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Subthalamic involvement in monetary reward and its dysfunction in parkinsonian gamblers

July 2014
Journal of Neurology, Neurosurgery, and Psychiatry 86(3)

DOI:10.1136/jnnp-2014-307912

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PubMed

Authors:

Manuela Fumagalli

Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico

Manuela Rosa

Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico

Gaia Giannicola

Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico

Sara Marceglia

University of Trieste

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Pathological gambling (PG) is an impulse control disorder that manifests in 2.2-7% of patients with Parkinson's disease (PD). Although the underlying neural mechanisms remain controversial, parkinsonian patients with PG show enhanced risk propensity, especially when assuming dopamine agonist drugs. The dopaminergic reward circuit, a neural network that participates in developing and monitoring motivated behaviours,1 includes the subthalamic nucleus (STN). Local field potentials (LFPs) recorded from macroelectrodes implanted in the STN for deep brain stimulation (DBS) show specific low-frequency oscillations in patients with PD with impulsive control disorders at rest and in patients with PG during the preparation of conflictual economics decisions.2 ,3 No study has yet investigated STN involvement in monetary reward processing, namely the phase that follows economics decisions, when participants face the outcome of their choice in patients with PD. Besides helping to understand the mechanisms underlying PG, this knowledge could promote the optimisation of therapies for impulse control disorders. We investigated the STN's role in risk-related monetary reward in parkinsonian patients. To do so, we studied the reward-related STN LFPs changes in patients with PD with and without PG engaged in an economics decision task.

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LETTER

Subthalamic involvement in

monetary reward and its

dysfunction in parkinsonian

gamblers

INTRODUCTION

Pathological gambling (PG) is an impulse

control disorder that manifests in 2.2–7%

of patients with Parkinson’s disease (PD).

Although the underlying neural mechan-

isms remain controversial, parkinsonian

patients with PG show enhanced risk pro-

pensity, especially when assuming dopa-

mine agonist drugs.

The dopaminergic reward circuit, a

neural network that participates in devel-

oping and monitoring motivated beha-

viours,

includes the subthalamic nucleus

(STN). Local ﬁeld potentials (LFPs)

recorded from macroelectrodes implanted

in the STN for deep brain stimulation

(DBS) show speciﬁc low-frequency oscilla-

tions in patients with PD with impulsive

control disorders at rest and in patients

with PG during the preparation of con-

ﬂictual economics decisions.

No study

has yet investigated STN involvement in

monetary reward processing, namely the

phase that follows economics decisions,

when participants face the outcome of

their choice in patients with PD. Besides

helping to understand the mechanisms

underlying PG, this knowledge could

promote the optimisation of therapies for

impulse control disorders.

We investigated the STN’s role in

risk-related monetary reward in parkin-

sonian patients. To do so, we studied the

reward-related STN LFPs changes in

patients with PD with and without PG

engaged in an economics decision task.

MATERIALS AND METHODS

We enrolled 12 patients with PD 4 days

after STN DBS macroelectrode positioning

surgery as described elsewhere

(for clinical

details, see table 1 from Ref. 3, patients

number 1–4, 8–12, 14, 15, 17). Of the 12

patients, 6 met the criteria for PG according

to the Diagnostic and Statistical Manual of

Mental Disorders (DSM IV-TR). All

patients gave informed consent. The study

was conducted in accordance with the

DeclarationofHelsinkiandwasapproved

by the institutional review board. Patients

were tested with the economics decision

task (ﬁgure 1A,C) during bilateral STN LFP

recording from DBS macroelectrode

contact pair 0–2.

LFPs were preampliﬁed, ﬁltered (band

pass 2–512 Hz), differentially ampliﬁed

(×100 000) and digitised with a 1024 Hz

sampling rate through the Galileo BE

Light EEG ampliﬁcation system (EBNeuro

Spa, Florence, Italy). LFPs were analysed

off-line with Matlab software (V.7.10, The

MathWorks, Natick, Massachusetts, USA).

First, to identify the main activated LFP

frequency band during economics feed-

back, we ran a time–frequency analysis.

Then, to obtain the mean frequency band

power in conﬂictual and non-conﬂictual

task conditions during the two task phases

(black screen, feedback) for each type of

feedback (risky positive, risky negative,

non-risky positive, non-risky negative),we

applied the Hilbert transform.

For behavioural analyses, the economics

strategy each patient used during task per-

formance was evaluated by calculating the

sum of risky choices in conﬂictual trials.

Differences between economics strategies

in patients with and without PG were

tested in a one-way analysis of variance

(ANOVA) using PG ( presence, absence) as

between factor.

A one-sample Kolmogorov-Smirnov test

was performed with electrophysiological

data to verify whether they have normal

distributions. To assess whether STN LFP

activity recorded during black screen

could be used as the baseline, we ﬁrst

compared mean power during the black

screen in conﬂictual and non-conﬂictual

trials using a two-way repeated measures

ANOVA with between factor PG and

within factor type of feedback.

After calculating the percentage power

change from the baseline for each trial,

three-way repeated measures ANOVA with

between factor PG,ﬁrst within factor task

phases and second within factor type of

feedback was run for conﬂictual trials. A

similar three-way ANOVA was run for

non-conﬂictual trials. One patient was

excluded from the analysis on non-

conﬂictual trials for artefacts due to elec-

trode extension cable movement.

Differences were considered signiﬁcant at

p<0.05.

RESULTS

During the economics task, patients with

PG adopted a signiﬁcantly more risk-

taking behavioural strategy than patients

without PG (F(1,10)=7.99; p=0.017).

The one-sample Kolmogorov-Smirnov

test showed that LFPs in the task phases

and in the types of feedback have a

normal distribution ( p>0.05 for all

variables).

In all patients, the time–frequency plot

for STN LFPs averaged across all trials

showed that the principal power modula-

tions during the feedback phase involved

low-frequency power (from 2.25±0.87 to

12.08±0.29 Hz; ﬁgure 1B).

When we applied the Hilbert trans-

form, the two-way ANOVA showed that

the factors PG and feedback type and

their interactions had no signiﬁcant effects

on low-frequency power during the black

screen phase in conﬂictual (F(3,66)=1.45;

p>0.05) and non-conﬂictual trials (F

(3,60)=1.38; p>0.05). We therefore con-

sidered the STN LFP low-frequency band

power recorded when we displayed the

black screen as the baseline.

Global three-way ANOVA showed signiﬁ-

cantly higher low-frequency power during

feedback than during black screen in con-

ﬂictual (task phases, F(1,22)=9.25;

p=0.005) and non-conﬂictual trials (task

phases, F(1,20)=4.45; p=0.047; ﬁgure 1D).

Three-way ANOVA detected a signiﬁ-

cant interaction between the three factors

only in conﬂictual trials (PG×task

phases×feedback type, F(3,66)=2.73;

p=0.050). Post hoc ANOVA showed a sig-

niﬁcant interaction (PG×feedback type,F

(1,22)=2.74; p=0.050). Post hoc ANOVA

showed signiﬁcant differences between

patients with and without PG only during

risky positive feedback (F(1,22)=5.07;

p=0.034). Speciﬁcally, when patients

received a positive feedback after a risky

choice, percentage changes in low-

frequency power were signiﬁcantly lower

in parkinsonian patients without than with

PG (ﬁgure 1E).

DISCUSSION

In general, our results ﬁrst provide the

neurophysiological evidence that the

human STN is involved in monetary

reward. Speciﬁcally, we found that the

reward-related STN neural activity

recorded during an economics decision

task shows distinct patterns in parkinson-

ian patients who gamble and those who

do not: whereas in gamblers, low-

frequency power increases during all types

of monetary feedback, that is, during

winning and losing, in non-gamblers, it

remains unchanged during the risky posi-

tive feedback, a low probable and high

win that in the long run leads to loss. This

neurophysiological pattern reﬂects the

behavioural strategy adopted by patients.

Patients without PG used a risk-avoiding

strategy, for instance, they tended to

choose stimuli associated with small but

more probable positive rewards (in our

economics task, a non-risky positive feed-

back). Conversely, patients with PG used a

risk-taking strategy, and preferred large

and less probable positive rewards (in our

J Neurol Neurosurg Psychiatry Month 2014 Vol 0 No 0 1

PostScript

JNNP Online First, published on July 12, 2014 as 10.1136/jnnp-2014-307912

group.bmj.com on September 19, 2014 - Published by jnnp.bmj.comDownloaded from

Figure 1 (A) The economics decision task. Each trial comprised two phases: the ‘feedback’phase displaying the money won or lost after the

patient’s choice, and the ‘black screen’. The red letters show the patient’s choice. (B) The time–frequency plot for the grand average subthalamic

nucleus local ﬁeld potential (STN LFP) power in all trials in patients with and without pathological gambling (PG). Note that the principal power

changes during the feedback phase involved the low-frequency band. (C) Feedback obtained during the economics task in conﬂictual and

non-conﬂictual trials. On the left, an example showing a conﬂictual trial between a non-risky stimulus ‘A’and a risky stimulus ‘C’. On the right, an

example showing a non-conﬂictual trial between two risky stimuli ‘B’and ‘C’. We classiﬁed four types of feedback according to risk taking: risky

positive (+100€), risky negative (−70€), non-risky positive (+60€), non-risky negative (−30€). The task was designed to reward non-risky stimuli

choices, so that the larger the number of non-risky stimuli choices, the higher was the amount of money earned. (D) On the left, the grand average

of low-frequency power modulations in conﬂictual trials during the feedback phase and the black screen phase in all parkinsonian patients with and

without PG. Low-frequency power modulations are expressed as percentage changes from the black screen phase. Red horizontal lines represent the

mean low-frequency power during the feedback and black screen phases. On the right, the grand average for low-frequency power modulations in

non-conﬂictual trials. Note that in all patients STN LFP low-frequency power increased during feedback in both conﬂictual and non-conﬂictual trials.

(three-way analysis of variance (ANOVA), p<0.05). (E) Histograms represent changes in low-frequency STN LFP power during feedback in patients

with and without PG in conﬂictual trials. Error bars represent the SE of the estimated mean. Below, time-frequency plots for the grand average STN

LFP power during risky positive feedback. Low-frequency power during risky positive feedback is signiﬁcantly lower in patients without than in

patients with PG (post hoc ANOVA, *p<0.05).

2J Neurol Neurosurg Psychiatry Month 2014 Vol 0 No 0

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task, a risky positive feedback). These

results suggest that the speciﬁc neuro-

physiological activity in non-gamblers that

remains unchanged during risky positive

feedback behaviourally reﬂects their scarce

tendency to choose this option.

Conversely, neurophysiological activity in

patients who gamble is modulated indif-

ferently by reward and gamblers behav-

iourally use a disadvantageous strategy.

Therefore, we conjecture that the spe-

ciﬁc STN LFP reward-related pattern in

response to the risky positive feedback

depends on the value that the STN ‘attri-

butes’to it in orienting the economics

choice: in patients with PG it suggests an

impaired learning in discriminating eco-

nomics rewards.

To understand the reward circuit better,

future research should also investigate cor-

tical modulation. It should also check

whether the feedback task involves other

cognitive processes related to decision-

making, including inhibition, learning,

probability encoding, stimuli salience and

reward encoding. Nonetheless, in general,

our results conﬁrm previous reports on

STN low-frequency involvement in emo-

tional and decisional processes

and agree

with reports that STN DBS can variably

modulate efﬁcacy in using feedback and

regulate impulsivity.

Our previous ﬁndings on the prepar-

ation of economics decision in parkinson-

ian patients with PG showed a

subthalamic dysfunction that makes their

decisional threshold highly sensitive to

risky options.

In this study, we extend

these results, suggesting that STN activity

is also affected by reward and that PG

could be related to a reward circuit

disorder.

Manuela Fumagalli,

Manuela Rosa,

Gaia Giannicola,

Sara Marceglia,

Claudio Lucchiari,

Domenico Servello,

Angelo Franzini,

Claudio Pacchetti,

Luigi Romito,

Alberto Albanese,

Mauro Porta,

Gabriella Pravettoni,

2,6

Alberto Priori

1,7

Centro Clinico per la Neurostimolazione, le

Neurotecnologie ed i Disordini del Movimento,

Fondazione IRCCS Ca’Granda, Ospedale Maggiore

Policlinico, Milan, Italy

Dipartimento di Economia, Management e Metodi

Quantitativi, Università degli Studi di Milano, Milan,

Italy

Neurochirurgia Funzionale e Clinica Tourette, IRCCS

Galeazzi, Milan, Italy

Fondazione IRCCS Istituto Nazionale Neurologico

Carlo Besta, Milan, Italy

Unità Operativa Parkinson e Disordini del Movimento,

IRCCS Istituto Neurologico Mondino, Pavia, Italy

Unità di Ricerca Applicata per le Scienze Cognitive e

Psicologiche, Istituto Europeo di Oncologia, Milan, Italy

Dipartimento di Fisiopatologia Medico-Chirurgica e dei

Trapianti, Università degli Studi di Milano, Milan, Italy

Correspondence to Professor Alberto Priori, Centro

Clinico per la Neurostimolazione, le

Neurotecnologie ed i Disordini del Movimento,

Fondazione IRCCS Ca’Granda, Ospedale Maggiore

Policlinico, Via Francesco Sforza 35, Milan 20122,

Italy; alberto.priori@unimi.it

Contributors MF and MR contributed equally to this

study. MF, MR and GG were involved in conception,

organisation and execution; design and execution and

writing of the ﬁrst draft. SM was involved in

conception; review and critique and writing of the ﬁrst

draft. CL was involved in conception; review and

critique. DS and AF were involved in conception,

organisation and execution; review and critique. CP and

LR were involved in review and critique. AA, MP, GP

and AP were involved in conception; review and

critique.

Funding ERANET-Neuron Grant ‘PhysiolDBS’

(Neuron-48-013).

Competing interests None.

Patient consent Obtained.

Ethics approval Fondazione IRCCS Ca’Granda

Ospedale Maggiore Policlinico Milano.

Provenance and peer review Not commissioned;

externally peer reviewed.

To cite Fumagalli M, Rosa M, Giannicola G, et al.

J Neurol Neurosurg Psychiatry Published Online First:

[please include Day Month Year] doi:10.1136/jnnp-

2014-307912

Received 18 February 2014

Revised 30 May 2014

Accepted 15 June 2014

J Neurol Neurosurg Psychiatry 2014;0:1–3.

doi:10.1136/jnnp-2014-307912

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Neuropsychopharmacology 2010;35:4–26.

2 Rodriguez-Oroz MC, Lopez-Azcarate J,

Garcia-Garcia D, et al. Involvement of the subthalamic

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3 Rosa M, Fumagalli M, Giannicola G, et al.

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4 Cavanagh JF, Wiecki TV, Cohen MX, et al.

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J Neurol Neurosurg Psychiatry Month 2014 Vol 0 No 0 3

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doi: 10.1136/jnnp-2014-307912

published online July 12, 2014J Neurol Neurosurg Psychiatry

Manuela Fumagalli, Manuela Rosa, Gaia Giannicola, et al.

gamblers

reward and its dysfunction in parkinsonian

Subthalamic involvement in monetary

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Full-text available

Feb 2018

Economic decision-making is disrupted in individuals with gambling disorder, an addictive behavior observed in Parkinson’s disease (PD) patients receiving dopaminergic therapy. The subthalamic nucleus (STN) is involved in the inhibition of impulsive behaviors; however, its role in impulse control disorders and addiction is still unclear. Here, we recorded STN local field potentials (LFPs) in PD patients with and without gambling disorder during an economic decision-making task. Reaction times analysis showed that for all patients, the decision whether to risk preceded task onset. We compared then for both groups the STN LFP preceding high- and low-risk economic decisions. We found that risk avoidance in gamblers correlated with larger STN LFP low-frequency (<12-Hz) fluctuations preceding task onset. In particular, the amplitude of low-frequency LFP fluctuations carried significant information about future decisions. Decisions of patients not affected by gambling disorder were instead not correlated with pretask STN LFP. Our results suggest that STN activity preceding task onset affects risk decisions by preemptively inhibiting attraction to high but unlikely rewards in favor of a long-term payoff.

Impulse Control and Related Disorders in Parkinson's Disease

Chapter

Jun 2017
INT REV NEUROBIOL

Impulse control disorders (ICDs), such as compulsive gambling, buying, sexual, and eating behaviors, are a serious and increasingly recognized complication in Parkinson's disease (PD), occurring in up to 20% of PD patients over the course of their illness. Related behaviors include punding (stereotyped, repetitive, purposeless behaviors), dopamine dysregulation syndrome (DDS) (compulsive medication overuse), and hobbyism (e.g., compulsive internet use, artistic endeavors, and writing). These disorders have a significant impact on quality of life and function, strain interpersonal relationships, and worsen caregiver burden, and are associated with significant psychiatric comorbidity. ICDs have been most closely related to the use of dopamine agonists (DAs), while DDS is primarily associated with shorter acting, higher potency dopamine replacement therapy (DRT), such as levodopa. However, in preliminary research ICDs have also been reported to occur with monoamine oxidase inhibitor-B and amantadine treatment, and after deep brain stimulation (DBS) surgery. Other risk factors for ICDs may include sex (e.g., male sex for compulsive sexual behavior, and female sex for compulsive buying behavior); younger age overall at PD onset; a pre-PD history of an ICD; personal or family history of substance abuse, bipolar disorder, or gambling problems; and impulsive personality traits. Dysregulation of the mesocorticolimbic dopamine system is thought to be the major neurobiological substrate for ICDs in PD, but there is preliminary evidence for alterations in opiate and serotonin systems too. The primary treatment of ICDs in PD is discontinuation of the offending treatment, but not all patients can tolerate this due to worsening motor symptoms or DA withdrawal syndrome. While psychiatric medications and psychosocial treatments are frequently used to treat ICDs in the general population, there is limited empirical evidence for their use in PD, so it is critical for patients to be monitored closely for ICDs from disease onset and routine throughout its course. In the future, it may be possible to use a precision medicine approach to decrease the incidence of ICDs in PD by avoiding DA use in patients determined to be at highest risk based on their clinical and neurobiological (e.g., motor presentation, behavioral measures of medication response, genetics, dopamine transporter neuroimaging) profile. Additionally, as empirically validated treatments for ICDs and similar disorders (e.g., substance use disorders) emerge, it will also be important to examine their efficacy and tolerability in individuals with comorbid PD.

Subthalamic nucleus stimulation reverses mediofrontal influence over decision threshold

Article

Full-text available

Sep 2011
NAT NEUROSCI

It takes effort and time to tame one's impulses. Although medial prefrontal cortex (mPFC) is broadly implicated in effortful control over behavior, the subthalamic nucleus (STN) is specifically thought to contribute by acting as a brake on cortico-striatal function during decision conflict, buying time until the right decision can be made. Using the drift diffusion model of decision making, we found that trial-to-trial increases in mPFC activity (EEG theta power, 4-8 Hz) were related to an increased threshold for evidence accumulation (decision threshold) as a function of conflict. Deep brain stimulation of the STN in individuals with Parkinson's disease reversed this relationship, resulting in impulsive choice. In addition, intracranial recordings of the STN area revealed increased activity (2.5-5 Hz) during these same high-conflict decisions. Activity in these slow frequency bands may reflect a neural substrate for cortico-basal ganglia communication regulating decision processes.

Involvement of the subthalamic nucleus in impulse control disorders associated with Parkinson’s disease

Article

Full-text available

Nov 2010
BRAIN

Behavioural abnormalities such as impulse control disorders may develop when patients with Parkinson's disease receive dopaminergic therapy, although they can be controlled by deep brain stimulation of the subthalamic nucleus. We have recorded local field potentials in the subthalamic nucleus of 28 patients with surgically implanted subthalamic electrodes. According to the predominant clinical features of each patient, their Parkinson's disease was associated with impulse control disorders (n = 10), dyskinesias (n = 9) or no dopaminergic mediated motor or behavioural complications (n = 9). Recordings were obtained during the OFF and ON dopaminergic states and the power spectrum of the subthalamic activity as well as the subthalamocortical coherence were analysed using Fourier transform-based techniques. The position of each electrode contact was determined in the postoperative magnetic resonance image to define the topography of the oscillatory activity recorded in each patient. In the OFF state, the three groups of patients had similar oscillatory activity. By contrast, in the ON state, the patients with impulse control disorders displayed theta-alpha (4-10 Hz) activity (mean peak: 6.71 Hz) that was generated 2-8 mm below the intercommissural line. Similarly, the patients with dyskinesia showed theta-alpha activity that peaked at a higher frequency (mean: 8.38 Hz) and was generated 0-2 mm below the intercommissural line. No such activity was detected in patients that displayed no dopaminergic side effects. Cortico-subthalamic coherence was more frequent in the impulsive patients in the 4-7.5 Hz range in scalp electrodes placed on the frontal regions anterior to the primary motor cortex, while in patients with dyskinesia it was in the 7.5-10 Hz range in the leads overlying the primary motor and supplementary motor area. Thus, dopaminergic side effects in Parkinson's disease are associated with oscillatory activity in the theta-alpha band, but at different frequencies and with different topography for the motor (dyskinesias) and behavioural (abnormal impulsivity) manifestations. These findings suggest that the activity recorded in parkinsonian patients with impulse control disorders stems from the associative-limbic area (ventral subthalamic area), which is coherent with premotor frontal cortical activity. Conversely, in patients with l-dopa-induced dyskinesias such activity is recorded in the motor area (dorsal subthalamic area) and it is coherent with cortical motor activity. Consequently, the subthalamic nucleus appears to be implicated in the motor and behavioural complications associated with dopaminergic drugs in Parkinson's disease, specifically engaging different anatomo-functional territories.

The Reward Circuit: Linking Primate Anatomy and Human Imaging

Article

Full-text available

Oct 2009
NEUROPSYCHOPHARMACOL

Although cells in many brain regions respond to reward, the cortical-basal ganglia circuit is at the heart of the reward system. The key structures in this network are the anterior cingulate cortex, the orbital prefrontal cortex, the ventral striatum, the ventral pallidum, and the midbrain dopamine neurons. In addition, other structures, including the dorsal prefrontal cortex, amygdala, hippocampus, thalamus, and lateral habenular nucleus, and specific brainstem structures such as the pedunculopontine nucleus, and the raphe nucleus, are key components in regulating the reward circuit. Connectivity between these areas forms a complex neural network that mediates different aspects of reward processing. Advances in neuroimaging techniques allow better spatial and temporal resolution. These studies now demonstrate that human functional and structural imaging results map increasingly close to primate anatomy.

Hold Your Horses: Impulsivity, Deep Brain Stimulation, and Medication in Parkinsonism

Article

Full-text available

Dec 2007
SCIENCE

Deep brain stimulation (DBS) of the subthalamic nucleus markedly improves the motor symptoms of Parkinson's disease, but causes cognitive side effects such as impulsivity. We showed that DBS selectively interferes with the normal ability to slow down when faced with decision conflict. While on DBS, patients actually sped up their decisions under high-conflict conditions. This form of impulsivity was not affected by dopaminergic medication status. Instead, medication impaired patients' ability to learn from negative decision outcomes. These findings implicate independent mechanisms leading to impulsivity in treated Parkinson's patients and were predicted by a single neurocomputational model of the basal ganglia.

Pathological Gambling in Parkinson's Disease: Subthalamic Oscillations During Economics Decisions

Article

Oct 2013
MOVEMENT DISORD

Pathological gambling develops in up to 8% of patients with Parkinson's disease. Although the pathophysiology of gambling remains unclear, several findings argue for a dysfunction in the basal ganglia circuits. To clarify the role of the subthalamic nucleus in pathological gambling, we studied its activity during economics decisions. We analyzed local field potentials recorded from deep brain stimulation electrodes in the subthalamic nucleus while parkinsonian patients with (n = 8) and without (n = 9) pathological gambling engaged in an economics decision-making task comprising conflictual trials (involving possible risk-taking) and non conflictual trials. In all parkinsonian patients, subthalamic low frequencies (2-12 Hz) increased during economics decisions. Whereas, in patients without gambling, low-frequency oscillations exhibited a similar pattern during conflictual and non conflictual stimuli, in those with gambling, low-frequency activity increased significantly more during conflictual than during non conflictual stimuli. The specific low-frequency oscillatory pattern recorded in patients with Parkinson's disease who gamble could reflect a subthalamic dysfunction that makes their decisional threshold highly sensitive to risky options. When parkinsonian patients process stimuli related to an economics task, low-frequency subthalamic activity increases. This task-related change suggests that the cognitive-affective system that drives economics decisional processes includes the subthalamic nucleus. The specific subthalamic neuronal activity during conflictual decisions in patients with pathological gambling supports the idea that the subthalamic nucleus is involved in behavioral strategies and in the pathophysiology of gambling. © 2013 Movement Disorder Society.