Influence of Multiple Ratio Split-belt Treadmill on Gait Asymmetry and Motor Learning in PD Patients With Freezing of Gait
Phase: NA
Conditions: Parkinson Disease, Freezing of Gait
Sponsor: KU Leuven

5. PROTOCOL S60876 
 
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Influence of Multiple Ratio Split-belt Treadmill on Gait 
Asymmetry and Motor Learning in PD patients with Freezing 
of Gait 
 
I. 
General information 
 
Version and date of protocol: version 5, 14/11/2017 
 
Funder:  
Jacques and Gloria Gossweiler Foundation, Switzerland 
 
Sponsor/Research Unit: Research Group for Neuromotor Rehabilitation, Faculty of 
Kinesiology and Rehabilitation Sciences, KU Leuven 
 
Principal investigator: Prof. Alice Nieuwboer 
 
Tervuursevest 101, 3000 Leuven 
 
Tel: 016/329119 
 
E-mail: alice.nieuwboer@kuleuven.be 
 
Sub-investigator: 
Nicholas D’Cruz 
 
Tervuursevest 101, 3000 Leuven 
 
Tel: 016/376003 
 
E-mail: nicholas.dcruz@kuleuven.be 
 
Study period:  
01/11/2017 – 31/10/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Signatures 
 
The undersigned confirm that the following protocol has been agreed and accepted and that 
the Principal Investigator agrees to conduct the trial in compliance with the approved 
protocol and will adhere to the principles outlined in the requirements for the conduct of 
clinical trials in the EU as provided for in "Directive 2001/20/EC”,  and any subsequent 
amendments, GCP guidelines, the Belgian law of May 7th 2004 regarding experiments on the 
human person, the Sponsor’s SOPs, and other regulatory requirements as amended. 
 
I agree to ensure that the confidential information contained in this document will not be 
used for any other purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of the Sponsor.  
 
I also confirm that I will make the findings of the trial publically available through publication 
or other dissemination tools without any unnecessary delay and that an honest accurate and 
transparent account of the trial will be given; and that any discrepancies from the trial as 
planned in this protocol will be explained. 
 
 
 
Principal Investigator (KU Leuven) 
 
 
 
 
Prof. Alice Nieuwboer 
 
 
 
 
11th October 2017 
………………………… 
 
………………………… 
 
………………………… 
Name & Title  
 
Signature 
 
 
Date 
 
 
 
 
Principal Investigator (participating site University Kiel) 
 
 
 
 
 
Dr. Christian Schlenstedt 
 
12th October 2017 
………………………… 
 
………………………… 
 
………………………… 
Name & Title  
 
Signature 
 
 
Date 
 
 
 
 
 

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II. 
Dutch summary of the protocol 
 
Titel onderzoeksproject: 
Invloed van multiple ratio split-belt loopbandtraining op stapasymmetrie bij personen met de 
ziekte van Parkinson en gangblokkades 
Deelnemers: 
32 patiënten met de ziekte van Parkinson, met ‘Freezing of Gait’ 
32 leeftijdsgematchte gezonde proefpersonen 
 
Type studie: 
Multi-centrische studie (Mono-centrisch in België) aan de Faculteit Bewegings- en 
Revalidatiewetenschappen 
Trainingsstudie 
Academische studie 
 
Metingen: 
Screeningstesten ter evaluatie van motorische en cognitieve functie bij ziekte van Parkinson 
Vragenlijsten naar ‘Freezing of Gait’, vermoedheid en cognitie 
Klinische meetschalen ter evaluatie van evenwicht en van de ernst van de ‘Freezing of Gait’  
5 m stappen buiten de loopband met en zonder een dubbeltaak 
 
Training protocol: 
Loopbandtraining van 6 x 5 min. Met telkens 1 min. zittende pauze 
 
Duur experiment: 
Patiënten met Parkinson en Freezing of gait: 2 sessies van 2 uur op 2 aparte testdagen 
Gezonde controles: 2 sessies van 2 uur op 2 aparte testdagen 
 
Plaats van de experimentele sessies: 
Faculteit Bewegings-en Revalidatiewetenschappen, KULeuven 
 
 
III. 
Background and rationale 
Parkinson’s disease (PD) is the second most common neurodegenerative disease [1, 2]. It has 
a substantial impact on patients’ quality of life as well as on the socio-economic cost for 
society [3]. Gait problems are very prevalent in PD and markedly reduce patients’ functional 
independence [4]. Freezing of gait (FOG) is without doubt the most disabling gait impairment 
and it constitutes an independent risk factor for falls [5]. This complex symptom is defined as 
an episode of substantial reduction or complete cessation of movement despite having the 
intention to move [6]. Current medical and surgical treatments only partly relieve FOG [7], 
strongly suggesting that non-dopaminergic mechanisms mediate its occurrence [8]. 
Therapeutic alternatives are, therefore, urgently needed. A growing body of literature 

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suggests that exercise and motor learning can significantly improve gait and mobility in PD 
[9, 10] with long term effects ranging from 4 to 48 weeks [11].  
FOG occurs when spatiotemporal motor control breaks down and is associated with gait 
cycle variability, reduced stride amplitude and hastening of gait timing. Furthermore, FOG is 
also related to between-limb coordination deficits and gait asymmetry [12-14]. The strong 
link between FOG and gait asymmetry [14, 15] is underscored by the fact that turning – which 
is a highly asymmetric task, is the most important trigger of FOG [16, 17].  
Split-belt treadmill walking, whereby the walking speed of each leg can be manipulated 
independently, is a useful tool to study both motor switching and modulating gait asymmetry. 
In a recent study at our lab, motor switching ability during different asymmetric split-belt 
conditions was studied in patients with and without FOG. It was shown that non-freezers were 
able to adapt spatial gait symmetry to different switching split-belt conditions similarly as 
healthy controls. However, adaptive capacity was reduced in freezers (figure 1A) [18]. The 
powerfulness of the split-belt paradigm was also confirmed by the fact that immediately after 
the switch, FOG was evoked in two cases. In another study from the group at Christian-
Albrechts University Kiel (CAUK), Germany, the short-term effects of 10 minutes split-belt 
walking were studied through reducing the belt velocity of either the body side with the 
longer or shorter step length in PD. Gait asymmetry, bilateral coordination and the 
consecutive reduction in step lengths were improved in the tied-belt condition after subjects 
walked with reduced velocity at the side with the longer step length ("better side reduction") 
(figure 1B) [19]. These exciting pilot results provide proof-of-principle evidence for the current 
project. To consolidate these findings, our research group in collaboration with the group at 
Kiel will undertake two studies, probing short term motor adaptation (present study) and 
prolonged motor learning (future study) to alleviate freezing-related gait deficits.  
Figure 1. A) Impaired adaptive capacity of patients with PD with FOG during split-belt gait 
(data from KUL: mod. according to Mohammadi et al. 2015); B) Step length during baseline, 
early and late split-belt adaptation (25% reduced belt's speed of the leg with the longer step 
length (best-side reduction)) and after effect (data from CAUK: mod. according to Fasano et 
al. 2016). 
A
B

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IV. 
Study objectives 
 
Motor adaptation refers to behavioural changes induced by new environmental dynamics, 
commonly studied by inducing an unfamiliar perturbation into an otherwise familiar task. 
Here, split-belt speed manipulations will be used to study implicit motor adaptation, i.e. 
without raising conscious attention to the adaptive behaviour nor demanding an explicit 
strategy [18]. Motor adaptation plays an important role in the acquisition (early) phase of 
motor learning, the hallmark of which is reaching a stable level of performance. In contrast, 
the late consolidation phase of motor learning is characterized by: 1) automatization, or the 
ability to withstand dual task interference; 2) transfer, or the ability to generalize to untrained 
circumstances and 3) retention, or the ability to sustain improvements after a period without 
practice. [20]. Our previous work has shown that despite disease-related damage, patients 
with PD can still reconfigure neural networks to optimize motor control and achieve partially 
consolidated motor learning gains [21]. Interestingly, from recent study on manual tasks, it 
appears that variable practice (random versus blocked) and practice requiring greater 
adaptation (with versus without contextual interference) led to worse immediate 
performance but better learning retention in PD and older adults. This strongly suggests that 
in order to enhance better storage in motor memory and automatic retrieval of practice gains, 
practice conditions are critical. In this project, we want to study these phenomena for the 
first time during gait. More specifically, we want to know how PD impacts upon maintenance 
of stride amplitude when adapting to varying split-belt conditions in order to achieve robust 
learning. 
  
Research Questions and Hypothesis 
We aim to investigate two research questions: 
We intend to better understand the impact of PD on the adaptive response to different split-
belt conditions relative to healthy age-matched controls. 
We will investigate the short-term effects of different split-belt conditions in order to 
determine the optimal conditions for long-term training in patients with FOG and test which 
condition leads to the best 24-hour retention.  
We hypothesize that being exposed to larger contrasts between split-belt speeds (ratio) will 
result in improved gait symmetry and better savings in motor memory, thus leading to better 
retention effects and this more so in controls than in PD. We also hypothesize that variable 
split-belt conditions (changing ratios) will lead to better adaptive capacity to transitions than 
steady split-belt walking with a consistent ratio.  
 
 
 
 
 
 

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V. 
Methodology of the research  
 
Number of participants: This pilot study investigating the short-term effects of split-belt 
walking on gait asymmetry and motor learning is conducted in collaboration with CAUK and 
will include a total number of 128 participants i.e 64 at each centre comprising 32 patients 
with PD and 32 healthy controls.  
 
Recruitment: Older adults will be recruited from an existing database of healthy volunteers. 
Recruitment of PD patients will be conducted via a database of patients that has been built up 
over the years in our laboratory in collaboration with the neurologist at the Movement 
Disorders clinic at UZ Leuven (Prof. Dr. Wim Vandenberghe). Flyers containing study 
information will be handed to people expressing interest to participate. 
 
Inclusion and Exclusion Criteria: PD patients with FOG who can walk at least 5 minutes at a 
stretch will be included in this study. Exclusion criteria are: participation in treadmill training 
in the 3 months prior to the study, other neurological impairments, orthopedic injuries that 
could influence gait or balance, cardiovascular exercise risk factors, dementia or self-reported 
DBS-related postural or gait disturbances. 
 
Design: Patients will be tested in the ON phase of medication on consecutive days in a session 
of about 2 hours. Figure 2 shows that the included subjects will be randomized into 4 
treatment groups to compare the impact of different (3:4 and 1:2) and changing ratios of split-
belt walking relative to traditional treadmill training (Tied-Belt). Effects will be analysed pre-
post (I-II) and after 24 hours (III) retention. The second training session (III-IV) will explore the 
possible benefits of repeated training and serves as a pilot for a larger training study. 
 
Standardization: Testing and training methods and protocol as well as patient instructions 
will be standardised across the two centres by documentation of procedures as well as 
through regular communication. Researchers from both groups will attend initial 
measurements and in addition, during the first 3 months of the project, a monthly skype call 
between researchers will be held to check the fidelity of procedures and ensure adherence. 
 

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Intervention 
Participants will first walk normally (5 x 5m) at a comfortable pace to assess overground 
walking speed and to assess which leg has the longer/shorter step length. Best/worst side 
will be further confirmed with a toe-tapping test and by asking the PD patients about their 
more/less affected PD side. Next, participants will walk on the treadmill for a maximum of 3 
minutes to get familiar with treadmill walking, reaching their overground gait speed. 
Intervention will consist of one training session of 6 x 5 min. treadmill gait with 1 min. rest in 
between [12]. Participants are not allowed to walk overground during the rest but a chair will 
be provided if necessary. Subjects are wearing a harness to prevent falling. Belt speed will be 
adjusted according to the individual’s comfortable overground gait velocity. Previous studies 
have shown improved gait symmetry after split-belt conditions with slower belt speed of 
the side with the longer step length ('best side reduction') in PD and stroke [19, 23]. As it has 
been shown that belt speed ratio but not absolute speed impacts on gait asymmetry 
(unpublished data), we chose to decrease the belt speed of the side with the longer step 
length rather than increasing the belt speed of the side with the shorter step length. Also, to 
avoid hastening, the ‘best side reduction’ principle will be adopted using a 3:4 or 1:2 ratios 
(table 1).  
 
Table 1: Belt speed of the 4 treatment groups 
Group 
Belt speed 
ratio 
Belt speed of the leg with 
the longer step length (% 
of overground gait speed) 
Belt speed of the leg with 
the shorter step length (% 
of overground gait speed) 
A-Steady Split-belt Treadmill  
3:4 
75% 
100% 
B-Steady Split-belt Treadmill 
1:2 
50% 
100% 
C-Transfer Split-belt Treadmill 
changing 
50-75% 
100% 
D-Treadmill (tied-belt) 
1:1 
100% 
100% 
 
Figure 2. Study design. 128 participants will be recruited across the two centres and data will 
be pooled for analysis. SBT, Split-belt Treadmill; PD, Parkinson's disease; HC, healthy control. 

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Outcome Measures  
Laboratory FOG assessment: A FOG ratio score will be calculated [24]. FOG will be analysed 
with accelerometer sensors (APDM) during FOG provoking tasks (360° turning in place 
(right/left side alternating) for 1 minute with and without a cognitive dual task. 
Overground gait analysis: the following gait variables will be analysed during 5 trials of 5m gait 
with comfortable pace (assessed via accelerometer sensors (APDM) and Vicon/Qualisys 
motion capture analysis): step length, gait asymmetry, gait variability, bilateral coordination 
[25] and gait velocity. 
Treadmill gait analysis: adaptive capacity during transitions will be assessed by analysing the 
above mentioned variables during changing split-belt conditions. Retroreflective markers will 
be placed bilaterally on the limbs to allow gait analysis at 100Hz with infrared cameras. 
Descriptors: MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) [26], New Freezing 
of Gait Questionnaire [27], Mini Mental State Exam (MMSE) [28], Montreal Cognitive 
Assessment (MoCA) [29], Frontal Assessment Battery, Falls Efficacy Scale International (FES-
I), Mini-BESTest [30], Borg Rating of Perceived Exertion, Visual Analogue Scale for fatigue and 
number of falls during the last 6 months. 
 
VI. 
Planned Statistical analysis & Data Management 
 
Data storage: Part of the data obtained on paper (e.g. questionnaires, informed consent 
forms) will be stored in an excel file. The data obtained by computerized measures will all be 
stored in the original digital files, and the main variables will be stored in excel datafiles. All 
data will regularly be backed up to a secure KU Leuven server. 
Statistics: Data from both centres will be pooled for the statistical analysis. The immediate 
effects and short term (24 hour) retention of split-belt treadmill training on overground gait 
symmetry and the freezing ratio during the turning task are the main outcomes of interest. 
Repeated measures ANOVA with group and training condition as between subjects factors will 
be employed in order to test this. Effect sizes will be determined and a post-hoc power 
calculation will be performed to ascertain sample sizes for a planned larger training study. 
 
VII. 
Safety 
 
Our laboratory has vast experience with testing patients with PD. Testing will be carried out 
in a standard movement laboratory setting when using their normal medication. Subjects will 
be asked to wear well-fitting, flat-heeled and comfortable shoes for walking during the session 
and a safety harness will be provided while on the treadmill to avoid falls at all times In 
between trials, sufficient seated rest periods will be inserted to avoid fatigue. Two 
experienced testers will be present at all times to ensure safety of the participants. If patients 
require their normal medication, this will be accommodated. No interference with normal 
intake is foreseen. 
 

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VIII. 
Costs 
 
Full reimbursement of travel expenses for the people with Parkinson’s disease and age-
matched controls (i.e. the healthy elderly) will be covered by the project. There will be no 
additional reimbursements. 
 
IX. 
Ethics 
 
The protocol is submitted for review to the local Ethics Committee of the KU Leuven 
(Commissie Medische Ethiek UZ Leuven, Herestraat 49, 3000 Leuven). The study will be 
performed in accordance with The Code of Ethics of the World Medical Association 
(Declaration of Helsinki, 1967) and the principles of GCP. Any subsequent protocol 
amendments will be submitted to the Ethics Committee and Regulatory Authorities for 
approval. 
After complete explanation of the study protocol, written informed consent will be obtained 
from all participants prior to participation in the experiment. 
The investigators will treat all information and data relating to the study confidentially and 
will not distribute this information to third parties or use it for any other purpose than the 
current study. Data will be coded and will be protected from disclosure outside the research 
environment. 
The collection, processing and disclosure of personal data, such as patient health and medical 
information is subject to compliance with applicable personal data protection and the 
processing of personal data (Directive 95/46/EC and Belgian law of December 8, 1992 on the 
Protection of the Privacy in relation to the Processing of Personal Data). 
X. 
Insurance 
 
In accordance with the Belgian Law relating to experiments on human persons dated May 7, 
2004, Sponsor shall assume, even without fault, the responsibility of any damages incurred 
by a Study Patient and linked directly or indirectly to the participation to the Study, and shall 
provide compensation therefore through its insurance. Sponsor delegates his insurance duty 
(pursuant to art 29 of the Belgian Law relating to experiments on human persons dated May 
7, 2004,) for participants in other countries than Belgium to the respective participating 
site(s) of that country, who hereby accept(s). 
 
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