IG movement (leading) versus practicing EG 
movement (following) versus a behavioral control (health education) for improved mobility and lower 
limb control, and 2) assess neural activity changes underlying improvements in lower limb control 
across training groups. The long-term goal is to optimize motor rehabilitative interventions for 
veterans with PD and understand the neural mechanisms through which the training is effective in 
order to further improve rehabilitation strategies for this and similar diseases. 
Specific Aim 1: Determine neural correlates of internally guided and externally guided foot-
tapping in individuals with and without PD. 
Hypothesis 1: In healthy controls, IG and EG foot-tapping are related to task-specific neural 
networks of the striato-thalamo-cortical and cerebello-thalamo-cortical circuits, respectively. In those 
with PD relative to controls, IG foot-tapping will result in increased activation of both the STC 
(posterosuperior putamen, ventral anterolateral thalamus, rostral supplementary motor area, primary 
motor cortex) and the CTC (cerebellum (Larsell lobules IV, V, and VI), ventral posterolateral 
thalamus, primary somatosensory cortex, ventral premotor cortex) circuits. EG foot-tapping will result 
in increased activation in the CTC circuit only. 
Specific Aim 2: Determine the effect, in individuals with PD, of internally guided versus 
externally guided training compared to a behavioral control on: 1) mobility, and 2) whether 
improved mobility and foot-tapping performance after training correlate with changes in 
activation and resting-state functional connectivity patterns in IG and EG foot-tapping 
networks. 
Hypothesis 1: If mobility gains are related to training in planning and selecting movements, then 
those in IG will demonstrate greater improvements than those in EG or control. If mobility gains are 
related to exploiting cues during training, then those in EG will demonstrate greater improvements 
than those in IG or control. 
Hypothesis 2: If improved IG foot-tapping performance and mobility (as determined in Aim 2, 
Hypothesis 1) are related to IG training and planning movement, then we will see IG training-related 
increased activation in the STC circuit and decreased activation in CTC circuitry. If improved EG foot-
tapping performance and mobility are related to EG training and attending to cues, then we will see 
corresponding increased activation in the CTC circuit. 
Hypothesis 3: Resting-state functional connectivity patterns will reflect training effects, with 
connectivity increases primarily in the STC circuit following IG training and in the CTC circuit after EG 
training; minimal changes will occur following the control intervention.
5. Study design and Methods
Overview: To accomplish Aim 1, we will use functional Magnetic Resonance Imaging (fMRI) to 
determine neural circuitry underlying IG and EG foot-tapping in 24 veterans with and 24 veterans 
without idiopathic, mild-moderate PD (Hoehn & Yahr stages II-III).  To accomplish Aim 2, we propose 
a randomized controlled trial to evaluate the relative effectiveness of IG and EG movement to 
improve mobility in veterans with PD. We will also measure corresponding changes in neural 
activation during IG and EG foot-tapping, as a result of intervention. Participants will be randomized 

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to receive EG, IG or behavioral control (BC; health education) training over 12 weeks. Participants will 
be tested on all outcome measures while “OFF” and “ON” medications at a standardized time of day. 
We are observing participants in outcome measures while OFF medications in order to avoid 
dyskinesia, and medication fluctuations that may impact functional activity of networks of interest. 
Participants will complete outcome measure testing for mobility, QOL, executive function, procedural 
learning, spatial cognition, and foot-tapping 1 week before training (pre), and 1 week (post) and one 
month (follow-up) after completing all training. Using fMRI we will also investigate the relationship of 
changes in neural activation in the participants before and immediately after training. 
Measures that will be used in screening and outcome assessments:
Descriptors
Health Screening: Participants will be screened for general health with the Project Health 
Questionnaire at the first testing session.
Vision: Measurement of visual acuity will be performed with Early Treatment for Diabetic Retinopathy 
Study acuity chart (ETDRS) at 3 m. Visual impairment will be determined as none (better than Snellen 
acuity 20/30), mild (between 20/30 and 20/60), moderate (20/60 and 20/200) or severe (greater than 
20/200) in the best eye (World Health Organization ICD-10, 2006). 
Hearing: All participants will be asked if they use a hearing aid, and if yes, the frequency with which 
they use it. Pure tone audiometry, using a GSI-61 Clinical Audiometer, will assess hearing sensitivity in 
an acoustically controlled environment (available at the Atlanta Rehab R&D CoE). Participants will be 
excluded if pure-tone threshold average sensitivity at 0.5, 1.0, and 2.0 kHz exceeds 40 dB.
Disease Severity: Participants with PD will be evaluated for disease severity at each evaluation with 
the Movement Disorder Society Unified Parkinson Disease Rating Scale (motor subscale III: UPDRS, 
Movement Disorder Society 2003) by a qualified and experienced rater blinded to study purposes
Mental Status: Participants will be assessed for mental status with the Montreal Cognitive 
Assessment (MoCA; Nasreddine et al., 2005).
Handedness and Leggedness Inventory: Participants will self-report their handedness with the 
Edinburgh Handedness Inventory to help baseline their movements for analysis. This inventory will 
indicate whether the participant is dominantly right- or left-handed (Edinburgh Handedness Inventory: 
Oldfield, R.C., 1971). We will also use the Survey of Handedness and Leggedness (Schneiders, 
2010)
Outcome Measures: Participants will undergo a comprehensive battery of motor, cognitive and 
psychosocial measures to evaluate the efficacy of the intervention. See table 2 for a summary of 
these measures, which are described in more detail below. 
Calendar of Adverse Events: Participants will be given calendars and asked to keep track of 
‘adverse events’, including falls and near misses. They will be asked about adverse events once per 
month, and at each evaluation. Their responses will be recorded.
Motor: 

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
Six minute walk test (6MWT; Guyatt et al., 1985). 6MWT is a valid and reliable measure of 
overall mobility and physical functioning in older people (Lord&Menz, 2002). 

Single and Dual Timed Up and Go test (TUG), (Morris S et al., 2001) - A measure of functional 
mobility, the TUG (Shumway Cook et al., 2000) has demonstrated validity and reliability. The 
participant is timed while they rise from a chair, walk 3 m as quickly as possible, turn around and 
return to the chair. Dual-task ability will be measured with the TUG cognitive (TUGc) and manual 
conditions (TUGm). In TUGc the participant counts backwards by 3s from a random number 
between 20 and 100. In TUGm the participant carries a full glass of water. Time ≥15 s for TUG-c 
and time ≥14.5 s for TUGm indicates impaired dual-task ability and increased fall risk. The PI 
noted improvements on this measure after adapted tango training within older adults with visual 
impairment, and in those with PD during piloted data collection completed in October 2011.

Four square step test- clinical test of dynamic standing balance (Dite & Temple 2002). It involves 
stepping over low objects (2.5cm) and movement in 4 directions. The Four square step test has 
high sensitivity, specificity and predictive value for identifying differences between groups in a 
population of older adults. 

30 second Chair Stand test: Lower body strength is associated with the ability to perform 
lifestyle tasks such as climbing stairs, getting in and out of a vehicle or bath, and will be measured 
with the 30-s chair stand (chair stand) test 15, in which the participant rises from a chair to full 
standing as many times as possible in 30 seconds.
Postural control & Fall Risk: 

Berg Balance scale (BBS; Berg et al., 1995). BBS is a performance-oriented measure of fall risk 
and balance in older adults, consisting of 14 items rated from 0 to 4. Aim 2 is powered with a 
predicted 4-point improvement in the BBS because this measure was improved repeatedly to 
clinical significance in previous studies. The BBS has excellent inter- and intra-rater reliability (0.98-
0.99) and a maximum score of 56 possible points

Dynamic gait index (DGI; Shumway-Cook & Woollacott, 1995). 8 items, including walking while 
changing speed and turning the head, walking over and around obstacles, and stair climbing. DGI 
scoring is based on a 4-point scale from 0 to 3: 0 indicates severe impairment and a score of 3 
indicates normal ability.  A total score < 20/24 indicates risk for falling. The DGI has been shown 
to have inter-rater reliability of .96, test-retest reliability of .96.

Fullerton Advanced Balance scale (Hernandez D, and Rose DJ, 2008). The FAB Scale includes 
items intended to better identify older adults who may be experiencing increased fall risk as a 
result of sensory system impairments.

Limits of Stability test and other tests of the Neurocom Equitest system – Evaluated with 
Neurocom Equitest systems, this computerized posturography test evaluates stability limits in 8 
directions with measures of maximum excursion and directional control. Adapted tango training 
will require participants to move their center of mass beyond their stability limits when stepping; 
therefore, we expect increased stability limits as a result of training. 

Gait- Spatiotemporal parameters of habitual (i.e., preferred, comfortable), backward and fast-as-
possible walking will be assessed by a 6 m computerized GAITRite walkway (CIR Systems, Inc. 
Havertown, PA, USA). Variables of interest include velocity, stride length, and stride variability, 
which have been improved previously through adapted tango training.
Psychosocial Function

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Depression- Two standardized, clinical measures of depression will be administered to all 
participants.

Geriatric Depression Scale-15 (GDS) will evaluate depression in oldest old adults, and has 
demonstrated high specificity, and predictive value for older adults (Yesavage et al., 1988).

Beck Depression Inventory II- recommended by the American Academy of Neurology, and 
suitable for screening individuals with PD. A cutoff of 18 is reliable for distinguishing 
individuals with PD with significant depression.
Incontinence (self-report): ICI-Questionnaire-this questionnaires asks four questions pertaining to 
how often someone urinates during the day, during the night, whether they have a sudden urge to go 
to the toilet to urinate, and whether they experience leakage right after feeling that sudden urge. 
Participants are also asked to rate how much each occurrence bothers them on a scale of 0-10 (0 
meaning not at all, 10 meaning a great deal).
Balance confidence: Activities-specific Balance Confidence scale (ABC; Whitney et al., 1998). This 
questionnaire is filled out by the participant and asks 16 questions related to confidence the 
participant would feel about “not losing their balance” in various life situations.
Quality of life:

Short Form -12- a widely used measure of general health.

Life Space Questionnaire (LSQ) (Stalvey et al., 1999), LSQ assesses the extent of an older 
person’s mobility and is useful for evaluating interventions designed to enhance mobility.

Exit Questionnaire – (administered only at evaluations occurring directly after completion of 
training). This non-disease specific instrument consists of items which ask whether the participant 
enjoyed the classes, whether they would continue, whether they notice improvement in various 
aspects of physical wellbeing, and a section for open-ended responses (Hackney et al., 2007a, 
2007b, Hackney & Earhart, 2009a, 2009b, 2009c, Hackney& Earhart NNR, 2010, Hackney & 
Earhart, J Nerv Ment Dis, 2010). Standardized measures that capture the same constructs do not 
exist. 

For those with PD only, the following questionnaires will be administered:
o
Freezing of Gait questionnaire- subjective evaluation of perception of freezing of gait 
phenomenon in the previous week (Giladi et al., 2001)
o
PDQ-39- health-related quality of life measure for persons with PD that is validated and 
widely used.
Participation

Impact on participation and autonomy scale- This is a self-report measure and includes 
multiple domains of participation along with a strong focus on an individual's autonomy in his/her 
choices for daily activity participation.

Physical Activity Scale for the Elderly- This scale is an easily administered and scored 
research instrument that measures the level of physical activity in individuals aged 65 years or 
older.
Cognitive function

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
Brooks spatial memory task -The participant is asked to visualize a 4x4 matrix in which the 
location of numbers 1 through 8 is described. Next, the participant is requested to repeat the 
numbers’ location. Participants practice with three instructions and progress up to 8 instructions. 
All levels are completed regardless of errors in performance and percentages correct (out of 50) 
will be used for analysis.

Body Position Spatial Task- We found no standardized measure of whole body spatial working 
memory, i.e., knowledge of spatial position and ability to navigate in a remembered path. Modeled 
after the Corsi Blocks 104, the PI developed this task. Instead of pointing to a spatial path of blocks, 
participants are asked to step in a spatial arrangement. The examiner verbally and visually 
demonstrates random combinations of 5 possible moves: step forward, step left, step right, 
quarter turn left, and quarter turn right. The examiner begins with 2 moves and progresses up to a 
maximum of 9 moves, (maximum correct: 16) with 2 trials per level. Participants continue to the 
next level if one trial is correctly performed. The test ends when participants miss both trials of a 
level. Span length and number of correct trials are considered for analyses.

Corsi Blocks task- (Kessels et al., 2008), this is a standardized, valid and reliable test of 
visuospatial ability

California Verbal learning test (to rule out other possible cognitive deficits not found by the 
MoCA)

Wisconsin card sorting test (64 cards) (Kongs et al., Western Psychological Services) - This 
test will probe the effects of EG training because participants will be required to respond and alter 
their decisions based on cues. The following will be outcome variables: Perseverative errors 
(fewer errors indicate better ability of the patient to switch to a new concept); Failure to maintain 
set (fewer failures indicate better ability to sustain course of action); Number of sorts (greater sorts 
indicate better concept formation.) 

Color Word Interference Test (Delis-Kaplan Executive Functions System) - Based on the 
Stroop, this test of executive function and attentional flexibility will also be administered to test the 
effects of EG training, because participant needs to inhibit their own responses and examine 
carefully the message that is being given, in spite of sometimes misaligning information.

Tower of London- This test of organizational planning and decision-making will be administered 
to explore the cognitive effects of IG training, because the test requires the participant to organize, 
and plan. We will use the Cambridge Neuropsychological Test Automated Battery-Tower Of 
London, because of impairments in individuals with PD.100 The participant will be shown two 
displays of three colored balls. The participant is required to rearrange the balls in the bottom half 
of the screen to match the arrangement in the top half of the screen. The outcome measures are: 
number of successfully completed problems, number of problems completed in the minimum 
number of moves and the total score. 
Table 2 provides a synopsis of the measures used in this study.
Table 2: Outcome measures of motor, psychosocial and cognitive function
Motor function
Instrument/scale
Functional mobility, strength
6-Minute Walk Test; single and 
dual task Timed Up and Go, 
Four-square Step Test, 30 s 
Chair Stand test
Preferred, backward, fast gait 
GaitRite walkway (CIR Systems)

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Postural control/ Fall Risk 
Dynamic Gait Index, Berg 
Balance Scale, Fullerton 
Advanced balance scale
Handedness
Edinburgh Handedness 
Inventory
Psychosocial function
Instrument/scale
Depression
Geriatric Depression Scale-15; 
BDI-II 
Incontinence- self report
ICIQ 
Balance confidence
Activities Balance Confidence 
Scale
Quality of life
Life Space Questionnaire, 
Incontinence IQ, Short Form 12 
PD ONLY: PDQ-39; Freezing of 
Gait
Participants’ program enjoyment/satisfaction (Immediately post-
training only)
Exit questionnaire- Evaluates 
participant satisfaction with 
physical activity programming, 
(Hackney & Earhart, in press).
Self-report measure encompassing multiple domains of 
participation; a strong focus on an individual's autonomy in his/her 
choices for daily activity participation
Impact on Participation and 
Autonomy questionnaire
 
Participation in physical activity amongst older adults
Physical Activity Scale for the 
Elderly
Cognitive function
Instrument/scale
Spatial ability span
Brooks spatial working memory 
task (Brooks, 1967)
Body-position spatial ability span
Body position spatial task
Level achieved, trials completed
Corsi blocks
Verbal memory
California Verbal Learning test
Executive function, task switching, response to cues
Wisconsin card sorting test 
Task switching, inhibition, attentional flexibility
Color Word Interference Test 
Planning, initiation, procedural learning
Tower of London
Procedural learning
Serial reaction time task
Screening
All participants will be screened for general health with a Project Health Questionnaire. All procedures 
will be videotaped. We will screen for both PD-related and non-PD related impairments that could 
compromise the study’s results. Therefore, while all outcome measures and scans will be performed 
in both the ON and the OFF state, mental status, sensory impairments, and depression will be 

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screened during optimal performance conditions: the ON state. However, we will assess disease 
severity in both ON and OFF states because some outcome measures could be confounded by 
antiparkinsonian medications. We will also assess disease severity before all outcome measure 
evaluations. 
Mental status: We will exclude individuals with known diagnoses of dementia or vascular cognitive 
impairment, and screen for mental status with the Montreal Cognitive Assessment (MoCA)74, which 
has been recommended by the Parkinson Study Group.75 We expect to exclude some individuals 
who pass the MoCA yet have severe primary memory deficits, possibly because of a PD/Alzheimer’s 
disease overlap. Therefore, we will also administer memory testing with delayed recall on the 
California Verbal Learning Test. 76 77 
Disease Severity: A qualified and experienced rater, blinded to study purposes, will rate participants 
with PD for disease severity with the Movement Disorders Society Unified Parkinson Disease Rating 
Scale Motor Subscale III 77(UPDRS) in videotaped assessments. Participants must have Hoehn & 
Yahr staging II-III. Participants will be evaluated for disease severity with the UPDRS at the beginning 
of all evaluations. Participants will also complete the Freezing of Gait questionnaire, a subjective 
evaluation of perception of freezing of gait (FOG) in the previous week.78 Participants will be 
considered “freezers” if they answer > 1 on item 3 of the FOG questionnaire, which indicates freezing 
frequency of more than once per week.79 
Sensory impairment: To screen for sensory impairments that could affect movement, we will screen 
for peripheral neuropathy, vision and hearing. We will screen for peripheral neuropathy with the 
5.07-10g Semmes Weinstein monofilament method and the vibration on-off method in a clean open 
space, using established criteria.80 Participants will be screened for best corrected/aided visual 
acuity better than 20/70 in the better eye (World Health Organization International Classification of 
Disease-10, 2006); Measurement will be performed with intake screening & chart review. Dr. 
Hackney will administer the Early Treatment in Diabetic Retinopathy Study Acuity test. Given the role 
that auditory cues will play in both evaluation (scanning will employ an auditory cue) and treatment 
(tango dance employs music), we will also screen participants for adequate hearing.
Depression: Participants will be screened for untreated depression with the BDI-II, recommended by 
the American Academy of Neurology, and suitable for screening individuals with PD.81 A cutoff of 18 
is reliable for distinguishing individuals with PD with significant depression.82 If participants are 
excluded for depression, but then receive treatment, they may be rescreened and considered for 
study recruitment.
Ongoing screening for fMRI: Participants will be screened with standard procedures for fMRI eligibility 
during an initial telephone screen. Then, before every scanning session, participants will answer a 
standard questionnaire to insure safety during the procedures and adherence to fMRI inclusion and 
exclusion criteria. Participants will be evaluated for disease severity with the MDS-UPDRS at the 
beginning of all evaluations.
Specific Aim 1: Determine neural correlates of internally guided and externally guided foot-
tapping in veterans with and without PD.
Rationale: We will examine brain activity involved in internally and externally guided lower limb 
movement, in order to characterize circuitry, which we hypothesize will be targeted by the IG and EG 
training proposed in Aim 2. Adapted tango has been shown to improve gait and mobility measures; 

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therefore, adapted tango should include the recruitment of neural systems of lower limb control. Foot-
tapping involves lower limb control, and is an action that occurs in adapted tango training. Foot-
tapping is also a measure of motor dysfunction on the UPDRS, and its circuitry has been investigated 
in fMRI studies of healthy controls 58 and individuals with PD.85 However, lower limb neural control of 
circuitry involved in externally and internally guided movements is not well studied. As such, we will 
use foot-tapping to provide a window into brain activation during IG and EG lower limb movements. 
With Aim 1, we seek to identify circuits and structures involved in IG and EG lower limb movement, in 
veterans with PD in comparison to age-matched controls. We believe that IG and EG lower limb 
circuitry will have similarities to that observed with finger tapping tasks because Keele at al (1985)59 
demonstrated that finger tapping, forefoot tapping and heel tapping are highly correlated. Therefore, 
we hypothesize that during IG tasks, the STC (posterosuperior putamen, ventral anterolateral 
thalamus, rostral supplementary motor area (SMA), and primary motor cortex) will be activated in 
controls. During EG tasks the CTC (cerebellum Larsell lobules IV, V, and VI), ventral posterolateral 
thalamus, primary somatosensory cortex, and the ventral premotor cortex) will be more active relative 
to rest in controls. We predict that in PD patients, during IG tasks, both the STC and CTC circuits will 
be activated, while only the CTC circuit will be functionally activated during EG tasks.
Rationale for hypothesized areas within circuits during IG and EG tasks: 
For IG networks, we expect to see activation in the following areas:  the posterosuperior 
putamen, because dopamine depletion in PD most adversely affects this part of the putamen, which 
is also less functionally connected to important motor structures i.e., the rostral SMA, in individuals 
with PD relative to controls;61 the ventral anterolateral thalamus because of its projections from the 
basal ganglia and because it is part of the IG network outlined by Lewis et al. (2007)6 and Sen et al. 
(2010)55;  the rostral SMA, because of its involvement in motor preparation and initiation56, and its 
activation during foot flexion/extension 58: the primary motor cortex, because of its activation during 
foot movements 58 and IG tasks in people with PD.56 
For EG networks, we expect to see activation in the following areas: Larsell lobules IV, V, and 
VI of the cerebellum, because these areas were functionally activated during cued foot movement in 
controls 58; the ventral posterolateral thalamus, because of its projections from sensory areas and 
cerebellar inputs, and because it is part of the circuit outlined by Lewis et al. (2007)6 and Sen et al. 
(2010)55; the primary somatosensory cortex, for its involvement in cued movement, both tactile and 
visual, with its expected localization being medial for foot movement; the ventral premotor cortex, 
because of its involvement in decision making based upon somatosensory signals, 86 activity that 
mirrors the actions of viewed subjects,87 and because of its response to externally cued stimuli.88
         
FMRI Data acquistion for Aim 1: 24 older veterans with PD and 24 veterans without PD will be 
scanned for approximately 1 hour inside the scanner. MR images will be acquired on a 3T Siemens 
Magnetom Trio TIM scanner with a 32-channel receiver array head coil. BOLD fMRI scans will be 
acquired with a conventional Echo Planar Imaging (EPI) sequence with Field of View (FOV) =220 

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mm, TR/TE/FA =2000 ms/24 ms/80°; forty-seven 3mm sagittal slices (no slice gap); 3mm x 3mm in-
plane resolution, and band width of 2414 Hz/pixel; Parallel Imaging: GRAPPA factor 2, 24 phase 
encode reference lines.  Prospective real-time motion correction 89 will be used with all EPI fMRI 
scans to minimize motion artifacts. A whole-brain 3D T1-weighted MPRAGE sequence (FOV=230 
mm; TR/TI/TE/FA=2250 ms/900 ms/3 ms/9°; 0.9mm x 0.9mm x 1mm resolution) will provide anatomic 
detail. All scans will be acquired with parallel imaging: (GRAPPA; acceleration factor = 2; 24 (for EPI) 
and 36 (for MPRAGE) phase encoding reference lines). A Biopac (Goleta, CA) respiration belt and 
finger pulse oximeter will be used to acquire physiological waveforms time-locked to fMRI acquisition.
Activation paradigm design: Participants with PD will be scanned while ON and OFF their anti-
parkinsonian medication at least 12 h after their last dopaminergic medication, a functionally defined 
“OFF”; 90 thereby maximizing the ability to see a therapeutic effect. Participants will spend about 1 h 
total in the scanner. The scanning protocol, including time spent in the scanner, will be clearly 
explained to all participants, and it will be verified that every participant fully understands and is 
prepared for the scanning procedure. Standard operating procedures for fMRI involves checking with 
participants throughout to make sure they are comfortable with scanning procedures and participants 
are removed from the magnet at any point should they require it. The experimenter or technologist 
will have frequent verbal contact with the participant throughout the scanning session to assure 
participant comfort. 
For ~20 minutes, participants will perform IG and EG sequences of foot-tapping movements 
inside the scanner using established methods 85. As such, the task will involve unilateral ankle 
dorsiflexion, to a maximum of 30º in a wooden apparatus with movements blocked by IG or EG 
condition. Participants will be provided foam padding and towels to restrain head motion. 
Participants’’ knees will be flexed to approximately 135º with a soft roll under the knees. An assistant 
will verify task performance timing and amplitude, 
as well as monitor for synkinesia from the other 
limb. If the patient is unable to keep the other 
limb still, the data will be excluded. Based on 
pilot scans that we recently collected in 15 
individuals with stage II and III PD, we expect 
20% attrition for excessive head movement. 
However, these participants were scanned while 
ON meds, which generally increases the 
presence of dyskinesia. Because we will a) test 
participants OFF meds, b) screen for excessive 
head and lower limb tremor, and c) target 
recruitment in order to account for 20% attrition, 
we expect to retain a sample size that will allow 
us to detect effects and make meaningful 
comparisons. Ankle range of motion will be 
recorded with an MR-compatible potentiometer 
and amplitude will be averaged over each 
condition. 
Absolute 
timing 
error 
will 
be 
determined by the potentiometer also, by 
comparing the timing of every other change in 
acceleration, with the ideal timing sequence. 
Thus, the time course of changes in acceleration 
will be effectively considered the timing of the 
participants’ taps.  Error will be averaged from the accumulated absolute value of the tapping errors 
which either over- or under-shoot the ideal timing. Tapping will occur at a frequency of 0.5 - 2 Hz, 

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given that individuals with PD demonstrate marked tapping performance deterioration above 2 Hz, in 
terms of increased movement rate, decreased amplitude and loss of movement phase.91
 IG and EG foot-tapping tasks: Before entering the scanner, participants will be given approximately 
20 minutes to learn one of three unique, 6-s rhythmic sequences of IG and EG foot-tapping. These 
rhythmic sequences will be similar to those learned during both the IG and EG trainings, i.e., slow and 
quick beats arranged in different sequences to form differing rhythmic pattern (See “Adapted Tango”). 
In the EG condition, foot-tapping will be paced by auditory cues from MR-compatible headphones. In 
the IG condition, because the actual response rate will vary slightly by participant, we will quantify 
timing interval consistency based on each individual's tap-by-tap deviation from an established “ideal 
timing” rhythm that will be instructed before entering the scanner.  We will determine each 
participant's average IG response rate (in taps/s) across all IG task blocks in the session, and then 
calculate the expected amount of time between sequential taps (quick or slow) based on this rate.  
We then will calculate the deviation from this expected tap time for each pair of sequential foot taps. 
Finally, we will average all deviations to determine the amount of variation there is in a participant's 
tapping pace within the scanning session.
In the scanner, participants will be asked to repeat the given foot-tap sequence continuously 
for 30 s/block. Sequence order will be counterbalanced across participants. IG and EG movement 
blocks of 30 s will alternate with 21 s of absolute rest. There will be 5 movement blocks and 6 rest 
blocks per foot, per condition (IG or EG). Both legs will be tested separately. See diagram illustrating 
the activation paradigm. 
             
fMRI Data Preprocessing for SA1:  Data will be processed using Statistical Parametric Mapping 
Software (SPM8; Wellcome Department of Imaging, Neuroscience, London, UK).  Preprocessing 
steps include head motion correction, co-registration of functional and structural data within sessions, 
and co-registration of structural data across sessions. Each individual subject’s structural and 
functional data will be spatially normalized to the SPM-standard T1 template, which is in Montreal 
Neurological Institute (MNI) space. Spatially normalized images will be smoothed with a 5mm full-
width-at-half-maximum (FWHM) Gaussian kernel. Low frequency drifts will be removed with a 
temporal high-pass filter (0.006 Hz). The fMRI scans will be acquired with prospective real-time 
motion correction.89 This sequence will correct for volume-to-volume (image-to-image) motion less 
than 3mm by updating the gradients real-time during scan acquisition. If for a given volume the 
residual motion after motion correction (estimated as the maximal voxel displacement by the image 
registration algorithm) is more than 3mm (one voxel dimension) that volume will be discarded during 
analysis and treated as missing at random (MAR) during statistical signal processing. If more than 
10% of the volumes in the fMRI time-series have to be discarded due to the criteria mentioned above, 
the subject data will likely be discarded from analyses. In previous studies examining a similar foot-
tapping task while OFF, PD head movement (0.46 mm ± 0.26 mm in either direction) was not much 
different from controls (0.56 mm ± 0.26 mm).85 However, we will recruit for 20% attrition, to account 
for unsuitable data. 
Specific Aim 2: Determine the effect, in veterans with PD, of internally guided versus 
externally guided training compared to a behavioral control on: 1) mobility, and 2) whether 
improved mobility and foot-tapping performance after training correlate with changes in 
activation and resting-state functional connectivity patterns in IG and EG foot-tapping 
networks. 
Rationale: As outlined in Background, there are differences in IG and EG training that may lead to 
distinct effects upon mobility; therefore, Aim 2 will tease out the relative effectiveness of IG and EG 

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adapted tango training for functional gains in mobility. Aim 2 will also determine whether improved 
mobility and foot-tapping performance after training correlate to changes in activation and resting 
state functional connectivity (RSfc) patterns in the IG and EG foot-tapping networks identified in Aim 
1. Because we hypothesize that IG and EG adapted tango will target their respective foot-tapping 
networks, we expect improvements in each to correlate to changes in activation patterns in the 
corresponding network. Specifically, improved functional performance after IG training will lead to 
increased activation within the STC network while improved functional performance after EG training 
will lead to increased activation within the CTC network. 
We will also determine how RSfc in the IG and EG foot-tapping networks is affected by 
training. A network perspective of PD is essential to understand the pathophysiology of the disease 
because the neurochemical alteration in the basal ganglia propagates throughout many dense striato-
cortical connections, altering the activity in each successive brain region 61 and because the 
pathology is widely distributed. 94 RSfc MRI allows investigation of large-scale functional networks at 
whole-brain level based on temporal correlation of spontaneous fluctuations in the BOLD signal at a 
low frequency (<0.1 Hz). Few studies have used this technique to characterize network activity in PD. 
61 Previous research has shown abnormal patterns of RSfc of motor planning in premotor areas and 
execution networks (motor cortex) in PD patients.56 57 63 95 By scanning the same participants before 
and after training, we hypothesize that if we observe improved foot-tapping after IG training, we will 
see increased STC connectivity and if we see improved foot-tapping after EG training we will see 
increased CTC connectivity. We postulate no changes will be noted in IG and EG foot-tapping 
networks after training in the behavioral control group.
Participant Randomization for Aim 2
After screening and consent), participants will be randomized to one of three groups (IG, EG or the 
behavioral control (BC, Education)). Participants will not be blinded to treatment group, but the 
instructors of the interventions will be blinded to performance on all outcome measures, and raters of 
all functional performance measures will be blinded to treatment group. The PI will train raters, 
qualified research assistants, in proper administration of all measures.
Intervention: IG and EG training in adapted tango classes for participants with PD
Dosage: Participants shall receive 1.5 hours of progressive IG or EG adapted tango dance, or BC, a 
health education class 2 days/week for 12 weeks, with a goal of 20 completed lessons, in the Atlanta 

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VA Rehabilitation R&D Center’s 41 ft x 34 ft Movement Studies Lab. To examine neural circuitry in 
conjunction with intervention, an effective dose of that intervention must be used, i.e., one with 
demonstrated improvements in mobility and balance via outcome measures of interest.5 Twenty 
sessions were used previously and were effective at improving mobility (See preliminary studies). We 
expect 20 lessons over 12 weeks will provide enough therapy for both functional improvements to 
manifest as well as neurological changes to have occurred, because one month after training 
cessation, observations revealed maintained gains in the absence of treatment.5 Thus, all participants 
must complete all 20 lessons to include their data in analyses. Participants will have ample 
opportunity to complete 20 lessons: there will be 4 lessons offered per week for 12 weeks (48 total 
sessions). If necessary, make up sessions will be offered. To date, we have experienced ~15 % 
attrition. Notably, in a recent pilot study in Atlanta examining intensive tango, there was 0% attrition. 
Adapted tango: Composed of simple steps, tango involves frequent movement initiation and 
cessation, multi-directional perturbations and varied rhythms. Participants focus on trunk control and 
stepping strategies, coordination, somatosensory awareness, attention to partner, path of movement, 
and aesthetics. Sessions will begin with a typical dance class warm-up consisting of breathing, 
limbering and postural alignment to upbeat music. Novel step elements will be introduced every class 
period. Those with PD will partner with an individual without PD. After novel step introduction, the 
instructor will present rhythmic training, which is indispensable to partnered dancing. Participants will 
learn ‘typical’ rhythms from tango and Latin dances, based upon the system of quicks (Q) and slows 
(S), ubiquitously used in ballroom dance training to understand the temporal relationship of 
movement to music. Two quick beats equal one slow beat. Accompanying new rhythms to simple 
moves first allows transfer of the rhythm to more complex steps. Thus, the instructor will physically 
introduce rhythms by having participants clap, then tap a foot, then march in place and then walk to 
the rhythm. 
In the last third of class, the new step of the day will be reviewed and added on to previously 
learned steps. We will maintain manageable class sizes (e.g., no more than10 pairs of participants 
with PD and partners) to maximize safety.  Participants will dance with new partners (without PD) 
every 10 minutes, a widely practiced method designed to enhance learning in partnered dance 
lessons. Steps will be performed in an adaptation of the traditional ballroom frame, holding each 
other’s bent elbows, maintaining forearms parallel to the floor. During the 20 classes, participants will 
be randomized to either IG or EG roles, i.e., to leading or to following. Leaders (randomized to IG 
group) will always dance as leaders, and followers (randomized to EG group) as followers. 
Those in IG training will choose direction, timing and amplitude of each successive step. Those 
in EG will learn to attend to sensory cues for movement direction, timing and amplitude of steps, 
communicated from their partner to them via the frame and center of mass. Choreographic 
biomechanical patterns will be very similar between IG and EG training. The only difference between 
leading and following will be whether or not external guidance of movement is provided, after steps 
are learned.
The instructor and healthy assistants, trained in spotting techniques, shall carefully monitor all 
participants’ safety. Participants will be encouraged to take regular breaks. Spouses, friends and 
caregivers will serve as dance partners. Also with methods used several times previously by the PI, 
student volunteers recruited from surrounding colleges and universities will serve as assistants and 
dance partners. The PI will educate student volunteers about PD- and aging-related posture and gait 
problems, proper assistance techniques to use for balance loss and methods for monitoring balance 
and anticipating falls. 
Behavioral Control (BC) Condition: Participants will attend group health education sessions as per 
Wolf et al., (1996)96 adapted to the needs and interests of individuals with PD. They will engage in 

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interactive small group, large group and partnered learning. Discussion will be greatly encouraged. 
Emory medical students as well as experts from Emory School of Medicine and other local 
universities or organizations will present information. Student volunteers will participate in these 
sessions by moderating the lectures, assisting with the presentation of information and leading 
discussions. Participants in this training will be instructed not to change their habitual exercise 
routines. After completing health education, participants may be assigned to an IG or EG training 
class but will not undergo evaluations. 
Outcome Measures of Functional Performance (Aim2, Hypothesis 1):
Measures of motor function, PD QOL and explanatory measures of executive function, procedural 
learning, and spatial cognition will be conducted at evaluations (pre, post and 1 month follow-up). All 
evaluations will be performed in the safety-monitored Movement Analysis Laboratory at the Atlanta 
VAMC. All outcome measures will be directly measured with an instrument or self completed by the 
participant, except for BBS and other scales judged by a trained rater, which will be videotaped for a 
blinded and qualified rater (e.g., trained physical therapy students or research assistants) not involved 
with the project otherwise.
Primary measure of motor function: The Berg Balance scale (BBS) 97
 
Secondary measures of motor function

Fullerton Advanced Balance test

6 minute walk test 

Single and Dual Timed Up and Go test 99 

Limits of Stability test 

Gait- assessed with a 6 m computerized GAITRite walkway (CIR Systems, Inc. Havertown, PA, 
USA). 
Explanatory variables
Participant QOL and satisfaction with program 

PD Questionnaire-39 (PDQ-39)Exit Questionnaire – (administered only at post-test within one 
week of completion of training). 3-5 36-38 70 
Executive function, procedural learning, and spatial cognition 
We will investigate aspects of executive function, procedural learning, and spatial working memory to 
characterize more effectively the therapy’s impact. The following cognitive measures are explanatory 
evaluative instruments: Executive function: Three standardized tests of executive function will be 
used:

Wisconsin card sorting test (64 cards) (Kongs et al., Western Psychological Services)

Color Word Interference Test (Delis-Kaplan Executive Functions System) 

Tower of London- from Cambridge Neuropsychological Test Automated Battery-Tower Of 
London, because of impairments in individuals with PD.100 
Procedural learning: Procedural learning will be used as a predictor for those who will benefit more 
from EG training, which makes use of automatic processes already learned. Procedural learning 
ability will be measured with the Serial Reaction Time Task,101. Procedural learning becomes more 
impaired with disease progression. 102 

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Spatial Cognition: Remembering spatial patterns and relationships to others is essential in dancing, 
and true of both IG and EG training The Body Position Spatial Task and Corsi Blocks test 
(previously described) will be also used as tests of spatial ability.
If we note improved cognition in conjunction with mobility improvement in both IG and EG groups, 
future studies will investigate neural areas related to the particular construct with fMRI. If we note 
cognitive improvements in one type of training, but not another, we will have additional information 
related to mechanisms by which particular forms of training are effective. 
Procedures and Outcome Variables of Aim 2, Hypotheses 2 and 3:
The same fMRI data acquisition, activation paradigm and preprocessing procedures, outlined in Aim 
1, will be used for participants in each of the IG, EG and BC groups to determine BOLD activation 
(Hypothesis 2) while performing IG and EG tasks. We will also perform RSfcMRI data acquisition and 
preprocessing (Hypothesis 3), detailed here:
Resting state functional connectivity MRI procedures: At each scanning session, we will collect 
approximately 9 minutes of fMRI data from participants as they rest quietly in the scanner. 
Participants will be provided foam padding and towels to restrain head motion, while they look at a 
gray screen. They will be instructed to keep their eyes open, not to think of anything in particular, nor 
to fall asleep. Examiners will monitor the participants’ eyes in a mirror and prevent them from falling 
asleep. We plan to compare changes in RSfc of the STC and the CTC pathways before and after IG 
and EG partnered training. The particular regions examined will be determined through analyses 
conducted on imaging data collected in Aim 1. We will also investigate whether these changes in 
functional connectivity correlate with improvement on the UPDRS and on IG and EG foot-tapping. 
Resting State Functional Connectivity Image Data Preprocessing for Aim 2, Hypothesis 3:  
RSfc data will be preprocessed to correct for head movements, linear drift, and physiological noise 
(pulse, respiration) and will be normalized to standard space. It is likely the first 8-10 scans will be 
discarded to account for saturation effects and for adaptation of participants to a novel situation. The 
RETROICOR algorithm will remove physiological noise arising from main frequency peaks of cardiac 
and respiratory fluctuations.105 Cardiac and respiratory function will be monitored with a 
photoplethysmograph on the left index finger and a respiratory belt around the abdomen. BOLD 
signal changes arising from low frequency fluctuations of cardiac and respiratory waveforms will be 
detrended using established methods. 106 The physiological noise corrected data will be low-pass 
filtered (cutoff frequency: 0.1 Hz) to further isolate low frequency resting state BOLD fluctuations.107
Potential Pitfalls/Alternative Approaches
1. If no differences are noted between IG training and EG training on outcome measures, but 
results match those of the original therapy 3-5, we will know that leading and following alone are 
likely as effective as the original dual, (interdigitated) IG/EG training for improving mobility. To 
inform motor rehabilitation, we will then suggest patients and providers have a choice of 
training type: follow cues, or plan and self-initiate movement. As we are not directly observing 
a dual IG-EG form of training in comparison to EG and IG, observed in isolation, we cannot 
determine whether EG or IG is better than dual IG-EG. Switching between leading and 
following in dual training demanded ‘set-switching’, impaired in individuals with PD.22 23 Future 
Merit proposals will examine the effects of set-switching on neural pathways, and conduct a 
definitive comparison of IG, EG and dual IG/EG training, by building on data gained from this 
project. An alternative approach is investigating sequential forms of treatment, i.e., IG then EG 
training, and comparing the cumulative effects to training in isolation. If, as predicted by our 

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hypotheses, connectivity patterns do reflect training effects, with connectivity increases 
primarily in the STC circuit following IG training and in the CTC circuit after EG training, then 
both circuits may need to be upregulated therapeutically. Future studies will determine optimal 
doses of each to make evidence-based guidelines for therapy.
2. While hand movement neural activity is relatively well studied, far less is known about brain 
activity of foot movements.58 We are making assumptions about brain activity in foot 
movements based upon hand literature. Given that the foot and hand differ in localization of 
representation in the sensorimotor cortex, 109 foot cortical control may differ fundamentally from 
that of the hand. Future work via the VA Merit system will more definitively characterize lower 
limb motor control, in conjunction with motor training for veterans with PD.
3. This project is novel in key domains: 1) the investigation of foot-tapping in IG and EG 
paradigms in PD is novel; 2) investigating IG and EG training effects on mobility and especially 
cognition is novel; 3) changes in neural activation in conjunction with training will be examined 
for the first time. Based on information we gather from this study, in the future we will conduct 
targeted studies to continue investigating cognitive differences and changes in neural 
activation between groups.
4. Future investigations will more definitively investigate what form of training, IG or EG, is best at 
a particular stage of disease, and for individual patients with particular symptomatology.
Risk to Subjects 
Sources of Materials: For blinded ratings and patient confidentiality, all measurement data will be 
coded.  Patient records will be stored in a locked cabinet in a locked office and will be accessible only 
to the PI.  Computer-based records will be maintained on a secure network with password protection. 
Collection, analyses and use of these data will be exclusively for research purposes.
Potential Risks: 
Risk of breach of confidentiality: One risk of participating in this study is the chance of a breach of 
confidentiality. Protection against risk of breach of confidentiality: The study team will try its best 
to prevent this by coding all measurement data. Patient records will be stored in a locked cabinet in a 
locked office and will be accessible only to the Principal Investigator at the Atlanta VA Medical 
Center.  Computer-based records will be maintained on a secure network with password protection at 
the Atlanta VA Medical Center. Collection, analyses and use of these data will be exclusively for 
research purposes. Videotapes of each trial will be available only to study personnel and kept in a file 
cabinet in a secure office at the Atlanta VA Medical Center. Permission to share video images and/or 
use these images as part of professional/scientific presentations will be obtained during the informed 
consent process.   
Protection against risk of breach of confidentiality with fMRI data: 
Neuroimaging Core Facilities: The Emory Neurology Department (in coordination with the VAMC) 
has dedicated approximately 700 sq ft of space for a functional neuroimaging laboratory called the 
Brain Imaging, Rehabilitation and Cognition (BIRC) Laboratory under the direction of Dr. Bruce 
Crosson (mentor/co-investigator). For data housing and analysis, the lab contains a high capacity (20 

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terabyte) storage system as well as 5 multi-processor Linux data analysis workstations, all of which 
reside on a private gigabit ethernet network within the Emory domain. Only approved VA personnel 
are allowed to access this data, as it is administered and maintained by the VA Rehabilitation R&D 
Center of Excellence in Atlanta. Data security is maintained through need-only permissions and 
access control, while secure, encrypted backups maintain integrity and longevity of datasets. 
Importantly, all data will be non-identified and scrubbed of all 18 HIPAA identifiers. All servers are 
housed in secure server rooms, monitored 24x7 by electronic video and security personnel.  Dr. 
Bruce Crosson will offer mentorship on this project and will give Madeleine Hackney, the PI, 
unfettered access to lab resources. While completing the proposed research study, Dr. Hackney will 
complete fMRI analysis at the neuroimaging lab and have the benefit of the use of its testing rooms, 
technicians and data storage capabilities. 
Physical risks: Physical activity interventions for PD-related motor impairments pose minimal risk of 
fatigue, and the possibility of delayed onset muscle soreness. However, previously we have not had 
complaints or reports of soreness resulting from physical activity associated with partnered dance 
programs for people with PD, for older frail adults with low vision, or for those with mental illness. The 
intervention to be employed, adapted tango, has previously been demonstrated to be effective at 
reducing fall risk as measured by a standardized balance scale, but all efforts will be made to ensure 
the safety of participants. Every participant will be frequently encouraged and reminded to take 
breaks ad libitum during testing and classes. Also, during all testing and classes, the PIs, the teacher 
trainees and trained assistants will continually monitor participants for: fatigue, instability and other 
reasons for discontinuing evaluations or training. 
Plans to minimize adverse physical sequelae during the intervention:
The following procedure, which was previously successful with other dance interventions for people 
with PD and oldest-old adults with low vision will be employed to minimize risk of falls and ensuing 
physical sequalae: 
During classes participants will be continually monitored by the teacher trainee and trained assistants 
for fatigue and instability. The trained assistants will be instructed that their primary purpose is to 
prevent falls or other adverse events. Furthermore, to avoid accident outside of the class time, 
participants will be instructed not to practice the dance steps they learn at home or elsewhere outside 
of the class. Participants will be instructed to practice dance steps only when supervised by the 
instructor and assistants. Participants will be asked about their fall history at each observation, 
monthly during the intervention and all events will be documented. 
Plans to minimize risks during Imaging:
No one with deep brain stimulator implants will be allowed to participate in imaging.
The risks associated with the imaging procedure are the same as those associated with conventional 
MRI. Specifically, movement or heating of metallic implants is a potential risk, and so subjects will be 
extensively screened to exclude people with metallic implants, fragments, or pacemakers. Some 
individuals experience claustrophobic reactions in the scanner. Subjects will be informed of this prior 
to the study, but because it is difficult to predict who will have such a reaction, this is not a specific 
exclusion criterion. During the scans themselves, any subject experiencing claustrophobia will be 
removed from the scanner immediately. There is no invasive component to this study; therefore, 
discomfort, bruising, and/or infection are not risks.

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There may be additional risks associated with scanning at 3T, which we address:
Effect of the static field: The FDA has approved for routine clinical use, scanners up to 4.0 T. 
The system that we will be using is FDA approved. There is no conclusive evidence for irreversible or 
hazardous bioeffects to acute, short-term exposures of humans up to 2.0 T (Shellock and Kanal, 
1996). Studies have indicated some side-effects at 4.0 T, namely unusual sensations including 
nausea, vertigo, and metallic taste (Schenck, 1991). However, there is no evidence that this is either 
irreversible or harmful. If subjects experience unusual sensations, they will be withdrawn.
Effect of the gradient field: MRI operates by rapidly changing small additional fields, called 
gradients. By Faraday’s induction law, a changing magnetic field will induce electrical currents in any 
conductor. Thus, rapid cycling of the gradient field can induce peripheral nerve stimulation. However, 
this is not substantially different at higher magnetic fields since the gradients are separate from the 
main magnet. Should participants experience peripheral nerve stimulation (e.g., tingling or twitching), 
the principal investigator and staff will withdraw the participant from the study.
Effect of the RF electromagnetic field: The fundamental principle of MRI is that protons are 
excited by sending in an RF pulse at their resonant frequency for the magnetic field. The FDA 
provides guidelines for the safe use of MR systems, which includes specific recommendations for 
how much RF power is safe. They use the “specific absorption rate,” or SAR. The SAR is the mass 
normalized rate at which RF power is coupled to biologic tissue and is typically indicated in units of 
watts per kilogram (W/kg) (NRCP, 1986). The FDA provides recommendations for two alternative 
safe levels of exposure to RF energy during MR procedures, primarily to control the risk of systematic 
thermal overload (heating) and local thermal injury. These are (FDA, 1988):
(a) The exposure to RF energy below the level of concern is an SAR of 0.4 W/kg or less 
averaged over the body, and 8.0 W/kg or less spatial peak in any 1 g of tissue, and 3.2 W/kg or less 
average over the head; 
OR
(b) The exposure to RF energy that is sufficient to produce a core temperature increase of 1 
deg C and localized heating to no greater extent than 38 deg C in the head, 39 deg C in the trunk, 
and 40 deg C in the extremities, except for patients with impaired systemic blood flow and/or 
perspiration.
We will adhere to the recommendations for the head, which is also monitored by Siemens’ built-in 
monitor. 
Potential Benefit to the Subject and Others:
Given great personal and financial costs of PD-associated movement and balance deficits, 
strategies are clearly needed to address these impairments. With the guidance of a partner, an 
individual without PD, individuals with PD may be afforded the ability to focus on key aspects of 
mobility- dynamic and static postural control, while expanding their motor repertoire. Participants and 
their caregivers may enjoy taking part in the intervention. If an intensive adapted-tango therapy 
improves physical function and quality of life in persons with PD, it could decrease fall risk, and 
reduce the associated injury and mortality. There is little information about cortical and sub-cortical 
changes in neural activity in those with PD that may accompany improved function resulting from 

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rehabilitative modalities. This study will be a first step in obtaining crucial information about brain 
activity during lower limb function, and plastic adaptations resulting from rehabilitative modalities in 
individuals with PD. 
Importance of Knowledge to be gained:
PD affects approximately 1 million Americans, 90% of which are older than 60 years. As the 
US population ages, cases of PD are predicted to nearly double by 2030 (Dorsey et al., 2007). 
Persons with PD have a 3.2 fold greater hip fracture risk than those without (Melton et al., 2006). The 
cost of care for hip fractures in PD is approximately $192 million per year in the United States alone 
(Melton et al., 2006). Quality of life issues are at stake. This work proposes to illumine information 
about brain function that is crucial to continued progress in rehabilitative care of those with Parkinson 
Disease. The pilot study and hypothesis-generating experience gained from this pilot work has the 
potential to impact greatly care and quality of life of older persons with and without PD.  
Relevance to Health Issues: There are extreme personal, financial and social costs associated with 
falls in older adults and PD in the US. However, increased physical and social activity can lengthen the span of 
robust function in older adults and those with PD. Results from this project will contribute to improved 
management of care for those with PD through enhanced knowledge about brain function during lower limb 
movement.
6. Participant Selection
Recruitment and Informed consent:
Recruitment: We will recruit 140 adults aged 40-85, with PD stages II-III and 24 age-matched 
controls. Individuals without PD (controls) will be recruited from the Atlanta VAMC RR&D CoE’s 
registry, the VA’s VINCI database, as well as at senior living communities with whom the PI has a 
relationship. All patient information will be stored on VA secure servers (room 3A 105) of the Atlanta 
VA Medical Center. Only authorized study team members will have access to this information 
because it will be stored on a private directory with limited access and password locked file.
We will request a partial HIPAA waiver to identify potential participants for recruitment 
purposes from IRB and related approvals from the local VA R&D committees. We will then obtain a 
list from the VA Movement Disorders clinic including patients likely to have a PD diagnosis, and send 
them a letter, with the director’s signature informing them about the study. Drs. Marian Evatt and 
Stewart Factor, among others, will assist. A follow-up call will be placed within two weeks of the 
veteran likely having received the letter. A telephone screen will determine eligibility for participating 
in fMRI. Also, study fliers will be posted in the medical center and a PowerPoint slide ad will be 
broadcast throughout the medical center closed circuit TV system, such that veteran self-referrals are 
possible. To aid recruitment efforts, the PI will initiate meetings with community providers to explain 
the research goals, and request them to send a letter describing the study to patients who may qualify 
and have interest. The PI and staff will also visit PD community support and educational groups to 
present information to potential participants. Specifically, the PI will present information about the 
study to potential subjects at the 10+ support groups meeting monthly, organized by the GA chapter 
of the American Parkinson Disease Association and other PD organizations. The PI will also draft 
information about the trial to be included in the APDA and other PD organizations’ newsletters and 
informational material, as well as the Michael J Fox, foxfinder website for clinical trials in PD. 
Though all efforts will be made to recruit from the veteran population served at AVAMC, to 
meet recruitment goals, it may be necessary to extend recruitment to non-veterans or veterans 
served by the Emory healthcare system. If so, we will then obtain a list of names from the Emory 
electronic Medical Records (EeMR) database that includes patients with a diagnosis of idiopathic PD, 

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and will then send a letter from a staff neurologist at the Movement Disorder program and Emory 
Movement Clinic, Emory School of Medicine. A follow-up call from the PI will be placed after the letter 
is likely to have been received by the subject (e.g., 10+ days after sending the letter). With IRB 
approval, the Emory Movement clinic will include this trial in a “pocket list” of trials for persons with 
PD.
Informed consent: The Emory University IRB and the VA R&D committee will approve the consent 
form and all recruiting materials. After being screened on the telephone for eligibility to participate in 
fMRI, interested potential participants will be invited to the Atlanta VAMC Rehab R&D center. To 
reduce veteran burden, transportation will be provided for all subjects to and from evaluations. At the 
first visit, the PI will present information about the study to potential participants with an approved 
script. In a private room devoted to research, subjects will give informed consent after the PI provides 
an overview of the study’s protocol, associated risks and benefits and subjects have given a verbal 
summary demonstrating they understand study requirements. At recruitment, study procedures for 
the fMRI component (Aims 1 & 2) and/or the intervention component (Aim 2) will be explained in great 
detail. All participants’ questions will be answered. Subjects will be given a copy of the consent.  
Participants will not be excluded for race, ethnicity or sex and will reflect the makeup of metro Atlanta. 
Human Subjects Involvement and Characteristics:  
Participants: Participants will be individuals age 18 - 85 with and without PD from the Atlanta VAMC 
as well as other communities. During fiscal year 2010, 500 veterans with PD were seen at the Atlanta 
VAMC and satellite clinics. As VA funded research is conducted for the benefit of veterans, we will 
prioritize their recruitment by first exhausting all available means by which we can identify, approach 
and recruit veterans for this study. After we exhaust all possible resources to recruit veterans with PD, 
we anticipate extending recruitment to university based movement disorders clinics and community 
clinics. We will do so because we intend to recruit 140 participants with PD, and 40% will be women, 
which reflects female representation in the PD population.71 The greater Atlanta region had 650,000 
people age 55 and over in the 2000 US Census (US Census Bureau). As the older population is 
expected to double by 2015, and given a PD prevalence of 1.5% of the population age 65 and older, 
we estimate there to be more than 4000 people with PD in the greater Atlanta area. Emory University, 
the Atlanta VAMC affiliate, has a Movement Disorders unit that follows more than 2000 patients with 
PD each year. 
We are targeting those aged 40-85 with stages II and III. Forty is the upper limit for young 
onset PD,72 which will effectively insure that we recruit individuals with idiopathic PD only. Eighty five 
years is an upper age limit because of vascular, hemodynamic, morphometric and neural changes 
with aging.73 A prior study conducted by the PI involved 78 individuals with PD, 70% of whom were 
under the age of 70 and 83% were stages II-III 18, which suggests that our intended recruitment for an 
intervention will be attainable. 
Table 4: Inclusion/Exclusion Criteria for All Participants (Controls and those with PD)
Inclusion
Exclusion

Age 18 -  85 years

Deep brain stimulator implants, Metallic 
implants, fragments, or pacemakers

Willingness to spend 1-h in a scanner 

MoCA score < 21

Able to walk with or without an assistive 
device ≥10 feet 

Pure-tone threshold sensitivity > 40 dB

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
Best corrected/aided acuity better than 
20/70 in the better eye

Peripheral neuropathy

Absence of dementia or vascular cognitive 
impairment

Untreated Major Depression

Absence of primary memory deficits

History of stroke, or traumatic brain 
injury
Inclusion/Exclusion Criteria for Participants without PD (Controls): In addition to the criteria 
noted in table 2, these participants must not have PD.
Inclusion/Exclusion Criteria for Participants with PD: In addition to the criteria noted above in 
Table 2, participants with PD must have clinical diagnosis of “definite PD”,83, based upon 
established criteria,84 and must have presented with asymmetric symptoms that included at least 3 of 
the cardinal signs of PD (rigidity, bradykinesia, tremor, postural instability). Each PD participant also 
must show clear symptomatic benefit from PD medications, e.g., levodopa. 
7. Statistical Analyses
Power Analysis for Specific Aim 1:  We anticipate that 20 participants in each group (total n=40) 
will be necessary to detect an adequate effect size at 80% power based on studies conducted to 
determine reasonable sample sizes for fMRI studies.92 Twenty-four participants per group will be 
recruited to accommodate 20% attrition. Analysis of variance (ANOVA) will be used to determine and 
distinguish circuits involved in IG and EG foot-tapping networks in participants with and without PD. 
The ANOVA will be sensitive to between subjects effect sizes of f=0.45 (F1, 38= 4.098), with a power 
of 0.80 at α=.05. 
Statistical Analysis Plan for Aim 1 

Participant characteristics: Descriptive statistics will describe groups, including disease severity 
and duration for those with PD. T-tests will compare means (e.g., age, mental status) of 
participants with and without PD. Data analyses will be completed in SPSS (v. 19).

Functional performance measures: Foot-tapping absolute timing error and average amplitude 
will be compared between groups with t-tests. These measures will also be correlated to fMRI 
data. 

fMRI Brain Activation Analyses: Following preprocessing and normalization to standard space, 
activation maps for the IG and EG tasks versus rest will be determined for each subject on a voxel 
by voxel basis. Regressors of interest will model IG and EG blocks of foot movement for each limb 
separately. Head motion parameters will be included as additional regressors. A similar approach 
has been used previously in PD.85 First level contrast maps (betas) for the IG and EG tasks 
versus rest derived in each subject will be submitted to a second-level, random-effects analysis 
with subject as a random factor.  Second-level t-maps will be thresholded at p <.05, corrected for 
multiple comparisons using the false discovery rate (FDR) method.93 These activation maps will 
be used to define circuitry for IG and EG foot-tapping. Average percent signal change for the IG 
and EG tasks (relative to rest) for each participant will be extracted from the centers of gravity of 
the activated regions and submitted to hierarchical regression analyses to determine whether they 
correlate with behavioral measures (absolute timing errors and average amplitude of foot-tapping). 
Disease severity and duration of illness will be covariates for individuals with PD. The primary 
outcome measure will be average percent signal change for the IG and EG tasks (relative to 

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rest) to determine and distinguish circuits involved in IG and EG foot-tapping networks in 
participants with and without PD. 
Power Analyses for Aim 2
Hypothesis 1: Power calculations for Aim 2 are based upon an assumed 4-point improvement and 
effect sizes > 0.8 on the BBS after 12 weeks of adapted tango, which was attained previously (see 
Preliminary Studies), and the minimal detectable change on the BBS in parkinsonism is 2.84 points.68 
Therefore, with a total sample size of 63 participants (21 participants in each of 3 groups: IG, EG, and 
BC) a repeated measures (RM) ANOVA with 3 levels of repeat will be sensitive to between-within 
interaction main effect size of f(v) = 0.44 (F4,114= 2.45) with a power of 0.80 at α=.05.  Post hoc 
sensitivity to effects between groups will be d = 0.90, and within groups, dz = 0.65. To reflect an 
anticipated 20% attrition, we will recruit an additional 4 participants per group. Thus we will recruit 25 
participants per group, for a total of 75 individuals with PD recruited for Aim 2.  Hypothesis 2: 25 
participants per group will be sufficient to detect effects for the imaging (activation and resting state) 
components of Aim 2 as well, based on studies conducted to determine reasonable sample sizes for 
fMRI studies,92 that demonstrate at least 20 participants in each group are necessary. Hypothesis 3: 
Differences in RSfc have been noted between different groups of individuals with PD in sample sizes 
of 16 per group;63 therefore, with 25 individuals per group, we will be able to detect differences 
between groups.
Statistical Analysis Plan for Aim 2, Hypothesis 1, 2 and 3: 

Participant demographics: Descriptive statistics will characterize groups. One-way ANOVA will 
determine differences, if any, between groups on baseline measures. 

Behavioral Outcome measures: A 3 group (IG, EG, BC) x 3 time (pre, post test, follow-up (1-
month later)) RM ANOVA will be used to detect main effects. Appropriate post hoc tests will be 
used to determine within- and between-group differences, p<0.05, for BBS, the primary outcome 
measure upon which Aim 2 is powered. Statistical tests run on all secondary variables will be 
corrected for multiple comparisons. 

Brain Activation Analyses for Aim 2, Hypothesis 2: Similar to Aim 1 procedures, average 
percent signal change for IG and EG tasks (relative to baseline) for each participant will be 
extracted from the centers of gravity of the activated regions and submitted to hierarchical 
regression analyses to determine whether they correlate with behavioral measures (foot-tapping 
absolute timing errors and average amplitude). Disease severity and PD duration will be 
covariates. To determine the effects of time and training status we will submit the percent signal 
change to a 3 group (IG, EG and BC) X 2 time (pre, post) RM ANOVA. Post-hoc analyses will be 
corrected for multiple comparisons. The primary outcome will be t-contrast maps and effect size 
maps from ANOVA, which will be evaluated for changes in STC and CTC circuits.

Brain Connectivity Analyses for Aim 2, Hypothesis 3: In Aim 2, Hypothesis 3, we will examine 
RSfc for increases or decreases as a function of training type and evaluate changes for 
correlations with improvement on behavioral outcomes. We will use regions of interest ROIs) 
informed by IG and EG foot-tapping fMRI analyses in Aim 1. Seed ROIs will be 10mm spheres 
around centers of gravity of clusters of activation in the group level activation maps for IG and EG 
foot-tapping, in STC areas (posterosuperior putamen, ventral anterolateral thalamus, rostral SMA, 
and primary motor cortex) and CTC areas (cerebellum Larsell lobules IV, V, and VI, ventral 
posterolateral thalamus, primary somatosensory cortex, and the ventral premotor cortex). Seed 
ROIs gained from the foot-tapping task provide one path of inquiry into neural network changes 
that may occur after training. As RSfcMRI analyses can be extended to other important areas of 
brain function, we will also use behavioral measures, which may have changed (e.g., spatial 

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cognition) to determine other ROIs for interrogation of changes in RSfc. For all participants, we will 
use Pearson’s correlation (r), to correlate the time series from the seed ROIs with the time series 
of all other brain voxels. R-maps will undergo Fisher’s r to z transformation and will be entered into 
a 2nd level random effects analysis for between group comparison using one way ANOVA in 
SPM8. T maps will be thresholded at p<.005 (Z>2.6). Correction for multiple comparisons will be 
carried out at cluster level according to random fields theory.108 Age will be a nuisance covariate in 
all statistical analysis. To account for head motion-related spurious differences in functional 
connectivity levels, a nuisance regressor based on the total amount of movement will be included 
in the design. To determine the effect of time and training status on each group, the z scores will 
be submitted to a 3 group (IG, EG, BC) x 2 time (pre, post) RM ANOVA. Post hoc analyses will be 
corrected for multiple comparisons. The primary outcomes for Aim 2, Hypothesis 3 will be 
changes in average connectivity strength across STC and CTC circuits, as measured by average 
cross correlation coefficient between the seed regions of the circuits. 
8. Adverse Event Reporting
All adverse events will be immediately reported to the IRB and VA Review committees following the 
guidelines for reportable events and using the Reportable Events Form on the eIRB website. 
9. Data and Safety Monitoring plan
Data Management
Safeguards are established to ensure the security and privacy of participants’ study records. The 
information collected from participants in this study has a low potential for abuse, since the data do 
not address sensitive issues. Nevertheless, appropriate measures are taken to prevent unauthorized 
use of study information. For blinded ratings and patient confidentiality, all measurement data will be 
coded.  Patient records will be stored in a locked cabinet in a locked office and will be accessible only 
to the PI, and patient recruiter at the Atlanta VA Medical Center.  The files matching participants' 
names and demographic information with research ID numbers are kept in a separate locked room 
and are stored in a locked file that uses a different key from that of all other files. Computer-based 
records will be maintained on a secure network with password protection. Only study personnel have 
access to these files. All data, collected at any location, will be fully de-identified. Collection, analyses 
and use of these data are exclusively for research purposes. Regular meetings will be held with 
research assistants to review accrual, data entry, and examine the database for outliers or database 
entry errors. After the study is completed, procedures for long-term storage of VA data will be 
followed. 
Neuroimaging Core Facilities: The Emory Neurology Department (in coordination with the Atlanta 
VAMC) has dedicated approximately 700 sq ft of space for a functional neuroimaging laboratory,the 
Brain Imaging, Rehabilitation and Cognition (BIRC) Laboratory under the direction of Dr. Bruce 
Crosson (mentor/co-investigator). For data housing and analysis, the lab contains a high capacity (20 
terabyte) storage system as well as 5 multi-processor Linux data analysis workstations, all of which 
reside on a private gigabit ethernet network within the Emory domain. Only approved VA personnel 
are allowed to access this data, as it is administered and maintained solely by the VA Rehabilitation 
R&D Center of Excellence in Atlanta. Data security is maintained through need-only permissions and 
access control, while secure, encrypted backups maintain integrity and longevity of datasets. 
Importantly, all data will be non-identified and scrubbed of all 18 HIPAA identifiers. All servers are 

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housed in secure server rooms, monitored 24x7 by electronic video and security personnel.  Dr. 
Bruce Crosson will offer mentorship on this project and will give Madeleine Hackney, the PI, 
unfettered access to lab resources. While completing the proposed research study, Dr. Hackney will 
complete fMRI analysis at the neuroimaging lab and have the benefit of the use of its testing rooms, 
technicians and data storage capabilities. 
MRI systems reside at the Emory Wesley Woods Center for Systems Imaging with which Dr. 
Hackney will have access due to her academic affiliation with Emory University. The MRI unit 
consists of a Siemens Medical Solutions (Malvern, PA) 3.0 Tesla Trio MRI scanner, a full body 
scanner (60 cm bore) with Sonata gradient set (gradient amplitude of 40mT/m, maximum slew rate of 
200T/m/sec, minimum gradient rise time of 200 microseconds). The system is actively shielded and is 
equipped with 32 RF channels and the total imaging matrix (TIM) suite. Multiple coils are available for 
the systems, including a 12 channel head matrix coil, 8 channel head coil, 4 channel carotid coil and 
a 24 channel spine coil. It runs the latest Siemens VB17 software and has a number of advanced 
Siemens product sequences including SWI, BLADE, Diffusion Tensor Imaging & Tractography, Auto 
Align feature for reproducible slice positioning based on a 3D MR brain atlas, BOLD imaging and in-
line analysis suite with 3D PACE realtime motion correction and single and multi-voxel spectroscopy. 
Stimulus/response controls for behavioral tasks concurrent with fMRI are supported by an array of 
hardware specifically designed to allow investigator flexibility and precision. Visual presentation is 
provided by a high resolution LCD projection system (1400x1050 SXGA, 4200 lumens, 1300:1 
contrast ratio) delivered from the back of the suite onto a custom fit screen mounted within the bore 
behind the participant’s head. Audio presentation is provided by an Avotec Silent Scan 3100 that has 
been calibrated to maintain sound pressure levels that are dependent directly on input (flat frequency 
response +/- 4dB, 200-4500Hz range). A fiber-optic ergonomic bilateral button response system from 
Psychology Software Tools exists, as well as a control unit to support custom response shapes 
(joysticks, steering wheels, wands) from Current Designs. All of the hardware is connected through a 
single switch that signals TTL trigger pulses and allows connectivity to an investigator’s laptop with 
any non-proprietary connections (USB, 1/8” minijack audio, VGA & DVI). A dedicated stimulus and 
response monitoring computer running Eprime 2.0 and Presentation stimulus programming software 
also exists.
Safety Monitoring
As aforementioned, the risks due to participation in this research are minimal. To minimize the 
potential risk of fatigue during testing and classes, participants will be allowed frequent breaks. To 
minimize the risk of dizziness or loss of balance during the mobility tests, trained research assistants 
trained in fall prevention maneuvers will closely monitor and guard the participant during testing. 
For fMRI the following procedures will be put into effect: 
Imaging:
No one with deep brain stimulator implants will be allowed to participate in imaging.
The risks associated with the imaging procedure are the same as those associated with conventional 
MRI. Specifically, movement or heating of metallic implants is a potential risk, and so subjects will be 
screened to exclude people with metallic implants, fragments, or pacemakers. Some individuals 
experience claustrophobic reactions in the scanner. Subjects will be informed of this prior to the 
study, but because it is difficult to predict who will have such a reaction, this is not a specific exclusion 
criterion. During the scans themselves, any subject experiencing claustrophobia will be removed from 

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the scanner immediately. There is no invasive component to this study; therefore, discomfort, 
bruising, and/or infection are not risks.
There may be additional risks associated with scanning at 3T, which we address:
Effect of the static field: The FDA has approved for routine clinical use, scanners up to 4.0 T. 
The system that we will be using is FDA approved. There is no conclusive evidence for irreversible or 
hazardous bioeffects to acute, short-term exposures of humans up to 2.0 T (Shellock and Kanal, 
1996). Studies have indicated some side-effects at 4.0 T, namely unusual sensations including 
nausea, vertigo, and metallic taste (Schenck, 1991). However, there is no evidence that this is either 
irreversible or harmful. If subjects experience unusual sensations, they will be withdrawn.
Effect of the gradient field: MRI operates by rapidly changing small additional fields, called 
gradients. By Faraday’s induction law, a changing magnetic field will induce electrical currents in any 
conductor. Thus, rapid cycling of the gradient field can induce peripheral nerve stimulation. However, 
this is not substantially different at higher magnetic fields since the gradients are separate from the 
main magnet. Should participants experience peripheral nerve stimulation (e.g., tingling or twitching), 
the principal investigator and staff will withdraw the participant from the study.
Effect of the RF electromagnetic field: The fundamental principle of MRI is that protons are 
excited by sending in an RF pulse at their resonant frequency for the magnetic field. The FDA 
provides guidelines for the safe use of MR systems, which includes specific recommendations for 
how much RF power is safe. They use the “specific absorption rate,” or SAR. The SAR is the mass 
normalized rate at which RF power is coupled to biologic tissue and is typically indicated in units of 
watts per kilogram (W/kg) (NRCP, 1986). The FDA provides recommendations for two alternative 
safe levels of exposure to RF energy during MR procedures, primarily to control the risk of systematic 
thermal overload (heating) and local thermal injury. These are (FDA, 1988):
(a) The exposure to RF energy below the level of concern is an SAR of 0.4 W/kg or less 
averaged over the body, and 8.0 W/kg or less spatial peak in any 1 g of tissue, and 3.2 W/kg or less 
average over the head; 
OR
(b) The exposure to RF energy that is sufficient to produce a core temperature increase of 1 
deg C and localized heating to no greater extent than 38 deg C in the head, 39 deg C in the trunk, 
and 40 deg C in the extremities, except for patients with impaired systemic blood flow and/or 
perspiration.
We will adhere to the recommendations for the head, which is also monitored by Siemens’ built-in 
monitor.
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