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Neurorehabilitation and Neural
http://nnr.sagepub.com/content/early/2014/11/14/1545968314545175
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DOI: 10.1177/1545968314545175
published online 21 November 2014Neurorehabil Neural Repair
Nieuwboer
Farshid Mohammadi, Sjoerd M. Bruijn, Griet Vervoort, Erwin E. van Wegen, Gert Kwakkel, Sabine Verschueren and Alice
Motor Switching and Motor Adaptation Deficits Contribute to Freezing of Gait in Parkinson's Disease
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Neurorehabilitation and
Neural Repair
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DOI: 10.1177/1545968314545175
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Original Article
Introduction
A considerable number of patients with Parkinson’s disease
(PD) suffer from freezing of gait (FOG), which is a dis-
abling clinical phenomenon characterized by a brief inabil-
ity to generate effective stepping despite the voluntary wish
to move.1 Recent neuroimaging work suggests that highly
integrated motor and cognitive functions of the basal gan-
glia and related frontal areas are differentially affected in
patients with FOG compared to those without.2,3 In addi-
tion, altered neural activity of the mesencephalic locomotor
region4,5 and white matter integrity changes in neurons con-
necting the mesencephalic locomotor region and frontal
cortical regions were found to be related to FOG.6,7
Behaviorally, freezers have more pronounced gait defi-
cits even during normal gait or more challenging situations
such as turning8 and walking through a doorway.9 However,
it is not clear to what extent these parameters are directly
related to FOG. FOG has been shown to occur more
frequently in situations that incur a progressive reduction in
step length10 and an increase of gait asymmetry.11 These
findings support the hypothesis that FOG can be induced by
several motor deficits that accumulate up to a freezing
threshold.12
Asymmetry has also been suggested to be one of the
potential triggers that could drive the motor system toward
545175NNRXXX10.1177/1545968314545175Neurorehabilitation and Neural RepairMohammadi et al
research-article2014
1KU Leuven, Leuven, Belgium
2VU University Amsterdam, Amsterdam, The Netherlands
3First Affiliated Hospital of Fujian Medical University, Fujian, People’s
Republic of China
4VU University Medical Center, Amsterdam, The Netherlands
Corresponding Author:
Alice Nieuwboer, PhD, Faculty of Kinesiology and Rehabilitation,
Department of Rehabilitation Sciences, KU Leuven, Tervuursevest
101 - Box 150, 3001 Heverlee, Belgium
Email: alice.nieuwboer@faber.kuleuven.be
Motor Switching and Motor Adaptation
Deficits Contribute to Freezing of Gait in
Parkinson’s Disease
Farshid Mohammadi, PhD1, Sjoerd M. Bruijn, PhD2,3, Griet Vervoort, MSc1,
Erwin E. van Wegen, PhD4, Gert Kwakkel, PhD4, Sabine Verschueren, PhD1,
and Alice Nieuwboer, PhD1
Abstract
Background. Patients with freezing of gait (FOG) have more difficulty with switching tasks as well as controlling the
spatiotemporal parameters of gait than patients without FOG. Objective. To compare the ability of patients with and
without FOG to adjust their gait to sudden speed switching and to prolonged walking in asymmetrical conditions. Methods.
Gait characteristics of 10 freezers, 12 non-freezers, and 12 controls were collected during tied-belt conditions (3 and 4
km/h), motor switching and reswitching (increase of speed in one belt from 3 to 4 km/h and vice versa), and adaptation
(adjustment to asymmetrical gait) and re-adaptation (returning to symmetrical gait) on a split-belt treadmill. Results.
Following switching, freezers showed the largest increase of step length asymmetry (P = .001). All groups gradually adapted
their gait to asymmetrical conditions, but freezers were slower and demonstrated larger final asymmetry than the other
2 groups (P = .001). After reswitching, freezers again showed the largest step length asymmetry (P = .01). During re-
adaptation, both controls and non-freezers reached symmetrical levels, but freezers did not. Interestingly, only immediately
after switching did one episode of FOG and one episode of festination occur in 2 different patients. Conclusions. Freezers
have more difficulties adapting their gait during both suddenly triggered and continued gait speed asymmetry. The impaired
ability of freezers during both switching and reswitching would suggest that they have an adaptive deficit rather than
difficulties with asymmetry per se. Future work needs to address whether these adaptation problems can be ameliorated
with rehabilitation.
Keywords
Parkinson’s disease, freezing, split-belt treadmill
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2 Neurorehabilitation and Neural Repair
FOG,11 as FOG frequently happens during motor tasks that
require locomotor asymmetry, such as turning,8 initiating
gait,13 and avoiding an obstacle.14 Fasano et al15 reported
direct evidence supporting the role of asymmetry in FOG.
They found that decreasing between-limb asymmetry
through a 50% reduction of subthalamic nucleus stimula-
tion voltage for the least affected limb led to reduced FOG
duration and frequency. In addition, increasing asymmetry
increased FOG duration. However, it was not clear in how
many patients FOG was provoked in this fashion. Therefore,
the direct contribution of imposing asymmetrical gait
demands needs further clarification.
A split-belt treadmill, in which 2 belts can move at the
same or different speeds, offers a controlled means to simu-
late asymmetrical tasks such as turning. It also allows the
time-varying speed manipulations to resemble the gait
demands encountered in daily life. Finally, it enables study-
ing the ability of participants to respond to switching, asym-
metry, and gait adaptation.16 During the immediate switch
to asymmetrical conditions, relative shortening of step
length of the limb on the faster belt occurs in healthy con-
trols.17 Freezers were observed in the clinical setting to have
difficulty altering their locomotor system according to sud-
den changes in the environment (ie, set-shifting).18 This was
confirmed in a treadmill study in which sudden obstacles
elicited short FOG episodes.14 Furthermore, cognitive set-
shifting deficits were specifically associated with FOG
severity18 but not to PD severity.19 Motor switching while
adapting to gait speed changes in a recent study on the split-
belt surprisingly did not show overt gait difficulties in
freezers compared to non-freezers.20 These negative results
may be due to averaging and pooling of the epochs in which
switching occurred and low belt speeds. Therefore, the first
aim of the current study was to test whether freezers adjust
their gait differently following sudden switching from
steady walking to an asymmetrical gait. We hypothesized
that switching would lead to impaired scaling of step length
and larger asymmetry in freezers than in non-freezers.
The second aim of the current study was to investigate
gait adaptation in response to prolonged asymmetrical load
on the gait pattern. Previous studies showed that this gradual
gait adaptation on split-belt might be dependent on the
cerebellum.17 This concurs with recent suggestions that the
cerebellum may exert an important compensatory role dur-
ing motor adaptation in PD.21,22 In addition, reduced struc-
tural connectivity between the cerebellum and other cortical
centers has been reported in freezers.7 Therefore, we hypoth-
esized that asymmetrical walking would lead to greater gait
asymmetry in freezers than in non-freezers. In line with this,
we also expected that re-adaptation is differentially affected
in freezers. Finally, through analyzing the relationship
between clinical measures and adaptive ability, we aimed to
gain insight into the gait adaptation difficulties in PD.
Materials and Methods
Subjects
The study was approved by the local medical ethics com-
mittee of KU Leuven, and all participants gave their writ-
ten informed consent before the experiment. Twenty-two
patients with idiopathic PD, including 10 freezers and 12
non-freezers and 12 age-matched controls were studied,
who met the following inclusion criteria: patients had to
be diagnosed based on the UK Parkinson’s Disease Brain
Bank Criteria23 by a neurologist. The exclusion criteria
for the patients were other neuromuscular disorders, the
inability to walk independently on the treadmill for 12
consecutive minutes while OFF medication and a score
below 24 on the Mini-Mental State Examination (MMSE)
for both patients and controls. Freezers were defined by a
score equal to 1 on item 1 of the New Freezing of Gait
Questionnaire (N-FOGQ).24 Freezing episodes were con-
firmed during previous gait tests in OFF in the laboratory
in all cases. The severity of clinical symptoms of PD
patients was assessed according to the Hoehn & Yahr rat-
ing scale (H&Y)25 and Unified Parkinson Disease Rating
Scale (UPDRS) III.26 In order to characterize the execu-
tive function of participants, we administered the
Montreal Cognitive Assessment (MoCA)27 and the audi-
tory Stroop task to specifically probe set-shifting abili-
ties. The latter task consisted of a high or low pitched
voice saying the words “high” or “low” in Dutch. Subjects
were required to indicate the pitch of the voice and to
ignore the word said. Hence, the auditory Stroop required
switching from congruent (identical pitch and word) to
incongruent (different pitch and word do not match) stim-
uli.16,28 Verbal responses to the Stroop task were recorded
by a microphone attached to a headphone worn while sit-
ting. All clinical motor and
cognitive testing was carried out in the morning OFF
medication, after at least 12-hour withdrawal from anti-
Parkinsonian medications. The side with the highest
UPDRS III score was determined as the disease-dominant
side. For controls, we used the non-dominant limb as a
comparison, determined by response to the question,
“Which leg would you use to kick a soccer ball?”
Procedure
The paradigm consisted of walking on a split-belt treadmill
(Motek Forcelink, Culemborg, The Netherlands). The belts
were moving either at the same (tied-belt) or different
speeds (split-belt). Before measurement, retroreflective
markers were placed bilaterally on the lateral malleoli. A
10-camera Vicon 3D motion analysis system (Vicon Nexus,
Oxford Metrics, Oxford, UK) captured the position of the
markers at a rate of 100 Samples/second. Three-dimensional
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Mohammadi et al 3
ground reaction forces were sampled at 1000 samples/sec-
ond through sensors embedded in the treadmill. For safety
reasons, all participants wore a harness around the upper
chest, which was mounted to the ceiling to prevent falls.
The harness did not support bodyweight nor interfered with
walking.
Before data collection, subjects were asked to walk on
the treadmill for 2 minutes (at 3 km/h) to allow familiariza-
tion. They were not given any practice on the split-belt
configuration. Subjects were instructed to look straight
ahead and lift their hands off the rail.
Figure 1A shows step lengths of a control subject during
6 testing conditions (each lasting 2 minutes): (1) slow tied-
belt condition (3 km/h); (2) split-belt walking following an
abrupt increase in speed of one side in a random manner to 4
km/h (speed switching), while the other belt still moved at 3
km/h to induce asymmetry and the adaptation to this speed
(adaptation phase); (3) tied belts at 3 km/h (reswitching) for
Figure 1. (A) Time course for the experimental paradigm showing the different tied- and split-belt conditions in a representative
control subject. The y-axis represents step lengths of the 2 legs (non-dominant leg in black and dominant leg in gray) during different
conditions, and the x-axis shows the number of strides over time. The paradigm consisted of testing periods of 2 minutes, including
slow tied-belt, speed switching, adaptation, speed reswitching, re-adaptation, and fast tied-belt conditions for the 2 legs. During the
first speed switching, the belt speed of the non-dominant leg (in black) increased from 3 km/h to 4 km/h and then returned to 3
km/h after reswitching. During the second speed switching, the belt speed of the dominant leg (in gray) increased from 3 km/h to 4
km/h and then returned to 3 km/h after reswitching. (B) Illustration of the method to calculate step length and limb excursion during
switching. Step length is calculated as the anterior–posterior distance between the ankle markers at foot strike of each leg. Limb
excursion is calculated as the anterior–posterior distance traveled by the ankle marker from foot contact to foot off within the same leg.
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4 Neurorehabilitation and Neural Repair
2 minutes (re-adaptation phase); (4, 5) the same adaptation
and re-adaptation sequences for the other leg; (6) fast tied-
belt condition (4 km/h). The 3 to 4 km/h speed contrast
proved sufficiently challenging to destabilize gait as was
determined during a pilot study. One freezer and one non-
freezer were unable to sustain walking at the 4 km/h speed.
For these subjects (and their matched healthy control), tread-
mill speeds were reduced to 2 and 3 km/h.
Outcome Variables
Gait events (foot strike and foot off) were detected from the
center of pressure trajectories.29 Limb excursion (the split-belt
treadmill-based estimate of stride length30) was calculated as
the anterior-posterior distance traveled by the ankle marker
from foot contact to foot off within the same leg, in the lab
reference frame. Step length was determined as the anterior-
posterior distance (in the lab reference frame) between the
ankle markers at foot strike of each leg (Figure 1B). Step
length asymmetry, suggested to be the most sensitive measure
of adaptation to split-belt walking,31,32 was calculated as
Right step lengthleftsteplength
Right step lengthleftstepleng
−
+tth
Values of zero mean symmetrical walking.31,32 For split-
belt walking conditions, step length asymmetry, corrected
for tied-belt asymmetry, was calculated as
Fast step lengthslowsteplength
Fast step lengthslowsteplength
−
+
Step time asymmetry was calculated in the same manner.
For tied-belt walking conditions, we calculated the mean of
all of these variables over the entire condition, as well as the
coefficient of variation (CV) (standard deviation/mean ×
100) of limb excursion. The mean values of the 2 legs were
used for analysis. To study the switching behavior, we calcu-
lated the difference between the mean of the last 5 strides of
tied-belt walking (3 km/h) and the mean of the first 5 strides
of switching/reswitching condition. In addition, to analyze
the time series of adaptation and re-adaptation conditions,
epochs of 10 strides were compared between groups and con-
ditions. For Stroop performance, the error rate (number of
incorrect responses/number of inputs × 100) was calculated
based on manual analysis of the audiotapes by an indepen-
dent tester for congruent and incongruent responses sepa-
rately. All other calculations were done using custom-made
Matlab programs (Mathworks, Natick, MA).
Statistical Analysis
Statistical analysis was performed using Statistical Package
for the Social Sciences (SPSS), version 19.0. Sets of one-way
analyses of variance (ANOVAs) were used to analyze differ-
ences in age and cognitive function between the 3 groups.
Independent t-tests were used to compare disease severity
and duration and falls between PD subgroups.
Differences between groups in tied-belt walking condi-
tions were assessed using 3 × 2 (Group × Speed) repeated-
measures ANOVAs. To test the switching behavior, 2
separate (for the 2 legs) 3 × 3 (Group × Condition, ie, tied-
belt, switching, and reswitching) repeated-measures
ANOVAs were performed for each outcome. To assess dif-
ferences in adaptation and re-adaptation between groups,
time series of step length and time asymmetry were divided
into epochs of 10 strides (10 epochs per condition) for each
subject. Two separate (for adaptation and re-adaptation)
Group × Epoch repeated-measures ANOVAs were used.
Tukey’s post hoc testing was used for multiple comparisons
when appropriate. As an exploratory analysis, paired t-tests
with Bonferroni corrections were performed to compare the
values between the most and least impaired legs of patients
during split-belt walking. We also compared the differences
in step length asymmetry at the end of adaptation and re-
adaptation with slow tied-belt speed between PD groups
using independent t tests. Spearman correlations were used
to assess the relationship between gait measures and clinical
parameters. The α level was set at .05 to determine statistical
significance, except when using Bonferroni corrections.
Results
There were no statistically significant differences between
the groups in terms of age and overall cognitive function
(MMSE and MoCA; see Table 1). In addition, freezers and
non-freezers were matched for disease severity (UPDRS III
OFF) and disease duration. There were no significant dif-
ferences between the groups in Stroop performance.
Freezers had significantly more falls during the last 6
months, compared to non-freezers (P = .02).
Tied-Belt Conditions and Effect of Walking
Speed
Freezers walked with significantly smaller mean and higher
variability of limb excursion and larger asymmetry than
non-freezers, and non-freezers than controls in both speeds
(P < .05). Increasing speed decreased the variability of limb
excursion only in freezers (P = .01) and non-freezers (P =
.02). Step length asymmetry showed a significant decrease
with increasing walking speed only in freezers (P = .03).
Split-Belt Conditions: Sudden Switching and
Reswitching
Step length asymmetry was negative after the switch, due to
shorter step lengths of the fast leg. After reswitching, values
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Mohammadi et al 5
became positive, as the fast leg took longer steps. The
changes of asymmetry during both switching and reswitch-
ing were significantly larger in freezers (significant group
by condition interaction, P = .001) compared to non-
freezers (P = .001), and in non-freezers compared to con-
trols (P = .03).
Figure 2 shows the difference between the average limb
excursions for the last 5 strides of tied-belt walking and the
first 5 strides after the switch to split-belt condition (Figure
2A) and reswitch to tied-belt walking (Figure 2B). The
increase in excursion after switching was smaller in freezers
(significant group by condition interaction, P < .05), com-
pared to non-freezers (P = .001), and in non-freezers com-
pared to controls (P = .04). Following reswitching, freezers
had a larger decrease in excursion, compared to non-freezers
(P = .01), and non-freezers, compared to controls (P = .03).
Freezers had a greater decrease in limb excursions of the
contralateral (slow) leg compared to non-freezers and controls
(both P < .05). The exploratory analysis of the effect of
disease-dominance on these results revealed that the differ-
ences between the 2 limbs did not survive Bonferroni correc-
tions. There were no significant differences between step time
asymmetry of the groups during switching and reswitching.
Gait Adaptation During Asymmetrical Gait and
Re-Adaptation to Tied-Belt Condition
Figure 3 shows that freezers had a slower adaptation of step
length asymmetry following the switch to split-belt walking
compared to the reference groups and recovered symmetry
slower (significant interaction of group by epoch, P = .001).
Freezers had larger asymmetry for all epochs compared to
the other 2 groups (P = .001), but the asymmetry of controls
and non-freezers was only different for the first 4 epochs (P =
.01).
During re-adaptation, as can be seen in Figure 4, there
was a significant interaction of group by epoch (P = .001).
Freezers had larger asymmetry for all epochs compared to
the other 2 groups (P = .001), but there were also significant
differences between asymmetry values of controls and non-
freezers for the first 3 epochs (P = .01).
Exploratory analysis of the effect of disease-
dominance on the results did not survive Bonferroni
corrections in any of the epochs. In the freezer group,
differences in step length asymmetry at the end of adap-
tation and re-adaptation phases with tied-belt value were
larger than in non-freezers (P = .01 and P = .03, respec-
tively). There were no significant between-group differ-
ences for step time asymmetry during adaptation and
re-adaptation.
Relationship Between Gait Measures and
Clinical Parameters
A significant positive correlation was found between
changes in step length asymmetry following switching
and UPDRS III scores in all patients (r = .45, P = .03) and
FOGQ scores in freezers (r = .56, P = .02). Higher FOGQ
scores were also related to larger asymmetry values at the
end of adaptation (r = .72, P < .001). There was a strong
correlation between the retropulsion test (item 30 of
UPDRS III, a routine measure of postural instability) in all
patients with PD and step length asymmetry following
switching (r = .75, P < .001), indicating that worse perfor-
mance on the pull test (higher scores) are associated with
larger step length asymmetry. There was no significant
correlation between switching parameters and MoCA or
Stroop scores.
Freezing Episodes
One patient experienced FOG (Figure 5A) and another one
had a festination episode (Figure 5B), immediately after
speed switching from 3 to 4 km/h for the most affected leg.
Interestingly, the patients who showed these abnormalities
also had larger increases of step length asymmetry (0.19
and 0.29) following switching compared to the other freez-
ers (0.16 ± 0.04).
Table 1. Demographic and Clinical Characteristics of 10
Freezers, 12 Non-freezers, and 12 Controls (Mean and Standard
Deviation).
Parameter Controls Non-freezers Freezers P Value
Age (years) 61.9 (6.2) 62.5 (7.4) 60.4 (5.4) .34
Gender (male/
female)
8/4 8/4 8/2 N/A
Disease duration
(years)
N/A 11.9 (4.8) 14.6 (5.7) .20
H&Y OFF (II/III) N/A 8/4 4/6 N/A
UPDRS III OFF
(0-132)
N/A 34.6 (10.5) 38.1 (7.8) .67
Postural instability
subscale (0-4)
N/A 0.8 (0.4) 1.2 (1.1) .19
Disease-dominant
side (right/left)
N/A 4/8 4/6 N/A
NFOG-Q (0-28) N/A 0 20.1 (5.4) N/A
MMSE (0-30) 28.8 (1.0) 27.8 (1.2) 27.6 (1.8) .44
MoCA (0-30) 28.0 (0.9) 26.8 (2.3) 26.5 (2.5) .26
Error rate of
congruent
Stroop (%)
13.03 (25.05) 19.10 (27.77) 8.58 (3.40) 0.228
Error rate of
incongruent
Stroop (%)
18.94 (26.15) 26.57 (30.36) 12.18 (18.62) 0.442
Falls during the
last 6 months
N/A 0.3 (0.9) 3.2 (2.9) .02a
Abbreviations: H&Y, Hoehn & Yahr Rating Scale; UPDRS III, Part III of the Unified
Parkinson Disease Rating Scale; NFOG-Q, New Freezing of Gait Questionnaire;
MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment;
N/A, not applicable; Postural instability subscale, Retropulsion test, Item 30 of
UPDRS III.
aGroups significantly different using Mann–Whitney U test.
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6 Neurorehabilitation and Neural Repair
Discussion
The novel finding of our study was that freezers modified
their gait less well when responding to immediate switching
of gait speed at one belt, compared to non-freezers and con-
trols. Freezers also had a slower adaptation during split-belt
walking and the following tied-belt walking than the other
groups. Based on these results, we propose that freezers
have a primary switching deficit as reduced switching per-
formance was correlated to the severity of freezing and
induced festination and freezing. In addition, switching
problems may be exacerbated by the inability to adapt gait
Figure 2. Differences in limb excursion between the last 5 strides of tied-belt walking and the first 5 strides after switching (A)/
reswitching (B) and the changes in the other legs in freezers, non-freezers, and healthy controls. The mean values of the changes for
the most and least affected legs of patients and dominant and non-dominant legs of controls were shown. Vertical bars represent
standard error of measurements. *Significant difference at P < .05, **Significant difference at P < .01, ***Significant difference at P < .001.
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Mohammadi et al 7
with time, which in turn may contribute to more variable
and asymmetrical gait during tied-belt walking in freezers
compared to non-freezers.
Sudden Switching and Reswitching
Tied-belt conditions induced gait abnormalities that were
more prominent in freezers than in non-freezers, as has
been reported before.11,20 In this study, we aimed to com-
pare how PD subgroups adjust their gait following speed
switching while they were unaware of the upcoming switch,
causing an automatic gait perturbation. Motor switching
from tied to split-belt walking caused a rapid adjustment of
gait in all groups. These modifications were previously
reported in healthy elderly, young subjects, stroke patients,
and patients with cerebellar deficits.17,31,32 However, as we
Figure 4. Step length asymmetry during re-adaptation period in freezers, non-freezers, and healthy controls. Data are represented
by means of the 2 re-adaptation conditions. Values greater than zero mean longer step lengths of the fast leg. Vertical bars represent
standard error of measurements.
Figure 3. Step length asymmetry during adaptation period in freezers, non-freezers, and healthy controls. Data are represented
by means of the 2 adaptation conditions. Values smaller than zero mean shorter step lengths of the fast leg. Vertical bars represent
standard error of measurements.
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8 Neurorehabilitation and Neural Repair
hypothesized, freezers showed a more severe switching
impairment compared to the other 2 groups. Earlier studies
in the cognitive domain indicated switching deficits under
time pressure to be more pronounced in freezers than in
non-freezers. This was interpreted as a primary deficit of
automatic response processing, which did not allow timely
compensation by more consciously generated executive
responses.28 Interestingly in the current study, freezers and
Figure 5. (A) Example of a freezing episode with a nearly complete loss of step length. Data are shown from a trial in which speed
switching from symmetric walking to split-belt walking for the most affected leg (in gray) provoked a freezing episode. The freezing
episode caused a reduction of step length below 50% of the normal step length for both most affected and least affected (in black)
legs. (B) Example of festination gait after the switch from symmetric walking to split-belt walking for the most affected leg (in gray).
The pattern was maintained during the whole adaptation period without any improvement of step length asymmetry. The patient
showed a reduction of step length below 50% of the normal step length for the most affected leg.
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Mohammadi et al 9
non-freezers performed similarly on the MoCA and Stroop
test, suggesting that cognitive set-shifting, a component of
executive function, was similar in both groups. In addition,
the split-belt switching outcomes were not correlated with
MoCA and Stroop scores, suggesting that the main problem
of freezers was motor switching and independent of cogni-
tive function. Structural and functional disconnections
between frontostriatal pathways in freezers may reduce
freezers’ ability to keep the ongoing motor responses on-
line while adjusting the motor program, resulting in inflex-
ibility to shift from one response set to another.2,6,18 The
work of Shine et al33,34 demonstrated in a virtual reality
functional magnetic resonance imaging study that imposing
high versus low cognitive load in freezers overloaded the
information processing capacity of neural networks in
freezers. This lead to breakdown of motor function, which
was not apparent in non-freezers. These results were inter-
preted as associated with the diminished neural reserve in
freezers, as evidenced by a functional decoupling between
the basal ganglia and the cognitive control networks.34
Earlier split-belt treadmill studies in healthy controls
interpreted the adjustments following speed switching as
modifications of the postural control system.17,32,35,36 As
freezers did not differ in clinical characteristics from their
non-freezing counterparts, except for frequency of falling,
differences between groups may also be explained by the
reduced capacity for postural adjustment in freezers, which
was previously shown during sudden obstacle appearance14
or sudden changes to platform perturbations.37 Correlation
analysis confirmed a strong association between the switch-
ing deficit and the retropulsion test in the patients. Both the
basal ganglia38 and structures at brain stem level have been
reported to be involved in modulating postural adjustment
and gait control.39 In a recent study, Nonnekes et al40 found
a deficient automatic release of motor responses during the
StartReact test in both gait initiation and ankle dorsiflexion
in freezers only. They suggested that FOG could be due to
dysfunctional pontomedullary reticular formation networks
in conjunction with the pedunculopontine nucleus (PPN),
involved in integrating anticipatory postural adjustments
with a subsequent stepping response. Furthermore, it was
proposed that time-varying gait demands, such as the
switching task in this study, would further increase the com-
putational load on these structures, leading up to gait break-
down. Hence, the possible neural mechanisms underlying
the observed differences could be the differentially altered
neural activity in these brainstem regions in freezers versus
non-freezers, which is in line with recent neuroimaging
data.4
Adaptation and Re-Adaptation
We also aimed to compare gait adaptation of PD sub-
groups in response to asymmetrical walking and the
following symmetrical gait. The results confirmed our
hypothesis that the ability to adapt the gait pattern would
be different for freezers during both phases, although
reverting back to symmetrical tied-belt gait was less
severely affected.
The reduced ability to adjust gait during both adaptation
and re-adaptation in split-belt paradigms has traditionally
been ascribed to functions of the cerebellum.17,32 A recent
review suggested that altered cerebellar activity is impli-
cated as part of the compensatory networks to generate
movement in patients with PD.21 Besides, the cerebellum
and its projections to the brainstem and basal ganglia are
also thought to be part of the so-called indirect gait pathway
involved in modulating complex gait.22 The deficient gait
adaptation found in freezers could be related to reduced
structural connectivity between the brainstem (PPN in par-
ticular) and the cerebellum,7 which was recently highlighted
using diffusion tensor imaging.6 Alternatively, the greater
adaptation difficulties in freezers could be interpreted as a
greater reliance on cerebellar compensatory function, which
may have reached a ceiling effect earlier in freezers than in
non-freezers.
Nanhoe-Mahabier et al20 reported increased stride time
variability during split-belt walking for freezers, but no dif-
ferences in spatial measures between PD subgroups. These
discrepant results may be explained by differences in calcu-
lating the gait parameters and the fact that they excluded the
first 30 seconds of switching and analyzed the 10 consecu-
tive strides. It has been suggested that at least 50 consecu-
tive steps are needed to have an accurate measure of gait
variability.41 Furthermore, variability is not a greatly useful
measure in split-belt walking, when the mean is slowly
changing. Although freezers and non-freezers were well-
matched for disease severity in this study, their patients had
lower UPDRS scores and the freezers had lower NFOG-Q
scores compared to the patients in the current study.
Roemmich et al36 investigated long-term adaptation and
aftereffects during split-belt conditions of patients with PD
in the ON state (the slow speed was 50% of the fast speed).
PD patients and their matched controls adapted their gait in
the same manner as reported in the current study. However,
patients did not improve their gait asymmetry as in our
study, which may reflect medication state and different dis-
ease profiles.
In this study, FOG episodes were rare, which is not an
uncommon finding in FOG research in general1,42 and dur-
ing treadmill walking in particular.14,20 Low freezing rates
may be due to the fact that the treadmill acted as an external
pacemaker.43 Also, split-belt walking is different from real
asymmetric gait during turning, which requires head and
trunk rotation to achieve a directional change.20 It is of note
that the episodes could be predicted by the response to
switching, in that patients with greater adaptive difficulties
also tended to have FOG.
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10 Neurorehabilitation and Neural Repair
Our results may have implications for rehabilitation of
freezers. Split-belt treadmill training has been used to
improve symmetry in stroke patients.17 The authors found
that this improvement maintained with repeated exposures
and partially transferred to over-ground walking.44 Such a
training protocol could be used for freezers as it may
enhance the perception of leg speed and remedy gait asym-
metry. Repetitive exposure to a split-belt treadmill may also
be helpful to facilitate rapid adjustments and gait adaptation
to novel situations. In addition, this form of implicit error-
based motor learning could enhance the involvement of the
cerebellum. These suppositions warrant further research.
Concluding, the results of the current study showed that
fast switching to asymmetrical walking was more affected
in patients with FOG compared to their non-freezing coun-
terparts. Although it is difficult to distinguish between
switching deficits and asymmetry problems in our study (as
switching and asymmetrical walking happened simultane-
ously), the results strongly suggest that switching is a pri-
mary deficit in freezers. In addition, freezers showed more
difficulty with slow gait adaptation to asymmetrical walk-
ing. These results are robust as subgroups were matched for
disease severity and cognitive ability. The findings point to
future rehabilitation interventions targeting these switching
deficits using split-belt training.
Acknowledgments
The authors would like to thank Jasper Van der Donck, Aniek
Bengevoord, and Pieter Ginis for their help with data collection.
With great sadness we want to acknowledge the death of Farshid
Mohammadi, the main author of this paper, on the 23rd of August
2014. He was a much appreciated colleague.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received the following financial support for the
research, authorship, and/or publication of this article: This research
was funded by the European Commission through MOVE-AGE, an
Erasmus Mundus Joint Doctorate Program (2011-2015), awarded to
Alice Nieuwboer, Gert Kwakkel and Erwin E. van Wegen.
Additional support for this study was provided through a grant from
the Research Council of KU Leuven, Belgium (contract OT/11/091).
Sjoerd M. Bruijn was supported by an F.W.O grant (G.0901.11) to
J. Duysens, and a grant from the Netherlands Organization for
Scientific Research (NOW#451-12-041).
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