J Neural Transm (2013) 120:543–557
DOI 10.1007/s00702-012-0964-y
NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE
Cognitive aspects of freezing of gait in Parkinson’s disease:
a challenge for rehabilitation
Elke Heremans • A. Nieuwboer • J. Spildooren
J. Vandenbossche • N. Deroost • E. Soetens •
E. Kerckhofs • S. Vercruysse
•
Received: 29 September 2012 / Accepted: 19 December 2012 / Published online: 18 January 2013
Ó Springer-Verlag Wien 2013
Abstract Freezing of gait (FOG) is a very disabling
symptom affecting up to half of the patients with Parkinson’s disease (PD). Evidence is accumulating that FOG is
caused by a complex interplay between motor, cognitive
and affective factors, rather than being a pure motor phenomenon. In the current paper, we review the evidence on
the specific role of cognitive factors in FOG. Results from
behavioral studies show that patients with FOG experience
impairments in executive functioning and response selection which predict that motor learning may be compromised. Brain imaging studies strengthen the neural basis of
a potential association between FOG and cognitive
impairment, but do not clarify whether it is a primary or
secondary determinant of FOG. A FOG-related reduction
of cognitive resources implies that adaptation of rehabilitation interventions is indicated for patients with FOG to
promote the consolidation of learning.
Keywords Freezing of gait Parkinson’s disease Cognition Rehabilitation
stooped posture, impaired balance and freezing of gait
(FOG). Clinically, FOG is defined as a ‘‘brief, episodic
absence or marked reduction of forward progression of the
feet despite the intention to walk’’ (Giladi and Nieuwboer
2008; Nutt et al. 2011). More and more evidence is
emerging that this phenomenon is not a motor problem
alone but rather represents motor, cognitive and affective
deficits, which may reinforce each other (Giladi and
Hausdorff 2006).
Because FOG is only responsive to dopaminergic
treatment up to a point, patients with FOG are often
referred to rehabilitation services. However, the very
complexity of FOG and its non-motor correlates pose a
challenge for learning-based interventions. The current
paper reviews the recent evidence on the role of cognitive
factors in the manifestation of FOG, and discusses their
impact on rehabilitation approaches for this clinical phenomenon. In addition, a review of the evidence of rehabilitation effects on FOG will be presented.
Clinical characteristics of FOG
Introduction
Patients with Parkinson’s disease (PD) typically show
prominent mobility problems such as shuffling gait,
E. Heremans (&) A. Nieuwboer J. Spildooren S. Vercruysse
Department of Rehabilitation Sciences, Katholieke Universiteit
Leuven, Tervuursevest 101, 3001 Heverlee, Belgium
e-mail: [email protected]
J. Vandenbossche N. Deroost E. Soetens E. Kerckhofs
Cognitive Psychology, Vrije Universiteit Brussel, Brussels,
Belgium
FOG is a common problem in PD, affecting about 50 % of
PD patients, and up to 80 % in the advanced stages (Morris
et al. 2008; Tan et al. 2011). It is a highly debilitating
symptom, as it may lead to falls, decrease quality of life
and induce loss of independence (Bloem et al. 2004; Moore
et al. 2007). It occurs both during OFF and ON medication
and generally has a complex response to levodopa treatment (Giladi and Nieuwboer 2008) and surgical intervention (Ferraye et al. 2008).
FOG is an episodic phenomenon, which can be triggered
and relieved by a number of factors, some of which are of a
cognitive origin. It occurs most frequently when subjects
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turn, start walking, pass through narrow doorways, negotiate obstacles or reach their destination (Almeida and
Lebold 2010; Cowie et al. 2012; Nutt et al. 2011;
Schaafsma et al. 2003; Snijders et al. 2012; Spildooren
et al. 2010). All these circumstances require a flexible
adaptation of the gait pattern, usually demanding an elevated level of attention. Not surprisingly, when patients are
asked to perform a secondary task while walking (dual
tasking), the risk for FOG further increases (Giladi and
Hausdorff 2006; Rahman et al. 2008). This was shown
specifically when 360° turning in combination with an
auditory response task was required and proved the most
important trigger for freezing (Snijders et al. 2012; Spildooren et al. 2010). Although not part of this review,
emotional factors such as stress or anxiety also play a role
in triggering FOG episodes (Giladi and Hausdorff 2006;
Moreau et al. 2008). This may explain why in daily life
FOG is often experienced in crowded areas or when trying
to reach a ringing telephone. On the other hand, emotion
and excitement sometimes reduce FOG and strategies
involving focused attention and external stimuli (cueing)
have also been shown to improve it (Nieuwboer et al. 2007;
Snijders et al. 2008). The fact that many of the factors that
precipitate and ameliorate FOG are of a cognitive origin
substantiates the idea that cognition plays a significant role
in the occurrence of FOG.
Etiology of FOG as a multisystem deficit
Current thinking about the origins of FOG has shifted from
a pure motor to a multisystem deficit (Giladi and Hausdorff
2006). Lewis and Barker (2009) ascribed this multisystem
involvement to the possibility of a greater reduction of the
normal segregation of basal ganglia (BG) loops. They
postulated that normally, the highly specified circuits of
the BG allow an integrative function of cognitive, motor
and affective commands for behavioral control. PD may
distort the neurochemical and neurophysiological balance between these anatomical subregions. As a result,
increased infiltration of non-motor information may disrupt
the BG motor loop and cause momentary movement
breakdown in freezers and not in non-freezers.
Since FOG is only partly affected by dopaminergic
medication, it has also been hypothesized that non-dopaminergic pathways are particularly involved in FOG (Nutt
et al. 2011). This line of thinking stems from increasing
evidence that cholinergic pathways of the pedunculopontine nucleus (PPN) in the brainstem and the nucleus basalis
of Meynert constitute the basis of dopa-resistant gait disorders, falls and cognitive dysfunction, as well as their
interplay (see Yarnall et al. 2011 for review). Recent
neurosurgical (Ferraye et al. 2010; Thevathasan et al. 2011)
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E. Heremans et al.
and neuroimaging studies of the PPN (Schweder et al.
2010; Snijders et al. 2011) support a role of brainstem
abnormalities in the origins of FOG. The exact underlying
neurochemical mechanisms, however, await further
investigation.
Somewhat counterintuitive to the idea that brainstem
locomotor centers play a central role in the etiology of
FOG, are the findings that freezing occurs in other movements than in gait. This work highlights that the kinematic
patterns of motor blocks occurring during upper limb
movements resemble those of freezing during gait (Vercruysse et al. 2012a). It points to the possibility that FOG is
not only multisystem but also generic in nature, affecting
the control of the timing-amplitude of repetitive movements more widely than hitherto acknowledged.
Behavioral evidence of cognitive impairments
in patients with FOG
Several behavioral studies have shown differences in the
cognitive profile of PD patients with FOG in comparison to
healthy controls and patients without FOG. Table 1 provides an overview of studies addressing these group differences when assessed in sitting and during ambulation. In
these studies, cognitive function was tested with global
cognitive screening tests and/or specific executive function
tests, examining the response to working memory load and
visuospatial challenges.
Evidence of global cognitive decline in patients
with FOG
As shown in Table 1, several studies found that global
cognitive decline was more pronounced in freezers compared to non-freezers when assessed by the Mini Mental
State Examination (MMSE) and the Scales for outcomes
in Parkinson’s disease-cognition (SCOPA-COG) (Kostic
et al. 2012; Spildooren et al. 2010; Vandenbossche et al.
2011, 2012a, 2012b; Vercruysse et al. 2012a). These
studies offer support for a relationship between FOG and
global cognitive dysfunctioning. However, caution is
warranted, as not all studies confirmed these findings
(Amboni et al. 2008; Naismith et al. 2010; Tessitore et al.
2012a) and results from some studies are ambiguous
because subject numbers were small (see Table 1 for an
overview). Importantly, clinical matching of subgroups
was sometimes incomplete or not reported (Kostic et al.
2012; Naismith et al. 2010). FOG typically occurs more
often during the advanced stages of the disease. Therefore,
studies that did not match for disease severity, such as the
ones by Kostic et al. (2012) and Naismith et al. (2010),
do not allow drawing conclusions about the selective
Participants
Naismith et al.
(2010)
Amboni et al.
(2010)
Worse MMSE and SCOPA-COG scores
Main results PD with FOG vs. PD without FOG
ON medication (6
drug naı̈ve) Selfreported FOG
14 FRs
No info
Verbal fluency
Spatial planning
Rule acquisition and
reversal
CANTAB
CANTAB IED stage
Digit span backwards
Verbal fluency test
Set-shifting
Working memory
TMTB
Visuomotor speed
Global cognition
TMTA
MMSE
2-year follow-up of Amboni et al. 2008
14 NFRs
Conflict resolution
Spatial programming
TPCPT
Stroop test (II and III)
Sequencing, planning,
inhibition
FAB
Verbal fluency
Verbal fluency test
12 FRs
17 NFRs
Self-reported ONstate FOG
ON medication
Global cognition
MMSE
TMTB higher correlation with FOGQ than TMTA
FOGQ (including both FRs and NFRs)
Worse TMTA&B scores associated with higher
4 FRs developed dementia
Worse TMTA&B in FRs
Worse scores in FRs, not in NFRs
Worse scores (including both FRs and NFRs) associated
with higher FOGQ
Worse scores on all tests (except MMSE and Stroop III)
SCOPA-COG score independent contributor of FOG in
multivariate model
Global cognition
Cognitive domain
Cognitive scores not correlated with FOGQ in freezer group
MMSE and SCOPA-COG
Assessment
Confirmed FOG
Similar disease duration
and severity
Similar disease severity
Matching
ON medication
23 FRs
24 NFRs
Executive functions
15 NFRs
Amboni et al.
(2008)
13 FRs
Vercruysse
et al. (2012a)
Global cognitive functions
Cognitive functions assessed while sitting
Article
Table 1 Overview of behavioral evidence of cognitive deficits in PD patients with FOG compared to PD patients without FOG
Cognitive aspects of freezing of gait in Parkinson’s disease
545
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123
Vandenbossche
et al. (2012a)
Vandenbossche
et al. (2012)
Vandenbossche
et al. (2011)
Article
Table 1 continued
14 CTRL
14 FRs
14 NFRs
Self-reported FOG
ON medication
14 CTRL
14 FRs
14 NFRs
Self-reported FOG
(ANT in ON and
OFF)
ON medication
10 CTRL
11 FRs
11 NFRs
Participants
Similar disease severity
(in OFF)
Similar disease severity
(in OFF)
Similar disease duration
and severity (in OFF)
Matching
Verbal fluency
Alerting, Orienting and
Executive (conflict
resolution) control
COWAT
ANT
Mental flexibility
Verbal Fluency
Implicit learning (IL)
IL under working
memory load
COWAT
SRT
SRT with DT
Alerting, Orienting and
Executive (conflict
resolution) control
Global cognition
Conflict resolution
Brixton Spatial Anticipation
Test
MMSE and SCOPA-COG
ANT
Manual Stroop test
Global cognition
Mental flexibility
Brixton Spatial Anticipation
Test
MMSE and SCOPA-COG
Problem solving
Problem solving
Global cognition
Cognitive domain
Wechsler Adult Intelligence
Scale–III
Matrix Reasoning subtest
MMSE and SCOPA-COG
Assessment
FRs showed impaired implicit sequence learning, especially
under DT conditions
MMSE and SCOPA-COG worse in FRs
Conflict resolution impairment in FRs in the ANT executive
control network (not evidenced by the Stroop test)
Attention subitems of SCOPA-COG lower in FRs
Medication improved orienting network RTs in FRs and
NFRs
No other group differences
FRs had impairment in executive control network of ANT
(conflict resolution) in ON and OFF
MMSE worse in FRs
Main results PD with FOG vs. PD without FOG
546
E. Heremans et al.
Nantel et al.
(2012)
Kostic et al.
(2012)
Tessitore et al.
(2012a, 2012b)
Article
Table 1 continued
Visual reasoning
Visuospatial processing
Matrix Reasoning subtest
Block design subtest
Confirmed FOG
Set-shifting
Set-shifting
Initiation/preservation
Wisconsin Card Sorting
Set-shifting
Sequencing, planning,
inhibition, visuospatial
abilities
Sequencing, planning,
inhibition
Attention, memory,
fluency, language,
visuospatial abilities
ON medication
18 FRs
11 NFRs
TMTB
EXIT-25
Self-reported FOG
OFF medication
Similar disease severity
(in OFF)
Attention
Cancellation attentional
matrices
MMSE
Global cognition
Spatial programming
TPCT
ACE-R
Verbal fluency
Sequencing, planning,
inhibition
FAB
Conflict resolution
Abstract non-verbal
reasoning
RCPM
Stroop test
Apraxia
CA
Verbal fluency test
Immediate and delayed
recall
Spatial/verbal memory
Global cognition
Cognitive domain
Rey auditory 15 word
learning test
Spatial and verbal span test
MMSE
Assessment
FAB
Similar disease duration
and stage, not severity
(in OFF)
Similar disease duration
and severity
Matching
34 CTRL
17 FRs
20 NFRs
Self-reported FOG
ON medication
15 CTRL
16 FRs
13 NFRs
Participants
Stronger correlation between MR and BD with FOG
severity compared to other EF tests
Worse scores on Matrix Reasoning (MR) and Block Design
Tests (BD) in FRs
FOGQ correlated to verbal fluency and visuospatial
subscores of ACE-R and FAB and EXIT-25 total scores
(including both FRs and NFRs)
FRs showed worse scores on MMSE and EXIT-25 and
tended to have poorer ACE-R and FAB performance
Worse scores on Rey immediate recall, FAB, Verbal
fluency and TPCT in FRs
Main results PD with FOG vs. PD without FOG
Cognitive aspects of freezing of gait in Parkinson’s disease
547
123
Participants
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Cowie et al.
(2012)
Almeida and
Lebold (2010)
16 NFRs
Self-reported FOG
STN-DBS
ON and OFF
ON and OFF
medication
10 CTRL
10 FRs
Confirmed FOG
/
Perceptual task: passage
judgment
Doorway scaled at 125 %
Doorway scaled at 150 %
Doorway scaled at 100 % of
shoulder width
1 turning condition (360°) 4
straight walking conditions:
No doorway
Normal doorway
Wide doorway
ON medication
Narrow doorway
3 walking conditions:
16 CTRL
16 FRs
Matched for disease
duration and severity
SCOPA-COG
Self-reported FOG
DT = color classification
task also:
Turning 0°–180°–360° with
or without DT
6 walking conditions:
DT = mental arithmetic task
Backward ? DT
Forward ? DT
Backward
Forward
4 walking conditions:
Assessment
MMSE
Matched for disease
duration and severity
(in ON)
Matched for disease
severity (in ON)
Matching
Gait tests: OFF and
cognitive tests: ON
medication
14 CTRL
14 FRs
14 NFRs
Self-reported FOG
ON medication
74 CTRL
35 FRs
43 NFRs
Visuospatial/visuomotor functions
Spildooren et al.
(2010)
Hackney and
Earhart (2009)
Dual tasking
Cognitive functions assessed while walking
Article
Table 1 continued
Perceptual processing
while sitting
Perceptual processing
during gait
Perceptual processing
during gait
Global cognition
Global cognition
Dual tasking
Dual tasking
Cognitive domain
Number of freezing events
No group differences in perceptual performance while
sitting
Greater gait alterations in FRs vs CTRL
Increased step duration variability
Reduction of doorway width induced:
Increased step length variability
Reduced step length
Only in FRs in narrow doorway passages:
No correlation between SCOPA-COG, DT interference and
actual FOG (including only FRs)
MMSE and SCOPA-COG (attention subitem) worse in FRs
Cognitive performance on DT of FRs worse than NFRs and
worsened during 360° turning vs 0°
DT doubled the number of FOG episodes during 360°
turning (no effect on 0° or 180° turning)
DT increased the number of steps only in FRs
Gait variables of FRs more affected by backward direction
and dual tasking
FRs tended to make more errors on mental arithmetic task
Main results PD with FOG vs. PD without FOG
548
E. Heremans et al.
Imagery task: imagined and
actual doorway passing
Self-reported FOG
OFF medication
10 CTRL
PD Parkinson’s disease, FOG freezing of gait, FRs freezers, NFRs non-freezers, MMSE Mini Mental State Examination, TMTA Trail Making test part A, TMTB Trail Making test part B,
CANTAB Cambridge Neuropsychological Test Automated Battery, IED Intra-Extra Dimensional task, COWAT Controlled Oral Word Association Test, ANT attention network test, DT dual
task, ACE-R Addenbrooke’s Cognitive Examination–Revised, FAB frontal assessment battery, EXIT-25 Executive Interview, SRT serial reaction time, SCOPA-COG Scales for Outcomes of
Parkinson’s disease-Cognition
FRs showed a mismatch between imagined and actual
walking through doorways
Motor imagery ability
Doorways scaled at varying
widths depending on
shoulder width
No group differences in perceptual judgment
Perceptual processing
while standing
Passability judgment
experiment:
Matched for disease
duration, not for
disease severity
13 NFRs
11 FRs
Cohen et al.
(2011)
Article
Table 1 continued
Participants
Matching
Assessment
Cognitive domain
Main results PD with FOG vs. PD without FOG
Cognitive aspects of freezing of gait in Parkinson’s disease
549
contribution of cognition to FOG. In addition, Spildooren
et al. (2010) found that although freezers had significantly
worse MMSE and SCOPA-COG scores than controls and
non-freezers, no correlations were observed between the
actual number and duration of FOG-trials and these global
cognitive outcomes.
Evidence of executive dysfunction in patients
with FOG
Table 1 also shows that a variety of specific cognitive
deficits were found in freezers in several domains of
executive functioning (EF) (Amboni et al. 2008; Kostic
et al. 2012; Naismith et al. 2010; Vandenbossche et al.
2011; Vandenbossche et al. 2012b; Tessitore et al. 2012a).
EF is well-documented in PD in general but may be particularly connected to FOG. EF is an umbrella term for a
set of abilities, involving inhibition, switching and updating, which guide behavior towards goals (Kudlicka et al.
2011; Miyake et al. 2000). From a cognitive psychology
perspective, EF has been conceptualized in a model of
working memory where a central executive system flexibly
controls and regulates attentional resources to multiple
facets of an ongoing task (Baddeley 2000; Baddeley and
Hitch 1974). A recent review concluded that medium to
large differences were apparent when comparing nondemented PD patients with controls on the five most
commonly used tasks for EF: verbal fluency tasks, digit
span, card sorting tests, Stroop tests, Tower tests and Trail
Making Tests (Kudlicka et al. 2011). As for the comparison
between patients with and without FOG, Amboni et al.
(2008) showed that FOG is related to cognitive frontal
dysfunction and that FOG severity was negatively correlated to executive test performance. The same group
(Amboni et al. 2010) also compared the progression of
cognitive dysfunction in 26 patients with and without FOG
over a 2-year follow-up period. They found that FOG was
correlated to a faster progression, while the cognitive status
of the non-freezers remained unchanged over this time
span. More recent studies (Kostic et al. 2012; Naismith
et al. 2010; Tessitore et al. 2012a) confirmed the potential
relationship between executive dysfunction and FOG using
a variety of tests that evaluated sequencing, planning,
spatial programming and other typical EF domains. As
pointed out above, however, interpretation of the results of
Kostic et al. (2012) and Naismith et al. (2010) is hampered
by the lack of matching between patients with and without
FOG for disease severity.
As for the question which executive dysfunction test is
mostly related to FOG, Naismith et al. (2010) reported
specific difficulties in set-shifting in patients with FOG as
measured by the Trail Making Test, while other executive
domains had weaker associations. This finding coincides
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clinically with the observation that FOG may be due to a
reduced ability to shift from one response set to another.
Recent results on FOG-related impaired inhibition of
unwanted responses and response selection under conflict
(jointly called conflict resolution) support and refine this
hypothesis (Vandenbossche et al. 2011, 2012b). In addition, problems in the executive domain have been shown to
extend to difficulties with automatic, implicit motor
learning (Vandenbossche et al. 2012a). Implicit sequence
learning deficits were more prominent in freezers during
single task learning than in non-freezers, and worsened
during dual-task conditions, which was explained by the
extra supplementary load placed on working memory
capacity during dual tasking. This body of work suggests
that there is an imbalance between automatic and controlled response selection processes in patients with FOG,
which may lead to a breakdown in both motor and cognitive response control (Vandenbossche et al. 2012a).
Evidence of visuospatial impairment in patients
with FOG
FOG has also been associated with impaired visuospatial
abilities (Giladi and Hausdorff 2006). Table 1 shows that
Almeida and Lebold (2010) found that walking towards
and passing through a doorway is more affected in freezers
than non-freezers, especially in narrow doorways. Freezing
may possibly be the result of an impaired visuospatial
ability that interferes with online movement planning. This
was partly confirmed by Cowie et al. (2012), showing that
freezers dramatically slowed their gait when approaching a
doorway. Most recently, Nantel et al. (2012) reported that
visuospatial tests discriminated freezers from non-freezers
better than tests for executive function and were more
strongly associated with severity and metrics of FOG.
However, no differences were found between PD patients
with and without FOG in the perceptual judgment of
doorway size while sitting (Cohen et al. 2011) or standing
(Cowie et al. 2012), contradicting that a lack of visuospatial ability per se would be primarily responsible for FOG.
Inconsistencies of current findings
Inconsistent findings with regard to the occurrence of
cognitive impairments in patients with FOG can partly be
attributed to specific limitations of the above-mentioned
studies. First, most of the studies summarized in Table 1
base the distinction between patients with and without
FOG on self-report, which was not experimentally verified
(Amboni et al. 2008, 2010; Cohen et al. 2011; Cowie et al.
2012; Kostic et al. 2012; Naismith et al. 2010; Vandenbossche et al. 2011, 2012b; Tessitore et al. 2012a). Historytaking from the patient or caregiver cannot always reliably
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E. Heremans et al.
determine whether a patient has FOG or not and supplementary objective tests are recommended (Nieuwboer et al.
2009a; Snijders et al. 2008). Second, a large variety of
cognitive tests have been used, and as a result findings may
be test-specific. Third, cognitive tests are often performed
in sitting, which might bring about different results than in
walking. Table 1 shows that two studies examined freezers’ ability to perform a secondary cognitive task while
walking (Hackney and Earhart 2009; Spildooren et al.
2010). Collectively, the findings indicate that dual tasking
had a more dramatic effect on gait parameters in patients
with FOG compared to those without. Future assessment of
cognitive processing during actual locomotor control as
well as in sitting may aid in understanding the primary
versus secondary nature of cognitive impairment in FOG.
Fourth, disease duration and severity were not always
adequately matched and may have had a confounding
influence on test performance (Cohen et al. 2011; Kostic
et al. 2012; Naismith et al. 2010). Fifth, correlation analysis
between cognitive variables and freezing severity was
mostly univariate and often included both freezer and nonfreezer groups. To investigate the relative contribution of
cognitive factors to the occurrence of FOG, multivariate
analysis, including motor and/or affective domains, has to
be considered in conjunction. Recently, we performed a
multivariate regression analysis on patients with and
without confirmed FOG matched for age and disease
severity (Vercruysse et al. 2012b). We studied cognitive,
motor and disease determinants. Interestingly, the results
showed that cognitive impairment was one of four independent determinants of FOG, but it explained less variance in the model compared to non-gait freezing (freezing
during other repetitive movements) and patients’ levodopa
equivalent dose.
To conclude, some of the above-mentioned studies
provide evidence that global cognitive functioning as well
as executive functioning may be more severely impaired in
freezers than non-freezers. Disease severity, however,
cannot entirely be ruled out as a possible contributing
factor as some of the studies did not match for this factor.
Set-shifting and conflict resolution seem particularly
involved and may play a primary role in FOG-eliciting
situations that require task prioritizing (e.g., dual-task
conditions) or a flexible adaptation of the gait pattern.
At present, it is not clear whether the detrimental contribution of cognitive impairment to FOG works through
reducing the compensatory capacity of the brain to maintain motor control, as patients with PD are known to
allocate attention to counteract the effects of reduced
automaticity. It has been suggested in a recent model of
FOG that an accumulation of several mild background gait
abnormalities may bring overall gait performance closer to
an imaginary threshold for susceptibility to FOG (Plotnik
Cognitive aspects of freezing of gait in Parkinson’s disease
et al. 2012). Reduced cognitive reserve to oppose these
motor abnormalities may thus bring patients closer to the
freezing threshold. Alternatively, specific cognitive deficits
may also be responsible for an inappropriate response to
environmental triggers, resulting in a so-called simultaneous mental and motor collapse (Moreau et al. 2008).
Neuroimaging evidence of cognitive impairments
of patients with FOG
Several neuroimaging studies have pointed to disturbances
in several FOG-related brain areas, amongst which feature
the orbitofrontal cortex, posterior cortical areas, supplementary motor cortex, midbrain locomotor region (MLR),
the pedunculopontine nucleus (PPN) and the cerebellum
(Nutt et al. 2011). In addition, recent brain imaging work
has highlighted the potential relationship between FOG and
cognitive neural circuits. Matsui et al. (2005) reported
decreased resting regional cerebral blood flow in the
orbitofrontal cortex [Brodmann area (BA) 11] in patients
with FOG compared to those without. The perfusion rate in
this limbic area, considered to be involved in reward and
reinforcement learning, was shown by single photon
emission computed tomography (SPECT) and correlated
with FOG severity. Imamura et al. (2012) confirmed that a
decreased perfusion was present bilaterally in BA10 and 11
and the left BA32 in patients with FOG. Bartels et al.
(2006) recorded hypometabolism in the posterior cortical
areas, predominantly in the right parietal cortex, in a
cluster representing the secondary sensory area S-II of the
parietal operculum in freezers. Furthermore, they found
lower caudate 18[F]-6-fluoro-L-dopa and 18[F]-fluordesoxyglucose uptake in freezers using positron emission
tomography (PET).
A recent combined functional magnetic resonance
imaging (fMRI) and voxel-based morphometry study
investigating FOG during motor imagery of gait indicated
differences between patients with and without FOG in
brain areas with a predominantly sensory-motor function,
such as the supplementary motor cortex and the MLR, just
dorsomedial to the PPN (Snijders et al. 2011). In contrast,
Kostic et al. (2012) reported a distributed pattern of gray
matter (GM) atrophy in non-motor fronto-occipital areas,
including the dorsolateral prefrontal, medial and lateral
temporal, inferior parietal and occipital cortices in patients
with FOG compared to their non-freezing counterparts.
The behavioral measures of the patients indicated that the
severity of FOG correlated with frontal executive deficits.
Structural damage to the frontal and parietal cortices in
patients with PD was also shown to be associated with
impairment of cognitive functions in PD, irrespective of
FOG (Huang et al. 2007). Additional evidence for a
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cognitive hypothesis of FOG was found by Tessitore et al.
(2012a, b) showing a relationship between FOG and GM
atrophy and resting state MRI changes in the right frontoparietal regions and the right occipito-temporal gyrus in
freezers.
In sum, the above-mentioned studies indicate that
patients with FOG may have a distinct neurocognitive
profile, which is reflected by corresponding alterations in
brain activation. These data do not allow interpretation of
whether these alterations reflect possible primary pathological origins of FOG or whether they reflect a lack of
secondary compensatory mechanisms to overcome the
freezing episodes.
Evidence on motor rehabilitation and FOG
Gait rehabilitation in PD implies the deployment of compensatory methods to ensure preserved or improved performance by use of alternative neural circuits to generate
walking. Consolidation and retrieval of these compensatory
strategies are pivotal if a robust training effect with impact
on daily life is to be achieved. Application and learning of
these strategies assume sufficiently preserved cognitive
abilities. Two commonly used compensatory strategies in
relation to FOG are: (1) providing patients with external
stimuli (cues) to prompt movement and (2) allocating
attention to specific gait components to prevent or overcome movement breakdown (Morris et al. 2009). Both
methods are based on shifting the patients’ motor control
from an automatic to an external or attention-demanding
modus of control. This helps to focus on alternative goaldirected behavior, so that resetting of the motor system is
possible to avoid or alleviate FOG (Nutt et al. 2011;
Redgrave et al. 2010). However, as discussed previously,
there are indications that patients with FOG suffer from
impaired cognition, and especially executive dysfunction
(see Table 1 for an overview). Although this has not
directly been investigated yet, it can be assumed that these
dysfunctions may lead to difficulties in employing attention-demanding compensatory strategies and would predict
that particularly patients with FOG may be less able to
retrieve these methods.
Table 2 summarizes the evidence on rehabilitation
interventions with FOG as a primary or secondary outcome. The first part of this table includes studies evaluating
the effects of on-line rhythmic auditory or visual cueing to
reduce FOG in one experimental session. In 6 out of the 10
studies reviewed, FOG frequency reduced in response to
cueing. Typically, in the four negative studies, FOG was
measured during ON and as a result probably occurred at a
too low frequency at baseline to be sensitive to change.
Three studies actually compared the response to cueing in
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552
E. Heremans et al.
Table 2 Overview of rehabilitation interventions targeted to reduce FOG
Article
Design
Treatment
Outcome on FOG
Pre-post
Randomized:
8 FRs
Parallel lines
FOG episodes reduced when stepping
over parallel lines during complex gait
Studies on the immediate effect of cueing
Dietz et al. (1990)
ON/OFF unclear
Modified inverted stick
Normal stick
Baseline
Kompoliti et al. (2000)
Pre-post
Randomized:
28 FRs with ON-
Laser beam stick
FOG
Modified inverted stick
No effect on FOG episodes during
complex gait
During ON
Baseline
Willems et al. (2006)*
Pre-post
10 FRs ? 10 NFRs
Randomized:
Baseline (first trial)
During ON
Aud cue at 5 frequencies
Gait speed improved in FRs ? NFRs
Nieuwboer et al. (2009b)*
Pre-post
Randomized:
8 FR froze during the protocol
68 FRs ? 65 NFRs
Baseline (first trial)
FOG in 69 % of baseline trials
During ON
Vis cue
FOG in 42 % of cued trials
Aud cue
(complex gait)
Arias and Cudeiro, (2010)
No FOG was registered during testing
(straight-line gait)
Somatosensory cue
Gait speed improved in FRs ? NFRs
Second baseline (last trial)
Cue withdrawal similar in FRs ? NFRs
Pre-post
Baseline
10 FRs
Aud cue (110 %)
Decreased number and mean duration of
FOG episodes during complex gait
‘‘End of dose’’
Bächlin et al. (2010)
10 FRs
Aud cue when FOG was detected
Subjective improvement in number and
duration of FOG episodes in 5 patients
during complex gait
Pre-post
Randomized:
No FOG was registered during testing
15 FRs
Baseline
During OFF
Lebold and Almeida,
(2010)
During ON
Parallel lines
Laserlight inducing dynamic flow
Griffin et al. (2011)
Pre-post
Baseline
FOG occurred only during OFF
19 PD of which 7 FRs
Decreased number of FOG episodes by
parallel lines but not by rhythmic cueing
During ON and
Placebo virtual reality glasses
(VRG)
Visual flow VRG
OFF
Rhythmic cueing VRG
Parallel lines
Second baseline
Nanhoe-Mahabier et al.
(2012)*
Pre-post
Treadmill walking
8 FRs ? 11 NFRs
Baseline
No FOG was registered during testing on
treadmill with and without obstacles
During OFF
Aud cue
Gait speed improved in FRs ? NFRs
Obstacle avoidance
Aud cue ? obstacle avoidance
Lee et al. (2012)
Pre-post
Randomized:
15 FRs
Baseline (first)
During OFF
Vis cue
Aud cue
123
Reduced FOG frequency using vis and
Aud cue during straight-line gait
Cognitive aspects of freezing of gait in Parkinson’s disease
553
Table 2 continued
Article
Spildooren et al. (2012)*
Design
Treatment
Outcome on FOG
Pre-post
Randomized:
Reduced FOG frequency during cued
turning
16 FRs ? 14 NFRs
Baseline (first)
Return of FOG after cue withdrawal
During OFF
Aud cue
Turn normalized during cueing in both
groups
One week home training with
metronome
No effect on number of FOG episodes
during complex gait
6 weeks training
Vis and Aud cues, balance
exercises
Improved FOGQ
No effect on FOG episodes during
complex gait
Randomized cross-over
3 weeks cued training versus no
training
5.5 % improved FOGQ
63 FR
Aud or somatosensory cues
Studies on training effects of exercise with and without cues
Cubo et al. (2004)
Pre-post
12 FR with ONFOG
During ON
Brichetto et al. (2006)
Pre-post
12 FR with ON FOG
During ON
Nieuwboer et al. (2007)
During ON
Frazzitta et al. (2009)
Allen et al. (2010)
RCT
4 weeks training
40 FR
During ON
Group 1 Treadmill ? cues
Group 2 Overground
walking ? cues
RCT
6 month training
48 PD with fall risk (some with
FOG)
Control group: fall prevention
advice
Training effects in both groups but greater
after treadmill ? cues
Improved FOGQ
Exercise group: cueing, strength
training and balance
Pelosin et al. (2010)
Donovan et al. (2011)
RCT
4 weeks training
18 FR (ON/OFF unclear)
Group 1 Strategies ? sham video
Reduced FOG episodes and improved
FOGQ in both groups
During ON/OFF
Group 2 Strategies ? action video
Better consolidation with action video
Randomized
1 month with cane or walker then
Improved FOGQ after visual cue cane
Cross-over
1 month using the same device
with laserlight visual cue
26 FR
ON/OFF unclear
Kadivar et al. (2011)
Matched pairs for H&Y
6 weeks training
7 FR (ON/OFF unclear)
Group 1: Externally paced
stepping
Improved FOGQ in the externally paced
stepping group up to 4 weeks posttraining
Group 2: Stepping training without
cues
FR freezer, Vis cue visual cue, Aud cue auditory cue
* Studies with an explicit comparison between freezers and non-freezers
freezers and non-freezers and showed very similar effects
on gait in both groups, irrespective of FOG (Nanhoe-Mahabier et al. 2012; Nieuwboer et al. 2009b; Willems et al.
2006). These studies did not specifically focus on the role
of cognition, but as it was found that the effects were
maintained during attention-demanding turns and obstacle
negotiation in both groups, they seem to indicate that also
in the freezer group the cognitive reserve was sufficient to
achieve an adequate motor-cue response integration
(Nanhoe-Mahabier et al. 2012; Nieuwboer et al. 2009b).
Hence, cueing may appeal to controlled rather than automatic response selection processes in patients and as such
prevent motor breakdown. However, some caution is needed in interpreting this work, as the afore-mentioned
studies pertain to rhythmical cues only and in one case
involved treadmill walking.
To fully appreciate the impact of cueing on FOG, it is
also useful to consider whether the effect of cue withdrawal
123
554
is similar in freezers and non-freezers. Comparing the
effects of withdrawing external cueing on turning during
ON, no differences were found between both groups
(Nieuwboer et al. 2009b). However, when cues were taken
away during turning in OFF, FOG episodes returned
immediately after cue withdrawal in the freezer group
(Spildooren et al. 2012). Vercruysse et al. (2012c) also
reported that the motor control of a repetitive bilateral
finger movement deteriorated dramatically in patients with
FOG when the cue was withdrawn, while this was not the
case in non-freezers. It is difficult to speculate at this point
whether the tendency towards cue-dependency and return
of motor breakdown in freezers is indicative of greater
motor or cognitive dysfunction or both. This awaits further
investigation.
Given their altered cognitive profile, it can also be
expected that freezers may show diminished rehabilitation
effects when long-term training is offered with the aim to
tackle FOG in daily life. An association between cognitive
dysfunction and implicit learning deficits has been demonstrated in PD in general (Deroost et al. 2006; Vandenbossche et al. 2009) and has recently been confirmed in
patients with FOG (Vandenbossche et al. 2012a). In this
study, freezers’ implicit learning deficit exaggerated under
dual-task conditions, offering support for the assumption
that freezers may have a different learning profile than
non-freezers. Also, sequence learning under dual-task
conditions was correlated to FOG, suggesting that more
cognitive resources are needed to make up for the dysfunctional automaticity thereby increasing the chance of
cognitive overload. However, up to now, conclusions can
only be tentative, and should be confirmed by future randomized controlled trials comparing learning in patients
with and without FOG.
The second part of Table 2 summarizes eight studies
investigating the effects of prolonged rehabilitation interventions for patients with FOG, varying from 1 week to
6 months duration. No comparison between freezers and
non-freezers was made in these learning-based interventions, which consisted of exercise, cued training, attentional strategies with or without action observation to
address FOG. Outcomes measures usually involved
assessment of freezing severity as measured by the freezing
of gait questionnaire (FOGQ) or observed FOG frequency.
With the exception of two studies, when FOG was measured in ON (Brichetto et al. 2006; Cubo et al. 2004), 6 out
of the 8 studies showed positive effects on freezing severity
as a result of such training (Arias and Cudeiro 2010;
Bächlin et al. 2010; Dietz et al. 1990; Griffin et al. 2011;
Kompoliti et al. 2000; Lebold and Almeida 2010; Lee et al.
2012; Willems et al. 2006; Nanhoe-Mahabier et al. 2012;
Nieuwboer 2008). Interestingly, retention of learning was
shown to be improved when movements were supported by
123
E. Heremans et al.
cueing (Kadivar et al. 2011) and action observation (Pelosin et al. 2010). In line with these positive effects of using
extra information to support learning, making it less
implicit, motor imagery might be advocated as a strategy to
prepare for the upcoming functional movements, priming
the motor program beforehand and as such reduce the
cognitive load during actual motor performance. Heremans
et al. (2011) reported well-preserved motor imagery ability
in patients with PD, particularly when performed in combination with external cueing (Heremans et al. 2012), but
did not compare patients with and without freezing of gait.
Adding extra information, however, to the learning environment, runs the risk of creating dependency and inflexibility, thereby reducing the robust transfer of learning. Up
to now, however, it is still unclear if and to which extent
the learning potential of patients with FOG is affected, and
to which extent they might become dependent on external
information which is provided during training. Future
studies are needed to further investigate the cognitive
profile as well as the best learning strategies for patients
with FOG.
Directions for future research
In this paper, we reviewed previous studies which provided
evidence on a potential relationship between cognitive
malfunctioning and freezing of gait. The results indicated a
larger decline in global cognitive as well as executive
functioning in freezers compared to non-freezers and
healthy controls. However, conclusions can only be tentative since most of these previous studies were lacking
methodological rigor. Future experimental designs should
ensure better control of the matching of clinical subgroups
with regard to disease severity and disease duration. As
well, studies are needed on larger samples, with subgroups
based on objective criteria instead of self-reports, and using
multivariate analyses. A first step in this direction has been
taken by Vercruysse et al. (2012b) who performed a multivariate regression analysis to investigate the relative
contribution of cognitive as well as other factors to the
occurrence of FOG on subgroups who were matched for
disease severity.
Theoretically, a great challenge lies in the further
investigation of the neural basis underlying FOG and
cognitive impairment and the integration of these results
with the outcomes from behavioral measures. It is of particular importance to investigate both the influence of
dopaminergic and cholinergic projections to cortical cognitive areas on cognitive problems in freezers.
Finally, a fruitful direction for future research lies in the
development of adequate rehabilitation strategies for
patients with FOG. Previous studies using interventions
Cognitive aspects of freezing of gait in Parkinson’s disease
based on external cueing show promising results. However,
it is still unclear how these interventions should be performed as to optimize patients’ performance and minimize
the development of cue-dependency.
Conclusion
The current review shows that cognition is probably one of
the main factors contributing to the manifestation of FOG,
the strongest evidence of which points to deficits in
response selection. Although cognitive dysfunction predisposes and contributes to FOG, patients with FOG
remain able to adopt compensatory cueing and reallocate
attention to alleviate this symptom. There are indications
that this altered cognitive profile may lead to greater cuedependency and less flexible learning strategies, but more
research is needed to clarify these points.
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