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Role of executive dysfunctions in unawareness of Parkinson’s Disease.

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 Palermo S, Amanzio M (2012). Role of executive dysfunction in the
unawareness of dyskinetic movements. In: Parkinson's Disease: Diagnosis,
Treatment and Prognosis. Chiyo Yoshida, Ami Ito Eds.
Nova Science Publishers, Hauppauge, NY. Chapter 6, 147-164.
___________________________________________________________

Chapter VI

ROLE OF EXECUTIVE DYSFUNCTION

IN THE UNAWARENESS OF
DYSKINETIC MOVEMENTS

Sara Palermo and Martina Amanzio 1

Department of Psychology, University of Turin, Via Verdi 10, 10123
Turin, Italy

ABSTRACT
Subjects suffering from Parkinson’s Disease (PD) are sometimes
partially or completely unaware of the deficits caused by the disease.
Specifically, PD patients may complain of drug-induced dyskinesias less
than their caregivers. An improved understanding of unawareness of
involuntary movements in PD is important in order to appreciate the
impact of the disease and the side effects of pharmacological treatment.
Since damage to prefrontal areas may cause a reduction in awareness
of movement disorders and since PD patients have difficulty with
executive tasks, the relationship between unawareness and executive
dysfunction is an interesting association to be further analyzed. On the
whole, three independent but correlated constructs could be involved: a)
shifting between tasks or mental sets; b) updating and monitoring of
working memory representation; c) inhibition of dominant or prepotent
responses.

1
Corresponding author: Department of Psychology, University of Turin, Via Verdi 10, 10123
Turin, Italy. Tel.: +39 11 6702468; E-mail: martina.amanzio@unito.it.
 Sara Palermo and Martina Amanzio

Reduced awareness of movement disorders in cognitively preserved

PD subjects also requires further analysis. In particular, this is the only
way in which unawareness of dyskinetic movements can be considered
specific and not secondary to cognitive impairment.
Starting from these considerations, the study by Amanzio et al.
(2010) assessed the awareness of motor deficits in non-demented PD
subjects using an extensive executive and neuropsychological evaluation.
This study addressed the question by comparing the on and off states and
using specific evaluations of awareness of movement disorders. Their
results led to the conclusion that reduced awareness of dyskinesias in the
on state is not related to the general level of cognitive impairment but to
executive dysfunction.
In this essay we conduct an extensive investigation of unawareness
of dyskinetic movements in PD subjects with the aim of analyzing the
hypothesis that disruption of the orbito-frontal pathway may lead to a
deficit in awareness, probably due to decreased attentional and self-
monitoring abilities with an important role played by metacognitive
processes.

Keywords: Parkinson’s disease, awareness of dyskinetic movements,

executive functions, metacognitive processes

1. DYSKINESIAS IN PARKINSON’S DISEASE.

CLINICAL FEATURES AND ASSESSMENT TOOLS
The majority of PD patients, mostly those with young onset, experience
levodopa-induced adverse effects, such as wearing-off and on-off effects or
involuntary movements, after a few years of treatment, with cross-sectional
prevalence ranging from 20 to 56% (Colosimo et al., 2010). Stereotypies,
ballism, dystonia and myoclonus are the most common forms of levodopa-
induced dyskinesias (LID). LID occur especially in the limbs, hands, trunk and
lingual-facial-buccal musculature. A core component of the pathophysiology
of dyskinestic movements is over-activity of the direct striatal output pathway.
This provides a direct GABAergic connection by which the striatum inhibits
the output regions of the basal ganglia (Fabbrini et al., 2007). LID generally
first appear in the foot ipsilateral to the most affected side of the body, with the
inversion of the foot and ankle. This can be explained by the early loss of
dopaminergic innervation in the dorsolateral striatum which corresponds
somatotopically to the foot area, innervated by the substantia nigra (Fabbrini et
al., 2007).
 Role of Executive Dysfunction in the Unawareness ...

LID can show several patterns of expression, being most severe at peak
anti-parkinsonian effect of levodopa, at the beginning and end of dose or when
off-treatment (Quinn, 1998). For this reason dyskinetic movements are
classified on the basis of their course and clinical phenomenology (see table
1). The three principal forms of LID are OFF-period dystonia (generally
correlated with akinesia), peak-dose dyskinesias and diphasic dyskinesias,
occurring in approximately 15-20% of patients (Jankovic, 2005). While peak-
dose dyskinesias are characterized by the sequence of parkinsonism -
Improvement - Dyskinesia - Improvement - parkinsonism (I-D-I), the diphasic
form is manifested by parkinsonism – Dyskinesia - Improvement - Dyskinesia
- parkinsonism (D-I-D).
The different types of LID are not mutually exclusive and various
combinations of motor involuntary movements often occur simultaneously in
the same PD patient. Although LID are sometimes fairly disabling, many
patients prefer being on with dyskinesias than being off without them
(Jankovic, 2005).
While in the research field LID are measured using different instruments
(such as Doppler ultrasound, electromyography, dynamometer and
accelerometers), the clinical diagnosis of dyskinesias is not easy (Hoff, van
Hilten & Roos, 1999). To date, validated assessment tools are limited and
poorly diffused. The design of a good clinical assessment tool is made difficult
by the intrinsic characteristics of LID, such as the extreme variability of
involuntary movements in relation to the time of observation and to the kind of
activity performed by the patient for evaluation purposes; moreover, rating
scales may be unable to discriminate between different types of dyskinesia or
between LID and parkinsonian tremor (Colosimo et al., 2010).

Table 1. Levodopa-Induced Dyskinesias (LID)

Controversial movements Less usual forms of LID typical forms

LID
Restlessness/hyperactivity Respiratory Off-period dystonia
Akathisia dyskinesias Peak-dose dyskinesias
Enhanced tremor Ocular dyskinesias Diphasic dyskinesias
Myoclonic dyskinesias

Due to the enormous impact that LID have on the overall level of
disability, autonomy in daily life and quality of life in patients with advanced
PD, the Movement Disorder Society (MDS) organized a systematic review of
 Sara Palermo and Martina Amanzio

the tools available for the assessment of dyskinetic movements (Colosimo et

al., 2010). Eight rating scales for LID in PD were identified:

• The Abnormal Involuntary Movement Scale (AIMS), which is a

clinician-rated instrument to assess the severity of abnormal
movements in different parts of the body (Guy, 1976);
• The Unified Parkinson’s Disease Rating Scale (UPDRS) part IV,
which is the most widely used clinical rating scale for PD and is made
up of four subscales: mental status, behavior and moods; activities of
daily living; motor examination; complication (Fahn & Elton, 1987);
• The Obeso Dyskinesia Rating Scale (CAPIT), which combines the
patient’s historical assessments and the examiner’s objective rating of
LID (Langston et al., 1992);
• The Rush Dyskinesia Rating Scale, which assesses the severity of LID
based on interference with three motor tasks: walking, drinking from a
cup and putting on and buttoning a coat (Goetz et al., 1994);
• The Clinical Dyskinesia Rating Scale (CDRS), which evaluates
hyperkinesias and dystonic posture, scored for each body region
(Hagel & Widner, 1999);
• The Lang-Fahn Activities of Daily Living Dyskinesia Scale
(LFADLDS), which is an attempt to capture disability not normally
manifested during a routine clinical assessment (Parkinson Study
Group, 2001);
• The Parkinson Disease Dyskinesia Scale (PDYS-26), which is a
patient-based measure for quantifying the impact of LID on activities
of daily living (Ratzenschlager et al., 2007);
• The Unified Dyskinesia Rating Scale (UdysRS), which combines the
patient’s historical assessments and the examiner’s objective rating
(Goetz, Nutt & Stebbins, 2008).

All the afore-mentioned scales have some important limitations (Colosimo

et al., 2010). First of all, objective assessment only sets a specific point in time
(the time of the clinical assessment). Patients’ self-evaluation (such as diaries
in which the subjects indicate the time, therapy-dose and chronology/features
of LID), conversely, reflects the overall LID-burden during the day but is more
prone to bias, as influenced by mood and the cognitive patient's current state
(Hauser et al., 2000). Furthermore, it is often difficult for patients to
distinguish between LID and parkinsonian tremor. Besides, each rating scale
 Role of Executive Dysfunction in the Unawareness ...

focuses on one or more aspects of LID (for example duration, intensity,

phenomenology, anatomical distribution, level of disability perceived and so
on) but none captures all these issues (Colosimo et al., 2010). Translation also
represents a major problem: while many of the oldest scales have not been
validated (Tonelli et al., 2003; Martinez-Martin et al., 1994), the newest are
not yet available (Colosimo et al., 2010). We must also add that these rating
scales were created using very different strategies, some as part of an extended
battery for the assessment of PD symptoms, others built specifically for the
evaluation of LID in Parkinson's disease, others created to assess dyskinesias
in other diseases and only later adapted to PD (Martinez-Martin & Cubo,
2007).
An ideal assessment tool should recognize PD patients’ perception, the
temporal features of dyskinesias (such as onset, duration, daily frequency),
their anatomical distribution, the objective impairment and the resulting level
of disability (Colosimo et al., 2010). To date, only two MDS revised scales
meet the recommended criteria for evaluating PD subjects: the AIMS and the
Rush Dyskinesia Rating Scale; all others are suggested (Colosimo et al.,
2010).
Amanzio et al. (2010) recently investigated LID using two clinician-rated
scales. In this study PD motor impairment was firstly detected on the basis of
section III of the UPDRS (Fahn & Elton, 1987), while section IV-A,
concerning complications of therapy, was used to evaluate the duration of LID
and related disability. Secondly, LID severity was assessed with the
Dyskinesias Rating Scale (DS-I), a four-item scale with scores ranging from 0
(absence of dyskinesias – difficulty or slowness of movements) to 3 (severe
dyskinesias – clearly evident and with a negative impact on the result of
execution of actions).

2. UNAWARENESS OF DYSKINESIAS AND ITS

NEUROPSYCHOLOGICAL ASSESSMENT
The difficulty in correctly diagnosing LID is not only due to the absence
of an adequate assessment tool. Indeed, there is another intervening factor that
must be emphasized: lack of awareness of dyskinesias is commonly observed
in clinical practice (Amanzio et al., 2010; Jenkinson et al., 2009; Vitale et al.,
2001; Seltzer et al., 2001). PD patients have a propensity not to recognize
dyskinetic movements and they are inclined not to refer these adverse effects
 Sara Palermo and Martina Amanzio

to the use of Levodopa. Caregivers judge LID more negatively than PD

patients, who nevertheless experience them in the first person (Marras & Lang,
2003). Thus, PD patients do not lament the presence of LID but simply
complain of parkinsonian symptomatology in general. When faced with the
possibility of modifying drug therapy to reduce dyskinesias, patients are
sometimes opposed to the idea, preferring the persistence of LID and possible
worsening of the parkinsonian symptoms (Hung et al., 2010).
Clinically, unawareness of LID is difficult to diagnose. Two approaches
are the most widely used, both with some important limitations. Unawareness
can be estimated as the discrepancy between the primary caregiver’s
evaluation of LID and that of the PD patient (Leritz et al., 2004). In this case it
is important to remember that the caregiver’s level of stress and related mood
changes can be the source of significant bias. Primary caregivers in particular
bear a significant burden which may lead them to overestimate impairments
(Antoine et al., 2004). Alternatively, it is possible to create a specific index
provided by the discrepancy between PD patients’ subjective ratings and their
actual performance on a task (Antoine et al., 2004). In this case, the kind of
task chosen by the examiner and the patient’s level of cognitive impairment
may be an important source of bias.
Amanzio and colleagues (2010) recently adopted a novel approach to
study unawareness of LID in cognitively preserved PD patients. Patients were
tested twice: first in the off state, with no medication coverage, and then in the
on state, under the effect of drug treatment. This allowed them to assess
awareness not only for hyperkinesias typical of the on state, but also
awareness of hypo- and bradykinesia typical of the off state, when symptoms
are not controlled. For the purpose of the study, they used three brief rating
scales: the Global Awareness of Movement Disorder Scale (GAM),
administered in the on and off states, the Dyskinesias Rating Scale (DS-I) and
the Hypo-Brady-Kinesia Rating Scale (HS-I). Each GAM consisted of 4 levels
(0-3), ranging from 0 (preserved awareness) to 3 (complete unawareness), for
which the scores were assigned by a neurologist experienced in movement
disorders and based on the degree of spontaneity with which patients reported
LID in the on state and hypo- and bradykinesia in the off state. Two awareness
indexes were calculated for DS-I and HS-I to rate discrepancy between the
examiner’s and PD patient’s judgments. Higher scores indicated more severe
impairment in terms of reduced awareness of movement disorders.
Aside from an academic interest, unawareness of LID has practical
clinical consequences (Seltzer et al., 2001). Although lack of awareness might
appear to be an advantage in some circumstances, as a defensive mechanism to
 Role of Executive Dysfunction in the Unawareness ...

avoid shame in social situations (Jenkinson et al., 2009) or depressive feelings

(Antoine et al., 2004), unaware PD patients may engage in potentially
dangerous activities, to compensate for their difficulties in performing
activities of daily living or to comply with therapy (Jenkinson et al., 2009).
Unawareness of LID may also be associated with caregiver stress and burden
(Al-Aloucy et al., 2011; Dourado et al, 2007). For all these reasons a better
understanding of unawareness of LID in Parkinson’s disease is crucial in order
to tailor care and counteract the side effects of Levodopa-treatment in the best
possible way.

3. LITERATURE FINDINGS ON UNAWARENESS OF

DYSKINESIAS AND ASSOCIATED FACTORS
Since PD is characterized by a selective neuropathological profile and
causes a limited range of neuropsychological deficits, it can be a useful model
for studying awareness of deficits in neurological diseases.
Unawareness of deficits is considered a hallmark of neurological diseases
involving cortical brain regions (Starkstein et al., 1993). Several portions of
the frontal lobe have strong connections with subcortical structures, as well as
with parts of the limbic system and somatosensory areas of the brain, and
damage to the circuits that bond these areas together can lead to deficits in
sensory perception as well as deficits in awareness of LID (Lazzarino &
Nicolai, 1991). Nonetheless, a small number of studies have focused on the
role of some subcortical structures (such as the thalamus, the nucleus caudatus
or the internal capsula), demonstrating that unawareness may emerge
following damage to the right hemisphere (Kumral et al., 1995; Stein & Volpe,
1983). This probably occurs because the subcortical structures have numerous
connections with the cortical regions and prefrontal lobes. Lack of awareness
was recently observed in patients with lesions to the basal ganglia (Mikos et
al., 2009), such as Wilson’s and Huntington’s diseases (Rosenblatt & Leroi,
2000) or PD ( Albin, Young & Penney, 1989). Patients suffering from
Huntington’s disease develop dyskinetic movements of which they rarely
complain (Vitale et al., 2001). Something similar happens in PD patients
(Vitale et al., 2001). As PD is associated with dopaminergic depletion of
neurons in the substantia nigra and, consequently, decreased activation of
various cortical regions, it is reasonable to speculate that PD patients, with
predominantly right basal ganglia dysfunction and left-sided symptoms, may
 Sara Palermo and Martina Amanzio

exhibit greater unawareness of deficits if compared with PD patients with

predominantly right-sided motor symptoms (Leritz et al., 2004). Vitale and
colleagues (2001) suggested that reduced awareness of dyskinetic movements
is inversely related to the severity of LID. As far as they are concerned, the
pathophysiological basis of unawareness of LID in PD is the dopaminergic
overstimulation of mesolimbocortical pathways and it operates independently
of side. These data bring further evidence to support the fact that lack of
awareness arises from generalized damage to subcortical lesions rather than
from lateralized damage. Leritz et al. (2004) also suggested that lack of
awareness of LID in PD is the result of damage to the frontal-subcortical
connections. These authors also stated that laterality is not decisive in
predicting unawareness (Leritz et al., 2004).
Further explanations for unawareness of LID have been provided by
studies on PD patients’ current cognitive and neuropsychiatric frameworks.
Seltzer et al. (2001) stressed that in PD subjects, unawareness extends to motor
dysfunctions. Taken on its own, it might have been possible to explain this
domain-specific characteristic as being due to disconnection of a conscious
awareness system from modality-specific modules most affected by the
disease (McGlynn & Schacter, 1989), whereas it is, instead, correlated with
memory impairment and other cognitive complaints. In actual fact, PD patients
with relatively preserved cognitive functions exhibit a well-sustained
awareness of their movement disorders (Seltzer et al., 2001). Controlling for
MMSE-scores reduces differences between patients’ and caregivers’
judgments about LID (Leritz et al., 2004). Jenkinson and colleagues (2009),
based on a well-established “forward” model of the motor system
(Wolpert,1997; Blakemore, Frith & Wolpert, 2001), went further, pointing out
that unawareness of LID is due to a breakdown of monitoring of intended and
actual movement. They interpreted unawareness of LID as a breakdown of the
error-detection process. Indeed, they speculated that a bug in the predictor
mechanism of the forward model, responsible for anticipating the expected
sensory feedback from intended movements, may mean that all movements
seem strange, given that the predictions generated by the malfunctioning
sensory predictor are different from those that would have be generated for the
same movements before illness onset (Jankinson et al., 2009).
Amanzio and colleagues (2010) recently showed that non-demented PD
patients had greater awareness and psychological suffering in the off state that
in the on state. Indeed, awareness scores varied notably between the two
phases: in the on state patients showed reduced awareness of LID as measured
on the GAM and on the DS-I, whereas in the off state awareness of
 Role of Executive Dysfunction in the Unawareness ...

hypokinesias and bradykinesia appeared well-preserved. PD patients were also

more worried by motor disabilities related to hypokinesias and had mood-
related symptoms and a perception of disability in activities of daily living in
the off state. Interestingly, in this study, PD patients only exhibited a selective
reduction of awareness of movement disorders associated with executive
functions (on the Wisconsing Card Sorting Test, WCST) and related to LID in
the on state, compared to preserved awareness of hypokinesias in the off state.
On the contrary, no association with executive functions was found in the off
state. As far as prefrontal involvement in Parkinson’s disease is concerned,
dopaminergic treatment improves executive functions related to the cortical–
subcortical network from the dorsolateral prefrontal cortex to the dorsal
caudate nucleus which is dopamine depleted. On the contrary, the same
dopaminergic treatment impairs functions connected to the orbitofrontal
cortex–ventral striatal circuitry (Cools, Barker, Sahakian, & Robbins, 2001).

4. PROCEDURES AND SCORING PROTOCOLS OF

SOME EXECUTIVE FUNCTION MEASURES USEFUL
IN PD ASSESSMENT

Table 2 presents a condensed version of procedures and scoring protocols

of some executive function measures useful in PD assessment. The WCST
appears to be a sensitive indicator of executive dysfunction in PD (Kanazawa,
Mizuno & Narabayashi, 2001). The WCST-64 also seems sensitive to the
subtle executive deficits demonstrated by PD patients without dementia (Paolo
et al., 1996).

5. THE CONSCIOUS AWARENESS MODEL (CAM)

Since the prefrontal lobe system is important for intact self-awareness and
since damage to the prefrontal lobe is prevalent in subcortical brain diseases
(Alexander et al., 1990), it seems reasonable to assume that damage to frontal-
subcortical connections may be the cause of unawareness of illness in PD.
Executive dysfunction is actually believed to be at the core of the cognitive
disturbances in PD and is usually one of the earliest symptoms found in these
patients (Dubois & Pillon, 1997), reaching the frequency of behavioral
 Sara Palermo and Martina Amanzio

dysexecutive syndrome in about 42% and of cognitive dysexecutive syndrome

in about 39% (Godefroy et al., 2010).

Table 2. Executive function measures useful in PD assessment

Test Task Scoring EFs measured

WCST Match response card to Categories, Set-shifting, rule
four key cards on the errors, deduction and
basis of color, form perseveration generation, mental
and number % flexibility
Phonemic Say as many words as Total number Information generation
Verbal possible beginning of words
Fluency with a specific letter (f, generated
a, s) in 60 seconds for
each letter
Stroop Read words, colors and Total time in Sensitivity to
test color words printed in seconds, interference
incongruous colored interference
ink difference
score
TOL Reconstruct showed Total time in Set elaboration and
configurations using seconds, planning
pegs and several beads number of
with different colors move
solution
TMT Unify 25 circles Total time in Attention, set-shifting,
A -B distributed over a sheet seconds mental flexibility
of paper
(Form A: numbers 1-
25, Form B: alternating
numbers 1-13 and
letters A-L )
FAB Similarities task, Profile scores Conceptualiza-tion,
phonological lexical mental flexibility,
fluency task, Luria’s motor programming,
motor series, sensitivity to
conflicting instruction interference, inhibitory
task, go/no-go task, control, environmental
evaluation of autonomy
prehension behavior
 Role of Executive Dysfunction in the Unawareness ...

BADS Rule shift cards, action Profile scores Perseverative tendency,

program, key search, planning, problem-
temporal judgment, solving, abstract
zoo maps, modified six thinking, time
elements management

“Executive functions” is a wide concept used to portray a broad range of

cognitive functions (Miyake et al., 2000). These functions are generally
referred to as supervisory cognitive processes because they engage higher
level organization and execution of complex thinking and conduct (Alvarez &
Emory, 2006). In line with the proposals of Miyake and colleagues (2010) and
particularly interesting for our purposes, it is possible to recognize three main
executive functions: inhibition of prepotent responses (inhibition); updating
and monitoring of working memory representations (updating); shifting
between tasks or mental sets (shifting).
We recently demonstrated in patients with early Alzheimer’s Disease
(AD) that disturbance of awareness may arise as a result of cognitive changes,
emphasizing the role of disabilities in specific executive function
subcomponents related to metacognitive processes such as the ability to shift
and inhibit a response (Amanzio et al., 2011). We also consider this a possible
fruitful theoretical approach for PD patients. Interestingly, previous research
has been able to identify the association between three main regions of the
prefrontal cortex and specific executive dysfunction in patients with PD such
as: the dorsolateral prefrontal cortex (DLPFC); the anterior cingulate cortex
(ACC) and the orbitofrontal cortex (OFC). The DLPFC is involved in set-
shifting, complex problem-solving, retrieval abilities, organizational strategies,
concept-formation and working memory; the ACC regulates response
initiation, intention, inhibition and conflict-monitoring; the OFC is associated
with decision-making based upon a reinforcement/reward schedule, impulse-
control, perseveration and mood (Zgaljardic et al., 2003). The frontal
hypoperfusion associated with reduced awareness of deficits in Alzheimer’s
disease has led to believe in the existence of a hypofunctioning prefrontal
pathway involving the right dorsolateral prefrontal cortex, inferior parietal
lobe, anterior cingulate gyri and limbic structures (Starkstein et al., 2007). In
actual fact, unawareness of deficits in early Alzheimer's disease is associated
with reduced functional recruitment of the cingulofrontal and parietotemporal
regions (Amanzio et al., 2011). Specifically, we recently found that unaware
patients showed reduced task-sensitive activity in the right anterior cingulate
area, in the rostral prefrontal cortex, in the right post-central gyrus, in the
 Sara Palermo and Martina Amanzio

associative cortical areas such as the right parietotemporal-occipital junction

and the left temporal gyrus, in the striatum and in the cerebellum. A
neurocognitive model of awareness in AD patients, the Conscious Awareness
Model (CAM), may also be helpful to understand the link between the
contribution of the executive system to metacognitive abilities related to
awareness (Litvan et al., 2003, Ryan et al., 2006) in PD patients. This model
includes a comparator system within the central executive to monitor
mismatches between a personal database and experienced cognitive failures
and successes. When a mismatch is detected, a signal is sent to the
metacognitive awareness system which leads to the conscious experience of
failure. If the executive system is not functioning correctly, as has been
observed in early AD patients, the comparator mechanism does not detect
mismatches. Consequently, a failure in cognitive performance may not reach
metacognitive output or conscious awareness, leading to an “executive
unawareness” in the CAM. The relationship between unawareness of deficits
and dysexecutive dysfunctions in AD patients has been demonstrated by many
studies using neuropsychological batteries to assess the prefrontal cortex, and
cerebral perfusion studies using PET and SPECT techniques. In this executive
unawareness a faulty appreciation of performance, with no recognition of
failure, leads to a lack of update of the patient’s personal database. Since these
comparator mechanisms are responsible for the monitoring of performance on
different cognitive tasks (as mentioned previously, memory is the most-studied
cognitive function) we believe that monitoring the information flow on tasks
requiring inhibition of responses provides a fruitful approach to study the
unawareness of deficits not only in early AD but also in PD patients. In figure
1 the ACC is represented as the monitoring attentional system. This system
serves to ensure that the elaboration processes in the other brain regions shown
in the figure are of the highest efficiency, in relation to the demands of the
tasks that are taking place. Interactions with the prefrontal cortex may select
the buffer of the working memory (WM). Interactions with the posterior
cortices may serve to amplify the activity of a particular form of perception
compared to others. Interactions with the posterior cortices may be direct or
mediated by connections with the prefrontal cortex.
Our hypothesis for explaining low awareness of dyskinesias in PD patients
- in line with the above-mentioned theorization - is that levodopa treatment
may have a detrimental effect on the function of the orbitofrontal and
cingulated frontal–subcortical circuits; these projections appear to be critical in
the awareness phenomenon (Amanzio et al., 2010; Leritz et al., 2004; Seltzer
et al., 2001). Our parkinsonian patients were selected for their intact cognitive
 Role of Executive Dysfunction in the Unawareness ...

status; however, low awareness of dyskinesias in the on state was found to be

related to poorer performance on the WCST and on a memory task in subscale
IV of the WMS (Amanzio et al., 2010). This finding supports the influence of
reduced functionality in the anterior cingulate cortex, during dopaminergic
stimulation, even without excluding a role of the frontostriatal circuits. A PET
study on healthy subjects (Lumme, Aalto, Ilonen, Någren, & Hietala, 2007)
actually showed a correlation between errors on the WCST and dopaminergic
D2/D3 binding in the right anterior cingulate cortex, suggesting a role of this
region in executive functioning. Functional neuroimaging studies have also
clarified the roles of different prefrontal regions involved in performing the
WCST; in particular, Monchi, Petrides, Petre, Worsley, and Dagher (2001)
demonstrated a role of the ventrolateral prefrontal cortex and anterior cingulate
cortex in terms of increased activity during the reception of negative feedback
from subjects on performance. Contextually, Monchi, Petrides, Mejia-
Constain, and Strafella (2007) recently investigated fMRI activation in the
prefrontal cortex (PFC) in a group of PD patients and healthy controls during
the execution of the WCST. In the PD group, a significant decrease in
activation was observed in those areas where activity, in healthy controls, was
linked with the striatum, namely the ventrolateral and the posterior PFC. The
authors also observed a selective engagement of the dorsolateral PFC during
the provision of feedback after each matching response by the subjects (Ko,
Monchi, Ptito, Petrides, & Strafella 2008); this evidence is consistent with the
hypothesis that dorsolateral PFC activity is closely related to the monitoring of
events in working memory. As regards the influence of cognitive status on the
awareness phenomenon, the anterior cingulated cortex had a crucial role in the
control of action, such as attention-for-action-/target selection (Posner,
Petersen, Fox, & Raichle, 1988), motor response selection (Paus, Petrides,
Evans, & Meyer, 1993; Turken & Swick, 1999) and performance-monitoring
by detecting errors (Gehring & Knight, 2000; Luu, Flaisch, & Tucker, 2000).
All these elements are important in awareness phenomena, as demonstrated in
our study by the correlation between low awareness and executive functions.
Low awareness, observed in our PD patients, could be caused by an impaired
judgment capacity or metacognitive competence. In particular, the
unawareness of deficits related to movement disorders in the on state observed
in our patients may be seen as a function of an inability to monitor one’s own
cognitive abilities. One study examining speech-monitoring skills in AD and
PD patients supports the conclusion that both classes of patients are less able
to monitor their cognitive performance (McNamara, Obler, Au, Durso, &
Albert, 1992). In particular, the failure to self-correct expressive speech errors
 Sara Palermo and Martina Amanzio

was thought to be related to attentional and frontal dysfunctions in these

patients. In addition, Flowers and Robertson (1985) stated that PD patients
seemed less able than controls to check their responses and inhibit errors
during a cognitive task, suggesting they may be somewhat impaired in general
response-monitoring. In line with these observations, we only found a relation
between GAM and WCST and GAM and WMS IV scores in the on state. This
was not observed for the Claridge and WMS VII, in which the general
response-monitoring ability probably has a lower impact (Amanzio et al.,
2010). Moreover, our data suggest that judgment ability and metacognitive
competence are likely involved in the self-assessment of activities of daily
living. The comparison between NUDS-I in the on state and NUDS-I in the off
state revealed no differences; this finding suggests that levodopa treatment
does not affect a global cognitive system of awareness, but only has a specific
effect on a system that monitors motor behavior in terms of movement
disorders. In the comparison between patients’ and caregivers’ evaluations on
the NUDS scale, caregivers did not judge patients to be more impaired in
either the off or on states compared to the patients’ own evaluations of their
disabilities. These findings also appear to exclude the hypothesis of a role of
pessimistic evaluation of parkinsonian patients by their caregivers (Carter et
al., 1998; Martínez-Martín et al., 2004).
 Role of Executive Dysfunction in the Unawareness ...

Figure 1. The ACC is represented as monitoring attentional system (adapted from

Posner and Reichle, 1994).

6. THEORY OF MIND AS ANOTHER POSSIBLE

CONTRIBUTING FACTOR
Unawareness of LID, for all we know at present, should not only be
assessed in the light of a relationship with executive functions and
metacognition. There is another possible intervening factor that must be
emphasized: the ability to mentalize, also defined as “Theory of Mind” (ToM),
the ability to understand the mental state of others and to predict behavior
based on those states (Premack & Woodruff, 1978). It is a crucial precondition
of human social interaction (Bodden, Dodel & Kalbe, 2010) and a major topic
of interest in recent studies on unawareness of disease in neuropsychiatric
disorders such as schizophrenia (Gambini, Barbieri & Scarone, 2004; Bora et
al., 2007). Interestingly, lack of insight can be considered a critical
manifestation of impaired ToM abilities, in terms of meta-representation
 Sara Palermo and Martina Amanzio

(Gambini, Barbieri & Scarone, 2004). This inference was confirmed by Bora
and colleagues (2007), who found that second-order false belief tasks seem to
be of critical importance for awareness of the disorder. This finding suggests
that awareness of the disorder and its consequences may also require the
ability to evaluate the self from the perspective of others (Bora et al., 2007).
There are five tasks typically employed in the assessment of ToM in PD
patients (Poletti et al., 2011): the first- and second-order false belief test, that
evaluates the cognitive component of mentalizing, the Reading the Mind in the
Eyes test, evaluating the affective component, the Faux Pas Recognition Test
and the Yoni test, both involving cognitive and affective components of
mentalizing (see table 3). Cognitive ToM requires cognitive understanding of
another’s mental state, while affective ToM requires an empathic appreciation
of the listener’s emotional state (Tsuruya, Kobayakawa & Kawamura, 2011).
As recently stressed by Poletti and colleagues (2011) the affective components
of ToM seem to be preserved in PD patients; on the contrary, they show
impaired performance on cognitive ToM tasks. These findings are in
disagreement with a previous study by Bodden and colleagues (2010): they
reported impaired affective ToM in medicated PD patients assessed using the
Reading the Mind in the Eye test and the Yoni test. Furthermore, Tsuruya,
Kobayakawa & Kawamura (2011) also affirmed that the affective aspects of
ToM, measured on the Reading the Mind in the Eye test, may be impaired in
PD patients. These divergent conclusions should be interpreted with caution
and need further confirmation.

Table 2. Most used Theory of Mind Tasks for the assessment of mentalizing
abilities in PD subjects

Test Task ToM Ability measured

component
First-order Understand a character Cognitive Infer that
false belief acting on a false belief someone has a
because he/she is mistaken belief
unaware of a prior about the world
event
Second-order Understand a character Cognitive Form beliefs
false belief acting on a false belief about the content
because he/she is of a third person’s
unaware of a prior mind
event
 Role of Executive Dysfunction in the Unawareness ...

Reading the Choose the word that Affective Empathy

Mind in the best describes what an
Eyes individual in a
photograph is thinking
or feeling
Faux Pas Understand the Faux Cognitive / Interpret social
Recognition Pas in a story affective situations that are
potentially
awkward
Yoni Choose the face that Cognitive / Form beliefs
best corresponds to a affective about a second
sentence person’s thoughts
and feelings

At present the data in the literature suggest that PD patients prevalently

have difficulties in tasks involving the cognitive component of ToM. These
finding could be partly explained by the executive dysfunctions that
differentiate PD patients from the untreated and early-medicated stages of the
illness (Muslimovic et al., 2005; Aarsland et al., 2009). Although ToM and
executive functions are often proposed as functionally independent (Fine,
Lumsden & Blair, 2001; Rowe et al., 2001), it has been demonstrated that
there is a correlation between performance on tasks evaluating executive
functions, especially those that assess working memory and response
inhibition, and performance on ToM tasks (Poletti et al., 2011).
Regarding the influence of dopaminergic therapies on ToM abilities in
PD, only one study has assessed patients in the on and off states (Peron et al.,
2009), finding no differences in the affective and cognitive components of
ToM. This fact suggests that the nigrostriatal and mesolimbic dopaminergic
pathways do not contribute to ToM abilities. In a recent study, Roca and
colleagues (2010) suggested that the affective components of ToM are not
dependent on medication usage. However, there are currently no data
concerning only the cognitive components of ToM in relation to patients on
and off dopaminergic therapy (Poletti et al., 2011).

CONCLUSIONS
Executive functions involve a complex network of frontal-cortical and
subcortical circuitries. Damage to these connections may lead to
 Sara Palermo and Martina Amanzio

neuropsychological executive dysfunctions and unawareness of LID. Indeed

poor awareness of movement disorders may occur in cognitively preserved PD
patients. This could be caused by impaired judgment capacity or
metacognitive competence. In particular, reduced awareness of LID in the on
state appears to be related to metacognitive deficits in the self-monitoring
system. (Amanzio et al., 2010). To date, only a few studies have investigated
unawareness of LID in PD: further studies are needed in view of the important
implications for the clinical management of such disorders.

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