A Single-center, Randomized, Double-blinded, Double-crossover Trial of Asymmetric Subthalamic Deep Brain Stimulation for Axial Motor Dysfunction in Parkinson's Disease
Phase: NA
Conditions: Parkinson Disease
Sponsor: University of Toronto

 
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Asymmetric STN-DBS for PIGD in PD 
 
 
 
A SINGLE-CENTER, RANDOMIZED, DOUBLE-BLINDED, 
DOUBLE-CROSSOVER TRIAL OF ASYMMETRIC  
SUBTHALAMIC DEEP BRAIN STIMULATION FOR AXIAL 
MOTOR DYSFUNCTION IN PARKINSON’S DISEASE 
 
 
Investigators: 
Alfonso Fasano, M.D., Ph.D. (P.I.) 
Karlo J. Lizarraga, M.D., M.S. 
Renato Munhoz, M.D. 
Connie Marras, M.D., Ph.D. 
Melanie Cohn, Ph.D., C.Psych.  
Andres Lozano, M.D., Ph.D. 
William Hutchison, Ph.D. 
George Tomlinson, Ph.D. 
 
 
Institution: 
Movement Disorders Center, Division of Neurology, Department of Medicine 
University of Toronto, Ontario, Canada 
 
 
Initial protocol approval: 
October 23, 2017 
 
Registration:  
ClinicalTrials.gov NCT03462082 
 
Registration date: 
March 11, 2018 
 
Protocol version 3  
 
Version approval date: 
October 8, 2019 
 
 
 

 
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Asymmetric STN-DBS for PIGD in PD 
 
 
 
TABLE OF CONTENTS 
Page 
 
LIST OF ABBREVIATIONS……………………………………………………………….……4 
 
PROTOCOL SUMMARY…..…………………………………………………………………..5 
 
1. GENERAL INFORMATION………………………………………………………………...8  
 
2. BACKGROUND INFORMATION………………………………………………………….8 
 
2.1 
Rationale ………...……………………………………………………………………8 
2.2 
Supporting Data …….………………………………….……………………………..8  
2.3 
Potential Risks and Benefits…………………………………………………………..9 
2.4 
Study Population……………………………………………………………………....9 
 
3. STUDY OBJECTIVES AND HYPOTHESIS….………………………………………..…10 
 
3.1 
Objectives and Purpose.….………………………………………………….……….10 
3.2  
Study Hypothesis…......………………………………………………………..…….11 
 
4. STUDY DESIGN…….……………………………………………………………...……..…11 
 
5. SELECTION OF SUBJECTS……………………………………………………...……….12 
 
 
5.1 
Subject Inclusion Criteria …………...………………………………………..…..…12 
 
5.2 
Subject Exclusion Criteria …………...…………………………………………..….12 
 
5.3 
Study Enrollment Procedures ………………………………………………….……13 
 
6. STUDY INTERVENTION………………………………………………………….……….13 
 
 
6.1 
Interventions, Administration, and Duration ...……………………………….……..13 
 
6.2 
Medications During the Study..…………….…………………………………….….14 
 
6.3 
Procedures for Monitoring Compliance……………………………………………...14 
 
7. ASSESSMENT OF EFFICACY…………………………………………………………….14 
 
 
7.1. 
Efficacy Parameters………………………………………………………………….14 
 
7.2. 
Assessment of Efficacy Parameters………………………………………………….15 
 
8. ASSESSMENT OF SAFETY………………………………………………………………..15 
 
 
8.1. 
Safety Parameters…………………………………………………………………….15 
 
8.2. 
Assessment of Safety Parameters……………….…………………………………...15 
 

 
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Asymmetric STN-DBS for PIGD in PD 
 
 
 
9. STATISTICS…….…………………………..…………………………………………...…..16 
 
 
9.1 
General Design Issues ………………………………………………………..……...16 
 
9.2 
Outcomes ……………………………………………………………………...…….17 
 
9.3 
Sample Size and Accrual ……………………………………………………..……..18 
 
9.4 
Data Monitoring ………………………………………………………………..……18 
 
9.5 
Data Analyses …………………………………………………………………...…..19 
 
10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS……………………………….19 
 
11. QUALITY CONTROL AND QUALITY ASSURANCE……………………………...…19 
 
12. ETHICS…………………...……………………………………………………………..….20 
 
 
12.1 
Informed Consent Process………………...................................................................20 
 
12.2 
Research Ethics Board ……………………………………………………………....20 
 
13. DATA HANDLING AND RECORD KEEPING….……………………………………...20 
 
14. FINANCING………………………………………………………………………………..21 
 
15. PUBLICATION POLICY……………………………………………………………...…..21 
 
16. SUPPLEMENTS……………………………………………………………………………21 
 
Schedule of Evaluations…………………………………………………………………...…22 
Model Informed Consent………………………………………………………………….....23 
Case Report Forms……..….…………………………………………………………………29 
Edinburgh Handedness Inventory……………………………………………………………32 
10-m Walk Test for Gait Speed (Primary Outcome)……………………………...…………34 
Mini-BESTest for PIGD ………………………………………………………………….…35 
UPDRS-PIGD subscale……………………………………………………………...............38 
FOG questionnaire………………………………………………………………...………....39 
39-item Parkinson’s Disease Questionnaire (PDQ-39)……………………………………...40 
 
17. REFERENCES……………………………………………………………………...………44 
 
 
 
 
 
 
 
 
 

 
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Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
LIST OF ABBREVIATIONS 
 
BL 
 
 
Bilateral 
 
DBS  
 
Deep brain stimulation 
 
FOG  
 
Freezing of gait 
 
FOGQ  
 
Freezing of gait Questionnaire 
 
LEDD  
 
Levodopa-equivalent daily dose 
 
Mini-BESTest  
Mini Balance Evaluation Systems Tests 
 
PIGD  
 
Postural instability and gait dysfunction 
 
PD 
 
 
Parkinson’s disease 
 
PDQ-39 
 
39-item Parkinson’s Disease Questionnaire 
 
STN 
 
 
Subthalamic nucleus 
 
UL 
 
 
Unilateral 
 
UPDRS 
 
Unified Parkinson’s disease rating scale 
 
MCID  
 
Minimal clinically-important difference 
 
MDS-UPDRS  
Movement Disorders Society unified Parkinson’s disease rating scale 

 
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Asymmetric STN-DBS for PIGD in PD 
 
 
 
PROTOCOL SUMMARY 
Study Title 
 
A single-center, randomized, double-blinded, double-crossover trial of asymmetric sub-
thalamic deep brain stimulation (STN-DBS) for axial motor dysfunction in Parkinson’s 
disease (PD). 
Sample Size and Study Population 
 
- Sample Size: 27 pts. 
- Study Population: Patients with PD who develop treatment-resistant postural instability 
gait dysfunction (PIGD) >6 months but <5 years after bilateral (BL) STN-DBS.  
* Treatment-resistant PIGD is defined as freezing of gait (FOG) and >6 points in the 
UPDRS or MDS-UPDRS PIGD subscales despite optimization of medications and sym-
metric BL STN-DBS programming. 
 
Accrual Period: 20 months 
Study Design (See figure) 
 
This single-center, randomized, double-
blinded, double-crossover clinical trial will 
study the effects of UL 50% voltage reduction 
in PIGD for PD patients that develop PIGD 
after BL STN-DBS. The primary outcome 
will be the change in gait velocity as meas-
ured with the 10-m walk test. Secondary out-
comes will be the changes in other PIGD, 
speech and motor scales as mentioned above. 
Study Duration 
 
- Start Date: October 1st 2017 (Anticipated) 
- End Date: June 30th 2019 (Anticipated) 
- Duration of each of the 3 DBS conditions 
per patient: 4 weeks. 
- Additional wash-out period for each of the 3 
DBS conditions if needed: 2 weeks. 
- Total duration per patient: 12–18 weeks. 
 
- During each of the 3 DBS conditions: 
* If UPDRS drops >30% return to baseline. 
* If UPDRS drops ≤30% increase dopaminergic medication dose, keeping track of the 
corresponding levodopa-equivalent daily dose (LEDD).  

 
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Asymmetric STN-DBS for PIGD in PD 
 
 
 
Return to baseline BL STN-DBS settings and LEDD after the 4-week DBS period and re-
spective double-blinded evaluation is completed. The randomized crossover to each of 
the remaining DBS conditions will be performed after 2 weeks of LEDD excess washout. 
Study Interventions 
 
1. Unchanged baseline BL STN-DBS (DBS condition 1) 
2. UL 50% voltage reduction (DBS condition 2) 
3. Contralateral 50% voltage reduction (DBS condition 3) 
Primary Objective 
 
To compare the effects of unilateral (UL) 50% voltage reduction in gait velocity meas-
ured during the 10-m walk test for patients with PD that develop postural instability/gait 
dysfunction (PIGD) after bilateral (BL) STN-DBS. 
 
Secondary Objectives 
 
1. To explore the effects of UL 50% voltage reduction for patients with PD that develop 
PIGD after BL STN-DBS in:  
1) PIGD measured by the mini-BESTest, 
2) PIGD measured by the Unified PD rating scale (UPDRS),  
3) quantitative PIGD analysis as per the Zeno walkway (stride length, cadence, 
phase coordination index, turning time),  
4) freezing of gait (FOG) questionnaire,  
5) quantitative speech analysis as per the Praat software (intelligibility, pitch, in-
tensity),  
6) MDS-UPDRS (total and motor scores), 
7) select cognitive tasks (verbal and semantic fluency, perception, verbal and 
visuospatial working memory, episodic memory), and 
8) quality of life measured by the 39-item PD Questionnaire (PDQ-39) 
 
2. To explore whether baseline clinical evidence for hemispheric lateralization of appen-
dicular motor control (Edinburgh handedness inventory), axial motor control (quantita-
tive PIGD analysis) or PD severity (MDS-UPDRS laterality index) correlates with the 
motor responses to UL 50% reduction in voltage of STN-DBS in patients with PD who 
develop PIGD after BL STN-DBS. 
 
3. To explore whether intraoperative electrophysiological evidence for STN asymmetry is 
associated with the motor responses to UL 50% reduction in voltage of STN-DBS in pa-
tients with PD who develop PIGD after BL STN-DBS. Intraoperative electrophysiologi-
cal data obtained from chart review will be analyzed for 1) order of DBS lead placement 
(right STN first vs. left STN first), 2) number of STN trajectories per side, 3) STN trajec-
tory lengths in millimeters, 4) STN mean firing rates in Hertz (local field potentials) and 
5) STN burst indices. 

 
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Asymmetric STN-DBS for PIGD in PD 
 
 
 
4. To explore whether the differences in volume of tissue activation (VTA) between the 3 
DBS conditions are associated with the motor responses to UL 50% reduction in voltage 
of STN-DBS in patients with PD who develop PIGD after BL STN-DBS. Comparative 
imaging analysis will be performed by estimating the VTA for each DBS condition per 
patient and overlapping the VTAs with the corresponding post-operative magnetic reso-
nance images. 
Primary Endpoint of the Study 
Gait velocity measured during the 10-m walk test for patients with PD that develop PIGD 
after BL STN-DBS. 
 

 
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Asymmetric STN-DBS for PIGD in PD 
 
 
 
1. GENERAL INFORMATION 
1.1. Protocol title: 
“A single-center, randomized, double-blinded, double-crossover trial of asymmetric sub-
thalamic deep brain stimulation for axial motor dysfunction in Parkinson’s disease.” 
1.2. Investigators and contact information: 
Alfonso Fasano, M.D., Ph.D. (Principal Investigator), Karlo J. Lizarraga, M.D., M.S.; 
Renato Munhoz, M.D.; Connie Marras, M.D., Ph.D.; Melanie Cohn, Ph.D., C.Psych.; 
Andres Lozano, M.D., Ph.D.; William Hutchison, Ph.D.; George Tomlinson, Ph.D.  
Movement Disorders Center, Toronto Western Hospital 
399 Bathurst Street, McL 7th Floor, Toronto, Ontario M5T 2S8 
Phone: 416-603-6422 
2. BACKGROUND INFORMATION 
2.1. Rationale: 
 
Axial motor dysfunction remains a significant source of disability, morbidity and mortali-
ty in patients with PD. Axial symptoms in PD include dysarthria and PIGD (including 
FOG). These symptoms do not necessarily improve with dopaminergic therapy, might 
not respond and could even worsen with BL STN-DBS.[1] 
Whereas left hemispheric dominance for appendicular motor control is well-established 
in humans, evidence for right hemispheric dominance for axial motor control in healthy 
individuals and PD patients is still growing.[2-4] For instance, PD patients with right-
greater-than-left nigrostriatal degeneration and subsequent left-sided appendicular symp-
tom predominance are at higher risk for developing FOG.[4] In this context, symmetric 
BL DBS programing might be contributing with the observed axial worsening after STN-
DBS. Moreover, cognitive abilities that lateralize to one hemisphere (such as verbal flu-
ency) can also decline after BL STN-DBS. Since BL STN-DBS is an established treat-
ment modality in PD, asymmetric programming is a feasible and unexplored alternative 
that could have a large beneficial impact for these patients. In fact, previous studies al-
ready suggest potential benefits of asymmetric programing for axial dysfunction in 
PD.[5,6] 
2.2. Supporting Data: 
 
Functional asymmetries have been observed in human cognition and locomotion. For ex-
ample, verbal memory lateralizes to the left hemisphere and normal stride length appears 
to be longer with the right foot. A possible explanation for the latter is that the right leg 
has greater muscle power and dominates gait propulsion, whereas the left leg has greater 
power absorption and dominates postural stabilization.[7] Normal gait asymmetry in hu-

 
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Asymmetric STN-DBS for PIGD in PD 
 
 
 
mans might therefore be associated with the posited hemispheric asymmetries for axial 
(right hemisphere/left leg) and appendicular (left hemisphere/right leg) motor control. 
The specific impairment of baseline gait coordination might be important for the devel-
opment of FOG in PD.[8] In fact, the interference of BL STN-DBS with potentially 
asymmetric circuits underlying normal asymmetric interlimb coordination during gait has 
been suggested as a cause of FOG.[5] In that study, FOG in patients with PD and BL 
STN-DBS improved more with UL 50% voltage reduction contralateral to the side with 
the longer stride length when compared with BL and UL 50% voltage reduction contrala-
teral to the side with the shorter stride length.[5] Given that normal stride length appears to 
be longer with the right foot, left-sided predominant PD might exaggerate this asymmetry 
by reducing stride length with the left foot, which could potentially explain the higher 
risk for FOG in these patients.[4] 
The differential effects of right-sided, left-sided and BL STN-DBS in the context of po-
tentially lateralized axial motor circuits have not been systematically studied. In a recent 
pilot study of 22 PD patients that developed PIGD after BL STN-DBS, stride length im-
proved 5 cm. more with right-sided ON/left-sided OFF versus left-sided ON/right-sided 
OFF, and 7 cm. more with BL-ON versus left-sided ON/right-sided OFF. The 2 cm. dif-
ference in favor of BL versus right-sided ON/left-sided OFF was not statistically signifi-
cant. Other gait parameters such as stride velocity and turning time were similar between 
BL and both UL STN-DBS conditions; however, motor and gait UPDRS scores im-
proved more with BL versus UL STN-DBS.[6] In that study, the potential benefits of 
asymmetric stimulation on axial symptoms were limited by the worsening of appendicu-
lar symptoms. Moreover, patients were evaluated for the 3 DBS conditions 45-60 minutes 
after changing DBS parameters during the same day.  
In this trial, we will evaluate patients 1 month after each DBS condition change to de-
crease the risk for carry-over effects and to allow for the full motor benefits of DBS to be 
established. Additionally, we hope to maintain the benefits of BL STN-DBS on appen-
dicular symptoms by reducing DBS voltage unilaterally by 50% instead of turning OFF 
the stimulation. 
 
2.3. Potential Risks and Benefits: 
 
As mentioned above, the potential benefits of asymmetric BL STN-DBS are improve-
ment in axial motor function for patients with PD. In previous studies of asymmetric BL 
STN-DBS, these potential benefits were limited by worsening of appendicular symptoms. 
Nevertheless, the stimulation was completely turned OFF during each of the DBS condi-
tions. In this trial, we will not turn OFF stimulation but we will decrease voltage by 50%. 
With this settings, we hope to maintain appendicular symptom control while assessing 
the potential benefits on axial symptoms. As mentioned later, we will attempt to manage 
symptom worsening with dopaminergic medications. 
 
2.4. Study Population: 
 
The study population will encompass patients with PD who develop treatment-resistant 
postural instability gait dysfunction (PIGD) >6 months but <5 years after bilateral (BL) 

 
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Asymmetric STN-DBS for PIGD in PD 
 
 
 
STN-DBS. Treatment-resistant PIGD is defined as freezing of gait (FOG) and >6 points 
in the UPDRS or MDS-UPDRS PIGD subscales despite optimization of medications and 
symmetric BL STN-DBS programming. 
3. STUDY OBJECTIVES AND HYPOTHESIS 
3.1. Objectives and Purpose: 
3.1.1. Primary Objective: 
 
The primary objective is to compare the effects of UL 50% voltage reduction in gait ve-
locity measured during the 10-m walk test for patients with PD that develop PIGD after 
BL STN-DBS.  
 
3.1.2. Secondary Objectives: 
 
1) To explore the effects of UL 50% voltage reduction for patients with PD that develop 
PIGD after BL STN-DBS in:  
1. PIGD measured by the mini-BESTest 
2. PIGD measured by the Unified PD rating scale (UPDRS) 
3. MDS-UPDRS (Total and motor subscales) 
4. FOG as per the FOG questionnaire 
5. Quantitative PIGD analysis as per the Zeno walkway (stride length, cadence, 
phase coordination index, turning time) 
6. Quantitative speech analysis as per the Praat software (intelligibility, pitch, in-
tensity)  
7. 39-item PD questionnaire (PDQ-39) 
 
2) To explore whether baseline clinical evidence for hemispheric lateralization of appen-
dicular motor control (Edinburgh handedness inventory), axial motor control (quantita-
tive PIGD analysis) or PD severity (MDS-UPDRS laterality index) correlates with the 
motor responses to UL 50% reduction in voltage of STN-DBS in patients with PD who 
develop PIGD after BL STN-DBS. 
 
3) To explore whether intraoperative electrophysiological evidence for STN asymmetry 
is associated with the motor responses to UL 50% reduction in voltage of STN-DBS in 
patients with PD who develop PIGD after BL STN-DBS. Intraoperative electrophysio-
logical data obtained from chart review will be analyzed for 1) order of DBS lead place-
ment (right STN first vs. left STN first), 2) number of STN trajectories per side, 3) STN 
trajectory lengths in millimeters, 4) STN mean firing rates in Hertz (local field potentials) 
and 5) STN burst indices. 
 
4) To explore whether the differences in volume of tissue activation (VTA) between the 3 
DBS conditions are associated with the motor responses to UL 50% reduction in voltage 
of STN-DBS in patients with PD who develop PIGD after BL STN-DBS. Comparative 

 
11 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
imaging analysis will be performed by estimating the VTA for each DBS condition per 
patient and overlapping the VTAs with the corresponding post-operative magnetic reso-
nance images. 
 
3.2. Study Hypothesis: 
 
The study hypothesis is that UL 50% voltage reduction results in an improvement of at 
least 0.10–0.16 m/s* in gait velocity when compared to baseline BL STN-DBS (Alterna-
tive hypothesis). 
*Minimum clinically-important difference in gait velocity for non-PD patients.[9] 
 
*Null hypothesis: UL 50% voltage reduction does not result in an improvement of at least 
0.10–0.16 m/s* in gait velocity when compared to baseline. 
 
4. STUDY DESIGN 
 
This single center, randomized, double-blinded, double-crossover clinical trial will study 
the effects of UL 50% voltage reduction in PIGD for PD patients that develop PIGD after 
BL STN-DBS.  
The primary endpoint will be the change in gait velocity as measured with the 10-m walk 
test. Secondary endpoints will be the changes in other PIGD, speech, motor scales, select 
cognitive tasks and quality of life as mentioned above. 
 
After informed consent, PD patients that de-
velop treatment-resistant PIGD more than 6 
months but less than 5 years after BL STN-
DBS surgery will be enrolled. Treatment-
resistant PIGD will be defined as the presence 
of FOG and a score of >6 points in the UP-
DRS-PIGD subscale despite optimization of 
dopaminergic medications as measured by the 
levodopa-equivalent daily dose (LEDD) and 
symmetric BL STN-DBS programming. 
Enrolled patients will have an initial assess-
ment of motor lateralization with the Edin-
burgh handedness inventory, as well as lat-
eralization scores from the UPDRS, quantita-
tive PIGD analysis and select cognitive tasks. 
After a baseline evaluation for primary and 
secondary outcome measures is performed, 
the patients will be randomized to 1 of 3 con-
ditions: BL (maintaining baseline symmetric 
programming), UL1 or UL2 (50% voltage re-
duction on either the left or right side). In a 

 
12 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
double-blinded fashion, primary and secondary outcome measures will be evaluated 4-
weeks after the first DBS condition began, followed by randomized cross-over to each 
the remaining 2 DBS conditions after the corresponding 4-week periods and repeated 
outcome evaluations. 
During the 4-week duration of each of the 3 DBS conditions, increases in LEDD will be 
allowed if the UPDRS drops ≤30%. After the 4-week DBS period and the respective 
double-blinded evaluation is completed, the patient will return to baseline BL STN-DBS 
settings and LEDD. The randomized crossover to each of the remaining DBS conditions 
will be performed after 2 weeks of LEDD excess washout. 
If the UPDRS drops >30% at any moment, the patient will return to the baseline BL 
STN-DBS settings and LEDD. After 2 weeks of LEDD excess washout, the patient will 
be given the option to: 1) be randomly crossed over to either of the remaining DBS con-
ditions or 2) to drop out from the study and return to standard of care. Expected duration 
of subject participation will therefore be between 12–18 weeks. All efforts will be done 
for patients to complete the study as the primary analysis will be intention-to-treat. 
5. SELECTION OF SUBJECTS 
5.1. Subject Inclusion Criteria: 
1. Patients with PD (previously diagnosed according to the UK brain bank crite-
ria) who develop treatment-resistant PIGD >6 months but <5 years after BL STN-
DBS. 
2. Treatment-resistant PIGD will be defined as FOG and UPDRS or MDS-
UPDRS PIGD subscales >6 points despite optimization of medications (measured 
by LEDD) and symmetric BL STN-DBS programming. 
3. Prior therapy: Dopaminergic medications will be documented by their respec-
tive LEDD. Changes in medication doses will be allowed as previously specified. 
Other therapies aimed at improving PIGD (e.g. amantadine, cholinergic agents, 
physical therapy) will not be allowed during this study. 
5.2. Subject Exclusion Criteria: 
1. Development of PIGD <6 months or >5 years after BL STN-DBS surgery. 
2. Development of PIGD responsive to optimization of LEDD or symmetric BL 
STN-DBS programming. 
3. Patients with cognitive impairment or psychiatric comorbidities (including sub-
stance abuse) that would interfere with the informed consent process, study ad-
herence or outcome assessments. 

 
13 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
4. Patients with advanced PD or any other neurological, cardiovascular or muscu-
loskeletal co-morbidities that would preclude or require assistance to complete the 
10-m walking test.  
5. Patients not able to comply with 4-week interval evaluations following their 
potential enrollment due to personal reasons. 
6. Serious illness (requiring systemic treatment and/or hospitalization) until sub-
ject either completes therapy or is clinically-stable on therapy, in the opinion of 
the site investigator, for at least 30 days prior to study entry. 
7. Inability or unwillingness of subject or legal guardian/representative to give 
written informed consent. 
5.3. Study Enrollment Procedures: 
1. Potential study patients will be screened at the DBS clinics at the University of 
Toronto Movement Disorders Center, where they undergo routine UPDRS and/or 
MDS-UPDRS testing at each 3-month visit as per protocol. This will facilitate 
recognition of PD patients with treatment-resistant PIGD after BL STN-DBS. 
2. Once a patient that meets the eligibility criteria is identified. Initial contact will 
be made by one of the members of the circle of care and the patient will be of-
fered participation in this study. The corresponding informed consent process will 
be started by one of the members of the study team as applicable. 
3. After the appropriate informed consent is obtained, a baseline assessment of 
primary and secondary outcome measures will be performed. Afterwards, the pa-
tient will be randomized and evaluated at 1-month intervals as described above, 
for a total study duration of 3 months per patient. 
6. STUDY INTERVENTION 
6.1. Interventions, Administration, and Duration: 
 
After the baseline outcome assessment, enrolled patients will be randomized to 1 of 3 
conditions: BL (maintaining the baseline symmetric STN-DBS), UL1 (50% voltage re-
duction in side 1 [either left or right]) or UL2 (50% voltage reduction in side 2 [either 
right or left]). The primary and secondary outcome measures will be assessed in a dou-
ble-blinded fashion 4-weeks after the initial randomization. Enrolled patients will then be 
randomly crossed over to 1 of the 2 remaining conditions and then same blinded evalua-
tion will be performed 4-weeks later. Patients will finally be crossed over to the remain-
ing condition and the same blinded evaluations will be performed 4-weeks later. Total 
study duration will therefore be a minimum of 12-weeks for each patient. 
In addition to the 3 evaluations after completing each of the 4-week DBS periods, pa-
tients will be called the day after and 2 weeks after each DBS condition change to ensure 

 
14 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
tolerability. Patients will be instructed to call the DBS clinic at any time for any issues. 
The study team will be available 24/7 to answer any questions related to the study. If 
there is worsening of PD symptoms at any time during the study, increases in LEDD will 
be allowed as long as the UPDRS drop is ≤30%. The increase in LEDD will be per-
formed as per the DBS clinic protocols by a physician un-blinded to study arm allocation. 
This same physician will keep record of the specific DBS parameters and will be in 
charge of the DBS condition changes, as well as the return to baseline BL STN-DBS and 
LEDD in case medication optimization is not sufficient to address symptom worsening. 
The rate and moment of PD symptom worsening and LEDD changes will be recorded, as 
it could represent a proxy of UL STN-DBS effects. 
After the 4-week DBS period and the respective double-blinded evaluation is completed, 
the patient will return to baseline BL STN-DBS settings and LEDD. The randomized 
crossover to each of the remaining DBS conditions will be performed after 2 weeks of 
LEDD excess washout. Maximum study duration will therefore be 18 weeks per patient. 
If the worsening of PD symptoms is reflected in a UPDRS drop of >30% at any moment 
during the study, the patient will return to the baseline BL STN-DBS settings and LEDD. 
After 2 weeks of LEDD excess washout, the patient will be given the option to: 1) be 
randomly crossed over to either of the remaining DBS conditions or 2) to drop out from 
the study and return to standard of care. A 20% patient drop-out is anticipated but all ef-
forts will be done for patients to complete the study as the primary analysis will be inten-
tion-to-treat. 
6.2. Medications during the study: 
As mentioned above, a movement disorders specialist with expertise in DBS program-
ming will be un-blinded to study arm allocation and will be in charge of programming the 
patients every 4–6 weeks to 1 of the 3 DBS conditions as per randomization. Optimiza-
tion of dopaminergic medications will be allowed in case PD symptoms deteriorate dur-
ing this study, as specified above. Dopaminergic medication changes will be tracked by 
the corresponding LEDD. Starting other medications specifically to address motor symp-
toms will not be allowed during this study. These medications include amantadine, cho-
linergic agents, norepinephrine and serotoninergic modulators. These medications will be 
continued as long as they are at a stable dose for at least 30 days before enrollment. 
Changes in their dosing during the study will not be allowed. 
6.3. Procedures for monitoring subject compliance:  
Compliance will be ensured by revision of previous DBS parameters during all the DBS 
programming visits (at least every 4 weeks) by the un-blinded physician as mentioned be-
fore. 
7. ASSESSMENT OF EFFICACY 
7.1. Efficacy Parameters: 
The efficacy of UL 50% voltage reduction in BL STN-DBS as treatment for axial dys-
function in PD will be primarily assessed by the changes in gait speed measured during 
the 10-m walk test. The 10-m walk test is a simple, widely used test that has been vali-

 
15 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
dated in patients with PD. Gait speed measurements provided by the 10-m walk test are 
reliable with good internal and external validity, as well as excellent clinimetric proper-
ties.[10] As presented below, normal ranges for gait speed in different age groups are es-
tablished and they correlate with different functional parameters. In addition, the minimal 
clinically important difference (MCID) has been established for patients with several 
neurologic conditions, but not for PD.[10] 
Other secondary efficacy parameters will be the changes in other scores that measure axi-
al symptoms, including the mini-BESTest, the PIGD score of the UPDRS, the FOG ques-
tionnaire, quantitative gait analysis performed with the Zeno walkway (which is available 
in the movement disorders center) and quantitative speech analysis performed with the 
Praat software (freely available). Finally, patients will also complete the PDQ-39 and a 
brief (<60min) cognitive assessment at baseline and at the end of each cross-over period.  
 
7.2. Assessment of Efficacy Parameters: 
The primary and secondary efficacy parameters mentioned above will be assessed for 
each patient at the time of study entry (baseline), and then more 3 times after completing 
the 4-weeks of each of the 3 DBS conditions (BL, UL1 or UL2). If needed, 2 additional 
assessments will be performed after the 2-week LEDD excess washout periods and be-
fore changing the DBS setting to either of the 2 remaining DBS conditions. Therefore, ef-
ficacy assessments will be performed a minimum of 4 times and a maximum of 6 times. 
 
The 10-m walk test will be performed in the movement disorders clinic as per standard 
protocol. For this test, the patients will be asked to walk first at a comfortable pace and 
then at a fast pace. A 10-m length of will be marked in the floor, which will be used for 
the patient to walk. Gait speed will be measured by measuring the time it takes for the pa-
tient to walk through the middle 6 meters of the 10-meter path. The mini-BESTest will 
also be performed in the movement disorders clinic as per standard protocol (See appen-
dix). The Zeno Walkway is located inside of one of the movement disorders clinic rooms. 
One of the computers in this room will also have installed the Praat software for speech 
analysis. The UPDRS, FOG questionnaire, brief cognitive assessment and PDQ-39 will 
also be performed in the movement disorders clinic (See appendix). 
8. ASSESSMENT OF SAFETY 
8.1. Safety Parameters: 
As seen in previous studies including our previous pilot data, the main safety concern 
with asymmetric STN-DBS is the worsening of appendicular PD symptoms contralateral 
to the side of reduced stimulation (tremor, bradykinesia, rigidity). As opposed to those 
studies, we will not turn OFF stimulation completely. Therefore, we hope to maintain the 
benefits of BL DBS on appendicular symptoms. This possible symptom deterioration will 
be assessed through phone calls, focused examination and the UPDRS scale. 
8.2. Assessment of Safety Parameters: 

 
16 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
The patients will be called on the day after and 2-weeks after each of the DBS changes. 
In addition, patients will be instructed to call the movement disorders clinic for any 
symptom change and the study team will be available 24/7 to assess these symptom 
changes. If symptom deterioration is clinically relevant on the opinion of the patients 
and/or clinician and/or investigator, the patient will be instructed to return to the move-
ment disorders clinic. At that time, a focused examination that includes the UPDRS will 
be performed. As previously specified, if symptom deterioration is associated with a drop 
in the UPDRS of ≤30%, we will allow for dopaminergic medication adjustments. If the 
symptoms deterioration is >30%, the patient will return to baseline BL STN-DBS and 
LEDD and will continue to be followed in the study protocol. 
9. STATISTICS 
9.1. General Design Issues: 
 
- 
Null hypothesis: UL 50% voltage reduction does not result in an improvement of at 
least 0.10–0.16 m/s* in gait velocity when compared to baseline. 
- 
Alternative hypothesis: UL 50% voltage reduction results in an improvement of at 
least 0.10–0.16 m/s* in gait velocity when compared to baseline. 
*Minimum clinically-important difference in gait velocity for non-PD patients.[9] 
 
- 
Primary outcome measure: Gait velocity during the 10-m walk test. The 10-m walk 
test has been validated in PD patients by independent groups, displaying good clini-
metric properties. This test is easy to administer and might be useful for identifying 
changes in gait speed over time in mild to moderate PD. A possible limitation is that 
the presence of FOG may affect gait speed. 
- 
Secondary outcome measures: (Other qualitative and quantitative measures of PIGD) 
o PIGD measured by the mini-BESTest. The mini-BESTest has been validated in 
PD patients and displays good clinimetric properties. It is a short test that can be 
administered in 10-15 min. A limitation is that its responsiveness has not yet been 
examined in a pure PD population. 
o PIGD measured by the UPDRS. The PIGD scores of the UPDRS has been exten-
sively and independently used in PD populations. A limitation is its possible floor 
effect making it less suitable for patients with mild disease. 
o FOG as per the FOG questionnaire: The FOG questionnaire is a short, reliable in-
strument that is easy to use and validated in PD. A limitation is that it includes 2 
gait items, implying that it is not a pure measure of FOG. In addition, it relies on 
self-report as opposed to objective ratings. 
o MDS-UPDRS. The total and motor scores of the MDS-UPDRS have been exten-
sively and independently validated in PD populations. Given its more recent de-
velopment, the PIGD score of the MDS-UPDRS is still not recommended over the 
PIGD score of the UPDRS.  
o Quantitative PIGD analysis as per the Zeno walkway (stride length, cadence, 
phase coordination index, turning time). The Zeno walkway by Protokinetics 
(http://www.protokinetics.com/zenowalkway.html) is a floor mat equipped with electronic 

 
17 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
sensors that are able to reliably measure spatiotemporal parameters of gait includ-
ing stride length and velocity, cadence, turning time. This has not yet been vali-
dated in PD patients. 
o Quantitative speech analysis as per the Praat software (intelligibility, pitch, inten-
sity). The Praat software is a freely available program that allows for the record-
ing and quantitative analysis of speech including pitch, intensity and intelligibil-
ity. This has not yet been validated in PD patients. 
o Brief cognitive assessment (<60 min): Select cognitive abilities that have been 
shown to decline after STN-DBS or that show a lateralization effect in the PD lit-
erature will be assessed. To assess left hemispheric function, tasks of verbal flu-
ency, verbal working memory and verbal episodic memory will be administered. 
To assess right hemispheric function, tasks of visuospatial working memory, visu-
al episodic memory, and spatial perception will be administered. 
o The PDQ-39 is a self-completion patient related outcome designed to address as-
pects of functioning and well-being for individuals affected by PD. Substantial ev-
idence suggests that the PDQ is reliable, valid, responsive and feasible for the as-
sessment of quality of life in PD patients. The PDQ-39 encompasses 39 questions 
with 8 discrete scales in mobility (10 items), activities of daily living (6 items), 
emotional well-being (6 items), stigma (4 items), social support (3 items), cogni-
tion (4 items), communication (3 items) and bodily discomfort (3 items). 
o Intraoperative electrophysiological evidence for STN asymmetry will be analyzed 
by comparing intraoperative electrophysiological recordings of the left and right 
STN per patient for 1) order of DBS lead placement (right STN first vs. left STN 
first), 2) number of STN trajectories per side, 3) STN trajectory lengths in milli-
meters, 4) STN mean firing rates in Hertz (local field potentials) and 5) STN burst 
indices. 
o Comparative imaging analysis will be performed by estimating the VTA for each 
DBS condition per patient and overlapping the VTAs with the corresponding post-
operative magnetic resonance images. 
- 
Outcome assessment will be performed in a blinded fashion by research assistants 
(including students and other movement disorders fellows). Outcome adjudication 
will be performed in a blinded fashion by a movement disorders specialist not in-
volved with the design of this study. 
- 
The choice of a randomized, double-blinded, double-crossover design will allow us to 
have baseline assessments for each patient, which will serve as his/her own control 
for comparison of changes that occur after each study intervention. As opposed to 
previous similar studies that employed a same-day crossover design, this study will 
have 1-month periods in between assessments in order to allow for the full motor ef-
fects of STN-DBS to develop, and will also serve as wash-out periods from the previ-
ous DBS condition and decrease the risk for any carry-over effect. 
9.2. Outcomes: 
Primary outcome: Gait velocity measured during the 10-m walk test. In this test, sub-
jects will be asked to walk at either their self-selected most comfortable speed over a 

 
18 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
10-m course. Timing will be performed over the middle 6-m to account for accelera-
tion and deceleration in the initial or final 2-m of the course.  
The patients will walk over the Zeno Walkway during this test in order to record and 
store the quantitative data as a back-up. 
Secondary outcomes:  
- PIGD measured by the mini-BESTest 
- PIGD measured by the UPDRS 
- MDS-UPDRS (Total and motor scores) 
- FOG as per the FOG questionnaire 
- Quantitative PIGD analysis as per the Zeno walkway (stride length, cadence, phase 
coordination index, turning time) 
- Quantitative speech analysis as per the Praat software (intelligibility, pitch, intensi-
ty) 
- Select cognitive abilities (verbal fluency, verbal working and episodic memory, 
visuospatial working memory, visual episodic memory and spatial perception) 
- Quality of life measured by the PDQ-39 
9.3. Sample Size and Accrual: 
 
A minimum sample size of 27 patients was calculated taking into account a 20% drop-out 
rate added to the actual sample size of 22 patients. The actual sample size of 22 patients 
was obtained using the sample size formula for paired t-test with an alpha of 0.025 (two-
tailed with Bonferroni correction for multiple comparisons), 80% power and anticipated 
gait velocity means in m/s (primary endpoint) from the following sources: 
1) From pilot study in 22 PD pts. with PIGD after BL STN-DBS:[6] 
(mean ± standard deviation) 
- BL STN-DBS OFF = 0.84 ± 0.07 
- Right STN-DBS ON = 0.92 ± 0.05, Left STN-DBS ON = 0.90 ± 0.05 
- BL STN-DBS ON = 0.95 ± 0.05  anticipated mean for group 2 (BL STN-DBS) (The 
standard deviation of 0.05 was increased to 0.1 given the reduced variability and small 
sample size in this pilot study) 
 
2) From the literature: 
-  Minimum clinically-important difference for non-PD = 0.10–0.16 [10] anticipated 
mean for group 1 (UL STN-DBS) = (0.95 ± 0.05) + 0.10–0.16 = 1.0–1.16 (1.08 ± 0.08) 
* Minimum clinically-important difference for PD = Unknown [10] 
Given the reported frequency of up to 20% patients with PD who develop PIGD in the 
first year after BL STN-DBS implantation [1,11], the number of PD patients that undergo 
BL STN-DBS surgery (4 new patients per month) and are followed at the Movement 
Disorders Center of the University of Toronto, we estimate that we will be able to enroll 
the minimum of 27 patients in the 1.5 years of planned study duration. The minimum ac-
crual would be of 1-2 patients per month. 
9.4. Data Monitoring: 

 
19 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
An interim data analysis will be performed one year after randomization of the first sub-
ject and when/if the drop-out rate exceeds the anticipated 20% despite all efforts. An in-
dependent data safety monitoring board that will include 2 movement disorders physi-
cians not involved in this study will analyze the data at this time and will recommend if 
the study should be stopped for safety or futility. Given the sample size of <30 patients 
and its relative short duration, this study will not be stopped for efficacy until completion. 
If patient recruitment slows down to <2-3 patients/month, all movement disorders physi-
cians in the DBS clinics will be reminded of the study protocol and enrollment criteria. 
9.5. Data Analyses: 
 
Intention-to-treat will be the primary analysis method and per-protocol will be the sec-
ondary analysis method if/as needed. Missing data, outliers, noncompliance and losses to 
follow-up will be reduced as much as possible with the close follow-up as mentioned 
above. In addition, gait speed will also be measured on the Zeno Walkway as explained 
above, which will allow for back-up data and further quantitative analysis. Finally, we 
expect patients to be highly motivated to comply with this study given the treatment-
resistant axial dysfunction that triggered their interest and participation. 
Covariance analysis using mixed models will be performed to evaluate the differences in 
least square means of gait speed changes (primary outcome) between the 3 STN-DBS 
conditions compared to baseline. The effects of UL STN-DBS preferentially targeting the 
body side most or least affected by PD, as well as dominant or non-dominant hemi-
spheres for appendicular and/or axial motor control will be compared.  
Covariance analysis using mixed models will also be performed to evaluate the differ-
ences in least square means of secondary outcomes between the 3 STN-DBS conditions. 
After these comparisons have been completed, we will determine if UL1 and UL2 corre-
sponded to 50% voltage reduction targeting: 1) the left or right hemisphere, 2) the domi-
nant or non-dominant hemispheres for appendicular and/or axial motor control and 3) the 
hemisphere ipsilateral or contralateral to the side most affected by PD.  
We will then perform multivariate linear regression to determine if any feature of motor 
control lateralization is associated with the change in gait velocity observed during the 3 
STN-DBS conditions: BL, left or right. 
10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Investigators will have direct access to the study documentation. The un-blinded physi-
cian will have additional access to the source data documentation (patient’s charts), for 
standard of care and appropriate symptom management as previously specified. All study 
related, source data and chart documentation will be available for monitoring, review or 
audits as deemed necessary by the institutional REB or any other regulatory agency. 
11. QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
Throughout the duration of this study, each participant will receive phone calls in a bi-
weekly fashion to ensure tolerability and to encourage compliance with the study proto-
col. In addition, adherence assessments will be performed during each of the study visits 

 
20 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
as previously specified. Study investigators assigned to perform the blinded outcome 
evaluations will first receive extensive training on the appropriate performance of the 10-
m walk test, the mini-BESTest, rating scales (UPDRS, MDS-UPDRS), FOG question-
naire, Zeno Walkway and Praat software. The use of the Zeno Walkway for quantitative 
gait analysis will allow for back-up data on gait speed, in addition to the one obtained 
with the 10-m walk test. The study team will meet to review all study documentation 
weekly. Data will be entered in the REDCap database after the consistency and quality of 
collected data is assured. The database will be available only in one of the computers of 
the movement disorders clinic, which will be password protected and locked when not in 
use by the study investigators. 
12. ETHICS 
12.1. Informed Consent Process: 
Patients will be screened for eligibility during their regular visits to the DBS clinic of the 
movement disorders center. All physicians in charge of providing standard of care during 
these visits will be aware of this study and will be able to identify potential study partici-
pants. Once a patient is deemed eligible for the study, one of the investigators will con-
tact them regarding the study. The patient will be extensively educated on the nature and 
purpose of the study, the procedures to be followed, and the risks and benefits of partici-
pation. The consent form will describe in English and French each of these topics in lay 
terms for the patient and/or legal guarding to be able to understand these points. The pa-
tient will be given the opportunity to ask questions regarding the study, which will be ful-
ly addressed by one of the investigators. A copy of the consent form will be given to the 
subject or legal guardian, and this fact will be documented in the subject’s record. A 
signed consent form will be obtained from the subject by one of the investigators, after 
the appropriate informed consent process and before enrollment in this study. A period of 
up to 30 days will be allowed from the time of screening for the patient to review the 
consent and make a decision regarding participation. The patient and/or legal guardian 
will be able to finish his/her participation in this study at any time without having reper-
cussions in the standard of care offered at the DBS clinic. An institutional translator will 
be available for subjects whose primary language is not English or French. For subjects 
who cannot consent for themselves, a legal guardian, or person with power of attorney, 
must sign the consent form; additionally, the subject's assent must also be obtained if he 
or she is able to understand the nature, significance, and risks associated with the study. 
 
12.2. Research Ethics Board: 
This protocol, the informed consent document and any subsequent amendments will be 
reviewed and approved by the REB before any study related procedures or implemented 
changes begin. 
13. DATA HANDLING AND RECORD KEEPING 
Study data will be initially recorded in a Case Report Form (CRF) designed for each of 
the study visits for each participant (See appendix). The completed CRFs will be re-
viewed by the study team (including the P.I.) every week to ensure accuracy, complete-

 
21 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
ness, legibility and timeliness. Afterwards, data will be transferred to the REDcap data-
base as mentioned above. All CRFs and other study documentation will be identified only 
by the Study Identification Number (SIN) to maintain subject confidentiality. All records 
will be kept in a password-protected computer kept in a locked room in the movement 
disorders clinic at Toronto Western Hospital. All database entry will be done using SINs 
only. Clinical information will not be released without written permission of the subject, 
except as necessary for monitoring by the institutional REB or other regulatory agencies. 
All records and documents pertaining to the study will be retained by the movement dis-
orders clinic for at least 25 years from the completion of the study, and will be available 
for inspection by regulatory agencies. The study may be modified or discontinued at any 
time by the institutional REB or other regulatory agencies as part of their duties to ensure 
that research subjects are protected. 
14. FINANCING 
This study will be funded by internal resources from the movement disorders clinic. 
15. PUBLICATION POLICY 
This clinical trial will be registered at clinicaltrials.gov. Publication of partial or final re-
sults of this trial will be governed by the policies and procedures of the University of To-
ronto Movement Disorders Center in the context of REB approval, and following all re-
quirements by the corresponding authorities. 
16. SUPPLEMENTS 
 

22 
 
 
        Asymmetric STN-DBS for PIGD in PD 
 
 
SCHEDULE OF EVALUATIONS 
 
Evaluation 
Screening 
(<30 days) 
Pre-Entry 
(<15 days) 
Entry 
(Baseline) 
2 
wk. 
42 
wk. 
62 
wk. 
82 
wk. 
102 
wk. 
122 
wk. 
142 
wk. 
Worsening 
at anytime 
Informed consent process 
X 
X 
X 
 
 
 
 
 
 
 
 
Documentation of disease 
X 
X 
X 
 
 
 
 
 
 
 
 
Medical/Treatment history 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Targeted physical exam (includ-
ing UPDRS or MDS-UPDRS) 
X 
 
X 
* 
X 
* 
X 
* 
X 
 
X 
Schedule study follow-up visits 
and review with patient 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Phone calls to assess tolerability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Edinburgh handedness inventory 
 
 
X 
 
 
 
 
 
 
 
 
MDS-UPDRS laterality index 
 
 
X 
 
X 
 
X 
 
X 
 
 
Randomization / crossover 
 
 
X 
 
X 
 
X 
 
 
 
 
Primary outcome assessment: 
Gait velocity / 10-m walk test 
 
 
X 
* 
X 
* 
X 
* 
X 
 
 
Secondary outcome assessments: 
 
 
X 
* 
X 
* 
X 
* 
X 
 
 
Mini-BESTest for PIGD 
 
 
X 
* 
X 
* 
X 
* 
X 
 
 
Quantitative gait analysis (Zeno) 
 
 
X 
* 
X 
* 
X 
* 
X 
 
 
FOGQ, cognitive tasks, PDQ-39 
 
 
X 
* 
X 
* 
X 
* 
X 
 
 
Quantitative speech analysis 
 
 
X 
* 
X 
* 
X 
* 
X 
 
 
Medication adjustment (LEDD 
increase if UPDRS drops ≤30%) 
 
 
 
* 
* 
* 
* 
* 
* 
 
* If UPDRS 
drops ≤30% 
LEDD excess washout  
(+2 wks. if LEED increased) 
 
 
 
 
X 
 
X 
 
X 
 
X 
Return to baseline if UPDRS 
drops >30% 
 
 
 
** 
** 
** 
** 
** 
** 
X 
** If UP-
DRS drops 
>30% 
Adherence Assessments 
 
 
 
 
X 
 
X 
 
X 
 
 

 
23 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
CONSENT FORM TO PARTICIPATE IN A RESEARCH STUDY 
 
Study Title:  
A single-center, randomized, double-blinded, double-crossover trial of asymmetric sub-
thalamic deep brain stimulation for axial motor dysfunction in Parkinson’s disease. 
 
Investigators/Study Doctors: 
Alfonso Fasano, M.D., Ph.D. (Principal Investigator); Karlo J. Lizarraga, M.D., M.S.; Re-
nato Munhoz, M.D.; Connie Marras, M.D., Ph.D.; Melanie Cohn, Ph.D., C.Psych. 
 
Contact Information: 
Movement Disorders Clinic, Toronto Western Hospital 
399 Bathurst Street, McL 7th Floor, Toronto, Ontario M5T 2S8 
Phone: 416-603-6422 
24-hour study pager: 416-714-7942 (will page the study team directly) 
 
Introduction:   
You are being asked to take part in a research study. Please read the information about 
the study presented in this form. The form includes details on study’s risks and benefits 
that you should know before you decide if you would like to take part. You should take 
as much time as you need to make your decision. You should ask the study doctor or 
study staff to explain anything that you do not understand and make sure that all of your 
questions have been answered before signing this consent form.  Before you make your 
decision, feel free to talk about this study with anyone you wish including your friends, 
family, and family doctor.  Participation in this study is voluntary. 
 
Background/Purpose: 
Parkinson’s disease affects motor and non-motor aspects of daily living. Motor symp-
toms such as tremor, rigidity and slowness of movement can initially respond to medica-
tions. With time, motor complications (dyskinesias, fluctuations) can develop. When 
these complications appear, deep brain stimulation is an effective treatment modality 
that allows for better motor symptom control. 
With disease progression, patients with Parkinson’s disease also develop other symp-
toms called axial motor symptoms (postural instability, gait difficulties including freezing 
of gait, speech problems). For unknown reasons, the development of axial motor symp-
toms in these patients can be faster and/or more severe after deep brain stimulation. 
Currently, the standard of care for this axial deterioration is to try to optimize Parkin-
son’s disease medications and/or deep brain stimulation parameters; however, in many 
cases there is unfortunately no improvement. 
There is growing scientific evidence that one side of the brain could be more important 
than the other for gait control. If this were the case, bilateral deep brain stimulation 
might be unnecessary for all patients and could be contributing with worse axial symp-
toms due to excessive stimulation. Moreover, previous studies suggest that these axial 
symptoms could improve with different stimulation parameters for each side of the brain. 
 

 
24 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
A minimum of 27 patients will participate in this study that will take approximately 2 
years to complete. 
 
Study Design: 
In this study, we are comparing the effects of 3 different types of deep brain stimulation 
in the motor symptoms of patients with Parkinson’s disease who develop worsening ax-
ial symptoms despite of treatment, more than 6 months but less than 5 years after deep 
brain stimulation surgery. The 3 stimulation parameters being compared are 1) bilateral, 
2) unilateral #1 (right more than left-sided stimulation) and 3) unilateral #2 (left more 
than right-sided stimulation). 
This is a randomized double blinded study.  If you decide to participate you will be “ran-
domized” into one of the study groups described below.  Randomization means that you 
are put into a group by change.  It is like flipping a coin.  Neither you nor your doctor can 
choose what group you will be in, but at the end of the study you will have received the 
3 types of deep brain stimulation described.  
The first time you are randomized, you will have a 1 in 3 chance of being placed in one 
of the 3 types of stimulation.  The second time you are randomized, you will have a 1 in 
2 chance of being placed in one of the other 2 types of stimulation.  The last type of 
stimulation you receive will be the remaining one.  Neither you nor your doctor will know 
which group you are in.  In an emergency, if the type of deep brain stimulation needs to 
be identified, the doctor can get this information. 
 
Study Visits and Procedures: 
All enrolled patients will undergo a baseline evaluation of motor and non-motor symp-
toms. After completion of this baseline evaluation, enrolled patients will be randomly as-
signed to one of the 3 types of stimulation. This initial stimulation parameter will be 
maintained for 4 weeks. Patients will undergo a second evaluation of motor and non-
motor symptoms after completion of these first 4 weeks. After this second evaluation is 
completed, enrolled patients will be randomly assigned to one of the 2 remaining types 
of stimulation. This second stimulation parameter will be maintained for another 4-week 
period. Patients will undergo a third evaluation of motor and non-motor symptoms after 
completion of this second 4-week period. After this third evaluation is completed, stimu-
lation will be changed to the remaining type. This third type of stimulation will be main-
tained for additional 4 weeks. Patients will undergo a fourth and last evaluation of motor 
and non-motor symptoms after completion of this third 4-week period. The study inves-
tigators and enrolled patients will not know which of the 3 types of stimulation is being 
evaluated at any particular moment. 
In summary, all enrolled patients will undergo a minimum of 4 evaluations in the move-
ment disorders clinic: 1 baseline evaluation and a minimum of 3 additional evaluations 
after completing 3 different types of stimulation for 4 weeks each. The minimum study 
duration will thus be 12 weeks per patient. 
If there is worsening of your Parkinson’s disease symptoms, please contact the move-
ment disorders clinic and we will call you back as soon as possible to evaluate the 
worsening with you. After discussing the worsening over the phone, you might need to 
come to the movement disorders clinic to be examined. We will have two options if your 
symptoms worsen during the study: 1) optimize the doses of your Parkinson’s disease 

 
25 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
medications or 2) return to the type of stimulation that you were on before entering the 
study. You will continue being closely followed with either of these options. 
If we needed to increase the Parkinson’s disease medications at any time, there will be 
an additional period of 2 weeks once you complete the corresponding 4-week period. 
Specifically, the type of stimulation and doses of your Parkinson’s disease medications 
will be returned to what they were before entering the study, and we will wait 2 weeks to 
ensure the additional amount of medication is out of your system. In addition, you would 
be evaluated for motor and non-motor symptoms again before you continue with the 
rest of the study. Therefore, the study duration could increase to a maximum of 18 
weeks and the evaluations could increase to a maximum of 7 evaluations (1 baseline, 3 
scheduled and 3 additional if needed). 
 
Risks: 
Taking part in this study has risks. Some of these risks we know about. There is also a 
possibility of risks that we do not know about and have not been seen in humans to 
date. Please call the study doctor if you have any side effects even if you do not think it 
has anything to do with this study.  
The risks we know of are possible worsening of some of the motor symptoms of Parkin-
son’s disease (tremor, rigidity, slowness of movement). The exact frequency and severi-
ty of this risk is unknown and we expect that this will vary depending on every patient’s 
different baseline symptoms and tolerance. In addition to being available for you any-
time, we will call you the day after and 2 weeks after changing the type of stimulation to 
ensure you are tolerating the new settings. 
 
Benefits: 
You may directly benefit from being in this study. Your gait, balance and/or speech 
could significantly improve during the study. After the study is completed, you will be 
given the opportunity to return to the type of stimulation that you were on before enter-
ing the study, or to be changed to any of the other types that helped your symptoms the 
most during the study. Information learned from this study may also help other patients 
with Parkinson’s disease that have similar problems. 
 
Reminders and Responsibilities: 
Your main responsibility would be compliance with the study visits and evaluations to 
the best of your abilities. As mentioned above, the minimum study duration would be 12 
weeks including evaluations of your symptoms every 4 weeks. The maximum study du-
ration would be 18 weeks including evaluations of your symptoms every 4 weeks and 
additional evaluations 2 weeks after medication changes.   
We will remind you of the scheduled study visits to the Movement Disorders Clinic dur-
ing the phone calls mentioned previously: the day after and 2 weeks after each stimula-
tion parameter change. 
 
Alternatives to Being in the Study:  
You do not have to join this study to receive treatment for your condition. If you decide 
not to participate in this study, you will continue receiving the standard of care at the To-
ronto Western Hospital movement disorders clinic. Nevertheless, your condition might 

 
26 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
not improve even after optimization of your Parkinson’s disease medications and/or 
deep brain stimulation. 
 
Confidentiality: 
Your data will be shared as described in this consent form or as required by law.  All 
personal information such as your name, address, phone number, OHIP number, and 
family physician’s name will be removed from the data and will be replaced with a num-
ber.  A list linking the number with your name will be kept by the study doctor in a se-
cure place, separate from your file. 
 
Personal Health Information 
If you agree to join this study, the study doctor and his/her study team will look at your 
personal health information and collect only the information they need for the study.  
Personal health information is any information that could identify you and includes your:  
 name,  
 address,  
 full date of birth,  
 new or existing medical records including types, dates and results of medical 
tests or procedures. 
The following people may come to the hospital to look at the study records and at your 
personal health information to check that the information collected for the study is cor-
rect and to make sure the study is following proper laws and guidelines: 
 Representatives of the University Health Network (UHN) including the UHN Re-
search Ethics Board 
 Representatives of Health Canada or other regulatory bodies (groups of people 
who oversee research studies) 
The study doctor will keep any personal health information about you in a secure and 
confidential location for 25 years as required. 
Your participation in this study will also be recorded in your medical record at this hospi-
tal. This is for clinical safety purposes. 
 
Research Information in Shared Clinical Records 
If you participate in this study, information about you from this research project may be 
stored in your hospital file and in the UHN computer system.  The UHN shares the pa-
tient information stored on its computers with other hospitals and health care providers 
in Ontario so they can access the information if it is needed for your clinical care.  The 
study team can tell you what information about you will be stored electronically and may 
be shared outside the UHN.  If you have any concerns about this, or have any ques-
tions, please contact the UHN Privacy Office at 416-340-4800, x6937 (or by email at 
privacy@uhn.ca). 
 
All information collected during this study, including your personal health information, 
will be kept confidential and will not be shared with anyone outside the study unless re-
quired by law.  You will not be named in any reports, publications, or presentations that 
may come from this study. 
 

 
27 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
Voluntary Participation:  
Your participation in this study is voluntary.  You may decide not to be in this study, or to 
be in the study now, and then change your mind later. You may leave the study at any 
time without any repercussion in the standard of care you will receive at the Toronto 
Western Hospital movement disorders clinic. We will give you any new information that 
is learned during the study that might affect your decision to stay in the study.   
 
Withdrawal from the Study: 
You might be withdrawn from this study if 1) your condition becomes so severe that you 
need assistance to walk, become wheelchair or bedbound; 2) you develop cognitive or 
psychiatric problems that preclude you from understanding the risks and benefits of this 
study at any time; 3) you develop a severe illness that precludes you from completing 
the planned or additional study visits.  
If you are withdrawn from the study, the standard of care you receive at the Toronto 
Western Hospital movement disorders clinic will not be affected. 
 
Costs and Reimbursement: 
We will reimburse you up to 30.00 CAD of the costs of each of the 4–7 study visits to 
the Toronto Western Hospital. 
 
Rights as a Participant: 
If you are harmed as a direct result of taking part in this study, all necessary medical 
treatment will be made available to you at no cost. 
By signing this form, you do not give up any of your legal rights against the investiga-
tors, sponsor or involved institutions for compensation, nor does this form relieve the 
investigators, sponsor or involved institutions of their legal and professional responsibili-
ties. 
 
Conflict of Interest:  
 Researchers have an interest in completing their studies and those interests should not 
influence your decision to participate in this study.  The study doctors do not have any 
other perceived conflict of interest related to this study. 
 
Questions about the Study: 
If you have any questions, concerns or would like to speak to the study team for any 
reason, please call the Toronto Western Hospital Movement Disorders Clinic at 416-
603-6422. If you have any questions about your rights as a research participant or have 
concerns about this study, call the Chair of the University Health Network Research Eth-
ics Board (UHN REB) or the Research Ethics office number at 416-581-7849. The REB 
is a group of people who oversee the ethical conduct of research studies. The UHN 
REB is not part of the study team. Everything that you discuss will be kept confidential.   
You will be given a signed copy of this consent form.  

 
28 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
 
Consent: 
This study has been explained to me and any questions I had have been answered. 
I know that I may leave the study at any time. I agree to the use of my information as 
described in this form. I agree to take part in this study.  
 
 
 
 
 
 
 
 
 
Print Study Participant’s Name 
 
Signature 
 
Date  
 
My signature means that I have explained the study to the participant named above. I 
have answered all questions. 
 
 
 
 
 
 
 
 
 
Print Name of Person 
 
Signature 
 
Date Obtain-
ing Consent 
 
Was the participant assisted during the consent process? 
 YES 
 NO 
If YES, please check the relevant box and complete the signature space below: 
 
 The person signing below acted as an interpreter, and attests that the study as set 
out in the consent form was accurately sight translated and/or interpreted, and that in-
terpretation was provided on questions, responses and additional discussion arising 
from this process. 
 
 
 
 
 
 
 
 
 
Print Name of Interpreter  
 
Signature 
 
Date 
 
 
 
 
 
Relationship to Participant 
 
Language 
 
 
 The consent form was read to the participant. The person signing below attests that 
the study as set out in this form was accurately explained to, and has had any questions 
answered. 
 
 
 
 
 
 
 
 
 
Print Name of Witness 
 
Signature 
 
Date 
 
 
 
 
Relationship to Participant 

 
29 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
 
CASE REPORT FORM FOR STUDY ENTRY  
Study identification number: _______ 
 
     Visit Date (MMM/YY): _______/______  
1) Date of Parkinson’s disease (PD) motor symptom onset (MMM/YY):       _______/______ 
2) Predominant motor symptom at onset: 
 
     tremor / rigidity / slowness / PIGD / FOG 
3) Side of the body most affected by motor symptoms at PD onset:   
       L / R / Both equal 
4) Date of bilateral STN-DBS surgery (MMM/YY):  
 
        _______/______ 
5) Predominant symptom just before surgery:  
    tremor / rigidity / slowness / PIGD / FOG 
6) Side of the body most affected by motor symptoms just before surgery:  L / R / Both equal 
7) Date of axial motor symptom development (MMM/YY):  
        _______/______ 
8) Predominant axial motor symptom:  
 
      
           PIGD / FOG / speech changes 
9) Side of the body most affected by motor symptoms now:  
 
       L / R / Both equal 
10) Current STN-DBS settings (baseline): 
 
Left-STN 
Right-STN 
Voltage 
 
 
Frequency 
 
 
Pulse width 
 
 
11) Current dopaminergic medication(s) and dose(s): 
Medication 
Dose (mg/day) 
Levodopa-equivalent dose (mg/day) 
 
 
 
 
 
 
 
 
 
12) Total levodopa-equivalent daily dose (mg/day):  ____________________ 
 

 
30 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
CASE REPORT FORM FOR BASELINE STUDY EVALUATION 
Study identification number: _______ 
 
     Visit Date (MMM/YY): _______/______  
1) From the 20 acts in the Edinburgh handedness inventory, calculate the laterality index as 100 
x [(R – L) / (R + L)], where R is the number of acts performed with the right, and L is the num-
ber performed with the left: 
 
 
 
 
 
 
______ 
2) 10-metter walk test: 
 
    * Calculated gait speed (Normal):  
______ m/s 
    * Calculated gait speed (Fast): 
 
______ m/s 
3) Mini-BESTest: 
 
    * Anticipatory: 
 
 
 
______/ 6 points 
    * Reactive postural control: 
 
______/ 6 points 
    * Sensory orientation: 
 
 
______/ 6 points 
    * Dynamic gait: 
 
 
 
______/ 10 points 
    * Total score: 
 
 
 
______/ 28 points 
4) UPDRS-PIGD sub score: 
    * Activities of daily living  
 
 
 
          * Falling: 
 
 
 
______/ 4 points 
          * FOG:  
 
 
 
______/ 4 points 
          * Walking: 
 
 
 
______/ 4 points 
 
 
 
    * Examination 
          * Gait:  
 
 
 
______/ 4 points 
          * Postural stability: 
 
 
______/ 4 points 
    * Total score: 
 
 
 
______/ 20 points 
5) MDS-UPDRS: 
    * MDS-UPDRS motor score (Part III) 
______  
    * MDS-UPDRS total score  
 
______ 
6) FOG questionnaire  
 
 
______/ 24 points 
7) 39-PDQ 
 
 
 
 
______  
  
 
 

 
31 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
CASE REPORT FORM FOR FOLLOW-UP STUDY EVALUATIONS 
Study identification number: _______ 
 
     Visit Date (MMM/YY): _______/______  
Visit type: 
 
Scheduled #1 / #2 / #3 
     Additional #1 / #2 / #3 
 
1) Current dopaminergic medication(s) and dose(s): 
Medication 
Dose (mg/day) 
Levodopa-equivalent dose (mg/day) 
 
 
 
 
 
 
 
 
 
2) Total levodopa-equivalent daily dose (mg/day):  ____________________ 
3) 10-metter walk test: 
    * Calculated gait speed (Normal):  
______ m/s 
    * Calculated gait speed (Fast): 
 
______ m/s 
4) Mini-BESTest: 
    * Anticipatory: 
 
 
 
______/ 6 points 
    * Reactive postural control: 
 
______/ 6 points 
    * Sensory orientation: 
 
 
______/ 6 points 
    * Dynamic gait: 
 
 
 
______/ 10 points 
    * Total score: 
 
 
 
______/ 28 points 
5) UPDRS-PIGD sub score: 
    * Activities of daily living  
 
 
 
          * Falling: 
 
 
 
______/ 4 points 
          * FOG:  
 
 
 
______/ 4 points 
          * Walking: 
 
 
 
______/ 4 points 
 
 
 
    * Examination 
          * Gait:  
 
 
 
______/ 4 points 
          * Postural stability: 
 
 
______/ 4 points 
    * Total score: 
 
 
 
______/ 20 points 
6) MDS-UPDRS: 
    * MDS-UPDRS motor score (Part III) 
______  
    * MDS-UPDRS total score  
 
______ 
7) FOG questionnaire  
 
 
______/ 24 points 
8) PDQ-39 
 
 
 
 
______ 

 
32 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
EDINBURGH HANDEDNESS INVENTORY 
Study Identification Number: __________ Date (MMM/YY): _____/_____ 
 
1) Have you ever had any tendency to left-handedness? 
YES  / NO 
2) Please indicate your preferences in the use of hands in the following activities by putting 
a + in the appropriate column.  Where the preference is so strong that you would never 
try to use the other hand unless absolutely forced to, put ++. If in any case you are really 
indifferent put + in both columns. Some of the activities require both hands. In these cas-
es, the part of the task, or object, for which hand preference is wanted is indicated in 
brackets. Please try to answer all the questions, and only leave a blank if you have no ex-
perience at all of the object or task. 
 
 
Activity 
Right 
Left 
1 
Writing 
 
 
2 
Drawing 
 
 
3 
Throwing 
 
 
4 
Scissors 
 
 
5 
Comb 
 
 
6 
Toothbrush 
 
 
7 
Knife (without fork) 
 
 
8 
Spoon 
 
 
9 
Hammer 
 
 
10 
Screwdriver 
 
 
11 
Tennis Racket 
 
 
12 
Knife (with fork) 
 
 

 
33 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
13 
Cricket bat (lower hand) 
 
 
14 
Golf Club (lower hand) 
 
 
15 
Broom (upper hand) 
 
 
16 
Rake (upper hand) 
 
 
17 
Striking Match (match) 
 
 
18 
Opening box (lid) 
 
 
19 
Dealing cards (card being dealt) 
 
 
20 
Threading needle (needle or thread according to 
which is moved) 
 
 
 
 
 
 
40 
Which foot do you prefer to kick with? 
 
 
41 
Which eye do you use when using only one? 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
34 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
10 METER WALK TEST (GAIT SPEED) 
Study Identification Number: __________ Date (MMM/YY): _____/_____ 
 
TEST PROTOCOL: Measure and mark a 10-meter (32.8 feet) distance. Then measure and mark 
2 meters (6.6 feet) from the start and 2 meters from the finish. The central 6 meters are timed, the 
2 meters on either side are not timed and are intended for acceleration and deceleration. Patient 
may use an assistive device, but this should be kept consistent and documented. If assistance is 
required, this test should not be performed. This tests may be performed for preferred gait speed 
or fast speed. 
 
Walking direction  (10 meters / 34.8 feet)  
2 meters 
6 meters 
2 meters 
6.6 feet 
19.7 feet 
6.6 feet 
 Starting line 
 START TIMING                 STOP TIMING           Finish line  
 
INSTRUCTIONS: 
 
- Start timing when the toes of the leading foot cross the first 2-meter mark. 
- Stop timing when the toes of the leading foot cross the second 2-meter mark (8 meters from the 
starting line, 6 meters from the first 2-meter mark) 
- Collect 3 trials and calculate the average of the three trials. 
NORMAL: “I will say ready, set, go. When I say go, walk at your normal comfortable speed un-
til I say stop.” 
FAST: “I will say ready, set, go. When I say go, walk as fast as you safely can until I say stop.” 
GAIT SPEED = 6 METERS / TIME TO COMPLETE 
(For example, the person takes 9 seconds to walk 6 meters  6/9 = 0.67 m/s) 
Patient’s performance (Normal):  
________ seconds 
Calculated gait speed (Normal):  
________ meters/second (m/s) (round to 2 decimal places) 
Patient’s performance (Fast):  
________ seconds 
Calculated gait speed (Fast):   
________ meters/second (m/s) (round to 2 decimal places) 
 
 

 
35 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
Mini-BESTest: Balance Evaluation Systems Test 
© 2015–2013 Oregon Health & Science University. All rights reserved. 
 
Study Identification Number: __________ Date (MMM/YY): _____/_____ 
 
ANTICIPATORY___________________________________________   SUB SCORE:              /6 
1. SIT TO STAND 
Instruction: “Cross your arms across your chest. Try not to use your hands unless you must. Do not let 
your legs lean against the back of the chair when you stand. Please stand up now.” 
(2) Normal: Comes to stand without use of hands and stabilizes independently. 
(1) Moderate: Comes to stand WITH use of hands on first attempt. 
(0) Severe: Unable to stand up from chair without assistance, OR needs several attempts with use of 
hands. 
2. RISE TO TOES 
Instruction: “Place your feet shoulder-width apart. Place your hands on your hips. Try to rise as high as 
you can onto your toes. I will count out loud to 3 seconds. Try to hold this pose for at least 3 seconds. 
Look straight ahead. Rise now.” 
(2) Normal: Stable for 3 s with maximum height. 
(1) Moderate: Heels up, but not full range (smaller than when holding hands), OR noticeable instability 
for 3 s. 
(0) Severe: ≤ 3 s. 
3. STAND ON ONE LEG 
Instruction: “Look straight ahead. Keep your hands on your hips. Lift your leg off of the ground behind 
you without touching or resting your raised leg upon your other standing leg. Stay standing on one leg as 
long as you can. Look straight ahead. Lift now.” 
Left:  Time in Seconds Trial 1:____ Trial 2: ____ 
Right: Time in Seconds Trial 1:____ Trial 2:___ 
(2) Normal: 20 s. 
 
 
 
 
(2) Normal: 20 s. 
(1) Moderate: < 20 s. 
 
 
 
 
(1) Moderate: < 20 s. 
(0) Severe: Unable 
 
 
 
 
(0) Severe: Unable 
*To score each side separately use the trial with the longest time. To calculate the sub-score and total 
score use the side [left or right] with the lowest numerical score [i.e. the worse side]. 
REACTIVE POSTURAL CONTOL______________________________ SUB SCORE:              /6 
4. COMPENSATORY STEPPING CORRECTION- FORWARD 
Instruction: “Stand with your feet shoulder-width apart, arms at your sides. Lean forward against my 
hands beyond your forward limits. When I let go, do whatever is necessary, including taking a step, to 
avoid a fall.” 
(2) Normal: Recovers independently with a single, large step (second realignment step is allowed). 
(1) Moderate: More than one step used to recover equilibrium. 
(0) Severe: No step, OR would fall if not caught, OR falls spontaneously. 
5. COMPENSATORY STEPPING CORRECTION- BACKWARD 
Instruction: “Stand with your feet shoulder-width apart, arms at your sides. Lean backward against my 
hands beyond your backward limits. When I let go, do whatever is necessary, including taking a step, to 
avoid a fall.” 
(2) Normal: Recovers independently with a single, large step. 

 
36 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
(1) Moderate: More than one step used to recover equilibrium. 
(0) Severe: No step, OR would fall if not caught, OR falls spontaneously. 
6. COMPENSATORY STEPPING CORRECTION- LATERAL 
Instruction: “Stand with your feet together, arms down at your sides. Lean into my hand beyond your 
sideways limit. When I let go, do whatever is necessary, including taking a step, to avoid a fall.” 
Left: 
 
 
 
 
 
 
Right: 
(2) Normal: Recovers independently with 1 step  
(2) Normal: Recovers independently with 1 step      
      (crossover or lateral OK) 
 
 
 
(crossover or lateral OK) 
(1) Moderate: Several steps to recover equilibrium.       (1) Moderate: Several steps to recover. 
(0) Severe: Falls, or cannot step.  
 
 
(0) Severe: Falls, or cannot step. 
*Use the side with the lowest score to calculate sub-score and total score. 
SENSORY ORIENTATION ___________________________________ SUB SCORE:              /6 
7. STANCE (FEET TOGETHER); EYES OPEN, FIRM SURFACE 
Instruction: “Place your hands on your hips. Place your feet together until almost touching. Look straight 
ahead. Be as stable and still as possible, until I say stop.” 
Time in seconds: ___________  
(2) Normal: 30 s.  
(1) Moderate: < 30 s.  
(0) Severe: Unable. 
8. STANCE (FEET TOGETHER); EYES CLOSED, FOAM SURFACE 
Instruction: “Step onto the foam. Place your hands on your hips. Place your feet together until almost 
touching. Be as stable and still as possible, until I say stop. I will start timing when you close your eyes.” 
Time in seconds: ___________  
(2) Normal: 30 s.  
(1) Moderate: < 30 s.  
(0) Severe: Unable. 
9. INCLINE- EYES CLOSED 
Instruction: “Step onto the incline ramp. Please stand on the incline ramp with your toes toward the top. 
Place your feet shoulder-width apart and have your arms down at your sides. I will start timing when you 
close your eyes.” 
Time in seconds: ___________  
(2) Normal: Stands independently 30 s and aligns with gravity.  
(1) Moderate: Stands independently < 30 s OR aligns with surface.  
(0) Severe: Unable. 
DYNAMIC GAIT __________________________________________ SUB SCORE:              /10 
10. CHANGE IN GAIT SPEED 
Instruction: “Begin walking at your normal speed, when I tell you ‘fast’, walk as fast as you can. When I 
say ‘slow’, walk very slowly.” 
(2) Normal: Significantly changes walking speed without imbalance.  
(1) Moderate: Unable to change walking speed or signs of imbalance.  
(0) Severe: Unable to achieve significant change in walking speed AND signs of imbalance. 

 
37 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
11. WALK WITH HEAD TURNS – HORIZONTAL 
Instruction: “Begin walking at your normal speed, when I say ‘right’, turn your head and look to the 
right. When I say ‘left’, turn your head and look to the left. Try to keep yourself walking in a straight 
line.” 
(2) Normal: Performs head turns with no change in gait speed and good balance.  
(1) Moderate: Performs head turns with reduction in gait speed.  
(0) Severe: Performs head turns with imbalance. 
12. WALK WITH PIVOT TURNS 
Instruction: “Begin walking at your normal speed. When I tell you to ‘turn and stop’, turn as quickly as 
you can, face then opposite direction, and stop. After the turn, your feet should be close together.” 
(2) Normal: Turns with feet close FAST (≤ 3 steps) with good balance. 
(1) Moderate: Turns with feet close SLOW (≥ 4 steps) with good balance.  
(0) Severe: Cannot turn with feet close at any speed without imbalance. 
13. STEP OVER OBSTACLES 
Instruction: “Begin walking at your normal speed. When you get to the box, step over it, not around it 
and keep walking.” 
(2) Normal: Able to step over box with minimal change of gait speed and with good balance. 
(1) Moderate: Steps over box but touches box OR displays cautious behavior by slowing gait.  
(0) Severe: Unable to step over box OR steps around box. 
14. TIMED UP & GO WITH DUAL TASK [3 METER WALK] 
Instruction TUG: “When I say ‘Go’, stand up from chair, walk at your normal speed across the tape on 
the floor, turn around, and come back to sit in the chair.” 
Instruction TUG with Dual Task: “Count backwards by threes starting at ____. When I say ‘Go’, stand 
up from chair, walk at your normal speed across the tape on the floor, turn around, and come back to sit 
in the chair. Continue counting backwards the entire time.” 
 
TUG: ______________ seconds; Dual Task TUG: ________________ seconds. 
(2) Normal: No noticeable change in sitting, standing or walking while backward counting when com-
pared to TUG without Dual Task. 
(1) Moderate: Dual Task affects either counting OR walking (>10%) when compared to the TUG without 
Dual Task. 
(0) Severe: Stops counting while walking OR stops walking while counting. 
*When scoring item 14, if subject’s gait speed slows more than 10% between the TUG without and with a 
Dual Task the score should be decreased by 1 point. 
  
 TOTAL SCORE:              /28 
 
 
 
 

 
38 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
UPDRS-PIGD SUBSCALE 
Study Identification Number: __________ Date (MMM/YY): _____/_____ 
ACTIVITIES OF DAILY LIVING (QUESTIONNAIRE) 
FALLING 
 
0 = None 
 
1 = Rare 
 
2 = Occasional (< 1/day) 
 
3 = Approximately once/day 
 
4 = More than once/day 
FREEZING OF GAIT 
 
0 = None 
 
1 = Rare, may have “start hesitation” 
 
2 = Occasional 
 
3 = Frequent with occasional falls 
 
4 = Frequently falls from freezing of gait 
WALKING 
 
0 = Normal 
 
1 = Mild difficulties. May not swing arms or may tend to drag leg 
 
2 = Moderate difficulties but requires little or no assistance 
 
3 = Severe disturbance, requiring assistance 
 
4 = Cannot walk even with assistance 
EXAMINATION 
GAIT 
0 = Normal 
1 = Walks slowly, may shuffle with short steps, but no festination or propulsion 
2 = Walks with difficulty, but requires little or no assistance. May have some festination, 
short steps, or propulsion 
3 = Severe disturbance requiring assistance 
4 = Cannot walk at all 
POSTURAL STABILITY 
0 = Normal 
1 = Retropulsion, but recovers unaided 
2 = Absence of postural response; would fall if not caught by examiner 
3 = Very unstable, tends to lose balance spontaneously 
4 = Unable to stand without assistance 
TOTAL UPDRS-PIGD SCORE: _________ points 
 

 
39 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
FREEZING OF GAIT QUESTIONNAIRE 
Study Identification Number: __________ Date (MMM/YY): _____/_____ 
1. During your WORST state – Do you walk: 
 
 
 
 
    __________ 
 
0 Normally 
 
1 Almost normally – somewhat slow 
 
2 Slow but fully independent 
 
3 Need assistance or walking aid 
 
4 Unable to walk 
2. Are your gait difficulties affecting your daily activities and independence? 
    __________ 
 
0 Not at all 
 
1 Mildly 
 
2 Moderately 
 
3 Severely 
 
4 Unable to walk 
3. Do you feel that your feet get glued to the floor while walking, making a turn or when trying 
to initiate walking (freezing)?  
 
 
 
 
 
 
    __________ 
 
0 Never 
 
1 Very rarely – about once a month 
 
2 Rarely – about once a week 
 
3 Often – about once a day 
 
4 Always – whenever walking 
4. How long is your LONGEST freezing episode?  
 
 
 
    __________ 
 
0 Never happened 
 
1 1–2 seconds 
 
2 3–10 seconds 
 
3 11–30 seconds 
 
4 Unable to walk for more than 30 seconds 
5. How long is your TYPICAL start hesitation episode (freezing when initiating the first step)? 
 
0 None 
 
 
 
 
 
 
 
 
    __________ 
 
1 Takes longer than 1 second to start walking 
 
2 Takes longer than 3 seconds to start walking 
 
3 Takes longer than 10 seconds to start walking 
 
4 Takes longer than 30 seconds to start walking 
6. How long is your TYPICAL turning hesitation (freezing when turning)? 
    __________ 
 
0 None 
 
1 Resume turning in 1–2 seconds 
 
2 Resume turning in 3–10 seconds 
 
3 Resume turning in 11–30 seconds 
 
4 Unable to resume turning for more than 30 seconds 

 
40 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
PARKINSON’S DISEASE QUALITY OF LIFE QUESTIONNAIRE (PDQ-39) 
Due to having Parkinson’s disease, 
how often during the last month have you… 
Please circle one answer for each question 
1. Had difficulty doing the leisure activities which you would like to do? 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
2. Had difficulty looking after your home, e.g. housework, cooking? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
3. Had difficulty carrying bags of shopping? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
4. Had problems walking half a mile? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
5. Had problems walking 100 yards? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
6. Had problems getting around the house as easily as you would like? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
7. Had difficulty getting around in public? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
8. Needed someone else to accompany you when you went out? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
9. Felt frightened or worried about falling over in public? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
10. Been confined to the house more than you would like? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
Please check that you have circled one answer for each question before going onto the next page 

 
41 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
Due to having Parkinson’s disease, 
how often during the last month have you… 
Please circle one answer for each question 
11. Had difficulty washing yourself? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
12. Had difficulty dressing yourself? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
13. Had problems doing up buttons or shoe laces? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
14. Had problems writing clearly? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
15. Had difficulty cutting up your food? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
16. Had difficulty holding a drink without spilling it? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
17. Felt depressed? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
18. Felt isolated and lonely? 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
19. Felt weepy or tearful? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
20. Felt angry or bitter? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
Please check that you have circled one answer for each question before going onto the next page 
 

 
42 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
Due to having Parkinson’s disease, 
how often during the last month have you… 
Please circle one answer for each question 
21. Felt anxious? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
22. Felt worried about your future? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
23. Felt you had to conceal your Parkinson’s from people? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
24. Avoided situations which involve eating or drinking in public? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
25. Felt embarrassed in public due to having Parkinson’s disease? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
26. Felt worried by other people’s reaction to you? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
27. Had problems with your close personal relationships? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
28. Lacked support in the ways you need from your spouse or partner? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
I do not have a spouse or partner 
29. Lacked support in the ways you need from your family or close friends? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
30. Unexpectedly fallen asleep during the day? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
Please check that you have circled one answer for each question before going onto the next page 

 
43 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
Due to having Parkinson’s disease, 
how often during the last month have you… 
Please circle one answer for each question 
31. Had problems with your concentration, e.g. when reading or watching TV? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
32. Felt your memory was bad? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
33. Had distressing dreams or hallucinations? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
34. Had difficulty with your speech? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
35. Felt unable to communicate with people properly? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
36. Felt ignored by people? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
37. Had painful muscle cramps or spasms? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
38. Had aches and pains in your joints or body? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
39. Felt unpleasantly hot or cold? 
 
Never  
Occasionally  
Sometimes 
 
Often  
Always 
Please check that you have circled one answer for each question. 
Thank you for completing the questionnaire. 
 
 

 
44 
Asymmetric STN-DBS for PIGD in PD 
 
 
 
 
 
17. REFERENCES 
 
1. St. George RJ, Nutt JG, Burchiel KJ, Horak FB. A meta-regression of the long-term 
effects of deep brain stimulation on balance and gait in PD. Neurology 2010; 
75(14):1292–1299. 
2. Swinnen SP. Intermanual coordination: from behavioral principles to neural-network 
interactions. Nature Rev Neurosci 2002; 3(5):348–359. 
3. Fling BW, Cohen RG, Mancini M, Nutt JG, Fair DA, Horak FB. Asymmetric pedun-
culopontine network connectivity in parkinsonian patients with freezing of gait. Brain 
2013; 136(Pt 8):2405–2418. 
4. Giladi N, McDermott MP, Fahn S, Przedborski S, Jankovic J, Stern M, Tanner C; 
Parkinson Study Group. Freezing of gait in PD: prospective assessment in the 
DATATOP cohort. Neurology 2001; 56(12):1712–1721. 
5. Fasano A, Herzog J, Seifert E, Stolze H, Falk D, Reese R, et al. Modulation of gait 
coordination by subthalamic stimulation improves freezing of gait. Mov Disord 2011; 
26(5):844–851. 
6. Lizarraga KJ, Jagid JR, Luca CC. Comparative effects of unilateral and bilateral sub-
thalamic nucleus deep brain stimulation on gait kinematics in Parkinson’s disease: a 
randomized, blinded study. J Neurol 2016; 263(8):1652–1656. 
7. Sadeghi H. Local or global asymmetry in gait of people without impairments. Gait 
Posture 2003; 17(3):197–204. 
8. Plotnik M, Giladi N, Balash Y, Peretz C, Hausdorff JM. Is freezing of gait in Parkin-
son’s disease related to asymmetric motor function? Ann Neurol 2005; 57(5):656–
663. 
9. Perera S, Mody SH, Woodman RC, Sudenski SA. Meaningful change and respon-
siveness in common physical performance in older adults. J Am Geriatr Soc 2006; 
54:743–749. 
10. Bloem BR, Marinus J, Almeida Q, Dibble L, Nieuwboer A, Post B, et al. The Move-
ment Disorders Society Rating Scales Committee. Measurement Instruments to As-
sess Posture, Gait, and Balance in Parkinson’s Disease: Critique and Recommenda-
tions. Mov Disord 2016; 31(9):1342–1355. 
11. van Neunen BF, Esselink RA, Munneke M, Speelman JD, van Laar T, Bloem BR. 
Postoperative gait deterioration after bilateral subthalamic nucleus stimulation in Par-
kinson’s disease. Mov Disord 2008; 23(16):2404–2406.