Attenuated neural response to gamble outcomes in drug-naive patients with Parkinson's disease

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DOI: 10.1093/brain/awt027 · Source: PubMed
Abstract
Parkinson's disease results from the degeneration of dopaminergic neurons in the substantia nigra, manifesting as a spectrum of motor, cognitive and affective deficits. Parkinson's disease also affects reward processing, but disease-related deficits in reinforcement learning are thought to emerge at a slower pace than motor symptoms as the degeneration progresses from dorsal to ventral striatum. Dysfunctions in reward processing are difficult to study in Parkinson's disease as most patients have been treated with dopaminergic drugs, which sensitize reward responses in the ventral striatum, commonly resulting in impulse control disorders. To circumvent this treatment confound, we assayed the neural basis of reward processing in a group of newly diagnosed patients with Parkinson's disease that had never been treated with dopaminergic drugs. Thirteen drug-naive patients with Parkinson's disease and 12 healthy age-matched control subjects underwent whole-brain functional magnetic resonance imaging while they performed a simple two-choice gambling task resulting in stochastic and parametrically variable monetary gains and losses. In patients with Parkinson's disease, the neural response to reward outcome (as reflected by the blood oxygen level-dependent signal) was attenuated in a large group of mesolimbic and mesocortical regions, comprising the ventral putamen, ventral tegmental area, thalamus and hippocampus. Although these regions showed a linear response to reward outcome in healthy individuals, this response was either markedly reduced or undetectable in drug-naive patients with Parkinson's disease. The results show that the core regions of the meso-cortico-limbic dopaminergic system, including the ventral tegmental area, ventral striatum, and medial orbitofrontal cortex, are already significantly compromised in the early stages of the disease and that these deficits cannot be attributed to the contaminating effect of dopaminergic treatment.
BRAIN
A JOURNAL OF NEUROLOGY
Attenuated neural response to gamble outcomes in
drug-naive patients with Parkinson’s disease
Joyce P. M. van der Vegt,
1,2
Oliver J. Hulme,
1
Simone Zittel,
3,4
Kristoffer H. Madsen,
1
Michael M. Weiss,
5
Carsten Buhmann,
4
Bastiaan R. Bloem,
2
Alexander Mu
¨
nchau
3,4
and
Hartwig R. Siebner
1
1 Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
2 Department of Neurology, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, 6500 HB
Nijmegen, The Netherlands
3 Department of Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lu¨ beck, 23562 Lu¨ beck,
Germany
4 Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
5 Department of Neurology, Christian-Albrechts-University, 24105 Kiel, Germany
Correspondence to: Prof. Hartwig R. Siebner (MD),
Danish Research Centre for Magnetic Resonance,
Copenhagen University Hospital Hvidovre,
Kettegaard Alle
´
30,
DK-2650 Hvidovre,
Denmark
E-mail: hartwig.siebner@drcmr.dk
Parkinson’s disease results from the degeneration of dopaminergic neurons in the substantia nigra, manifesting as a spectrum of
motor, cognitive and affective deficits. Parkinson’s disease also affects reward processing, but disease-related deficits in re-
inforcement learning are thought to emerge at a slower pace than motor symptoms as the degeneration progresses from dorsal
to ventral striatum. Dysfunctions in reward processing are difficult to study in Parkinson’s disease as most patients have been
treated with dopaminergic drugs, which sensitize reward responses in the ventral striatum, commonly resulting in impulse
control disorders. To circumvent this treatment confound, we assayed the neural basis of reward processing in a group of newly
diagnosed patients with Parkinson’s disease that had never been treated with dopaminergic drugs. Thirteen drug-naive patients
with Parkinson’s disease and 12 healthy age-matched control subjects underwent whole-brain functional magnetic resonance
imaging while they performed a simple two-choice gambling task resulting in stochastic and parametrically variable monetary
gains and losses. In patients with Parkinson’s disease, the neural response to reward outcome (as reflected by the blood oxygen
level-dependent signal) was attenuated in a large group of mesolimbic and mesocortical regions, comprising the ventral puta-
men, ventral tegmental area, thalamus and hippocampus. Although these regions showed a linear response to reward outcome
in healthy individuals, this response was either markedly reduced or undetectable in drug-naive patients with Parkinson’s
disease. The results show that the core regions of the meso-cortico-limbic dopaminergic system, including the ventral tegmental
area, ventral striatum, and medial orbitofrontal cortex, are already significantly compromised in the early stages of the disease
and that these deficits cannot be attributed to the contaminating effect of dopaminergic treatment.
Keywords: fMRI; reward; mesolimbic system; Parkinson’s disease; drug-naive
doi:10.1093/brain/awt027 Brain 2013: 136; 1192–1203 | 1192
Received October 8, 2012. Revised December 7, 2012. Accepted December 27, 2012. Advance Access publication February 26, 2013
ß The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
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Introduction
Although Parkinson’s disease is primarily characterized as a move-
ment disorder, there has been growing attention towards the
non-motor disturbances in sensory, affective and cognitive do-
mains (Lyons and Pahwa, 2011; Chen et al., 2012). The clinical
spectrum of Parkinson’s disease comprises a wide range of
non-motor symptoms such as autonomic dysfunction, hyposmia
and psychiatric and sleep disorders (Langston, 2006; Gallagher
et al., 2010). These non-motor symptoms are increasingly recog-
nized as important factors affecting the patient’s quality of life
(Langston, 2006; Soh et al., 2011). Several recent studies have
shown that many non-motor symptoms, in particular depression,
anxiety, rapid eye movement sleep disorder and hyposmia may
precede the onset of motor symptoms in Parkinson’s disease
(Alonso et al., 2009; Jacob et al., 2010; Kano et al., 2011;
Lyons and Pahwa, 2011; Wu et al., 2012; Yu et al., 2012).
Along similar lines, personality changes such as increasing intro-
version and decreased novelty seeking have been identified as
possible preclinical signs (Kano et al., 2011), and have been
hypothesized to result from a relatively early degeneration of the
mesolimbic dopaminergic pathways that extend beyond classical
nigrostriatal motor circuits (Ross et al., 2000; Braak et al., 2003,
2004; Kano et al., 2011). Such deficits in novelty seeking and
approach behaviour are congruent with the emerging consensus
that dopamine is a transmitter involved in the computation of
short-term reward prediction errors (phasic dopamine) and the
long-term reward expectations (tonic dopamine) (Dayan and
Balleine, 2002; Montague et al., 2004; Berridge, 2007; Glimcher,
2011).
Some non-motor symptoms that are associated with Parkinson’s
disease reflect deficits in motivational drive and reward processing.
Many patients suffer from depression and apathy, defined as a
loss of motivation and interest and a reduction in effortful
behaviour (Aarsland et al., 2012; Gallagher and Schrag, 2012).
For instance, in a prospective study on 80 patients with
Parkinson’s disease, 50% showed signs of apathy, and 30% of
these did not express co-morbidity with depression (Kirsch-Darrow
et al., 2006).
Another major motivational dysfunction, encountered in up to
13.6% of patients receiving dopamine replacement therapy, is the
inability to appropriately control impulses to engage in rewarding
behaviours. The clinical spectrum is broad and includes hypersexu-
ality, compulsive shopping, pathological gambling, punding, com-
pulsive eating, as well as compulsive use of dopaminergic
medication (Weintraub et al., 2010; Ambermoon et al., 2011;
Voon et al., 2011; Vilas et al., 2012). These impulse control dis-
orders often have major adverse consequences on the quality of
life of the patient and their caregivers (Wolters et al., 2008).
Multiple intrinsic and extrinsic factors are thought to contribute
to impulse control disorders in Parkinson’s disease. Male gender,
early disease onset, depression, pre-existing recreational drug or
alcohol use, and novelty seeking personality traits are associated
with a higher prevalence of impulse control disorders. However,
dopamine replacement therapy, in particular the treatment with
dopamine agonists, constitutes the main risk factor for developing
impulsive behaviours (Weintraub et al., 2010; Ambermoon et al.,
2011; Cilia and van Eimeren, 2011). The relevance of dopamine
treatment for the manifestation of impulse control disorders is
further supported by the fact that untreated patients with
Parkinson’s disease do not differ in impulse control disorder
frequency from healthy control subjects (Antonini et al., 2011;
Cilia et al., 2011). Because the mesolimbic dopaminergic system
is relatively less affected by the neurodegenerative process than
the mesostriatal dopaminergic system, the occurrence of impulse
control disorders has been attributed to a relative overstimulation
of the mesolimbic system by dopamine treatment (Morrish et al.,
1996; Booij et al., 1999; Cools et al., 2003; Braak et al., 2004).
Complementary to the ‘overdose hypothesis’, it has been
hypothesized that a pre-existing dysfunction of the mesocortico-
limbic pathway may predispose to impulse control disorders in
patients with Parkinson’s disease (Balarajah and Cavanna, 2012).
The high prevalence of motivational deficits such as depression
or apathy, which often precede the onset of motor symptoms, as
well as the risk of inducing impulse control deficits when starting
dopamine treatment suggest that the meso-cortico-limbic circuits
are already dysfunctional early in the disease before the adminis-
tration of dopamine medication. However, this hypothesis remains
to be explicitly addressed, since reward function in Parkinson’s
disease has almost exclusively been probed in patients who had
ongoing or prior dopamine therapies. Such studies reveal that pa-
tients with Parkinson’s disease tend to make suboptimal choices
(relative to healthy control subjects) in gambling tasks, and appear
to be hypersensitive to rewards and hyposensitive to punishment
(Robinson and Berridge, 1993; Czernecki et al., 2002; Thiel et al.,
2003; Perretta et al., 2005; Abou-Sleiman et al., 2006; Mimura
et al.,
2006; Berridge, 2007; Schott et al., 2007; Kobayakawa
et al., 2008, 2010; van Eimeren et al., 2009; Frosini et al. ,
2010; Housden et al., 2010; Schonberg et al., 2010; Voon
et al., 2010). A hypersensitivity to rewarding cues appears to be
particularly associated with impulse control disorders. In two
11
C-raclopride PET studies, patients with impulse control disorders
showed a greater endogenous dopamine release during gambling
(Steeves et al., 2009) and in the context of reward-related cues
(O’Sullivan et al., 2011) relative to patients without an impulse
control disorder. While most of this evidence is congruent with a
hyper-dopaminergic dysfunction, it remains to be shown whether
this reflects a primary dysfunction or is driven by the confounding
effects of dopamine treatment.
Using functional MRI, this study was designed to characterize
the function of meso-cortico-limbic circuits in de novo patients
who have been newly diagnosed with Parkinson’s disease. Given
that the disease process is most likely related to a hypo-
dopaminergic state (Schott et al., 2007; Bodi et al., 2009), our
central hypothesis was that in the absence of ongoing or prior
dopamine treatment, the reward responsivity of the meso-
cortical-limbic system would already be attenuated in the early
motor stage of Parkinson’s disease. Additionally, we hypothesized
that this impaired reward responsivity would correlate with clinical
measures of disease severity as reflected by the Movement
Disorder Society Unified Parkinson’s Disease Rating Scale score
(Goetz et al., 2007). We tested these hypotheses by probing func-
tional responses of the mesolimbic and mesocortical systems while
Reduced reward sensitivity in PD Brain 2013: 136; 1192–1203 | 1193
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recently diagnosed drug-naı¨ve patients with Parkinson’s disease
engaged in a simple probabilistic gambling task.
Materials and methods
Subjects
Thirteen de novo patients with Parkinson’s disease (eight males, mean
age: 58 10 years) who were naive to dopamine medication and 12
healthy control subjects (five males, mean age: 60 7 years) without
a history of impulse control disorders or other psychiatric or neuro-
logical symptoms participated in the study (Table 1). Written consent
was obtained from all participants according to the Declaration of
Helsinki, and the study was approved by the local research ethics
committee. Newly diagnosed patients with Parkinson’s disease were
prospectively recruited from the outpatient clinic for movement dis-
orders at the Department of Neurology, University Medical Centre
Hamburg-Eppendorf, Hamburg, Germany. Diagnosis of Parkinson’s
disease had been made within a 2-week period before testing by a
movement disorder specialist (C.B.) in accordance with the UK
Parkinson’s Disease Society Brain Bank clinical diagnostic criteria. The
inclusion criterion was that patients had not previously been treated
with dopamine drugs. Additionally, patients should not have under-
gone a diagnostic levodopa test in the 12 months before the study.
Three patients had a low dose acute levodopa test in the past (42
years ago), but had not used any dopamine medication since then.
The reported onset of motor symptoms ranged from 0.5 to 5 years
(median symptom duration: 3 years).
Prior to scanning, all subjects were examined using the Movement
Disorder Society Unified Parkinson’s Disease Rating Scale (Goetz et al.,
2007) motor rating scale (part III) and classified according to the
Hoehn and Yahr (Hoehn and Yahr, 1967; Goetz et al., 2004) and
Schwab and England scales (Schwab, 1968). Global cognitive function
was assessed using the Mini-Mental State Examination (Folstein et al.,
1975). Presence of depression was measured using Beck Depression
Inventory II (Psychological Corporation). To rule out increased
risk-taking behaviour or the presence of problematic gambling, we
used the Barratt Impulsiveness Scale (Patton et al., 1995) and the
Gambling Addiction Questionnaire of the Berlin Gamblers Advisory
Committee. Through a clinical interview with the patients and if
available through their spouses, we ascertained that none of the
patients had explicit recall of any impulse control disorder-like behav-
iours or reported typical symptoms associated with impulse control
disorders such as pathological gambling, compulsive sexual behaviour,
compulsive shopping, compulsive/binge eating or punding.
Gambling task
During each functional MRI acquisition session (60 trials), participants
engaged in a simple gambling task (Fig. 1) that has been shown to
reliably elicit reward-related responses in the basal ganglia (Yacubian
et al., 2006). A similar version of the gambling task has been used in
a previous study that revealed abnormalities in reward responsivity
in ventral striatum in pathological gamblers (Reuter et al., 2005).
At the onset of each trial, two playing cards were presented
alongside iconic representations of the money (low-stake = 2 E,or
high-stake = 5 E) which could be lost or won. Subjects were required
to decide within 3 s which card to gamble on. Subjects indicated their
decision by a button press (right index for left, or middle for right) and
after a jittered period (1–7 s, flat probability distribution) the outcome
was revealed. Between trials there was also a jittered resting period (1–
7 s, flat probability distribution). Outcome contingencies were set and
explicitly instructed to the participants, so that red cards resulted in
winning the stake, black cards in losing. A running total amount of
cumulative gains and losses was displayed above the card at all times
during the trial.
Each subject was randomly assigned to one of five preset
pseudo-randomized sequences of gambling trials. In macaque mon-
keys, phasic dopaminergic responses have been shown to be max-
imally responsive to unpredictable outcomes, and at the single cell
level within the ventral tegmental area and substantia nigra, firing
rates are commonly maximal for reward probabilities of 0.5 (Schultz
et al., 2008). Therefore, gamble probabilities were set to 0.5 for win-
ning versus losing. Stimuli were presented by back-projection, viewed
using a head-coil mirror. Task presentation and recording of behav-
ioural responses were performed using the software Presentation
(Neurobehavioral Systems, Inc.). Before scanning, subjects received a
standardized verbal description of the task, in which they were in-
structed not to press the same button constantly, and truthfully in-
formed of the outcome probabilities and that the cumulative total
would be realized in physical currency at the end of the experiment
after 60 gambles. To ensure task competence, subjects were trained
on the task outside the scanner (10–15 trials).
Functional magnetic resonance imaging
data acquisition and analysis
Functional MRI scanning was performed on a 3 T MRI Scanner
(Siemens Trio, Siemens) with a 12-channel head coil. Thirty-eight
transversal slices (slice thickness 3 mm) were acquired in each
volume (repetition time: 2.5 s; echo time 34 ms; flip angle: 90
: field
of view 216 mm) using gradient echo T
2
*-weighted echo planar ima-
ging. The first three volumes of each participant were discarded to
eliminate T
1
saturation effects. High-resolution (1 mm
3
voxel size)
T
1
-weighted images were acquired for each subject, using a
MP-RAGE sequence.
Our regions of interest in the basal ganglia are vulnerable to accu-
mulation of iron in Parkinson’s disease (Bartzokis et al., 1994;
Pfefferbaum et al., 2010). We therefore compared the individual
signal strength in the basal ganglia (defined according to WFU
Pickatlas; Maldjian et al., 2003) between groups to rule out whether
Table 1 Demographics, test scores and task performance of
unmedicated
de novo
patients with Parkinson’s disease and
control subjects
Patients Controls
Number (males) 13 (8 males) 12 (5 males)
Age (years) 58 ( 10) 60 ( 7)
Disease duration (years) 3.0 Not applicable
UPDRS motor score (SD) 25.6 ( 8.7) 0.1 ( 0.3)
MMSE (SD) 29.7 ( 0.7) 29.6 ( 0.8)
BIS 66.0 ( 5.6) 65.3 ( 5.8)
GAQ 0.3 ( 1.1) 0.25 ( 0.62)
Mean response times (s) 1.06 ( 0.19) 1.08 ( 0.23)
Missed card choices % (range) 3.3 (0–11.7) 0.8 (0–11.7)
BIS = Barratt Impulsiveness Scale; GAQ = Gambling Addiction Questionnaire;
MMSE = Mini-Mental State Examination; UPDRS = Unified Parkinson’s
Disease Rating Scale.
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blood oxygen level-dependent signal changes in the basal ganglia
were due to structural or morphological confounds.
Data preprocessing and analysis were performed using statistical
parametric mapping 8 (SPM8; Wellcome Department of Imaging
Neuroscience, London, UK). Data preprocessing consisted of realign-
ment (rigid body motion correction), segmentation of the high-
resolution T
1
image, to which the functional images then were
co-registered. All images were spatially normalized to Montreal
Neurological Institute (MNI) space using the normalization parameters
obtained from the segmentation procedure and subsequently
smoothed with a Gaussian kernel of 8 mm full-width at half maximum.
First level data analysis was performed on each subject using the
general linear model in which events of interest were modelled as stick
functions convolved with a canonical haemodynamic response
function, as implemented in SPM8. To model the choice phase, we
constructed two regressors time-locked to the onset of the choice to
independently model high and low stake trials. Note that the choice
phase included both the button-press and a period of outcome antici-
pation, which could not be separated in this design due to their
complete co-linearity. To model the outcome phase we constructed
four regressors (time-locked to onset of the outcome) for all factorial
combinations of outcome (win versus loss), and value (high versus
low). Twenty-four movement regressors were extracted to model
residual effects of movement after rigid body realignment (Friston
et al., 1996). Modelling of residual effects of movement after rigid
body realignment was handled by adding a Volterra expansion of the
movement parameters as nuisance regressors in the general linear
model. This filter contains the six motion parameters estimated from
the rigid body realignment procedure as well as the parameters from
the previous volume to take care of spin history effects. Also the filter
is expanded to second order (movement parameters squared) giving a
total of 24 additional free parameters in the estimation of the general
linear model.
After model estimation the planned contrasts for each event type
were computed using one sample t-tests (unless otherwise specified).
The contrast images from each subject were entered in a group-level
random effects analysis. We computed one-way ANOVAs separately
for all choice and outcome events. To compare motor activity at the
time of button press in the choice phase, we created a first order
contrast for (Choice) between groups on the second level. We created
a first-order parametric linear t-contrast for (wins versus losses) for the
groups separately and between groups.
All statistical inferences applied a significance threshold of P 5 0.05
after correction for multiple comparisons. Correction was performed
using the family-wise error (FWE) at the cluster level using the
family-wise error correction method as implemented in SPM. We
used an uncorrected threshold of P 5 0.001 to define the extent of
each cluster.
The mesolimbic and mesocortical regions defined as regions of inter-
est, included the ventral tegmental area, ventral striatum, putamen,
caudate nucleus, thalamus, hippocampus and medial orbitofrontal
cortex. Where region of interest analysis was performed, correction
for number of regions of interest was performed, unless otherwise
stated. For each region of interest we used the anatomical region as
defined in the WFU Pickatlas (Maldjian et al., 2003). For activations
outside the predefined regions of interest, FWE correction considered
all voxels in the brain. Note that all statistical parametric maps shown
were thresholded at an uncorrected P 5 0.001 for display purposes.
Relative blood oxygen level-dependent signal changes were computed
using the rfxplot toolbox (Glascher, 2009), and x, y, z in figures refer
to the coordinates of the peak voxel in MNI stereotactic space. Unified
Parkinson’s Disease Rating Scale motor scores and Barratt
Impulsiveness Scale scores were taken to the random effects level as
covariates of interest, where age was treated as a nuisance covariate.
Reaction times and other behavioural data were statistically analysed
using SPSS (SPSS Inc.). For behavioural data analyses, significance level
was set at P 5 0.05 and group data are given as mean standard
deviation (SD).
Results
Behavioural data and motor scores
The clinical data as well as the group data for each test are listed
in Table 1. Thirteen dopamine-naive patients with Parkinson’s dis-
ease and 12 healthy control subjects completed the experiment
(additionally one patient with Parkinson’s disease and six control
subjects were excluded due to non-compliance and technical
problems). Mean Unified Parkinson’s Disease Rating Scale motor
score of the 13 drug-naive patients was 25.6 ( 8.7 SD). At the
time of study, clinical tests and a detailed clinical interview yielded
no evidence of depressive disorder (Beck Depression Inventory II
mean 5.8 4.6 SD, maximal Beck Depression Inventory II score:
63), dementia (Mini-Mental State Examination 29.7 0.7 SD,
cut-off point: 25), increased risk-taking behaviour (Barratt
Impulsiveness Scale 66 5.6 SD, maximal Barratt Impulsiveness
Scale score: 120), or pathological gambling (Gambling Addiction
Questionnaire 0.3 1.1 SD, maximal Gambling Addiction
Questionnaire score: 20).
Response times for gamble performance did not differ between
groups [patients with Parkinson’s disease: 1.06 0.19 s versus
healthy control subjects: 1.08 0.23 s; two-sample t-test:
Figure 1 Design of the gambling task. At trial onset (choice
phase) participants were dealt two playing cards, alongside
iconic representation of the money at stake, either 2 E
(low-stake) or 5 E (high-stake). Subjects were instructed to
select, with a right-hand button press (index finger for left card,
middle for right), which card to select within 3 s. During a jittered
period of anticipation (1–7 s) the card was revealed resulting in
the monetary gain or loss of the stake (red card signalled
winning outcomes, black losses). Between trials there is a jittered
period of rest (1–7 s). A cumulative total was displayed above
the card at all times during the trial. Probability of winning was
50% and remained constant throughout.
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P = 0.81, confidence interval (CI): 0.16–0.20] and there was no
significant difference in choice probability between right or left
card choices within (paired t-test: patients with Parkinson’s dis-
ease: P = 0.38, CI: 10.3–4.3; healthy control subjects: P = 0.94
CI: 10.7–10.0) and between groups (two-sample t -test: Right:
P = 0.57, CI: 7.9–4.5; Left: P = 0.73, CI: 4.7–6.7). The per-
centage of trials in which the choice period expired without a
choice was negligible (median, patients with Parkinson’s dis-
ease = 3.3%, control subjects = 0.8%) and not significantly differ-
ent between groups (Mann–Whitney U-test, Z = 1.44, P = 0.15,
healthy control subjects mean rank: 10.88, patients with
Parkinson’s disease mean rank: 14.96).
Functional magnetic resonance imaging
Comparison of signal strength
We compared the signal strength in the basal ganglia between
groups, to evaluate whether blood oxygen level-dependent
signal changes in our regions of interest (putamen and caudate
nucleus) were not due to structural or morphological differences.
We found no significant difference for the signal strength in pu-
tamen between patients and healthy control subjects (Mann–
Whitney U-test Z = 0.54, P=0.59, healthy control subjects mean
rank: 12.17, patients with Parkinson’s disease mean rank: 13.77)
and caudate nucleus (Mann–Whitney U-test Z = 0.49, P=0.62,
healthy control subjects mean rank: 12.25, patients with
Parkinson’s disease mean rank: 13.69).
As this was a very simple task, no differences in the movement-
related blood oxygen level-dependent response between the two
groups were expected. The comparison of the activation induced
by the button press did not show any significant differences in
activation of the motor areas between control subjects and pa-
tients. However, patients showed a weak trend towards a higher
activation in the pre-supplementary motor area when the statis-
tical model included individual Unified Parkinson’s Disease Rating
Scale score and age as regressors (peak difference: Z = 2.89 at x,
y, z =3, 1, 61).
Increases in regional activity with reward outcome value
The main aim of our analysis was to identify brain regions where
regional activity showed a linear increase with reward outcome.
Therefore, analysis focused on the gamble outcome phase.
Because our statistical model included separate regressors for
each outcome value (from high losses to high wins), we were
able to compute weighted contrasts that test for the positive
linear effect of outcome value on regional activity. As expected,
this contrast showed a widespread distribution of functional acti-
vation for healthy control subjects (Fig. 2). Activations included
many of the core hedonic and affective regions of interest
within the meso-cortical-limbic system, which are expected to be
critically involved in processing of reward outcome value. Linear
increases in activity with reward outcome were found in the ven-
tral striatum, ventral tegmental area, caudate nucleus, thalamus,
hippocampus and medial orbitofrontal cortex (Table 2). Region of
interest analysis revealed that positive linear responses in the
hippocampus and ventral tegmental area were significant. For
ventral striatum, caudate nucleus, thalamus, and medial orbito-
frontal cortex, the linear increases were significant even after cor-
rection for multiple comparisons across the whole brain.
In contrast, patients showed no significant activations in any of
the predefined regions of interest or elsewhere in the brain, even
at an exploratory threshold (P 5 0.001 uncorrected). Only when
we applied a very liberal threshold (P 5 0.01 uncorrected), the
ventral putamen (bilateral), orbitofrontal cortex (right) and the
occipital lobe (bilateral) displayed weak statistical trends towards
a linear increase in activity with reward outcome value (Fig. 2).
Equivalent contrasts testing the negative linear effect of outcome
value did not show any significant effects for either group, even at
trend level.
Between-group differences in reward related activity
Within the predefined regions of interest, patients with Parkinson’s
disease showed a significantly reduced neural response to increas-
ing reward outcome values compared with healthy control sub-
jects. The positive linear relationship between reward outcome and
outcome-related activity was attenuated in the ventral and dorsal
putamen, ventral tegmental area, thalamus, the caudate nucleus,
hippocampus, medial frontal gyrus, inferior frontal gyrus and oc-
cipital visual areas (P 5 0.05 FWE, Table 2). The results show that
core regions of the meso-cortico-limbic dopaminergic system,
including the ventral tegmental area, ventral striatum, and
medial orbitofrontal cortex, are already significantly compromised
in the early stages of the disease. Additionally, the insula, cerebel-
lum, premotor and superior frontal area showed a similar trend
towards a reduced responsiveness to reward outcome value at a
more liberal exploratory threshold (P 5 0.001 uncorrected), but
these decreases did not survive whole-brain correction (Fig. 3).
The same group comparison for the negative linear effect of out-
come value did not show any significant effect, even at trend
level.
Attenuation in the patients’ linear response to reward outcome
could be due to a deficit in the magnitude of responses to either
losses, gains or to both. To distinguish these possibilities we per-
formed the same contrast independently for wins and losses.
Testing for the between group difference (healthy control sub-
jects 4 patients with Parkinson’s disease) in the positive linear re-
sponses to value for wins, patients showed significantly attenuated
responses in the dorsal putamen, caudate nucleus, thalamus, ven-
tral tegmental area, posterior parietal cortex, inferior and medial
frontal gyrus and the left motor cortex and right cerebellum
(Fig. 4A). Isolating the high magnitude wins from the low
showed this effect was mainly produced by the high magnitude
outcomes. The converse contrast, testing the negative linear effect
for wins, did not show any significant effect.
Testing for group differences (healthy control subjects 4 pa-
tients with Parkinson’s disease) in the positive linear response to
losses, we found no significant effect. The converse contrast test-
ing the negative linear response to losses, showed significantly less
deactivation in patients with Parkinson’s disease compared with
control subjects in the ventral putamen, parahippocampal gyrus
and hippocampus, thalamus and medial and superior frontal
gyrus (Fig. 4B). Separating high losses and low losses shows this
effect was mainly carried by high losses. Statistical conjunction of
1196 | Brain 2013: 136; 1192–1203 J. P. M. van der Vegt et al.
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linear effects and a more liberal inclusive mask contrast for both
wins and losses showed no significant regions.
Increases in reward related activity with Unified
Parkinson’s Disease Rating Scale or Barratt
Impulsiveness Scale scores
In the patient group, we regressed the individual Unified
Parkinson’s Disease Rating Scale score against the outcome
value-based parameter estimates to identify brain regions where
neural responses to reward outcome showed a linear relation with
clinical impairment. Outcome-related activity in the bilateral
ventral premotor region (left 4 right) centred on the junction be-
tween inferior frontal sulcus and precentral sulcus—also referred
to as the inferior frontal junction region—and the right inferior
frontal gyrus showed a trend towards a positive linear increase
with outcome value (P 5 0.001 uncorrected). This statistical
trend suggests increased responsivity to reward outcome values
with severity of motor symptoms. The converse contrast for nega-
tive linear reward responses showed no significant activations. As
with the analysis above, we computed the Unified Parkinson’s
Disease Rating Scale regression independently for wins and
losses. Surprisingly, for wins-only we did not find any region
Figure 2 Linear effect of outcome value. The effect of outcome value on outcome-related neural activity tested by computing the
weighted contrasts of the separate regressors set for each outcome value (from high losses to high wins). (A) Statistical parametric maps
showing widespread increases in activity with reward outcome value, including many of the hedonic and affective regions of interest
within the basal ganglia and mesocortical dopamine system. The statistical maps are thresholded at P 5 0.001 (uncorrected). The bar gives
the colour coding of T-values for each voxel. P = posterior; A = anterior; L = left; R = right. (B) The corresponding statistical parametric
maps in patients with Parkinson’s disease showed only trend activations in ventral putamen, right orbitofrontal cortex and occipital visual
areas bilaterally, when applying a more liberal threshold [P 5 0.01 (uncorrected)]. (C) Activation profile of outcome-related activity for
regional peak activation in right ventral striatum. Healthy controls (left) show a stronger increase in outcome-related activity with outcome
value than drug-naive de novo patients with Parkinson’s disease (right, Z = 2.94). PD = Parkinson’s disease.
Reduced reward sensitivity in PD Brain 2013: 136; 1192–1203 | 1197
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that correlated (positively or negatively) with Unified Parkinson’s
Disease Rating Scale. The loss-specific contrast showed the same
profile of regions as the full value (wins and losses) regression
indicating that it is the loss-specific response that was carrying
this effect.
To identify brain regions where the reward response covaried
with risk-taking propensities (across subjects) we regressed the
individual Barratt Impulsiveness Scale scores onto the
subject-specific linear effect of outcome value. In right dorsal pu-
tamen, left thalamus, left insula and right inferior frontal gyrus, the
linear increase in neural response with outcome value correlated
positively with individual Barratt Impulsiveness Scale scores (cluster
level, P 5 0.05 FWE, Fig. 5). Neither the converse contrast for
negative linear reward responses, nor the independent analyses
for wins or losses showed a significant linear relationship with in-
dividual Barratt Impulsiveness Scale scores.
Discussion
This is the first functional neuroimaging study to investigate
the neural basis of reward sensitivity in a group of recently
diagnosed, drug-naive patients with Parkinson’s disease. By
including only untreated patients with Parkinson’s disease, we
avoided any confounding effects of anti-parkinsonian medication
that would modify dopaminergic transmission. We found
that early Parkinson’s disease is associated with a marked and
widespread attenuation of the neural response to gamble
outcomes across a broad distribution of the mesocortical and
mesolimbic systems, extending into classical motor areas (Fig. 2).
Compared with healthy control subjects, DOPA-naı¨ve patients
with Parkinson’s disease showed either a substantially attenuated
or undetectable linear representation of rewards and punishments
in the ventral putamen, ventral tegmental area, thalamus
and subthalamic nucleus, the caudate nucleus, hippocampus,
insula, medial frontal, inferior frontal and superior frontal
areas (Fig. 3). Additionally, deficits were evident in motor cortices,
the ventral premotor cortex and cerebellum (anterior lobe) and
even in the visual cortical areas of the occipital lobe. The finding
that patients with Parkinson’s disease expressed significantly atte-
nuated neurometric reward response functions was further corro-
borated by the absence of a linear main effect of outcome value in
any of the mesocortical or mesolimbic networks of interest. The
lack of discernable signals is particularly remarkable given that
monetary losses or gains have consistently been shown to
induce strong and reproducible effects on blood oxygen
level-dependent responses in these regions (Knutson et al.,
2000, 2001; Yacubian et al., 2006; Schott et al., 2008; Urban
et al., 2012).
Table 2 Functional MRI results of reward outcome
Anatomical area
x
,
y
,
zt
-stat Cluster size
Control group: linear increase in regional activity with reward outcome value (
P
_ 0.05, FWE corrected for whole brain)
Right anterior putamen 15, 8, 2 8.72 297
Left anterior putamen 15, 11, 1 9.30 163
Right thalamus 9, 16, 1 7.03 297
Left thalamus 9, 16, 1 8.83 61
Right occipital cortex 36, 88, 7 10.00 2134
Left occipital cortex 27, 94, 10 9.57 2134
Medial orbitofrontal gyrus 6, 41, 5 8.15 76
Left inferior frontal gyrus 39, 50, 4 6.79 434
Right caudate nucleus 12, 11, 2 7.83 95
Left caudate nucleus 12, 11, 2 8.28 78
Right hippocampus 30, 13, 17 6.04 20
Left hippocampus 33, 19, 17 5.44 32
Right ventral tegmental area 3, 19, 14 4.97 7
Left ventral tegmental area 3, 19, 14 5.24 7
Stronger increase in reward outcome related activity in the control group relative to the patient group (
P
_ 0.05, FWE after region of
interest analyses corrected for number of regions of interest)
Right putamen 18, 8, 2 4.74 143
Left putamen 18, 11, 1 4.68 153
Right thalamus 6, 19, 1 4.97 143
Left thalamus 12, 13, 13 4.98 120
Medial orbitofrontal gyrus 6, 41, 5 4.62 77
Left inferior frontal gyrus 42, 53, 4 4.60 49
Right caudate nucleus 15, 8, 2 4.53 13
Left caudate nucleus 15, 11, 1 4.80 13
Right hippocampus 30, 16, 14 4.80 37
Left ventral tegmental area 3, 19, 11 3.98 4
Right occipital cortex 36, 76, 28 4.83 12
Anatomical areas with their (x, y, z) coordinates and statistical values indicated.
1198 | Brain 2013: 136; 1192–1203 J. P. M. van der Vegt et al.
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Figure 3 Differences in the linear responses to reward outcome value between healthy control subjects and patients with Parkinson’s
disease. (A) Axial statistical parametric maps displaying regions showing a stronger increase in activity with reward outcome value for
control subjects than for patients. Significant value related differences for healthy control subjects versus patients with Parkinson’s disease
are present in the ventral and dorsal putamen, ventral tegmental area, thalamus and subthalamic nucleus, the caudate nucleus,
hippocampus, insula, cerebellum, medial frontal, inferior frontal and superior frontal areas, premotor and occipital visual areas. The
statistical maps are thresholded at P 5 0.001 (uncorrected), extent threshold 50 voxels. The bar gives the colour coding of T-values for
each voxel. P = posterior; A = anterior; L = left; R = right. (B–D) Parameter estimates for outcome-related activity for regional peak
activation in left putamen (B), left ventral tegmental area (C) and right hippocampus (D). All areas show a flattened or undetectable linear
increase in neural response with outcome value in patients with Parkinson’s disease, whereas healthy control subjects show a clear linear
reward value related activity in these key regions of the mesolimbic system. PD = Parkinson’s disease.
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In all of the aforementioned regions, attenuation in the patient’s
linear response to outcome values was present for both gains
and losses. In mesolimbic structures, the caudate nucleus and
ventral tegmental area showed a marked attenuation of neural
responses to gain magnitude, whereas the ventral putamen
showed a significantly reduced responsiveness to loss magnitude
(Fig. 4) and no region expressed a statistical conjunction of
attenuation effects for both wins and losses. This shows
that early in the presentation of Parkinson’s disease, specific
subregions of the mesolimbic system become more insensitive to
losses whereas others selectively lose their sensitivity to gains
(Fig. 4). One possible underlying cause of the diminished
linear response would be that the neurodegenerative process
in Parkinson’s disease induced substantial non-linearity in the
neurometric response function to outcome value. Although our
paradigm only elicited two magnitudes of gains/losses and
therefore does not allow for non-linear inference, our parameter-
ization of the response function does allow independent estima-
tion of the response to each magnitude. The four independent
main effects for each outcome value show substantially
the same result as discussed above, mainly carried by high wins
and high losses, and thus the between group difference can-
not be due to suboptimal parameterization of the response
function.
Figure 4 Differences in the linear responses to reward outcome value between healthy control subjects and patients with Parkinson’s
disease for wins and losses, respectively. (A) Axial statistical parametric map showing significantly higher win related activation for healthy
control subjects versus patients with Parkinson’s disease, in the dorsal putamen, caudate nucleus, thalamus, ventral tegmental area,
posterior parietal cortex, inferior and medial frontal gyrus and the left motor cortex and right cerebellum. (B) Axial statistical parametric
map showing significantly less loss-related deactivation in patients with Parkinson’s disease compared with healthy control subjects in the
ventral putamen, parahippocampal gyrus and hippocampus, thalamus and medial and superior frontal gyrus. The statistical maps are
thresholded at P 5 0.001 (uncorrected). The bar reflects the colour coding of T-values for each voxel. P = posterior; A = anterior; L = left;
R = right.
Figure 5 Interindividual differences in risk-taking behaviour as reflected by the Barratt Impulsiveness Scale score are associated with
increased reward-value related activity in the right putamen and left thalamus in the patient group. (A) Axial parametric map showing a
cluster in the right putamen (peak t-score = 7.97 at x = 24, y = 10, z = 7, cluster extent = 46 voxels) and left thalamus (peak
t-score = 7.34 at x = 18, y = 16, z = 7, cluster extent = 46 voxels), where reward-related activity showed a positive linear relationship
with the individual Barratt Impulsiveness Scale score. The statistical maps are thresholded at P 5 0.001 (uncorrected). The bar reflects the
colour coding of T-values for each voxel. P = posterior; A = anterior; L = left; R = right. (B) The scatter plot illustrates the positive linear
increase in the estimated reward related blood oxygen level-dependent response with the Barratt Impulsiveness Scale score for the peak
voxel of the right putamen, indicating higher sensitivity to reward outcome value with increased risk-taking behaviour. BOLD = blood
oxygen level-dependent.
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To test whether intersubject variability in clinical severity corre-
lated with neural response to gamble outcomes, we tested for a
linear relationship between the individual Unified Parkinson’s
Disease Rating Scale III score and regional response profile to
reward value (to both gains and losses). Activity in the right in-
ferior frontal gyrus and inferior frontal junction region only
showed a trend towards increased responsiveness to reward out-
come values with severity of motor symptoms. Intersubject vari-
ability in risk-taking behaviour correlated with neural responses to
gamble outcomes in patients. The individual Barratt Impulsiveness
Scale scores showed a positive linear relationship with reward out-
come value responses in the right dorsal putamen, left thalamus,
left insula and right inferior frontal gyrus. This relation indicates
higher reward responsiveness in the right dorsal putamen and left
thalamus in patients with stronger risk-taking behaviour (Fig. 5).
This finding shows that the pre-existing risk-taking trait enhances
the responsiveness of cortical and subcortical brain regions to re-
warding outcomes. We speculate that such enhanced responsive-
ness might influence the individual susceptibility to impulse control
disorders in response to dopamine therapy. Since the present
study was not designed to address potential links between
pre-existing impulsivity and dopamine-triggered impulse control
disorders, this interesting question needs to be addressed in
larger prospective functional MRI studies
Taken together, the evidence presented here suggests that the
encoding of reward and punishment outcomes is already signifi-
cantly impoverished in newly diagnosed patients with Parkinson’s
disease before the initiation of dopamine replacement pharmaco-
therapy. It shows that the remaining reward sensitivity may be
curtailed down from large swathes of mesolimbic, mesocortical,
motor and occipital regions down to a few islands within orbito-
frontal cortex, ventral putamen and occipital cortex. It is of inter-
est that even for these remaining regions, there is a significant
reduction in the response magnitude compared with healthy con-
trol subjects (Fig. 2). Thus, the results indicate that this attenuated
responsiveness to reward outcome value is widespread and in-
volves the majority of regions within the reach of dopaminergic
transmission. This includes classical reward structures of the basal
ganglia and medial orbitofrontal cortex, but also extending into
classical motor structures.
Our findings are of importance for current pathophysiological
concepts of Parkinson’s disease for a number of reasons. As
pointed out above, it has been postulated that the mesolimbic
system is only marginally affected at the early stages of
Parkinson’s disease due to a later involvement of the ventral stri-
atum relative to dorsal striatum (Fearnley and Lees, 1991; Morrish
et al., 1996; Cools et al., 2001; Braak et al., 2004). Our results
challenge the concept of relatively intact limbic circuits in the ear-
liest phases by showing that the reward responses of the meso-
limbic and mesocortical system are already significantly impaired.
This has implications for the dopamine ‘overdose theory’, which
predicts that dopamine medication causes aberrant reinforcement
behaviour by excessive stimulation of a relatively intact reward
processing in the mesolimbic system. Our data suggest that in
early stages of Parkinson’s disease there is a significantly reduced
reward responsivity in the ventral striatum before dopamine re-
placement therapy has started. This could be analogous to the
findings in pathological gamblers (without Parkinson’s disease),
who show decreased reward activity in the mesolimbic system
(Reuter et al., 2005; van Holst et al., 2010; Cilia and van
Eimeren, 2011; Miedl et al., 2012). The enhanced level of dopa-
mine induced by the dopamine medication leading to pathological
gambling in patients with Parkinson’s disease could consequently
be analogous to the heightening of dopamine release in the meso-
limbic system in pathological gamblers caused by gambling. This
aberrant increase in dopamine transmission could trigger errone-
ous expectancy coding and beliefs regarding the probability of
winning and thus contribute to continuation of gambling despite
heavy losses (Schultz, 2007; Clark et al., 2009; van Eimeren et al.,
2010), as has been suggested before (van Eimeren et al., 2010;
O’Sullivan et al., 2011). This, in combination with higher loss sen-
sitivity correlated with Unified Parkinson’s Disease Rating Scale,
could explain why patients with Parkinson’s disease without dopa-
mine medication tend to learn better from punishment and show
loss avoidant behaviour (i.e. ‘learning by stick’). This would then
convert to increased risk-seeking behaviour and learning from
positive rewards after the initiation of dopamine medication (i.e.
‘learning by carrot’), in accordance with what was also recently
shown in a behavioural study in mainly drug naı¨ve patients with
Parkinson’s disease (Frank et al., 2004, 2007; Schott et al., 2007;
Bodi et al., 2009), which still supports the basic tenet of the ‘over-
dose theory’.
The behavioural correlates of this early neuronal deficit remain
to be fully tested, and will be the target of future investigation. Of
particular clinical importance will be assessing the degree to which
these functional responses are clinically useful as an endopheno-
typic predictor of the response to dopamine treatment and its side
effects, as well as predicting pathological and behavioural trajec-
tories. Neurobiological insight into the drug-naive state thus
provides an essential window into the nascence of Parkinson’s
disease and its future remedy.
Funding
This work was supported by the Netherlands Organisation for
Scientific Research (NWO; VIDI grant No. 16.076.352 to B.R.B.)
and a grant of excellence by the Lundbeck Foundation on the
Control of Action (ContAct; grant No. R59 A5399 to H.R.S.)
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    • "Finally, it is also possible that cultural differences, which are known in PD (Weintraub et al., 2010 ) are responsible for the results presented here. It is unlikely that early decisions in our patient cohort are driven by immediate reward seeking behaviour, given the lack of effect of punishment condition for incorrect choices in this task and results of a recent functional magnetic imaging study in drug naïve PD patients, showing attenuated mesolimbic and mesocortical regions during gambling (van der Vegt et al., 2013). As the beads task is also related to temporal discounting () we obtained a temporal discounting questionnaire to assess whether jumping to conclusion is driven by " waiting impulsivity " , which is the inability to wait for a larger but delayed reward over a small immediate gratification. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Jumping to conclusions due to impulsivity has been shown to be a sensitive marker for dopamine dysregulation and addictive behaviour patterns in treated patients with Parkinson's disease (PD). It is unknown whether drug naïve PD patients, who have never received dopaminergic therapy also have deficits in information sampling. Methods: Twenty five de novo PD patients and twenty matched healthy controls were recruited and tested on the beads task, which is a validated information sampling task to assess reflection impulsivity and a temporal discounting questionnaire. Results: Patients gathered significantly less information and made more irrational choices than matched controls. There was, however, no group difference on the temporal discounting questionnaire. Conclusions: Poor information sampling and irrational decision making may be an inherent component of the neuropsychological deficit in Parkinson's disease. These findings suggest that underlying impulsivity detected by a metric task is common in de novo PD.
    Article · Mar 2016
    • "Additionally, impulsive and/or compulsive behaviours are overexpressed in healthy family members of PD patients (Kim and Jeon, 2014 ), suggesting a familial neurobiological vulnerability, perhaps unmasked by treatment with dopamine agonists (Vriend et al., 2014; Kehagia et al., 2013 ). Furthermore, deficits in reward processing associated, with attenuated mesolimbic and mesocortical regional activation, have been reported in a group of medication naïve, newly diagnosed PD patients (van der Vegt et al., 2013). Candidate genes within the dopaminergic, the serotonergic and, to a lesser extent, the glutamatergic systems have been considered as culprits imparting susceptibility to impaired inhibitory cognitive control in PD. "
    [Show abstract] [Hide abstract] ABSTRACT: Executive function entails the interplay of a group of cognitive processes enabling the individual to anticipate consequences, attain self-control, and undertake appropriate goal-directed behaviour. Serotonin signalling at serotonin 2A receptors (5-HT2AR) has important effects on these behavioural and cognitive pathways, with the prefrontal cortex (PFC) as the central actor. Indeed, the 5-HT2ARs are highly expressed in PFC, where they modulate cortical activity and local network oscillations (brain waves). Numerous psychiatric and neurodegenerative diseases result in disrupted executive function. Animal and human studies have linked these disorders with alterations in the 5-HT2AR system, making this an important pharmacological target for the treatment of disorders with impaired cognitive function. This review aims to describe the current state of knowledge on the role of 5-HT2AR signalling in components of executive function, and how 5-HT2AR systems may relate to executive dysfunctions occurring in psychiatric and neurodegenerative diseases. We hope thereby to provide insight into how pharmacotherapy targeting the 5-HT2AR may ameliorate (or exacerbate) aspects of these disorders.
    Full-text · Article · Feb 2016
    • "The FrA has been proposed in a human study to be important for go/no-go task performance [20]. The go/no-go task measures attention and response inhibition control [21], and interestingly these are functions impaired in newly diagnosed drug na¨ıvena¨ıve PD patients [6]. The differences in receptor binding levels observed in the AS overexpressing mice were not accompanied by differences in gene expression. "
    [Show abstract] [Hide abstract] ABSTRACT: The 5 - H T 2 A receptor is highly involved in aspects of cognition and executive function and seen to be affected in neurodegenerative diseases like Alzheimer’s disease and related to the disease pathology. Even though Parkinson’s disease (PD) is primarily a motor disorder, reports of impaired executive function are also steadily being associated with this disease. Not much is known about the pathophysiology behind this. The aim of this study was thereby twofold: (1) to investigate 5 - H T 2 A receptor binding levels in Parkinson’s brains and (2) to investigate whether PD associated pathology, alpha-synuclein (AS) overexpression, could be associated with 5 - H T 2 A alterations. Binding density for the 5 - H T 2 A -specific radioligand [ 3 H]-MDL 100.907 was measured in membrane suspensions of frontal cortex tissue from PD patients. Protein levels of AS were further measured using western blotting. Results showed higher AS levels accompanied by increased 5 - H T 2 A receptor binding in PD brains. In a separate study, we looked for changes in 5 - H T 2 A receptors in the prefrontal cortex in 52-week-old transgenic mice overexpressing human AS. We performed region-specific 5 - H T 2 A receptor binding measurements followed by gene expression analysis. The transgenic mice showed lower 5 - H T 2 A binding in the frontal association cortex that was not accompanied by changes in gene expression levels. This study is one of the first to look at differences in serotonin receptor levels in PD and in relation to AS overexpression.
    Full-text · Article · Jan 2016
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