Post on 24-Apr-2023
Journal of Parkinson’s Disease 3 (2013) 105–138DOI 10.3233/JPD-120165IOS Press
105
Review
A Systematic Review of Impulse ControlDisorders in Parkinson’s Disease
Mette Buhl Callesena,b, Jørgen Scheel-Krugerb, Morten L. Kringelbachb,c and Arne Møllera,b
aDepartment of Nuclear Medicine and PET-Centre, Aarhus University Hospital, Aarhus, DenmarkbCenter of Functionally Integrative Neuroscience, Aarhus University, Aarhus, DenmarkcDepartment of Psychiatry, Oxford University, UK
Abstract. Throughout the past decade it has been recognized that dopaminergic medication administered to remedy motorsymptoms in Parkinson’s disease is associated with an enhanced risk for impulse control disorders and related compulsivebehaviors such as hobbyism, punding, and the dopamine dysregulation syndrome. These complications are relatively frequent,affecting 6–15.5% of patients, and they most often appear, or worsen, after initiation of dopaminergic therapy or dosage increase.Recently, impulse control disorders have also been associated with subthalamic nucleus deep brain stimulation. Here we presenta systematic overview of literature published between 2000 and January 2013 reporting impulse control disorders in Parkinson’sdisease. We consider prevalence rates and discuss the functional neuroanatomy, the impact of dopamine-serotonin interactions,and the cognitive symptomatology associated with impulse control disorders in Parkinson’s disease. Finally, perspectives forfuture research and management of impulse control disorders in Parkinson’s disease are discussed.
Keywords: Impulse control disorders, Parkinson disease, dopamine, serotonin, neuroanatomy, decision making
INTRODUCTION
Parkinson’s disease (PD) is a progressive neu-rodegenerative disorder associated with a dopaminedeficiency in the substantia nigra zona compacta andthe ventral tegmental area in the midbrain causingabnormalities in movement, behavior, cognition, andemotion. Based on observations, James Parkinson firstdescribed the disorder as the “shaking palsy” in 1817.At that time, the senses and intellect of patients suf-fering from PD were believed to be unaffected by thedisease [1]. Half a century later this assumption wasrevised by “the father of modern neurology” the Frenchneurologist, Jean-Martin Charcot (1825–93), who
∗Correspondence to: Mette Buhl Callesen, Department ofNuclear Medicine and PET-Centre, Aarhus University Hospital,Noerrebrogade 44, Building 10 G, 8000 Aarhus C, Denmark. Tel.:+45 78464405; E-mail: buhl@pet.auh.dk.
suggested that the patients’ state of mind is alteredas the disease progresses. Nevertheless, in the generalclinic, PD is still largely considered to be a movementdisorder characterized by cardinal motor symptoms.According to the UK Brain Bank criteria for PD, pres-ence of bradykinesia accompanied by at least one ofthe following: resting tremor, muscular rigidity, or pos-tural instability, are required for a diagnosis of PD.Furthermore, at least three supportive criteria includ-ing: unilateral onset, excellent response to levodopa,resting tremor, severe levodopa-induced chorea, pro-gressive disorder, levodopa response for over 5 years,persistent asymmetry affecting the side of onset most,or clinical course of over 10 years, must be present fora definite diagnosis.
Recently it has been established that even at earlydisease stages, PD is associated with cognitive impair-ments involving executive functions, working memory,
ISSN 1877-7171/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved
This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial
License.
106 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
impulse control, reversal learning, and decision-making, as well as emotional disturbances includingdepression, apathy, and anxiety causing a generallydecreased quality of life [2–9]. These non-motor mani-festations of PD are to a great extent considered toresult from a deficient dopaminergic innervation oflimbic and prefrontal cortical brain regions followingdisease progression and are thus more pronounced atlater disease stages. The syndromes may be furtherdeteriorated by additional degeneration of the choliner-gic, noradrenergic, and serotonergic neurotransmittersystems [10–13]. Moreover, the medical and surgicaltreatments administered to relieve motor symptomsplay complex roles via their indirect influence on un-affected brain regions potentially inducing cognitiveand emotional dysfunctions. Weintraub and Nirenberg[8] , Crossman [14], and Cools et al. [3, 4] recently dis-cussed and presented results supporting the hypothesisthat the behavioral syndromes depend on disturbancesin the balance between the depleted dorsal striatum andthe dominance of the relatively intact ventral striatum(including the nucleus accumbens) in early stages ofthe disease [3, 4, 6]. Though dopaminergic treatmentin early PD relatively successfully recovers the nor-mal function within the dorsal striatum involved in thesensory-motor circuit, the dopaminergic agents may“overdose” the ventral striatum, potentially resultingin affective disturbances and impulse control disorders(ICDs) [2–4].
In the DSM-IV [15], ICDs define a category ofbehavioral disorders characterized by recurrent mal-adaptive disinhibited behavior despite personal andrelational consequences. Among these are pathologi-cal gambling, compulsive buying, hypersexuality, andbinge eating. Since the early case report by Seedatet al. in 2000 [16], it has been well documented thatdopaminergic medication in a subgroup of PD patientsinduces ICDs and related compulsive disorders suchas hobbyism, punding (i.e. various behavioral stereo-typies), and the dopamine dysregulation syndrome(DDS) characterized by addiction-like self-medicationof high doses of levodopa and short-acting dopamineagonists [8, 17]. The behavioral complications mostoften appear, or worsen, after initiation of D2/D3dopamine agonist therapy or dosage increase. In addi-tion, symptoms tend to improve or disappear upondosage decrease or discontinuation of the dopamineagonist treatment [8, 18–22]. The various syndromesaffect 6–15.5% of PD patients [21, 23–28] comparedto a prevalence of ICDs of 1.1–1.6% in the generaladult population [23, 24, 29, 30]. Moreover, ICDs havebeen associated with subthalamic nucleus deep brain
stimulation (STN DBS) in subgroups of patients [23,31–42], where the results still present important con-troversies and disagreements [32, 42–44]. We return tothis discussion later.
The etiology and pathogenesis of treatment-inducedICDs in PD remain unknown, though altered activityof the mesolimbic dopamine system has been sug-gested to be responsible for the phenomenon [23,45]. Besides a high dose of dopamine agonists, addi-tional risk factors associated with ICDs in PD includeyoung age at PD onset (often in early forties), malegender, a novelty seeking personality, a personal orfamily history of addictive behaviors, and genetic fac-tors [25, 28, 45–53]. A recent study added depressivesymptoms to the list of important risk factors sug-gesting that the variance in the risk for developingICDs is more attributable to the presence of depres-sive symptoms than to the above-mentioned factors[54]. This gained further support through a follow-upstudy describing 22 PD patients without ICDs at base-line, who at follow-up displayed behavioral symptomssignificantly associated with an increase in depressivesymptoms [55]. This is very interesting since depres-sion is a major comorbidity in PD affecting 30–45%of patients, and in fact neuronal loss in the substantianigra is significantly more pronounced in PD patientswith comorbid depression compared to patients with-out depression [9]. Moreover, findings of improvedmood disorder symptoms subsequently to treatmentwith dopamine agonists such as pramipexole serveadditional backup to linking depression and ICDs inPD [9, 56]. For a further discussion of the epidemi-ology of ICDs in PD, we refer to a recent review byWeintraub and Nirenberg [8].
Here we present a systematic review of literaturepublished between 2000 and January 2013 reportingICDs in PD [16, 18–22, 26, 27, 32–39, 41, 42, 45,48, 51, 53–55, 57–132]. We consider prevalence ratesand discuss distinctive forms of cognitive impairmentsassociated with ICDs in PD. Furthermore, comple-menting the work of Weintraub and Nirenberg [8],we add a discussion of the functional neuroanatomyand the dopamine-serotonin interactions implicatedin ICDs in PD. Finally, we consider perspectives forfuture research and suggest possible implications forthe management of ICDs in PD.
The studies included in this review have been iden-tified through PubMed using the following searchwords: Parkinson’s disease, impulse control disor-ders, impulsivity, cognition, and decision-making.The initial search strategy, which combined thewords Parkinson’s disease + impulse control disorders,
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 107
identified 346 articles on January 18th 2013. We endedup including 98 empirical studies in the review amongwhich 64 reports examining both PD patients with andwithout ICDs are presented in Table 1 below. Inclusioncriteria were: Empirical studies examining PD patientswho developed ICDs or experienced a worsening ofICD symptoms subsequent to initiation of dopaminer-gic medication or dosage increase. Exclusion criteriawere: Reviews or other theoretical studies; studiesfocusing exclusively on other neurological diseasesthan PD such as multiple system atrophy or restlesslegs syndrome; studies on ICDs in unmedicated PDpatients; studies focusing solely on treatment of ICDsin PD. However, we will return to the latter topic inour final discussion. A more extensive overview of all98 studies is presented in the Supplementary Tables 1and 2.
SUMMARY AND DISCUSSION OF THELITERATURE REVIEW
Based on the 98 reviewed reports, we concludethat ICDs occur relatively frequently in PD secondaryto dopaminergic therapy. In total 17,286 PD patientswere examined during 2000 and January 2013, andin this material 2,455 (14.2%) displayed prior orcurrent symptoms of ICDs during dopamine replace-ment therapy. However, evaluating prevalence andcharacteristics of ICDs in PD, we only consideredepidemiological studies suitable for this purpose. Wereviewed 29 epidemiological studies describing a totalof 14,929 patients with PD, including 1,495 patientswith ICDs, which corresponds to a mean overall preva-lence of 10% across different cultures. Pathologicalgambling and hypersexuality appear to be the mostprevalent ICDs reported equally frequent in 518 (3.5%)and 524 (3.5%) of the 14,929 PD patients with ICDs,respectively. Binge eating was observed in 383 patients(2.6%) and compulsive buying in 374 patients (2.5%).Related compulsive conditions such as punding andhobbyism were reported in 549 patients (3.7%) andDDS in 53 (0.4%), see Fig. 1. In total 377 patientsreported symptoms of more than one ICD (2.5%).
The prevalence estimates are based on informa-tion available in the epidemiological studies in spiteof the fact that not all of them assess all types ofICDs and compulsive disorders. Particularly, informa-tion on DDS is often not reported, and some papers lackinformation on which specific types of ICDs patientsexperienced. Thus, the true prevalence rates might besomewhat higher, which is in fact what Cilia and vanEimeren [133] summarizes on the basis of the DOMIN-
ION study by Weintraub et al. [26]. Moreover, a veryrecent study in Finnish PD patients reports frequenciesof pathological gambling and hypersexuality amount-ing to 8.8% and 22.8%, respectively [54], whereaspathological gambling as deviant from other studieswas only prevalent in 0.7% of Turkish PD patients,since gambling is illegal in Turkey [125]. This sug-gests that cultural differences might exist. Interestinglythough, the prevalence rates in Asian samples werealmost similar to prevalences in Western samples. Limet al. [99] demonstrate that approximately 15% of PDpatients in Malaysia display symptoms of ICDs rela-tive to approximately 14% reported by Weintraub etal. on the basis of the largest cohort to date of 3,090North American and Canadian PD patients [26]. Thus,it seems that the overall prevalence of ICDs in Asianand Western PD populations are comparable. Insteadit seems that the most noticeable cultural differenceis the relatively lower doses of dopamine agonistsused in Asian samples compared to Western samples[99]. According to Lim et al. [99], piribedil, whichlike pramipexole and ropinirole is selective for D2/D3dopamine receptors, is the most available dopamineagonist in Asian countries and this compound hasalso been associated with ICDs [99]. Nevertheless,in the Malaysian sample where piribedil accountedfor approximately two thirds of the dopamine agonistusage, only ropinirole and pramipexole were signifi-cantly associated with ICD symptoms [99].
Almost all PD patients with ICDs were treated withdopaminergic medication at the time of examination.The majority received a combination of levodopa anddopamine agonists. The most frequently used directD2/D3 dopamine agonists were pramipexole, ropini-role, and pergolide, and generally, the daily dose ofdopaminergic medication was higher in patients withICDs. Based on the epidemiological studies, the meantotal levodopa equivalent daily dose (LEDD, levodopaand dopamine agonists) in PD patients with ICDs was1,030 mg/day compared to a total LEDD in PD patientswithout ICDs of only 679 mg/day. The mean dopamineagonist LEDD was 243 mg/day in PD patients withICDs compared to 132 mg/day in PD patients withoutICDs. It is important to note, however, that LEDDsare most likely calculated based on different formu-las, which complicates a direct comparison of LEDDsacross studies [134].
Overall, ICD symptoms predominantly occurredsubsequent to treatment initiation or dosage increase,and seemed particularly related to the effects of theD2/D3 dopamine agonists [20, 22, 59, 63, 65, 69,71, 72, 74, 84, 85, 88]. This tendency is reflected in
108 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
Tabl
e1
Ove
rvie
wof
64em
piri
cals
tudi
eson
ICD
sin
PDpu
blis
hed
betw
een
2000
–Jan
.201
3co
mpa
ring
PDpa
tient
sw
ithan
dw
ithou
tIC
Ds
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,
Mea
n(S
D)
mg/
day
Cas
e-co
ntro
lstu
dies
Mol
ina
etal
.(20
00)
[18]
250
12(1
:11)
PDI:
NA
56(9
)43
(9)
PG:1
2L
evod
opa:
12Pu
ndin
g:3
BE
:1R
omito
etal
.(20
02)
[33]
304
(1:3
)L
evod
opa
Pre-
DB
S:53
41H
S:4
Perg
olid
eL
evod
opa:
400–
1200
STN
DB
SPe
rgol
ide:
5–6
Eva
nset
al.(
2004
)[6
1]50
17(5
:12)
PDI:
PDI:
1,70
7PD
I:59
PDI:
44Pu
ndin
g:17
Lev
odop
a:16
PDC
:1,1
30,p
<0.
000
PDC
:63
PDC
:49
HS:
4Pe
rgol
ide:
2PG
:1B
rom
ocri
ptin
e:1
DD
S:10
PDC
:L
evod
opa:
33Pe
rgol
ide:
10B
rom
ocri
ptin
e:2
Ava
nzie
tal.
(200
6)[2
1]98
6(3
:3)
PDI:
PDI:
760
(208
)68
(6)
PDI:
60(2
)PG
:6L
evop
dopa
:6PD
C:7
17(4
63)
PDC
:63
(4)
DD
S:2
DA
:4V
oon
etal
.(20
07)
[25]
6321
(6:1
5)L
evod
opa
in20
PDI:
874
(496
)60
(9)
PDI:
51(9
)PG
:21
Pram
ipex
ole:
5D
AL
ED
D:2
68(1
94)
PDC
:58
(10)
Rop
inir
ole:
8PD
C:7
47(3
23)
Perg
olid
e:7
DA
LE
DD
:192
(105
)Is
aias
etal
.(20
08)
[91]
5014
(7:7
)PD
I:PD
I:65
6(2
52)
PDI:
60(9
)PD
I:51
CB
:5(4
:1)
Pram
ipex
ole:
8PD
C:6
22(2
94)
PDC
:65
(9)
PDC
:57
Inte
rmitt
ente
xplo
sive
diso
rder
:1(1
:0)
Rop
inir
ole:
1Pe
rgol
ide:
1H
S:2
(1:1
)PG
:1(1
:0)
Mul
tiple
ICD
s:5
(0:5
)
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 109Ta
ble
1(c
onti
nued
)
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,M
ean
(SD
)m
g/da
y
Cili
aet
al.(
2008
)[1
08]
5111
(1:1
0)PD
I:PD
I:81
2(2
29)
PDI:
57(6
)PD
I:50
(5)
PG:1
1L
evod
opa:
11D
AL
ED
D:2
89(5
8)PD
C:5
5(7
)PD
C:4
6(7
)H
S:5
Pram
ipex
ole:
6PD
C:8
77(2
89)
BE
:2R
opin
irol
e:2
DA
LE
DD
:340
(157
)C
B:2
Perg
olid
e:3
Hob
byis
m:1
PDC
:L
evod
opa:
40Pr
amip
exol
e:20
Rop
inir
ole:
7Pe
rgol
ide:
10C
aber
golin
e:3
Imam
ura
etal
.(20
08)
[122
]48
11(0
:11)
PDI:
PDI:
573
(548
)PD
I:60
(7)
PDI:
50(1
3)PG
:11
Lev
odop
a:7
Pram
ipex
ole:
4(2
)PD
C:6
2(1
)PD
C:5
4(1
2)Pr
amip
exol
e:7
PDC
:879
(558
)R
opin
irol
e:1
Pram
ipex
ole:
3(2
),p
<0.
001
PDC
:L
evod
opa:
32Pr
amip
exol
e:12
Rop
inio
rle:
3H
albi
get
al.(
2009
)[4
2]53
6(N
A)
Lev
odop
a:44
PDw
ithD
BS:
682
(427
)PD
with
DB
S:64
(10)
PDw
ithD
BS:
52PD
with
DB
S:3
DA
:21
PDw
ithou
tDB
S:58
2(4
60)
PDw
ithou
tDB
S:66
(11)
PDw
ithou
tDB
S:60
PG:1
STN
DB
S:16
CB
:2PD
with
outD
BS:
3PG
:1C
B:2
HS:
1T
rich
otill
oman
ia:1
Mul
tiple
ICD
s:2
110 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
Tabl
e1
(con
tinu
ed)
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,M
ean
(SD
)m
g/da
y
Sant
ange
loet
al.(
2009
)[1
23]
3015
(4:1
1)PD
I:PD
I:77
4(3
20)
PDI:
62(1
0)PD
I:53
(10)
PG:1
5L
evod
opa:
13D
AL
ED
D:2
80(2
09)
PDC
:62
(9)
PDC
:55
(9)
DA
:12
PDC
:651
(284
)(P
ram
ipex
ole:
10)
DA
LE
DD
:293
(180
)PD
C:
Lev
odop
a:12
DA
:14
(Pra
mip
exol
e:9;
Rop
inir
iole
:2)
Siri
etal
.(20
10)
[114
]63
21(3
:18)
Lev
odop
aPD
I:73
1(2
84)
PDI:
60(8
)PD
I:53
(9)
PG:2
1D
AD
AL
ED
D:2
68(1
14)
PDC
:65
(6),
p=
0.01
PDC
:57
(7)
PDC
:787
(284
)D
AL
ED
D:2
39(1
31)
Voo
net
al.(
2010
)[7
5]28
14(4
:10)
Lev
odop
a:20
PDI:
589
(301
)PD
I:52
(8)
NA
PG:9
Pram
ipex
ole:
18D
AL
ED
D:1
62(4
3)PD
C:5
5(1
3)C
B:5
Rop
inir
ole:
10PD
C:6
10(2
98)
DA
LE
DD
:156
(57)
Vita
leet
al.(
2011
)[7
8]63
49L
evod
opa:
54PD
I:71
9PD
I:65
PDI:
57PG
:14
(4:1
0)Pr
amip
exol
e:41
DA
LE
DD
:243
PDC
:61
PDC
:53
HS:
13(0
:13)
Rop
inir
ole:
11PD
C:6
30(3
12)
BE
:12
(6:6
)D
AL
ED
D:2
67(2
01)
Mul
tiple
ICD
s:10
(1:9
)Z
ahod
neet
al.(
2011
)[3
6]96
36D
A:4
2%PD
BE
:563
(251
)PD
BE
:68
(5)
PDB
E:5
8(8
)B
E:9
(3:6
)D
BS:
22PD
with
outB
E:6
81(4
90)
PDw
ithou
tBE
:66
(10)
PDw
ithou
tBE
:PG
:17
STN
DB
S:16
56(1
3)C
B:1
1G
PiD
BS:
6H
S:1
STN
DB
S:4
PDB
E(4
4%)
Pund
ing:
8M
ultip
leIC
Ds:
67%
ofPD
BE
Mul
tiple
ICD
s:29
%PD
with
outB
E
STN
DB
S:14
%of
PDw
ithou
tBE
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 111
Tabl
e1
(con
tinu
ed)
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,M
ean
(SD
)m
g/da
y
Ler
oiet
al.(
2011
)[8
6]99
35(N
A)
Lev
odop
a14
2(1
65)
63(1
1)55
(12)
PG:1
2D
AL
ED
Dra
nge:
0–61
0m
g/d
HS:
9C
B:5
BE
:3D
DS:
3Pu
ndin
g:3
Biu
ndo
etal
.(20
11)
[87]
5935
(NA
)L
evod
opa
PDI:
557
(305
)PD
I:61
(10)
PDI:
53(1
1)PG
:2D
AD
AL
ED
D:1
87(1
49)
PDC
:70.
4(6
.8),
p<
0.00
1PD
C:6
1(1
0),p
=0.
012
HS:
16PD
C:4
97(3
41)
CB
:17
DA
LE
DD
:166
(109
)B
E:1
Pund
ing:
3H
obby
ism
:7M
ultip
leIC
Ds:
12V
oon
etal
.(20
11)
[80]
564
282
(91:
191)
Lev
odop
aPD
I:94
6(3
6)PD
I:61
(1)
PDI:
54(1
)PG
:54
(14:
40)
DA
DA
LE
DD
:266
(14)
PDC
:61
(1)
PDC
:54
(1)
CB
:59
(28:
31)
PDC
:809
(36)
HS:
47(1
:46)
DA
LE
DD
:265
(14)
BE
:41
(20:
21)
Cili
aet
al.(
2011
)[9
4]30
15(1
:14)
Lev
odop
aPD
I:84
8(2
53)
PDI:
59(8
)PD
dura
tion:
PG:1
5D
AD
AL
ED
D:2
96(1
48)
PDC
:59
(7)
PDI:
9(3
)PD
C:8
80(2
45)
PDC
:9(2
)D
AL
ED
D:3
17(1
16)
Cha
zero
net
al.(
2011
)[1
09]
115
PG:1
Lev
odop
am
onot
hera
py:4
0A
llpa
tient
s:A
llpa
tient
s:A
llpa
tient
s,PD
dura
tion:
7(4
)Pr
oble
mga
mbl
ing:
14D
Am
onot
hera
py:4
Lev
odop
aL
ED
D:6
31(4
36)
67(6
)H
S:2
Lev
odop
a+
DA
:61
DA
LE
DD
:130
(168
)N
ole
vodo
paor
DA
:10
112 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
Tabl
e1
(con
tinu
ed)
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,
Mea
n(S
D)
mg/
day
Ben
tivog
lioet
al.(
2012
)[9
7]34
17(3
:14)
Lev
odop
aPD
I:60
6(3
19)
PDI:
62(1
0)PD
dura
tion:
HS:
8D
AD
AL
ED
D:1
73(1
12)
PDC
:64
(9)
PDI:
7(4
)C
B:2
PDC
:616
(368
)PD
C:7
(4)
PG:1
0D
AL
ED
D:1
93(8
9)B
E:6
Mul
tiple
ICD
s:7
Dja
msh
idia
net
al.(
2012
)[1
13]
4326
(4:2
2)L
evod
opa
PDI:
934
(407
)PD
I:59
(10)
PDI:
48(1
0)H
S:12
PDI:
PDC
:740
(369
)PD
C:6
5(5
),p
<0.
001
PDC
:55
(7),
p=
0.00
2PG
:13
DA
:13
CB
:5PD
C:
Pund
ing:
7D
A:2
1E
xper
imen
tals
tudi
esE
vans
etal
.(20
06)
[79]
168
(NA
)L
evod
opa
PDI:
1,51
7PD
I:51
PDI:
39D
DS:
8D
APD
C:8
48PD
C:6
0PD
C:4
8Pu
ndin
g:8
Stee
ves
etal
.(20
09)
[74]
147
(2:5
)L
evod
opa:
14PD
I:85
6(4
07)
PDI:
47–7
2PD
dura
tion:
PG:7
DA
:14
DA
LE
DD
:138
(172
)PD
C:5
1–74
PDI:
7(3
)PD
I:PD
C:7
56(4
00)
PDC
:6(3
)Pr
amip
exol
e:5
DA
LE
DD
:167
(113
)R
opin
irol
e:2
Rao
etal
.(20
10)
[92]
189
(2:7
)L
evod
opa:
16PD
I:41
8(3
06)
PDI:
56(1
1)PD
I:49
BE
:5D
A:1
7D
AL
ED
D:2
78(1
16)
PDC
:54
(10)
PDC
:47
PG:4
PDC
:309
(171
)C
B:3
DA
LE
DD
:319
(187
)H
S:4
Mul
tiple
ICD
s:4
Cili
aet
al.(
2010
)[9
5]29
8(1
:7)
Lev
odop
a:29
PDI:
831
(294
)PD
I:61
(8)
PDdu
ratio
n:PG
:8D
A:2
9D
AL
ED
D:2
41(1
18)
PDC
:60
(9)
PDI:
6(2
)H
S:5
PDC
:852
(301
)PD
C:6
(2)
BE
:3D
AL
ED
D:2
52(1
21)
CB
:2M
ultip
leIC
Ds:
6
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 113
Tabl
e1
(con
tinu
ed)
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,M
ean
(SD
)m
g/da
y
Voo
net
al.(
2010
)[9
6]28
14(4
:10)
PDI:
PDI:
508
(301
)PD
I:52
(8)
NA
PG:9
Lev
odop
a:10
DA
LE
DD
:162
(43)
PDC
:55
(13)
CB
:5Pr
amip
exol
e:9
PDC
:610
(298
)R
opin
irol
e:5
DA
LE
DD
:155
(57)
PDC
:L
evod
opa:
10Pr
amip
exol
e:9
Rop
inir
ole:
5W
uet
al.(
2010
)[1
10]
155
(NA
)L
evod
opa
NA
NA
NA
NA
Van
Eim
eren
etal
.(20
10)
[107
]14
7(N
A)
Lev
odop
aPD
I:77
2(3
18)
PDI:
60(1
0)PD
dura
tion:
PG:7
DA
DA
LE
DD
:143
(105
)PD
C:6
2(1
1)PD
I:7
(3)
PDI:
PDC
:700
(323
)PD
C:7
(3)
Pram
ipex
ole:
6D
AL
ED
D:1
22(8
5)R
opin
irol
e:1
Fros
inie
tal.
(201
0)[1
12]
147
(NA
)L
evod
opa
PDI:
520
(219
)PD
I:58
(11)
PDdu
ratio
n:PG
:7PD
I:D
AL
ED
D:4
08(1
56)
PDC
:58
(9)
PDI:
6(2
)B
E:1
Pram
ipex
ole:
4PD
C:4
62(2
29)
PDC
:7(4
)H
S:1
Rop
inir
ole:
3D
AL
ED
D:3
25(5
0)PD
C:
Pram
ipex
ole:
4R
opin
irol
e:3
Rod
rigu
ez-O
roz
etal
.(20
11)
[38]
2810
(1:9
)L
evod
opa
PDI:
1041
(689
)PD
I:53
(11)
PDI:
44PG
:5D
APD
dysk
ines
ia:1
170
(531
)PD
dysk
ines
ia:6
2(4
)PD
dysk
ines
ia:4
6H
S:5
STN
DB
S:28
PDC
:102
4(4
65)
PDC
:59
(5)
PDC
:48
CB
:5B
E:2
DD
S:5
Pund
ing:
5M
ultip
leIC
Ds:
7V
oon
etal
.(20
11)
[45]
2814
(4:1
0)PD
I:PD
I:58
9(3
01)
PDI:
52(8
)N
APG
:9Pr
amip
exol
e:9
DA
LE
DD
:162
(43)
PDC
:55
(13)
CB
:5R
opin
irol
e:5
PDC
:610
(298
)PD
C:
DA
LE
DD
:156
(57)
Pram
ipex
ole:
9R
opin
irol
e:5
114 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
Tabl
e1
(con
tinu
ed)
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,M
ean
(SD
)m
g/da
y
Cla
asse
net
al.(
2011
)[5
1]41
22(9
:13)
Lev
odop
a:26
PDI:
736
(451
)PD
I:61
(6)
PDdu
ratio
n:PG
:2D
A:4
1D
AL
ED
D:2
92(1
61)
PDC
:64
(8)
PDI:
10(7
)H
S:13
PDC
:613
(325
)PD
C:6
(4)
CB
:12
DA
LE
DD
:230
(124
)B
E:1
0H
obby
ism
:17
O’S
ulliv
anet
al.(
2011
)[1
11]
1811
(3:8
)L
evod
opa:
18PD
I:69
8(3
37)
PDI:
57(8
)PD
I:45
(11)
HS:
5D
AD
AL
ED
D:6
2(9
2)PD
C:5
8(1
1)PD
C:4
7(9
)B
E:5
PDC
:949
(253
)PG
:5D
AL
ED
D:2
41(1
43)
CB
:5D
DS:
5Pu
ndin
g:5
Mul
tiple
ICD
s:8
Ray
etal
.(20
12)
[82]
147
(NA
)L
evod
opa:
13PD
I:88
8(4
80)
PDI:
60(1
1)PD
dura
tion:
PG:7
DA
:12
PDC
:644
(338
)PD
C:6
1(1
0)PD
I:10
(6)
PDC
:8(5
)Jo
utsa
etal
.(20
12)
[105
]20
10(0
:10)
PDI:
PDI:
635
(ran
ge:2
50–8
76)
PDI:
62(r
ange
:45–
71)
PDI:
53(r
ange
:40–
64)
PG:5
Lev
odop
a:9
DA
LE
DD
:172
(ran
ge:0
–280
)PD
C:6
2(r
ange
:53–
70)
PDC
:57
(ran
ge:4
7–63
)H
S:4
DA
:9PD
C:8
26(r
ange
:210
–112
7)B
E:1
PDC
:D
AL
ED
D:2
00(r
ange
:0–3
20)
Lev
odop
a:9
DA
:9E
pide
mio
logi
cals
tudi
esD
rive
r-D
unck
ley
etal
.(20
03)
[59]
1,88
49
(2:7
)L
evod
opa:
9PD
IPD
I:57
46PG
:9Pr
amip
exol
e:52
9L
evod
opa
LE
DD
:883
Rop
inir
ole:
421
Pram
ipex
ole:
4Pe
rgol
ide:
331
Perg
olid
e:5
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 115Ta
ble
1(c
onti
nued
)
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,M
ean
(SD
)m
g/da
y
Pezz
ella
etal
.(20
05)
[98]
202
7(2
:5)
PDD
DS:
Lev
odop
a:6
PDD
DS:
961
(282
)PD
DD
S:59
(5)
PDD
DS:
51(3
)D
DS:
7D
A:7
PDw
ithou
tDD
S:67
5(3
72)
PDw
ithou
tDD
S:63
(5)
PDw
ithou
tDD
S:52
(3)
Com
puls
ive
beha
vior
:2
of7
PDw
ithou
tDD
S(n
=32
):H
S:1
of7
Lev
odop
a:12
Vio
lent
beha
vior
:3of
7D
A:2
0
Ard
ouin
etal
.(20
06)
[64]
598
7(1
:6)
PDI:
NA
<70
year
sN
APG
:7L
evod
opa:
7H
S:5
Bro
moc
ript
ine:
5C
B:2
Rop
inir
ole:
1B
E:2
DD
S:4
Gro
sset
etal
.(20
06)
[65]
388
17(6
:11)
PDI:
PDI:
PDI:
56(7
)PD
I:52
PG:1
7L
evod
opa:
9L
evod
opa
LE
DD
:430
PDC
:69
(10)
PDC
64Pr
amip
exol
e:9
Pram
ipex
ole:
5R
opin
irol
e:7
Rop
inir
ole:
12Pe
rgol
ide:
1Pe
rgol
ide:
1Im
amur
aet
al.(
2006
)[6
7]1,
411
6(0
:6)
PDI:
PDI:
61(r
ange
:53–
71)
51PG
:6L
evod
opa:
4L
evod
opa:
100–
1000
HS:
1Pr
amip
exol
e:4
Pram
ipex
ole:
3–6
Rop
inir
ole:
1R
opin
irol
e:5
Wei
ntra
ubet
al.(
2006
)[9
0]27
211
(1:1
0)PD
I:PD
I:92
6(5
35)
PDI:
60(9
)PD
I:48
HS:
7L
evod
opa:
11PD
C:5
69(3
69)
PDC
:67
(10)
,p=
0.00
6PD
C:
PG:6
Perg
olid
e:3
62(6
),p
=0.
04C
B:1
Pram
ipex
ole:
5R
opin
irol
e:3
Sing
het
al.(
2007
)[4
8]30
058
Lev
odop
a:24
4D
A:1
6PD
I:61
NA
HS:
25R
opin
irol
e:13
5PD
C:5
8PG
:0.5
–10
year
sPG
:17
(1:1
6)Pr
amip
exol
e:16
5
116 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
Tabl
e1
(con
tinu
ed)
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,M
ean
(SD
)m
g/da
y
Gila
diet
al.(
2007
)[6
9]19
327
(6:2
1)L
evod
opa:
24N
AN
APD
I:52
(12)
PG:6
Rop
inir
ole:
9PD
C:5
9(1
2)C
B:6
Perg
olid
e:4
BE
:7H
S:17
Mul
tiple
ICD
s:10
Ond
oet
al.(
2008
)[7
2]21
17
(3:4
)L
evod
opa:
148
Tota
lsam
ple:
Tota
lsam
ple:
64(1
0)To
tals
ampl
e:54
(12)
PG:7
Pram
ipex
ole:
141
Lev
odop
a:66
7(3
25)
PDI:
59(6
)PD
I:49
(11)
CB
:3R
opin
irol
e:57
DA
:3(1
)H
S:1
Perg
olid
e:12
PDI:
Bro
moc
ript
ine:
1D
A:4
(2)
Cro
ckfo
rdet
al.(
2008
)[7
3]14
013
(4:9
)L
evod
opa:
99%
PDI:
602
(355
)PD
I:62
(8)
NA
Prob
lem
gam
blin
gD
A:8
8%PD
C:7
75(4
72)
PDC
:66
(12)
Coo
per
etal
.(20
09)
[120
]14
16
(1:5
),4.
3%PD
I:N
ATo
tals
ampl
e:68
(10)
PDI:
50(3
)H
S:6
Lev
odop
a:4
PDI:
61(r
ange
:52–
74)
PDC
:62
(1),
p<
0.05
HS
sym
ptom
s:15
DA
:5W
icks
etal
.(20
09)
[127
]20
827
(13%
,NA
)PD
I:N
ATo
talP
Dsa
mpl
e:58
(10)
PDdu
ratio
n:PG
:13%
DA
:65%
Tota
lPD
sam
ple:
8(7
)PD
C:
DA
:59%
Fan
etal
.(20
09)
[128
]31
211
(1:1
0)PD
I:PD
I:48
8(2
89)
PDI:
64(7
)PD
I:59
(7)
PG:1
Lev
odop
a:9
DA
LE
DD
:142
(101
)PD
C:6
6(1
1)PD
C:6
0(1
1)H
S:6
Piri
bedi
l:10
PDC
:392
(225
)B
E:1
Pram
ipex
ole:
1D
AL
ED
D:3
5(5
0),p
=0.
005
DD
S:2
Am
anta
dine
:4Pu
ndin
g:1
Tota
lPD
sam
ple:
Lev
odop
a:25
4D
A:1
30A
man
tadi
ne:9
7
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 117
Tabl
e1
(con
tinu
ed)
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,M
ean
(SD
)m
g/da
y
Wei
ntra
ubet
al.(
2010
)[2
6]30
9042
0(1
53:2
67)
Lev
odop
ain
86.8
%Pr
amip
exol
eL
ED
D:3
07(1
68)
PDI:
60(8
)PD
I:m
edia
n=
53Pr
oble
mga
mbl
ing:
154
DA
in66
.0%
:R
opin
irol
eL
ED
D:2
78(1
65)
PDC
:64
(8),
p<
0.00
1.PD
C:m
edia
n=
58PG
:89
DB
S:Pe
rgol
ide
LE
DD
:287
(169
)H
S:10
8PD
I:36
CB
:177
PDC
:264
BE
:132
Mul
tiple
ICD
s:12
0W
eint
raub
etal
.(20
10)
[131
]30
8542
0(1
53:2
67)
PDon
aman
tadi
ne:I
CD
:128
(18%
)PD
onam
anta
dine
:PD
onam
anta
dine
:62
(8)
Med
ian
PDdu
ratio
n:PD
onam
anta
dine
:PG
:54
(7.4
%)
HS:
37(5
.1%
)C
B:5
8(8
%)
BE
:32
(4.4
%)
PDof
fam
anta
dine
:PG
:100
(4.2
%),
p<
0.00
1H
S:71
(3%
),p
<0.
01C
B:1
19(5
%),
p<
0.01
BE
:100
(4.2
%)
PDof
fam
anta
dine
:292
(12%
),p
<0.
001
Lev
odop
a:26
78D
A:2
038
DB
S:30
0
Med
ian
levo
dopa
LE
DD
:469
PDof
fam
anta
dine
:Med
ian
levo
dopa
LE
DD
:450
,P
<0.
001
DB
S:PD
onam
anta
dine
:94
(12.
9%)
PDof
fam
anta
dine
:206
(9%
),p
<0.
01
PDof
fam
anta
dine
:64
(8)
Age
<65
:PD
onam
anta
dine
:446
(61%
)PD
off
aman
tadi
ne:1
177
(50%
),p
<0.
0001
PDon
aman
tadi
ne:1
0PD
off
aman
tadi
ne:6
,p
<0.
0001
118 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
Tabl
e1
(con
tinu
ed)
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,M
ean
(SD
)m
g/da
y
Wei
sset
al.(
2010
)[5
3]25
032
(NA
)L
evod
opa
NA
Ons
etof
ICD
:PD
dura
tion
befo
reIC
Don
set:
7(5
)PG
:8Pr
amip
exol
e57
(9)
Prob
lem
gam
blin
g:5
Rop
inir
ole
HS:
16C
B:1
1B
E:6
Rec
kles
ssp
endi
ngan
ddr
ivin
g:1
Mul
tiple
ICD
s:12
Bha
rmal
etal
.(20
10)
[121
]14
66
(2:4
)PD
I:PD
I:PD
I:58
(7)
PDdu
ratio
n:PG
:6L
evod
opa
mon
othe
rapy
:012
26(r
ange
:600
–217
9)To
tals
ampl
e:68
(10)
,p<
0.05
PDI:
12Pr
amip
exol
e:5
Pram
ipex
ole:
5(r
ange
:2–8
)To
tals
ampl
e:M
ales
:9(7
)Pe
rgol
ide:
1Pe
rgol
ide:
3Fe
mal
es:1
0(5
)To
tals
ampl
e:To
tals
ampl
e:N
AL
evod
opa
mon
othe
rapy
:80
Pram
ipex
ole:
41Pe
rgol
ide:
11R
opin
irol
e:9
Bro
moc
ript
ine:
5K
enan
gile
tal.
(201
0)[1
25]
554
33(6
:27)
,5.9
%PD
I:PD
I:70
2(3
69)
PDI:
58(1
0)PD
I:49
(9)
Pund
ing:
19(5
7.5%
)L
evod
opa
DA
LE
DD
:368
(181
)PD
C:6
0(1
0)PD
C:5
2(1
1)H
S:14
(42.
4%)
Perg
olid
e:12
PDC
:640
(357
)B
E:9
(27.
2%)
Cab
ergo
line:
7D
AL
ED
D:3
19(2
08)
CB
:8(2
4.2%
)Pr
amip
exol
e:7
DD
S:7
(21.
1%)
Rop
inir
ole:
4PG
:4(1
2.1%
)Pi
ribe
dil:
10PD
C:
Lev
odop
aPe
rgol
ide:
9C
aber
golin
e:14
Pram
ipex
ole:
25R
opin
irol
e:1
Piri
bedi
l:15
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 119Ta
ble
1(c
onti
nued
)
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,M
ean
(SD
)m
g/da
y
Lee
etal
.(20
10)
[129
]11
6711
8(5
5:63
)To
tals
ampl
e:To
tals
ampl
e:65
9(3
87)
PDI:
61(1
2)PD
I:53
(11)
CB
:29
Lev
odop
a:10
94PD
I:PD
C:6
5(1
0)PD
C:5
9(1
0)PG
:15
DA
:850
DA
LE
DD
:145
(150
)H
S:33
PDI:
PDC
:B
E:4
0D
A:9
4D
AL
ED
D:9
9(1
23)
Pund
ing:
49PD
C:7
56M
ultip
leIC
Ds:
34A
uyeu
nget
al.(
2011
)[8
5]21
315
(2:1
3)PD
I:PD
I:12
15(6
36)
PDI:
60(6
)PD
I:46
(6)
Lev
odop
a:15
DA
LE
DD
:277
(148
)PD
C:6
8(1
0),p
<0.
001
PDC
:59
(11)
,p<
0.00
1D
A:1
4PD
C:6
34(3
31)
Bro
moc
ript
ine:
11D
AL
ED
D:8
5(9
9)L
imet
al.(
2011
)[9
9]20
048
Tota
lsam
ple:
Tota
lsam
ple:
528
(387
)To
tals
ampl
e:To
tals
ampl
e:A
nyIC
D:3
0L
evod
opa:
81%
DA
LE
DD
:74
(84)
63(1
0)56
(12)
BE
:17
DA
:53%
Am
anta
dine
:41
(106
)H
S:16
Piri
bedi
l:33
.5%
CB
:7Pr
amip
exol
e:11
.5%
PG:5
Rop
inir
ole:
8%Pu
ndin
g/ho
bbyi
sm:2
7B
rom
ocri
ptin
e:0.
5%D
DS:
4A
man
tadi
ne:1
5%M
ultip
leIC
D:1
9D
BS:
5.5%
Has
san
etal
.(20
11)
[130
]32
169
(20:
49)
Lev
odop
aPD
hobb
yism
:PD
hobb
yism
:56
(ran
ge:3
4–72
)PD
I:51
(10)
PG:2
5D
APr
amip
exol
e:2
(ran
ge:1
–5)
Oth
erw
ise
NA
PDC
:59
(10)
,p<
0.00
01H
S:24
PDI:
Rop
inir
ole:
14(r
ange
:8–2
5)B
E:1
2C
B:1
8H
obby
ism
:8Pu
ndin
g:12
The
rape
utic
DA
dose
(>6
mg
ropi
niro
leor
>2
mg
pram
ipex
ole)
:59
Targ
etD
Ado
se(>
12m
gro
pini
role
or>
4.5
mg
pram
ipex
ole)
:39
DB
S:9
Oth
erw
ise
NA
120 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
Tabl
e1
(con
tinu
ed)
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,M
ean
(SD
)m
g/da
y
PDC
:T
hera
peut
icD
Ado
se(>
6mg
ropi
niro
leor
>2
mg
pram
ipex
ole)
:147
Targ
etD
Ado
se(>
12m
gro
pini
role
or>
4.5
mg
pram
ipex
ole)
:67
DB
S:12
Lim
otai
etal
.(20
12)
[83]
1040
97(N
A)
Lev
odop
aPD
I:11
22(6
44)
PDI:
64(1
0)PD
I:52
(10)
ICD
:89
DA
DA
LE
DD
:292
(184
)PD
C:7
1(1
0),p
<0.
001
PDC
:60
(12)
,p<
0.00
1D
DS:
14PD
C:7
79(5
43),
p<
0.00
1PD
DD
S:66
(12)
PDD
DS:
53(1
0)IC
D+
DD
S:6
DA
LE
DD
:142
(176
),p
<0.
001
PDC
:71
(11)
PDC
:59
(12)
Pund
ing:
11PD
DD
S:17
13(8
69)
DA
LE
DD
:309
(199
)PD
C:7
96(5
46),
p<
0.00
1D
AL
ED
D:1
52(1
81),
p<
0.00
3K
imet
al.(
2012
)[2
7]29
746
(19:
27)
PDI:
PDI:
844
(376
)PD
I:66
(11)
PDI:
60(1
2)PG
:4D
A:2
9D
AL
ED
D:1
71(1
87)
PDC
:71
(8)
PDC
:66
(9)
HS:
21PD
C:
PDC
:614
(348
),p
<0.
001
P<
0.00
9P
<0.
001
BE
:9D
A:1
10,p
<0.
016
DA
LE
DD
:90
(140
),p
<0.
002
CB
:3Pu
ndin
g:14
Hob
byis
m:5
Wal
kabo
ut:3
DD
S:7
Mul
tiple
ICD
s:15
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 121
Tabl
e1
(con
tinu
ed)
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,M
ean
(SD
)m
g/da
y
Mou
met
al.(
2012
)[3
2]15
9IC
D:2
4D
DS:
7Pr
e-D
BS
ICD
:6(3
:3)
Pre-
DB
SD
DS:
4(0
:4)
Pre-
DB
SIC
D+
DD
S:1
(0:1
)
DA
:4PD
I;0
PDD
DS;
1PD
I+
DD
S;81
PDC
DB
S:15
9(S
TN
orG
Pi)
STN
DB
S:3
PDD
DS;
4PD
IG
PiD
BS:
1PD
DD
S;2
PDI;
1PD
I+D
DS
Pre-
DB
S:PD
I:73
5(3
88)
PDD
DS:
1271
(744
)PD
I+D
DS:
2250
PDC
:877
(511
),p
<0.
03
NA
PDI:
44(7
)PD
DD
S:45
(1)
PDI+
DD
S:40
PDC
:49
(10)
Jout
saet
al.(
2012
)[5
4]57
519
2(4
8:14
4)M
ultip
leIC
Ds:
69PG
:48
HS:
124
CB
:55
BE
:64
Hob
byis
m:1
25Pu
ndin
g:87
Wal
kabo
ut:3
2
Lev
odop
a:45
1D
A:4
30M
edia
nL
ED
D:5
61(r
ange
:26
–323
0)M
edia
nD
AL
ED
D:1
60(r
ange
:105
–210
)
Med
ian
age:
64(r
ange
:43
–90)
Med
ian
PDdu
ratio
n:6
(ran
ge<
1–29
)
Pere
z-L
lore
teta
l.(2
012)
[104
]20
352
(14:
38)
PDI:
LE
DD
>10
50:
Age
<68
:PD
dura
tion:
HS:
20L
evod
opa:
48PD
I:PD
I:14
patie
nts
(26%
)PD
I:9
(1)
CB
:13
DA
:52
34pa
tient
s(6
3%)
PDC
:86
patie
nts
(56%
)PD
C:9
(1)
PG:5
Am
anta
dine
:2PD
C:
BE
:28
PDC
:63
patie
nts
(42%
)M
ultip
leIC
Ds:
11L
evod
opa:
130
DA
:109
Am
anta
dine
:7
122 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
Tabl
e1
(con
tinu
ed)
Ref
eren
ceTo
talN
N(f
:m),
PDpa
tient
sT
reat
men
t:N
Tota
lLE
DD
,Mea
nA
geA
geat
PDon
set
with
PDw
ithIC
Ds
(SD
)m
g/da
yM
ean
(SD
)ye
ars
Mea
n(S
D)
year
sD
AL
ED
D/D
Ado
se,M
ean
(SD
)m
g/da
y
Jout
saet
al.(
2012
)[5
5]29
0A
tba
selin
e:11
9A
tbas
elin
e:A
tbas
elin
e:A
tbas
elin
e:A
tbas
elin
e:M
ultip
leIC
Ds:
43PD
I:PD
with
stab
leIC
D(n
=82
):PD
with
stab
leIC
D(n
=82
):62
PDw
ithst
able
ICD
(n=
82):
56PG
:33
Lev
odop
a:88
Med
ian
LE
DD
:609
PDC
(n=
135)
:65
PDC
(n=
135)
:58
HS:
73D
A:9
2M
edia
nD
AL
ED
D:2
10C
B:3
6A
man
tadi
ne:6
PDC
(n=
135)
:B
E:4
0PD
C:
Med
ian
LE
DD
:508
Hob
byis
m:7
3L
evod
opa:
118
Med
ian
DA
LE
DD
:160
Pund
ing:
48D
A:1
23W
alka
bout
:17
Am
anta
dine
:9B
astia
ens
etal
.(20
13)
[100
]16
418
of46
(9:9
)PD
I:PD
I:PD
I:62
(10)
PDI:
57(1
0)B
E:1
6(7
:9)
Lev
odop
a:7
Med
ian
LE
DD
:150
(ran
ge:0
–2,3
20)
PDC
:62
(11)
PDC
:57
(9)
HS:
6(1
:5)
DA
:10
Med
ian
DA
LE
DD
:106
(ran
ge:0
–450
)C
B:5
(3:2
)A
man
tadi
ne:3
PDC
:PG
:1(1
:0)
PDC
:M
edia
nL
ED
D:1
50(r
ange
:0–1
,510
)Pu
ndin
g:12
Lev
odop
a:13
Med
ian
DA
LE
DD
:0(r
ange
:0–4
50)
Mul
tiple
ICD
s:8
DA
:11
Am
anta
dine
:0
N=
num
bero
fpat
ient
s(f
:m=
fem
ales
:mal
es).
PD=
Park
inso
n’s
dise
ase.
ICD
s=im
puls
eco
ntro
ldis
orde
rs.P
G=
path
olog
ical
gam
blin
g.H
S=
hype
rsex
ualit
y.C
B=
com
puls
ive
buyi
ng.B
E=
bing
e-ea
ting.
DD
S=
dopa
min
edy
sreg
ulat
ion
synd
rom
e.PD
I=PD
patie
ntsw
ithIC
Ds.
PDC
=PD
cont
rols
.DA
=do
pam
ine
agon
ist.
DB
S=
deep
brai
nst
imul
atio
n.ST
N=
subt
hala
mic
nucl
eus.
GPi
=gl
obus
palli
dus
pars
inte
rna.
LE
DD
=le
vodo
paeq
uiva
lent
daily
dose
.NA
=no
tapp
licab
le.p
-val
ues
indi
cate
sign
ifica
ntdi
ffer
ence
sbe
twee
nPD
Ian
dPD
C.
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 123
Fig. 1. Illustrates the number of PD patients with ICDs across the specific kinds of ICDs: pathological gambling; hypersexuality; binge eating;compulsive buying; punding; and dopamine dysregulation syndrome. In total 377 patients reported having more than one ICD (2.5%). Hence,the sum of patients across ICDs (2,289) is larger than the total number of patients (1,495) in the in the epidemiological studies reporting ICDs,since those with multiple ICDs are counted in all respective specific ICDs. Furthermore, the prevalence of DDS is probably underestimated,since information on DDS was unavailable in many of the reviewed report.
a higher frequency of ICDs of up to 17.1% amongPD patients treated with dopamine agonists relative to6.9% in patients not treated with dopamine agonists[26]. Generally, ICD symptoms improved or resolvedafter reduction or discontinuation of dopamine ago-nist therapy [18–22, 38, 48, 58, 62, 66, 67, 70–72,84, 88, 89], even when increasing levodopa dose ascompensation for the lacking agonist treatment [81,88]. Nevertheless, in most cases described it remainsunclear whether ICD onset is a direct result of treat-ment initiation (or increase) or a consequence ofprolonged dopaminergic therapy. Furthermore, mostlikely individual differences in PD symptomatology,age at disease onset, gender, personality, and psychi-atric history influence the treatment-induced ICDs toan unknown degree. In addition, ICDs were alreadypresent prior to PD onset or treatment initiation in atleast 28 patients (1.1%), a frequency correspondingto the prevalence of ICDs in the general population.These patients reported a worsening of symptoms fol-lowing medication. Moreover, at least 58 (2.4%) PDpatients with ICDs had a prior history of substanceuse disorders, while at least 179 (7.3%) and 79 (3.2%)patients with comorbid ICDs reported current or priorsymptoms of a mood disorder or anxiety, respectively.Unfortunately, such details of information are simplynot available in all included reports. Hopefully, thenew screening instruments discussed by Weintraub andNirenberg [8] may contribute to solving some of theseissues in the future.
The presented findings support the concept oftreatment-induced ICDs in PD, which we will discuss
in a neuro-cognitive perspective taking distinct brainregions, dopamine-serotonin interactions, and cogni-tive impairments into account.
THE FUNCTIONAL ROLE OF THESUBTHALAMIC NUCLEUS IN ICDS IN PD
In the reviewed literature, it has been reported thata minimum of 86 patients with DBS in STN experi-enced occurrence, worsening, or no improvement ofICD symptoms following surgery [32, 33, 36, 37, 39,42, 93, 118], which corresponds to 3.5% of patientswith ICDs. In contrast, ICD symptoms declined or werefully alleviated in at least 36 other cases (correspond-ing to 1.5% of patients with ICDs) upon DBS in STN,an effect, which is most likely related to the markedreduction in dopaminergic medication following DBS[32, 35, 37, 38, 40, 41, 64]. These deviating resultsstrongly suggest that STN DBS influences both motorand non-motor functioning in PD in complex waysvia its neuronal network connections. It remains opento speculation whether the discrepancies relate to thecoordinates of stimulation or alternatively result fromchanges of the basal tonus of endogenous or exogenousdopamine in the basal ganglia-cortical loops [135]. Oneassumption might be that stimulation of the ventrome-dial STN through its close connection to the nucleusaccumbens via the ventral pallido-medial STN neu-ronal loop potentially induces ICD symptoms, sincethe ventral striatum, and the nucleus accumbens inparticular, is crucial in impulse control, motivational
124 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
processes, and addictive behaviors [38]. Understandingthe underlying mechanisms behind these issues isfurther complicated by different frequencies of stim-ulations leading to very different outcomes probablyinfluencing both the ventromedial and lateral STN.Contrasting incidences have been reported where STNDBS has not only been linked to increased impulsivityand ICDs [44, 136], but also to lack of motivation andeven severe apathy and anhedonia [9, 137]. Accordingto Tang and Strafella [9] and Volkmann et al. [138], apa-thy, often co-occurring with depression, is one of themostcommonadverseeffectsofSTNDBSdocumentedin 24.6% of PD patients three years after surgery. How-ever, a decrease in apathy severity within 3–6 monthsafter surgery has been observed, indicating that perhapsapathy is only related to medication withdrawal or DBSitself in the immediate postoperative period. This sug-gests, that apathy could be a consequence of diseaseprogression as well, that might be relieved by dopaminereplacement therapy [9, 56, 138, 139]. Thus it appearsthat ICDs and apathy in PD, though representing oppo-site extremes of a continuum, are somehow related tothe same brain structures and networks mediated bydopaminergic therapy [138, 140, 141].
It remains a current hypothesis that DBS applied tothe lateral STN region supports sensory-motor loops,whereas DBS applied to the medial STN influencesventral mesolimbic-nucleus accumbens-frontostriatalcircuitry. Rodriguez-Oroz et al. [38] demonstrated thatPD patients with ICDs and PD patients with severemotor dyskinesia secondary to STN DBS both displaytheta-alpha (4–10 Hz) activity, but at different frequen-cies. PD patients with ICDs thus display activity (meanpeak at 6.71 Hz) 2–8 mm below the intercommissuralline, whereas PD patients with dyskinesia displaytheta-alpha activity (mean peak at 8.38 Hz) 0–2 mmbelow the intercommissural line [38]. In PD patientswith ICDs, cortico-subthalamic coherence was mostfrequent at 4–7.5 Hz in scalp electrodes placed atfrontal regions anterior to the primary motor cortex.This indicates that activity stems from associative-prefrontal and emotional loops involved in cognitiveand motivational processes mediated via frontal cor-tical innervations of the STN. However, it remainsuncertain whether the activity upon STN stimulationrelates to a reversed STN activation of the cortexor relates to the subcortical loops. In contrast, inPD patients with dyskinesia the cortico-subthalamiccoherence was most frequent at 7.5–10 Hz in elec-trodes placed over the primary and supplementarymotor areas. This suggests that the recorded activityin this group of patients stems from sensory-motor
circuits regulating motor control and coordination[38].
It seems obvious that the role of the STN in PD,on both a motor and cognitive level, still needs furtherinvestigations. Nevertheless, the STN clearly appearsto be situated at an essential position within the basalganglia playing a central role in not only sensory-motor loops, but also in associative-prefrontal andemotional circuits [14, 31, 38]. A relatively new tar-get for DBS alleviating motor symptoms of PD, whichhas received increased attention in recent years, is thepedunculopontine nucleus (PPN) [142–144]. The PPNis a tegmental mesopontine nucleus composed of bothcholinergic and non-cholinergic neurons with strongreciprocal connections to key output stations of thedorsal and ventral mesolimbic systems of the basalganglia [142]. The subregions of the PPN are thusinvolved in the modulation and control of motor perfor-mance, attention, procedural learning, reinforcement,and reward processing [142, 145, 146]. Interestingly,deep brain stimulation in PPN, unlike STN DBS, hasso far only been associated with the development ofICDs in PD in a single case [118], making it a relevanttarget for future research.
THE ROLE OF THE NUCLEUSACCUMBENS AND FRONTAL CORTEX INICDS IN PD
The ventral striatum, and in particular the nucleusaccumbens, plays a pivotal role in ICDs and in emo-tional, cognitive, and addictive processes [147, 148].It represents a crucial anatomical substrate within theneural networks involving the prefrontal, orbitofrontal,and associative-prefrontal cortical loops, which influ-ence the essential dysfunctional elements present in PDpatients with ICDs such as reward evaluation, reversallearning, impulsivity, and temporal discounting [94,149, 150]. In the following we discuss the impact ofthese neuronal networks in relation to ICDs in PDbased on different neuroimaging techniques.
Using functional magnetic resonance imaging(fMRI), Voon et al. [45] showed a decreased activ-ity within the orbitofrontal cortex and the anteriorcingulate cortex during risky decision-making in PDpatients with ICDs. They demonstrated an associationbetween dopamine agonists and increased sensitivitytowards risk in PD patients with ICDs accompaniedby a decreased activity in the ventral striatum. Like-wise, Rao et al. [92] observed that PD patients withICDs had a significantly reduced blood oxygenationlevel dependent (BOLD) activity in the right ventral
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 125
striatum during risk taking compared to PD patientswithout ICDs. These results point at a bias towardsrisky choices in PD patients with ICDs, which mightbe the behavioral consequence of an impaired risk eval-uation following dopamine agonist therapy [45]. Incontrast, Voon et al. [96] demonstrated a dopamineagonist-induced increase in ventral striatum activityrelated to positive prediction error signifying a “bet-ter than expected” outcome in PD patients with ICDspotentially resulting in a reward bias. This effect wasnot seen in PD patients without ICDs. Additionally, PDpatients with ICDs had an overall greater orbitofrontalcortex activity to gains and loss omissions and loweractivity to losses than PD patients without ICDs [96].Similarly, Frosini et al. [112] showed an increasedBOLD response upon gambling cues bilaterally in theanterior cingulate cortex and in the left ventral striatumin PD patients with pathological gambling comparedto PD patients without pathological gambling. In addi-tion, this finding was associated with a cue-inducedcraving, which resembles that in individuals sufferingfrom addiction [112].
These discrepancies might be explained by differ-ences in the used paradigms. Graef et al. [150], recentlyshowed that while levodopa improved PD patients’performance on an instrumental learning task withconstant stimulus-reward contingencies depending ondorsal striato-frontal circuits, treatment impaired per-formance on a reversal learning task with varyingreward contingencies relying on ventral striato-frontalloops. The findings by Graef et al. [150] support the“overdose hypothesis” assuming harmful effects ofdopaminergic medication on reward evaluation andother cognitive functions depending on less affectedbrain regions in PD, such as the ventral striatum,and in particular the nucleus accumbens, in earlydisease stages [2–4, 150]. This hypothesis is fur-ther supported by van Eimeren et al.s [107] positronemission tomography (PET) findings of increasedactivity in the lateral orbitofrontal cortex, the ros-tral cingulate zone, the amygdala, and the externalpallidum upon apomorphine intake in PD patientswithout pathological gambling while performing aprobabilistic card game. In contrast, PD patients withpathological gambling showed the opposite reactionof apomorphine-induced deactivation of these brainregions resulting in impaired impulse control andresponse inhibition [107]. Moreover, using single-photon emission computed tomography (SPECT),Cilia et al. [108] reported hyperactivity during rest inthe orbitofrontal cortex, the hippocampus, the amyg-dala, the insula, and the ventral pallidum in PD patients
with ICDs. They argued, that the abnormal restingstate in the mesocorticolimbic circuit in this subgroupof patients provided additional support to the “over-dose hypothesis” by suggesting a medication-inducedoverstimulation of the relatively intact reward-relatedneuronal networks [108].
FunctionalPETstudiesofaddictionandpathologicalgambling, have shown an abnormally enhanced pha-sic dopamine release in the ventral striatum in addictedindividuals when confronted with cues of their addic-tion [20, 61, 62, 147, 151–155]. A similar dysfunctionaldopaminergic response upon gambling has been shownin PD patients with comorbid pathological gambling[74]. Steeves and colleagues [74], reported a lowerbaseline binding potential for the dopamine D2/D3radioligand [11C]-raclopride in the ventral striatum ofPD patients with pathological gambling compared toPD patients without pathological gambling and a rel-atively greater decrease in [11C]-raclopride bindingduring gambling. This finding may suggest a relativelyhigher endogenous ventral striatal dopamine releaseupon gambling in PD patients with pathological gam-bling than in the PD control group. Similar findings ofdecreased [11C]-raclopride binding in the ventral stria-tumandthecaudatenucleuswhenexposed to rewardingversus neutral visual stimuli were reported by the teamof O‘Sullivan and Wu in PD patients with ICDs com-pared to PD controls [110, 111] indicating an enhancedendogenous dopamine release. In a SPECT study usingthe radiotracer FP-CIT, Cilia et al. [95] showed thatPD patients with pathological gambling had a lowertracer binding in the ventral striatum compared to PDpatientswithoutgamblingproblems.AccordingtoCiliaet al. [95], these results might reflect either a reduc-tion of mesolimbic projections, or a lower dopaminetransporter density combined with increased synapticdopamine levels as previously suggested [74, 108].
The findings in PD patients with ICDs translate tofindings in both human and animal studies of addictionsuggesting low baseline dopamine receptor availabil-ity to be associated with vulnerability of addiction[156–158]. Interestingly, low striatal dopamine recep-tor availability has also recently been demonstrated inindividuals suffering from morbid obesity due to bingeeating [159, 160]. Following this line of arguments,individuals with ICDs and other types of addictions, arelikely to seek more potential rewarding events, e.g. thepossible gains related to gambling, in order to compen-sate for a reward deficiency syndrome characterizedby a chronic dopamine craving [74, 161]. However,Joutsa et al. [162] very recently argued that a striataldopamine release during gambling irrespective of out-
126 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
come in fact challenges this hypothesis, which predictsblunted mesolimbic dopamine responses to gamblingin pathological gamblers. Thus according to this argu-ment, the findings by Voon et al. [45] and Rao et al.[92] support the reward deficiency hypothesis, whereasthe findings by Voon et al. [96], Frosini et al. [112]and Steeves et al. [74] contradict the hypothesis. Theexpectation of receiving a reward seems to be enough toinduce a striatal dopamine release in PD patients withpathological gambling, which is also seen in patholog-ical gamblers without PD [151, 152, 162]. Moreover,the experience of wanting or craving induced merely byvisual gambling cues or following loss might serve asanother hypothesis for explaining the observed striataldopamine release [112].
The processing of reward involves aspects of moti-vation, prediction, and pleasure, also referred to as thepsychological components of “wanting”, “learning”,and “liking” [163, 164]. In addictive behaviors, want-ing to a great extent equals craving. Recent studies haveshown that even though individuals suffering fromaddiction do potentially get a dopaminergic enhance-ment from engaging in the addictive behavior, theymight not feel any hedonic impact from the reward ofthe action. Exactly this is seen in a group of PD patientswith DDS [79]. Using PET imaging, Evans et al. [79]demonstrated an increased dopamine release in theventral striatum upon levodopa intake in PD patientswith DDS, which correlated with the patients’ subjec-tive feelings of drug wanting (craving) but not liking[79]. This finding hints at liking and wanting com-ponents involving different neurotransmitter systems,where wanting seems closely related to the dopamin-ergic system, and liking seems associated with theopiate system [164]. In fact, the ability to learn toseek reward remains intact in rats lacking up to 99%of dopamine in the nucleus accumbens, they merelylack the motivation to use the skills they have learned[164]. Thus, consistent with the findings by Graef etal. [150], one could argue that the reward system isnot only a dopamine-driven system rather it includes acombination of a dopaminergic motivational part andan opioid dependent pleasure part.
In summary, the nucleus accumbens certainly seemsto play a key role during the acquisition phase ofaddictive behaviors, whereas the dorsal striatum is par-ticularly important in maintaining an addiction [147,150, 165]. This transition seems to be facilitated bythe direct D2/D3 dopamine agonists on hypersensi-tive postsynaptic dorsal striatal dopamine receptors.Anatomically, the shift from initiation to consolidationof an addiction might reflect an equivalent shift from
limbic to associative-prefrontal and sensory-motorcircuits via the ventral tegmental area and the sub-stantia nigra zona compacta dopaminergic ascendingloops innervating the dorsal striatum [150, 165, 166].The discussed findings highlight the importance ofthe orbitofrontal cortex, the anterior cingulate cortex,and the ventral striatum in risk evaluation, which ismediated by dopamine agonists in ICDs in PD. Thus,these findings might explain why dopamine agonistsare important risk factors for developing ICDs in PD[45, 51, 167]. Furthermore, several studies show analtered dopaminergic activity within the ventral stria-tum in PD patients with concomitant ICDs resemblingthe dopaminergic activity observed in non-PD individ-uals suffering from other kinds of addiction. However,these issues are still not sufficiently investigated, andresearch suggests that dopamine and dopaminergictherapy are not the only agents that may impact thecourse of the disease. Other neurotransmitters aredepleted in PD as well, and in the following we discussthe influence of serotonin in ICDs in PD.
THE ROLE OF SEROTONIN IN IMPULSECONTROL DISORDERS IN PARKINSON’SDISEASE
It is obvious that dopamine agonists are not ableto fully compensate for the natural physiologicaltonic/phasic release of dopamine or the inactivationby the re-uptake transporter following its release,since the dopaminergic nerve terminals are degener-ated in PD. Among other important neurotransmittersdepleted in PD is serotonin, whose impact on non-motor manifestations of the disease is still subject tomuch debate [9–12]. Furthermore, the possible role ofa decrease in serotonergic activity in PD patients withICDs with regard to impulsivity, response inhibition,and temporal discounting remains to be established.The serotonin innervations originating from the dor-sal raphe nucleus supplies approximately 80% of theserotonergic innervation to the prefrontal and motorcortices as well as to the subcortical structures involvedin PD (striatum, pallidum, STN, substantia nigra,and PPN) [168]. In PD, the role of serotonin isvery important in relation to both ICDs and emo-tional disturbances associated with the disease, suchas depression, apathy, and anxiety [10]. It is beyondthe scope of this review to discuss the complex detailsregarding the interactions between dopamine and sero-tonin, since this topic has already been covered byexcellent reviews [169–171]. Consequently, only a few
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 127
highlights from the published literature will be dis-cussed.
In conjunction with dopamine, serotonin seems toplay an essential role in the modulation of impulsecontrol, risk taking, and decision-making, and theactivity of serotonin has been associated with enhancedreversal learning and attentional shifting, increasedresponse inhibition, and decreased delay discounting[158, 170, 172–176]. Moreover, Campbell-Meiklejohnet al. [177] recently found that serotonin and dopaminecomplement each other in loss chasing (i.e. gambling torecover losses) in pathological gamblers. While sero-tonin activity seems related to persistent loss chasing,dopamine activity appears to regulate the magnitudeof the losses being chased [177]. In addition, Longet al. [178] demonstrated that serotonin depletionshapes risky decision-making in macaque monkeystrained to perform a simple gambling task for rewards.Reducing serotonin synthesis resulted in a decreasedpreference for more conservative options in the gam-bling task, resulting in riskier decision-making in themonkeys. These findings introduce an important issueconcerning the balance between high and low levelsof serotonin leading to different, sometimes almostopposite, neural network activations and behavioraloutcomes. Macoveanu et al. [175] recently demon-strated that high and low levels of serotonin hadopposite effects on activity in the dorsomedial pre-frontal cortex and the amygdala related to negativeoutcomes following low-risk decisions in a gamblingtask. In the dorsomedial prefrontal cortex, low levels ofserotonin increased the negative outcome-related neu-ral activity, whereas high levels of serotonin resulted ina decreased activity [175]. The opposite neural reac-tion to negative outcomes in the gambling task waspresent in the left amygdala, where high levels of sero-tonin led to increased activity relative to a decreasedactivity associated with low levels of serotonin [175].
The balance between high and low levels ofserotonin is furthermore implicated in impulsivity.Miyazaki et al. [176] demonstrated the importanceof serotonin in temporal discounting through findingsof increased serotonergic firing facilitating waitingbehavior towards future rewards. These results sug-gest that in addition to the implications of dopaminedepletion, low levels of serotonin, e.g. as a result ofserotonergic degeneration in PD, might be essentialin explaining the inability in PD patients with ICDsto wait for a reward and hence contributing to theirmaladaptive behavior.
To summarize, the presented results suggest thatboth the dopaminergic and the serotonergic systems are
implicated in temporal discounting and risk-sensitivedecision-making in general as well as in pathologicalgambling and other ICDs. Furthermore, the findingscautiously hint at potential dose-dependent pharmaco-logical therapies for ICDs and addiction. Consistentwith preclinical findings, a case study demonstrateda positive treatment response in a patient admin-istered fluvoxamine to treat pathological gambling[179]. Whether similar selective serotonin reuptakeinhibitors, or perhaps direct serotonergic agonists aim-ing at specific receptor subtypes, might amelioratepathological gambling and other ICDs in early PD,perhaps at least in patients with comorbid depression,remains an open question for future research to address[49, 180]. In addition, it appears highly clinically rele-vant to further investigate how ICDs in PD impact thepatients’ daily functioning. In the following, we dis-cuss cognitive impairments associated with ICDs inPD.
COGNITIVE SYMPTOMATOLOGY INIMPULSE CONTROL DISORDERS INPARKINSON’S DISEASE
Cognitive processes such as attention, planning, andanticipation are of ultimate importance in social inter-action, learning, and decision-making [3, 4, 6, 181,182]. It is well known that PD patients without ICDsexperience cognitive difficulties in domains relatedto the fronto-striatal loops as their disease progresses[11–13, 28, 183, 184]. According to Hirano et al. [13],the mesocortical dopamine system affected in PD isassociated with executive functions and is mediatedvia levodopa medication and dopamine metabolism.Cholinergic impairment in PD is also implicated inattention and working memory and the role of acetyl-choline in development of dementia is supported byacetylcholinesterase PET imaging [13]. Furthermore,research indicates that despite relatively preservedfunctions of the orbital and ventromedial prefrontalcortex in early disease stages, cognitive impairmentsmight even occur in early PD, though most likely asa consequence of dopaminergic treatment [185, 186].Below, we discuss findings based on a selection ofcognitive tasks dependent on frontal cortical functionscomparing PD patients with and without ICDs.
Executive functioning
The Stroop test and the Wisconsin Card Sorting Testrepresent two widely used tasks to evaluate executivefunctions. The Stroop test, which measures selective
128 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
attention, cognitive flexibility, and speed of cognitiveprocessing, has been associated with activation in theanterior cingulate cortex and the dorsolateral prefrontalcortex [187]. Similarly, the Wisconsin Card SortingTest is a test of set shifting measuring cognitive flexi-bility. This test has been associated with activation ofthe dorsolateral prefrontal cortex as well as the ventro-lateral prefrontal cortex and the caudate nucleus, whichalso modulate working memory functions [188–190].Various studies have shown that PD patients performpoorly on both of these tests revealing a deficit in alter-ation or maintenance of a learned strategy based ontask-dependent feedback and impaired impulse controlregulation [183, 184, 191–195]. However, findings ofpreserved executive functions in PD exist as well, atleast in early PD [196].
In PD patients with concurrent ICDs, Vitale et al.[78] recently demonstrated deficits on executive tasksexploring cognitive flexibility and spatial planning. Inaddition, they noticed that the cognitive difficultiesassociated with ICDs in PD differed depending on thespecific kind of ICD patients presented. PD patientswith hypersexuality and multiple ICDs performedworse on verbal learning and memory tests com-pared to PD patients with pathological gambling [78].Particularly, the PD patients with comorbid hypersex-uality revealed more general cognitive deficits, poorerinhibitory control, and reduced immediate and delayedmemory compared to PD patients with pathologicalgambling [78]. These findings suggest that hyper-sexuality in PD is associated with a more profounddeficiency in the balance of the associative-prefrontaland emotional-limbic circuits than pathological gam-bling in PD. Additionally, compared to PD patientswithout pathological gambling, Santangelo et al. [123]reported impaired performance in PD patients withpathological gambling on cognitive tasks evaluat-ing long-term memory and frontal lobe functions,including the Frontal Assessment Battery, phonologi-cal fluency, and the Trail Making Test. In contrast, Siriet al. [114] demonstrated preserved executive functionsin PD patients with pathological gambling. Comparedto PD patients without pathological gambling, patientswith gambling problems revealed higher general cog-nitive abilities and performed better on attention andverbal fluency [114].
Reversal and reinforcement learning
Closely related to cognitive flexibility is reinforce-ment and reversal learning, which has also been foundto be compromised in PD, at least in medicated patients
[186, 197]. Reversal learning impairments appear tobe particularly pronounced following treatment withthe dopamine D2/D3 receptor agonist pramipexole [3,198, 199]. In line with our previous discussion of thefunctional neuroanatomy of ICDs in PD, the resultson cognitive impairments in PD might be explainedby a treatment-induced disruption of functional activ-ity within the nucleus accumbens, which is involved inalteration of behavioral strategy. Interestingly, Cools etal. [148] demonstrated that reversal learning was in factaccompanied by increased nucleus accumbens activityonly in medicated PD patients. Current neuroanatom-ical studies strongly suggest that the modulatoryinfluence on cognition via the nucleus accumbensappears to be mediated by its upstream neuronallooping through the ventral pallidum and thalamic pro-jections to the frontal cortex [166, 200]. Furthermore,the aforementioned fMRI study by Voon et al. [96]demonstrated that dopamine agonists increase the rateof learning from gain and enhanced ventral striatalactivity to positive prediction error in PD patients withICDs, an effect that was not present in PD patientswithout ICDs. In contrast, dopamine agonists induceda decrease in learning from loss in PD patients withoutICDs but not in PD patients with ICDs [96]. Lastly,PD patients with ICDs had greater orbitofrontal cortexactivation upon gains relative to lower activation uponlosses compared to PD patients without ICDs both onand off medication [96]. However as previously dis-cussed, Graef et al. [150] showed that dopaminergictreatment affects tasks implicating diverse neuronalnetworks differently.
Decision-making under ambiguity
A wide range of cognitive tasks is designed toexamine decision-making. Among these are the IowaGambling Task, the Cambridge Gambling Task, theGame of Dice Task, the Balloon Analogue Risk Task,and the Beads Task, which are all associated withthe limbic-orbitofrontal-striatal loop [201]. The IowaGambling Task is most often used to measure decision-making under ambiguous scenarios with implicit rulesand it is known that patients with deficits in theorbitofrontal and ventromedial prefrontal cortex andthe amygdala perform poorly on this task [201–203].Also, PD patients have revealed impaired performanceon the Iowa Gambling Task [97, 194, 196, 204–208]and this has even been found in early disease stagesdespite preserved executive functions [196]. In con-trast, Euteneuer et al. [201] observed intact IowaGambling Task performance in PD patients without
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 129
ICDs in spite of impaired performance on the Game ofDice Task and executive dysfunctions. Furthermore,Bentivoglio et al. [97] recently reported that com-pared to PD patients without ICDs, PD patients withICDs tend to lose more money and make more riskydecisions on the task resembling the performance ofpathological gamblers without PD [151, 152].
Djamshidian et al. [113] investigated decision-making under ambiguity in PD patients with andwithout ICDs using the Beads Task, which assessesreflective impulsivity under ambiguous conditions[209]. Overall, PD patients made more impulsive deci-sions than controls, reflecting a tendency in PD patientsto make rapid decisions based on insufficient informa-tion [113]. A similar trend has been associated withDBS in STN. Frank et al. [44] showed that STN DBSinterferes with the normal capacity to slow decision-making processes down when faced with ambiguousdecision-making scenarios. In fact, they found that PDpatients with DBS made more hasty decisions underhigh-conflict conditions [44].
Decision-making under risk
Decision-making under risk requires intact dorso-lateral prefrontal cortex activity [6, 201] and can beassessed using the Game of Dice Task and the Cam-bridge Gambling Task, on which PD patients haveshown poor performance [5, 201, 210, 211]. In partic-ular, medicated patients seem to be impaired on thesetasks, as suggested by Torta et al. [211] who found thatpatients receiving higher doses of dopaminergic medi-cation performed worse and were more impulsive thanpatients receiving lower treatment doses.
Another way of measuring risky decision-makingis by using the Balloon Analogue Risk Task [212], inwhich loss aversion has been associated with increasedanterior cingulate cortex activity, whereas increasedventromedial prefrontal cortex activity has been asso-ciated with reward seeking [213]. In PD patients,this task seems to be modulated by dopaminergicmedication, at least in PD patients with concurrentICDs. Claassen et al. [51] recently demonstrated thatdopamine agonists increased risk taking in PD patientswith ICDs on this task, whereas no effect of dopamineagonists on risk taking was observed in PD patientswithout ICDs.
Temporal discounting
Temporal discounting refers to a preference towardsmore immediate rewards and a parallel devaluation of
delayed rewards, a clinical finding very common inindividuals suffering from ICDs and addictions. Justa few years ago, Voon et al. [75] linked dopamineagonist medication to an elevated delay discountingin PD patients with pathological gambling and com-pulsive buying relative to PD patients without ICDs.Furthermore, PD patients with ICDs revealed moreworking memory deficits than PD controls [75]. Inter-estingly, in another study Voon et al. [80] demonstratedincreased impulsive decision-making in PD patientswith compulsive buying and pathological gambling,but not in patients with binge eating or hypersexuality.Housden et al. [214] presented a similar finding in PDpatients with comorbid ICDs indicating an inability towait for a reward despite intact reward learning [149,214]. Overall, these findings suggest that a tendency inPD patients with ICDs towards devaluation of delayedrewards, though differences across ICDs might exist.Furthermore, the disinhibited behavior appears to beenhanced by dopamine agonists and strongly associ-ated with an elevated preference for immediate overfuture rewards [75, 80, 149, 214].
In summary, the aspects of cognition discussedabove are highly relevant in PD since patients oftensuffer significant impairments as the disease progressesand following prolonged treatment. The issue of execu-tive and decision-making dysfunctions associated withICDs in PD is far from resolved, but it appears that acommon feature for cognitive deficits associated withICDs in PD involve disturbances in impulsivity, tempo-ral discounting, cognitive flexibility, and reinforcementand reversal learning that is particularly related to theventral striatum and the frontal cortex [13]. Never-theless, inconsistent findings reinforce the need foradditional studies to determine whether ICDs in PD areaccompanied by further cognitive deficits and whetherdifferent ICDs are associated with different behavioraland cognitive profiles in PD.
CONCLUSIONS AND PERSPECTIVES
We have reviewed the literature from the past 12years reporting ICDs in PD and conclude that a contin-uously growing number of studies support the conceptof treatment-induced ICDs in PD. Both pharmacolo-gical and surgical therapies have been associated withthe development of ICDs. Particularly, the direct D2/D3dopamine agonists appear to be linked to this behav-ioral complication. Furthermore, we have argued thatboth the subthalamic nucleus and the nucleus accum-bens play key roles in ICDs, potentially leading to
130 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
serious consequences for the individual on financial,interpersonal, and cognitive levels. However, to fullyunderstand why ICDs affect up to 15.5% of PDpatients, it is not enough to consider the contributionsof the dopaminergic system. Additional neurotransmit-ters need to be taken into account. We highlighted theimpact of serotonin in the non-motor manifestationsof PD and touched upon the role of opioids in addic-tive behaviors, since both neurotransmitters seem tobe important mediators in reward processing and riskevaluation.
Despite an increasing interest in the field, we lacksufficient knowledge regarding therapy in ICD symp-tomatology in PD. Thus, there is a great need for futureresearch to take a closer look at the functional neu-roanatomy of ICDs and related cognitive deficits asevaluated by PET [74, 79, 82, 105, 107, 110, 111],SPECT [94, 95, 108], fMRI [45, 92, 96, 112], orMEG studies [215] in order to fully understand whyPD patients appear to be at greater risk of develop-ing ICDs than the general population. We have arguedthat both the orbitofrontal and anterior cingulate cor-tices and the ventral striatum are linked to impairedrisk evaluation, which is mediated by dopamine ago-nists in PD patients suffering from comorbid ICDs.This serves as just one possible explanation of whydopamine agonists are among important risk factorsfor developing ICDs in PD [45, 51]. Another possi-ble explanation is related to the “overdose hypothesis”and attributes the cognitive deficits in PD patientswith ICDs to the depleted caudate nucleus, and thedorsal striatum in general, altering the cognitive func-tions associated with the prefrontal cortex. This is thenfurther compromised as the relatively intact ventralstriatum in early PD is overdosed by dopaminergictreatment.
Likewise, an important step for future researchis to assess how ICDs and other non-motor man-ifestations of PD affect the daily functioning andpsychological well-being of the patients. Potentially,this could lead to faster identification of PD patientsat risk for developing ICDs and improved manage-ment of adverse effects of treatment. A recent studydemonstrated that in PD patients with ICDs symptomseverity and related psychiatric disturbance improvedfollowing cognitive-behavioral therapy, unfortunatelywithout relieving caregiver distress or burden markedly[216, 217]. It is important in this regard to empha-size that the detection of ICDs relies very much oncaregivers, who play an important role in the dailymedical care and supervision of psychiatric symptomsfollowing withdrawal of dopamine agonists [53, 98,
216, 218]. Still, reduction of dopamine agonists isthe primary strategy in managing ICDs in PD, butit is often associated with the development or wors-ening of depression, anxiety, or apathy, which havebeen found to occur in up to 19% of patient duringdopamine agonist withdrawal [219]. Pharmacologicalmanagement of ICDs in PD has received increasingattention in recent years and several different com-pounds have been scientifically tested. Among theseare zonisamide [220] and donepezil [221], which areused to treat cognitive impairments and dementia inPD [222]. Also valproate, which is traditionally used totreat e.g. epilepsy, anorexia nervosa, anxiety, and bipo-lar disorders, has been shown effective in treating bothpathological gambling in non-PD patients and ICDsin PD [34, 223]. Other possible candidates includeselective serotonin reuptake inhibitors, at least in thesubgroup of patients with ICD who displays comor-bid depressive symptoms, the noradrenaline reuptakeinhibitor atomoxetine, which is sometimes prescribedto patients with ADHD, since this compound leavesthe ventral striatal dopamine system intact; and theopioid antagonist nalmefene [224, 225]. Undoubtedly,it is an important topic for future studies to investi-gate this in more detail, since mixed results have beenreported so far [226, 227]. Additionally, future researchshould investigate whether dopamine agonist with anextended release are associated with ICDs as well, orwhether these compounds could serve as an alternativeto the more short-acting dopamine agonists in pre-venting the increased risk of developing ICDs in PD[226].
SUPPLEMENTARY MATERIAL
Supplementary Table 1: Extensive overview of98 reports on ICDs in PD published between2000–January 2013 including case reports, case series,case-control studies, experimental studies, and epi-demiological studies. The table provides informationon sample size, gender distribution, treatment, age, andPD duration.
Supplementary Table 2: Extensive overview of98 reports on ICDs in PD published between2000–January 2013 including case reports, case series,case-control studies, experimental studies, and epi-demiological studies. The table provides informationon prior history of ICDs, psychiatric symptoms, Hoehn& Yahr, UPDRS, and additional information. The sup-plementary tables can be found here: http://iospress.metapress.com/content/e83v319qq21204m1/
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 131
ACKNOWLEDGMENTS
We thank Malene Flensborg Damholdt, TrineGjerløff, and Anne Landau for commenting on aprevious version of this review. We thank the DanishAgency for Science, Technology and Innovation forfinancial support, grant number 2102-07-0005.
CONFLICT OF INTEREST
The authors have no conflict of interest to report.
REFERENCES
[1] Parkinson J (1817) An Essay on the Shaking Palsy.[2] Rowe JB, Hughes L, Ghosh BC, Eckstein D, Williams-Gray
CH, Fallon S, Barker RA, & Owen AM (2008) Parkinson’sdisease and dopaminergic therapy – differential effects onmovement, reward and cognition. Brain, 131(Pt 8), 2094-2105.
[3] Cools R (2006) Dopaminergic modulation of cognitivefunction-implications for L-DOPA treatment in Parkinson’sdisease. Neurosci Biobehav Rev, 30(1), 1-23.
[4] Cools R, Frank MJ, Gibbs SE, Miyakawa A, Jagust W, &D’Esposito M (2009) Striatal dopamine predicts outcome-specific reversal learning and its sensitivity to dopaminergicdrug administration. J Neurosci, 29(5), 1538-1543.
[5] Brand M, Labudda K, Kalbe E, Hilker R, Emmans D, FuchsG, Kessler J, & Markowitsch HJ (2004) Decision-makingimpairments in patients with Parkinson’s disease. BehavNeurol, 15(3-4), 77-85.
[6] Gleichgerrcht E, Ibanez A, Roca M, Torralva T, & ManesF (2010) Decision-making cognition in neurodegenerativediseases. Nat Rev Neurol, 6(11), 611-623.
[7] Rodriguez-Oroz MC, Jahanshahi M, Krack P, Litvan I,Macias R, Bezard E, & Obeso JA (2009) Initial clini-cal manifestations of Parkinson’s disease: Features andpathophysiological mechanisms. Lancet Neurol, 8(12),1128-1139.
[8] Weintraub D, & Nirenberg MJ (2012) Impulse Control andRelated Disorders in Parkinson’s Disease. NeurodegenerDis, 11(2), 63-71.
[9] Tang J, Strafella AP (2012) The frontostriatal circuitry andbehavioral complications in PD. Parkinsonism & relateddisorders, 18(Suppl 1), S104-S106.
[10] Kano O, Ikeda K, Cridebring D, Takazawa T, Yoshii Y, &Iwasaki Y (2011) Neurobiology of depression and anxietyin Parkinson’s disease. Parkinsons Dis, 2011, 143547-.
[11] Bonnet AM, Jutras MF, Czernecki V, Corvol JC, & Vidail-het M (2012) Nonmotor symptoms in Parkinson’s diseasein 2012: Relevant clinical aspects. Parkinsons Dis, 2012,198316-.
[12] Dubois B, & Pillon B (1997) Cognitive deficits in Parkin-son’s disease. Journal of Neurology, 244(1), 2-8.
[13] Hirano S, Shinotoh H, & Eidelberg D (2012) Functionalbrain imaging of cognitive dysfunction in Parkinson’s dis-ease. Journal of Neurology, Neurosurgery, and Psychiatry,83(10), 963-969.
[14] Crossman AR (1990) A hypothesis on the pathophysio-logical mechanisms that underlie levodopa- or dopamineagonist-induced dyskinesia in Parkinson’s disease: Implica-tions for future strategies in treatment. Movement Disorders:
Official Journal of the Movement Disorder Society, 5(2),100-108.
[15] APA APA (1994) Diagnostic and Statistical Manual of Men-tal Disorders, Fourth Revision (DSM-IV). Washington DC:American Psychiatric Association.
[16] Seedat S, Kesler S, Niehaus DJ, & Stein DJ (2000) Patholog-ical gambling behaviour: Emergence secondary to treatmentof Parkinson’s disease with dopaminergic agents. DepressAnxiety, 11(4), 185-186.
[17] Weintraub D, Papay K, & Siderowf A (2013) Screeningfor impulse control symptoms in patients with de novoParkinson disease: A case-control study. Neurology, 80(2),176-180.
[18] Molina JA, Sainz-Artiga MJ, Fraile A, Jimenez-Jimenez FJ,Villanueva C, Orti-Pareja M, & Bermejo F (2000) Pathologicgambling in Parkinson’s disease: A behavioral manifes-tation of pharmacologic treatment? Mov Disord, 15(5),869-872.
[19] Avanzi M, Uber E, & Bonfa F (2004) Pathological gam-bling in two patients on dopamine replacement therapy forParkinson’s disease. Neurol Sci, 25(2), 98-101.
[20] Dodd ML, Klos KJ, Bower JH, Geda YE, Josephs KA, &Ahlskog JE (2005) Pathological gambling caused by drugsused to treat Parkinson disease. Arch Neurol, 62(9), 1377-1381.
[21] Avanzi M, Baratti M, Cabrini S, Uber E, Brighetti G,& Bonfa F (2006) Prevalence of pathological gamblingin patients with Parkinson’s disease. Mov Disord, 21(12),2068-2072.
[22] Weintraub D, & Potenza MN (2006) Impulse control disor-ders in Parkinson’s disease. Curr Neurol Neurosci Rep, 6(4),302-306.
[23] Moro E (2009) Impulse control disorders and subthalamicnucleus stimulation in Parkinson’s disease: Are we jumpingthe gun? Eur J Neurol, 16(4), 440-441.
[24] Voon V, Hassan K, Zurowski M, de Souza M, Thomsen T,Fox S, Lang AE, & Miyasaki J (2006) Prevalence of repet-itive and reward-seeking behaviors in Parkinson disease.Neurology, 67(7), 1254-1257.
[25] Voon V, Thomsen T, Miyasaki JM, de Souza M, Shafro A,Fox SH, Duff-Canning S, Lang AE, & Zurowski M (2007)Factors associated with dopaminergic drug-related patho-logical gambling in Parkinson disease. Arch Neurol, 64(2),212-216.
[26] Weintraub D, Koester J, Potenza MN, Siderowf AD, StacyM, Voon V, Whetteckey J, Wunderlich GR, & Lang AEImpulse control disorders in Parkinson disease: A cross-sectional study of 3090 patients. Arch Neurol, 67(5), 589-595.
[27] Kim J, Kim M, Kwon DY, Seo WK, Kim JH, Baik JS, & KohSB (2012) Clinical characteristics of impulse control andrepetitive behavior disorders in Parkinson’s disease. Journalof neurology, 260(2), 429-437.
[28] Poletti M, & Bonuccelli U (2012) Impulse control disordersin Parkinson’ disease: The role of personality and cognitivestatus. Journal of Neurology, 259(11), 2269-2277.
[29] Potenza MN, Kosten TR, & Rounsaville BJ (2001) Patho-logical gambling. JAMA, 286(2), 141-144.
[30] Dagher A, & Robbins TW: (2009) Personality addiction,dopamine: Insights from Parkinson’s disease. Neuron, 61(4),502-510.
[31] Temel Y, Blokland A, Steinbusch HW, & Visser-VandewalleV (2005) The functional role of the subthalamic nucleus incognitive and limbic circuits. Prog Neurobiol, 76(6), 393-413.
132 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
[32] Moum SJ, Price CC, Limotai N, Oyama G, Ward H, Jacob-son C, Foote KD, & Okun MS (2012) Effects of STN andGPi deep brain stimulation on impulse control disordersand dopamine dysregulation syndrome. PLoS One, 7(1),e29768.
[33] Romito LM, Raja M, Daniele A, Contarino MF, BentivoglioAR, Barbier A, Scerrati M, & Albanese A (2002) Transientmania with hypersexuality after surgery for high frequencystimulation of the subthalamic nucleus in Parkinson’s dis-ease. Movement disorders: Official Journal of the MovementDisorder Society, 17(6), 1371-1374.
[34] Sriram A, Ward HE, Hassan A, Iyer S, Foote KD, RodriguezRL, McFarland NR, & Okun MS (2012) Valproate as atreatment for dopamine dysregulation syndrome (DDS) inParkinson’s disease. Journal of Neurology, 260(2), 521-527.
[35] Witjas T, Baunez C, Henry JM, Delfini M, Regis J, CherifAA, Peragut JC, & Azulay JP (2005) Addiction in Parkin-son’s disease: Impact of subthalamic nucleus deep brainstimulation. Mov Disord, 20(8), 1052-1055.
[36] Zahodne LB, Susatia F, Bowers D, Ong TL, Jacobson CEt,Okun MS, Rodriguez RL, Malaty IA, Foote KD, & Fer-nandez HH (2011) Binge eating in Parkinson’s disease:Prevalence, correlates and the contribution of deep brainstimulation. The Journal of Neuropsychiatry and ClinicalNeurosciences, 23(1), 56-62.
[37] Smeding HM, Goudriaan AE, Foncke EM, Schuurman PR,Speelman JD, & Schmand B (2007) Pathological gamblingafter bilateral subthalamic nucleus stimulation in Parkin-son disease. J Neurol Neurosurg Psychiatry, 78(5), 517-519.
[38] Rodriguez-Oroz MC, Lopez-Azcarate J, Garcia-Garcia D,Alegre M, Toledo J, Valencia M, Guridi J, Artieda J, &Obeso JA (2011) Involvement of the subthalamic nucleusin impulse control disorders associated with Parkinson’sdisease. Brain: A journal of neurology, 134(Pt 1), 36-49.
[39] Lim SY, O’Sullivan SS, Kotschet K, Gallagher DA, LaceyC, Lawrence AD, Lees AJ, O’Sullivan DJ, Peppard RF,Rodrigues JP, et al. (2009) Dopamine dysregulation syn-drome, impulse control disorders and punding after deepbrain stimulation surgery for Parkinson’s disease. J ClinNeurosci, 16(9), 1148-1152.
[40] Knobel D, Aybek S, Pollo C, Vingerhoets FJ, & BerneyA (2008) Rapid resolution of dopamine dysregulation syn-drome (DDS) after subthalamic DBS for Parkinson disease(PD): A case report. Cognitive and Behavioral Neurology:Official Journal of the Society for Behavioral and CognitiveNeurology, 21(3), 187-189.
[41] Bandini F, Primavera A, Pizzorno M, & Cocito L (2007)Using STN DBS and medication reduction as a strategy totreat pathological gambling in Parkinson’s disease. Parkin-sonism Relat Disord, 13(6), 369-371.
[42] Halbig TD, Tse W, Frisina PG, Baker BR, Hollander E,Shapiro H, Tagliati M, Koller WC, & Olanow CW (2009)Subthalamic deep brain stimulation and impulse control inParkinson’s disease. Eur J Neurol, 16(4), 493-497.
[43] Robert G, Drapier D, Verin M, Millet B, Azulay JP, &Blin O (2009) Cognitive impulsivity in Parkinson’s diseasepatients: Assessment and pathophysiology. Movement Dis-orders: Official Journal of the Movement Disorder Society,24(16), 2316-2327.
[44] Frank MJ, Samanta J, Moustafa AA, & Sherman SJ (2007)Hold your horses: Impulsivity, deep brain stimulation, andmedication in parkinsonism. Science, 318(5854), 1309-1312.
[45] Voon V, Gao J, Brezing C, Symmonds M, Ekanayake V, Fer-nandez H, Dolan RJ, & Hallett M (2011) Dopamine agonistsand risk: Impulse control disorders in Parkinson’s disease.Brain: A Journal of Neurology, 134(Pt 5), 1438-1446.
[46] Gallagher DA, O’Sullivan SS, Evans AH, Lees AJ, & SchragA (2007) Pathological gambling in Parkinson’s disease: Riskfactors and differences from dopamine dysregulation. Ananalysis of published case series. Mov Disord, 22(12), 1757-1763.
[47] Wu K, Politis M, & Piccini P (2009) Parkinson diseaseand impulse control disorders: A review of clinical fea-tures, pathophysiology and management. Postgrad Med J,85(1009), 590-596.
[48] Singh A, Kandimala G, Dewey RB Jr & O’SuilleabhainP (2007) Risk factors for pathologic gambling and othercompulsions among Parkinson’s disease patients takingdopamine agonists. J Clin Neurosci, 14(12), 1178-1181.
[49] Delaney M, Leroi I, Simpson J, & Overton PG (2012)Impulse control disorders in Parkinson’s disease: A psy-chosocial perspective. J Clin Psychol Med Settings, 19(3),338-346.
[50] Lee JY, Jeon BS, Kim HJ, & Park SS (2012) Genetic vari-ant of HTR2A associates with risk of impulse control andrepetitive behaviors in Parkinson’s disease. Parkinsonism &related disorders, 18(1), 76-78.
[51] Claassen DO, van den Wildenberg WP, Ridderinkhof KR,Jessup CK, Harrison MB, Wooten GF, & Wylie SA (2011)The risky business of dopamine agonists in Parkinson dis-ease and impulse control disorders. Behav Neurosci, 125(4),492-500.
[52] Cormier F, Muellner J, & Corvol JC (2012) Genetics ofimpulse control disorders in Parkinson’s disease. Journal ofNeural Transmission, 120(4), 665-671.
[53] Weiss HD, Hirsch ES, Williams JR, Swearengin L, & MarshL (2010) Detection of impulse control disorders in Parkinsondisease patients. The Neurologist, 16(6), 406-407.
[54] Joutsa J, Martikainen K, Vahlberg T, Voon V, & Kaasinen V(2012) Impulse control disorders and depression in Finnishpatients with Parkinson’s disease. Parkinsonism & RelatedDisorders, 18(2), 155-160.
[55] Joutsa J, Martikainen K, Vahlberg T, Kaasinen V (2012)Effects of dopamine agonist dose and gender on the prog-nosis of impulse control disorders in Parkinson’s disease.Parkinsonism & Related Disorders, 18(10), 1079-1083.
[56] Tokunaga N, Choudhury ME, Nishikawa N, Nagai M, TujiiT, Iwaki H, Kaneta M, & Nomoto M (2012) Pramipexoleupregulates dopamine receptor D(2) and D(3) expression inrat striatum. J Pharmacol Sci, 120(2), 133-137.
[57] Giovannoni G, O’Sullivan JD, Turner K, Manson AJ, &Lees AJ (2000) Hedonistic homeostatic dysregulation inpatients with Parkinson’s disease on dopamine replace-ment therapies. J Neurol Neurosurg Psychiatry, 68(4), 423-428.
[58] Gschwandtner U, Aston J, Renaud S, & Fuhr P (2001) Patho-logic gambling in patients with Parkinson’s disease. ClinNeuropharmacol, 24(3), 170-172.
[59] Driver-Dunckley E, Samanta J, & Stacy M (2003) Patholog-ical gambling associated with dopamine agonist therapy inParkinson’s disease. Neurology, 61(3), 422-423.
[60] Kurlan R (2004) Disabling repetitive behaviors in Parkin-son’s disease. Mov Disord, 19(4), 433-437.
[61] Evans AH, Katzenschlager R, Paviour D, O’Sullivan JD,Appel S, Lawrence AD, & Lees AJ (2004) Punding inParkinson’s disease: Its relation to the dopamine dysreg-ulation syndrome. Mov Disord, 19(4), 397-405.
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 133
[62] Klos KJ, Bower JH, Josephs KA, Matsumoto JY, & AhlskogJE (2005) Pathological hypersexuality predominantly linkedto adjuvant dopamine agonist therapy in Parkinson’s diseaseand multiple system atrophy. Parkinsonism Relat Disord,11(6), 381-386.
[63] Larner AJ (2006) Medical hazards of the internet: Gamblingin Parkinson’s disease. Mov Disord, 21(10), 1789.
[64] Ardouin C, Voon V, Worbe Y, Abouazar N, Czernecki V,Hosseini H, Pelissolo A, Moro E, Lhommee E, Lang AEet al. (2006): Pathological gambling in Parkinson’s diseaseimproves on chronic subthalamic nucleus stimulation. MovDisord, 21(11), 1941-1946.
[65] Grosset KA, Macphee G, Pal G, Stewart D, Watt A, Davie J,& Grosset DG (2006) Problematic gambling on dopamineagonists: Not such a rarity. Mov Disord, 21(12), 2206-2208.
[66] Drapier D, Drapier S, Sauleau P, Derkinderen P, Damier P,Allain H, Verin M, & Millet B (2006) Pathological gamblingsecondary to dopaminergic therapy in Parkinson’s disease.Psychiatry Res, 144(2-3), 241-244.
[67] Imamura A, Uitti RJ, & Wszolek ZK (2006) Dopamineagonist therapy for Parkinson disease and pathological gam-bling. Parkinsonism Relat Disord, 12(8), 506-508.
[68] Voon V, & Fox SH (2007) Medication-related impulse con-trol and repetitive behaviors in Parkinson disease. ArchNeurol, 64(8), 1089-1096.
[69] Giladi N, Weitzman N, Schreiber S, Shabtai H, & Peretz C(2007) New onset heightened interest or drive for gambling,shopping, eating or sexual activity in patients with Parkin-son’s disease: The role of dopamine agonist treatment andage at motor symptoms onset. J Psychopharmacol, 21(5),501-506.
[70] Wong SH, Cowen Z, Allen EA, & Newman PK (2007)Internet gambling and other pathological gambling inParkinson’s disease: A case series. Mov Disord, 22(4), 591-593.
[71] McKeon A, Josephs KA, Klos KJ, Hecksel K, Bower JH,Michael Bostwick J, & Eric Ahlskog J (2007) Unusualcompulsive behaviors primarily related to dopamine agonisttherapy in Parkinson’s disease and multiple system atrophy.Parkinsonism Relat Disord, 13(8), 516-519.
[72] Ondo WG, & Lai D (2008) Predictors of impulsivity andreward seeking behavior with dopamine agonists. Parkin-sonism Relat Disord, 14(1), 28-32.
[73] Crockford D, Quickfall J, Currie S, Furtado S, Suchower-sky O, & El-Guebaly N (2008) Prevalence of problem andpathological gambling in Parkinson’s disease. J Gambl Stud,24(4), 411-422.
[74] Steeves TD, Miyasaki J, Zurowski M, Lang AE, PellecchiaG, Van Eimeren T, Rusjan P, Houle S, & Strafella AP (2009)Increased striatal dopamine release in Parkinsonian patientswith pathological gambling: A [11C] raclopride PET study.Brain, 132(Pt 5), 1376-1385.
[75] Voon V, Reynolds B, Brezing C, Gallea C, Skaljic M,Ekanayake V, Fernandez H, Potenza MN, Dolan RJ, & Hal-lett M (2010) Impulsive choice and response in dopamineagonist-related impulse control behaviors. Psychopharma-cology (Berl), 207(4), 645-659.
[76] Wylie SA, Ridderinkhof KR, Elias WJ, Frysinger RC,Bashore TR, Downs KE, van Wouwe NC, & van den Wilden-berg WP (2010) Subthalamic nucleus stimulation influencesexpression and suppression of impulsive behaviour inParkinson’s disease. Brain: A Journal of Neurology, 133(Pt12), 3611-3624.
[77] Vergani F, Landi A, Pirillo D, Cilia R, Antonini A, & Sganz-erla EP (2010) Surgical, medical, and hardware adverse
events in a series of 141 patients undergoing subthalamicdeep brain stimulation for Parkinson disease. World Neuro-surg, 73(4), 338-344.
[78] Vitale C, Santangelo G, Trojano L, Verde F, Rocco M, GrossiD, & Barone P (2011) Comparative neuropsychologicalprofile of pathological gambling, hypersexuality, and com-pulsive eating in Parkinson’s disease. Movement disorders:Official journal of the Movement Disorder Society, 26(5),830-836.
[79] Evans AH, Pavese N, Lawrence AD, Tai YF, Appel S, DoderM, Brooks DJ, Lees AJ, & Piccini P (2006) Compulsive druguse linked to sensitized ventral striatal dopamine transmis-sion. Annals of Neurology, 59(5), 852-858.
[80] Voon V, Sohr M, Lang AE, Potenza MN, Siderowf AD,Whetteckey J, Weintraub D, Wunderlich GR, & Stacy M(2011) Impulse control disorders in Parkinson disease: Amulticenter case – control study. Annals of Neurology, 69(6),986-996.
[81] Giugni JC, Tschopp L, Escalante V, & Micheli F (2012)Dose-dependent impulse control disorders in piribedil over-dose. Clinical Neuropharmacology, 35(1), 49-50.
[82] Ray NJ, Miyasaki JM, Zurowski M, Ko JH, Cho SS, Pel-lecchia G, Antonelli F, Houle S, Lang AE, & StrafellaAP (2012) Extrastriatal dopaminergic abnormalities ofDA homeostasis in Parkinson’s patients with medication-induced pathological gambling: A [11C] FLB-457 and PETstudy. Neurobiol Dis, 48(3), 519-525.
[83] Limotai N, Oyama G, Go C, Bernal O, Ong T, Moum SJ,Bhidayasiri R, Foote KD, Bowers D, Ward H, et al. (2012)Addiction-like manifestations and Parkinson’s disease: Alarge single center 9-year experience. Int J Neurosci, 122(3),145-153.
[84] Avila A, Cardona X, Martin-Baranera M, Bello J, & Sastre F(2011) Impulsive and compulsive behaviors in Parkinson’sdisease: A one-year follow-up study. J Neurol Sci, 310(1–2),197-201.
[85] Auyeung M, Tsoi TH, Tang WK, Cheung CM, Lee CN,Li R, & Yeung E (2011) Impulse control disorders inChinese Parkinson’s disease patients: The effect of ergotderived dopamine agonist. Parkinsonism & Related Disor-ders, 17(8), 635-637.
[86] Leroi I, Ahearn DJ, Andrews M, McDonald KR, Byrne EJ, &Burns A (2011) Behavioural disorders, disability and qual-ity of life in Parkinson’s disease. Age Ageing, 40(5), 614-621.
[87] Biundo R, Formento-Dojot P, Facchini S, Vallelunga A,Ghezzo L, Foscolo L, Meneghello F, & Antonini A (2011)Brain volume changes in Parkinson’s disease and their rela-tionship with cognitive and behavioural abnormalities. JNeurol Sci, 310(1–2), 64-69.
[88] Spengos K, Grips E, Karachalios G, Tsivgoulis G, &Papadimitriou G (2006) Reversible pathological gamblingunder treatment with pramipexole. Nervenarzt, 77(8), 958-960.
[89] Mamikonyan E, Siderowf AD, Duda JE, Potenza MN, HornS, Stern MB, & Weintraub D (2008) Long-term follow-upof impulse control disorders in Parkinson’s disease. Move-ment disorders: Official Journal of the Movement DisorderSociety, 23(1), 75-80.
[90] Weintraub D, Siderowf AD, Potenza MN, Goveas J, MoralesKH, Duda JE, Moberg PJ, & Stern MB (2006) Associationof dopamine agonist use with impulse control disorders inParkinson disease. Archives of Neurology, 63(7), 969-973.
[91] Isaias IU, Siri C, Cilia R, De Gaspari D, Pezzoli G, &Antonini A (2008) The relationship between impulsivity
134 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
and impulse control disorders in Parkinson’s disease. Move-ment Disorders: Official Journal of the Movement DisorderSociety, 23(3), 411-415.
[92] Rao H, Mamikonyan E, Detre JA, Siderowf AD, Stern MB,Potenza MN, & Weintraub D (2010) Decreased ventral stri-atal activity with impulse control disorders in Parkinson’sdisease. Movement Disorders: Official Journal of the Move-ment Disorder Society, 25(11), 1660-1669.
[93] Sensi M, Eleopra R, Cavallo MA, Sette E, Milani P, Qua-trale R, Capone JG, Tugnoli V, Tola MR, Granieri E, etal. (2004) Explosive-aggressive behavior related to bilateralsubthalamic stimulation. Parkinsonism Relat Disord, 10(4),247-251.
[94] Cilia R, Cho SS, van Eimeren T, Marotta G, Siri C, Ko JH,Pellecchia G, Pezzoli G, Antonini A, & Strafella AP (2011)Pathological gambling in patients with Parkinson’s diseaseis associated with fronto-striatal disconnection: A path mod-eling analysis. Movement Disorders: Official Journal of theMovement Disorder Society, 26(2), 225-233.
[95] Cilia R, Ko JH, Cho SS, van Eimeren T, Marotta G, Pel-lecchia G, Pezzoli G, Antonini A, & Strafella AP (2010)Reduced dopamine transporter density in the ventral stria-tum of patients with Parkinson’s disease and pathologicalgambling. Neurobiol Dis, 39(1), 98-104.
[96] Voon V, Pessiglione M, Brezing C, Gallea C, FernandezHH, Dolan RJ, & Hallett M (2010) Mechanisms underlyingdopamine-mediated reward bias in compulsive behaviors.Neuron, 65(1), 135-142.
[97] Bentivoglio AR, Baldonero E, Ricciardi L, De Nigris F, &Daniele A (2012) Neuropsychological features of patientswith Parkinson’s disease and impulse control disorders.Neurological Sciences: Official Journal of the Italian Neu-rological Society and of the Italian Society of ClinicalNeurophysiology.
[98] Pezzella FR, Colosimo C, Vanacore N, Di Rezze S, Chi-anese M, Fabbrini G, & Meco G (2005) Prevalence andclinical features of hedonistic homeostatic dysregulation inParkinson’s disease. Mov Disord, 20(1), 77-81.
[99] Lim SY, Tan ZK, Ngam PI, Lor TL, Mohamed H, ScheeJP, Tan AK, Goh JY, Ooi E, & Soh PC (2011) Impulsive-compulsive behaviors are common in Asian Parkinson’sdisease patients: Assessment using the QUIP. Parkinsonism& Related Disorders, 17(10), 761-764.
[100] Bastiaens J, Dorfman BJ, Christos PJ, & Nirenberg MJ(2013) Prospective cohort study of impulse control disor-ders in Parkinson’s disease. Movement Disorders: OfficialJournal of the Movement Disorder Society, 28(3), 327-333.
[101] Vitale C, Santangelo G, Erro R, Errico D, Manganelli F,Improta I, Moccia M, & Barone P (2013) Impulse con-trol disorders induced by rasagiline as adjunctive therapyfor Parkinson’s disease: Report of 2 cases. Parkinsonism &Related Disorders, 19(4), 483-484.
[102] Hinnell C, Hulse N, Martin A, & Samuel M (2011)Hypersexuality and compulsive over-eating associated withtransdermal dopamine agonist therapy. Parkinsonism &Related Disorders, 17(4), 295-296.
[103] Solla P, Cannas A, Marrosu MG, & Marrosu F (2012)Dopaminergic-induced paraphilias associated with impulsecontrol and related disorders in patients with Parkinson dis-ease. Journal of Neurology, 259(12), 2752-2754.
[104] Perez-Lloret S, Rey MV, Fabre N, Ory F, Spampinato U,Brefel-Courbon C, Montastruc JL, & Rascol O (2012)Prevalence and pharmacological factors associated withimpulse-control disorder symptoms in patients with Parkin-son disease. Clinical Neuropharmacology, 35(6), 261-265.
[105] Joutsa J, Martikainen K, Niemela S, Johansson J, Fors-back S, Rinne JO, & Kaasinen V (2012) Increasedmedial orbitofrontal [18F]fluorodopa uptake in Parkin-sonian impulse control disorders. Movement Disorders:Official Journal of the Movement Disorder Society, 27(6),778-782.
[106] Weintraub D, Xie S, Karlawish J, & Siderowf A(2007) Differences in depression symptoms in patientswith Alzheimer’s and Parkinson’s diseases: Evidencefrom the 15-item Geriatric Depression Scale (GDS-15).International Journal of Geriatric Psychiatry, 22(10),1025-1030.
[107] van Eimeren T, Pellecchia G, Cilia R, Ballanger B, SteevesTD, Houle S, Miyasaki JM, Zurowski M, Lang AE, &Strafella AP (2010) Drug-induced deactivation of inhibitorynetworks predicts pathological gambling in PD. Neurology,75(19), 1711-1716.
[108] Cilia R, Siri C, Marotta G, Isaias IU, De Gaspari D, CanesiM, Pezzoli G, & Antonini A (2008) Functional abnormali-ties underlying pathological gambling in Parkinson disease.Archives of Neurology, 65(12), 1604-1611.
[109] de Chazeron I, Llorca PM, Chereau-Boudet I, Blanc O,Perriot J, Ouchchane L, Ulla M, Debilly B, Derost P, &Durif F (2011) Hypersexuality and pathological gamblingin Parkinson’s disease: A cross-sectional case-control study.Movement Disorders: Official Journal of the Movement Dis-order Society, 26(11), 2127-2130.
[110] Wu K, O’Sullivan S, Politis M, Bose S, Lees A, & PicciniP (2010) Rewarding visual cues increase dopamine neuro-transmission in Parkinspn’s patients with impulse controldisorders: A PET study. J Neurol Neurosurg Psychiatry, 81,e29-e30.
[111] O’Sullivan SS, Wu K, Politis M, Lawrence AD, EvansAH, Bose SK, Djamshidian A, Lees AJ, & Piccini P(2011) Cue-induced striatal dopamine release in Parkin-son’s disease-associated impulsive-compulsive behaviours.Brain: A Journal of Neurology, 134(Pt 4), 969-978.
[112] Frosini D, Pesaresi I, Cosottini M, Belmonte G, Rossi C,Dell’Osso L, Murri L, Bonuccelli U, & Ceravolo R (2010)Parkinson’s disease and pathological gambling: Resultsfrom a functional MRI study. Movement Disorders: OfficialJournal of the Movement Disorder Society, 25(14), 2449-2453.
[113] Djamshidian A, O’Sullivan SS, Sanotsky Y, Sharman S,Matviyenko Y, Foltynie T, Michalczuk R, Aviles-Olmos I,Fedoryshyn L, Doherty KM et al. (2012) Decision making,impulsivity, and addictions: Do Parkinson’s disease patientsjump to conclusions? Movement Disorders: Official Journalof the Movement Disorder Society, 27(9), 1137-1145.
[114] Siri C, Cilia R, De Gaspari D, Canesi M, Meucci N,Zecchinelli AL, Pezzoli G, & Antonini A (2010) Cognitivestatus of patients with Parkinson’s disease and pathologicalgambling. Journal of Neurology, 257(2), 247-252.
[115] Kimber TE, Thompson PD, & Kiley MA (2008) Resolutionof dopamine dysregulation syndrome following cessation ofdopamine agonist therapy in Parkinson’s disease. Journal ofClinical Neuroscience: Official Journal of the NeurosurgicalSociety of Australasia, 15(2), 205-208.
[116] Tschopp L, Salazar Z, Gomez Botello MT, Roca CU, &Micheli F (2010) Impulse control disorder and piribedil:Report of 5 cases. Clinical Neuropharmacology, 33(1),11-13.
[117] Wingo TS, Evatt M, Scott B, Freeman A, & Stacy M (2009)Impulse control disorders arising in 3 patients treated withrotigotine. Clinical Neuropharmacology, 32(2), 59-62.
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 135
[118] Stefani A, Galati S, Brusa L, Pierantozzi M, Peppe A, &Stanzione P (2010) Pathological gambling from dopamineagonist and deep brain stimulation of the nucleus tegmentipedunculopontine. BMJ Case Rep, 2010.
[119] Fernandez FM, & Gonzalez TM (2009) Pathological gam-bling and hypersexuality due to dopaminergic treatmentin Parkinson’s disease. Actas Esp Psiquiatr, 37(2), 118-122.
[120] Cooper CA, Jadidian A, Paggi M, Romrell J, Okun MS,Rodriguez RL, & Fernandez HH (2009) Prevalence ofhypersexual behavior in Parkinson’s disease patients: Notrestricted to males and dopamine agonist use. Int J GenMed, 2, 57-61.
[121] Bharmal A, Lu C, Quickfall J, Crockford D, & SuchowerskyO (2010) Outcomes of patients with Parkinson disease andpathological gambling. Can J Neurol Sci, 37(4), 473-477.
[122] Imamura A, Geda YE, Slowinski J, Wszolek ZK, BrownLA, & Uitti RJ (2008) Medications used to treat Parkinson’sdisease and the risk of gambling. Eur J Neurol, 15(4), 350-354.
[123] Santangelo G, Vitale C, Trojano L, Verde F, Grossi D, &Barone P (2009) Cognitive dysfunctions and pathologicalgambling in patients with Parkinson’s disease. MovementDisorders: Official Journal of the Movement Disorder Soci-ety, 24(6), 899-905.
[124] Kolla BP, Mansukhani MP, Barraza R, & Bostwick JM(2010) Impact of dopamine agonists on compulsive behav-iors: A case series of pramipexole-induced pathologicalgambling. Psychosomatics, 51(3), 271-273.
[125] Kenangil G, Ozekmekci S, Sohtaoglu M, & Erginoz E(2010) Compulsive behaviors in patients with Parkinson’sdisease. The neurologist, 16(3), 192-195.
[126] Bonfanti AB, & Gatto EM (2010) Kleptomania, an unusualimpulsive control disorder in Parkinson’s disease? Parkin-sonism & Related Disorders, 16(5), 358-359.
[127] Wicks P, & MacPhee GJ (2009) Pathological gamblingamongst Parkinson’s disease and ALS patients in an onlinecommunity (PatientsLikeMe.com). Movement Disorders:Official Journal of the Movement Disorder Society, 24(7),1085-1088.
[128] Fan W, Ding H, Ma J, & Chan P (2009) Impulse controldisorders in Parkinson’s disease in a Chinese population.Neurosci Lett, 465(1), 6-9.
[129] Lee JY, Kim JM, Kim JW, Cho J, Lee WY, Kim HJ, & JeonBS (2010) Association between the dose of dopaminergicmedication and the behavioral disturbances in Parkinsondisease. Parkinsonism & Related Disorders, 16(3), 202-207.
[130] Hassan A, Bower JH, Kumar N, Matsumoto JY, FealeyRD, Josephs KA, & Ahlskog JE (2011) Dopamine agonist-triggered pathological behaviors: Surveillance in the PDclinic reveals high frequencies. Parkinsonism & RelatedDisorders, 17(4), 260-264.
[131] Weintraub D, Sohr M, Potenza MN, Siderowf AD, StacyM, Voon V, Whetteckey J, Wunderlich GR, & Lang AE(2010) Amantadine use associated with impulse control dis-orders in Parkinson disease in cross-sectional study. Annalsof Neurology, 68(6), 963-968.
[132] Serrano-Duenas M (2002) Chronic dopaminetic drug addic-tion and pathological gambling in patients with Parkinson’sdisease – presentation of four cases. German J Psychiatry,5, 62-66.
[133] Cilia R, & van Eimeren T (2011) Impulse control disordersin Parkinson’s disease: Seeking a roadmap toward a betterunderstanding. Brain Struct Funct, 216(4), 289-299.
[134] Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, & ClarkeCE (2010) Systematic review of levodopa dose equivalencyreporting in Parkinson’s disease. Movement Disorders: Offi-cial Journal of the Movement Disorder Society, 25(15),2649-2653.
[135] Mallet L, Schupbach M, N’Diaye K, Remy P, Bardinet E,Czernecki V, Welter ML, Pelissolo A, Ruberg M, Agid Y, etal. (2007) Stimulation of subterritories of the subthalamicnucleus reveals its role in the integration of the emotionaland motor aspects of behavior. Proc Natl Acad Sci U S A,104(25), 10661-10666.
[136] Rogers RD, Wielenberg B, Wojtecki L, Elben S, Campbell-Meiklejohn D, & Schnitzler A (2011) Deep brain stimulationof the subthalamic nucleus transiently enhances loss-chasing behaviour in patients with Parkinson’s disease. ExpNeurol, 231(1), 181-189.
[137] Funkiewiez A, Ardouin C, Caputo E, Krack P, Fraix V,Klinger H, Chabardes S, Foote K, Benabid AL, & PollakP (2004) Long term effects of bilateral subthalamic nucleusstimulation on cognitive function, mood, and behaviour inParkinson’s disease. Journal of Neurology, Neurosurgery,and Psychiatry, 75(6), 834-839.
[138] Volkmann J, Daniels C, & Witt K (2010) Neuropsychiatriceffects of subthalamic neurostimulation in Parkinson dis-ease. Nat Rev Neurol, 6(9), 487-498.
[139] Adam R, Leff A, Sinha N, Turner C, Bays P, Draganski B,& Husain M (2012) Dopamine reverses reward insensitivityin apathy following globus pallidus lesions. Cortex, 49(5),1292-1303.
[140] Leroi I, Andrews M, McDonald K, Harbishettar V, ElliottR, Byrne EJ, & Burns A (2012) Apathy and impulse con-trol disorders in Parkinson’s disease: A direct comparison.Parkinsonism & Related Disorders, 18(2), 198-203.
[141] Ahearn DJ, McDonald K, Barraclough M, & Leroi I (2012)An exploration of apathy and impulsivity in Parkinson dis-ease. Curr Gerontol Geriatr Res, 2012, 390701.
[142] Jenkinson N, Nandi D, Muthusamy K, Ray NJ, GregoryR, Stein JF, & Aziz TZ (2009) Anatomy, physiology, andpathophysiology of the pedunculopontine nucleus. Move-ment Disorders: Official Journal of the Movement DisorderSociety, 24(3), 319-328.
[143] Androulidakis AG, Mazzone P, Litvak V, Penny W, DileoneM, Gaynor LM, Tisch S, Di Lazzaro V, & Brown P (2008)Oscillatory activity in the pedunculopontine area of patientswith Parkinson’s disease. Exp Neurol, 211(1), 59-66.
[144] Thevathasan W, Silburn PA, Brooker H, Coyne TJ, KhanS, Gill SS, Aziz TZ, & Brown P (2010) The impact oflow-frequency stimulation of the pedunculopontine nucleusregion on reaction time in parkinsonism. Journal of Neurol-ogy, Neurosurgery, and Psychiatry, 81(10), 1099-1104.
[145] Okada K, Toyama K, Inoue Y, Isa T, & Kobayashi Y (2009)Different pedunculopontine tegmental neurons signal pre-dicted and actual task rewards. The Journal of Neuroscience:The Official Journal of the Society for Neuroscience, 29(15),4858-4870.
[146] Kobayashi Y, & Okada K (2007) Reward prediction errorcomputation in the pedunculopontine tegmental nucleusneurons. Ann N Y Acad Sci, 1104, 310-323.
[147] Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Chil-dress AR, Jayne M, Ma Y, & Wong C (2006) Cocaine cuesand dopamine in dorsal striatum: Mechanism of craving incocaine addiction. The Journal of neuroscience: The OfficialJournal of the Society for Neuroscience, 26(24), 6583-6588.
[148] Cools R, Lewis SJ, Clark L, Barker RA, & Robbins TW(2007) L-DOPA disrupts activity in the nucleus accumbens
136 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
during reversal learning in Parkinson’s disease. Neuropsy-chopharmacology: Official Publication of the AmericanCollege of Neuropsychopharmacology, 32(1), 180-189.
[149] Voon V, & Dalley JW (2011) Parkinson disease: Impul-sive choice-Parkinson disease and dopaminergic therapy.Nat Rev Neurol, 7(10), 541-542.
[150] Graef S, Biele G, Krugel LK, Marzinzik F, Wahl M, WotkaJ, Klostermann F, & Heekeren HR (2010) Differential influ-ence of levodopa on reward-based learning in Parkinson’sdisease. Front Hum Neurosci, 4, 169.
[151] Linnet J, Moller A, Peterson E, Gjedde A, & Doudet D(2011) Dopamine release in ventral striatum during IowaGambling Task performance is associated with increasedexcitement levels in pathological gambling. Addiction,106(2), 383-390.
[152] Linnet J, Peterson E, Doudet DJ, Gjedde A, & Moller A(2010) Dopamine release in ventral striatum of pathologicalgamblers losing money. Acta Psychiatr Scand, 122(4), 326-333.
[153] Peterson E, Moller A, Doudet DJ, Bailey CJ, HansenKV, Rodell A, Linnet J, & Gjedde A (2010) Patho-logical gambling: Relation of skin conductance responseto dopaminergic neurotransmission and sensation-seeking.Eur Neuropsychopharmacol, 20(11), 766-775.
[154] de Ruiter MB, Veltman DJ, Goudriaan AE, Oosterlaan J,Sjoerds Z, & van den Brink W (2009) Response perse-veration and ventral prefrontal sensitivity to reward andpunishment in male problem gamblers and smokers. Neuro-psychopharmacology: Official Publication of the AmericanCollege of Neuropsychopharmacology, 34(4), 1027-1038.
[155] Reuter J, Raedler T, Rose M, Hand I, Glascher J, & BuchelC (2005) Pathological gambling is linked to reduced activa-tion of the mesolimbic reward system. Nature Neuroscience,8(2), 147-148.
[156] Nader MA, Morgan D, Gage HD, Nader SH, Calhoun TL,Buchheimer N, Ehrenkaufer R, & Mach RH (2006) PETimaging of dopamine D2 receptors during chronic cocaineself-administration in monkeys. Nature Neuroscience, 9(8),1050-1056.
[157] Volkow ND, Fowler JS, & Wang GJ (2002) Role ofdopamine in drug reinforcement and addiction in humans:Results from imaging studies. Behav Pharmacol, 13(5-6),355-366.
[158] Dalley JW, Fryer TD, Brichard L, Robinson ES, TheobaldDE, Laane K, Pena Y, Murphy ER, Shah Y, Probst K, etal. (2007) Nucleus accumbens D2/3 receptors predict traitimpulsivity and cocaine reinforcement. Science, 315(5816),1267-1270.
[159] Volkow ND, Wang GJ, Telang F, Fowler JS, Thanos PK,Logan J, Alexoff D, Ding YS, Wong C, Ma Y, et al. (2008)Low dopamine striatal D2 receptors are associated with pre-frontal metabolism in obese subjects: Possible contributingfactors. Neuroimage, 42(4), 1537-1543.
[160] Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT,Zhu W, Netusil N, & Fowler JS (2001) Brain dopamine andobesity. Lancet, 357(9253), 354-357.
[161] Volkow ND, Fowler JS, Wang GJ, & Goldstein RZ (2002)Role of dopamine, the frontal cortex and memory circuitsin drug addiction: Insight from imaging studies. NeurobiolLearn Mem, 78(3), 610-624.
[162] Joutsa J, Johansson J, Niemela S, Ollikainen A, HirvonenMM, Piepponen P, Arponen E, Alho H, Voon V, Rinne JO, etal. (2012) Mesolimbic dopamine release is linked to symp-tom severity in pathological gambling. Neuroimage, 60(4),1992-1999.
[163] Kringelbach ML, & Berridge KC (2010) The functional neu-roanatomy of pleasure and happiness. Discov Med, 9(49),579-587.
[164] Berridge KC (2007) The debate over dopamine’s role inreward: The case for incentive salience. Psychopharmacol-ogy (Berl), 191(3), 391-431.
[165] Everitt BJ, & Robbins TW (2005) Neural systems of rein-forcement for drug addiction: From actions to habits tocompulsion. Nature Neuroscience, 8(11), 1481-1489.
[166] Haber SN, & Knutson B (2010) The reward circuit: Linkingprimate anatomy and human imaging. Neuropsychophar-macology: Official Publication of the American College ofNeuropsychopharmacology, 35(1), 4-26.
[167] Voon V, Mehta AR, & Hallett M (2011) Impulse controldisorders in Parkinson’s disease: Recent advances. CurrentOpinion in Neurology, 24(4), 324-330.
[168] Di Matteo V, Pierucci M, Esposito E, Crescimanno G,Benigno A, & Di Giovanni G (2008) Serotonin modulationof the basal ganglia circuitry: Therapeutic implication forParkinson’s disease and other motor disorders. Prog BrainRes, 172, 423-463.
[169] Cools R (2008) Role of dopamine in the motivational andcognitive control of behavior. Neuroscientist, 14(4), 381-395.
[170] Cools R, Nakamura K, & Daw ND (2011) Serotonin anddopamine: Unifying affective, activational, and decisionfunctions. Neuropsychopharmacology: Official Publicationof the American College of Neuropsychopharmacology,36(1), 98-113.
[171] Rogers RD (2011) The roles of dopamine and serotoninin decision making: Evidence from pharmacological exper-iments in humans. Neuropsychopharmacology: OfficialPublication of the American College of Neuropsychophar-macology, 36(1), 114-132.
[172] Robinson ES, Dalley JW, Theobald DE, Glennon JC, PezzeMA, Murphy ER, & Robbins TW (2008) Opposing roles for5-HT2A and 5-HT2C receptors in the nucleus accumbenson inhibitory response control in the 5-choice serial reactiontime task. Neuropsychopharmacology, 33(10), 2398-2406.
[173] Homberg JR (2012) Serotonin and decision making pro-cesses. Neuroscience and Biobehavioral Reviews, 36(1),218-236.
[174] Kirby LG, Zeeb FD, & Winstanley CA (2011) Contributionsof serotonin in addiction vulnerability. Neuropharmacology,61(3), 421-432.
[175] Macoveanu J, Rowe JB, Hornboll B, Elliott R, Paulson OB,Knudsen GM, & Siebner HR (2012) Playing it safe but los-ing anyway-Serotonergic signaling of negative outcomes indorsomedial prefrontal cortex in the context of risk-aversion.Eur Neuropsychopharmacol, in press.
[176] Miyazaki K, Miyazaki KW, & Doya K (2012) The role ofserotonin in the regulation of patience and impulsivity. MolNeurobiol, 45(2), 213-224.
[177] Campbell-Meiklejohn D, Wakeley J, Herbert V, CookJ, Scollo P, Ray MK, Selvaraj S, Passingham RE,Cowen P, & Rogers RD (2011) Serotonin and dopamineplay complementary roles in gambling to recover losses.Neuropsychopharmacology: Official Publication of theAmerican College of Neuropsychopharmacology, 36(2),402-410.
[178] Long AB, Kuhn CM, & Platt ML (2009) Serotonin shapesrisky decision making in monkeys. Soc Cogn Affect Neu-rosci, 4(4), 346-356.
[179] Chung SK, You IH, Cho GH, Chung GH, Shin YC, KimDJ, & Choi SW (2009) Changes of functional MRI findings
M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 137
in a patient whose pathological gambling improved withfluvoxamine. Yonsei Med J, 50(3), 441-444.
[180] Raja M, & Bentivoglio AR (2012) Impulsive and compul-sive behaviors during dopamine replacement treatment inParkinson’s Disease and other disorders. Curr Drug Saf,7(1), 63-75.
[181] Kringelbach ML, & Rolls ET (2003) Neural correlates ofrapid reversal learning in a simple model of human socialinteraction. Neuroimage, 20(2), 1371-1383.
[182] Clark L, Cools R, & Robbins TW (2004) The neuropsy-chology of ventral prefrontal cortex: Decision-making andreversal learning. Brain and Cognition, 55(1), 41-53.
[183] Levin BE, Tomer R, & Rey GJ (1992) Cognitive impair-ments in Parkinson’s disease. Neurol Clin, 10(2), 471-485.
[184] Brown RG, & Marsden CD (1990) Cognitive function inParkinson’s disease: From description to theory. Trends Neu-rosci, 13(1), 21-29.
[185] Poletti M, Cavedini P, & Bonuccelli U (2011) Iowa gamblingtask in Parkinson’s disease. J Clin Exp Neuropsychol, 33(4),395-409.
[186] Poletti M, & Bonuccelli U (2012) Orbital and ventrome-dial prefrontal cortex functioning in Parkinson’s disease:Neuropsychological evidence. Brain and Cognition, 79(1),23-33.
[187] Carter CS, & van Veen V (2007) Anterior cingulate cortexand conflict detection: An update of theory and data. CognAffect Behav Neurosci, 7(4), 367-379.
[188] Konishi S, Nakajima K, Uchida I, Kameyama M, NakaharaK, Sekihara K, & Miyashita Y (1998) Transient activationof inferior prefrontal cortex during cognitive set shifting.Nature Neuroscience, 1(1), 80-84.
[189] Monchi O, Petrides M, Petre V, Worsley K, & Dagher A(2001) Wisconsin Card Sorting revisited: Distinct neural cir-cuits participating in different stages of the task identified byevent-related functional magnetic resonance imaging. TheJournal of neuroscience: The official journal of the Societyfor Neuroscience, 21(19), 7733-7741.
[190] Frank MJ, Loughry B, & O’Reilly RC (2001) Interactionsbetween frontal cortex and basal ganglia in working mem-ory: A computational model. Cogn Affect Behav Neurosci,1(2), 137-160.
[191] Raskin SA, Borod JC, & Tweedy J (1990) Neuropsycholog-ical aspects of Parkinson’s disease. Neuropsychol Rev, 1(3),185-221.
[192] Pillon B, Deweer B, Vidailhet M, Bonnet AM, Hahn-BarmaV, & Dubois B (1998) Is impaired memory for spatial loca-tion in Parkinson’s disease domain specific or dependent on‘strategic’ processes? Neuropsychologia, 36(1), 1-9.
[193] Stocchi F, & Brusa L (2000) Cognition and emotion in dif-ferent stages and subtypes of Parkinson’s disease. Journalof Neurology, 247(Suppl 2), II114-II121.
[194] Pagonabarraga J, Garcia-Sanchez C, Llebaria G, Pascual-Sedano B, Gironell A, & Kulisevsky J (2007) Controlledstudy of decision-making and cognitive impairment inParkinson’s disease. Mov Disord, 22(10), 1430-1435.
[195] Flensborg Damholdt M, Shevlin M, Borghammer P, LarsenL, & Ostergaard K (2012) Clinical heterogeneity in Parkin-son’s disease revisited: A latent profile analysis. ActaNeurologica Scandinavica, 125(5), 311-318.
[196] Gescheidt T, Czekoova K, Urbanek T, Marecek R, MiklM, Kubikova R, Telecka S, Andrlova H, Husarova I, &Bares M (2012), Gambling Task in patients with early-onset Parkinson’s disease: Strategy analysis. Neurologicalsciences: Official journal of the Italian Neurological Soci-
ety and of the Italian Society of Clinical Neurophysiology,33(6), 1329-1335.
[197] Swainson R, Rogers RD, Sahakian BJ, Summers BA, PolkeyCE, & Robbins TW (2000) Probabilistic learning and rever-sal deficits in patients with Parkinson’s disease or frontal ortemporal lobe lesions: Possible adverse effects of dopamin-ergic medication. Neuropsychologia, 38(5), 596-612.
[198] Cools R, Altamirano L, & D’Esposito M (2006) Reversallearning in Parkinson’s disease depends on medication statusand outcome valence. Neuropsychologia, 44(10), 1663-1673.
[199] Cools R, Barker RA, Sahakian BJ, & Robbins TW (2001)Enhanced or impaired cognitive function in Parkinson’s dis-ease as a function of dopaminergic medication and taskdemands. Cereb Cortex, 11(12), 1136-1143.
[200] Humphries MD, Khamassi M, & Gurney K (2012)Dopaminergic Control of the Exploration-ExploitationTrade-Off via the Basal Ganglia. Front Neurosci, 6, 9.
[201] Euteneuer F, Schaefer F, Stuermer R, Boucsein W, Tim-mermann L, Barbe MT, Ebersbach G, Otto J, Kessler J,& Kalbe E (2009) Dissociation of decision-making underambiguity and decision-making under risk in patients withParkinson’s disease: A neuropsychological and psychophys-iological study. Neuropsychologia, 47(13), 2882-2890.
[202] Bechara A, Damasio AR, Damasio H, & Anderson SW(1994) Insensitivity to future consequences following dam-age to human prefrontal cortex. Cognition, 50(1–3), 7-15.
[203] Bechara A, Damasio H, Damasio AR, & Lee GP (1999)Different contributions of the human amygdala and ventro-medial prefrontal cortex to decision-making. The Journalof Neuroscience: The Official Journal of the Society forNeuroscience, 19(13), 5473-5481.
[204] Mimura M, Oeda R, & Kawamura M (2006) Impaireddecision-making in Parkinson’s disease. Parkinsonism &Related Disorders, 12(3), 169-175.
[205] Ibarretxe-Bilbao N, Junque C, Tolosa E, Marti MJ, Vallde-oriola F, Bargallo N, & Zarei M (2009) Neuroanatomicalcorrelates of impaired decision-making and facial emotionrecognition in early Parkinson’s disease. Eur J Neurosci,30(6), 1162-1171.
[206] Kobayakawa M, Koyama S, Mimura M, & Kawamura M(2008) Decision making in Parkinson’s disease: Analysis ofbehavioral and physiological patterns in the Iowa gamblingtask. Movement Disorders: Official Journal of the MovementDisorder Society, 23(4), 547-552.
[207] Perretta JG, Pari G, & Beninger RJ (2005) Effects of Parkin-son disease on two putative nondeclarative learning tasks:Probabilistic classification and gambling. Cogn Behav Neu-rol, 18(4), 185-192.
[208] Rossi M, Gerschcovich ER, de Achaval D, Perez-LloretS, Cerquetti D, Cammarota A, Ines Nouzeilles M, FahrerR, Merello M, & Leiguarda R (2010) Decision-making inParkinson’s disease patients with and without pathologicalgambling. Eur J Neurol, 17(1), 97-102.
[209] Phillips LD, & Edwards W (1966) Conservatism in a simpleprobability inference task. J Exp Psychol, 72(3), 346-354.
[210] Cools R, Barker RA, Sahakian BJ, & Robbins TW (2003)L-Dopa medication remediates cognitive inflexibility, butincreases impulsivity in patients with Parkinson’s disease.Neuropsychologia, 41(11), 1431-1441.
[211] Torta DM, Castelli L, Zibetti M, Lopiano L, & GeminianiG (2009) On the role of dopamine replacement therapy indecision-making, working memory, and reward in Parkin-son’s disease: Does the therapy-dose matter? Brain andcognition, 71(2), 84-91.
138 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism
[212] Lejuez CW, Read JP, Kahler CW, Richards JB, Ramsey SE,Stuart GL, Strong DR, & Brown RA (2002) Evaluation ofa behavioral measure of risk taking: The Balloon AnalogueRisk Task (BART). J Exp Psychol Appl, 8(2), 75-84.
[213] Fukunaga R, Brown JW, & Bogg T (2012) Decision makingin the Balloon Analogue Risk Task (BART): Anterior cin-gulate cortex signals loss aversion but not the infrequency ofrisky choices. Cogn Affect Behav Neurosci, 12(3), 479-490.
[214] Housden CR, O’Sullivan SS, Joyce EM, Lees AJ,& Roiser JP (2010) Intact reward learning but ele-vated delay discounting in Parkinson’s disease patientswith impulsive-compulsive spectrum behaviors. Neuropsy-chopharmacology: Official Publication of the AmericanCollege of Neuropsychopharmacology, 35(11), 2155-2164.
[215] Rømer Thomsen K, Joensson M, Lou HC, Møller A, Gross J,Kringelbach ML, & Changeux JP (2013) Altered paralimbicinteraction in behavioral addiction. PNAS, 110(12), 4744-4749.
[216] Macphee GJ, & Carson A (2013) Impulse control disordersin Parkinson disease: Is cognitive-behavioral therapy wortha wager? Neurology.
[217] Okai D, Askey-Jones S, Samuel M, O’Sullivan SS, Chaud-huri KR, Martin A, Mack J, Brown RG, & David AS (2013)Trial of CBT for impulse control behaviors affecting Parkin-son patients and their caregivers. Neurology, 80(9), 792-799.
[218] Leroi I, Harbishettar V, Andrews M, McDonald K, Byrne EJ,& Burns A (2012) Carer burden in apathy and impulse con-trol disorders in Parkinson’s disease. International Journalof Geriatric Psychiatry, 27(2), 160-166.
[219] Rabinak CA, & Nirenberg MJ (2010) Dopamine agonistwithdrawal syndrome in Parkinson disease. Archives of Neu-rology, 67(1), 58-63.
[220] Bermejo PE, Ruiz-Huete C, & Anciones B (2010)Zonisamide in managing impulse control disorders inParkinson’s disease. Journal of Neurology, 257(10), 1682-1685.
[221] Ivanco LS, & Bohnen NI (2005) Effects of donepezil oncompulsive hypersexual behavior in Parkinson disease: Asingle case study. Am J Ther, 12(5), 467-468.
[222] Jankovic J, & Poewe W (2012) Therapies in Parkinson’sdisease. Current Opinion in Neurology, 25(4), 433-447.
[223] Hicks CW, Pandya MM, Itin I, & Fernandez HH (2011)Valproate for the treatment of medication-induced impulse-control disorders in three patients with Parkinson’s disease.Parkinsonism & Related Disorders, 17(5), 379-381.
[224] Baarendse PJ, & Vanderschuren LJ (2012) Dissociableeffects of monoamine reuptake inhibitors on distinct formsof impulsive behavior in rats. Psychopharmacology (Berl),219(2), 313-326.
[225] Grant JE, Odlavg BL, Potenza MN, Hollander E, & WonKim S (2010) Nalmafene in the treatment of pathologi-cal gambling: Multicentre, double-blind, placebo-controlledstudy. BJPsych, 197, 330-331.
[226] Muller T (2012) Drug therapy in patients with Parkinson’sdisease. Transl Neurodegener, 1(1), 10.
[227] Connolly BS, & Fox SH (2012) Drug treatments for the neu-ropsychiatric complications of Parkinson’s disease. ExpertRev Neurother, 12(12), 1439-1449.