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Alterations of the Brain Reward Systemin

Antipsychotic Nave Schizophrenia Patients


Mette degaard Nielsen, Egill Rostrup, Sanne Wulff, Nikolaj Bak, Henrik Lublin, Shitij Kapur, and
Birte Glenthj
Background: Various schizophrenic symptoms aresuggestedtobelinkedtoa dysfunctionof thebrainrewardsystem. Several studies have
found alterations in the reward processing in patients with schizophrenia; however, most previous ndings might be confounded by
medication effects.
Methods: Thirty-one antipsychotic-nave schizophrenia patients and 31 age- and gender-matched healthy control subjects were exam-
ined with functional magnetic resonance imaging while playing a variant of the monetary incentive delay task. The task variant made it
possible to separate overall salience (dened as arousing events) into behavioral salience (events where a predicted reward requires
performance) andvalence anticipation(the anticipationof a monetarily signicant outcome). Furthermore, the evaluationof monetary gain
and loss was assessed.
Results: During reward anticipation, patients had a signicant attenuation of the activation in ventral tegmentum, ventral striatum, and
anterior cingulate cortex during presentation of salient cues. This signal attenuation in ventral striatum was correlated with the degree of
positivesymptoms. Signal attenuationwas most pronouncedfor behavioral salienceandnonsignicant for valueanticipation. Furthermore,
patients showed a changed activation pattern during outcome evaluation in right prefrontal cortex.
Conclusion: Our results suggest that changes during reward anticipation in schizophrenia are present from the beginning of the disease.
This supports a possible involvement of rewarddisturbances in the pathophysiology of schizophrenia. The most pronouncedchanges were
seen in relation to overall salience. In ventral striatum these changes were associated with the degree of positive symptoms.
Key Words: Functional magnetic resonance imaging, negative
symptoms, positive symptoms, reward, schizophrenia, ventral
striatum
B
rainrewardcircuits are involvedinmultiple processingsteps,
with regard to biologically important stimuli: an outcome
must be allocated positive or negative value, a relationship
to a conditioning cue must be learned, and the need for a behav-
ioral response must be indicated (1). In this process, dopaminergic
neurons projecting from ventral tegmental area (VTA) to ventral
striatum (VS) are essential for signaling salience, dened as stimuli
beingarousingandtowhichattentional or behavioral resources are
preferentially redirected (26). Medial prefrontal cortex (MPFC)
plays an important role in value representation and pleasure expe-
rience (7,8), whereas dorsolateral prefrontal cortex (DLPFC) is be-
lieved to be central in translating the achieved value into future
goal-directed behavior (9,10).
Schizophrenia patients are thought to have a disruption of
striato-cortico-thalamic macro circuits and frontal microcircuits in-
volving disturbances in several transmitter systems, including the
glutamatergic, serotonergic, -aminobutyric acid-ergic, cholin-
ergic, noradrenergic, and dopaminergic systems (1114). Irrespec-
tive of the primary abnormality in individual patients, increased
dopaminergic turnover in striatum has been hypothesized as the
nal common pathway leading to positive psychotic symptoms
(15). Several studies have demonstrated an increased synthesis of
dopamine (1619) and a heightened striatal dopamine release in
response to an impulse (2022) in patients with schizophrenia dur-
ing psychotic episodes. Likewise, a well-established relationship
exists between the dopamine-type 2 receptor blockade in striatum
and the resolution of positive symptoms (23,24). Literature also
points to a decisive role for frontal dopaminergic activity and
schizophrenic symptomatology (12,14) and to a relationship be-
tween cortical and subcortical dopamine activity (25).
Studies havedemonstrateda central roleof dopamineinreward
processing (3,26,27), and in functional magnetic resonance imag-
ing(fMRI), the event-relatedsignal in VS duringrewardanticipation
is most likely caused by dopamine activity (2830). In medication-
free schizophrenia patients an attenuated signal in VS for reward
predicting cues has been found (31,32). This attenuation correlated
with the degree of negative symptoms and at a trend level with the
degree of positive symptoms (31). InPFC, a decreaseddistinctionof
the signal during processing of unexpected and expected out-
comes has been found (32), but no fMRI studies have looked at
changes in relation to processing of valence in PFC in medication-
free patients. Studies using positron emission tomography (PET)
have reported reduced pleasure-related activation in PFC and lim-
bic areas in unmedicated patients (33,34). Functional MRI studies in
medicatedpatients have describeda negative correlation between
pleasure-related activity in PFC and the degree of negative symp-
toms (3537).
Increased dopaminergic tone in VS has been suggested to
result in attenuated event-related blood oxygen leveldepen-
dent (BOLD) response (38). Thus we expect antipsychotic-nave
rst-episode schizophrenia patients to have an attenuated BOLD
response during anticipation, and we expect this change to corre-
late with the degree of positive symptoms. During outcome evalu-
ation, we expect patients to have an attenuated pleasure-related
BOLDresponse in PFC when receiving a reward, and we expect this
Fromthe Center for Clinical Intervention and Neuropsychiatric Schizophre-
nia Research, Center for Neuropsychiatric Schizophrenia Research
(MN, SW, NB, HL, BG); Functional Imaging Unit (ER), Copenhagen Uni-
versity Hospital, Glostrup, Denmark; and the Institute of Psychiatry (SK),
Kings College London, United Kingdom.
Address correspondence to Mette degaard Nielsen, M.D., Ph.D. student,
Copenhagen University Hospital, Center for Neuropsychiatric Schizo-
phrenia Research, CNSR, Psychiatric Center Glostrup, Nordre Ringvej
29-67, 2600 Glostrup, Denmark; E-mail: mette@cnsr.dk.
Received Aug 4, 2011; revised and accepted Feb 3, 2012.
BIOL PSYCHIATRY 2012;71:898905 0006-3223/$36.00
doi:10.1016/j.biopsych.2012.02.007 2012 Society of Biological Psychiatry
attenuationtocorrelate withthe degree of negative symptoms. We
used an fMRI paradigm that enabled distinction between behav-
ioral salience (dened as events, where the positive or negative
outcomes were performance-contingent) and valence anticipation
(anticipation of a monetarily signicant outcome). Because cues
indicating behavioral salience and positive valence have been
foundtoactivate VS (39), we expect attenuatedresponse tobothof
these in patients.
Methods and Materials
Conducted in accordance with the declaration of Helsinki II, the
project was approved by the Danish National Committee on Bio-
medical Research Ethics (H-D-2008-088). All participants approved
participation by signed informed consent.
Participants
As part of a large rst-episode project, 36 antipsychotic-nave
schizophrenia patients 18-45 years of age were recruited frompsy-
chiatric hospitals and outpatient psychiatric centers in the Capital
Region of Denmark. The ICD-10
1
diagnoses of schizophrenia or
schizoaffective psychoses were based on a structured diagnostic
interview(Schedule of Clinical Assessment in Neuropsychiatry, ver-
sion 2.1). Patients with a current diagnosis of drug dependency
accordingtoICD-10 were excluded, but previous diagnoses of drug
dependency or current occasional use of drugs were accepted.
Current drug status was measured by urine test (Rapid Response,
Jepsen HealthCare, Tune, Denmark). None of the patients had ever
received any antipsychotic medication or Ritalin. Treatment with
antidepressants within the last month was also an exclusion crite-
rion. Patients were allowed to receive benzodiazepines or sleeping
medication but not later than 12 hours before scans (see Table 1 for
details on drugs and benzodiazepines). Healthy control subjects
were recruited from the community and were matched on age,
gender, and parental socioeconomic status. They underwent a
Schedule of Clinical Assessment in Neuropsychiatry interview to
ensure they had no former or present psychiatric illness, drug-
abuse, or any rst-degree relatives with psychiatric diagnoses. Both
patients and healthy control subjects were required to have a nor-
mal physical and neurological examination and no history of major
head injury.
Clinical Measures
Psychopathology of the patients was measured with the Posi-
tive and Negative Syndrome Scale (PANSS) (40) and Global Assess-
ment of Functioning (GAF). Edinburg Handedness Inventory (EHI)
(41) was used to assess participant handedness.
Experimental Design and Task
We used a modied variant of monetary incentive delay task
described by Knutson (7,42) and modied by Cooper and Knutson
(39) to elicit VS activation in response to cues indicating monetary
gain and loss (Figure S1 in Supplement 1).
In each trial, participants were presented initially with a cue
indicating the trial condition. After a short delay, a visual target
appeared briey on the screen, and participants were instructed to
press a button while the target was on screen. After another delay,
participants receivedfeedback onthe outcome of the trial andhow
much money they had earned in total. Initial target duration for all
participants and trial conditions was 300 msec, but an automated
adaptive timing algorithm adjusted target time to maintain a hit
rate of approximately 66% over the experiment. After the scan,
participants were paid the amount of money they won, typically
4585 for each session.
There were six different trial conditions representing two levels
of uncertainty (certain and uncertain), crossed with three levels of
value expectation (gain, neutral, and loss). In uncertain gain and
loss conditions, the outcome dependedonwhether the buttonwas
pressed in time. In uncertain-gain trials, a participant could make
7 on a hit but earn nothing on a miss. In uncertain-loss trials, a
participant could make 0 on a hit but would lose 7 on a miss. In
the two certain conditions, outcome was pre-determined and non-
contingent on the response, and a participant would gain or lose
7 regardless of pressing the button in time. In the two neutral
trials, participants knewthe outcome would be 0. After each trial,
the recent and total amount won or lost was displayed on the
screen. Participants were instructed to respond rapidly on all trials,
regardless of whether they involved uncertain, certain, or neutral
outcomes. Before scans, participants were instructed about the
meaning of each cue. They performed a 10-min training version of
the task. Participants were not told about the adaptive timing algo-
rithm.
Duration of one trial was 15 sec. Each of the six trial conditions
was presented in a block-wise, randomized order 12 times in each
of the two runs. Total task time was 36 min (18 min/run). Presenta-
1
In ICD-10 and DSM-IV the major difference in the diagnostic criteria for
schizophrenia is the duration of symptoms. In ICD-10 it is 1 month,
whereas in DSM-IV it is 6 months. A few of the patients in this rst-
episode study did not meet the duration criteria in DSM-IV when they
were included in the study.
Table 1. Participant Demographic Data
Schizophrenia
Patients (n 31)
Healthy Control
Subjects
(n 31)
Age, Years: Mean (SD) 25.9 (6.4) 25.7 (5.8)
Gender: Male/Female 22/9 22/9
Handedness: Mean EHI-Score (SD) 61 (61) 54 (77)
Education, Years 11.9 (2.3) 15.7 (2.7)
a
Parental Socioeconomic Status
b
4/17/10 6/17/8
Smokers (Cigarettes/Day) 21 (16.1) 8 (12.2)
a
PANSS Total, Mean (SD) 86 (15)
PANSS Positive 21 (4.4)
PANSS Negative 22 (6.9)
PANSS General 43 (8.0)
GAF Score 42 (10)
Duration of Untreated Illness, Weeks 77 (72)
Diagnosis Subtype, n (%)
Paranoid 17 (55)
Undifferentiated 10 (32)
Hebephrenic 1 (3)
Simplex 1 (3)
Schizoaffective
c
2 (7)
Lifetime Abuse 13
Cannabis/alcohol/amphetamine 12/2/3
Current Abuse (Last Month) 7
Cannabis/alcohol/amphetamine 6/1/0
Urine test positive 6 (5 THC, 1 benzo)
Benzodiazepines Last Week (Range)
d
5 (530 mg/day)
Sleeping Medication Last Week
d
2 (7.5 mg/day)
Benzo, benzodiazepines; EHI, Edinburg Handedness Inventory; GAF,
Global Assessment of Functioning; PANSS, Positive andNegative Syndrome
Scale; THC, tetrahydrocannabinol.
a
Signicant group difference, p .01.
b
High/moderate/low.
c
One was in a neutral mood, and one was in a sub-manic mood with
rst-rank psychotic symptoms.
d
Mean daily doses of oxazepam and zopiclone during the last week.
M.. Nielsen et al. BIOL PSYCHIATRY 2012;71:898905 899
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tionof thetask andrecordingof thebehavioral dataweredonewith
Presentation software (Neurobehavioral Systems, Albany, Califor-
nia).
Imaging
Functional and structural MRIs were performed with a Philips
Achieva 3.0T whole body MRI scanner (Philips Healthcare, Best, The
Netherlands) with an 8-channel SENSE Head Coil (Invivo, Orlando,
Florida). For each participant, we acquired 1080 (540/run) whole-
brain functional echo-planar images (38 slices, thickness 2.4 mm,
voxel size 2.4 2.9 2.9 mm, ipangle 75, repetitiontime 2 sec,
echo time 25 msec), and whole-brain three-dimensional (3D)
high-resolution T1-weighted structural images were acquired for
anatomical reference (repetition time 10 msec, echo time 4.6
msec, ip angle 8, voxel size .79 .79 .80 mm).
Data Analysis
Analyses were performed with BrainVoyager 2.20 (Brain Innova-
tion B.V., Maastricht, The Netherlands). Images were corrected for
slice-timing effects, and 3D motion correction was performed with
trilinear interpolation. Spatial smoothing was performed with a
4-mm full-width at half maximal Gaussian kernel, and a high pass
lter (200 sec) was applied to reduce low frequency noise. Func-
tional images were then coregistered to the 3D anatomical images
and transformed into Talairach space.
General Linear Model
A general linear model was constructed for statistical analysis.
For anticipation to act, the six different cues were modeled as
separate predictors: uncertaingain(ug); certaingain(cg); uncertain
loss (ul); certain loss (cl); uncertain neutral (un); and certain neutral
(cn). Target onset and the delay to outcome was modeled with two
different predictors not included in any contrast (one for uncertain
events, andonefor certainandneutral events). Theoutcomeperiod
was modeled with seven predictors, one for each of the possible
outcomes. There were two situations for winning: certain win (cw),
and uncertain win (uw). Similarly, there were two situations for
losing: certain lose (ocl), and uncertain lose (oul). There were three
economically neutral but emotionally different outcomes: zero
miss (zm), when failing to win in uncertain trial; zero hit (zh), when
avoiding to lose in uncertain trials; and zero neutral (zn), which was
the outcome of neutral trials. All explanatory variables were con-
volved with the hemodynamic response function, and six realign-
ment parameters were included. Due to the repetitive nature of the
stimulation, considerable oscillations were observed at the para-
digm frequency (1/15 Hz). To reduce any trivial effects of the main
frequency of the stimulation paradigm, we further included sine
and cosine regressors at this frequency (1/15 Hz).
Contrasts
During reward anticipation, we were interested in the overall
effect of salience (the joined effect of uncertainty and value
expectation) modeled by uncertain cues versus neutral cues
[ugulcnun]. To highlight the motivational component and
eliminate the value component, we constructed a behavioral sa-
lience contrast by contrasting uncertain versus certain cues
[ugulcgcl] (43,44). Finally, the effect of valence anticipation
was dened as a contrast between cues indicating gain versus
those indicating loss [cgugclul] (39).
During the outcome phase we dened two contrasts of interest:
1) winning modeled by all money-receiving outcomes versus zero
neutral [cwuwzn]; and 2) losing modeled by all money-losing
outcomes versus zero neutral [ocloulzn].
Statistics
We analyzedthe imagingdata witha randomeffects model. The
statistical threshold for all voxel-wise analyses was dened as
whole-brain false discovery rate (FDR) q .05. All contrasts were
analyzed with a one-way analysis of variance (ANOVA), with group
as between factor. All analyses were performed with and without
three covariates: age, gender, and smoking status (smoker or non-
smoker).
Behavioral data of the monetary incentive delay task, demo-
graphic data, and the psychopathological ratings were analyzed
with SPSS (version 11.0, SPSS, Chicago, Illinois). Simple group com-
parisons were performed with two-sample t tests, whereas more
complex comparisons of behavioral data were performed with re-
peated measures ANOVA.
Regions of Interest
Alongwiththe whole-brainanalyses, we performedgroupcom-
parisons of the average effect size (regression coefcient, ) in six
predened regions of interest (ROIs). We dened regions in VTA/
substantia nigra, right and left VS, and anterior cingulate cortex
(ACC)known to be active during reward anticipationand re-
gions in MPFC and right DLPFCknown to be active during out-
comeevaluation(7,42,44,45). Withintheseregions weselectedvox-
els that were functionally dened by being active in the relevant
contrast (overall salience contrast during anticipation and winning
during outcome evaluation). Thus the nal ROI denition was the
intersectionof theanatomically andfunctionally denedareas (Fig-
ure S3 and Table S2 in Supplement 1).
Results
Initially, 36 antipsychotic-nave schizophrenia patients and 32
healthy control subjects were recruited. Five patients were ex-
cluded (three patients experienced symptom exacerbation during
the examination period and started medication urgently; one pa-
tient had a minor, structural brain lesion; and in one patient func-
tional scanning was lost due to technical problems). One healthy
control subject was excluded due to incidental nding of structural
brain lesion, leaving us with 31 patients (22 men) and 31 age- and
gender-matched healthy control subjects (Table 1).
Behavioral Data
A two-sample t test showed no signicant differences between
the groups with regard to the total amount won (patients vs. con-
trol subjects: 61 21 vs. 64 15/run). The rest of the behavioral
data was analyzed with 2 3 2 ANOVA, with group as between
factor and valence (gain, loss, neutral) and certainty (certain, uncer-
tain) as within factors.
2
With regard to the hit rate, there was a main effect of certainty
[F(1,60) 33, p .001] and valence [F(1,60) 24, p .001] but no
effect of group. There was no group certainty valence interac-
tion, but we found a certainty valence [F(1,60) 9.3, p .003]
anda groupvalence interaction[F(1,60) 13.8, p .001]. The hit
rate was highest in uncertain trials in both groups. In healthy con-
trol subjects, the lowest hit rate was seen in neutral trials; however,
inpatients thelowest hit-ratewas seenincertaingainandloss trials.
With regard to reaction times, we found a main effect of cer-
tainty [F(1,59) 14.1, p .001], valence [F(1,59) 6.1, p .02], and
2
In a few cases (1 patient and 1 control subject) there were no or very few
responses in the certain gain condition, so that response times for that
condition could not be reliably measured. Performing all analysis (be-
havioral and fMRI) with or without these subjects did not alter the
results, but this explains why degree of freedom is 59 in analyses of
reaction time.
900 BIOL PSYCHIATRY 2012;71:898905 M.. Nielsen et al.
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group [F(1,59) 5.1, p .03]. There were no signicant interac-
tions, although there was a group valence interaction at a trend
level (p.06). Responses were generally faster on uncertain trials
compared with certain trials and on gain and loss trials com-
pared with neutral trials. Patients were slower overall than
healthy control subjects. The trend-wise interaction was caused
by an increased reaction time to neutral trials in healthy control
subjects (HC), which was not found in patients (Figure S2 and
Table S1 in Supplement 1).
fMRI Data
Initially, we performed voxel-wise analyses for the entire
group. During anticipation to act, the overall salience contra-
sts [ugulcnun] and the behavioral salience contrasts
[ugulcgcl] showed activation of very large, conuent brain
areas at the statistical level of FDR q .05. To reveal the most
relevant clusters for these contrasts, we increased the threshold to
whole-brain FDR q .001. At this threshold, there were several
active clusters in both contrasts, including VS bilaterally, ACC, and
an area in VTA in the overall salience contrast but only left VS in the
behavioral salience contrast (Figure S4 and Tables S3 and S4 in
Supplement 1).
Thevalenceanticipationcontrast [ugcgulcl] showedthreesmall
clusters surviving FDR q .05. Two of these clusters were in the most
ventral part of striatum(FigureS5andTableS5inSupplement 1).
During outcome evaluation, the main effect of winning
money revealed 12 active clusters surviving FDR q .05. Several
of them were located in the frontal area, Brodmann area (BA)
910, whereas there was no activation in VS (Figure S6 and Table
S6 in Supplement 1).
The main effect of losing money revealed two signicant clus-
ters at FDRq.05, a negative cluster inBA10, anda positive cluster
in BA 18 (Figure S6 and Table S7 in Supplement 1).
Whole-Brain Group Comparison
A voxel-wise group comparison was conducted for each con-
trast of interest. There was signicant groupdifferences inthe over-
all salience contrast [ugulcnun] at FDR q .05. The patients
showed an attenuated activation in several areas, including ACC,
the midbrain, thalamus, cerebellum, and striatum bilaterally. This
was not altered after correction for smoking, gender, and age (Fig-
ure 1 and Table S8 in Supplement 1).
Voxel-wise group comparison of the behavioral salience con-
trast and the valence anticipation contrast revealed no group dif-
Figure 1. (A) The voxel-wise group
comparison of the overall salience
contrast [ugulcnun] corrected
for whole-brain false discovery rate
(FDR), q .05. Widespread group
differences exist; all of them are
caused by attenuated activation in
the schizophrenia patients. Lower
panels: the activation map for each
of the groups: (B) healthy control
subjects, and (C) antipsychotic-na-
ve schizophrenia patients. For the
healthy control subjects, the FDR
level was lowered to q .001 to
emphasize the most relevant areas.
A, anterior; Bonf, Bonferroni; cn,
certain neutral; COR, coronal; L, left;
P, posterior; R, right; SAG, sagital;
TRA, transversal; ug, uncertaingain;
ul, uncertain loss; un, uncertain
neutral.
Figure 2. Response to different cues during reward antic-
ipation in predened regions of interest divided by
groups. In all of the regions the healthy control subjects
showedalarger bloodoxygenleveldependent signal on
uncertain trials relative to certain and neutral trials. The
blood oxygen leveldependent signal in patients was re-
duced under all conditions, but the most pronounced
difference was seen on trials with cues to uncertain out-
comes. Error-bars indicate standard error. ACC, anterior
cingulate cortex; cg, certain gain; cl, certain loss; cn, cer-
tain neutral; ug, uncertain gain; ul, uncertain loss; un, un-
certain neutral; VTA, ventral tegmental area.
M.. Nielsen et al. BIOL PSYCHIATRY 2012;71:898905 901
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ferences. Similarly, we found no group differences during outcome
evaluation. This was unchanged after including the covariates.
Anticipation Phase: ROI Analyses, VS, VTA, and CG
Because we found signicant group differences in or very close
to our predened ROIs with the voxel-wise approach, we did not
nd it necessary to perform a ROI-wise group comparison of the
overall salience contrast. However, we wanted to examine possible
group differences for behavioral salience and anticipated valence
on the ROI level. In the behavioral salience contrast, we found
signicant groupdifferences inleft VS [F(1,60) 8.9, p.004], right
VS [F(1,60) 4.9, p .031], and VTA[F(1,60) 4.1, p .046]. There
were no signicant group differences in ACC in the behavioral
salience contrast or in any of the regions in the valence contrast.
There were no signicant effects of the covariates.
Finally, to understand the changes of the activation pattern in
the patients, we plotted the mean ROI parameter estimates for all
cues during anticipation by group (Figure 2). Patients generally
showed an attenuated activation for all cues, although this was
most pronounced for cues indicating uncertain gain and loss.
Outcome Phase: ROI Analyses, MPFC, and DLPFC
Because the outcome-relevant ROIs were dened by being ac-
tive during winning, we only analyzed the winning contrast. There
werenosignicant groupdifferences inMPFC, but patients showed
a trend toward attenuated response in DLPFC (p .06). There were
no signicant effects of the covariates. When we extracted the
parameter estimates for the individual regressors in DLPFC, one of
the healthy control subjects was an extreme outlier ( values in all
predictors 3 SDbelowmean). The mean values were plotted with
and without the outlier. We found a changed activation pattern
with an increased BOLD response in the neutral condition in pa-
tients (Figure 3).
Correlation with Psychopathology
We found a negative correlation between PANSS positive score
andthe average signal change of the overall salience contrast inthe
right andleft VS ROI (r .41, p .02 andr .36, p .04) (Figure
4). There was no correlation between the VS, MPFC, or DLPFC acti-
vation and PANSS negative symptoms score.
Analyses of Substance Abuse
Additional analyses were performed comparing healthy control
subjects with patients with and without previous or ongoing sub-
stance abuse. Voxel-wise comparison of the overall salience con-
trast showed similar signal attenuation in the two groups of pa-
tients. Comparison of the two subgroups of patients showed one
area in ACC with an attenuated signal in the abusing patients. The
ROIs showed no difference in activation in the two subgroups of
patients in any contrasts (Figures S7 and S8 in Supplement 1).
Discussion
This is the rst study to use a voxel-wise approach to look at
alterations of the brain reward system in a large group of schizo-
Figure 3. Response todifferent outcomes inpredenedregions of interest dividedby groups. There was nodifference inthe medial prefrontal cortex (MPFC).
Indorsolateral prefrontal cortex (DLPFC), patients showedelevatedsignals inresponsetoneutral outcome, whichwas not seeninthehealthycontrol subjects.
For DLPFC the means are shown with (corner) and without the extreme outlier found in the healthy control subjects. Error bars indicate standard error. cl,
certain loss; cw, certain win; ul, uncertain loss; uw, uncertain win; zh, zero hit; zm, zero miss; zn, zero neutral.
Figure 4. There was a negative correlation between the
degree of positive symptoms andthe signal change inthe
right and left striatum during anticipation of uncertain
outcomes relative to neutral outcomes. The highest pos-
itive score on the Positive and Negative Syndrome Scale
(PANSS) was found in the patients with the least (most
abnormal) signal change in the contrasts between the
conditions. cn, certain neutral; ug, uncertain gain; ul, un-
certain loss; un, uncertain neutral; VS, ventral striatum.
902 BIOL PSYCHIATRY 2012;71:898905 M.. Nielsen et al.
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phrenia patients who have never received antipsychotic medica-
tion. Patients showed attenuated activation in multiple brain areas
during reward anticipation as compared with control subjects, and
in VS this correlated with the degree of positive symptoms. There
were nogroupdifferences duringoutcome evaluationwitha voxel-
wise approach, but we observed a changed activation pattern in
right DLPFC during outcome evaluation.
Behavioral Level
On the behavioral level, there was a generally slower mean
reaction time in patients, as described in a previous study on un-
medicated patients (32). There was a trend-wise group valence
interaction, withhealthy control subjects showingalonger reaction
time in neutral events compared with positive and negative certain
and uncertain events. This discrimination was not seen in patients
who seemed to have a relatively accelerated reaction time in neu-
tral trials. This has previously been reported and interpreted as
aberrant assignment of motivation (46). Furthermore, the group
valence interaction in the hit-rate indicated that healthy control
subjects were better at improving accuracy in gain and loss com-
pared with neutral events. Nevertheless, uncertainty had a signi-
cant inuence on reaction time and hit-rate in both groups. This
indicates that all participants understood the behavioral impor-
tance of the uncertain trials, but it might introduce a slightly differ-
ent motor-activation between the trials.
fMRI
Similar to previous fMRI studies, we found an attenuated BOLD
response in VS during reward anticipation (31,32). Positron emis-
siontomography studies report anincreaseddopaminergic activity
in schizophrenia (17,4749), and the increased dopaminergic tone
has been suggested to result in an elevated baseline in fMRI. Thus,
the event-related BOLD responses are often smaller, because pha-
sic-dopamine responses might not sufciently differentiate them-
selves from tonic dopamine levels (38). Knutson et al. (28) demon-
strated this in healthy control subjects by increasing the
dopaminergic tone with amphetamine, which resulted in a de-
creased event-related BOLD response in VS. Furthermore, Taylor et
al. (50) found an elevated tonic activity but a reduced immediate
response to salient pictures in VS in unmedicated schizophrenia
patients.
Phasic dopamine release in VS has been suggested to mediate
the incentive salience of cues indicating a possible reward or pun-
ishment (4,51). This understanding of dopaminergic function was
used by Heinz (52) and Kapur (53) to link dopaminergic hyperactiv-
ityinstriatumtothedevelopment of psychotic symptoms inschizo-
phrenia. The salience hypotheses suggest that increased dopami-
nergic activity in striatum leads to an aberrant assignment of
salience tootherwise irrelevant stimuli, resultingindevelopment of
psychotic symptoms. In our patients, we found that attenuated
activation in relation to salience in VS was correlated with the de-
gree of positive symptoms, with the most attenuated BOLD re-
sponse in the most psychotic patients. If a decreased event-related
BOLD response is a consequence of an increased dopaminergic
tone, this correlation supports the link between an increased dopa-
minergic tone and the development of psychotic symptoms, as
suggested by Heinz and Kapur.
In our study the contrast showing the effect of overall salience
revealed signicant group differences in several brain areas. When
we divided salience into components of motivation (behavioral
salience) and value expectation, there were no signicant group
differences in the voxel-wise analyses. This indicates that the atten-
uated response in schizophrenia patients during presentation of
salient cues is a combination of changes in value expectation and
motivation. Although changes related to motivation account for
the majority of the difference (being marginally signicant in the
ROI analyses), an additional difference might be added by the an-
ticipated gain or loss, although it is too small to be detected on its
own, even in a study with a moderate sample size (36). This nding
is consistent with schizophrenia patients reporting decreasedplea-
sure anticipation (54).
During outcome evaluation, we found an intact BOLD response
in patients in relation to winning money in MPFC, which is in line
with previous results in medicated patients (35,55). In medicated
patients, a correlation between PFC activation during reward out-
come evaluation and negative symptoms has been reported (35
37,56). However, inour study, where negative symptoms cannot be
caused by present or previous treatment, this relation was not
found. It would be interesting to relate the brain response to moti-
vation and pleasure experienced during the game, but these as-
pects were not assessed.
We observed a trend toward decreased activation in patients in
relation to winning money in right DLPFC. This seemed to be
caused, lookingat the activation-pattern in the ROI (Figure 3), by an
increased BOLD-response in relation to neutral events in patients.
This might indicate primary disturbances incortical processingdur-
ing rewardoutcome evaluation andis in line with previous ndings
on unmedicated patients (32), where a decreased difference in
activity during evaluation of successful and unsuccessful outcomes
in MPFC was related to the development of delusional beliefs
(32,57).
Thevoxel-wiseapproachadditionally revealedsignicant group
differences in thalamus, large areas of cerebellum, and occipital
lobe in the overall salience contrast. These areas are known to be
active during reward processing of particularly motivating events
(44). As reviewed by Picard et al. (58), networks involving these
areas have shown alterations during fMRI in different cognitive
tasks. The reward task used in our study is not cognitively demand-
ing, but it requires payingspecial attentiontouncertainevents. Our
results suggest that schizophrenia patients havedecits infocusing
attention on these specic events.
Study Limitations
A large group of schizophrenia patients have a previous or on-
going use of drugs. To increase external validity of our ndings and
to be able to collect a large group of patients, we allowed previous
or current sporadic drug abuse in patients, although drug abuse is
known to affect reward-related activation (59,60). We examined
this confounder and found an overall identical group difference
between healthy control subjects and the two sub-groups of pa-
tients. Nonetheless, the nding of a region in ACC with a decreased
activation in the abusing patients supports that inclusion of abus-
ing patients represents a limitation of the study (see Supplement 1
for a discussion of this topic).
Another limitation of our study is that the control groupwas not
matched on smoking. Even though smoking was limited 1 hour
before the scans, smoking status might have affected the BOLD
response (61,62). However, there was no signicant effect from
smoking as a covariate. This strongly supports the contention that
the alterations in schizophrenia patients reported here are not ex-
plained by group differences in smoking or drug abuse habits.
This study was supported by the Danish Medical Research Council,
the Lundbeck Foundation, and the Mental Health ServicesCapital
Region of Denmark. We would like to thank the various departments
for helping us recruit patients and the patients for their participation.
M.. Nielsen et al. BIOL PSYCHIATRY 2012;71:898905 903
www.sobp.org/journal
We are grateful to the Radiological Department, Glostrup Hospital, for
clinical evaluation of the obtained images.
Shitij Kapur has received grant support from AstraZeneca and
Glaxo Smith Kline and has served as consultant and/or speaker for
AstraZeneca, Bioline, Bristol-Myers Squibb, Otsuka, Eli Lilly, Janssen
(JohnsonandJohnson), Lundbeck, NeuroSearch, Pzer, Roche, Servier,
and Solvay Wyeth. Henrik Lublinhas servedas aspeaker or chairmanfor
AstraZeneca, H. Lundbeck, Bristol-Myers Squibb, and Eli Lilly; and has re-
ceived research grants from H. Lundbeck. All other authors reported no
biomedical nancial interests or potential conicts of interest
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