For Peer Review O

nly

Selective IGT Decision Making Impairment in a Patient with

Juvenile Parkinson’s Disease and Pathological Gambling. A Role for Dopaminergic Therapy?

Journal: Neurocase

Manuscript ID: NCS-BR 11-036.R2

Manuscript Type: Brief Report

Date Submitted by the Author:

11-Oct-2011

Complete List of Authors: Pignatti, Riccardo; Istituto Auxologico Italiano IRCCS Ospedale S. Giuseppe, Psychology Laboratory Brioschi, Andrea; Istituto Auxologico Italiano IRCCS Ospedale S. Giuseppe, Department of Neurology Zamarian, Laura; Medical University, Clinical Department of Neurology

Wenter, Johanna; Medical University, Clinical Department of Neurology Mauro, Alessandro; Istituto Auxologico Italiano IRCCS Ospedale S. Giuseppe, Department of Neurology; University of Torino, Department of Neurosciences Semenza, Carlo; University of Padova, Department of Neuroscience; Ospedale S. Camillo IRCCS

Keywords: Pathological Gambling, Parkinson’s Disease, Iowa Gambling Task,

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

For Peer Review O

nly

Dopamine, Neuropsychological Assessment, Executive Functions, Decision-making, Reward deficiency syndrome, Impulsivity

Page 1 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

1

Introduction

The influence of dopamine on behaviour in patients with Parkinson’s Disease (PD) is a current

matter of debate in the literature. The striatofrontal loop and the mesolimbic dopaminergic system

are structures involved in motivation and sensibility to reinforcements, and both are typically

impaired in PD (Czernecki et al., 2002). Some PD patients are found to dramatically change their

behaviour after dopamine replacement therapy, showing symptoms that are included in the so-

called “Dopamine Dysregulation Syndrome”. Behavioural effects of this syndrome include a

compulsive search of the dopamine replacement therapy itself (Lawrence, Evans, & Lees, 2003), a

compulsive search of pleasure by “unnatural rewards” such as alcohol and drugs, and/or a

compulsive search of pleasure by activities such as gambling, eating, sex, and risk-taking

behaviours (Ceravolo, Frosini, Rossi, & Bonuccelli, 2010; Comings & Blum, 2000; Comings,

Saucier, & MacMurray, 2002). Following dopamine agonist therapy, from 8% up to 14% of

patients with PD develop impulse control disorders such as hypersexuality, frequent gambling, and

compulsive shopping (for a review, Ceravolo, Frosini, Rossi, & Bonuccelli, 2009).

The Iowa Gambling Task (IGT) is a neuropsychological device that has been specifically

created to study impairments in personal and social decision making (Bechara, Damasio, Damasio,

& Anderson, 1994; Bechara, Damasio, Tranel, & Damasio, 1997), and has been frequently used in

the literature for detecting risk-taking disorders in neurological and psychiatric patients (for a

review, Dunn, Dalgleish, & Lawrence, 2006). The IGT has, for example, helped to evidence

failures in making long-term advantageous choices in patients with ventromedial prefrontal cortex

damage (Bechara, Damasio, Damasio, & Lee, 1999; Bechara, Tranel, Damasio, & Damasio, 1996;

Cavedini, Riboldi, Keller, D'Annucci, & Bellodi, 2002; Manes et al., 2002). Typically, these

patients make very risky decisions in real life situations and appear to be insensitive to the future

consequences of their choices, even when their behaviour may produce severe economical,

physical, or social damages. Ventromedial prefrontal cortex patients perform very poorly on the

Page 2 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

2

IGT by selecting prevalently the alternatives with the higher immediate rewards that are also

associated with the higher long-term punishments.

The IGT also represents the gold standard for studies about the “Somatic Marker Hypothesis”

(SMH) (Bechara, et al., 1996; Damasio, Tranel, & Damasio, 1991). The SMH suggests that

emotion-based biasing signals arising from the body are integrated in higher brain regions, in

particular the ventromedial prefrontal cortex, to regulate emotional decision-making in conditions

of ambiguity. Also some non-brain damaged patients, such as drug-addicted individuals (Wardle,

Gonzalez, Bechara, & Martin-Thormeyer, 2010) or patient with Anorexia Nervosa (Tchanturia et

al., 2007) can experience increased difficulties in addressing their behaviour during such conditions.

The absence of “marker” signals (anticipatory skin conductance responses) could account for these

difficulties and therefore expose subjects to risk-taking behaviours, as well as to poor IGT

performances.

Some studies have investigated impulse control disorders in PD patients by means of

psychiatric interviews or questionnaires and by relating the obtained measures to clinical features

such as depression, obsessive-compulsive symptoms, disinhibition, irritability, and appetite

disturbances (for a review, see Weintraub & Potenza, 2006). Recent studies have used gambling

tasks such as the IGT (Bechara, Tranel, & Damasio, 2000) or the Game of Dice Task (GDT) (Brand

et al., 2004) to assess risk-taking disorders in non-demented and non-gamblers PD patients (Brand,

et al., 2004; Euteneuer et al., 2009; Ibarretxe-Bilbao et al., 2009; Mimura, Oeda, & Kawamura,

2006; Perretta, Pari, & Beninger, 2005).

In particular, the GDT is a computerised decision-making task, in which rules for gains and

losses and winning probabilities are evident and unwavering. Thus, the GDT is considered a risky

situation task. By contrast, the IGT is a more complex task, whose hallmark is the necessity to adopt

an efficient choice strategy over time. Brand and colleagues (2004, cit.) found that PD patients were

impaired in the GDT performance and that the frequency of disadvantageous choices correlated

with both executive functions and feedback processing. Therefore, they suggested that decision-

Page 3 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

3

making deficits of PD patients in explicit gambling situations might be associated with dysfunctions

in two different fronto-striatal loops: the limbic-orbitofrontal-striatal loop, involved in the emotional

feedback of decision-making, and the dorsolateral prefrontal-striatal loop, involved in executive

functions. Euteneuer and colleagues (2009) administered, for the first time, both GDT and IGT to

non-demented and non-depressed PD patients. Their results indicated that PD patients performed

worse on GDT, but not on IGT, with respect to healthy controls and, therefore, authors concluded

that only choices under risk, measured via the GDT, were related to executive functioning and to

the integrity of the dorsolateral prefrontal loop.

To the best of our knowledge, only one small group study has investigated the differences in

decision-making performance between 7 PD patients with Pathological Gambling (PG) and 13 PD

patients without PG (Rossi et al., 2010). Results of this study indicate that both PD groups perform

poorly on the IGT as well as on several neuropsychological measures of executive functioning (for

similar results, see also Santangelo et al., 2009). However, patients with PG developed the worst

strategy while performing the IGT, as they selected disadvantageous alternatives more frequently

than the advantageous and did not shift their performance in the latter half of the task. In particular,

they chose most frequently the disadvantageous deck B, which is associated with higher immediate

gains than the other decks, but with a negative long-term outcome, regardless of the odds of

winning. By contrast to the work of Euteneuer and colleagues, the inadequate behaviour of PG

patients in the IGT is not observed in other tasks used to evaluate decision-making under risk, like

the GDT. Group differences were significant for the IGT, but not for executive-function tests,

although many of them, such as the Wisconsin Card Sorting Test and the Stroop Color and Word

Test, were abnormal in both groups of PD patients according to standardized scores from normal

controls. The decision-making performance pattern of the pathological PD gamblers on the IGT

resembles to some extent the one described for ventromedial prefrontal cortex patients, and points

to severe emotion regulation and impulse control disorders in pathological PD gamblers with

executive-function deficits. Furthermore, only one case with PG and hoarding problems as initial

Page 4 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

4

symptoms, but with a diagnosis of Frontotemporal Lobar Degeneration, has been described via the

IGT by Nakaaki et al. (2007).

In this study, we assess a juvenile PD patient with high-cognitive functioning and PG problems

that were dramatically invasive in their everyday life. We compare performance of this patient to

that of high-functioning non-gambler PD patients on the IGT, aiming at verifying whether, and to

what extent, the IGT is sensitive to decision-making disorders even when no other cognitive deficits

are present. Our expectation is that the IGT should be more helpful than other neuropsychological

tests in describing these patients and that it should quantify the decision-making disruption. Should

the IGT reveal impairment, this may account for a specific orbitofrontal role in the emotional

decision-making disruption, mediated by dopamine agonists. To-date, literature has just provided

ambiguous results because a mixed orbitofrontal and dorsolateral deficit has been usually observed

in previous studies on PD patients. In addition to that, we wish to increase the literature on PD with

real-life PG by the description of a young prototypical patient who is experiencing a selective PG

problem without dementia nor age-related interfering difficulties.

Case Report

Patient LT is a woman, married, with 4 male sons, and with 11 years of education. She was

admitted to our Neurological Department, when she was 42 years old, because of a sudden

appearance of compulsive gambling disorders. Diagnosis of PD was made eight years before this

study. At that time, a low dose L-dopa therapy, which has been gradually increased over time, was

introduced. Five years later, patient LT developed facial and cervical dystonia, and pramipexole and

cabergoline were added to her therapy. Behavioural disorders emerged one year before this

investigation and were characterized by selective and dramatic compulsive gambling in videopoker

and other games of chance (bingo). The urge to bet was so much invasive that she used to escape

secretly from home by night to reach the nearest pub in which she could play. This behaviour was

Page 5 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

5

considered very impolite by the patient herself, as she was living in a small town and everyone

could see her and therefore “judge” her negative attitude. Disorders were so enhanced to cause

important economic and social problems. Thereafter, patient LT was admitted twice (with a six-

month interval) to our Neurological Department for a full clinical screening. Diagnosis of PG was

made after an extensive psychiatric assessment according to the criteria of the American Psychiatric

Association (DSM-IV-TR, 2000). At neurological examination, a hypertonic hypokinetic

extrapyramidal syndrome was found, with a prevalence of disturbance in the right side. Standard

MRI of the brain showed some lacunar hyperintensities in the frontal white matter. A cerebral

SPECT (I123 ioflupane) showed a reduction of perfusion in the putamen bilaterally, with

prevalence in the anterior left part, which is concordant with her diagnosis of PD. Genetic analysis

of DYT-5 was negative for L-dopa responsive dystonia.

At the time of the first hospitalisation (T1), patient LT performed an extensive

neuropsychological assessment (Spinnler & Tognoni, 1987) (Tab.1) and the IGT. The IGT was also

administered at the time of the second hospitalisation (T2), 6 months after T1. Patient LT’s

performance on the IGT was compared with that of a control group of idiopathic PD patients (CGP)

who were under dopaminergic treatments (both L-dopa and dopamine agonists) but had apparently

no gambling problems. A second control group was composed by 16 healthy subjects (CGH),

matched to LT for age and education level (Tab. 2). Exclusion criteria were reduced visual and

auditory functions, concurrent neurological or psychiatric diseases, and presence of dementia or

Mild Cognitive Impairment (DSM-IV-TR criteria). Prior to enrolment, CGP subjects were screened

for cognitive disorders by means of the Mini-Mental State Examination (MMSE) (Folstein,

Folstein, & McHugh, 1975) and a neuropsychological background battery including tests of short-

term memory, long-term memory, executive functions, reasoning, visuo-perception, and visuo-

constructive abilities (Appollonio et al., 2005; Caffarra, Vezzadini, Dieci, Zonato, & Venneri, 2002;

Carlesimo et al., 2002; Carlesimo, Caltagirone, & Gainotti, 1996; Orsini et al., 1987; Spinnler &

Tognoni, 1987). Only patients who scored above 26 in the MMSE and showed no impaired

Page 6 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

6

performance in any cognitive domain assessed by the neuropsychological background battery were

included in the control group (n = 15). CGP subjects had a mean age of 64.27 years, a mean

education of 10.20 years, and a mean MMSE score of 28.31 (SD 1.11, range 27-30). All

participants gave written consent to the investigation, which was approved by a local Ethic

Commission. Performance of patient LT on the IGT was compared with those of CGP and CGH by

means of SingleBayes_ES (Crawford & Garthwaite, 2007; Crawford, Garthwaite, & Porter, 2010),

which is a statistical program dedicated to single case studies and uses Bayesian Monte Carlo

methods to test whether an individual’s score is significantly different to scores of a control group.

The program also provides a point and interval estimate of the abnormality of the case's score, as it

estimates the percentage of the population that would obtain a lower score.

IGT. In the computerized version, four card decks are presented (for details, see Bechara, et al.,

2000). Participants have to pick up one card at a time, till the game will end, after 100 card

selections (participants are unaware of the total number of selections). Card selections from decks A

and B result in large monetary gains followed by large penalties at certain unpredictable times. As

the accumulated penalties are larger than the accumulated gains, decks A and B are

“disadvantageous” in the long run. Card selections from decks C and D result in small immediate

gains followed by small unpredictable losses. As the accumulated penalties are smaller than the

accumulated gains, decks C and D are “advantageous” in the long run. Participants are instructed to

win as much money as possible (the starting capital is $ 2,000). They are also informed that some

decks are better than others and that, to win, they have to avoid the disadvantageous decks and keep

selecting from the advantageous decks. Participants are informed of how much money they won or

lost after each trial. Following convention, performance was analyzed by dividing the 100 trials into

five blocks of 20 card selections and calculating the difference – net score – between the number of

selections from advantageous decks (C+D) and the number of selections from disadvantageous

decks (A+B). Scores above zero indicate that more advantageous cards were selected than

Page 7 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

7

disadvantageous cards; scores below zero indicate that more disadvantageous cards were selected

than advantageous cards.

Results

Patient LT reported no depressive symptoms in the Hamilton Depression Rating Scale

(Hamilton, 1960). She does not differ from CGH for age, but she is younger than CGP (Bayesian

one-tailed p-value = 0.030); she is fully comparable for education to both CGP and CGH (Bayesian

one-tailed p-value = not significant). On the neuropsychological background assessment, she scored

at ceiling in almost all tests, demonstrating intact short-term memory, long-term memory, executive

functions, reasoning, visuo-perception, and visuo-constructive abilities (Tab. 1). By contrast,

performance on the IGT revealed severe decision-making problems. At T1, patient LT obtained a

very negative total net score (-36), by selecting more frequently cards from the disadvantageous

desks (A+B) than cards from the advantageous decks (C+D) (Tab. 2). Her total net score was

significantly lower than that of CGP (Bayesian one-tailed p-value = 0.029, Bayesian point estimate

of percentage of control population falling below case’s score = 2.87%) and than that of CGH

(Bayesian one-tailed p-value = 0.026, Bayesian point estimate of percentage of control population

falling below case’s score = 2.56%). The difference among patient LT, CGP, and CGH was

significant even when the comparison was carried out on the net score computed for the last 50

trials of the task (the Bayesian one-tailed p-values were 0.020 and 0.007, and the corresponding

Bayesian point estimate of percentage of control population falling below case’s scores were 2.02%

and 0.71%, respectively). Besides that, LT switched more times deck of cards after a win trial

(50%) than after a loss trial (41.93%).

Analysis of IGT performance by blocks of 20 cards (blocks 1–5) provides a survey of learning

and strategy used by participants across the trials. A 2 (groups) x 5 (blocks) ANOVA was carried

out to compare performances from CGP and CGH. Results did not indicate any significant

Page 8 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

8

difference between the two control groups. The mean block net scores for each group compared

with LT’s results at T1 and at T2 are presented in Figure 1.

(Table 1 about here)

(Table 2 about here)

(Figure 1 about here)

Although some improvement was evident at T2 (6-month follow-up), performance of patient

LT on the IGT was still clearly pathological. A significant difference between patient LT’s

performance at T2 and CGP performance was found when the analysis was performed on the net

score computed for the first 50 trials of the IGT (Bayesian one-tailed p-value = 0.049, Bayesian

point estimate of percentage of control population falling below case’s score = 4.91%). The

comparison of the total net score reached no significance1. At T2, she switched much more times

decks with respect to T1, but she was still changing more decks after win trials than after loss

trials (respectively, 84.93% and 76.92%). When, at conclusion of the IGT, patient LT was asked to

identify the advantageous and disadvantageous decks, she correctly indicated the task’s

contingencies at both T1 and T2, but told to be unable to inhibit the risky selections because

attracted by the immediate high reward cards.

Discussion

1 Previous studies with healthy individuals have found age-related effects in performance on the IGT (Fein,

McGillivray, & Finn, 2007; Zamarian, Sinz, Bonatti, Gamboz, & Delazer, 2008), with the healthy older individuals

deciding on average less advantageously than the healthy younger individuals. Although in this study the PD control

group was slightly older than patient LT, control patients performed significantly better than LT.

Page 9 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

9

We described the neuropsychological profile and the decision-making performance pattern on the

IGT of a patient with juvenile PD, who showed a severe PG disorder in everyday life.

Patient LT showed preserved episodic memory, executive functions, reasoning, visuo-

perception, and visuo-constructive abilities on a formal neuropsychological assessment, and had no

symptoms of depression. In contrast, patient LT had a very poor decision-making performance on

the IGT by selecting prevalently the risky alternatives. Furthermore, LT showed less response shifts

after net losses compared to after rewards, in both testing occurrences. These results are fully in line

with literature about the performance of PG patients and substance dependents on IGT (Bechara et

al., 2001; Cavedini, et al., 2002; Goudriaan, Oosterlaan, de Beurs, & van den Brink, 2005; Grant,

Contoreggi, & London, 2000; Petry, 2001). Noteworthy, although she demonstrated full

understanding of the risky conditions of the task, patient LT stated to be unable to inhibit her risky

choices. Patient LT’s decision-making performance on the IGT was significantly different from

those of two control groups, both healthy subjects and PD patients who were under standard L-dopa

medication and did not present with PG problems in real life.

Previous group studies suggest that decision-making difficulties in PD may be related to

overstimulation of the orbitofrontal-ventral striatum circuit after dopaminergic medication

(“overdosing” hypothesis) (Cools, 2008; Cools, Barker, Sahakian, & Robbins, 2003). For example,

Delazer et al. (2009) found that both non-demented PD patients and demented PD patients (PDD)

under L-dopa medication perform more poorly than healthy age-matched controls on the IGT. More

specifically, the frequency of advantageous selections markedly increased over the task for healthy

controls, but not for both PD and PDD patients. Our results from CGP are, instead, fully

comparable to those obtained by Poletti et al. (2010), who reported no deficits for de novo PD

patients in the IGT, however their patients were not under a dopaminergic therapy.

As indicated by both neuropsychological and neuroimaging studies (for reviews, Brand,

Labudda, & Markowitsch, 2006; Dunn, et al., 2006), functions such as reward-based learning,

reversal learning, feedback processing, and inhibition that are related to the non-motor circuit

Page 10 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

10

linking the orbitofrontal and ventromedial prefrontal cortex and the anterior cingulate cortex to the

ventral striatum are critical for advantageous decision making in the IGT. The perseverative

behaviour of LT shifting less times after loss trials than after win trials is in line with a recent study

conducted with brain perfusion single photon emission tomography on PD patients with PG (Cilia

et al., 2011). In fact, this study has enlightened a disconnection between the Nucleus Accumbens

and the striatum which could account for the inability to adjust the subjects’ behaviour after

repeated reward omissions and thus explain the proneness to perseverate in self-destructive risk-

taking behaviours, as already described in compulsive drug-seeking states (Li & Sinha, 2008). At

the time of this investigation, patient LT was on high-dose dopaminergic medications (both low

dosage of L-Dopa and two dopamine agonists), and this may have accounted for her decision-

making disorders in the IGT as well as in real life situations. In fact, her behavioural dysregulations

appeared only after the adjustment of L-dopa therapy by adding the two dopamine agonists. This

observation particularly fits the results of the work by Bodi et al. (2009) who found, in some young

patients with PD, cognitive and personality modifications leading to impulse control disorders as

side-effects of dopamine agonist therapy. Similar results were also obtained in a study on the

Restless Legs Syndrome (Dang, Cunnington, & Swieca, 2011), which showed that the PG was the

most frequent symptom (83,3% of cases) among the impulse control disorders that suddenly

appeared in a group of patients treated with dopamine agonists. Together with these results, the case

of LT should account for the hypothesis that the decision-making defect in medicated patients is

mainly a consequence of the influence of dopaminergic stimulation on the orbitofrontal striatal

circuits (Gotham, Brown, & Marsden, 1986). The case of LT should provide an explanation for this

hypothesis better than the quoted study by Rossi et al. (2010). In fact, in that study, PD patients

with PG had worse performances also in other neuropsychological tests, which required a

dorsolateral prefrontal cortex activity. Recent studies indicate that cognitive functions such as

flexibility, categorisation, and set-shifting, which are summed under the umbrella term of

“executive functions” and rely on the dorsolateral prefrontal cortex (e.g., Salmon & Collette, 2005),

Page 11 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

11

may be involved in performance on the IGT when participants figure out the rules of the task (for a

discussion, Brand, et al., 2006). Although good flexibility, reasoning, and categorisation abilities

may help performing the last trials of the IGT once rules have been found out, results of this study

suggest, for the first time, that high cognitive functioning and preserved executive functions are no

guarantee for advantageous decision making on this task, even when the patient is given the

opportunity to repeat the task and demonstrates good insight into the task’s contingencies.

A role for impulsivity has been assigned to poor performances on the IGT. For example,

healthy subjects who were more prone to chose from long-term disadvantageous decks in the last

blocks of IGT showed also a higher tendency to be overstimulated by immediate reward at a Delay

Discounting (DD) questionnaire (Sweitzer, Allen, & Kaut, 2008), as well as people with obesity and

Binge Eating Disorder did (Davis, Patte, Curtis, & Reid, 2010). Remarkably, also the severity of

gambling behaviour is associated to the impulsivity in a DD task for a group of patients with PG

(Alessi & Petry, 2003). In fact, the DD paradigm describes the impulsive choice as a subjective

preference for immediate over delayed outcomes, even where the delayed outcomes are more

advantageous (for an investigation on DD task, see Robles & Vargas, 2008). In the frame of DD

paradigm, a specific role for dopamine and the orbitofrontal cortex in managing impulsiveness has

been clearly evidenced both in humans and animals (Koffarnus, Newman, Grundt, Rice, & Woods,

2011; Peters & Buchel, 2011; Pine, Shiner, Seymour, & Dolan, 2010; Zeeb, Floresco, &

Winstanley, 2010). Furthermore, as reported by Wiecki & Frank (2010), PD patients medicated

with L-Dopa showed an increased preference to seek rewarding stimuli and reduced preference to

avoid non-rewarding or punishing stimuli (Bodi, et al., 2009; Cools, 2008; Frank, Samanta,

Moustafa, & Sherman, 2007; Frank, Seeberger, & O'Reilly, 2004; Moustafa, Cohen, Sherman, &

Frank, 2008; Palminteri et al., 2009). The behaviours of LT on the IGT and in her real life seem to

be in line with both the DD paradigm and the dopamine hypotheses. In particular, she demonstrates

an evident cognitive-behavioural dissociation between her rational thoughts about what she was

doing and the impulsive behaviour she could not inhibit.

Page 12 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

12

Wiecki & Frank (2010) also describe that the polymorphism of the DRD2 gene, associated with

D2 receptor function, has been consistently related to the degree of learning from negative

outcomes. In fact, those genotypes associated with reduced striatal D2 receptor density (Hirvonen et

al., 2005) are accordingly associated with reduced NoGo learning (Frank, Doll, Oas-Terpstra, &

Moreno, 2009; Frank & Hutchison, 2009; Frank, Moustafa, Haughey, Curran, & Hutchison, 2007;

Klein et al., 2007). Thus it is possible that the PD patients who are most susceptible to PG from

dopamine medications are those who are genetically predisposed to exhibit reduced learning from

negative outcomes. Our results can provide more evidence to the specific role of L-Dopa, because it

could act on behaviours by the exacerbation of a supposed pre-existing D2 defect, but with minor or

no effects on self-beliefs. A predisposition is also necessary to hypothesize why only some

individuals develop PG after L-Dopa treatment.

In fact, another point of interest is that patients with PD and impulse controls disorders

frequently deny or minimize the extent of their disorders, or do not regard their actions as abnormal,

when administered with common self-rated questionnaires (Weiss, Hirsch, Williams, Swearengin,

& Marsh, 2010). Bypassing the bias of self-, or third person observation, our study also highlights

the usefulness of the IGT as a neuropsychological tool for the correct detection of decision-making

deficits in patients with high-cognitive functioning and specific PG behaviour in everyday life.

It has been proposed (Pagonabarraga et al., 2007; Wolters, van der Werf, & van den Heuvel,

2008) that control inhibition disorders should be more frequent among the young, non-demented,

PD patients than among the demented PD patients. In fact, a more preserved cognitive status might

enable the PD patients to get more involved in the reward outcomes of the task, making the

emotional dysfunction more evident. Our results are consistent with this hypothesis. Therefore, a

broader application of neuropsychological tests that are sensitive to prefrontal damage is suggested

for the detection of risk-taking behaviours, most of all in cognitively intact neurological patients

who could, for example, still manage money independently.

Page 13 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

13

A possible limitation to the generalization of our conclusions can be represented by the high SD

observed in both control groups. This effect can be explained by the use of very different personal

strategies in approaching the IGT, as many people (belonging both to CGP or to CGH) can be

affected by a partial misunderstanding of task requirements, as they can think that IGT is a chance

game, or, furthermore, they can experience low motivation and attentional flatness during the task.

A questionnaire investigating strategies utilized by subjects while performing the IGT could

moderate this limitation during further researches.

Page 14 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

14

Acknowledgements. L.Z. receives research support from FWF, Austrian Science Fund, Project-

Nr. P21636-B18. J.W. receives research support from Leopold-Franzens University Innsbruck

(Doktoratsstipendium).

Page 15 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

15

References

Alessi, S. M., & Petry, N. M. (2003). Pathological gambling severity is associated with impulsivity in a delay

discounting procedure. Behavioural Processes, 64(3), 345-354. American Psychiatric Association. (2000). Diagnostic and Statistical Manual of Mental Disorders (Fourth ed.).

Washington, DC: American Psychiatric Association. Appollonio, I., Leone, M., Isella, V., Piamarta, F., Consoli, T., Villa, M. L., et al. (2005). The Frontal Assessment

Battery (FAB): Normative values in an Italian population sample. Neurological Sciences, 26(2), 108-116. Bechara, A., Damasio, A. R., Damasio, H., & Anderson, S. W. (1994). Insensitivity to Future Consequences Following

Damage to Human Prefrontal Cortex. Cognition, 50(1-3), 7-15. Bechara, A., Damasio, H., Damasio, A. R., & Lee, G. P. (1999). Different contributions of the human amygdala and

ventromedial prefrontal cortex to decision-making. Journal of Neuroscience, 19(13), 5473-5481. Bechara, A., Damasio, H., Tranel, D., & Damasio, A. R. (1997). Deciding advantageously before knowing the

advantageous strategy. Science, 275(5304), 1293-1295. Bechara, A., Dolan, S., Denburg, N., Hindes, A., Anderson, S. W., & Nathan, P. E. (2001). Decision-making deficits,

linked to a dysfunctional ventromedial prefrontal cortex, revealed in alcohol and stimulant abusers. Neuropsychologia, 39(4), 376-389.

Bechara, A., Tranel, D., & Damasio, H. (2000). Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions. Brain, 123 ( Pt 11), 2189-2202.

Bechara, A., Tranel, D., Damasio, H., & Damasio, A. R. (1996). Failure to respond autonomically to anticipated future outcomes following damage to prefrontal cortex. Cerebral Cortex, 6(2), 215-225.

Bodi, N., Keri, S., Nagy, H., Moustafa, A., Myers, C. E., Daw, N., et al. (2009). Reward-learning and the novelty-seeking personality: a between- and within-subjects study of the effects of dopamine agonists on young Parkinson's patients. Brain, 132(Pt 9), 2385-2395.

Brand, M., Labudda, K., Kalbe, E., Hilker, R., Emmans, D., Fuchs, G., et al. (2004). Decision-making impairments in patients with Parkinson's disease. Behavioural Neurology, 15(3-4), 77-85.

Brand, M., Labudda, K., & Markowitsch, H. J. (2006). Neuropsychological correlates of decision-making in ambiguous and risky situations. Neural Networks, 19(8), 1266-1276.

Caffarra, P., Vezzadini, G., Dieci, F., Zonato, F., & Venneri, A. (2002). Una versione abbreviata del test di Stroop: dati normativi nella popolazione italiana. Nuova Rivista di Neurologia, 12(4), 111-115.

Carlesimo, G. A., Buccione, I., Fadda, L., Graceffa, A., Mauri, M., Lorusso, S., et al. (2002). Standardizzazione di due test di memoria per uso clinico: Breve Racconto e Figura di Rey. Nuova Rivista di Neurologia, 12, 1-13.

Carlesimo, G. A., Caltagirone, C., & Gainotti, G. (1996). The Mental Deterioration Battery: normative data, diagnostic reliability and qualitative analyses of cognitive impairment. The Group for the Standardization of the Mental Deterioration Battery. Eur Neurol, 36(6), 378-384.

Cavedini, P., Riboldi, G., Keller, R., D'Annucci, A., & Bellodi, L. (2002). Frontal lobe dysfunction in pathological gambling patients. Biological Psychiatry, 51(4), 334-341.

Ceravolo, R., Frosini, D., Rossi, C., & Bonuccelli, U. (2009). Impulse control disorders in Parkinson's disease: definition, epidemiology, risk factors, neurobiology and management. Parkinsonism & Related Disorders, 15

Suppl 4, S111-115. Ceravolo, R., Frosini, D., Rossi, C., & Bonuccelli, U. (2010). Spectrum of addictions in Parkinson's disease: from

dopamine dysregulation syndrome to impulse control disorders. Journal of Neurology, 257(Suppl 2), S276-283.

Cilia, R., Cho, S. S., van Eimeren, T., Marotta, G., Siri, C., Ko, J. H., et al. (2011). Pathological gambling in patients with Parkinson's disease is associated with fronto-striatal disconnection: A path modeling analysis. Movement

Disorders, 26(2), 225-233. Comings, D. E., & Blum, K. (2000). Reward deficiency syndrome: genetic aspects of behavioral disorders. Cognition,

Emotion and Autonomic Responses: The Integrative Role of the Prefrontal Cortex and Limbic Structures, 126, 325-341.

Comings, D. E., Saucier, G., & MacMurray, J. P. (2002). Role of DRD2 and other dopamine genes in personality traits. In J. Benjamin, R. P. Ebstein & R. H. Belmaker (Eds.), Molecular genetics and the human personality (pp. 165-191). Washington, D.C.: American Psychiatric Publishing.

Cools, R. (2008). Role of dopamine in the motivational and cognitive control of behavior. Neuroscientist, 14(4), 381-395.

Cools, R., Barker, R. A., Sahakian, B. J., & Robbins, T. W. (2003). L-Dopa medication remediates cognitive inflexibility, but increases impulsivity in patients with Parkinson's disease. Neuropsychologia, 41(11), 1431-1441.

Crawford, J. R., & Garthwaite, P. H. (2007). Comparison of a single case to a control or normative sample in neuropsychology: Development of a Bayesian approach. Cognitive Neuropsychology, 24(4), 343-372.

Page 16 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

16

Crawford, J. R., Garthwaite, P. H., & Porter, S. (2010). Point and interval estimates of effect sizes for the case-controls design in neuropsychology: Rationale, methods, implementations, and proposed reporting standards. Cognitive

Neuropsychology, 27(3), 245-260. Czernecki, V., Pillon, B., Houeto, J. L., Pochon, J. B., Levy, R., & Dubois, B. (2002). Motivation, reward, and

Parkinson's disease: influence of dopatherapy. Neuropsychologia, 40(13), 2257-2267. Damasio, A. R., Tranel, D., & Damasio, H. (1991). Somatic markers and the guidance of behaviour: theory and

preliminary testing. In H. S. Levin, H. M. Eisenberg & A. L. Benton (Eds.), Frontal Lobe Function and

Dysfunction (pp. 217-229). New York: Oxford University Press. Dang, D., Cunnington, D., & Swieca, J. (2011). The emergence of devastating impulse control disorders during

dopamine agonist therapy of the restless legs syndrome. Clinical Neuropharmacology, 34(2), 66-70. Davis, C., Patte, K., Curtis, C., & Reid, C. (2010). Immediate pleasures and future consequences. A neuropsychological

study of binge eating and obesity. Appetite, 54(1), 208-213. Delazer, M., Sinz, H., Zamarian, L., Stockner, H., Seppi, K., Wenning, G. K., et al. (2009). Decision making under risk

and under ambiguity in Parkinson's disease. Neuropsychologia, 47(8-9), 1901-1908. Dunn, B. D., Dalgleish, T., & Lawrence, A. D. (2006). The somatic marker hypothesis: a critical evaluation.

Neuroscience and Biobehavioral Reviews, 30(2), 239-271. Euteneuer, F., Schaefer, F., Stuermer, R., Boucsein, W., Timmermann, L., Barbe, M. T., et al. (2009). Dissociation of

decision-making under ambiguity and decision-making under risk in patients with Parkinson's disease: A neuropsychological and psychophysiological study. Neuropsychologia, 47(13), 2882-2890.

Fein, G., McGillivray, S., & Finn, P. (2007). Older adults make less advantageous decisions than younger adults: Cognitive and psychological correlates. Journal of the International Neuropsychological Society, 13(3), 480-489.

Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12(3), 189-198.

Frank, M. J., Doll, B. B., Oas-Terpstra, J., & Moreno, F. (2009). Prefrontal and striatal dopaminergic genes predict individual differences in exploration and exploitation. Nature Neuroscience, 12(8), 1062-U1145.

Frank, M. J., & Hutchison, K. (2009). Genetic Contributions to Avoidance-Based Decisions: Striatal D2 Receptor Polymorphisms. Neuroscience, 164(1), 131-140.

Frank, M. J., Moustafa, A. A., Haughey, H. M., Curran, T., & Hutchison, K. E. (2007). Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning. Proceedings of the National Academy of

Sciences of the United States of America, 104(41), 16311-16316. Frank, M. J., Samanta, J., Moustafa, A. A., & Sherman, S. J. (2007). Hold your horses: Impulsivity, deep brain

stimulation, and medication in parkinsonism. Science, 318(5854), 1309-1312. Frank, M. J., Seeberger, L. C., & O'Reilly, R. C. (2004). By carrot or by stick: Cognitive reinforcement learning in

Parkinsonism. Science, 306(5703), 1940-1943. Gotham, A. M., Brown, R. G., & Marsden, C. D. (1986). Levodopa treatment may benefit or impair "frontal" function

in Parkinson's disease. Lancet, 2(8513), 970-971. Goudriaan, A. E., Oosterlaan, J., de Beurs, E., & van den Brink, W. (2005). Decision making in pathological gambling:

A comparison between pathological gamblers, alcohol dependents, persons with Tourette syndrome, and normal controls. Cognitive Brain Research, 23(1), 137-151.

Grant, S., Contoreggi, C., & London, E. D. (2000). Drug abusers show impaired performance in a laboratory test of decision making. Neuropsychologia, 38(8), 1180-1187.

Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry, 23, 56-62. Hirvonen, M., Laakso, A., Nagren, K., Rinne, J. O., Pohjalainen, T., & Hietala, J. (2005). C957T polymorphism of the

dopamine D2 receptor (DRD2) gene affects striatal DRD2 availability in vivo (vol 9, pg 1060, 2005). Molecular Psychiatry, 10(9), 889-889.

Ibarretxe-Bilbao, N., Junque, C., Tolosa, E., Marti, M. J., Valldeoriola, F., Bargallo, N., et al. (2009). Neuroanatomical correlates of impaired decision-making and facial emotion recognition in early Parkinson's disease. European

Journal of Neuroscience, 30(6), 1162-1171. Klein, T. A., Neumann, J., Reuter, M., Hennig, J., von Cramon, D. Y., & Ullsperger, M. (2007). Genetically determined

differences in learning from errors. Science, 318(5856), 1642-1645. Koffarnus, M. N., Newman, A. H., Grundt, P., Rice, K. C., & Woods, J. H. (2011). Effects of selective dopaminergic

compounds on a delay-discounting task. Behav Pharmacol, 22(4), 300-311. Lawrence, A. D., Evans, A. H., & Lees, A. J. (2003). Compulsive use of dopamine replacement therapy in Parkinson's

disease: reward systems gone awry? Lancet Neurology, 2(10), 595-604. Li, C. S., & Sinha, R. (2008). Inhibitory control and emotional stress regulation: neuroimaging evidence for frontal-

limbic dysfunction in psycho-stimulant addiction. Neuroscience & Biobehavioral Reviews, 32(3), 581-597. Manes, F., Sahakian, B., Clark, L., Rogers, R., Antoun, N., Aitken, M., et al. (2002). Decision-making processes

following damage to the prefrontal cortex. Brain, 125, 624-639. Mimura, M., Oeda, R., & Kawamura, M. (2006). Impaired decision-making in Parkinson's disease. Parkinsonism &

Related Disorders, 12(3), 169-175.

Page 17 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

17

Moustafa, A. A., Cohen, M. X., Sherman, S. J., & Frank, M. J. (2008). A Role for Dopamine in Temporal Decision Making and Reward Maximization in Parkinsonism. Journal of Neuroscience, 28(47), 12294-12304.

Nakaaki, S., Murata, Y., Sato, J., Shinagawa, Y., Hongo, J., Tatsumi, H., et al. (2007). Impairment of decision-making cognition in a case of frontotemporal lobar degeneration (FTLD) presenting with pathologic gambling and hoarding as the initial symptoms. Cognitive and Behavioral Neurology, 20(2), 121-125.

Orsini, A., Grossi, D., Capitani, E., Laiacona, M., Papagno, C., & Vallar, G. (1987). Verbal and spatial immediate memory span: normative data from 1355 adults and 1112 children. Ital J Neurol Sci, 8(6), 539-548.

Pagonabarraga, J., Garcia-Sanchez, C., Llebaria, G., Pascual-Sedano, B., Gironell, A., & Kulisevsky, J. (2007). Controlled study of decision-making and cognitive impairment in Parkinson's disease. Movement Disorders,

22(10), 1430-1435. Palminteri, S., Lebreton, M., Worbe, Y., Grabli, D., Hartmann, A., & Pessiglione, M. (2009). Pharmacological

modulation of subliminal learning in Parkinson's and Tourette's syndromes. Proceedings of the National

Academy of Sciences of the United States of America, 106(45), 19179-19184. Perretta, J. G., Pari, G., & Beninger, R. J. (2005). Effects of Parkinson disease on two putative nondeclarative learning

tasks - Probabilistic classification and gambling. Cognitive and Behavioral Neurology, 18(4), 185-192. Peters, J., & Buchel, C. (2011). The neural mechanisms of inter-temporal decision-making: understanding variability.

Trends Cogn Sci, 15(5), 227-239. Petry, N. M. (2001). Substance abuse, pathological gambling, and impulsiveness. Drug and Alcohol Dependence, 63(1),

29-38. Pine, A., Shiner, T., Seymour, B., & Dolan, R. J. (2010). Dopamine, time, and impulsivity in humans. J Neurosci,

30(26), 8888-8896. Poletti, M., Frosini, D., Lucetti, C., Del Dotto, P., Ceravolo, R., & Bonuccelli, U. (2010). Decision Making in De Novo

Parkinson's Disease. Movement Disorders, 25(10), 1432-1436. Robles, E., & Vargas, P. A. (2008). Parameters of delay discounting assessment: number of trials, effort, and sequential

effects. Behav Processes, 78(2), 285-290. Rossi, M., Gerschcovich, E. R., de Achaval, D., Perez-Lloret, S., Cerquetti, D., Cammarota, A., et al. (2010). Decision-

making in Parkinson's disease patients with and without pathological gambling. European Journal of

Neurology, 17(1), 97-102. Salmon, E., & Collette, F. (2005). Functional imaging of executive functions. Acta neurologica Belgica, 105(4), 187-

196. Santangelo, G., Vitale, C., Trojano, L., Verde, F., Grossi, D., & Barone, P. (2009). Cognitive dysfunctions and

pathological gambling in patients with Parkinson's disease. Movement Disorders, 24(6), 899-905. Spinnler, H., & Tognoni, G. (1987). Italian standardization and classification of Neuropsychological tests. The Italian

Group on the Neuropsychological Study of Aging. Italian Journal of Neurological Sciences, Suppl 8, 1-120. Sweitzer, M. M., Allen, P. A., & Kaut, K. P. (2008). Relation of individual differences in impulsivity to nonclinical

emotional decision making. J Int Neuropsychol Soc, 14(5), 878-882. Tchanturia, K., Liao, P. C., Uher, R., Lawrence, N., Treasure, J., & Campbell, I. C. (2007). An investigation of decision

making in anorexia nervosa using the Iowa Gambling Task and skin conductance measurements. Journal of

the International Neuropsychological Society, 13(4), 635-641. Wardle, M. C., Gonzalez, R., Bechara, A., & Martin-Thormeyer, E. M. (2010). Iowa Gambling Task performance and

emotional distress interact to predict risky sexual behavior in individuals with dual substance and HIV diagnoses. Journal of Clinical and Experimental Neuropsychology, 32(10), 1110-1121.

Weintraub, D., & Potenza, M. N. (2006). Impulse control disorders in Parkinson's disease. Current Neurology and

Neuroscience Reports, 6(4), 302-306. Weiss, H. D., Hirsch, E. S., Williams, J. R., Swearengin, L., & Marsh, L. (2010). Detection of impulse control disorders

in Parkinson disease patients. Neurologist, 16(6), 406-407. Wiecki, T. V., & Franck, M. J. (2010). Neurocomputational models of motor and cognitive deficits in Parkinson's

disease. In A. Bjorklund & M. A. Cenci (Eds.), Progress in Brain Research (Vol. 183, pp. 275-297): Elsevier. Wolters, E., van der Werf, Y. D., & van den Heuvel, O. A. (2008). Parkinson's disease-related disorders in the

impulsive-compulsive spectrum. Journal of Neurology, 255 Suppl 5, 48-56. Zamarian, L., Sinz, H., Bonatti, E., Gamboz, N., & Delazer, M. (2008). Normal aging affects decisions under

ambiguity, but not decisions under risk. Neuropsychology, 22(5), 645-657. Zeeb, F. D., Floresco, S. B., & Winstanley, C. A. (2010). Contributions of the orbitofrontal cortex to impulsive choice:

interactions with basal levels of impulsivity, dopamine signalling, and reward-related cues. Psychopharmacology (Berl), 211(1), 87-98.

Page 18 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Table 1 - Results from the neuropsychological evaluation of the patient LT.

Tests Raw Score Weighted

Score

Cut off Clinical Stage

Global Cognitive Status

Mini Mental State Examination (MMSE) 29/30 27 24 Normal

Short-Term Memory

Digit Span Forward 6 6 3.75 Normal-High

Corsi’s Span Forward 5 4.75 3.75 Normal-High

Long-Term Memory

Short Tale Recall (“Anna Pesenti”) 20/28 19 8 Normal-High

Rey-Osterrieth Figure Delayed Recall 15/36 13 9.47 Normal-High

Frontal & Executive Functions

Phonological Fluency 42 43.1 17.35 Normal-High

Semantic Fluency 53 54 25 Normal-High

Frontal Assessment Battery 18/18 18 11.60 Max Score

Stroop Test – Execution Time (sec) 14.5 16.25 36.91 Normal-High

Stroop Test – Errors 0/30 0 4.23 Max Score

Trail Making Test – Part B (sec) 55 28 282 Normal-High

Trail Making Test – Part (B-A) 13 0 186 Normal-High

Processing Speed

Attentional Matrices 46/60 43.4 24 Normal-High

Trail Making Test – Part A (sec) 42 35 93 Normal-High

Page 19 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Reasoning & Categorisation

Raven’s Colored Progressive Matrices

(A, AB, B series)

36/36 36 18.96 Max Score

Weigl’s Test 15/15 15 4.50 Max Score

Visuo-perception Abilities

Street’s Gestalt Completion Test 11/14 9 2.25 Normal-High

Visuo-constructive Abilities

Rey-Osterrieth Figure Copy 32/36 31 28.88 Normal

Hamilton Depression Scale 8 14 Normal

Page 20 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Table 2 - Results obtained from the patient LT, from the Control Group Parkinson (CGP), and

from the Control Group Healthy (CGH) on the Iowa Gambling Task (IGT). Data are expressed

in terms of the difference (net score) between the number of selections from advantageous

decks (C+D) and the number of selections from disadvantageous decks (A+B). One-tailed

significance with respect to CGP: * p < .05, and with respect to CGH: ° p < .05.

Age Education IGT Total net

score

IGT First 50

choices net

score

IGT Last 50

choices net

score

LT at T1 -36*° -6 -30*°

LT at T2 (6-month follow-up) 42* 11

-16 -12* -4

CGP (num. 15) mean ± SD 64.27 ± 10.50 10.20 ± 4.81 8.80 ± 20.96 1.87 ± 7.58 7.47 ± 16.06

CGH (num. 16) mean ± SD 41.56 ± 13.91 11.94 ± 3.49 14.62 ± 23.18 2.13 ± 12.03 12.50 ± 14.87

Page 21 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Fig. 1 - Mean net scores ([C&D – A&B]) for blocks 1 – 5 for each group. Positive scores reflect advantageous performance while negative scores reflect disadvantageous performance. Error bars

represent + 1 standard deviation for CGP and - 1 standard deviation for CGH. 210x166mm (96 x 96 DPI)

Page 22 of 21

URL: http:/mc.manuscriptcentral.com/nncs Email: hbc@mail.med.upenn.edu

Neurocase

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960