Effect of SMARTfit Training on Motor, Cognitive Functions and Brain Connectivity in Individuals With Parkinson's Disease: a Pilot Study
Phase: NA
Conditions: Parkinson Disease, Exercise Training, Cognitive Change
Sponsor: University of Southern California

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PROTOCOL NUMBER: HS-17-00928 
 
 
 
 
TITLE: Effect of SMARTfit training on motor, cognitive functions and brain connectivity in 
individuals with Parkinson’s disease: a pilot study 
 
 
 
 
PRINCIPAL INVESTIGATOR(S):  Charles Liu, MD, PhD 
                                                            
 
 
 
 
 
 
CO-INVESTIGATOR(S):   Beth Fisher, PhD, PT, FAPTA  
 
Judy Pa, PhD 
 
 
  
 
 
 
 
SPONSOR: None 
 
 
 
 
PARTICIPANTS/LOCATIONS: Individuals with Parkinson’s disease/ Division of Biokinesiology and 
Physical Therapy (CHP building) and Stevens Neuroimaging and 
Informatics Institute 
 
 
 
 
AMENDMENTS/REVISIONS: Version 1 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
 
 
 
 
 
PAGE 
 
1.0 
BACKGROUND AND HYPOTHESES  
__3__ 
 
2.0 
OBJECTIVES AND PURPOSE 
__4__ 
 
3.0 
STUDY DESIGN  
__4__ 
 
4.0 
DRUG/DEVICE INFORMATION 
__9__ 
 
5.0  
SELECTION AND WITHDRAWAL OF SUBJECTS 
__9__ 
 
6.0 
DESCRIPTIVE FACTORS/STRATIFICATION/RANDOMIZATION SCHEME 
__10_ 
 
7.0  
STUDY AGENT ADMINISTRATION OR INTERVENTION AND TOXICITY     
MANAGEMENT PLAN 
__10_ 
 
 
 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY 
__10_ 
 
 
9.0 
CLINICAL AND LABORATORY EVALUATIONS 
__11_ 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS  
 
__12_  
 
11.0 
SPECIAL INSTRUCTIONS  
 
 
 
 
 
 
__12_ 
 
12.0 
DATA COLLECTION AND MONITORING 
__13_ 
 
13.0 
STATISTICAL CONSIDERATIONS  
__13_ 
 
14.0 
REGISTRATION GUIDELINES  
__13_ 
 
15.0 
BIOHAZARD CONTAINMENT 
__13_ 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
__13_ 
 
17.0 
REFERENCES 
 
 
 
 
 
 
 
 
__14_ 
 
APPENDICES 
 
 

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 1.0 
BACKGROUND AND HYPOTHESES 
 
Although Parkinson’s disease (PD) has been mainly viewed as a movement disorder, the 
pathophysiology of declined motor function incorporates impairments of multiple systems (sensory, motor, and 
cognition). Specifically, it has been demonstrated that cognitive function may play an essential role in daily motor 
function for individuals with PD1,2. Cognitive dysfunction involving set-shifting and attentional control has been 
found to be associated with movement slowness in performing a finger sequence task and freezing of gait3–8. The 
above results are in line with the clinical observations that motor performance in individuals with PD is degraded 
when the cognitive load of motor tasks increases, such as talking on the phone while walking or maneuvering 
between people in a crowded mall. Furthermore, a recent rodent model indicates that cognitive dysfunction may 
occur prior to the onset of motor symptoms8. Human studies also show that 25-30% of individuals with PD exhibit 
cognitive impairments at the time of diagnosis 9,10. The overall evidence suggests that cognitive dysfunction may 
contribute to degraded motor function. 
 
Interestingly, emerging evidence demonstrate that aerobic exercise and resistance training can improve 
cognitive function in individuals with PD11–15. One study done by Ridgel et al. (2009) shows enhanced cognitive 
function after 30-min passive cyclying12. The findings indicate that there is a tight interplay between motor and 
cognitive function in individuals with PD. Therefore, targeting cognitive function and incorporating cognitive 
training into physical rehabilitation may be important as it may better help individuals with PD to transfer the 
learned skill into real-world daily activities. Although there is mounting evidence for the benefits of physical 
exercise in PD, few studies investigate whether combining cognitive training with physical exercise can provide 
additional benefits than physical exercise alone. 
 
It has been suggested that exercise exerts its beneficial effects in PD, at least partially, through changes in 
the brain16. However, few studies have linked these improvements in motor and cognitive function with 
alterations of the brain and the exact nature of these alterations is not completely understood. Neuroimaging 
studies using functional magnetic resonance imaging (fMRI) have documented altered brain functional 
connectivity in PD17,18. Relative to non-disabled adults, people with PD showed reduced functional connectivity in 
mesolimbic-striatal and corticostriatal loops, with strengthened connectivity between cortical areas, such as pre-
SMA and M1. Exercise has been shown to change altered brain functional connectivity, as demonstrated by 
inducing an increase in cortico-subcortical connectivity and a decrease in cortico-cortical connectivity after 
cycling training19,20. In addition, it remains to be answered whether physical exercise can also modulate the 
disease progress in PD. Blood-based α-synuclein and DJ-121–24, as well as quantitative electroencephalogram 
(qEEG)25,26 have been demonstrated to be predictive biomarkers related to disease progress and cognition decline 
in individuals with PD. EEG is a routine test procedure commonly used in clinical neurology and a gross measure 
of neural electric activities from the scalp. Amplitude of a given activity reflects the degree of neuronal 
synchronization underneath the recording lead. The relative magnitude distribution among different frequency 
bands reflects the brain status whether in sleep, relaxation or vigilance. In addition to the epileptic spikes found in 
seizure patients, individuals with different mental disorders often have different patterns in their EEG profile. 
More recent studies in conjunction with other neural imaging measures have shown that EEG may predict the 
state energy metabolism in the brain as well as how the cognitive information is processed. The characteristics of 
EEG resonance were further found to be closely associated with how cognitive information is encoded in the 
brain27. Significant deviation of the alpha EEG (8-12 Hz) from the norm was found in various illnesses. 
Quantitative EEG is a non-invasive, information rich, and easy-to-use objective test. Recent studies have 
demonstrated that it is sensitive to detect minor neurological changes. Exploring the changes in biomarkers 
following physical training will provide more insights into potential mechanisms underlying training-induced 
benefits in PD. We expect that EEG changes will be seen along with physical and cognitive changes. 
 
The SMARTfit (https://smartfitinc.com/) is a novel technology that provides an opportunity to combine 
physical training with cognitive training. SMARTfit technology focuses on providing a multi-sensory approach 
for exercise by simultaneously using visual and auditory stimuli/feedback while delivering physical and cognitive 
training games. SMARTfit intends to design physical training with game technology by using time and score to 
ignite engagement and enjoyment during physical training, as well as providing cognitive challenges. In 
consideration of the imbedded cognitive and motivational components in SMARTfit, it can be utilized as a model 
to investigate the benefits of combining cognitive challenges with physical training on individuals with PD. Thus, 
the purpose of this pilot study is to investigate the effectiveness of a SMARTfit training in individuals with PD. 
Our hypothesis is that SMARTfit training will promote motor and cognition improvements over conventional 
physical training by altering brain functional connectivity. To test the hypothesis, individuals with mild PD will 
receive both SMARTfit training and conventional physical training in a counterbalanced order with a washout 

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period. For each training program, participants will receive a 1-hour training session 3 times per week for 8 
weeks. The changes in disease biomarkers before and after training will also be explored. 
 
Parkinson’s disease: Approximately 630,000 people in the US were diagnosed with Parkinson’s disease 
(PD) in 2010 and it is estimated that PD prevalence will double by 204028. PD progression leads to decreased 
independence and quality of life, as well as increased reliance on the healthcare system. The economic impact of 
PD, including treatment, social security payments, and lost income from inability to work, exceeded $14.4 billion 
in 201028. There is no known cure for this degenerative disease that results in progressive deterioration of motor 
skills along with reduced sensory and cognitive function. The current treatment for PD is medication (levodopa, 
dopamine agonists) and surgical intervention (deep brain stimulation). These treatments only partially treat the 
symptoms and are less effective over time. Furthermore, they often have undesirable side effects. In the past 15 
years, mounting evidence has shown that exercise can ameliorate PD symptoms. Even though exercise has been 
demonstrated to be beneficial for improving PD motor symptoms, significant gaps in this knowledge limit the 
ability to create specific exercise prescription to optimize neuroplastic changes in the PD brain16. 
 
 
2.0 
OBJECTIVES AND PURPOSE 
 
The aims of this pilot study are: 
1) to examine the changes in clinical and physical performance measures after SMARTfit training and 
conventional physical training. Outcome measures will include MDS-UPDRS III (motor) score and the 
modified Physical Performance Test (mPPT) before and after SMARTfit training and conventional 
physical training. We hypothesize that clinical and physical performance will improve after SMARTfit 
training more than after conventional physical training. 
2) to examine the changes in cognitive function measures after SMARTfit training and conventional 
physical training. Outcome measures will include Trail-Making test (TMT) and Parkinson’s Disease-
Cognitive Rating Scale (PD-CRS) before and after SMARTfit training and conventional physical training. 
We hypothesize that cognitive function will improve after SMARTfit training more than after 
conventional physical training. 
3) to examine the changes in brain connectivity after SMARTfit training and conventional physical training. 
Functional magnetic resonance imaging during rest and a cognitive task will be measured before and 
after SMARTfit training and conventional physical training. We hypothesize that cortico-subcortical 
connectivity will increase and cortico-cortical connectivity will decrease after SMARTfit training more 
than after conventional physical training. 
4) to examine the changes in biomarkers after SMARTfit training and conventional physical training. 
Blood-based α-synuclein and DJ-1, as well as quantitative EEG will be measured before and after 
SMARTfit training and conventional physical training. 
 
 
3.0 
STUDY DESIGN 
 
3.1 Methods 
 
Sample size and participants 
 This pilot study aims to investigate the effects of 8-week SMARTfit training versus conventional 
physical training on motor function, cognition and brain functional connectivity in individuals with PD. The target 
sample size is a maximum of 12 participants with PD. Recruitment to this study at this time is based primarily on 
word of mouth from prior participants. We will also recruit through the use of flyers posted on campus and its 
immediate vicinity, and through a website. All eligible recruits will sign a written informed consent to participate 
in the experimental protocol approved by the Institutional Review board of the University of Southern California. 
All participants will be screened for inclusion and will be excluded from the study if they do not meet the 
inclusion criteria.  
Prior to their arrival, participants will complete one brief (about 5 minutes) intake questionnaire that 
includes questions about their medical and psychiatric history and their current use of alcohol, nicotine and 
prescription or non-prescription drugs to screen their eligibility for MRI. The purpose of the interview is to obtain 
more detailed information about any factors that may influence either their eligibility to participate in the 
procedures or the results of the procedures themselves. Potential subjects will also be screened for 
contraindications for MRI experiment such as pregnancy, pacemakers and implants. 
 
Procedures and tasks 

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This pilot study is a cross-over trial to estimate the effects of 8-week SMARTfit training versus 
conventional physical training on behavior, brain measures and biomarkers in individuals with Parkinson's disease. 
Participants will receive both 8-week SMARTfit training and 8-week conventional physical training with an 8-
week washout period in between. The order of received training will be counterbalanced between participants. 
Each training regimen will consist of 24 training sessions over an 8-week period (3 days/week).  Motor function, 
cognitive function, the Unified Parkinson's Disease Rating Scale (UPDRS) measures and functional connectivity 
of the brain will be assessed before and after each training program. 
  
Ten individuals with mild Parkinson's disease, who are medically approved for both intense exercise and 
(MRI), will be recruited for the study if they are willing to consent. Each participant's personal physician will be 
contacted and involvement in the study will be discussed and approved by the physician. All participants will 
undergo informed consent as approved by the Internal Review Board of the University of Southern California. 
Following assessment by either the principal investigator or the study coordinator to assure that the participant 
meets rule-in and rule-out criteria to be in the study. All participants will be given standard instructions to ensure 
reliability for each evaluation. The following tests will be conducted on participants at the following time points: 
baseline, 8 weeks, 16 weeks and 24 weeks. The first baseline measures will be taken within the week prior to 
beginning the first training program. The first post-training evaluation (8 weeks) will be taken during the week 
after the first training has been completed (after 24 training sessions which occur over an 8-week period). A 
second baseline evaluation (16 weeks) will be taken after an 8-week washout period following the first 
training,and within the week prior to beginning the second training. The second post-training assessment (24 
weeks) will be taken during the week after the second training has been completed. Data will be coded to protect 
the confidentiality of the participants and will be stored in a locked office and password-protected computer 
accounts. Data entry will also not disclose the identity of the participants. 
 
 
 
Clinical assessments 
 MDS Unified Parkinson's disease Rating Scale (UPDRS): The UPDRS is an assessment of Parkinson's 
disease severity and progress. The UPDRS has four sections. The first section assesses mentation, mood, and 
behavioral changes. The second section assesses historical activities of daily living. The third section is the motor 
examination portion of the UPDRS and includes evaluations of tremor, rigidity, bradykinesia, gait, and postural 
instability.  The fourth section evaluates complications of therapy including motor fluctuations and dyskinesias. A 
5-point scale is used a well-defined criterion. The UPDRS will be administered by a blinded research investigator 
who has been trained using the Movement Disorders UPDRS training videos. The UPDRS has universal 
acceptance as a rating scale for individuals with PD and it has been shown to be reliable and valid. This measure 
will be used to determine symptom severity. MDC will be 2.5 points between baseline and post-training. 
 
 
 Modified Physical Performance Test (mPPT): The mPPT is a 9-item test that assesses multiple 
dimensions of physical function (basic and complex activities of daily living) with different levels of difficulty. 
This measure correlates well with degree of disability, loss of independence, and early mortality. It is also 
significantly correlated to UPDRS III and Hoehn and Yahr scale in PD. It is a reliable measure with a high inter- 
and intra-rater reliability. Standard instructions will be given to ensure reliability. Participants will be asked to 
complete functional tasks (i.e. writing a sentence, simulated eating, lift a book and put it on a shelf, turning 360 
degrees, 50-foot walking test, stair climbing etc.). Participants’ performance will be videotaped and the score of 
each task will be rated based on the completion time. 
 
 Self-Efficacy for Exercise (SEE) scale: The SEE is to capture an individual’s confidence in their ability 
to continue exercising in the face of barriers to exercise. The SEE consists of 9 items describing potential barriers 
to participation in exercise (eg, “too busy with other activities,” “did not enjoy exercise,” “felt pain with exercise,” 
“bored by the exercise”). For each item, participants circled a number from 0 (“not confident”) to 10 (“very 
confident”) that best described their belief that they could exercise 3 times a week for 20 minutes. Reliability, 
validity, and internal consistency have been established for the SEE. 
 
 Quotient test: The Quotient test is an innovative device that objectively measures three domains of 
cognition: hyperactivity, inattention and impulsivity. This easy-to-administer tool uses advanced motion tracking 
technology to track micromovements while participants complete a computerized test that takes less than half an 
hour. Below is an example of the cognitive task involved, it consists of a simple go/no go task which is generally 
used to clinically assess frontal lobe function. After the test is completed, patterns of motion, accuracy of the 
responses, and fluctuations in attention state are quickly analyzed and scored using proprietary algorithms based 
on 19 or more parameters. The motion detection includes 6 movement metrics. The Attention Response Analysis 

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includes measures of accuracy, omission errors, commission errors, latency, variability, and response time 
variability. Data for each patient is compared to age and gender matched cohorts. Scores and test data provide 
both the existence of related deficits and the magnitude of those deficits. Quotient is cleared by the FDA with the 
intended use to provide objective measures of hyperactivity, impulsivity and inattention to aid in the clinical 
assessment. 
 
 
 
 
 Trial-Making Test (TMT): The Trail Making Test is a neuropsychological test of visual attention and 
task switching. It consists of two parts in which the participant is instructed to connect a set of 25 dots as quickly 
as possible while still maintaining accuracy. The test can provide information about visual search speed, scanning, 
speed of processing, mental flexibility, as well as executive functioning.  
 
 Parkinson’s Disease-Cognitive Rating Scale (PD-CRS): The PDCRS is is a valid, reliable and useful 
neuropsychological battery designed to cover the full spectrum of cognitive defects associated with PD. The PD-
CRS includes 10 ‘subcortical-type’ items (attention, working memory, Stroop test, four verbal fluencies, 
immediate and delayed verbal memory, clock drawing), and two ‘cortical-type’ items (naming, copy of a clock). 
Total score ranges from 0 to 204, subcortical score from 0 to 174, and cortical score from 0 to 30, with higher 
scores indicating a better functioning. 
 
Magnetic resonance imaging (MRI) protocol 
All participants will be screened using the MRI screen questionnaire. The MRI scans will be performed 
at the Stevens Neuroimaging and Informatics Institute at the USC Health Sciences Campus. Participants will 
undergo MRI tests at 4 time points (baseline, 8 weeks, 16 weeks and 24 weeks).  
 
MRI preparation and procedures 
 Participants will be instructed in a behavioral task that they will be asked to do as part of a functional 
imaging study. In some cases, they will go through sample trials of the task as part of a familiarization period. The 
participants will then be asked to lie on the bed of the MRI scanner and will be given headphones and ear-
protectors. In some cases, a comfortable head restraining device (such as cloth tape or pads on the sides of the 
head) may be used to reduce excess head motion. The duration of the MRI procedure will be 1 hour. The 
participants will lie with their head motionless and either relax passively or perform the required behavioral task. 
 
The MRI equipment makes a variety of noises during scanning from repetitive tapping to beeping noises. 
Anyone in the scanner room while the scanner is in operation must use hearing protection in the form of earplugs 
and/or headphones to avoid hearing injury from the acoustic noise generated by the scanner. The earplugs and/or 
headphones provided reduce the noise levels to a level comfortably below the FDA guidelines. The scanners are 
equipped with a squeeze bulb that allows the participant to set off an audible alarm to attract the operator’s 
attention. The squeeze bulb will be made available to participants. After completion of the imaging, the participant 
will be removed from the instrument. We interview the participants informally for any adverse or unexpected 

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reactions that may have taken place during the study.  
 
Blood oxygen level dependent (BOLD) functional MRI (fMRI): fMRI is one of the most widely used MRI 
techniques for studying human brain function. Since the seminal discovery of functional connectivity (FC) 
between distributed brain areas during the resting state, resting state fMRI (rs-fMRI) has become a major tool for 
characterizing the dynamic organization of large scale brain networks. With the recent development of 
simultaneous multi-slice (SMS) or multiband imaging, whole brain BOLD fMRI using gradient-echo echo-planar 
imaging (GE-EPI) can be performed with an isotropic spatial resolution of a few mm3 and a temporal sampling 
rate of a few hundred milliseconds per volume, as demonstrated by the Human Connectome Project (HCP29). At 
ultrahigh magnetic fields, fMRI with a sub-millimeter spatial resolution has been applied for studying human 
brain function at the cortical layer or column level. Each test session consists of fMRI during a cognitive task and 
at resting state. 
 
Task-based fMRI: Participants will perform a word-color Stroop paradigm that has been previously 
adapted for use in fMRI experiments30. The task is composed of two conditions: congruent and 
incongruent, interspersed with periods of no stimuli (baseline). The visual stimuli consist of four words: 
red, blue, green and yellow. In the congruent condition, words appear in their matching colors, whereas 
in the incongruent condition, the colors do not match their content. Participants will be instructed to press 
the buttons as quickly as possible according to the color of the ink presented while disregarding the 
meaning of the word. Responses will be made using the index and middle finger of both the left and right 
hand using a response box that contained four buttons. The same number of stimuli is given to the left 
and right hand. The color of the four buttons is presented on the top of the computer screen. Stimuli will 
be presented at a rate of 1 sec for color word interleaved with 2 sec of a blank screen. Each task block 
contains 12 different words of which 1/3 are distracters (congruent in incongruent trials and vice versa), 
interleaved with a 10 sec baseline which consists of a red fixation point at the center of the screen. There 
are seven alternating blocks of the two conditions (four incongruent and three congruent) and eight 
baseline blocks. For all participants, adequate task performance will be assured by familiarization and 
practice of the task prior to entering the MRI scanner. 
 
Resting state fMRI: Participants will be instructed to keep their eyes open fixation on a projected image 
of a white cross on a black background, to remain motionless, and to not to think of anything in particular. 
The scanning session will last for 6 mins. 
 
Quantitative electroencephalogram (qEEG) protocol 
A 19-channel EEG acquisition system (Deymed Diagnostic, TruScan 32) will be used in recording. 
Participants will be instructed to sit quietly with eyes closed whilst wearing a skull cap. An electrode cap designed 
according to standard International 10-20 Montage system is placed over the head with proper skin preparation to 
ensure each electrode is well contacted (impedance < 5k). Ten minutes of rest data will be collected. Data will be 
amplified and digitized at 512 point/c and stored on a computer hard disk for off-line analysis. 
 
Blood sample collection protocol 
A venous blood sample of up to 40 ml will be obtained from participants. The amount drawn from 
participants will not exceed the lesser of 50ml or 3ml per kg of the participant’s weight in an 8 week period. 
 
Training program 
All participants will receive the following trainings with a counter-balanced order. Training sessions will 
take place at the Division of Biokinesiology and Physical Therapy (CHP building). 
 
(1) SMARTfit training 
(2) Conventional physical training. 
 
For both SMARTfit training and conventional physical training, participants receive three 1-hour training sessions 
per week for 8 weeks. During each week, participants will receive physical training focused on six tasks, which 
are the functional tasks individuals with PD commonly have difficulty with. The six tasks are paired into 3 pairs 
(see Table 1). Participants will focus on practicing one pair of tasks during each session. 
 
 
 
Table 1. Functional task training 
Pair 
Task 1 
Task 2

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1 
Sit-to-stand 
Multi-plane locomotor tasks (obstacle course)  
2 
Gait  
Reach & Grasp  
3 
Floor-to-stand; Stand-to-floor 
Single limb standing  
 
For each of the trained task, the five components (movement amplitude/speed; endurance; balance; vision; 
accuracy) can be manipulated to scale up and down based on each participant’s capability. Each component has 
three difficulty levels. Please see Appendix 1 for the details of three difficulty levels for each component. This 
provides the training therapist a standardized guideline to adjust the task difficulty to fit each participant’s priority 
and participants’ progress over 8 weeks to make sure that each training session is at the optimal challenge point  in 
order to maximize the effect of training31. For the SMARTfit training, there is an additional cognition component 
that can be manipulated using features provided by SMARTfit. After each training session, participants’ rating of 
perceived exertion (RPE) will be obtained using a 1-10 Borg scale. Participants’ RPE should be between 6 to 8. If 
the participant’s RPE exceeds 8, then in the next training session the challenge level of trained task will be scaled 
down until they are at or below 8 on the Borg scale. At any point during the session, participants are allowed to 
terminate by telling the researcher that they would like to stop.  
 
3.2 Dependent measures 
Primary outcome measure 
1. Modified Physocal Performance Test score (mPPT) 
Secondary outcome measures 
1. UPDRS score 
2. Self-Efficacy for Exercise scale (SEES) 
3. Trail-making test (TMT) 
4. Parkinson’s Disease-Cognitive Rating Scale (PDCRS) 
5. Quotient system test 
6. Functional connectivity 
7. Quantative EEG measures 
8. α-synuclein and DJ-1 
 
3.3 Data processing 
Statistical Parametric Mapping will be used to process the fMRI data. The fMRI analysis focuss on the 
whole brain. An inclusion criterion for fMRI image analysis is head motion < 2 mm in any direction. The 
functional images are subjected to geometric distortion (field map) correction and motion correction. The 
structural images will be co-registered to the mean unwarped and motion corrected functional image for each 
participant and functional and structural images will be normalized to Montreal Neurological Institute (MNI) 
space. Functional volumes will be smoothed with a Gaussian kernel of 8 mm3 (FWHM). Correlational analyses 
between the BOLD signal from an a priori selected seed and every other brain voxel during the entire acquisition 
condition will be run to provide seed-to-voxel connectivity estimations for each participant. Movement parameters 
will be entered as first-level covariates in the model. Before averaging individual voxel data, the waveform of 
each brain voxel will be filtered using a bandpass filter to reduce the effect of low-frequency drift and high-
frequency noise. Several sources of spurious variance along with their temporal derivatives will then be removed 
from the data through linear regression: signal from movement, signal from ventricular regions, and signal from 
the white matter. Because further steps include between-sessions comparisons, temporal connectivity maps will be 
generated for each participant across the conditions. These images will be then included in a second-level analysis. 
 
EEG will be recorded using Deymed acquisition system and then converted to *.EDF format for offline 
analysis. Raw data will be carefully inspected and edited to reject all movement artifacts. Total of 4-min artifact 
free epochs will be included in the quantitative analyses. All data will be analyzed by a fast Fourier transform 
routine using 1,024 point FFT window to yield a power density spectrum for each channel. According to clinical 
EEG convention, power density will be calculated at the following frequencies: delta (<4Hz), theta (4-8Hz), alpha 
(8-12Hz), and beta (12-30), respectively. In addition to fast Fourier transform, we will calculate cross-channel 
correlation in time domain, coherence in frequency domain and power density mappings. A contour map will also 
be generated for each frequency band using the nearest neighbor algorithm. NBRL NeuroRef, which applies 
LORETA technology to convert EEG voltage signals into current density, will be applied to map out the 
distribution in 3-D space by overlapping with a morphed MRI image. Individual’s data will be further analyzed 
and compared with an FDA approved normative EEG database licensed from NYU to determine degrees of 
deviation of respected variables from the norm. Multivariate discriminant function analysis will be used to 
determine degrees of deviation of individual’s data from norm by linear composite of variances from the means of 

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database. Z-scores will be calculated for the following measures: (1) absolute power of all frequencies in all 
channels, (2) relative power of all frequencies in all channels, (3) mean frequency of alpha rhythm in all channels, 
(4) 19 X 19 coherence matrix and mappings for each frequency, and (5) 3-D current density mappings for 
interested frequency using sLORETA technology. Results of analyses will be exported to a spreadsheet for further 
statistical analysis.   
 
Blood samples labeled with participant ID will be frozen and shipped to the Laboratory of Molecular 
Psychiatry at University of California, Irvine for data processing and analysis. Alpha-synuclein and DJ-1 levels 
will be measured using an established protocol in previous research32. 
 
4.0 
DRUG/DEVICE INFORMATION 
 
The following devices will be utilized in this pilot study: 
1. MRI: The MRI scanning procedure requires that the participants be confined in a small, partially enclosed 
space. The sound of the MRI scanner can be loud, but will be reduced by special ear plugs. The tasks may be 
boring or difficult. In addition, the magnetism of the machine attracts certain metals; therefore, people with 
these metals in them (specifically pacemakers, infusion pumps, aneurysm clips, metal prostheses, joints, rods, 
or plates) will be excluded from the study. The "metal" in dental fillings is less susceptible to magnetism and 
is therefore allowed. There are no known adverse effects resulting from exposure to the MRI scan. There are 
no other known risks when the scanner is operated within its nominal range as discussed above. The FDA 
Center for Devices and Radiological Health, released the document "Criteria for Significant Risk 
Investigations of Magnetic Resonance Diagnostic Devices" on July 15, 2003. This describes their current 
evaluation of risk related to MRI. Notably, both software and hardware features of the instrument prevent this 
software from executing commands outside of a well-defined range defined as safe by the FDA. 
2. Quantitative EEG: TruScan 32 EEG Acquisition System (Deymed Diagnostics, Payette, ID), including EEG 
cap, EEG amplifier and EEG adapter, will be used in the study.  
3. Quotient system: Quotient® (formerly known as MMAT, the McLean Motion and Attention Test) is a non- 
invasive device providing objective measures of an individual’s ability to inhibit motor activity, sustain 
attention and suppress impulsive response. Quotient uses motion tracking technology to track an individual’s 
micromovements while he or she completes a 15-20 minute computerized test. After the test is completed, 
patterns of motion, accuracy of the responses, and fluctuations in attention state will be analyzed and scored 
using proprietary algorithms. Quotient is cleared by the FDA with the intended use to provide objective 
measures of hyperactivity, impulsivity and inattention to aid in the clinical assessment of ADHD.  
4. SMARTfitTM Mini 9 On-Frame: The SMARTfitTM Mini 9 On-Frame is a vertical frame-mounted 9 target 46″ 
x 46″ Panel with CPU controller, timeclock, score display, sound system and 4 tracks of themable 
voice/tones/music. The SMARTfitTM Mini 9 On-Frame can capture the accuracy and movement time, which 
serve as performance feedback to participants. 
 
5.0  
SELECTION AND WITHDRAWAL OF SUBJECTS 
 
 
5.1 
Inclusion Criteria: 
1) 50-85 years of age 
2) Diagnosis of idiopathic Parkinson’s disease using the UK Brain Bank criteria (as determined by the 
study movement disorders neurologist) with Hoehn and Yahr stage 1-2 
3) No contraindications to exercise including untreated cardiovascular disease or stroke 
4) Medically stable and optimized on their medications 
5) Able to ambulate independently with or without device 
6) No other neurologic, neuromuscular, or orthopedic disease 
7) No serious cognitive deficits and able to participate in the informed consent process 
8) With medical clearance from primary care physician to participate in the physical therapy 
intervention 
9) No contraindications for MRI 
 
 
5.2 
Exclusion Criteria 
 
 
Participants will be excluded from participation if they have: 
1) Severe cardiac disease (New York Heart Association classification II-IV) 
2) Systolic blood pressure reduction of greater than 20 mmHg with standing 
3) A history of poorly controlled or brittle diabetes 
4) A history of lower limb amputation 

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5) Been prescribed any new dopamine replacement medications or new mood stabilizer medications. 
6) Presence of a lower limb non-healing ulcer 
7) Montreal cognitive assessment score of less than 21 
8) The presence of any medical condition which the investigator believes might present an unacceptable 
health risk to the subject should they participate in the study 
9) Electrically, magnetically, or mechanically activated implant (such as cardiac pacemakers or 
intracerebral vascular clip) 
10) Metal in any part of the body including metal injury to the eye 
11) History of brain lesions (such as stroke), seizures, or unexplained spells of loss of consciousness 
12) Pregnant or breast-feeding 
13) With other neurologic, neuromuscular, or orthopedic disease that would interfere with ability to 
participate in exercise training 
14) Currently participating in other studies 
 
Cardiac Tolerance 
Cardiac conditions that would cause exclusion from the study include (but are not limited to) 
unstable angina within last 3 months, myocardial infarction within last 3 months, serious cardiac 
dysrhythmia, right main coronary artery disease, aortic stenosis, currently decompensated heart 
failure of pulmonary edema, severe system hypertension (SBP > 180 or DBP > 110), fixed-rate 
artificial pacemaker, hypertrophic cardiomyopathy, pulmonary embolus or infarction within the last 
6 months. Each participant's cardiac status will be verified with his/her physician. 
 
Blood Pressure/Heart Rate at rest and with exercise33 
Resting:  Participants in the study must have a resting SBP<180 and DBP<110.  Heart rate must be 
<100 at rest and systolic blood pressure must not drop > 20 with standing.   
Exercise:  Participants in the study must have a SBP<200 and DBP<110 when measured after 2 
minutes rest from exercise. 
 
Participants whose heart rate or blood pressure is greater than the values stated above will be 
excluded from the study.   
 
5.3 
Withdrawal Criteria 
 
 
Participants will have the option to withdraw from this study at any time. Withdrawal from this study will 
not affect their participation in any other study within the USC Neurorestoration center. The investigators 
may also choose to terminate a participant from this study, if he or she suffers a severe adverse event, 
does not follow study requirements, or investigators feel that continued participation will put the 
participant at a greater risk than indicated. 
 
6.0 
 STRATIFICATION/DESCRIPTIVE FACTORS/RANDOMIZATION SCHEME 
 
Participants will be assigned to receive the SMARTfit training or conventional physical training first with 
stratified randomization. Specifically, Hoehn and Yahr stage I and II will be used as the two strata. Randomization 
will be performed within each Hoehn and Yahr stage (I and II) using sealed envelopes with a 1:1 allocation ratio 
between the two training orders. The number of participants with Hoehn and Yahr stage I and II will be evenly 
assigned to the two training orders to ensure equivalent disease severity. 
 
7.0 
STUDY AGENT ADMINISTRATION OR INTERVENTION AND TOXICITY MANAGEMENT PLAN 
 
For training protocol, see section 3.1 at page 7. Training will be discontinued if participants continue experiencing 
a RPE above 8 or show signs of cardiac intolerance (shortness of breath, leg cramps, agina, lightheadness, 
confusion, nausea, blood pressure above guidelines lists in Section 5.2).  Individuals whose symptoms resolve 
after training is discontinued will be invited to participate in the next training session (48 hours later). If these 
symptoms occur a second time, individuals will be removed from the study and will be encouraged to see a 
physician as soon as possible. 
 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY 
 
 
8.1 
Side effects/Toxicities to be monitored. 
 

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11
The risks to participants associated with this study include the time needed to complete the physical 
therapy sessions and the potential for muscle soreness, strains, or sprains that is a natural part of 
participating in a training program. 
 
 
 
The overall risk classification is greater than minimal risk but less than significant risks. 
 
 
 
Potential Risks of Exercise 
 
There are minimal risks associated with participation in exercise and physical training. These risks 
include muscle strains and/or sprains and muscle soreness, in addition to cardiovascular events such as 
heart attack and stroke. Physical training in this proposed study is considered safe and effective for 
improving motor performance in PD. To minimize these risks, all sessions will be monitored by research 
personnel that are CPR/First Aid certified. Additionally, the participant to researcher (1:1) ratio will be 
low so that research personnel can provide adequate attention to participants during training. 
 
Potential Risks of EEG  
 
The use of EEG is largely low risk although placement of disks may cause slight scalp irritation in that 
the discs must be placed directly on the scalp. To prevent more than minimal discomfort we will be in 
constant communication with the participants on how the placement of the EEG cap feels and will 
modify placement based on reported comfort level. If the cap becomes too uncomfortable for the 
participant to bear then the cap will be removed and the participant is free to discontinue participation in 
the study.  
 
 
 
The gel used to put the EEG discs on the head is sometimes sticky and the discs may scratch the outer 
layer of scalp skin. Investigators will take care to try to minimize scratching the scalp skin during 
application. 
 
Potential Risks of blood sample collection 
 
There are minimal risks associated with blood sample collection. There is a small risk of bruising and 
fainting, and a rare risk of infection. 
 
 
 
Summary of MRI risks 
The FDA considers MRI devices to be of non-significant risk if they meet the following criteria (we 
summarize only the relevant portions of this document): 
a. Field strength less than 8 Tesla 
b. RF power deposition (measured as the specific absorption rate or SAR) to the patient is limited by 
law, and by the instrument, to less than 3 W/kg in the head. Notably, human imaging with SAR of 
double that has been demonstrated to be safe in normal subjects34. 
c. Any time rate of change of gradient fields (dB/dt) sufficient to produce severe discomfort or painful 
nerve stimulation. 
d. A-weighted root mean square (rms) sound pressure level greater than 99 dBA with hearing protection 
in place. 
 
Under no circumstances will our instrument be operated outside of these non-significant ranges on 
human subjects. The small risk of metal objects being dislodged will be reduced by the screening process 
previously described. Headphones and ear protectors will be used to reduce any discomfort that might be 
associated with the scanner noise. The use of headphones and video systems will minimize the potential 
discomfort of claustrophobia. 
 
 
 
Protection against MRI risk 
 
The 3T Prisma whole-body MRI systems installed at the Center of Image Acquisition (CIA), Stevens 
Neuroimaging and Informatics Institute located at HSC, which offers state-of-the-art imaging platforms 
to characterize TMS induced physiological, metabolic and functional changes of human brain. 
 
The participants will be screened for appropriateness for study participation using the inclusion and 
exclusion criteria. In addition, participants will be introduced to exercise activities and monitored by a 
trained Physical Therapist (PT) at each visit. The PT will keep documentation records for each treatment 
session that will monitor 1) the subjects cardiovascular exercise tolerance through vital sign assessment 
and 2) any signs of musculoskeletal adverse response. The PT will be instructed to contact the PI 
immediately if an adverse response that requires medical intervention occurs. Participants will practice 

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12
the activities with the PT in the clinical setting and will receive feedback to ensure proper form and 
safety during each session. In addition, subjects will be notified that they can call the PI at any time if any 
adverse effects occur. 
 
 
Ongoing monitoring of risks and benefits will occur by a monthly site visit by the PI who will review all 
documentation. The PI will determine the balance between risks and benefits and will notify the IRB if a 
change in the intervention protocol in order to minimize risk is required. In the case of an actual adverse 
event, the PI will complete the “IRB Report of an Internal Adverse Event” form and report the event to 
the IRB within 5 days of the event.  
 
 
 
8.2 
Dosage change based on toxicity. 
 
Not applicable. No modification of medication will be included.  
 
 
8.3 
Adverse Event Reporting 
 
 
 
All adverse events will be reported to the IRB on the USC Health Sciences Campus. Any unexpected, 
severe, or fatal adverse events will be reported to the IRB within 24 hours. Minor adverse events will be 
summarized and included in the annual continuation review and final report. 
 
 
 
8.4 
Data Monitoring Committee (if applicable) 
 
 
 
Not applicable. 
 
9.0 
CLINICAL AND LABORATORY EVALUATIONS AND STUDY CALENDAR 
 
Evaluation 
1st Pre-training 
assessment 
1st Post-training 
assessment 
2-month washout period 
2nd Pre-training 
assessment 
2nd Post-training 
assessment 
Demographics form 
X 
 
 
 
Montreal Cognitive Assessment 
(MoCA) 
X 
 
 
 
Activities-specific Balance 
Confidence Scale (ABC) 
X 
 
 
 
History of Falls Questionnaire 
X 
 
 
 
Physical Activity Questionnaire 
X 
 
 
 
Geriatric Depression Scale (GDS) 
X 
 
 
 
Modified Physical Performance test 
(mPPT) 
X 
X 
X 
X 
Movement Disorder Society-
sponsored revision of the Unified 
Parkinson's Disease Rating Scale 
(MDS-UPDRS) 
X 
X 
X 
X 
Self-Efficacy for Exercise Scale 
(SEES) 
X 
X 
X 
X 
Trail-making test (TMT) 
X 
X 
X 
X 
Parkinson’s Disease-Cognitive 
Rating Scale (PD-CRS) 
X 
X 
X 
X 
Quotient system test 
X 
X 
X 
X 
Functional MRI 
X 
X 
X 
X 
Quantatitive EEG 
X 
X 
X 
X 
α-synuclein and DJ-1 
X 
X 
 
X 
X 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
All participants will be evaluated on the dependent variables listed in section 3.2. Additionally, basic information 
(such as past medical history and course of Parkinson’s disease) will be collected via paper documents. The 
endpoint will occur once we have enrolled 12 participants. 

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13
 
11.0 
SPECIAL INSTRUCTIONS: 
 
 
Not applicable. 
 
12.0 
DATA COLLECTION AND MONITORING 
 
All data in paper documents, such as clinical assessments and questionnaires, will be stored in locked cabinets in 
the USC Neurorestoration center. Trail-making test will be digitally recorded using PEBL test battery and saved in 
Excel35. Digitally recorded data, including some of the clinical assessment, MRI data and EEG data will be saved 
and secured in password-protected computer accounts in a computer located in the USC Neurorestoration center. 
All digital MRI data will also be archived onto secure, biometrically access-controlled integrated data archive 
(IDA) servers in a locked room within Stevens Neuroimaging and Informatics Institute. 
 
The EEG and MRI data will be stored digitally. Prior to any transfer of information among investigators, or into 
any summary publication, all identifying information about the participants will be removed. Files will be 
identified by study and by an identification number assigned to the participant at the beginning of the study. The 
coding between participant name and ID will be maintained digitally in the records of the laboratory and, as 
needed, by the individual investigators in their private lab files and password-protected computers. For all 
scientific uses, the data will be displayed without identifying information. 
 
The data will be recorded digitally on computer using only a coded designation. Specifically, EEG will be 
recorded Deymed acquisition system in *.dat data format. MR imaging in DICOM file format will be recorded 
using vender-provided data acquisition platform for 3T Siemens Magnetom Prisma (Siemens Medical Solutions 
USA, Inc., Malvern, PA; https://usa.healthcare.siemens.com/magnetic-resonance-imaging/3t-mri-
scanner/magnetom-prisma). No one will have access to the codes or data except the study personnel. Participant 
data will not be released to anyone without written consent of the participant. When the study is completed, the 
data will be kept secure in the USC Neurorestoration center for seven years. 
 
Blood samples labeled with participant ID will be frozen and shipped to the Laboratory of Molecular Psychiatry at 
University of California, Irvine (UCI) for data processing and analysis. The Laboratory of Molecular Psychiatry is 
responsible for receiving the de-identified blood sample from this pilot study, processing the samples, and 
analyzing the data. As such, the Laboratory of Molecular Psychiatry is not required to have IRB approval from 
UCI for the processing of the samples. The Laboratory of Molecular Psychiatry has no access to the link between 
the de-identified sample code and any identifying information. 
 
13.0 
STATISTICAL CONSIDERATIONS 
 
The overall objective of this pilot study is to to estimate the effects of SMARTfit training versus conventional 
physical training on changes in motor and cognitive function, brain functional connectivity as well as disease 
biomarker measures. Three-way repeated measures ANOVA will be used to test the effect of training, training 
order and disease severity (Hoehn and Yahr stage) on the changes in motor and cognitive function, brain 
functional connectivity as well as disease biomarkers follow the SMARTfit training and conventional physical 
training. Baseline value of outcome measures before each training will be used as covariates to account for the 
potential impact of carryover benefit. The significance level is set at p < .05. 
 
The projected sample size for this pilot study is 10 based on the recommondations for pilot studies36,37. Our 
expected goal is to have 10 participants to complete the training. Considering the potential drop-out rate, totally 12 
participants will be recruited. The preliminary data will be used to estimate the effect size and calculate required 
sample size for future studies to achieve sufficient power. 
 
14.0 
REGISTRATION GUIDELINE 
 
Individuals with Parkinson’s disease interested in enrolling in the study will be directed to call (323) 442-1006 for 
more information. Once eligibility is confirmed and informed consent is signed, participants will be assigned to 
one of the two training orders (SMARTfit- conventional; conventional- SMARTfit). At the time of registration, 
two copies of a signed and dated Informed Consent form with Bill of Rights will be available (an original for 
patient’s medical chart; one copy for the participant; and the other for the PI’s file). 
 

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14
15.0 
BIOHAZARD CONTAINMENT 
 
 
 
Not applicable. 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
All institutional and Federal regulations concerning the Informed Consent form will be fulfilled. The study will be 
conducted in adherence to ICH Good Clinical Practice. 
 
17.0 
REFERENCES 
 
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interference in “off” state Parkinson’s Disease. Gait Posture. 2010;31(2):169-174. 
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Lee Y-YA. Neural substrates associated with context-dependent learning. 2013. 
4.  
Peterson DS, Fling BW, Mancini M, Cohen RG, Nutt JG, Horak FB. Dual-task interference and brain structural 
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5.  
Peterson DS, King LA, Cohen RG, Horak FB. Cognitive Contributions to Freezing of Gait in Parkinson Disease: 
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Domellöf ME, Elgh E, Forsgren L. The relation between cognition and motor dysfunction in drug-naive newly 
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8.  
Poletti M, Frosini D, Pagni C, et al. Mild cognitive impairment and cognitive-motor relationships in newly 
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Elgh E, Domellöf M, Linder J, Edström M, Stenlund H, Forsgren L. Cognitive function in early Parkinson’s 
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Aarsland D, Brønnick K, Fladby T. Mild Cognitive Impairment in Parkinson’s Disease. Curr Neurol Neurosci Rep. 
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Tabak R, Aquije G, Fisher BE. Aerobic Exercise to Improve Executive Function in Parkinson Disease. J Neurol 
Phys Ther. 2013;37(2):58-64. 
12.  
Ridgel AL, Kim C-H, Fickes EJ, Muller MD, Alberts JL. Changes in executive function after acute bouts of 
passive cycling in Parkinson’s disease. J Aging Phys Act. 2011;19(2):87-98. 
13.  
Tanaka K, Quadros AC de, Santos RF, Stella F, Gobbi LTB, Gobbi S. Benefits of physical exercise on executive 
functions in older people with Parkinson’s disease. Brain Cogn. 2009;69(2):435-441. 
14.  
Duchesne C, Lungu O, Nadeau A, et al. Enhancing both motor and cognitive functioning in Parkinson’s disease: 
Aerobic exercise as a rehabilitative intervention. Brain Cogn. 2015;99:68-77. 
15.  
David FJ, Robichaud JA, Leurgans SE, et al. Exercise improves cognition in Parkinson’s disease: The PRET-PD 
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16.  
Petzinger GM, Fisher BE, McEwen S, Beeler JA, Walsh JP, Jakowec MW. Exercise-enhanced neuroplasticity 
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17.  
Wu T, Long X, Wang L, et al. Functional connectivity of cortical motor areas in the resting state in Parkinson’s 
disease. Hum Brain Mapp. 2011;32(9):1443-1457. 
18.  
Gao L, Wu T, Jankovic J, et al. The study of brain functional connectivity in Parkinson’s disease. Transl 
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19.  
Shah C, Beall EB, Frankemolle AMM, et al. Exercise Therapy for Parkinson’s Disease: Pedaling Rate Is Related to 
Changes in Motor Connectivity. Brain Connect. 2016;6(1):25-36. 
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Beall EB, Lowe MJ, Alberts JL, et al. The Effect of Forced-Exercise Therapy for Parkinson’s Disease on Motor 
Cortex Functional Connectivity. Brain Connect. 2013;3(2):190-198. 
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Mehta SH, Adler CH. Advances in Biomarker Research in Parkinson’s Disease. Curr Neurol Neurosci Rep. 
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Jin Y, Potkin SG, Rice D, et al. Abnormal EEG responses to photic stimulation in schizophrenic patients. 
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Uǧurbil K, Xu J, Auerbach EJ, et al. Pushing spatial and temporal resolution for functional and diffusion MRI in 
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Lin X, Cook TJ, Zabetian CP, et al. DJ-1 isoforms in whole blood as potential biomarkers of Parkinson disease. Sci 
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33.  
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Hertzog MA. Considerations in determining sample size for pilot studies. Res Nurs Health. 2008;31(2):180-191. 
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Appendix 1 
 
Pair 1: Sit-to-Stand  
Level Amplitude/speed  
Endurance
Balance
Vision
Accuracy
Cognition
1 
Perform task big enough that 
able to complete task in one 
attempt – 18 inch height chair  
Complete 10 
repetitions  
Both feet on the ground and allowed to use 
upper extremity support  
No manipulation Not using back of 
legs on the chair and 
standing up to full 
upright posture; no 
‘toes up’  
Simple reaction time task 
2 
Perform task big enough that 
able to complete task in one 
attempt – 16 inch height chair  
Complete 20 
repetitions  
Both feet on the ground with goal of no upper 
extremity support  
Sunglasses or no 
body glasses  
   
Choice reaction time task 
3 
Perform task big enough that 
able to complete task in one 
attempt – 14 inch height chair  
Complete 40+ 
repetitions  
No upper extremity support with pelvis or feet 
on an unstable surface (i.e., dynadisk; airex)  
Eyes closed  
Maintain end upright 
posture – no 
wobbling, no toes up 
end position  
Working memory loading 
(e.g., counting backwards, 
adding numbers)  
Pair 1: Multi-plane Locomotor Tasks: Turns, Stepping over, around and between obstacles, steps or stairs, (see obstacle course layout for this activity)
Level Amplitude/speed  
Endurance
Balance
Vision
Accuracy
Cognition
1 
Largest step at comfortable 
speed  
15 minutes 
with unlimited 
# of rest breaks 
PT UE support
  
  
Stable surface but obstructed 
path with obstacles to walk 
around and over (short objects)  
No manipulation Not knocking over 
any obstacles  
Simple reaction time task 
2 
Maintain largest step length and 
increase speed  
15 minutes 
with 1 -2 rest 
breaks allowed 
Cane  
Stable with obstacles to walk 
around and over (tall objects) 
and Unstable surfaces (thick 
floor mat)  
Sunglasses or 
no-body glasses 
Predictable start and 
stops and 90° turns  
Choice reaction time task 
3 
Maintain largest step length and 
as fast as possible safely  
15 minutes 
with no rest 
breaks  
No Support  
Stable with obstacles to walk 
around and over (tall objects 
and Unstable surfaces (step on 
airex pads or river stones)  
Scanning 
environment 
with head turns  
Unpredictable start 
and stops and turns of 
90° (2-steps), 180° 
(max of 4 steps), or 
360° (max of 8 steps) 
Working memory loading 
(e.g., counting backwards, 
adding numbers)  
 
 
 

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17
Pair 2: Gait  
Level 
Amplitude/speed  
Endurance
Balance
Vision  
Accuracy
Cognition
1 
Largest step at comfortable speed  
15 minutes 
with greatest 
number of 
rest breaks  
Forward, side-ways 
and backward 
walking with PT in 
front giving UE 
support  
No manipulation No accuracy manipulation Simple reaction time 
task 
2 
Maintain largest step length and increase speed  
15 minutes 
with 1 -2 
rest breaks 
allowed  
Forward, side-ways 
and backward 
walking with a cane  
Sunglasses or 
no-body glasses  
PT directed stop and start  Choice reaction time 
task 
3 
Maintain largest step length and as fast as possible 
safely  
15 minutes 
with no rest 
breaks  
Forward, side-ways 
and backward 
walking with no UE 
support  
Sunglasses or 
no-body glasses 
canning 
environment 
with head turns  
Stop and start and regular 
turns (left, right, 180° or 
reversal from forward to 
back or side stepping 
direction  
Working memory 
loading (e.g., 
counting backwards, 
adding numbers)  
Pair 2: Reach & Grasp  
Level 
Amplitude/speed  
Endurance
Balance
Vision  
Accuracy
Cognition
1 
Sitting – maximum excursion (DISTANCE) of the 
reach with variations in both HEIGHT: Shoulder 
height, up & down AND DIRECTION: forward, 
lateral, and across  
10 reaches 
each arm  
Blocked direction 
and blocked height  
No manipulation Large object (water bottle) 
- palmer grasp  
Simple reaction time 
task 
2 
Standing – Maximum excursion (DISTANCE) of 
the reach with variations in both HEIGHT: Shoulder 
height, up & down AND DIRECTION: forward, 
lateral, and across  
20 reaches 
each arm  
Blocked height 
variable direction  
Sunglasses or 
no-body glasses  
Grasp highlighter  
Choice reaction time 
task 
3 
Standing: step and reach;  
Maximum excursion (DISTANCE) of the reach with 
variations in both HEIGHT: Shoulder height, up & 
down AND DIRECTION: forward, lateral, and 
across  
40 reaches 
each arm  
Variable height and 
direction  
Look at object 
and then close 
eyes for reach 
and grasp  
Grasp paper clip with 
pincer grasp  
Working memory 
loading (e.g., 
counting backwards, 
adding numbers)  
 
 
 
 
 
 
 
 
 

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18
Pair 3: Floor-to-stand; Stand-to-floor  
Level 
Amplitude/speed  
Endurance
Balance
Vision  
Accuracy
Cognition
1 
With chair in front – down to knees 
and back up  
5 repetitions  
Using chair for upper 
extremity support  
No manipulation  
Best posture possible but 
OK if trunk is flexed; 
minimal sway or instability 
through the transition and 
in end positions  
Simple reaction 
time task 
2 
Down onto hands and knees and 
back up  
10 repetitions  
Not using chair  
Sunglasses or no-
body glasses  
Maintenance of extension 
in trunk; minimal sway or 
instability through the 
transition and in end 
positions  
Choice reaction 
time task 
3 
All the way down into prone and 
back up  
20 repetitions  
Using least number of 
limbs possible (arms & 
legs)  
Eyes closed  
Maintenance of extension 
in trunk; minimal sway or 
instability through the 
transition and in end 
positions  
Working memory 
loading (e.g., 
counting 
backwards, adding 
numbers)  
Pair 3: Single limb standing  
Level 
Amplitude/speed  
Endurance
Balance
Vision  
Accuracy
Cognition
1 
Lift one foot up slightly to hip/knee 
flexion 15°, and to hip abduction 10°  
5 repetitions  
hand contact on an 
object as support  
No manipulation  
Maintain for 5 s per 
repetition  
Simple reaction 
time task 
2 
Lift one foot up to hip/knee flexion 
30°, and to hip abduction 20°  
10 repetitions  
Hands on hip  
Sunglasses or no-
body glasses  
Maintain for 10 s per 
repetition  
Choice reaction 
time task 
3 
Lift one foot up to hip/knee flexion 
45°, and to hip abduction 30°  
20 repetitions  
With bilateral shoulder 
abduction/flexion 90°  
Eyes closed  
Maintain for 20 s per 
repetition  
Working memory 
loading (e.g., 
counting 
backwards, adding 
numbers)