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The Journal of Neuroscience, 2001, 21:RC159:1-5
RAPID COMMUNICATION
Anticipation of Increasing Monetary Reward Selectively Recruits
Nucleus Accumbens
Brian
Knutson,
Charles M.
Adams,
Grace W.
Fong, and
Daniel
Hommer
National Institute on Alcohol Abuse and Alcoholism, National
Institutes of Health, Bethesda, Maryland 20892-1610
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ABSTRACT |
Comparative studies have implicated the nucleus accumbens (NAcc) in
the anticipation of incentives, but the relative responsiveness of this
neural substrate during anticipation of rewards versus punishments
remains unclear. Using event-related functional magnetic resonance
imaging, we investigated whether the anticipation of increasing
monetary rewards and punishments would increase NAcc blood oxygen
level-dependent contrast (hereafter, "activation") in eight healthy
volunteers. Whereas anticipation of increasing rewards elicited both
increasing self-reported happiness and NAcc activation, anticipation of
increasing punishment elicited neither. However, anticipation of both
rewards and punishments activated a different striatal region (the
medial caudate). At the highest reward level ($5.00), NAcc activation
was correlated with individual differences in self-reported happiness
elicited by the reward cues. These findings suggest that whereas other
striatal areas may code for expected incentive magnitude, a region in
the NAcc codes for expected positive incentive value.
Key words:
nucleus accumbens; caudate; reward; anticipation; FMRI; human
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INTRODUCTION |
The
ventral striatum has been implicated as a critical neuroanatomical
substrate for the anticipation of rewards in mammals (Ikemoto and
Panksepp, 1999 ). For example, electrophysiological studies of monkeys
indicate that dopamine projections from the ventral tegmental
area of the midbrain to the nucleus accumbens (NAcc) of the
ventral striatum fire selectively in response to presentation of reward
cues (Schultz et al., 1992). However, theorists have questioned the
selectivity of NAcc dopamine release for anticipation of rewards versus
punishments, because rat studies indicate that stressors can also
increase dopamine release in the NAcc and that NAcc lesions can impair
active avoidance as well as approach behaviors (Salomone et al.,
1997).
Comparative research also suggests that dopamine release occurs more
robustly in the NAcc during reward anticipation than during reward
consumption (Berridge and Robinson, 1998; Ikemoto and Panksepp, 1999).
However, no human brain-imaging studies that have examined ventral
striatal activity during incentive tasks have explicitly focused on the
anticipation of rewards versus punishments (Thut et al., 1997; Koepp et
al., 1998; Delgado et al., 2000; Elliott et al., 2000; Knutson et al.,
2000; O'Doherty et al., 2001). In the present study, we were able to
visualize brain activity during anticipatory intervals because
of the enhanced temporal resolution afforded by event-related
functional magnetic resonance imaging (FMRI) (~2 sec for multislice
volumes) relative to other brain imaging modalities such as positron
emission tomography (PET). In addition, we were able to focus on neural
responses in small regions of the ventral striatum (e.g., the NAcc)
because of the relatively fine spatial resolution of FMRI (~4 mm).
Based on primate work (Schultz et al., 1997), we have adapted a
paradigm for FMRI that elicits anticipation of monetary reward or
punishment, called the monetary incentive delay (MID) task (Knutson et
al., 2000). During the MID task, participants see cues that indicate
that they may win or lose money, then wait for a variable anticipatory
delay period, and finally respond to a rapidly presented target with a
single button press to try to either win or avoid losing money. In this
study, we used a parametric version of the MID task to examine whether
the NAcc would respond during anticipation of varying amounts of
potential reward versus punishment in a graded manner and whether this
activity would be related to cue-elicited emotional responses. If
anticipation of increasing reward most potently recruits the NAcc, we
hypothesized that (1) regions of the NAcc would show increased
activation during anticipation of monetary reward versus anticipation
of no monetary consequences, and (2) these same areas should show
increased activation during anticipation of larger versus smaller
monetary rewards.
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MATERIALS AND METHODS |
Eight physically and psychiatrically healthy volunteers (four
women and four men, right-handed, mean age 31) participated in
the study. Before entering the scanner, participants completed a
practice version of the task lasting 10 min. This practice task both
minimized later learning effects and produced an estimate of each
individual's reaction time for standardizing task difficulty in the
scanner. Participants were also shown the money that they could earn by
performing the task successfully. All participants correctly believed
that they would receive money at the end of the experiment. Once in the
scanner, anatomical and functional scans were collected. Participants
engaged in two 10 min sessions of the MID task during functional scan
acquisition. After each session, participants retrospectively rated how
they felt when they saw each of the seven cues on four-point Likert
scales indexing cue-elicited affective valence (i.e., "happy" and
"unhappy"). All participants gave written informed consent, and the
study was approved by the Institutional Review Board of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
MID task. Each of the two MID task
sessions consisted of 72, 6 sec trials, yielding a total of 144 trials.
During each trial, participants saw one of seven cue shapes (cue, 250 msec), fixated on a crosshair as they waited a variable interval
(delay, 2000-2500 msec), and then responded to a white target square
that appeared for a variable length of time (target, 160-260 msec)
with a button press. Feedback (feedback, 1650 msec), which followed the
disappearance of the target, notified participants of whether they had
won or lost money during that trial and indicated their cumulative
total at that point. On incentive trials, participants could win or avoid losing money by pressing the button during target presentation. Task difficulty, based on reaction times collected during the practice
session before scanning, was set such that each participant should
succeed on ~66% of his or her target responses. FMRI volume acquisitions were time-locked to the offset of each cue and thus were
acquired during anticipatory delay periods (Fig.
1).
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Figure 1.
Task design and orthogonal regressors of interest,
which contrasted (1) general anticipation versus response
and feedback, (2) anticipation of monetary reward versus no
monetary outcome, (3) anticipation of monetary punishment
versus no monetary outcome, (4) anticipation of a large
(+$5.00) versus small (+$0.20) monetary reward, and (5)
anticipation of a large ( $5.00) versus small ($0.20) monetary
punishment.
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Cues signaled potential reward (n = 54; denoted by
circles), potential punishment (n = 54; denoted by
squares), or no monetary outcome (n = 36; denoted by
triangles). Reward cues signaled the possibility of winning $0.20
(n = 18; a circle with one horizontal line), $1.00
(n = 18; a circle with two horizontal lines), or $5.00
(n = 18; a circle with three horizontal lines).
Similarly, punishment cues signaled the possibility of losing $0.20
(n = 18; a square with one horizontal line), $1.00
(n = 18; a square with two horizontal lines), or $5.00
(n = 18; a square with three horizontal lines). Trial
types were pseudorandomly ordered within each session (Knutson et al.,
2000).
FMRI acquisition. Imaging was performed using a 1.5 T
General Electric MRI scanner (General Electric, Milwaukee, WI)
and a standard quadrature head coil. Sixteen 3.8-mm-thick slices
(in-plane resolution, 3.75 × 3.75 mm) centered around the
intrahemispheric fissure were sagittally acquired with no interslice
gap. This plane of acquisition and voxel size provided adequate
resolution of subcortical regions of interest, such as the NAcc and
amygdala, as well as of the anterior orbital frontal cortex, although
the posterior orbital frontal cortex showed signal dropout because of
proximity to tissue boundaries. Functional scans were acquired using a
T2*-sensitive gradient echo sequence with the parameters of repetition
time (TR) (2000 msec), echo time (TE) (40 msec), flip (90°), and
number of volumes (432). Structural scans were acquired using a
T1-weighted spoiled grass sequence (TR, 100 msec; TE, 7 msec; flip,
90°), which facilitated localization and coregistration of functional data.
FMRI analysis. Analyses focused only on changes in blood
oxygen level-dependent (BOLD) contrast that occurred during
anticipatory delay periods and were conducted using Analysis of
Functional Neural Images software (Cox, 1996). For
preprocessing, voxel time series were interpolated to correct for
nonsimultaneous slice acquisition within each volume (using sinc
interpolation and the rightmost slice as a reference), concatenated
across both task sessions, and then corrected for three-dimensional
motion (using the third volume of the first session as a reference).
Visual inspection of motion-correction estimates confirmed that no
participant's head moved >1.5 mm in any dimension from one volume
acquisition to the next.
Preprocessed time series data for each individual were analyzed by
multiple regression (Neter et al., 1996), which allowed us to
statistically covary out "nuisance" variables related to head
motion and scanning session, to optimally localize functionally relevant volumes of interest (VOIs). The regression model consisted of
a set of five orthogonal regressors of interest, six regressors describing residual motion, and four regressors modeling baseline differences and linear trends for each of the two experimental sessions. Regressors of interest were convolved with a
 -variate function that modeled a prototypical hemodynamic
response before inclusion in the regression model (Cohen, 1997).
Maps of t statistics representing each of the regressors of
interest were transformed into Z scores, which were
spatially normalized by warping to Talairach space, slightly spatially
smoothed to approximate the original voxel size (rms, 4 mm), and
combined into a group map using a meta-analytic formula [average
Z * square root (n)] (Table
1) (Knutson et al., 2000;
Donaldson et al., 2001). Separate conjunction maps were calculated for
reward and punishment by thresholding (0, no activation; 1, activation)
and multiplying orthogonal regressor maps for incentive versus neutral anticipation (p < 0.05) with maps for high
versus low incentive anticipation (p < 0.05)
(Friston et al., 1999). In addition to yielding a conjoined probability
threshold appropriate for the NAcc VOIs
(p < 0.0025; n = ~10 voxels
on either side), these conjunction maps allowed us to test for
parametric incentive effects in the VOIs without assuming a linear
relationship between incentive magnitude and brain activation response.
Overlapping thresholded regions that met both functional criteria and
also fell within the anatomical boundaries of the regions of interest
(Breiter et al., 1997) were used to construct right NAcc and right
caudate VOIs.
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Table 1.
Regressor of interest Z scores and Talairach
coordinates of peak activation foci right/anterior/superior (RAS)
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The percentages of change in BOLD contrast for the anticipatory periods
of each trial type (modeled with a 4 sec lag) were extracted from these
VOIs and averaged (n = 18 per cue). The mean percentage
BOLD contrast change scores were then analyzed with 4 (magnitude,
within) × 2 (valence, within) repeated-measures ANOVAs.
The mean performance and cue-elicited affect for each trial type were
analyzed with similarly constructed ANOVAs. Differences between various
incentive conditions were tested using Tukey's honestly significant
difference post hoc paired comparisons. For VOI
correlational analysis with brain activation, a cue-elicited effect was
mean-corrected within each item and within each participant across
different incentive conditions.
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RESULTS |
Hit rate (i.e., proportion of successful button presses during
target presentation) (mean, 70%; SD, 7.62%) and reaction times for
hits (mean, 200.73 msec; SD, 17.66 msec) did not significantly differ across incentive conditions. Thus, participants maintained a
consistent rate of effort across trials, regardless of incentive condition, as instructed by the experimenter. However, the incentive value of each cue did alter affect ratings. Interactions of cue valence
and magnitude indicated that participants' ratings of cue-elicited
"happiness" increased as reward cue magnitude increased (F(3,21) = 11.84; p < 0.001). Specifically, paired comparisons indicated that participants
reported experiencing more happiness when +$1.00 and +$5.00 cues
appeared, relative to +$0.00 cues (p < 0.01).
In contrast, ratings of cue-elicited unhappiness increased as the
magnitude of punishment cues increased
(F(3,21) = 5.57; p < 0.01). Accordingly, paired comparisons indicated that participants reported more unhappiness when presented with $0.20, $1.00, and
$5.00 cues, relative to $0.00 cues (p < 0.01).
Conjunction of orthogonal regressor maps indicated that brain regions
showing overlapping activation for both anticipation of reward versus
no outcome as well as anticipation of large versus small rewards
included foci in the right nucleus accumbens, bilateral caudate, and
thalamus. However, brain regions showing overlapping activation to
anticipation of punishment versus no outcome as well as anticipation of
large versus small punishments included foci in the right caudate and
thalamus but not in the nucleus accumbens (Table 1). The right NAcc
[Tailairach coordinates (TC), 12,17,2; 495 mm3) and right caudate (TC, 8,3,10; 1525 mm3] striatal VOIs that met both
reward-related functional criteria and fell within the anatomical
boundaries of those subcortical regions were selected for additional analysis.
A main effect of magnitude (F(3,21) = 9.63; p < 0.001) indicated that on average, the right
caudate VOI showed significantly increased activation during
anticipation of both $5.00 punishments and $5.00 rewards relative to
anticipation of no monetary outcome (p < 0.001)
(Fig. 2). However, an interaction of
valence and magnitude (F(3,21) = 6.36;
p < 0.01) indicated that on average, the right NAcc
VOI showed significantly increased activation only during anticipation
of $5.00 rewards, relative to anticipation of no monetary outcome
(p < 0.001).
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Figure 2.
Caudate group regressor maps for anticipation of
large versus small reward (a), reward versus no
outcome (b), large versus small punishment
(c), and punishment versus no outcome
(d); anterior = +3. Overlapping areas for
a and b were conjoined to construct a
right caudate VOI, from which the mean (±SEM) percentage of activation
change was extracted and depicted in the graph
(n = 18 trials per condition per participant).
Anticipation of both $5.00 punishment and $5.00 reward led to a
significant percentage of activation change in this VOI, relative to
anticipation of no outcome.
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To examine whether individual differences in positive affective
reaction to reward cues were associated with individual differences in
NAcc activity, we correlated +$5.00 cue-elicited happiness (mean-corrected) with the right NAcc and right caudate VOI mean percentage of activation change during anticipation of winning a
potential $5.00 reward. This correlational analysis revealed a
significant positive relationship between right NAcc activity and $5.00
cue-elicited happiness (r = 0.74; n = 8; p < 0.05) but not between right caudate activity
and $5.00 cue-elicited happiness (r = 0.55; NS)
(Fig. 3).
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Figure 3.
Nucleus accumbens group regressor maps for
anticipation of large versus small reward (a),
reward versus no outcome (b), large versus small
punishment (c), and punishment versus no outcome
(d); anterior = +18. Overlapping areas for
a and b were conjoined to construct a
right NAcc VOI, from which the mean (±SEM) percentage of activation
change was extracted and depicted in the graph (n = 18 trials per condition per participant). Anticipation of a $5.00
reward only led to a significant percentage of activation change in
this VOI relative to anticipation of no outcome. The scatterplot
depicts the correlation of the percentage of activation change during
anticipation of a potential $5.00 reward and mean-corrected ratings of
$5.00 reward cue-elicited happiness.
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DISCUSSION |
To our knowledge, this is the first study to demonstrate
proportional activation of the NAcc in humans anticipating increasing rewards but not punishments. The selectivity of the NAcc response for
reward anticipation cannot necessarily be predicted on the basis of
comparative research, because NAcc dopamine release has been reported
in both appetitive and aversive circumstances in other species
(Salomone et al., 1997). However, inclusion of human subjects in the
present study enabled us to compare anticipation of symbolically
equivalent rewards and punishments. Although anticipation of both
rewards and punishments increased activation in the medial caudate,
only anticipation of reward significantly increased activation in the
ventral striatal NAcc. These results suggest a functional dissociation
in which the medial caudate codes for expected incentive magnitude,
whereas the NAcc codes for expected positive incentive value.
Anticipation of increasing rewards elicited increasing self-reported
happiness in our participants. Within the large reward condition and
across participants, NAcc activity was also correlated with
self-reported happiness. Increased NAcc activation may be associated
with dopamine release, because NAcc dopamine release can increase NAcc
BOLD contrast in rats (Marota et al., 2000). In addition, PET studies
have demonstrated positive correlations between stimulant-induced
dopamine release in the ventral striatum and ratings of euphoria in
humans (Volkow et al., 1999; Drevets et al., 2001). Thus, the
association between NAcc BOLD contrast and increased ratings of
happiness observed in this study might be accounted for, in part, by
dopamine release in the ventral striatum.
Although these results support a positive hedonic interpretation of
NAcc function, another FMRI study suggests that NAcc activity is
modulated by unpredictability of delivery of fluid rewards (Berns et
al., 2001). Although primate research confirms that delivery of
unpredictable rewards enhances activity in the ventral striatum
(Schultz et al., 1997), delivery of unpredictable punishments does not
necessarily have this effect (Mirenowicz and Schultz, 1996). In the
present study, anticipated success at gaining rewards and avoiding
punishments was kept constant across different incentive conditions,
and participants did not significantly vary in their performance across
incentive conditions. Thus, although the NAcc may be modulated by
reward unpredictability, the present findings suggest that it also
plays a selective role in the anticipation of rewards versus
punishments. However, reward unpredictability may magnify both
immediate positive hedonic reactions as well as anticipation of
subsequent rewards. These possibilities would be consistent with the
current findings and pose intriguing possibilities for future research.
Our present focus on anticipation necessitated that we compare
activations that occurred only 4 sec after anticipatory intervals. This
conservatively short lag was selected to minimize potentially confounding activations because of cue perception, which occurred before anticipatory intervals, and also motor response or feedback, which occurred after anticipatory intervals. Comparison of anticipatory activation that occurred before reward feedback versus nonreward feedback revealed no significant differences, demonstrating that brain
activity during subsequent reward feedback did not contaminate the
activation observed during the anticipatory intervals. However, hemodynamic lags in peak BOLD response may vary across different regions of the brain as well as across different individuals (Buckner, 1998). In addition, reward feedback may induce more prolonged activation than either punishment or neutral feedback in the caudate (Delgado et al., 2000). Thus, the 4 sec lag may have failed to illuminate later or more sustained activations evoked by anticipation of incentives. Nonetheless, comparisons of activations that occurred at
a later lag (6 sec) yielded similar results, which were less robust in
the NAcc and more robust in the caudate. Therefore, although the NAcc
may respond earlier or more phasically than the caudate during reward
anticipation, the observed pattern persists over time.
Although we report an apparently lateralized response of the right
NAcc, reduction of significance thresholds for the group maps revealed
similar activation patterns in the left NAcc during anticipation of
reward (p < 0.10, uncorrected) but not during anticipation of punishment. The apparently unilateral finding reported
here may result from asynchronies in the timing of slice acquisition,
rather than from true lateralization of function. Choice of a small
voxel size (~4 mm on each side) and smoothing kernel (4 mm rms) may
have enabled us to better resolve the NAcc focus of activity and to
minimize partial voluming effects. Our group activation focus fell
squarely within the anatomical boundaries of the rostral NAcc, in
contrast to other ventral striatal foci reported in FMRI studies of
monetary reward feedback such as the putamen (Elliott et al., 2000) and
sublenticular extended amygdala (Delgado et al., 2000). Although rat
studies implicate the shell of the NAcc more prominently than the core
of the NAcc in reward anticipation (Ikemoto and Panksepp, 1999), the
NAcc shell shows anatomical dispersion across different areas of the
ventral striatum in primates (Gerfen et al., 1985). Thus, the current
spatial resolution of brain imaging technology cannot resolve
activation associated with NAcc subcompartments (Drevets et al.,
2001).
Notably, all of the regions defined by conjunction maps (i.e., those
that responded in a parametric manner) lay below the cortex. This
subcortical localization is in contrast to the prominent mesial
cortical activations that we observed in a previous study of incentive
response (Knutson et al., 2000) and is in contrast to the orbitofrontal
cortical activations reported by others in studies of reward feedback
(Thut et al., 1997; Elliott et al., 2000; O'Doherty et al., 2001).
Unlike electrophysiological studies in monkeys, we did not observe
parametric activation during reward delays in the ventral orbitofrontal
cortex (Hikosaka and Watanabe, 2000; Schultz et al., 2000). However,
our scanning protocol was designed to focus on the ventral striatum,
and signal dropout in the posterior (but not anterior) orbitofrontal
cortex may have compromised our ability to detect activation there. In
addition to the NAcc and caudate, we also observed parametric
activation of the anterior thalamus, which shares reciprocal
connections with both mesial and orbitofrontal cortices (Price, 1999),
so activations in those cortical regions may have been compromised by
their relatively greater anatomical variability. However, primate electrophysiology studies show that striatal, not orbitofrontal, neurons continue to fire during delays between reward presentation and
responses to obtain rewards (Schultz et al., 2000). Future brain
imaging studies of a similar design with improved orbitofrontal resolution will be better suited to elucidate the role of the orbitofrontal cortex in human reward anticipation.
Despite the prominence of the amygdala in many current neuroimaging
studies of emotional processes, conjunction analysis at exploratory
thresholds did not reveal obvious parametric amygdalar activation
during anticipation of incentives. This absence may result from our
intentional minimization of learning components in the MID task,
because the amygdala shows the most robust activation during
acquisition of incentive associations but habituates rapidly thereafter
in FMRI studies (Breiter et al., 1996; Whalen, 1998; Buchel et al.,
1999). Instead, the present results suggest that reward anticipation
may carry a distinct "signature" characterized not only by positive
affect but also by activation of the nucleus accumbens.
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FOOTNOTES |
Received April 12, 2001; revised May 9, 2001; accepted May 17, 2001.
This work was supported by the National Institute on Alcohol Abuse and
Alcoholism Intramural Research Program. We thank Jerald Varner, Michael
Kerich, Thomas Lionetti, and Jonathan Walker for support, as well as
Peter Bandettini, Steven Grant, and Wayne Drevets for comments on
earlier drafts of this manuscript.
Correspondence should be addressed to Dr. Brian Knutson, National
Institute on Alcohol Abuse and Alcoholism, National Institutes of
Health, Building 10, Room 6S240, MS 1610, Bethesda MD 20892-1610. E-mail: knutson{at}odin.niaaa.nih.gov.
This article is published in
The Journal of Neuroscience, Rapid Communications Section,
which publishes brief, peer-reviewed papers online, not in print. Rapid
Communications are posted online approximately one month earlier than
they would appear if printed. They are listed in the Table of Contents
of the next open issue of JNeurosci. Cite this article as:
JNeurosci, 2001, 21:RC159 (1-5). The
publication date is the date of posting online at
www.jneurosci.org.
| |
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TOP
ABSTRACT
INTRODUCTION
