Cocaine dependence and pa hological gambling ( elabelled
gambling diso de
1
) ha e ecen ly been join ly classi ied as
addic i e diso de s, based on e idence o o e lap in e ms o
clinical p esen a ion, neu obiological p o ile and gene ic liabili y.
1
In ea men -seeking samples, bo h diso de s a e cha ac e ised by
pe sis en engagemen wi h he ha m ul beha iou despi e i s
ad e se consequences in in e pe sonal and occupa ional domains.
This pe sis ence e lec s cogni i e in lexibili y in upda ing and
in eg a ing he alues o po en ial ac ions wi h e e ence o
p e ious and expec ed ou comes.
2
In addi ion o i s ele ance o
heo ies o addic ion, cogni i e in lexibili y is also clinically
ele an because pe se e a i e esponding is a signi ican p edic o
o poo e addic ion ea men ou comes.
3
Pe sis en esponding in
he ace o nega i e eedback can be modelled expe imen ally
using he e e sal lea ning pa adigm, a disc imina ion ask in
which pa icipan s lea n o espond o a ein o ced s imulus,
bu mus hen lea n o espond o ano he , p e iously i ele an ,
s imulus.
4
Two complemen a y aspec s o e e sal lea ning a e
ele an o addic i e beha iou s: he s ong mo i a ional endency
o espond o p e iously ein o ced s imuli and a di icul y
in lexibly shi ing owa ds no el ein o cing s imuli, which a e
collec i ely indica ed by ‘pe se e a ion’.
5
Beha iou al s udies indica e ha bo h cocaine use s and
pa hological gamble s exhibi e e sal lea ning pe se e a ion
compa ed wi h con ols.
6
In cocaine use s, pe se e a ion is mainly
obse ed ollowing changes in esponse–ou come con ingencies
(i.e. in e e sal lea ning asks in ol ing p obabilis ic wins and
losses).
7,8
By con as , lexible esponding is ela i ely p ese ed
in non- ewa ded s imulus-disc imina ion asks in ol ing ixed
schedules.
9
In pa hological gamble s, he e is educed lexibili y
a e e e sal o p e iously ewa ded con ingencies.
10
Re e sal
lea ning is unde pinned by neu al ci cui y comp ising
do somedial, do sola e al and en ola e al p e on al co ex
(dmPFC, dlPFC and lPFC espec i ely) and hei connec ions
wi h he s ia um and amygdala.
11
Acco dingly, e e sal lea ning
pe se e a ion has been associa ed wi h abno mal dmPFC and
dlPFC unc ion in cocaine use s
12,13
and dec eased ac i a ion o
igh lPFC in pa hological gamble s.
14
Mo eo e , he e is
e idence ha e e sal lea ning is gene ically media ed by
dopamine D2 exp ession, as heal hy olun ee s ca ying he
DRD2/ANKK1 Taq1A A1 allele (linked o dec eased D2 ecep o
a ailabili y) exhibi poo e beha iou al pe o mance, and blun ed
lPFC ac i a ion du ing shi ing.
15
The A1 allele has also been
associa ed wi h cocaine and gambling addic ions.
16
Accep ing he subs an ial neu obiological o e lap be ween
hese diso de s, cocaine addic ion ne e heless in ol es signi ican
d ug-induced, ac i e, de imen al e ec s on he dopamine gic
sys em.
17–19
P eclinical s udies ha e demons a ed ha p olonged
cocaine adminis a ion induces signi ican e e sal lea ning
de ici s,
20
and ha hese changes a e media ed by D2-dopamine
ansmission.
21
In humans, compa able e ec s a e indica ed by
co ela ions agains cocaine ch onici y in neu opsychological
s udies
22,23
bu he e is no e idence ega ding he speci ici y o
hese de ici s wi h espec o he beha iou al addic ions. We
easoned ha cocaine-induced neu oadap i e changes should be
absen in pa hological gamble s.
24
As such, pa hological gambling
can se e as a con ol g oup o disambigua e he ac i e
de imen al e ec s o cocaine dependence on e e sal lea ning
while accoun ing o sha ed ulne abili y and ein o cemen
his o y.
25,26
The p ima y aim o his s udy was o con as b ain
ac i a ion pa e ns associa ed wi h cogni i e shi ing and esponse
pe se e a ion in indi iduals diagnosed wi h cocaine dependence .
158
Neu al subs a es o cogni i e lexibili y
in cocaine and gambling addic ions
An onio Ve dejo-Ga cia, Luke Cla k, Juan Ve dejo-Roma
´n, Na alia Albein-U ios,
Jose
´M. Ma inez-Gonzalez, Blanca Gu ie ez and Ca les So iano-Mas
Backg ound
Indi iduals wi h cocaine and gambling addic ions exhibi
cogni i e lexibili y de ici s ha may unde lie pe sis ence o
ha m ul beha iou s.
Aims
We in es iga ed he neu al subs a es o cogni i e in lexibili y
in cocaine use s . pa hological gamble s, aiming o
disambigua e common mechanisms . cocaine e ec s.
Me hod
Eigh een cocaine use s, 18 pa hological gamble s and 18
con ols pe o med a p obabilis ic e e sal lea ning ask
du ing unc ional magne ic esonance imaging, and we e
geno yped o he DRD2/ANKK Taq1A polymo phism.
Resul s
Cocaine use s and pa hological gamble s exhibi ed educed
en ola e al p e on al co ex (PFC) signal du ing e e sal
shi ing. Cocaine use s u he showed inc eased
do somedial PFC (dmPFC) ac i a ion ela i e o pa hological
gamble s du ing pe se e a ion, and dec eased do sola e al
PFC ac i a ion ela i e o pa hological gamble s and con ols
du ing shi ing. P elimina y gene ic indings indica ed ha
cocaine use s ca ying he DRD2/ANKK Taq1A1+ geno ype
may de i e unique s imula o y e ec s on shi ing- ela ed
en ola e al PFC signal.
Conclusions
Reduced en ola e al PFC ac i a ion du ing shi ing may
cons i u e a common neu al ma ke ac oss gambling and
cocaine addic ions. Addi ional cocaine- ela ed e ec s ela e
o a wide pa e n o ask- ela ed dys egula ion, e lec ed in
signal abno mali ies in do sola e al and dmPFC.
Decla a ion o in e es
L.C.: The Cen e o Gambling Resea ch a UBC is unded by
suppo om he P o ince o B i ish Columbia and he B i ish
Columbia Lo e y Co po a ion. The o he au ho s decla e no
con lic s o in e es conce ning his s udy.
Copy igh and usage
BThe Royal College o Psychia is s 2015.
The B i ish Jou nal o Psychia y (2015)
207, 158–164. doi: 10.1192/bjp.bp.114.152223
h ps://doi.o g/10.1192/bjp.bp.114.152223 Published online by Camb idge Uni e si y P ess
pa hological gambling. We hypo hesised ha cocaine dependence,
compa ed o a beha iou al addic ion, would be associa ed wi h
dis inc i e al e a ions in p e on al egions ec ui ed by e e sal
lea ning. As a seconda y explo a o y aim, we sough o examine
whe he his b ain dys egula ion was dopamine gically linked,
by s udying associa ions wi h he DRD2/ANKK1 Taq1A gene ic
a ian .
Me hod
Pa icipan s
The sample consis ed o 54 pa icipan s: 18 indi iduals mee ing
DSM-IV-TR c i e ia o cocaine dependence (cocaine use s) no
mee ing c i e ia o any o he Axis I o Axis II diso de , 18
indi iduals mee ing DSM-IV-TR c i e ia o pa hological
gambling (gamble s) no mee ing c i e ia o any o he Axis I o
Axis II diso de , and 18 heal hy compa ison indi iduals who did
no mee DSM-IV-TR c i e ia o Axis I o Axis II diso de s
(con ols). Table 1 p esen s sociodemog aphic in o ma ion. The
h ee g oups did no di e signi ican ly in age, yea s o educa ion,
o IQ measu ed by he Kau man B ie In elligence Tes .
27
Table 1
also p esen s d ug/gambling use cha ac e is ics (mon hly amoun
and du a ion o use) as eco ded by he In e iew o Resea ch on
Addic i e Beha io s
28
and psychological symp oms as measu ed
by he Gene al Heal h Ques ionnai e.
29
Pa icipan s had e y
limi ed exposu e o d ugs o he han cocaine, alcohol o obacco;
less han 20% o pa icipan s had used cannabis, app oxima ely
5% had used MDMA o hallucinogens, and no pa icipan s had
used amphe amines o opia es. Table 1 also displays da a on
sel - epo ed abs inence du a ion. In cocaine use s he mean
du a ion o abs inence was 2.7 mon hs and in gamble s he mean
du a ion o abs inence was 5.7 mon hs. In addi ion, abs inence was
moni o ed o 3 weeks du ing he s udy, measu ed wi h u ine es s
o alcohol and d ug use and c oss-checked sel - and colla e al
epo s o gambling. Table 1 also displays DRD2/ANKK Taq1A
geno ype dis ibu ions. In ag eemen wi h popula ion-based
da a,
30,31
he A1+ geno ype was ound in be ween 30 and 40%
o pa icipan s wi hin each g oup. Sociodemog aphic, d ug/gam-
bling use and psychological cha ac e is ics by geno ype subg oups
a e p esen ed in online Table DS1.
Online Fig. DS1 displays a lowcha o he ec ui men
p ocess. Cocaine use s we e ec ui ed as hey commenced
ea men in he ou pa ien clinic Cen o P o incial de
D ogodependencias in G anada (Spain). Gamble s we e ec ui ed
as hey commenced ea men in he ou pa ien clinic Asociacio
´n
G anadina de Jugado es en Rehabili acio
´n in G anada (Spain).
Bo h clinics p o ide psychological he apies o addic i e
diso de s. The inclusion c i e ia we e as ollows: (a) aged be ween
18 and 45 yea s; (b) es ima ed IQ le els abo e 80; (c) mee ing
DSM-IV-TR c i e ia o cocaine dependence o pa hological
gambling – as assessed by he S uc u ed Clinical In e iew o
159
Neu al subs a es o cogni i e lexibili y
Table 1 Demog aphic and clinical cha ac e is ics o he h ee s udy g oups
Demog aphic a iables
Con ols n=18
Mean (s.d.)
Gamble s n=18
Mean (s.d.)
Cocaine use s n=18
Mean (s.d.) P
Age (yea s) 31.17 (4.74) 33.56 (7.97) 34.27 (6.87) 0.349
Gende (male/ emale) 17/1 16/2 17/1 0.774
La e ali y ( igh -le ) 17/1 17/1 14/4 0.193
Yea s o educa ion 10.56 (1.92) 10.28 (2.11) 9.78 (1.66) 0.468
Ve bal IQ 106.89 (8.98) 102.67 (7.39) 100.94 (7.58) 0.082
DRD2/ANKK Taq1A1+geno ype
A1+ 675
A1– 121013
Clinical a iables
Cocaine (0 HC/ 0 PG/ 18 CDI)
Age a onse cocaine use (yea s) 21.28 (5.83)
Mon hly amoun cocaine use s (g) 16.86 (25.49)
Du a ion cocaine (mon hs) 43.75 (36.32)
Abs inence cocaine (mon hs) 2.73 (5.43)
Gambling (0 HC/ 18 PG/ 0 CDI)
Age a onse gambling (yea s) 22.17 (8.71)
Mon hly amoun gambling (h) 42.53 (41.47)
Du a ion gambling (mon hs) 26.12 (24.56)
Abs inence gambling (mon hs) 7.69 (6.51)
Tobacco (8 HC/ 8 PG/ 14 CDI)
Age a onse obacco use (yea s) 17.75 (5.55) 15.50 (3.51) 15.71 (2.58) 0.411
Mon hly obacco use (cig) 286.25 (222.90) 667.50 (278.55) 564.29 (362.21) 0.051
Du a ion obacco (mon hs) 76.37 (104.25) 175.50 (101.00) 137.57 (121.16) 0.219
Alcohol (7 HC/ 14 PG/ 15 CDI)
Age a onse alcohol use (yea s) 19.14 (5.53) 16.29 (1.70) 17.87 (4.55) 0.411
Mon hly alcohol use (SDU) 10.07 (9.75) 17.43 (20.09) 31.69 (20.70) 0.038
Du a ion alcohol (mon hs) 83.75 (56.21) 75.43 (63.31) 88.69 (93.90) 0.928
Cannabis (4 HC/ 1 PG/ 6 CDI)
Age a onse alcohol use (yea s) 18.75 (3.77) 25 18.71 (7.47) 0.664
Mon hly cannabis use (join s) 0.96 (0.75) 4 107.83 (125.57) 0.267
Du a ion cannabis (mon hs) 19.25 (19.35) 4 110 (137.33) 0.405
GHQ soma ic symp oms 0.39 (0.85) 1.72 (2.33) 1.43 (1.86) 0.079
GHQ anxie y 1.28 (2.19) 1.64 (2.34) 2.12 (2.50) 0.577
GHQ social dys unc ion 0.83 (1.65) 1.00 (1.84) 1.25 (1.91) 0.796
GHQ dep ession 0.44 (0.98) 1.27 (2.15) 1.50 (2.42) 0.248
s.d., s anda d de ia ion; IQ, in elligence quo ien ; g, g ams; h, hou s; cig, ciga e es; SDU, s anda d d inking uni s, GHQ, Gene al Heal h Ques ionnai e. In addi ion o he epo ed
equencies o o he d ugs in ake, ou CDI epo ed occasional use o MDMA (mean li e ime use = 6 uni s), while o he wo CDI epo ed occasional use o hallucinogens (mean
li e ime use = 14 uni s). No pa icipan s epo ed amphe amines o opia es use.
h ps://doi.o g/10.1192/bjp.bp.114.152223 Published online by Camb idge Uni e si y P ess
Ve dejo-Ga cia e al
DSM-IV Diso de s – Clinician Ve sion (SCID-I-CV);
32
(d) being
ea men commence s; and (e) abs inence du a ion >15 days. Ab-
s inence in he cocaine use s was con i med by wo u ine es s pe
week plus an ad hoc es on he scanning day i sel . Posi i e u ine
oxicologies o any o he d ug we e also exclusiona y. Gambling
abs inence in he pa hological gamble s was assessed by sel - epo
c oss- alida ed by spouses o ela i es. The exclusion c i e ia
we e: (a) p esence o any o he Axis I o Axis II diso de s, wi h
he excep ions o alcohol misuse and nico ine dependence; (b) his-
o y o head inju y o neu ological, in ec ious, sys emic o any
o he diseases a ec ing he cen al ne ous sys em; (c) ha ing ol-
lowed o he ea men s wi hin he 2 yea s p eceding s udy onse
and (d) ha ing en e ed ea men by cou eques . Como bid
Axis I diso de s we e assessed wi h he SCID-I-CV. Axis II diso -
de s we e assessed using he In e na ional Pe sonali y Diso de s
Examina ion (IPDE).
33
We also used he Conne s’ Adul ADHD
Diagnos ic In e iew o DSM-IV (CAADID)
34
o assess adul
ADHD (which was also exclusiona y). Con ols we e ec ui ed
om local employmen agencies. In addi ion o he o me
exclusion c i e ia, heal hy con ols could no mee any diagnosis
o subs ance use diso de s – wi h he excep ion o nico ine
dependence. Axis I and II diso de s we e also assessed in his
g oup using he SCID-I-CV, he IPDE and he CAADID. All he
diagnoses we e made by a egis e ed clinical psychologis .
The s udy was app o ed by he E hics Commi ee o Resea ch
in Humans o he Uni e si y o G anada (Spain). All pa icipan s
signed an in o med consen o m ce i ying hei olun a y
pa icipa ion
Func ional MRI ( MRI) ask
We used he p obabilis ic e e sal lea ning ask, as desc ibed in
Cools e al.
11
In each ial, pa icipan s we e equi ed o choose
be ween wo s imuli (abs ac , colou ed pa e ns) p esen ed o he
le and igh isual ields (loca ion was andomised). Pa icipan s
we e old ha , acco ding o a p ede ined ule, one s imulus was
co ec on each ial ( he CS+), and he o he s imulus ( he
CS7) was inco ec . A a ious poin s h oughou he ask, he
ule deciding he co ec s imulus would change; he pa icipan
should change hei esponse when hey we e con iden ha he
ule had changed. The ask employed p obabilis ic eedback such
ha he CS+ was ewa ded ~85% o imes, and he CS7was
ewa ded ~15% o imes. This ga e ise o wo ypes o e o s:
p obabilis ic e o s (whe e pa icipan s chose he co ec s imulus
bu ecei ed nega i e eedback), and pe se e a i e e o s (whe e
pa icipan s keep esponding o he p e iously ein o ced s imuli,
despi e nega i e eedback). The ask was ained be o e scanning
(using sligh ly di e en s imuli) and hen implemen ed inside
he scanne in 3 consecu i e blocks o 11 min each. Each block
consis ed o 10 disc imina ion s ages, yielding 9 e e sals. Re e sal
o he s imulus– ewa d con ingency occu ed a e 10 o 15
co ec esponses (including p obabilis ic e o s). The numbe
o p obabilis ic e o s be ween each e e sal a ied om 0 o 4.
S imuli we e p esen ed h ough magne ic- esonance-compa ible
liquid-c ys al display goggles (Resonance Technology, No h idge,
CA, USA). Beha iou al esponses we e eco ded h ough a i e-
bu on box, E oke Response Pad Sys em (Resonance Technology
Inc.). On each ial, s imuli we e p esen ed o 2000 ms, wi hin
which ime he esponse had o be made (o else a ‘ oo la e’ mes-
sage was p esen ed). Pa icipan s esponded using he le o igh
bu on on a bu on box posi ioned on pa icipan s’ ches .
Feedback was a g een ‘smiley’ ace o co ec esponses, and
a ed sad ace o inco ec esponses, and was p esen ed
immedia ely a e he pa icipan s’ esponse. The eedback aces
we e p esen ed cen ally o 500 ms, du ing which ime he s imuli
also emained on he sc een. Following eedback, he e was a
a iable in e - ial in e al (a ixa ion c oss) ha was adjus ed
so ha he o e all in e s imulus in e al was 3253 ms, enabling
p ecise desynch onisa ion om he epe i ion ime (TR) (o
2000 ms) and su icien sampling ac oss he hemodynamic
esponse unc ion.
Beha iou al measu es
The main pe o mance measu es we e hi a es (p opo ion o co ec
esponses by o al ials), numbe o pe se e a i e e o s, and
pe se e a ion e o a es (numbe o pe se e a i e e o s di ided
by numbe o sequences on which he pe se e a ion c i e ion
was me ). To mee he pe se e a ion c i e ion, pa icipan s had
o make a leas one consecu i e esponse o he p e iously
ewa ded s imulus immedia ely ollowing e e sal.
Imaging da a acquisi ion and p ep ocessing
We used a 3.0 Tesla clinical MRI scanne , equipped wi h an eigh -
channel phased-a ay head coil (In e a Achie a, Philips Medical
Sys ems, Eindho en, The Ne he lands). Du ing acquisi ion, h ee
T2*-weigh ed echo-plana imaging (EPI) was ob ained
(TR = 2000 ms, echo ime (TE) = 35 ms, ield o iew
(FOV) = 2306230 mm, 96696 ma ix, lip angle = 908,214-mm
axial slices, 1-mm gap, 330 scans each). A sagi al h ee-dimensional
T1-weigh ed u bo-g adien -echo sequence (160 slices, TR = 8.3 ms,
TE = 3.8 ms, lip angle = 88, FOV = 2406240, 1 mm
3
oxels) was
ob ained in he same expe imen al session o ana omical localisa-
ion o unc ional indings.
The b ain images we e analyzed using S a is ical Pa ame ic
Mapping so wa e (Wellcome Depa men o Cogni i e Neu ology,
Ins i u e o Neu ology, Queen Squa e, London, UK), unning
unde Ma lab R2009 (Ma hWo ks, Na ick, MA, USA). P ep ocessing
s eps we e slice iming co ec ion, e-slicing o he i s image o he
ime se ies, no malisa ion (using a ine and smoo hly non-linea
ans o ma ions) o an EPI empla e in he Mon eal Neu ological
Ins i u e space, and spa ial smoo hing by con olu ion wi h a 3D
Gaussian ke nel ( ull wid h a hal maximum (FWHM) = 8 mm).
DRD2/ANKK1 Taq1A geno yping
The DRD2/ANKK Taq1A polymo phism ( s1800497) is loca ed in a
pu a i e subs a e binding domain o he ANNK1 gene and esul s in
a Glu713Lys subs i u ion. In ou s udy, his polymo phism was
cha ac e ised using a TaqMan allelic disc imina ion assay om
Li e Technologies.Cycling was pe o med on a S epOne Plus
he mocycle wi h condi ions ecommended by Li e Technologies.
Th ee geno ypes o he dopamine DRD2/ANNK1-TaqIa locus
can be di e en ia ed: he A1A1 geno ype, he A1A2 geno ype, and
he A2A2 geno ype. Because o he small p e alence o he A1A1
geno ype (3% o he heal hy Whi e popula ion), A1A1 and
A1A2 pa icipan s a e commonly g ouped as A1+ pa icipan s,
whe eas A2A2 pa icipan s a e e e ed o as A1– pa icipan s.
The p e alence o a leas one A1 allele (A1+ g oup) has been
associa ed wi h an up o 30% educ ion in D2 ecep o densi y.
35
S a is ical analyses
Beha iou al analyses
Beha iou al da a we e analysed wi h SPSS e sion 19. We
conduc ed one-way ANOVAs ollowed by Tukey es s o compa e
he h ee g oups on he e e sal lea ning beha iou al measu es.
We also conduc ed wo-way ANOVAs (wi h G oup and DRD2/
ANKK Taq1A geno ype as ac o s) o examine di e ences be ween
geno ype subg oups.
160
h ps://doi.o g/10.1192/bjp.bp.114.152223 Published online by Camb idge Uni e si y P ess
Neu al subs a es o cogni i e lexibili y
Neu oimaging analyses
The ime se ies we e high-pass il e ed (128 s), and a canonical
hemodynamic esponse unc ion was modeled o a del a unc ion
a pa icipan s’ esponse on each ial, which co-occu ed wi h he
p esen a ion o he eedback. The ollowing e en s we e modeled:
(a) co ec esponses; (b) pe se e a i e e o s (e o s ollowing a
ule change whe e pa icipan s ail o swi ch esponse); (c) inal
e e sal e o s (las nega i e eedback in he se ies o pe se e a i e
e o s ollowed by a esponse swi ch); and (d) p obabilis ic e o s
(co ec esponses o which misleading nega i e eedback was
gi en). E o ials ha could no be classi ied as p obabilis ic o
e e sal e o s we e no included in he model. The main con as
o in e es was inal e e sal e o s . pe se e a i e e o s, which
e lec s he beha iou al shi componen . We also calcula ed he
co ec . inco ec (and he e e sed inco ec . co ec ) con as
o map posi i e and nega i e eedback- ela ed ac i a ion, and
pe se e a i e minus p obabilis ic e o s o map pe sis en
esponding con olling o nega i e eedback.
One-sample - es s we e conduc ed on he esul ing i s -le el
con as images o assess wi hin-g oup ac i a ions in each o he
con as s. These esul s we e co ec ed o mul iple compa isons
wi h a combina ion o oxel in ensi y and clus e ex en
h esholds. The spa ial ex en h eshold was de e mined by 1000
Mon e Ca lo simula ions using AlphaSim,
36
as implemen ed in
he SPM REST oolbox.
37
The inpu pa ame e s included b ain
mask o 152 295 oxels, an indi idual oxel h eshold p obabili y
o 0.005 and a clus e connec ion adius o 5 mm, a 10.2, 10.4
and 9.1 FWHM smoo hness o he con as s co ec . inco ec ,
inal e e sal e o s . pe se e a i e e o s and pe se e a i e .
p obabilis ic e o s, espec i ely. A minimum clus e ex en o
262, 260 and 212 oxels espec i ely was es ima ed o sa is y a
amily-wise e o (FWE) co ec ed P- alue o P
FWE
50.05. Nex ,
we conduc ed a se ies o h ee g oup ANOVAs o assess
be ween-g oup di e ences using he same i s -le el con as
images. S a is ical signi icance in hese es s was de ined by he
same inpu pa ame e s, masking esul s by he ac i a ion maps
de i ed om he one-sample - es s. The e o e, o he con as s
co ec . inco ec (and inco ec . co ec ), inal e e sal e o s .
pe se e a i e e o s and pe se e a i e minus p obabilis ic e o s,
espec i ely, a minimum clus e ex en o 104, 14, 47 and 12 oxels
(wi hin b ain masks o 41 129, 1812, 14 149 and 1009 oxels), was
es ima ed o sa is y a P
FWE
50.05. In hose con as s yielding
signi ican g oup di e ences, we conduc ed addi ional analyses
in SPSS o assess G oup6DRD2/ANKK Taq1A Geno ype in e -
ac ions on b ain ac i a ion clus e s di e ing be ween g oups.
Speci ically, we conduc ed wo-way ANOVAs (wi h G oup and
DRD2/ANKK Taq1A geno ype as ac o s) on peak ac i a ions
de i ed om he MRI con as s, ollowed by ele an pai wise
compa isons. To exclude a po en ial pe o mance con ound, all
analyses we e eplica ed con olling o he beha iou al measu es
o inal e e sal e o s and pe se e a i e e o s. Resul s we e
equi alen in bo h app oaches, and hence we only epo he
o iginal, non-co a ied analyses. Likewise, since bo h obacco
and alcohol use ha e been linked o e e sal pe o mance and
dopamine gic unc ion, we conduc ed addi ional analyses
including he mon hly amoun and du a ion o use o hese
subs ances as co a ia es. Fu he , we conduc ed a se ies o wo-
way ANOVAs o examine whe he smoking use o cannabis use
s a us in e ac ed wi h G oup o DRD2/ANKK Taq1A geno ype
e ec s on peak ac i a ions de i ed om he MRI con as s.
Co ela ion analyses
Co ela ion analyses we e pe o med in SPSS using he peak
ac i a ions de i ed om he MRI con as s. The be a eigen alues
co esponding o each egion we e ex ac ed o each pa icipan ,
and hen co ela ed wi h he beha iou al measu es o numbe o
pe se e a i e e o s and pe se e a ion e o a es. We also
co ela ed he be a eigen alues co esponding o each egion wi h
sel - epo es ima es o abs inence du a ion.
Resul s
Beha iou al measu es
Beha iou al measu es a e p esen ed in Table 2. The h ee g oups
only di e ed in he a e o pe se e a i e e o s, wi h cocaine
use s commi ing mo e pe se e a i e e o s han pa hological
gamble s o con ols. In addi ion, in he cocaine g oup,
pe se e a ion e o s we e co ela ed posi i ely wi h li e ime
du a ion o cocaine use ( = 0.470, P= 0.025). By con as ,
pe se e a ion e o a es we e nega i ely co ela ed wi h ime since
gambling onse in he pa hological gamble s ( =70.409,
P= 0.049). G oup x DRD2/ANKK Taq1A geno ype analyses
showed no signi ican in e ac ion e ec s on beha iou al measu es.
Neu oimaging
Co ec
.
inco ec esponses
Collapsing ac oss g oups, co ec ( . inco ec ) esponses we e
associa ed wi h inc eased signal in s ia um, supe io and medial
on al gy i, la e al o bi o on al co ex, an e io and pos e io
cingula e, pos e io insula, amygdala, supe io empo al gy i,
angula gy i and occipi al egions. The e e se con as indica ed
signal associa ed wi h nega i e eedback in igh dlPFC, igh
insula and supplemen a y mo o a ea (see online Table DS2 and
Fig. DS2). Be ween-g oup compa isons indica ed no eliable
di e ences in hese con as s.
Final e e sal e o s
.
pe se e a i e e o s
Shi ing (i.e. inal e e sal e o s) was associa ed wi h signi ican
signal inc eases ac oss all g oups in do sal an e io cingula e
co ex, bila e al an e io insula /o bi o on al co ex, igh do so-
la e al p e on al and en ola e al p e on al co ices, in e io
161
Table 2 Beha io al measu es summa ising pe o mance in he p obabilis ic e e sal lea ning ask in cocaine use s, non-d ug
using gamble s and non-d ug using con ols
Con ols
Mean (s.d.)
Gamble s
Mean (s.d.)
Cocaine use s
Mean (s.d.) P
Hi a e (% co ec esponses) 64.25 (7.29) 63.39 (8.32) 62.02 (8.53) 0.705
Pe se e a i e e o s 21.72 (9.38) 20.94 (8.53) 27.61 (12.79) 0.120
Sequences on which c i e ion o pe se e a ion was me 14.94 (6.71) 14.72 (6.72) 15.56 (6.56) 0.927
Pe se e a ion e o a e 1.49 (0.26) 1.48 (0.40) 1.87 (0.75) 0.039
To al ials o comple e he ask 508.50 (70.45) 517.50 (77.66) 530.17 (85.64) 0.707
s.d., s anda d de ia ion.
h ps://doi.o g/10.1192/bjp.bp.114.152223 Published online by Camb idge Uni e si y P ess
Ve dejo-Ga cia e al
pa ie al co ex, s ia um, halamus and pos e io isual a eas
ex ending o he usi o m gy us. Final e e sal e o s we e also
associa ed wi h educed signal in he os al an e io cingula e
and medial on al gy i, he pos e io cingula e gy us and he
le angula and pa ahippocampal gy i (online Fig. DS3 and
Table DS3).
Pai wise be ween-g oup compa isons showed ha bo h
cocaine use s and pa hological gamble s had signi ican ly
dec eased ac i a ion in he igh lPFC (in e io on al gy us)
compa ed o con ols. In addi ion, he cocaine use s had
signi ican ly dec eased ac i a ion in he igh dlPFC (middle
on al gy us) compa ed wi h bo h pa hological gamble s and
con ols (online Fig. DS3 and Table DS3). We ound no signi ican
co ela ions wi h beha iou al measu es.
Pe se e a i e
.
p obabilis ic e o s
Pe se e a ion was associa ed wi h signi ican ac i a ion in supe io
and medial on al gy i and os al an e io cingula e gy us.
Be ween-g oup compa isons showed no signi ican di e ences
be ween cocaine use s o gamble s compa ed o con ols, al hough
he cocaine use s did display signi ican ly highe ac i a ion han
pa hological gamble s in he medial on al gy us (see online Fig.
DS4). Medial on al gy us ac i a ion was also nega i ely co ela ed
wi h he numbe o pe se e a i e e o s in cocaine use s
( =70.470, P= 0.025), bu posi i ely co ela ed wi h he numbe
o pe se e a i e e o s in pa hological gamble s ( = 0.467,
P= 0.025, see online Fig. DS4).
G oup6DRD2/ANKK Taq1A geno ype in e ac ions
Clus e s showing signi ican be ween-g oup di e ences we e
u he examined in ela ion o G oup6DRD2/ANKK Taq1A
geno ype analyses. The e was a signi ican g oup6geno ype in e -
ac ion (F(2,46) = 4.81, P= 0.013) in he igh lPFC, d i en by
opposing e ec s o he dopamine geno ype in he cocaine use s
ela i e o he o he wo g oups (see online Fig. DS5). Pai wise
analyses showed ha wi hin A17ca ie s, cocaine use s had
lowe ac i a ion han bo h pa hological gamble s and con ols.
Con e sely, cocaine A1+ ca ie s had signi ican ly highe
ac i a ion han pa hological gamble s o he same geno ype. No
u he signi ican in e ac ions we e obse ed.
Co ela ion be ween pa e ns o b ain ac i a ion and abs inence
du a ion
We did no ind signi ican co ela ions be ween ask- ela ed b ain
ac i a ions and du a ion o abs inence o cocaine o gambling use.
Sensi i i y analyses
Co a ia e models including mon hly amoun and du a ion o
alcohol and obacco use did no change he o e all pa e n o
esul s. Fu he , smoking s a us (smoke s . non-smoke s) and
cannabis use s a us (cannabis use s . non-use s) showed no
signi ican in e ac ions wi h G oup o Geno ype on any o he
peak ac i a ions de i ed om MRI analyses.
Discussion
Ou esul s demons a e ha educed signal in igh lPFC du ing
shi ing is common o bo h cocaine use s and pa hological
gamble s. This sha ed e ec was supplemen ed by a wide pa e n
o ask- ela ed dys egula ion in he cocaine use s, wi h dec eased
igh dlPFC ac i a ion du ing shi ing, and inc eased medial
p e on al co ex ac i a ion du ing pe se e a ion. These b ain
ac i a ion di e ences we e pa alleled by beha iou al esul s, whe e
he cocaine use s commi ed mo e pe se e a i e e o s compa ed
wi h bo h pa hological gamble s and con ols. P elimina y
explo a o y gene ic analyses o he DRD2/ANKK Taq1A geno ype
sugges an unde lying dopamine gic con ibu ion o e e sal-
ela ed b ain ac i i y: bo h con ols and pa hological gamble s
ca ying he (high isk) A1+ geno ype had dec eased swi ch-
ela ed lPFC signal, bu his pa e n was e e sed in he cocaine
g oup, in which he A1+ ca ie s exhibi ed g ea e shi ing- ela ed
ac i a ion.
Ou ask ac i a ion esul s eplica e he well-desc ibed pa e n
o do sal p e on al/insula ac i a ions in esponse o e o - ela ed
nega i e eedback, in conce wi h ec ui men o mo e en al
and la e al aspec s o p e on al co ex, an e io cingula e and
s ia um du ing shi ing.
11,38
Bo h cocaine use s and pa hological
gamble s showed diminished ac i a ion o he igh lPFC du ing
shi ing, consis en wi h he pa e n p e iously desc ibed in pa ho-
logical gamble s pe o ming a simila e e sal ask.
14
The igh
lPFC is a key egion o success ul sel -con ol o beha iou
and emo ional egula ion.
39
Fu he , p e ious MRI s udies ha e
shown ha igh lPFC ac i a ion is dis inc i ely inc eased in
indi iduals wi h high esilience o addic ion,
40
and dec eased
in indi iduals wi h amily isk o addic ion.
41
We in e ha
dys unc ion o his egion is commonly in ol ed in bo h cocaine
and gambling addic ions. The inc eased shi ing- ela ed ac i a ion
in cocaine use s ca ying he (high isk) A1 allele compa ed o
pa hological gamble s ca ying he same allele migh be explained
by he dopamine in e ed-U p inciple, by which A1+ ca ie s,
wi h lowe disposi ional dopamine unc ion, may de i e
s imula o y ‘bene i s’ om cocaine-induced changes.
42
Fo exam-
ple, ea men wi h he dopamine D2- ecep o agonis cabe goline
in heal hy olun ee s p o oked opposi e e ec s in A17 . A1+
ca ie s, also mani es ed in he ac i a ion o he igh lPFC.
43
Howe e , because o he small sample size o geno ype subg oups,
hese indings should be ea ed as p elimina y, and could
al e na i ely be explained by linked in ol emen o o he
dopamine gene polymo phisms. Fo example, ecen e idence
sugges s ha he dopamine agonis olcapone has unique
s imula o y e ec s on p e on al co ex ac i i y in smoke s
ca ying he COMT al/ al geno ype, which is also associa ed wi h
lowe dopamine unc ion.
44
Fu u e, adequa ely powe ed,
molecula gene ic s udies a e wa an ed o es he no ion
o whe he indi iduals wi h low disposi ional dopamine
ansmission de i e s imula o y b ain e ec s om cocaine
consump ion.
In addi ion o o e lapping de ici s, cocaine use s showed
dec eased igh dlPFC ac i a ion (BA 9) compa ed wi h gamble s
and con ols du ing shi ing, and inc eased medial on al gy us
ac i a ion (BA 10) compa ed wi h gamble s du ing pe se e a ion.
BA 9 has been speci ically in ol ed in he upda ing o he wo king
memo y s o es ha se s imulus- esponse con ingencies,
45
whe eas BA10 has been p ima ily in ol ed in he con ol o
s imulus-o ien ed a en ion.
46
The e o e, bo h indings a e
compa ible wi h he model-based . model- ee sys ems app oach
o e e sal lea ning.
2
Acco ding o his model, cocaine-induced
changes a ec sys ems in ol ed in he upda ing o s imulus-
ou come alues ha se e o adjus p edic ions abou u u e
ou comes. P eclinical s udies ha e shown cocaine-induced neu al
adap a ions in he a p elimbic co ex ( he unc ional homologue
o he human dlPFC),
47,48
which is c i ical o he lea ning o
no el s imulus-ou come associa ions.
49
Simila ly, in humans,
du a ion o cocaine use is nega i ely associa ed wi h BA 9 g ay
ma e olumes.
50
As a consequence o neu oadap a ions in b ain
egions in ol ed on model-based p edic ions, cocaine use s may
become mo e dependen on sys ems handling model- ee cached
162
h ps://doi.o g/10.1192/bjp.bp.114.152223 Published online by Camb idge Uni e si y P ess

Neu al subs a es o cogni i e lexibili y
ep esen a ions o s imulus-ou come alues.
2
We p opose ha his
compensa o y mechanism would be exempli ied by signi ican ly
inc eased medial p e on al ac i a ion du ing pe se e a ion in
cocaine use s compa ed o gamble s. The e o e, ou esul s sugges
ha cocaine use s equi e addi ional ec ui men o medial
p e on al egions o compensa e o comp omised la e al p e-
on al egions specialised in he upda ing o s imulus-ou come
p edic ions. Con e sely, pa hological gamble s engage his egion
o a lesse ex en han bo h cocaine use s and con ols, and his
pa e n co ela es wi h ewe pe se e a ions wi hin his g oup
(see Domb o ski e al
51
o a simila e ec in dep ession,
which migh be explained by hese popula ions being o e ly
sensi i e o misleading p obabilis ic eedback, hence less likely o
pe se e a e in his ask). This in e p e a ion is also consis en wi h
he neu opsychological p o ile we ha e desc ibed p e iously o
his coho , whe e he cocaine use s ha e a selec i e impai men
in wo king memo y compa ed o he pa hological gamble s (i.e.
poo e upda ing o s imulus-ou come alues), whe eas he
pa hological gamble s ha e s eepe delay discoun ing (i.e.
enhanced ein o cemen sensi i i y).
52
Ou esul s illus a e he neu al unde pinnings o e e sal
lea ning in cocaine and gambling addic ions. Since e e sal
lea ning is a well- alida ed ansla ional model o in lexibili y/
pe se e a ion, and is linked o addic ion se e i y and clinical
p ognosis, hese esul s in o m bo h mechanis ic and clinical
esea ch in addic i e diso de s. In ega ds o clinical implica ions,
ou indings sugges ha b ain s imula ion and/o cogni i e
enhancemen in e en ions a ge ing he dlPFC may con ibu e
o he alle ia ion o pe se e a ion in he con ex o cocaine
addic ion.
53
We no e ha ou MRI p ocedu e did no de ec
signi ican beha iou al al e a ions in e e sal lea ning
pe o mance be ween gamble s and con ols. One possible
in e ence is ha signs o o e compulsi i y may be less in
pa hological gamble s, compa ed wi h cocaine addic ion.
Howe e , he p obabilis ic ask in ol ed se ial e e sals on a
semi- egula schedule in o de o op imise case-by-case
ec ui men o on o-s ia al neu al ci cui y, bu wi h educed
beha iou al sensi i i y o g oup di e ences. The obse a ion ha
gamble s showed a di e en ial pa e n o e e sal- ela ed b ain
ac i i y is compa ible wi h he neu opsychological di e ences
ound in p e ious s udies using beha iou -sensi i e e e sal
asks.
10
In his ega d, ou indings sugges ha b ain s imula ion
and/o cogni i e enhancemen in e en ions a ge ing he lPFC
and i s key unc ions (e.g. cogni i e con ol, esponse
inhibi ion) could ha e u ili y in he ea men o pa hological
gambling. Clinicians may also adap s anda d in e en ions o
bu e he impac o en ola e al dys unc ion on eal-li e
unc ioning (i.e. ins uc ing clien s o pay a en ion o nega i e
eedback and aining hem o gene a e and ehea se al e na i e
s a egies).
Ou s udy has se e al s eng hs, including he di ec
compa ison o cocaine and gambling g oups wi h minimum
exposu e o alcohol/o he d ugs and wi hou he con ounding
e ec s o psychia ic como bidi ies. Mo eo e , ec ui men was
based on consecu i e admissions o public ea men cen es,
hence making he sample uly clinically ep esen a i e. Fu he ,
bo h g oups we e ca e ully supe ised o con inuous abs inence
du ing he s udy, hus uling ou con ounding e ec s o acu e
d ug use/gambling, wi hd awal o c a ing. Cu en d ug use was
objec i ely moni o ed h oughou s udy comple ion using
ongoing u ine oxicologies ha uled ou any use o cocaine and
o he d ugs. The e is howe e a po en ial limi a ion in he
supe ision o gambling abs inence in he gambling g oup, which
was based on epo s om bo h pa icipan s and signi ican
o he s, bu is s ill suscep ible o epo ing biases.
54,55
Mo eo e ,
he gene ic analyses in pa icula should be in e p e ed in he
con ex o he ela i ely small sample size and he examina ion
o a single cogni i e domain and, as such, should be app aised
as p elimina y. Fu u e s udies a e wa an ed o examine he
addi i e con ibu ion o di e en polymo phisms ac oss he
dopamine gene ic pa hway, and he clinical ele ance o his
e e sal lea ning- ela ed neu oimaging pheno ype o cocaine
and gambling ea men ou comes.
An onio Ve dejo-Ga cia, PhD, School o Psychology and Psychia y, Monash
Uni e si y, Melbou ne, Aus alia, Ins i u e o Neu oscience F. Olo iz, Uni e sidad de
G anada, G anada, Spain and Red de T as o nos Adic i os, Uni e sidad de G anada.
G anada, Spain; Luke Cla k, PhD, Depa men o Psychology, Cen e o Gambling
Resea ch a UBC, Uni e si y o B i ish Columbia, Canada; Juan Ve dejo-Roma
´n,
MSc, Ins i u e o Neu oscience F. Olo iz, Uni e sidad de G anada, G anada, Spain;
Na alia Albein-U ios, PhD, Ins i u e o Neu oscience F. Olo iz, Uni e sidad de
G anada, G anada, Spain; Jose
´M. Ma inez-Gonzalez, PhD, Red de T as o nos
Adic i os, Uni e sidad de G anada, G anada, Spain and Cen o P o incial de
D ogodependencias, Dipu acion de G anada, G anada, Spain; Blanca Gu ie ez,
PhD, Ins i u e o Neu oscience F. Olo iz, Uni e sidad de G anada, G anada, Spain,
Depa men o Psychia y, Uni e sidad de G anada, G anada, Spain and CIBERSAM,
Ca los III Heal h Ins i u e, Ba celona, Spain; Ca les So iano-Mas, PhD, Depa men o
Psychia y, Bell i ge Biomedical Resea ch Ins i u e-IDIBELL, Ba celona, Spain and
CIBERSAM, Ca los III Heal h Ins i u e, Ba celona, Spain, Depa men o Psychobiology
and Me hodology o Heal h Sciences, Uni e si a Au o
`noma de Ba celona, Spain
Co espondence: An onio Ve dejo-Ga cia, School o Psychology and
Psychia y, Monash Uni e si y, 3800 Welling on Rd. Clay on Campus, Melbou ne,
Aus alia. Email add ess: An onio.Ve [email protected]
Fi s ecei ed 1 Jun 2014, inal e ision 18 No 2014, accep ed 23 No 2014
Funding
This s udy has been unded by g an s om he Spanish Minis y o Heal h; p ojec g an
COPERNICO, D ug Abuse Plan (Plan Nacional sob e D ogas Con oca o ia 2009) and
p og am g an RETICS, Ca los III Heal h Ins i u e (Ins i u o de Salud Ca los III, Red de
T as o nos Adic i os). CS-M is unded by a ‘Miguel Se e ’ con ac om he Ca los III
Heal h Ins i u e (CP10/00604).
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