Impaired awareness of movement disorders in Parkinson’s disease
Martina Amanzioa,f,*, Silvia Monteverdia, Alessandra Giordanob, Paola Soliveric, Paola Filippid,e,
aDepartment of Psychology, University of Torino, Via Verdi 10, 10123 Torino, Italy
bDepartment of Neuroscience, University of Torino, Italy
cIstituto Nazionale Neurologico ‘‘Carlo Besta”, Department of Neurology I Milano, Italy
dAzienda Sanitaria Ospedaliera San Luigi Gonzaga, Neurology Unit, Orbassano, Torino, Italy
eOspedale Maria Vittoria, Neurology Unit, Torino, Italy
fNeuroscience Institute of Turin, NIT, University of Torino, Italy
a r t i c l e i n f o
Accepted 19 October 2009
Available online 14 November 2009
Awareness of movement disorders
a b s t r a c t
Background: This study analyzed the presence of awareness of movement disorders (dyskinesias and
hypokinesias) in 25 patients with Parkinson’s disease (PD) and motor fluctuations (dyskinesias, wearing
off, on–off fluctuations). Of the few studies that have dealt with this topic, none have analyzed the differ-
ences in the awareness of motor deficits by comparing the on and off states using motor scales and an
extensive battery of tests to assess cognitive and behavioral functioning.
Methods: PD patients were compared on three different scales that we have devised to measure aware-
ness of movement disorders: Global Awareness of Movement (GAM) Disorders, dyskinesia/hypo-brady-
kinesia rating scales.
Results: Data showed that PD patients had greater awareness and psychological suffering in the off state
than in the on state. In particular, they were troubled by motor disabilities related to hypokinesias and
had mood-related symptoms and a perception of disability in activities of daily living. Interestingly,
patients only showed a selective reduction of awareness of movement disorders associated with execu-
tive functions and related to dyskinesias in the on state, compared to a preserved awareness of hypoki-
nesias in the off state. On the contrary, no association with executive functions was found in the off state.
Conclusion: Our findings suggest that the dopaminergic overstimulation of mesocorticolimbic pathways
may cause a dysfunction of prefrontal–subcortical connections related to the impaired insight.
? 2009 Elsevier Inc. All rights reserved.
Parkinson’s disease (PD) is a progressive, neurodegenerative
disorder, characterized by complex motor impairment with both
hypokinetic (hypo-bradykinesia) and hyperkinetic (resting tremor)
symptoms. The neuropathological hallmark of PD is the degenera-
tion of dopaminergic neurons of the substantia nigra pars com-
pacta (Jellinger, 1987), leading to dopaminergic denervation of
the striatum, which is the first aspect to occur. Subsequently, as
the disease progresses, other dopaminergic systems are involved;
in particular, the mesocorticolimbic dopaminergic depletion dif-
fuses to the ventral striatum (Agid et al., 1993; Kish, Shannak, &
Hornykiewicz, 1988) producing mild executive function deficits
and behavioral alterations (Owen et al., 1992; Taylor, Saint-Cyr,
& Lang, 1986). The role of dopaminergic treatment on motor,
behavioral and cognitive dysfunctions is complex. From a motor
perspective, the efficacy of treatment with levodopa (precursor of
dopamine) is complicated by motor fluctuations with dyskinesias
and wearing off or on–off states.
Although PD is characterized by a complex and changeable
spectrum of symptoms, the subjective perception of motor impair-
ment is an interesting phenomenon that has been inadequately
analyzed. Reduced awareness of neurological symptoms, defined
as ‘‘anosognosia”, can involve a wide domain of situations (Wein-
stein & Kahn, 1950). In particular, in the domain of motor functions
the most widely investigated symptoms are anosognosia for hemi-
plegia and anosognosia for dyskinetic movements (Myslobodsky,
1986; Shenker, Wylie, Fuchs, Manning, & Heilman, 2004). The phe-
nomenon of anosognosia could be considered in terms of at least
two different theoretical frames. For the motor-sensorial domains
of anosognosia, such as hemiplegia, an impairment of a modular
system of awareness can be hypothesized (Bisiach & Geminiani,
1991). On the other side, prefrontal–striatal dysfunction of the
executive monitoring system could have a role in other domains
of reduced awareness (McGlynn & Schacter, 1989). For example,
it has been suggested that a dysfunction of the Central Executive
System (Baddeley, 1986) may account for the lack of awareness
in Alzheimer’s disease (AD) patients (Amanzio & Torta, 2009;
0278-2626/$ - see front matter ? 2009 Elsevier Inc. All rights reserved.
* Corresponding author. Address: Department of Psychology, University of
Torino, Via Verdi 10, 10123 Torino, Italy. Fax: +39 11 6702061.
E-mail address: email@example.com (M. Amanzio).
Brain and Cognition 72 (2010) 337–346
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Lopez, Becker, Somsak, Dew, & DeKosky, 1994). This second type
of unawareness due to executive dysfunctions has not yet been
reported in patients with PD.
Unawareness of deficits appears to be associated not only with
damage to cortical brain regions (McGlynn & Kaszniak, 1991;
Starkstein et al., 1996), but also with subcortical damage (Godef-
roy, Rousseaux, Pruvo, Cabaret, & Leys, 1994; Healton, Navarro,
Bressman, & Brust, 1982; Jacome, 1986), in particular anosognosia
of dyskinetic movements (Lazzarino & Nicolai, 1991). Few studies
have examined the role of unawareness of deficits in PD patients.
Starkstein et al. (1996), comparing AD and PD patients on an exten-
sive battery of neuropsychological and psychiatric measures, found
a higher level of deficit unawareness among AD patients than PD
patients and a disinhibitive syndrome, showing in the AD popula-
tion a frontotemporal dysfunction of cortical structures. Another
study evaluated the unawareness of dyskinesias in PD and Hun-
tington’s disease (HD) patients and found that both groups were
impaired in detecting the presence of their dyskinetic movements,
suggesting that this aspect of anosognosia could be related to sub-
cortical dysfunction (Vitale et al., 2001). In particular, in PD pa-
tients the level of unawareness was inversely related to the
severity of the dyskinesias, while in HD patients it was directly re-
lated to the duration of the disease. However, this study had some
important limitations: the parkinsonian patients were not studied
on the basis of a neuropsychological and neuropsychiatric assess-
ment, cognitive deterioration was not excluded and no measure
of awareness of hypokinetic disorders was considered. Another
study (Seltzer, Vasterling, Mathias, & Brennan, 2001), comparing
AD and PD patients, showed that the unawareness exhibited by
the PD group was more strongly related to neuropsychological dys-
functions, in terms of poor overall cognitive function, especially
those assessing memory; in this direction, the authors underlined
that PD patients with intact cognitive functions display relatively
preserved awareness of motor deficits. In particular, this study
demonstrated a correlation between the attention subscale of the
Dementia Rating Scale and the discrepancy between patients’
and caregivers’ evaluations of motor deficit; however, as the
authors themselves admit, this can only be considered as weak
confirmation of the link between this type of awareness and exec-
utive dysfunctions. It is important to underline that the study by
Seltzer et al. (2001) did not analyze differences in awareness of
motor deficits comparing on and off states and neuropsychological
and neuropsychiatric variables in the same patients. Finally, a more
recent study (Leritz, Loftis, Crucian, Friedman, & Bowers, 2004)
investigating self-awareness of non-demented PD patients showed
discrepancies between patients’ and caregivers’ reports on auton-
omy in activities of daily living (IADL). In particular, patients de-
scribed themselves as less impaired compared to caregivers’
evaluations of the patients’ level of disability. This effect was more
pronounced in patients with left-side motor symptoms (greater
right basal ganglia dysfunction); the authors concluded that basal
ganglia dysfunction might alter insight into the severity of illness
more prevalently in patients with right hemisphere lesions. How-
ever, even this study did not analyze unawareness of motor deficits
by differentiating between motor fluctuations in the on and off
From the above considerations, an analysis of the connection
between the frontal lobes and the basal ganglia would appear to
be a useful model for explaining the presence of unawareness of
deficits in subcortical cognitively intact PD patients. With this
aim we analyzed the awareness of movement disorders related
to pharmacological therapy in the on and off states. We thus ex-
pected to find a reduced awareness of hyperkinetic deficits in the
on state, associated with the detrimental role of dopaminergic
treatment on the prefrontal–subcortical loops producing executive
disabilities and a preserved awareness of hypo-bradykinesia in the
off state. We also hypothesized an association between patients’
judgments concerning hypokinetic movement disorders and anxi-
ety-depression mood orientation, attesting a preserved awareness
of their disabilities during the off state. Finally, we considered a
comparison between PD patients’ predominantly left versus pre-
dominantly right-side motor symptoms at onset of disease, to as-
sess the role of this phenomenon in the awareness of motor
Twenty-five patients (13 women, 12 men) with idiopathic Par-
kinson’s disease, motor fluctuations (Hughes, Daniel, Kilford, &
Lees, 1992) and receiving levodopa treatment (combined with car-
bidopa or benserazide), often associated with dopamine agonists,
were recruited to participate in the study. The demographic and
clinical data of the PD population are summarized in Tables 1
and 2. Patients were enrolled from a series of consecutive out-pa-
tients seen at the Neurology Units of the Carlo Besta hospital
(Milano, Italy) and the San Luigi Gonzaga hospital (Orbassano,
Italy). The inclusion criteria were good clinical response to levo-
dopa with presence of wearing off or on–off phenomena (patients
with random on–off were excluded) and peak-of-dose dyskinesias
(patients with early morning and painful dystonia were also
Patients were excluded from the study if they (1) had major
depression or dysthymia, based on DSM-IV criteria (1994), (2)
had a Mini Mental State Examination score <24 (MMSE, Folstein,
Folstein, & McHugh, 1975), (3) had a history of neurological and
psychiatric disorders (other than PD), in particular if they had
hedonistic homeostatic dysregulation, HHD (Giovannoni, O’Sulli-
van, Turner, Manson, & Lees, 2000; Pezzella et al., 2003), (5) were
taking medications that could directly impact cognitive function-
ing, other than dopaminergic therapy, such as antidepressants,
neuroleptics and anxiolytics, (6) were unable to perform neuropsy-
chological assessment in the off state.
The patients who fulfilled the above criteria were selected for
inclusion in the study.
Twenty-five referring spouses and/or caregivers of the PD pop-
ulation took part the study in order to provide information about
patients’ ability in daily living activities. Collaterals had normal
neurological and psychiatric evaluations; mental deterioration
was excluded by clinical examination and MMSE. Overall, the care-
giver comparison group was demographically similar to the patient
group based primarily on socio-economic status. Both patients and
caregivers were required to complete the North-Western Univer-
sity Disability Scale, NUDS (Canter, De Latorre, & Mier, 1961), pro-
viding an evaluation both in the on and off states.
Patients and caregivers participated willingly in the study and
all gave their informed consent. The study was approved by the
Ethics Committee of the Department of Psychology, University of
2.2. Motor, cognitive and neuropsychiatric assessment
PD patients were assessed using an extensive motor, cognitive
and psychiatric evaluation. The PD population was also analyzed
in terms of side of onset with predominantly right-side or left-side
Motor screening was performed using the Unified Parkinson
Disease Rating Scale (UPDRS, Fahn & Elton, 1987), which was
administered by trained clinicians (neurologists) blind to the aim
of the study. In particular, parkinsonian motor impairment was
M. Amanzio et al./Brain and Cognition 72 (2010) 337–346
assessed on the basis of Section III of the UPDRS. The score for each
item on the scale ranged from 0 (absence of symptoms) to 4 (se-
vere symptoms). Section IV-A concerning complications of therapy
was also used to evaluate the duration of dyskinesias and related
disability (for the importance of an accurate assessment of these
motor complications, see Koller, Hutton, Tolosa, & Capilldeo,
1999; Marras & Lang, 2003). The stage of disease was determined
using the Hoehn and Yahr (1967) rating scale, range 1–5.
Neuropsychological assessment included MMSE to detect the
presence of a general cognitive deterioration; a modified version
of the Claridge Test (Claridge, 1967; Hume & Claridge, 1965) was
administered for auditory selective attention and at the same time
to evaluate the impact of a psychomotor interference in a go-/no-
go task condition. Executive functions were analyzed using the
modified version of the Wisconsin Card Sorting Test, WCST (Laiac-
ona, Inzaghi, De Tanti, & Capitani, 2000; Nelson, 1976) and the Pho-
nemic Fluency Test (Novelli et al., 1986). Lastly, memory abilities
were analyzed using subscales IV and VII of the Wechsler Memory
Scale (WMS) (Wechsler, 1987). Neuropsychiatric assessment in-
cluded the Hamilton Anxiety and Depression Scales (HAM-A and
Demographic, clinical, neuropsychological and neuropsychiatric measures expressed by mean (±SD). Maximum scores of the tests are shown in square parentheses.
PD patients, N = 25 Mean (±SD), Min.–Max.On stateOff state
Duration of disease (months)
Duration of motor fluctuations (months)
Duration of levodopa pharmacological treatment (months)
Dose of levodopa (mg per day)a
Unified Parkinson Disease Rating Scale (UPDRS) III*
59.12 (8.98), 39–74
10 (4.90), 5–18
137.60 (42.03), 84–240
52.48 (36.19), 6–156
114.32 (44.05), 48–228
845.0 (359.92), 400–1500
Claridge modified test*
Total score: 4.60 (3.04)3.08 (3.03)
Wechsler Memory Scale
Subtest IV: 
Subtest VII: 
WCST, modified version
Total score: 
Phonemic Fluency Test
Brief Psychiatric Rating Scale*: 
Hamilton anxiety scale*: 
Hamilton depression scale*: 
For MMSE lower scores indicate more severe cognitive impairment.
For Claridge, WMS IV and VII, WCST, Phonemic Fluency Tests higher scores indicate better performance. For the Phonemic Fluency Test the cut off is >16.
For BPRS, HAM-A and HAM-D higher scores indicate more severe symptoms.
Cut off values for: MMSE: 624, Claridge: 64, WCST (Nelson, 1976): >50% of perseverative errors, BPRS: >39, HAM-D: >15, HAM-A: >18.
aAnti-parkinsonian medications were expressed as levodopa equivalent daily dosage (LEDD).
*p < 0.03.
Detailed clinical characteristics of patients. Maximum score for UPDRS III is 56; maximum score for UPDRS-IV, part A is 13. Higher scores indicate severe symptoms.
of LD treatmenta
Duration of diseasea, duration
of motor fluctuationsa
Medication and dosage
600 mg levodopa; 1.5 mg pramipexole
1000 mg levodopa; 20 mg ropinirole
1300 mg levodopa; 3 mg pramipexole
400 mg levodopa; 3 mg pramipexole
1000 mg levodopa; 20 mg ropinirole
1500 mg levodopa; 4.5 mg pramipexole
1149 mg levodopa
1400 mg levodopa
1400 mg levodopa; 2 mg cabergoline
1400 mg levodopa
400 mg levodopa; 4.5 mg pramipexole
600 mg levodopa
800 mg levodopa; 6 mg ropinirole
600 mg levodopa
400 mg levodopa
600 mg levodopa
800 mg levodopa; 3 mg pramipexole
700 mg levodopa; 15 mg ropinirole
1100 mg levodopa; 3 mg pramipexole
400 mg levodopa
1000 mg levodopa; 6 mg pramipexole
400 mg levodopa; 4.5 mg pramipexole
800 mg levodopa; 15 mg ropinirole
800 levodopa; 1.5 mg pramipexole
600 mg levodopa; 15 mg ropinirole
aVariables expressed in months.
M. Amanzio et al./Brain and Cognition 72 (2010) 337–346
HAM-D, Hamilton, 1959, 1960) and the Brief Psychiatric Rating
Scale (BPRS) (Overall & Gorham, 1962). The neuropsychologists
who administered the tests and scales were blind to the aim of
2.3. Assessment of awareness of movement disorders (see Appendix A)
Before undergoing the neuropsychological assessment all pa-
tients were evaluated in terms of their awareness of movement
disorders using three brief scales: (1) the Global Awareness of
Movement (GAM) disorders scale, administered in the on and off
states (2A) the Dyskinesias Rating Scale and (2B) the Hypo-brady-
kinesia Rating Scale.
(1) As far as the GAM was concerned, two simple rating scales,
for global assessment of hypo/bradykinesia and dyskinesia aware-
ness, were created by adapting them from the scale of anosognosia
for hemiplegia suggested by Bisiach, Vallar, Perani, Papagno, and
Berti (1986). Each GAM consisted of 4 levels (0–3), ranging from
good to no awareness of motor deficits. Scores were assigned by
a neurologist experienced in movement disorders and based on
the degree of spontaneity with which subjects reported dyskine-
sias in the on state versus hypokinesias/-bradykinesias in the off
state. Therefore, a high score corresponded to a high level of
unawareness of movement disorders in relation to symptoms of
dyskinesia and hypokinesia.
(2A and 2B) The severity of hypo-bradykinesias and dyskinesias
was evaluated separately by the PD patients and the examiner. Pa-
tients were requested to perform the following simple actions:
write a short sentence, execute some verbal command. Scores were
assigned from 0 (total absence of Dyskinesia and/or Hypo-bradyki-
nesia) to 3 (severe Dyskinesia and/or Hypo-bradykinesia).
Two awareness indexes were calculated by subtracting the pa-
tients’ judgements from those of the neuropsychologists’ on hyper
and hypo-bradykinesias awareness. The two variables were labeled
as the Dyskinesias Subtracted Index (DS-I) and the Hypo-bradyki-
nesias Subtracted Index (HS-I). Higher scores indicated a more se-
vere impairment in terms of reduced awareness of movement
2.4. Awareness of disabilities in activities of daily living and autonomy
level on the NUDS scale
The North University Disability Scale, NUDS (Canter et al., 1961)
was used to evaluate the level of independence versus inability in
basic and instrumental activities of daily living, i.e. walking, getting
dressed, personal hygiene, eating and talking, considered sepa-
rately in the on and off states.
The NUDS consists of 10 questions that were administered both
to our 25 patients and to one of their caregivers/significant other/
close relatives, in order to compare the level of awareness of the
disability. Caregivers provided their evaluations in another room,
separately from the patients, on the same day as the patient’s
assessment. In analyzing the data we considered both patients’
and caregivers’ evaluations of the patients’ disabilities. This scale
was chosen for its relatively good reliability and validity in mea-
suring the impact of motor deficits in activities of daily living (Ra-
maker, Marinus, Stiggelbout, & Van Hilten, 2002).
The awareness index was obtained by subtracting patients’
evaluations of level of autonomy from caregivers’ evaluations of
the patients’ level of disability, and labeled the NUDS Subtracted
Index (NUDS-I) for the on and off states.
Parkinsonian subjects were assessed both the morning before
and after their first daily dose in the off and on states; in particular
about 60–90 min after their morning dose of levodopa, during the
period of maximum benefit from the medication. In the off state
they were assessed after about 12 h of therapeutic withdrawal.
Participants were tested on two different consecutive days. They
were randomly divided into two subgroups: the on subgroup with
12 patients examined first in the on state and the following day in
the off state; and the off subgroup with 13 patients examined first
in the off state and the following day in the on state.
The neuropsychological assessment, in which patients had to
perform on the Claridge, WCST modified version, Phonemic Flu-
ency, subscales IV and VII of the WMS and MMSE were performed
in about 1 h, whereas the complete evaluation session lasted
approximately 2 h.
2.6. Data analysis
Statistical analyses were performed using STATISTICA Software
for Windows (version 4.5 Stat Soft, Inc., 1993). Parametric statistics
were used since an initial exploration of the data set suggested an
acceptable distribution (Skewness <1.00; Kurtosis <3.00). On the
other hand, non-parametric statistics were used for the variables
assessing the awareness of movement disorders.
The sequence of the state effect (on–off versus off–on) was as-
sessed using an ANOVA analysis with the group (on-first then-
off; off-first then-on) as a between-subjects factor and the type
of neuropsychological measurement (i.e.: Claridge in-on versus
Claridge in-off) as a within-subjects factor and post hoc tests. On
the other hand, a series of Kruskal–Wallis tests were run to evalu-
ate the effect of predominantly left versus predominantly right-
side motor symptoms at the onset of disease on the awareness of
Finally, Spearman’s correlation coefficients were used to assess
the relationships between awareness measurements and other
variables. In this case we adopted a Bonferroni correction of the al-
pha value to control for multiple tests.
The caregivers obtained an MMSE score of 28.48 (±1.19) reveal-
ing no difference with the MMSE scores of PD patients in the on
3.1. Motor and cognitive data: on versus off states
Tables 1 and 2 show the demographic and clinical data of all PD
subjects and for each patient. Anti-parkinsonian medications were
expressed as levodopa equivalent daily dosage (LEDD).
All PD patients had no significant difference between states on
their MMSE scores. Parkinsonian patients had a low level of motor
impairment in the on state compared to the off state, assessed on
the basis of UPDRS (part III) data [ANOVA F(1, 48) = 161.991,
p < 0.000001].
3.2. Awareness of movement disorders (see Tables 3 and 4)
Neurologists’ assessments of patients’ unawareness of move-
ment disorders on the GAM were significantly higher for dyskinetic
H(1, 50) = 23.550, p < 0.000001]. A comparison between patients’
and neuropsychologists’ evaluations of awareness of dyskinesias
revealed a significant difference in the on state [Kruskal–Wallis
H(1, 50) = 7.090, p = 0.0078], whereas no significant difference
was observed between patients’ and examiners’ evaluations of
awareness of hypokinesias in the off state [Kruskal–Wallis
H(1, 50) = 0.060, p = 0.807]. Hence, we found a significant differ-
M. Amanzio et al./Brain and Cognition 72 (2010) 337–346
ence between the two indexes of awareness of motor symptoms:
Dyskinesias Subtracted Index (DS-I) and Hypo-bradykinesias Sub-
tracted Index (HS-I), in the on and off states respectively, attesting
the presence of greater unawareness of dyskinesias [Kruskal–Wal-
lis H(1, 50) = 14.997, p = 0.0001].
3.3. Awareness of disabilities in activities of daily living and autonomy
level on the NUDS scale (see Table 5)
A significant difference was observed when comparing disabil-
ity assessment in the on and off states; more specifically, on the
NUDS scale patients described themselves as less impaired in the
on versus the off state [ANOVA F(1, 48) = 51.830, p < 0.000001].
Likewise, caregivers described patients as less impaired in the on
versus the off state [ANOVA F(1, 48) = 77.852, p < 0.000001]. No
differences were observed between the evaluation of the level of
impairment by caregivers and patients in the on state [ANOVA
F(1, 48) = 1.642,
p = 0.206] and
F(1, 48) = 2.378, p = 0.129].
in the offstate [ANOVA
3.4. Influence of sequence (on-first then-off versus off-first then-on) on
demographical and clinical variables
A one-way ANOVA was performed with sequence (on versus
off) as the between factor. No significant difference was observed
between the two subgroups, in terms of age, education, duration
of disease, Hoehn and Yahr stage in the on or off states, UPDRS mo-
tor score in the on and off states, and dose of L-Dopa.
3.5. Influence of sequence (on-first then-off versus off-first then-on) on
The analysis revealed no significant difference between the
groups in terms of sequence and GAM in the on and off states
H(1, 25) = 0.0034769,
H(1, 25) = 0.0121382, p = 0.9123 respectively] and sequence and
DS-I [Kruskal–Wallis H(1, 25) = 0.0009692, p = 0.9752] and HS-I
[Kruskal–Wallis H(1, 25) = 0.8814142, p = 0.3478]. Moreover, anal-
ysis of NUDS-I showed no significant difference in terms of se-
p = 0.9530;
Global Awareness of Movements (GAM) scale of dyskinesias and hypo-bradykinesia
on each patient in the on and off states. Higher scores indicate more severe
impairment in terms of reduced awareness of movement disorders.
Patient codeGAM dyskinesias GAM hypo-bradykinesia
Awareness measures of each PD patient considering dyskinesias (DS-I) and hypo-
bradykinesia (HS-I) motor symptoms. In most cases, considering DS-I, patients
evaluate their symptoms as less serious. DS-I: Dyskinesias Subtracted Index; HS-I:
Hypo-Bradykinesia Subtracted Index.
On stateOff state
Awareness of disabilities in activities of daily living and autonomy level on the NUDS
scale in the on and off states. NUDS-I: NUDS Subtracted Index.
On state Off state
NUDS-I Caregiver PatientNUDS-ICaregiver Patient
The range of scores at NUDS scale is 0–50 points with higher scores indicating more
M. Amanzio et al./Brain and Cognition 72 (2010) 337–346
quence [ANOVA F(1, 23) = 2.7809, p = 0.1089] or in terms of NUDS-
I in the on and off states [ANOVA F(1, 23) = 0.97999, p = 0.3325].
The interaction between sequence and NUDS-I in the on versus
off statesrevealedno significant
F(1, 23) = 0.1330, p = 0.7186].
3.6. Influence of sequence (on-first then-off versus off-first then-on) on
neuropsychological and neuropsychiatric assessment
In particular, the neuropsychological test data were analyzed
using an ANOVA-mixed design with the ‘‘neuropsychological task”
in the on and off states as the within-subjects factor and
‘‘sequence” (on-first-then-off versus off-first-then-on) as the be-
tween-subjects factor. For the Claridge Test the analysis showed
no significant difference between groups in terms of sequence
[F(1, 23) = 0.03, p = 0.87]; on the other hand the Claridge test
[F(1, 23) = 5.18, p = 0.03]. We found no interaction between se-
quence and this type of task performed in the on versus off states
[F(1, 23) = 0.20, p = 0.66].
The analysis of executive functions measured using the WCST
modified version and Phonemic Fluency Test showed no significant
difference asregards sequence
F(1, 23) = 0.33, p = 0.57, respectively] or the task performed in the
on and off states [F(1, 23) = 1.75, p = 0.22; F(1, 23) = 0.79, p = 0.38,
respectively]. The interaction between sequence and these types
of tasks performed in the on versus off states revealed no signifi-
cant difference [F(1, 23) = 0.02, p = 0.90; F(1, 23) = 0.001, p = 0.97,
The analysis of memory measured on subscales IV and VII of the
WMS showed no significant difference in term of sequence
[F(1, 23) = 0.005, p = 0.94; F(1, 23) = 1.173, p = 0.69, respectively]
and interaction between sequence and these types of tasks per-
formed in the on versus off states [F(1, 23) = 1.03, p = 0.34;
F(1, 23) = 2.44, p = 0.157, respectively]. Subscale IV of the WMS
showed no significant difference in terms of tasks performed in
the on and off states [F(1, 23) = 0.014, p = 0.91], whereas subscale
VII did [F(1, 23) = 8.61, p = 0.02].
The analysis of the neuropsychiatric assessment using the BPRS,
HAM-A and HAM-D scales showed no significant difference in
termsofsequence[F(1, 23) = 0.36971,
F(1, 23) = 1.22740, p = 0.279365; F(1, 23) = 0.6467, p = 0.429523,
respectively]. The analysis revealed significant differences between
these three measures in the on and off states, in particular PD pa-
tients scored higher in the off state compared to the on state
[F(1, 23) = 42.90372,
p = 0.000001;
p < 0.000001; F(1, 23) = 168.3730, p < 0.000001, respectively]. In
particular, for the BPRS, the higher scores in the off state were
mainly due to items investigating anxiety and apathetic-depres-
sive symptoms. The interaction between sequence and these three
measures collected in the on versus off states did not reveal a sig-
nificantdifference[F(1, 23) = 0.72993,
F(1, 23) = 0.02929, p = 0.865607; F(1, 23) = 1.9786, p = 0.172903
in theoff and on states
[F(1, 23) = 0.007,
p = 0.94;
p = 0.549122;
F(1, 23) = 55.98681,
p = 0.401717;
3.7. Influence of side of onset on awareness assessment
The analysis revealed no significant differences between the
groups in terms of side of onset and GAM in the on and off states
H(1, 25) = 0.9022219,
H(1, 25) = 0.3499671, p = 0.5541 respectively] and side of onset
and DS-I [Kruskal–Wallis H(1, 25) = 0.1660, p = 0.6837] and HS-I
[Kruskal–Wallis H(1, 25) = 0.0295188, p = 0.8636]. Moreover, the
analysis of NUDS-I showed no significant difference in terms of
side of onset [ANOVA F(1, 23) = 0.8797, p = 0.358] or in terms of
NUDS-I in the on and off states [ANOVA F(1, 23) = 0.9460,
p = 0.3422;
p = 0.341]. The interaction between side of onset and NUDS-I in
the on versus off states revealed no significant difference [ANOVA
F(1, 23) = 0.0027, p = 0.959].
3.8. Correlations between awareness of motor deficits and disability
(NUDS) and the other variables
We used a Bonferroni correction of the alpha value to control for
the multiple test effect. For instance, given that we compared the
three measures of awareness for seven variables of interest (Cla-
ridge and WCST modified version total scores, subscales IV and
VII of the WMS, Phonemic Fluency Test, duration of disease and
LEDD), the adjusted significance level was set at 0.05/7 = 0.007143.
In detail, in the on state, the global assessment of PD patients’
levels of awareness of movement disorders (GAM) was signifi-
cantly related to executive functions in terms of WCST modified
version total scores (R = ?0.53, p = 0.006), suggesting that PD pa-
tients with reduced awareness of motor deficits in the on state per-
formed worse in this executive function task. In the same direction,
we found a significant relationship between subtest IV of the WMS
and the GAM scale (R = ?0.61, p = 0.001). Finally, we observed a
positive relationship between the GAM scale and LEDD (R = 0.55,
p = 0.004).
On the contrary, in the off state we did not observe any relation-
ship between global assessment of PD patients’ levels of awareness
of movement disorders (GAM) and the executive function vari-
ables: WCST modified version total scores (R = ?0.17, p = 0.63)
and with the Phonemic Fluency Test (R = ?0.01, p = 0.95). Nor did
the other variables appear to be related to GAM scores in the off
Analyzing the relationship between DS-I and the other variables
we found no association with neuropsychological tests, but did ob-
serve a relationship between DS-I and duration of disease (R = 0.55,
p = 0.004), suggesting a more severe disease in patients with a
more reduced awareness of their dyskinesia symptoms.
On the contrary, we did not observe significant relationships be-
tween HS-I and other variables, and the NUDS subtracted Index
(NUDS-I) in both the on and off states was not related with the
other variables of interest.
The primary aim of our study was to investigate the awareness
of different movement disorders in PD patients in the on versus the
off state. In our study, converging evidence of a lower awareness of
dyskinesias, compared to a better-preserved awareness of hypo-
bradykinesia, resulted from different and independent evaluations.
Significant differences were found in the comparison between
awareness of dyskinesias in the on state and awareness of hypo-
bradykinesias in the off state assessed by a neurologist using
GAM scales. In particular, the neurologist’s assessment showed re-
duced awareness of dyskinesias in 22 out of 25 patients (see Ta-
ble 3, patients with a score P1), but reduced awareness of hypo-
bradykinetic movement disorders in only 6 out of 25 patients
(see Table 3, patients with a score = 1). On the same line, levels
of movement disorder awareness in the on state appeared to be re-
duced in our parkinsonian patients when analyzing the discrep-
assessments of the severity of dyskinesias (DS-I) and between pa-
tients’ and neuropsychologists’ assessments of severity of hypo-
bradykinesia (HS-I). We also observed a significant difference be-
tween patients’ and neuropsychologists’ scores for dyskinesias in
the on state, whereas in the off state we did not observe a signifi-
cantdifference between patients’
M. Amanzio et al./Brain and Cognition 72 (2010) 337–346
Low awareness of dyskinesias depends on a number of ele-
ments, e.g. the complex influence of dopaminergic treatment
on cognitive, behavioral and executive functions. As far as cogni-
tive status and awareness of movement disorders are concerned,
previous studies in parkinsonian patients (Leritz et al., 2004;
Seltzer et al., 2001) found a relationship between these, although
they did not analyze unawareness of motor problems differenti-
ating the on and off states. In particular, Leritz et al. (2004) at-
tested that unawareness may become more evident when
general cognition is more compromised, as in the later stages
of disease, when the cortical brain regions become more af-
fected. In line with this observation, Seltzer et al. (2001), using
patient-caregiver report discrepancies to assess awareness of
deficits in a sample of AD and PD patients, showed that when
the PD group was broken down into cognitively impaired and
cognitively intact, the intact group demonstrated appropriate
awareness across all domains; this study also suggested that
the level of cognitive functioning is a critical mediating variable
in awareness of deficits. This statement was not confirmed by
our findings. In particular, in our cognitively intact PD patients
we only observed unawareness of movement disorders in the
on state, attesting the importance of dopaminergic therapy
inducing dyskinesias by acting on the basal ganglia and by stim-
ulating mesocorticolimbic pathways. In analyzing cognitive func-
tions in PD, Gotham, Brown, and Marsden (1988) observed a
positive effect of levodopa on alternating fluency (we reached
the same result with the Phonemic Fluency Test), but a negative
effect on conditional associative learning. These differences could
be explained by the fact that the dopaminergic effects on behav-
ioral and cognitive functions depend on the baseline level of per-
formance (Kimberg, D’Esposito, & Farah, 1997; Mattay et al.,
2000; Mehta et al., 2000). In particular, if the circuit is depleted,
dopaminergic treatment improves the function; on the contrary,
a detrimental effect occurs in case of dopaminergic overstimula-
tion of a non-depleted circuit. As far as prefrontal involvement in
Parkinson’s disease is concerned, dopaminergic treatment im-
proves executive functions related to the cortical–subcortical
network from the dorsolateral prefrontal cortex to the dorsal
caudate nucleus (for example, switching between two tasks as
in the case of the Claridge test), which is dopamine depleted.
On the contrary, the same dopaminergic treatment impairs func-
tions connected to the orbitofrontal cortex–ventral striatal cir-
cuitry, such as probabilistic reversal learning (Cools, Barker,
Sahakian, & Robbins, 2001). A comparison between the on and
off states in our PD patients showed differences in clinical, neu-
ropsychological and neuropsychiatric assessment. In detail, in
the on state, as expected, parkinsonian patients showed better
motor performance than in the off phase of the disease (see
UPDRS-part III scores). Moreover, cognitive and neuropsychiatric
assessment revealed differences between the off and on states.
In particular, performance on the Claridge modified test was bet-
ter in the on state, with fewer omissions and false alarms, sug-
gesting a slight impairment in executive functions, in terms of
selective attention, in the off state. As also reported by other
authors, the inability to perform several types of attention tasks
(Pahwa & Koller, 1998; Raskin, Borod, & Tweedy, 1990; Ridenour
& Dean, 1999) observed in PD patients appears to be predomi-
nantly secondary to impaired inhibitory mechanisms (Zgaljardic,
Borod, Foldi, & Mattis, 2003). Our patients in the off state also
exhibited poor performance on a memory task of the VII sub-
scale of the WMS, compared to the on state. Other authors have
attributed this phenomenon to frontal executive deficits (Taylor
et al., 1986). In particular, difficulty in initiating and effectively
maintaining search strategies, despite preserved encoding and
recognition, is reportedly mediated by the dorsolateral prefrontal
cortex (Lichter, 2000), supporting the notion that the memory
impairments described in PD most likely reflect an executive
behavioral, in the off state PD patients also showed higher levels of
anxiety, depressive and apathetic symptoms, as revealed by scores
in the on phase had a low level of depressive mood; in fact no pa-
tientshad been diagnosed as having major depression or dysthymia
based on DSM-IV criteria (1994). This is an important element to be
considered when studying awareness, because depressed patients
may view themselves negatively, and be biased toward reporting
confirmed that most of our PD patients in the off state showed signs
and behavior (lack of interest and reduced emotional responsive-
ness). These neurobehavioral findings could be related to physical
minergic treatment may also have a relief effect on apathetic symp-
tomatology in the on state (Czernecki et al., 2002). Apathetic
syndrome is reported to be frequent in PD patients (Aarsland, Cum-
mings, & Larsen, 2001; Aarsland et al., 1999; Aarsland, Litvan, & Lar-
sen, 2001; Isella, Melzi, & Grimaldi, 2002; Pluck & Brown, 2002;
tion due to nigro-striatal dopaminergic loss caused the capacity of
the frontal cortex to select, initiate, maintain and shift a program
of actions to be impaired (Levy & Dubois, 2006). Czernecki et al.
onstrated a significant difference in the severity of apathy between
the off and on states in fluctuating PD patients, suggesting that apa-
thy is at least partly a dopamine–dependent syndrome. Both cogni-
the off state could be related to a slight dysfunction in the frontal–
subcortical associative loops (Alexander, DeLong, & Strick, 1986).
Our hypothesis for explaining low awareness of dyskinesias is
that levodopa treatment may produce a detrimental effect on the
function of the orbitofrontal and cingulated frontal–subcortical
loops; these projections appear to be critical in the awareness phe-
nomenon (Leritz et al., 2004; Seltzer et al., 2001). Our parkinsonian
patients were selected for their intact cognitive status; however,
low awareness of dyskinesias in the on state was found to be re-
lated to poorer performance in the WCST and on a memory task
of subscale IV of the WMS. This finding supports the influence of
a reduced functionality in the anterior cingulated cortex, during
dopaminergic stimulation, even without excluding a role of the
frontostriatal circuits. A recent PET study on healthy subjects
(Lumme, Aalto, Ilonen, Någren, & Hietala, 2007) actually showed
that errors in the WCST correlated with dopaminergic D2/D3 bind-
ing in the right anterior cingulated 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 ventrolat-
eral prefrontal cortex (BA 47/12) and anterior cingulate cortex (BA
32) in terms of increased activity during the reception of negative
feedback from subjects on performance. Contextually, Monchi, Pet-
rides, Mejia-Constain, and Strafella (2007) recently investigated
the fMRI activation of 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
M. Amanzio et al./Brain and Cognition 72 (2010) 337–346
activity is closely related to the monitoring of events in working
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
error detection in performance monitoring (Gehring & Knight,
2000; Luu, Flaisch, & Tucker, 2000). All these elements are impor-
tant 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 im-
paired judgment capacity or metacognitive competence. In partic-
ular, 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 sup-
ports 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 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 found a relation
between GAM and WCST and GAM and WMS IV scores on ‘‘med”
only. This was not observed for Claridge and WMS VII, in which
probably the general response monitor competence may have a
Judgement ability and metacognitive competence are likely in-
volved in the self-assessment of activities of daily living; the com-
parison between NUDS-I in the on state and NUDS-I in the off state
did not show any difference; 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 be-
tween 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 seem 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).
The main interpretative problem related to our topic was the
difficulty of disentangling the role of levodopa treatment (on state
versus off state) and the role of movement disorder (hyperkinesia
versus hypokinesia) in low awareness of dyskinesias. Low aware-
ness of hyperkinesias has been found in other neurological dis-
eases, for example in Huntington’s disease (Deckel & Morrison,
1996; Ho, Robbins, & Barker, 2006; Snowden, Craufurd, Griffiths,
& Neary, 1998; Vitale et al., 2001), in tardive dyskinesia (Cohen &
Cohen, 1993) and in patients with lesions of the basal ganglia (Laz-
zarino & Nicolai, 1991). These studies may support a crucial rela-
tionship between dyskinesias and low awareness observed in our
study. Dyskinesias are usually absent in parkinsonian patients in
the off state; however, if we consider the hyperkinetic domain of
movement disorders, resting tremor can be found in the off state.
It is important to underline that we did not investigate awareness
of tremor in our patients because in many cases this symptom was
absent or only slight and had no important influence on actions.
Even in those few cases, patients with tremor did not show
unawareness of this hyperkinetic symptom in the off state.
In PD patients the progression of dopaminergic degeneration,
also in situations complicated by motor fluctuations, as in our par-
kinsonian group, could involve the dorsal part of the striatum more
than the ventral striatum (Agid et al., 1993; Kish et al., 1988). Levo-
dopa treatment limits motor impairment, associated with the dor-
sal striatum; therefore, high dosages of levodopa improve
parkinsonian motor symptoms but could have a detrimental effect
on the ventral system and account for the low awareness of dyski-
nesias in the on state; the relationship between low awareness of
dyskinesias (GAM-scale) in the on state and LEDD supports this
hypothesis. In line with this interpretation, we observed relation-
ships between the discrepancy between patients’ and neuropsy-
chologists’ assessments of severity of dyskinesias (DS-I) and
duration of disease. Both duration and severity of disease may be
associated with frontal lobe impairment (especially of the ventro-
lateral prefrontal cortex) as shown in HD subjects (Folstein, Fol-
stein, & Brandt, 1990).
It is also important to underline the relationship between the
mesocorticolimbic dopaminergic system and reward mechanisms
in PD patients. This appears to be an important point to be consid-
ered in this area of research as some patients with particular neu-
Dysregulation (HHD) develop severe but surprisingly well-toler-
ated drug-induced dyskinesias, which do not particularly bother
them. Since HHD is not a common phenomenon (Giovannoni,
O’Sullivan, Turner, Manson, & Lees, 2000), and this psychiatric dis-
order was not represented in our PD population, we can exclude
that this type of dysfunction in the mesocorticolimbic dopaminer-
gic system related to reward and addiction represents a biasing
factor in our results. However, we are aware of the importance of
including specific tests in future studies to directly explore the
activity of the mesocorticolimbic network, i.e. probabilistic learn-
ing (Cools et al., 2001) and the prospect of a reward.
In conclusion, our findings demonstrate that unawareness of
movement disorders may also occur in cognitively unaffected PD
patients. This element has important implications for managing
this particular class of pathology. In particular, low awareness of
dyskinesias in the on state appears to be related to metacognitive
deficits in the self-monitoring system. Finally, in our study we did
not find the side of onset of disease to be salient in predicting
unawareness of movement disorders as shown by Leritz et al.
(2004). A possible explanation for this difference is the selection
of PD patients. In particular, we selected a sample with a more se-
vere degree of the disease, in which the degeneration asymmetries
are probably attenuated.
The authors thank the three anonymous reviewers for their
contribution to the improvement of the manuscript. This work
was supported by grants from Fondazione CRT, Progetto Alfieri.
A.1. The Global Awareness of Movement (GAM) Disorders scale1
(0) When questioned by the examiner, about his/her state of
health, the patient spontaneously reported the presence of
involuntary movements (in the on state if present) or motor
hindrance (in the off state if present).
(1) The patient reported the presence of involuntary move-
ments (in-on) and motor hindrance (in-off), but only after
an explicit request by the examiner concerning those motor
1The GAM scales were created by adapting them from the scale of Bisiach et al.
M. Amanzio et al./Brain and Cognition 72 (2010) 337–346
(2) The patient only admitted the presence of involuntary
movements and motor hindrance after focusing attention
on his/her evident dyskinesias on any part of the body and
after a request to perform fine movements (i.e. a prona-
tion/-supination hand task), which was done with evident
difficulty or slowness (not due to his/her dyskinesias).
(3) The patient did not admit the presence of his/her evident
motor disturbances, even after the above mentioned
A.2. The patient was requested to perform the following three simple
– Write down a sentence: ‘‘Oggi e’ una bella giornata di prima-
vera” (Today is a lovely spring day).
– Hold a half-full glass in his/her hands, bring it up to the mouth
and put it down again (patient is sitting at the table).
– Stand up from a chair, walk for two meters, go back to the chair
and sit down again.
The actions were rated using the following scales of dyskinesias
[2A] and hypo-bradykinesias [2B]
2A. Dyskinesias Rating Scale
(1) Slight dyskinesias (slightly visible).
(2) Moderate dyskinesias (clearly evident but without signifi-
cant impact on the result of the execution of the actions,
except in particularly fine tasks).
(3) Severe dyskinesias (clearly evident and with a negative
impact in the result of the execution of the actions).
ofdyskinesias(unusual and involuntary
2B. Hypo-bradykinesias rating scale
(0) Absence of hypo-bradykinesias (difficulty or slowness of
(1) Slight hypo-bradykinesias (slightly evident, only during the
execution of fine movements, such as writing).
(2) Moderate hypo-bradykinesias (clearly evident but without
impacton the execution
(3) Severe hypo-bradykinesias (clearly evident and impacting
on the execution of actions).
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