Diekhof 2008 Rewproc Decmakin

B RA I N R E SE A R CH RE V I EW S 59 ( 20 0 8 ) 1 6 41 8 4
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s r e v
Review
Functional neuroimaging of reward processing and

decision-making: A review of aberrant motivational and
affective processing in addiction and mood disorders
Esther Kristina Diekhof , Peter Falkai, Oliver Gruber
Systems Neuroscience Unit, Department of Psychiatry and Psychotherapy, Georg August University,
Von-Siebold-Strasse 5, D-37075 Goettingen, Germany
A R T I C LE I N FO
AB S T R A C T
Article history:
The adequate integration of reward- and decision-related information provided by the
Accepted 11 July 2008
environment is critical for behavioral success and subjective well being in everyday life.
Available online 21 July 2008
Functional neuroimaging research has already presented a comprehensive picture on affective

and motivational processing in the healthy human brain and has recently also turned its
Keywords:
interest to the assessment of impaired brain function in psychiatric patients. This article
Substance abuse disorder
presents an overview on neuroimaging studies dealing with reward processing and decision-
Major depression
making by combining most recent findings from fundamental and clinical research. It provides
Bipolar disorder
an outline on the neural mechanisms guiding context-adequate reward processing and
fMRI
decision-making processes in the healthy brain, and also addresses pathophysiological
PET
alterations in the brain's reward system that have been observed in substance abuse and mood
ALE meta-analysis
disorders, two highly prevalent classes of psychiatric disorders. The overall goal is to critically
evaluate the specificity of neurophysiological alterations identified in these psychiatric
disorders and associated symptoms, and to make suggestions concerning future research.
2008 Elsevier B.V. All rights reserved.
Contents
1.
2.
3.
4.
5.
6.
7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Learning to predict reward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Representation of reward and punishmentrelevance detectors in the brain . . . . . . . . . . . . . . . . . .
Parsing rewardAffective value and motivational significance . . . . . . . . . . . . . . . . . . . . . . . . . .
Deciding advantageouslyReversal-learning, prospective planning and impulsive choice . . . . . . . . . . .
Implications for psychiatric disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1. Activation likelihood estimation (ALE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Substance (ab)use disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1. Regional distribution of activation associated with drug-related stimulation in addictionActivation
Estimation Estimation
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Likelihood
7.2. Substance (ab)use disordersConclusions and outstanding questions . . . . . . . . . . . . . . . . . .
Corresponding author. Fax: +49 551 39 2798.

E-mail addresses: eschlue@gwdg.de (E.K. Diekhof), pfalkai@gwdg.de (P. Falkai), ogruber@gwdg.de (O. Gruber).
0165-0173/$ see front matter 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.brainresrev.2008.07.004
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Likelihood
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B RA I N RE SE A R CH RE V I EW S 59 ( 20 0 8 ) 1 6 41 8 4
8.
Mood disordersChanges in motivational relevance and affective processing . . . . . .

8.1. Regional distribution of activation associated with mood-congruent processing
Estimation
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Likelihood Estimation
8.2. Mood disordersConclusions and outstanding questions . . . . . . . . . . . . .
9.
General conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10. Limitations of ALE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.
Introduction
Reward is no unitary concept, but subsumes several components including learning-related, motivational, affective and
decisional aspects (Chau et al., 2004). Organisms form
predictions, compare different reward opportunities with
regard to their relative value and balance immediate reward
with long-term utility to guarantee overall behavioral success.
In the healthy brain the integration of reward-related
information is ensured by several cortical and subcortical
regions that form the brain's reward circuit, which is also
involved in the selection and initiation of goal-directed
behavior (O'Doherty, 2004). Adaptive decision-making further
relies on regions that represent higher-order cognitive control
processes (e.g., planning) and help to balance affectively
guided impulsive choice and rational future-oriented considerations in order to maximize long-term behavioral
success (Trepel et al., 2005).
Disturbances within the reward system have detrimental
effects on behavior. Especially mood disorders and substance
abuse disorders have already been reported to involve overt
behavioral deficits in emotional processing leading to abnormal motivational and affective processing. Recent neuroimaging studies have provided a useful means that allowed to
relate these overt deficits to their underlying neural substrates
and to identify specific regional disturbances within the
reward system of psychiatric patients. Nevertheless, to
completely understand pathophysiological alterations it is
also necessary to be aware of the neurophysiology of reward
processing and decision-making in the healthy brain. This
review will therefore provide a brief outline on brain regions
that in the healthy brain predict rewards, sense rewarding
outcomes, process them in a context-sensitive way and finally
decide upon the actions that lead to the direct acquisition of
reward by also balancing it with long-term reward utility. We
will thereby briefly address recent functional neuroimaging
studies on healthy human subjects, before in a second step we
will deal with their relevance for the pathophysiology of
psychiatric disorders. The focus will be on substance abuse
disorders and mood disorders, two highly prevalent classes of
psychiatric disorders, which can be characterized by overt
motivational deficits, disordered affective processing and
impairments in decision-making. The aim of this article is to
review and evaluate neuroimaging findings from the last
decade with regard to their contribution to the understanding
of pathophysiological processes and their disorder-related
specificity regarding alterations in the reward system. From
this, we will be able to derive useful suggestions for future
neuroimaging research by also pointing to potential intercon-
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in MDDActivation
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Likelihood
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nections with other experimental approaches (e.g., psychopharmacological research).
2.
Learning to predict reward
The prospective organization of goal-directed behavior requires

the correct prediction of when and where rewards will occur.
Decisive information for the formation of such predictions has
thereby been assumed to be mainly derived from the observation of environmental regularities (e.g., the contingency
between a certain action and its outcome; O'Doherty, 2004). As
the major source for the release of a neural teaching signal
providing the organism with important information on changing reward contingencies, midbrain dopamine projections to
the striatum and frontal cortex have been found to communicate an error in reward prediction. Accordingly, in animals
unexpected or bigger than expected rewards and also unexpected reward-predicting stimuli elicited a positive response in
these neurons, whereas the same dopaminergic neurons
remained unresponsive to a completely expected reward
(Schultz, 1998). In addition, dopaminergic neurons have also
been observed to be responsive to a large category of salient and
arousing events, including aversive, high intensity and novel
stimuli without any rewarding property (see Horvitz, 2000 for a
comprehensive review). It has hence been suggested that
dopamine neurons represent an essential component in the
process of attentional and behavioral switching by preparing the
organism for the appropriate reaction to all kinds of salient
environmental changes regardless of their affective valence
(Redgrave et al., 1999; Horvitz, 2000), even though this view has
not remained undisputed (Ungless, 2004).
In humans, activations observed in subcortical dopamine
target sites like the ventral striatum resembled the reward
prediction error signal found in nonhuman primates (O'Doherty et al., 2003a, 2004; Davidson et al., 2004; Abler et al. 2006;
Wrase et al., 2007a), but also represented salient events in
general (Zink et al., 2003, 2006). Dopaminergic function may
thereby have a direct modulatory influence on striatal activity
and behavioral choice, which has recently been demonstrated
through pharmacological probe (Pessiglione et al., 2006).
Within this context, a further distinction has to be made
between prediction error-related activation in the ventral
striatum that coded the difference between the actual and
expected outcome during Pavlovian conditioning and activation in dorsal striatal areas that occurred preferentially during
instrumental conditioning and positive reinforcement learning (O'Doherty et al., 2004). This observation indicated that the
dorsal striatum supposedly serves a central function in the
166
establishment of stimulusresponse(reward) contingencies,

while ventral striatal activity represents outcome-related
predictions, even independent of affective value (see also
Wrase et al., 2007a). These complementary functions of
ventral and dorsal striatal regions may well accord with
models of reinforcement learning and instrumental conditioning (e.g., the actorcritic model; Sutton and Barto, 1998;
Holroyd and Coles, 2002). Accordingly, the prediction error
response in the ventral striatum may allow organisms to
update predictions of expected reward or punishment,
whereas the response in the dorsal striatum supposedly
optimizes reward-related action choice and thus helps the
organism to maximize expected long-term reward (O'Doherty
et al., 2004; Wrase et al., 2007a).
Other regions involved in both predictive learning of
positive and aversive events in humans were the amygdala
(pain relief; Seymour et al., 2005; monetary loss; e.g., Yacubian
et al., 2006) and frontal dopamine target sites, whose activity
was associated with reward-related learning processes. These
frontal areas included the medial orbitofrontal cortex (OFC;
Berns et al., 2001; O'Doherty et al., 2003a; Tobler et al., 2006),
but also lateral parts of the OFC (Tobler et al., 2007). Other parts
of the medial prefrontal cortex like the anterior cingulate
cortex (ACC) were activated by successfully obtained reward in
a manner that scaled to the amount of the respective outcome
(Knutson et al., 2003), or responded to unexpected events that
required the withholding of an already prepared response,
which indicated that this region may have been involved in
guiding behavioral choice based on highly salient environmental events (Davidson et al., 2004).
After learning has occurred, reward-related neural responses have been observed to shift from the actual reward to
the reward-predicting stimulus or response (O'Doherty, 2004).
Activation in the ventral striatum (in particular in the nucleus
accumbens) has thereby been reported to convey the motivational significance of emotionally laden stimuli. Ventral
striatal responses represented either the magnitude of an
anticipated gain predicted by a visual cue (Breiter et al., 2001;
Knutson et al., 2001; Galvan et al., 2005; Knutson et al., 2005), or
the anticipation of an aversive stimulus (Jensen et al., 2003).
Similarly, the OFC also exhibited increased activation in
response to the anticipation of a sweet taste reward (O'Doherty
et al., 2002) and to a rewarding outcome occurring contingent
on a manual response (Galvan et al., 2005). Amygdala activation has more often been observed during the anticipation of
aversive events (e.g., Breiter et al., 2001; Glaescher and Bchel,
2005), even though there is also evidence for its involvement in
the prediction of positive events (Gottfried et al., 2003). This
also underlines the important role of these regions in
conditioning and stimulusreward association learning, in
which the reward value of a reinforcer is transferred to a
reward-predicting cue (e.g., Cox et al., 2005; Gottfried et al.,
2003).
3.
Representation of reward and punishment
relevance detectors in the brain
Besides the establishment of predictions of when and where
rewards will occur, adaptive behavior requires the ability to
represent the current motivational value of available rewards,

which permits context-sensitive behavioral choices between
different rewards. Within the human brain's reward circuit, the
OFC has thereby been most consistently found to represent the
rewarding outcomes and the relative value of reinforcers
(O'Doherty, 2004). Particularly, activations in posterior parts of
the OFC were associated with the positive motivational value of
natural reinforcers (e.g., food) depending on current need state
(O'Doherty et al., 2000; Morris and Dolan, 2001; Gottfried et al.,
2003; Kringelbach et al., 2003), which was independent of
stimulus identity (e.g., both verbal feedback and monetary
reward activated an identical region, but to a different degree;
Kirsch et al., 2003). Thus, activity in these brain regions may
provide a collective motivational currency for adaptive (behavioral) decisions (Montague and Berns, 2002; Kringelbach, 2005).
Additionally, some studies further proposed a similar role for
the amygdala, the ventral striatum and the ACC (Gottfried et al.,
2003). However, in contrast to the OFC, amygdala activations
failed to parallel the decision for or against a reinforcer (Arana
et al., 2003), and the ACC and the ventral striatal response
supposedly rather seemed to play an important role in the
response selection process (Gottfried et al., 2003).
Interestingly, activity in most of these regions was also
observed during processing of aversive and punishing outcomes.
In the amygdala increased activation also occurred in association
with fear- or threat-cues, especially facial expressions (Whalen,
1998; Calder et al., 2001; Williams, 2006), and the posterior OFC
was also responsive to aversive events like unpleasant odors
(e.g., Gottfried et al., 2002 but see Rolls et al., 2003). This indicated
that the amygdala and at least posterior parts of the OFC may
have rather coded the emotional relevance than the actual
affective valence of environmental stimuli, which was also
supported by the findings of a valence-independent representation of all motivationally significant events in the amygdala
(Garavan et al., 2001; Liberzon et al., 2003; Phan et al., 2004;
Fitzgerald et al., 2006) and a general representation of motivational significance in the posterior OFC (unpublished data from
our laboratory). These relevance detectors may therefore be
devoted to the processing of a broader category of the motivational relevance of biologically significant stimuli independent of
affective valence (see also Sander et al., 2003).
4.
Parsing rewardAffective value and
motivational significance
The existence of valence-independent relevance detectors
implies that it may be critical to make a clear distinction
between the affective value of a stimulus (i.e., positive or
negative) and its actual motivational significance for the
organism. Although these two components usually occur
collectively in the environment, at least in animals there is
evidence that they recur on different neural substrates.
Dopamine has been assumed to represent the motivational
wanting component of reward (eliciting approach or avoidance responses), while the hedonic or pleasure component
remained widely unaffected by manipulations of the dopaminergic system. Instead affective liking supposedly recurs on
opioid neurotransmission onto GABAergic spiny neurons in
the nucleus accumbens (for an elaborate review on the neuro-
biological basis of the concepts of motivation and pleasure

please refer to Berridge and Robinson, 2003). Neuroimaging
evidence for a regional dissociation of the two reward components is sparse, but there may be some hints for candidate
regions that supposedly (exclusively) represent positive hedonic value (e.g., the medial orbitofrontal cortex; O'Doherty et al.,
2001).
5.
Deciding advantageously
Reversal-learning, prospective planning and
impulsive choice
Decision-making refers to the process of forming preferences,
selecting and executing actions, as well as evaluating (possible
or anticipated) outcomes (Ernst and Paulus, 2005). It requires
the ability to accurately evaluate elements of outcome,
including motivational value, outcome predictability, and
risk. On the most basic level, organisms base their behavioral
decisions on simple stimulusresponseoutcome associations. Significant changes in the motivational value of environmental stimuli should thereby directly modulate behavioral
choice, because alternative options might provide the chance
to increase overall profit or to avoid future failure. Accordingly,
in humans, cortical activation related to rapid behavioral
adjustments in response to environmental change have
mainly been observed in parts of the orbitofrontal and the
cingulate cortex. Interestingly, the lateral OFC was thereby
exclusively responsive to negative feedback that was followed
by a subsequent change in or an immediate optimization of
behavior, but remained unresponsive to negative feedback per
se (O'Doherty et al., 2001; Cools et al., 2002; Kringelbach and
Rolls, 2003; O'Doherty et al., 2003b; Wrase et al., 2007a). This
indicated that the lateral OFC may play an important role in
flexible guidance of behavior by supporting inhibitory control
processes and helping organisms to overcome perseverative
responding (Elliott and Deakin, 2005). The active response-selection component of reward-based decision-making in the
reversal-learning paradigm has further been assigned to the
ACC and associated parts of the medial frontal cortex (Bush
et al., 2002; Kringelbach and Rolls, 2003; see also Kringelbach,
2005) and activation of the ACC has also been observed during
learning from punishment in that it correlated with behavioral
adjustments following punishment-related information (e.g.,
Wrase et al., 2007a). In addition, striatal subregions may also
serve important functions during goal-directed decisionmaking based on simple stimulusresponseoutcome associations. The specific topography of focal projections from
various parts of the frontal cortex may thereby predispose
corresponding striatal regions for differential, but nevertheless complementary functions during reward-related decision-making (Haber et al., 2000, 2006). Accordingly, the ventral
striatum and adjacent parts of the dorsomedial and central
striatum, which are densely connected with ACC, OFC and
ventromedial frontal cortex, may integrate various aspects of
reward evaluation including reward predictability, expectation and salience and may thus coordinate behavioral guiding
rules (see also Section 2 of this review). In contrast, dorsal and
rostral aspects of the striatum receive dense projections from
the dorsolateral prefrontal cortex, which partly converge with
167
inputs from ACC and OFC, suggesting a central role for dorsal
striatal compartments in the synchronization of different
aspects of reward-related learning operations. Through these
connections the dorsal striatum may establish the linkage
between reward and subsequent behavior, integrate incentive
drive with long-term planning or facilitate habit formation
(Haber et al., 2000, 2006; see also Balleine et al., 2007).
Although on many occasions direct stimulusoutcome or
reward-related information may suffice to guide adaptive
behavior (e.g., in reversal-learning or reinforcer devaluation
paradigms), there are many decisions that nevertheless
require subjects to deliberate about future consequences of
current choices to maximize overall future prospects. This
necessitates the ability to balance the direct emotional
wanting of immediate gratification and cognitive futureoriented strategic planning to achieve optimal choice behavior. For instance, in the Iowa Gambling Task (IGT) subjects
have to abstain from a short-term benefit to maximize longterm monetary profit (Bechara et al., 1996). On the neural level,
especially the dorsolateral prefrontal cortex (DLPFC) has been
assumed to organize the temporal integration of decisionrelated information in humans in that particular task (Trepel
et al., 2005). Resting-state cerebral blood flow in this region
showed a significant correlation with IGT performance (Adinoff et al., 2003; Northoff et al., 2006), while patients with lesions
of the DLPFC failed to choose optimally in this task (Fellows
and Farah, 2005). In addition, the ventromedial prefrontal
cortex (including the OFC) has also been reported to be
associated with success in the IGT (Northoff et al., 2006).
Nevertheless, this association may rather be assigned to the
direct reversal-learning component of the task (i.e., to the
inability to shift from the initially preferred bad decks to the
good decks; Fellows and Farah, 2005) that may equally
account for the observed relation between activation in
other medial frontal areas and behavioral success in the IGT
(Fukui et al., 2005).
6.
Implications for psychiatric disorders
Overt behavioral impairments of motivational and affective

processing like an overvaluing of some reward categories (e.g.,
drugs in patients with substance use disorders) at the expense
of others or a mood-congruent bias towards a certain category
of affective stimuli (e.g., sad faces in depressives) have been
reported to significantly compromise everyday life of psychiatric patients. Despite small sample sizes and obvious confounds in clinical populations in comparison to healthy
control subjects (e.g., medication effects or differential compliance), neuroimaging studies provide a powerful means for
revealing the underlying pathophysiological alterations that
relate to behavioral impairments in psychiatric populations,
which may further help to identify disorder-specific markers
in the brain.
The first part of this article provided a brief outline on
neuroimaging findings from studies on reward processing and
decision-making in healthy human subjects. Evidence from
fundamental research thereby suggested that partially miscellaneous but nevertheless overlapping circuits allow the
prediction and anticipation of positive or negative outcomes
168
and help to guide adaptive behavioral adjustments in response

to changing reward contingencies allowing maximization of
(expected) long-term profit during decision-making and reinforcement learning. In the second part of this article we will
provide a comprehensive review of the results from recent
neuroimaging studies using either the method of functional
magnetic resonance imaging (fMRI) or positron emission
tomography (PET) to reveal the underlying pathophysiology
of affective, motivational and decision-making deficits in
addiction and mood disorders. The focus thereby lies on
neuropsychiatric studies that dealt with reward prediction,
general processing of reward feedback or motivational cues
(e.g., mood-congruent stimuli in depression or drug-related
stimulation in addiction) or with reward-related decisionmaking. The specific aims of our review of the psychiatric
neuroimaging literature from the last decade are (1.) to provide
a systematic, comprehensive overview of (disorder-specific)
characteristics of neural aberrations during motivational and
affective processing in psychiatric patients with mood disorders or addiction, with a direct reference to overt symptoms
and behavioral alterations in these disorders, and (2.) to
achieve a critical appraisal of the literature that allows us to
highlight factual confounds and shortcomings of previous
neuropsychiatric research. Finally, we also would like to (3.)
draw conclusions that help us to point out currently unanswered questions that (4.) allow us to present suggestions for
future neuroimaging research.
For this purpose we pursued a systematic MEDLINE search
for substance abuse disorders (or addiction, drug abuse or
craving), major (or unipolar) depression and bipolar
(affective) disorder by including the name of the respective
disorder in the search termini and combining it (AND) with
reward, decision-making or emotion in combination with
fMRI or PET. We thereby restricted our search to relevant
articles published within the last decade (between 1997 and
2007). Since we wanted to focus on functional neuroimaging
research in adults with mood disorders or substance abuse
disorders, studies that dealt with pediatric or adolescent cases
or reported results from structural imaging were excluded.
Also, neuroimaging studies assessing the neural correlates of
behavioral addictions (e.g., pathological gambling) were not
included in our systematic literature review.
In all, combination of the search termini and subsequent
application of the exclusion criteria yielded 57 articles. Of the
26 neuroimaging studies on addiction, 17 articles dealt with
cue-induced craving in subjects during various states of
abstinence (5 articles dealt with alcohol abuse, 6 with cocaine
abuse, 1 with opiate abuse and 5 tested healthy smokers). In yet
another 5 studies subjects were tested with paradigms
assessing the effects of monetary reward or feedback (1 in
alcohol abusers, 2 in cocaine abusers, 1 in opiate addicts and 1
in healthy smokers). The IGT was employed by 3 studies on
reward-related decision-making in addiction (2 in cocaine and
1 in marijuana abusers) and the Cambridge Risk Task was used
by one study (in heroin abusers). For the search term major (or
unipolar) depression we found 18 studies that used motivationally relevant cues of different affective value in mostly
medicated patients (9 studies employed either emotional
pictures or words, 5 used emotional facial displays, 1 presented
performance-related feedback, 1 used a reward expectation
paradigm and 2 studies employed a mood-provocation task).

Finally, thirteen neuroimaging studies dealt with motivational
processing in medicated patients with bipolar disorder (in 8 of
these studies the sample was in the state of mania or a mixed
state, four assessed only euthymic patients and 1 dealt with
patients in a depressive state). Of these studies, 5 used affective
facial displays of varying value to assess explicit and implicit
affect processing, 6 presented emotional words or pictures, 1
employed a reward expectation paradigm and 1 assessed risktaking performance in bipolar patients in the state of mania.
The results of these functional imaging studies are listed in
Tables 13, which delineate affected brain regions and report
neural activation levels in relation to the specific experimental
tasks employed (in comparison to either a healthy control
group or to neutral stimulation). Supplementary Tables 1 to 5
provide additional and more detailed information on individual studies (e.g., information on imaging method, sample
size, medication status and subtraction-contrasts). In the
following sections we will summarize these findings to
achieve a comprehensive and conclusive picture on current
evidence from neuroimaging research in mood disorders and
substance abuse.
6.1.
Activation likelihood estimation (ALE)
In addition, to our systematic literature review we also pursued a meta-analysis using activation likelihood estimation
(ALE) as implemented in the GingerALE software (Laird et al.,
2005a; see also Turkeltaub et al., 2002). This voxel-based
approach allows the analysis of the spatial distribution and
concordance of coordinates collected from a predefined set of
studies that dealt with a specific domain or psychiatric
disorder in human brain mapping. ALE models report a focus
of activation as the center of a Gaussian probability distribution and create a whole-brain statistical map that estimates
the likelihood of activation for each voxel for that task as
determined by the complete set of studies (see also Laird et al.,
2005b). Pursuing a quantitative meta-analysis was intended to
complement the systematic literature review, which was
mainly based on anatomical labels assigned by authors, by
providing an increased spatial level of distinction. In particular, we wanted to examine the consistency within the
regional distribution of drug-cue-related hyperactivity in
addiction and further assess the spatial concordance of hyperactivation to mood-congruent or negative stimuli in major
depression (MDD) when compared to the healthy population.
This meta-analysis is understood as an initial attempt to
identify disorder-specific alterations in the pathophysiological
mechanisms leading to a bias in salience attribution towards a
certain category of stimuli in two highly prevalent neuropsychiatric disorders and to derive suggestions as well as possible
hypotheses for future research.
For this purpose we extracted Talairach-coordinates
reported by the relevant studies. Coordinates reported in
the stereotactic space of the template from the Montreal
Neurological Institute (MNI) were converted to Talairach
space using the Lancaster transform (icbm2tal) in GingerALE
(Laird et al. 2005a). We only selected activation maxima that
either occurred in patients in association with a relevant
condition-of-interest (e.g. drug-related cues in addiction)
compared to a neutral control condition and/or showed a

significant difference in patients and healthy control subjects during processing of a condition-of-interest (see
Supplementary Tables 6 and 7). In case both comparisons
were reported, only the latter comparison was used. If a
study reported results from both direct subtraction-contrasts
and correlation analyses, only the former were included in
the meta-analysis. From studies that reported neighboring
peaks that lay maximally 2 voxels apart we selected only the
peak with the highest p-value reported within that particular
region. This was intended to avoid a bias of the metaanalytic results in favor of a subset of articles when
including multiple contrasts from the same article and also
to increase the reliability of activation by not allowing
studies that report more peaks within one region to
contribute disproportionately. Studies that reported separate
results for male and female subjects were entered as
combined data.
Studies were excluded if they only reported anatomical
labels without coordinates (Addiction: Wang et al., 1999;
Wexler et al., 2001; McClernon et al., 2005; MDD: Sheline et
al., 2001; Siegle et al., 2002), or only assessed medication
effects on brain function (MDD: Tremblay et al., 2005). With
regard to MDD studies were also not included if they only
presented positive stimuli (Elliott et al., 1998; Kumari et al.,
2003; Schaefer et al., 2006), or reported no differential
activation in the direct comparison of controls and patients
during negative stimulation (Lawrence et al. 2004; Keedwell et
al., 2005a).
ALE maps were created according to the procedure
described by Turkeltaub et al. (2002). Reported foci of maximal
anatomical difference were modeled as the peaks of threedimensional Gaussian probability density functions with a
full-width half-maximum (FWHM) of 10 mm. These probabilities were combined to construct a map of the ALE score at
each voxel. A permutation test (5000 permutations) was
performed in order to determine the statistical significance
of randomly generated foci using the same FWHM value and
an identical number of foci as in the computation of ALE
values. Probability maps were then corrected for multiple
comparisons using the false discovery rate (FDR) and thresholded at p < 0.05 with a minimal cluster extent of 100 voxels
(see also Laird et al., 2005a). Separate ALE maps were
computed for addiction and MDD in order to assess regional
concordance in activation patterns within groups.
After application of the exclusion criteria 14 of 17 studies
that reported hyperactivation in association with drug-related
stimulation in addiction remained in the sample, yielding a
total of 122 foci (see Supplementary Table 6). Displaying these
foci in Talairach space with the Java-based BrainMap application Sleuth (Laird et al., 2005c) revealed a diffuse pattern of
activation across the whole-brain with some convergence in
frontal areas (see Fig. 1). This pattern appeared to be quite
similar for different drugs of abuse.
For MDD, 10 out of 17 studies could be included in the
meta-analysis comprising 74 foci of hyperactivation related
to negative stimulation (see Supplementary Table 7). In
Talairach space peaks were distributed diffusely with
somewhat higher density in anterior parts of the brain
(see Fig. 2).
7.
169
Substance (ab)use disorders
Addiction may be best described as a pathology of incentive

motivation and behavioral control. As the most prominent
behavioral feature, patients commonly exhibit a decreased
ability to control the desire to obtain drugs, despite knowledge
about the aversive consequences following drug intake or the
low expectation of actual pleasure expected from the drug (see
Schoenbaum et al., 2006). The compulsive character of drug
seeking, the obvious lack of inhibitory control and the lacking
ability to integrate information on aversive outcomes into
behavioral choice may therefore be assigned to a pathological
attribution of motivational relevance to the drug of abuse or to
cues predicting the drug, which makes the drug maximally
salient at the expense of other available (naturally) rewarding
stimuli affecting all stages of reward processing (see Robinson
and Berridge, 2003).
Aberrant brain activations appear to play a role in several
components of maladaptive behavior observed in substance
abuse, including the motivational bias in reward expectancy,
reward evaluation and craving as well as impaired decisionmaking abilities (London et al., 2000). Learned, drug-related
cues thereby produced brain activations comparable to those
seen with non-drug evocative reward stimuli in healthy
comparison subjects and affected roughly the same brain
regions that in healthy subjects had been found to be involved
in reward evaluation and prediction (see above). In more detail,
addiction to various kinds of substances including alcohol,
nicotine, cocaine and opiates was accompanied by abnormal
blood flow and altered activation patterns in reward-sensitive
dopamine-dependent sites in the striatum, the amygdala as
well as in parts of the frontal cortex like the OFC, the ACC and
the DLPFC (see Goldstein and Volkow, 2002). These brain
regions showed an activity bias towards the drug of abuse or
drug-related stimuli and exhibited increased activation to
drug-related stimuli compared to neutral stimuli in abstinent
individuals, especially during the state of craving or acute
withdrawal (e.g., Wrase et al., 2002; see also: Goldstein and
Volkow, 2002; Dom et al., 2005; see also Table 1 and Supplementary Table 1). Since addiction to different kinds of
substances (nicotine: Franklin et al., 2007; alcohol: Hermann et
al., 2006; and partly also opiate and cocaine: Sell et al., 2000;
Risinger et al., 2005) appeared to lead to similar activation
increases in the relevance detectors OFC and amygdala as
well as other regions of the medial and dorsal frontal lobe
during drug-related stimulation (see Fig. 1), the neural mechanism of the motivational bias in addiction may be best
characterized as a general neural reward evaluation deficit.
Apart from an overvaluing of drug-reward, patients also
exhibited a decreased sensitivity to the relative value of other
available non-drug rewards, which was also obvious on the
neural level. Despite the limited number of neuroimaging
studies that directly assessed reward valuation independently
of drug-related stimuli (cf., Table 1 and Supplementary Table
2), evidence suggests that at least some substance abusers
may be compromised in their sensitivity for different amounts
of monetary reward and verbal feedback. The deficit observed
in some patients was reflected in either reduced or even
absent activations of the relevance detectors' OFC, amygdala
170
Table 1 Activations in regions of the brain's reward circuit in patients with substance abuse disorders or in healthy
smokers observed during performance of emotional and reward-processing tasks
Region
MPFC
Direction of
activation
Activation increase
Activation decrease
ACC
Mid cingulate
gyrus
PCC
OFC
LPFC6
Activation increase
Task
Passive perception of craving-related stimuli
Monetary feedback
Passive viewing of sex-related stimuli
Decision-making in IGT
Activation decrease
Activation increase
Cocaine-related imagery
Craving for cocaine self-administration
Active perception of emotional stimuli
Implicit perception of smoking-related stimuli
in a target detection task
Verbal feedback
Activation decrease
Interview about cocaine themes
Activation increase
Activation decrease

Verbal feedback
Reward evaluation
Activation increase
Verbal feedback
Cambridge Risk Task
Activation increase
Activation decrease

Reward evaluation
Monetary reward
Verbal feedback
Anticipation of monetary loss
Reward evaluation
Verbal feedback
Amygdala
Activation increase
Midbrain
Striatum7
Activation decrease
Activation increase
Activation increase
Reward evaluation
Verbal feedback
Study
Garavan et al. (2000)2; Grsser et al. (2004)1;
Heinz et al. (2004)1; Hermann et al. (2006)1;
McBride et al. (2006)4
Martin-Soelch et al. (2001a)5
Bonson et al. (2002)2
Garavan et al. (2000)2
Bolla et al. (2003)2
Brody et al. (2002)4; Brody et al. (2004)4;
Garavan et al. (2000)2, Grsser et al. (2004)1;
McBride et al. (2006)4; Wrase et al. (2002)1
Kilts et al. (2004)2
Risinger et al. (2005)2
Wexler et al. (2001)2
McClernon et al. (2005)4
Adinoff et al. (2003)2
Hermann et al. (2006)1
Martin-Soelch et al. (2001b)4
Franklin et al. (2007)4; Garavan et al. (2000)2;
McBride et al. (2006)4; Sell et al. (2000)5
Wang et al. (1999)2
Bonson et al. (2002)2; Brody et al. (2002)4 ;
Franklin et al. (2007)4; Hermann et al. (2006)1;
Wrase et al. (2002)1; McBride et al. (2006)4;
Sell et al. (2000)5
Goldstein et al. (2007a)2;
Goldstein et al. (2007b)2
Ersche et al. (2006)5
Bonson et al. (2002)2; Brody et al. (2002)4;
Hermann et al. (2006)1; McBride et al. (2006)4 ;
Sell et al. (2000)5; Wrase et al. (2002)1
Wrase et al. (2007b)1
Adinoff et al. (2003)2
Bonson et al. (2002)2
Goldstein et al. (2007a)2
Bolla et al. (2003)2;
Bonson et al. (2002)2; Franklin et al. (2007)4;
Schneider et al. (2001)1
Grsser et al. (2004)1; Heinz et al. (2004)1;
McBride et al. (2006)4; Wrase et al. (2002)1
171
Table 1 (continued)
Region
Striatum7
Direction of
activation
Task
Activation increase
Craving for cocaine-self-administration
Anticipation of monetary gain
Anticipation of monetary loss
Activation decrease
Study
Either in the between-group comparison (versus controls) or within group in comparison with neutral stimuli; 1alcohol; 2cocaine; 3marijuana;
nicotine; 5opiates; 6including DLPFC, VLPFC and APFC; 7including putamen, nucleus caudatus, pallidum and nucleus accumbens.
List of abbreviations; ACC anterior cingulate cortex; APFC anterior prefrontal cortex; DLPFC dorsolateral prefrontal cortex; IGT
Iowa gambling task; LPFC lateral prefrontal cortex; MPFC medial prefrontal cortex; OFC orbitofrontal cortex; PCC posterior
cingulate cortex; VLPFC ventrolateral prefrontal cortex.
and striatum as well as of sensory processing regions during

processing of monetary feedback (in opiate abusers and
healthy smokers: Martin-Soelch et al., 2001a,b; in abstinent
cocaine abusers: Goldstein et al., 2007a). In one study abstinent alcohol-dependent subjects further exhibited an
inverse correlation between craving severity during anticipation of monetary gain and activation in the ventral striatum
(Wrase et al., 2007b). In addition, sex-related stimuli were also
associated with a reduced responsiveness in the brain's
reward circuit in abstinent cocaine abusers when compared
to responses to cocaine-related stimulation or responses
observed in healthy controls, despite similar ratings in both
groups, which ruled out that decreases in brain activations
were simply a function of decreased task engagement
(Garavan et al., 2000). However, especially monetary reward
may not be the best stimulus to test reward-sensitivity outside
of the drug context, because money may as well represent a
drug-related cue that has the propensity to elicit craving,
which should be expected to also impair the ability to correctly
evaluate varying amounts. In fact, in one study there was
evidence that the ability to correctly evaluate different reward
amounts negatively correlated with the degree of craving-like
responses in OFC and amygdala during evaluation of different
monetary amounts (Goldstein et al., 2007b). This observation
further complicates the picture of the underlying pathophysiology of addiction as it underlines that in some patient
populations increased activation within reward-sensitive
regions are not necessarily indicative of a preserved reward
processing ability when dealing with monetary gain.
There is evidence that deficits in reward-sensitive regions
were also related to impulsive choice and temporal discounting of the future in patients with substance abuse disorders,
particularly when tested with drug stimuli (Coffey et al., 2003)
or in a drug-deprived context (Giordano et al., 2002). For
instance, Bechara and colleagues (2002) reported a significant
decrease in IGT performance in substance abusers similar to
the one observed in patients with orbitofrontal and dorsolateral frontal damage (e.g., Fellows and Farah, 2005), which
was accompanied by decreased activation in both right lateral
OFC and DLPFC in one study (in abstinent marijuana abusers;
Bolla et al., 2005). Patients who did not show such a clear
behavioral deficit instead displayed an increased activation in
the right anterior OFC, which positively correlated with task

performance and thus could have represented a countervailing response that compensated for reduced activation in
both right DLPFC and left MPFC (abstinent cocaine abusers;
Bolla et al., 2003; see also Table 1 and Supplementary Table 3).
Performance on this task was further found to be positively
correlated with DLPFC and ACC metabolism at rest (Adinoff et
al., 2003). It therefore seems to be highly likely that a
disturbed balance between activation in limbic regions,
favoring immediate gratification, and frontal regions, integrating future-oriented deliberation into behavioral choice,
may have caused the observed decision-making deficits
whereby a pathologically increased impulsivity may have
led to a preference for immediate monetary gratification
regardless of detrimental long-term effects.
7.1.
Regional distribution of activation associated with
drug-related stimulation in addictionActivation Likelihood
Estimation
The results from the ALE meta-analysis widely supported the
results of our systematic literature review, which had already
indicated that the overvaluing of drug-related stimuli with the
propensity to elicit craving is associated with activation in a
brain circuit that comprises orbitofrontal, limbic (i.e. cingulate
cortex and amygdala) as well as striatal subregions (see Table
4A; Fig. 3A). The highest ALE value within regions of the brain's
reward system was thereby observed in right ACC with a
cluster extent of 3720mm3. In addition, we also found clusters
in the left striatum, in the amygdalae, the left OFC and ACC as
well as in the left PCC. Outside of the reward system, the metaanalysis yielded a cluster in the left precuneus with the
highest ALE value of all clusters and a cluster extent of
1552mm3. In addition, another 4 clusters were observed that
appeared in the superior temporal gyrus bilaterally, the left
middle temporal gyrus and the right superior frontal gyrus.
7.2.
Substance (ab)use disordersConclusions and
outstanding questions
Drug addiction appears to affect a wide variety of motivational
and decision-making processes of every day life. The best
172
Table 2 Activations in regions of the brain's reward circuit in patients with MDD observed during performance of emotional
and reward-related tasks
Region
Direction of activation
MPFC
Activation increase
Expectation of negative pictures

Threat-related words
Happy mood induction
Activation decrease
Emotional rating after challenge with

dextroamphetamine
Pictures of social interaction
Cognitive generation of positive affect
Happy words
Positive monetary outcome (gain)
Anticipation of monetary gain
Implicit facial affect processing per se
Presentation of negative pictures
ACC5
Activation increase
Activation decrease
Mid cingulate
gyrus
PCC
Activation increase
Activation increase
Activation decrease
OFC
Activation increase
Activation decrease
LPFC6
Activation increase
Task
Implicit processing of sad facial expressions

Presentation of positive pictures
Implicit processing of happy facial expressions
Cognitive generation of negative affect
Happy words
Sad mood induction
Sad words
Guessing
dextroamphetamine
Sad mood induction
Threat-related words
Sad mood induction
Activation decrease
Amygdala
Striatum7
Activation increase
Activation decrease
Activation increase

dextroamphetamine
Presentation of negative pictures
Negative words
Happy words
Emotional facial expressions per se
Implicit processing of fearful facial expressions
Negative words
Happy words
Study
Abler et al. (2007a,b)3
Canli et al. (2004)2
Keedwell et al. (2005a)2;
Keedwell et al. (2005b)2
Tremblay et al. (2005)2
Schaefer et al. (2006)2
Kumari et al. (2003)4
Elliott et al. (2002)2
Knutson et al. (in press)2
Fu et al. (2004)2
Abler et al. (2007a,b)3;
Davidson et al. (2003a,b)2
Gotlib et al. (2005)2
Keedwell et al. (2005a)2
Fu et al. (2004)2
Davidson et al. (2003a,b)2
Gotlieb et al. (2005)2
Siegle et al. (2002)1
Canli et al. (2004)2;
Fu et al. (2004)2
Sheline et al. (2001)2
Fu et al. (2004)2,
Surguladze et al. (2005)2
Sheline et al. (2001)2
Fu et al. (2004)2
173
Table 2 (continued)
Region
Direction of activation
Striatum7
Activation decrease
Task
Study
Feedback per se
Positive monetary outcome (gain)
Emotional rating after challenge with dextroamphetamine
Positive words
Implicit processing of positive facial expressions

Epstein et al. (2006)2
Either in the between-group comparison (versus controls) or within group in comparison with neutral stimuli; 1remission; 2depressive state;
sub- or postacute; 4treatment-resistant depression; 5including the subgenual cingulate cortex; 6including DLPFC, VLPFC and APFC; 7including
putamen, nucleus caudatus, pallidum and nucleus accumbens.
List of abbreviations; ACC anterior cingulate cortex; APFC anterior prefrontal cortex; DLPFC dorsolateral prefrontal cortex;
IGT Iowa gambling task; LPFC lateral prefrontal cortex; MDD major depression; MPFC medial prefrontal cortex; OFC
orbitofrontal cortex; PCC posterior cingulate cortex; VLPFC ventrolateral prefrontal cortex.
replicated finding is that patients showed a motivational bias

towards the drug-of-abuse and related stimuli, which was
particularly evident in increased responses for drug-related
stimulation in the ACC, the relevance detector OFC, but also in
the amygdala and other regions of the brain's (dopaminergic)
reward system, which could be inferred from both the
systematic literature review and the results of the ALE-metaanalysis. Further, a reduced neural sensitivity to drug-unrelated reward could also be observed in some patients, which
may in part be a result of a shift of activation towards the drug
of abuse at the expense of other drug-unrelated rewards.
Alternatively, diminished responses in reward-sensitive
regions could have also occurred as a function of successful
suppression of craving-related responses when patients tried
to correctly evaluate different amounts of monetary rewards
(Goldstein et al., 2007b). Future research needs to more
carefully test the behavioral and neural sensitivity to drugunrelated reward by also including primary reinforcers (e.g.,
food) that have no potential to elicit craving, and compare it to
activation induced by drug-related stimulation.
Nevertheless, similar neural responses to drug-related (and
partly also to drug-unrelated) stimuli in addiction for various
types of substances (see Fig. 1) and high ALE values in rewardsensitive regions, which reflected strong concordance between
studies, indicate that especially the neurobiological mechanisms underlying the processing of drug-related cues that
trigger craving or relapse may recur on similar neural
substrates independent of the drug of abuse. In fact, the neural
mechanisms that accompany the acquisition of drug use and
its maintenance have been assumed to be similar for different
drug classes. Reward circuits including the ventral striatum
and the amygdala may thereby be crucial for the initiation of
drug self-administration (see Volkow and Fowler, 2000). By
contrast, the compulsive aspects of drug seeking have been
assumed to be secondary to intermittent drug-induced dopaminergic activation and an overall decrease in dopaminergic
function that affects other regions like the orbitofrontal and
cingulate cortices. This disrupts adaptive incentive processing
by eventually leading to compulsive drug behaviors that
persist even in the presence of adverse reactions (see Kalivas
et al., 2006; Volkow et al., 2003, 2007). As drug seeking becomes
well established there is also evidence for a progressive shift
from motivated seeking of goals dependent on the ventral
striatum to stimulusresponse habits mediated by the dorsal
striatum (see also Hyman et al., 2006). It should therefore be

promising to further investigate similarities between mechanisms mediating different aspects of substance abuse and those
involved in other addiction-like disorders that have similarly
shown to be associated with a biased response to a certain
category of motivationally significant events in the environment. Behavioral and substance addictions share common
core clinical features and also exhibit phenomenological,
genetic and neurobiological links that relate to the impulsive
as well as the compulsive aspects of addiction (see Grant et al.,
2006). Evidence for a correspondence between neural deficits
observed in substance abuse and pathological gambling
associated with a deficient ventral frontal and striatal
response to rewarding stimuli already exists (Reuter et al.,
2005; see also Potenza et al. 2006). Further, pathologically obese
subjects also show similarities to substance abusers (e.g., a
reduction in striatal dopamine D2-receptors; Wang et al., 2004),
which recently led to a redefinition of obesity as a substance
dependence disorder (James et al., 2004; see also Trinko et al.,
2007). Neuroimaging approaches that compare these motivational disorders might be useful to further understand the
neurophysiological basis of dependency from a more general
perspective and are expected to provide new directions for
treating the growing epidemic of eating-disorders. Also, the
neural basis of reward-related processing in substance dependence for drugs that directly affect the dopamine system (e.g.,
cocaine) compared to those with indirect effects (marijuana)
remain to be further elucidated, as marijuana dependence
seemed to be underrepresented by current neuroimaging
research, especially when regarding the frequency of marijuana abuse in the population.
Another important question that cannot be answered by
current research is why some patients want to become clean
and others do not and whether these patient populations
differ in their affective processing ability. Although, it has also
been proposed by some researchers (e.g. Robinson and
Berridge, 2003) that the motivational component of drug
seeking behavior (drug wanting) may be completely
detached from affective processing, a reduction of hedonic
drug effects (i.e., the increasing tolerance towards the hedonic
effects of the drug and thus the reduction in feelings of
pleasure) may be another potential reason for an increased
motivation to seek the effects of cocaine, which reverse the
hedonic deficit (e.g., Ahmed, 2004). In humans, there are at
174
Table 3 Activations in regions of the brain's reward circuit in patients with BD observed during performance of emotional
and reward-related tasks
Region
Direction of
activation
MPFC
Activation increase
ACC
Activation increase
Mid cingulate gyrus

PCC
Activation decrease
Activation decrease
Activation increase
OFC
Activation increase
Activation decrease
LPFC4
Activation increase
Task
Implicit processing of mild happy facial expressions
Decision-making/Risk-taking
Happy distractor words
Implicit and explicit processing of happy facial expressions
Implicit processing of intense sad facial expressions
Explicit facial affect processing per se
Implicit processing of mild sad facial expressions
Emotional words per se
Cognitive generation of affect per se
Implicit processing of mild happy expressions
Sad distractor words
Implicit processing of sad expressions
Activation decrease
Midbrain
Activation increase
Activation decrease
Amygdala
Activation increase
Activation decrease
Striatum5
Activation increase
Activation decrease
Implicit and explicit processing of fearful facial expressions

Emotional words per se
Decision-making/Risk-taking
Implicit and explicit processing of (mild) fearful facial
expressions
Emotional prosody
Implicit and explicit processing of fearful facial expressions
Implicit processing of intense happy facial expressions
Implicit processing of mild happy facial expressions
Implicit and explicit processing of (intense) fearful facial
expressions
Implicit processing of mild fearful facial expressions
Emotional prosody
Implicit and explicit processing of happy faces
Implicit and explicit processing of fearful facial
expressions
Implicit processing of mild sad facial expressions
Reward anticipation and receipt of monetary reward
Study
Malhi et al. (2004a)3;
Malhi et al. (2007)1
Lawrence et al. (2004)1,3
Rubinsztein et al. (2001)2
Chen et al., (2006)3
Lennox et al. (2004)2
Altshuler et al. (2005)2
Malhi et al. (2004a3,b)2;
Malhi et al. (2004a3,b)2;
Rubinsztein et al. (2001)2
Yurgelun-Todd et al. (2000)1;
Mitchell et al. (2004)1
Chen et al., (2006)2,3
Altshuler et al. (2005)2
Malhi et al. (2004a)3
Yurgelun-Todd et al. (2000)1;
Mitchell et al. (2004)1
Chen et al., (2006)3;
Malhi et al. (2004b)2
Chen et al., (2006)2,3;
Abler et al. (2007b)2
Either in the between-group comparison (versus controls) or within group in comparison with neutral stimuli;1mixed or euthymic; 2(hypo-)
manic; 3depressive; 4including DLPFC, VLPFC and APFC; 5including putamen, nucleus caudatus, pallidum and nucleus accumbens.
List of abbreviations; ACC anterior cingulate cortex; APFC anterior prefrontal cortex; BD bipolar disorder; DLPFC dorsolateral
prefrontal cortex; LPFC lateral prefrontal cortex; MPFC medial prefrontal cortex; OFC orbitofrontal cortex; PCC posterior
cingulate cortex; VLPFC ventrolateral prefrontal cortex.
175
Fig. 1 Activation foci included in the addiction meta-analysis (n = 122). Foci are presented in Talairach space in the BrainMap
Sleuth environment (Laird et al., 2005c). Different color/symbol combinations identify studies dealing with different drugs
(cocaine = black squares; alcohol = blue triangles; cigarettes = green circles; opiates = brown crosses).
Fig. 2 Activation foci included in the MDD meta-analysis (n = 74). Foci are presented in Talairach space in the BrainMap Sleuth
environment (Laird et al., 2005c). Different colors identify individual studies.
176
least some indications for a physiologic link between cocainecue responses and normal dysphoric states, as craving-related
activations in one study resembled responses to sad stimuli
normally observed in healthy controls (Wexler et al., 2001).
Further, during pharmacological challenge, the magnitude of
dopamine release in the anterior ventral striatum, but not in
the dorsal caudate, was positively correlated with the hedonic
response (euphoria) to dextroamphetamine (Drevets et al.,
2001), which implied that stimulant-associated drug wanting may not be entirely uncoupled from a positive affective
experience of hedonic liking and may be particularly
important for initiation of drug self-administration (see also
Volkow and Fowler, 2000; Grant et al., 2006). Patients with
comorbid affective disorders should thus be of high interest
for future research. In fact, some psychiatric symptoms may
also be a cause for comorbid chronic drug abuse (e.g., drugtaking as self-medication in depression) and chronic drug
abuse may in term exacerbate the symptoms of other preexisting mental disorders (Bruijnzeel et al., 2004; Currie et al.,
2005). It thus remains to be tested how comorbid depression
alters the neural response to different kinds of rewards and
whether this response is similar to the one observed in
depression per se or in addiction without depressive symptoms or whether it is rather unique. Knowledge about those
interactions may help to identify disorder-specific neural trait
markers for addiction or may alternatively lead to a redefinition of disorders (e.g., through an introduction of an addiction-subtype' in schizophrenia; Mancini-Mare et al., 2006),
which could even help to guide subtype-specific treatment
interventions in the future.
8.
Mood disordersChanges in motivational
relevance and affective processing
Mood disorders like major depressive and bipolar disorder (BD)
have been characterized by significant changes in both
motivational and affective processing (see Davidson et al.,
2003a,b; Leppnen, 2006). Dominated by persistent dysphoric
emotions and thoughts (e.g., anhedonia) even in the absence
of acute stressors depressive patients have been reported to
exhibit a decreased motivation to seek and a reduced ability to
experience reward (Drevets, 2001; Chau et al., 2004). In
contrast, episodes of mania in patients with BD have been
typically characterized by elated or irritable mood, disinhibition and a compromised judgment leading to damaging future
consequences (Malhi et al., 2004a,b). On the behavioral level,
the most prominent features of both MDD and BD observed in
experimental studies on emotional processing were (1) an
emotional bias (Leppnen et al., 2004), (2) an impaired recognition accuracy in recognizing emotional expressions (Getz
et al., 2003; Surguladze et al., 2004), and (3) an enhanced
memory for negative valent stimuli in the depressive state
(Moritz et al., 2005; Leppnen, 2006).
In accordance with behavioral findings, patients with
mood disorders showed significant alterations in brain
activity at rest that mainly affected the brain's reward
system including the amygdala, regions of the mesolimbic
dopamine system and frontal cortices (see Drevets, 1999;
Davidson et al., 2002 for comprehensive reviews). In addition,
regions that commonly processed stimuli with positive
emotional content in healthy human subjects (e.g., Elliott et
Table 4 Results of the ALE meta-analyses of hyperaction related to either stimulation by drug-related cues in addiction or to
negative stimuli in MDD
Anatomical region
Brodmann area
(A) Regional concordance in hyperactivation related to

R ACC
L/R striatum
L amygdala
R amygdala
L OFC
L PCC
L ACC
L precuneus
L superior temporal gyrus
R superior temporal gyrus
L middle temporal gyrus
R superior frontal gyrus
stimulation by drug-cues in addiction

32
6 44 4
subcortical
6 8 6
subcortical
202 12
subcortical
206 12
30 0 20
47
32 18 16
23
638 24
24
8 22 22
31
1058 30
38
56 12 20
41
4834 8
21
362 22
10
18 52 14
(B) Regional concordance in hyperactivation related to negative stimuli in MDD

L striatum
subcortical
R pregenual ACC
L subthalamic nucleus
L thalamus
L insula
L middle frontal gyrus
L inferior parietal lobe
L inferior temporal cortex/uncus
R lingual gyrus
Coordinates
32
subcortical
subcortical
13
8
40
20
17
28 2 16
104 16
20 16 16
6 38 16
1210 8
2030 2
40 0 2
44 14 44
2640 50
30 0 42
16102 8
ALE
Volume (mm3)
0.0135
0.0125
0.0118
0.0093
0.0076
0.0093
0.0090
0.0079
0.0159
0.0133
0.0106
0.0088
0.0099
3720
4616
560
424
200
368
392
320
1552
512
952
568
392
0.0132
0.0131
0.0067
0.0122
0.0141
0.0109
0.0097
0.0071
0.0067
0.0067
0.0066
1136
1008
112
1224
2728
608
840
336
248
144
112
Fig. 3 ALE maps for cue-related hyperactivation in

addiction and hyperactivation related to negative stimulation
in MDD at p < 0.05. (A) Addiction: in the ALE meta-analysis
significant activation likelihood was seen in the right ACC, in
the striatum (right putamen, right nucleus accumbens and
left ventral caudate), in the amygdalae and in the left
posterior OFC. (B) MDD: the ALE meta-analysis revealed
significant activation likelihood in the right pregenual ACC,
somewhat above the cluster observed in addiction, in the left
lateral striatum (putamen), but neither in the amygdalae nor
in the posterior OFC.
al., 2002; Surguladze et al., 2005) also showed an affective bias

of varying extent towards negative stimulation (e.g., sad
expressions). For instance, the relevance detector' amygdala
exhibited a shift in activation in favor of mood-congruent
affective stimuli, which was particularly evident in the
depressive or untreated state of MDD (e.g., Fu et al., 2004; see
also: Table 2 and Supplementary Table 4). In addition,
increased responses during negative emotional stimulation
have also been observed in other reward-sensitive regions
(e.g., the ACC), although not always consistently (Table 2).
Differences in the emotional stimulation between studies (see
below) and the possibility that different subtypes of depression may exist on the neural level can supposedly account for
these inconsistencies. There is evidence that patients with a
treatment-resistant form of MDD were characterized by an
177
overall reduced anterior cingulate responsiveness to emotional stimuli per se (Kumari et al., 2003), and to affectively
negative stimulation (Davidson et al., 2003a,b) pointing to a
possible subtype of MDD. In patients with a clear negative bias
prior to treatment, treatment success was accompanied by a
significant attenuation of activation in the affected regions
(e.g., Fu et al., 2004; Sheline et al., 2001) and also led to an
increased responsiveness to other emotional stimuli (Schaefer
et al., 2006), which suggested that these alterations may have
represented a disorder-related state measure in this subgroup
of depressive patients.
At the same time, the neural responsiveness of rewardsensitive regions (e.g., of the ventral striatum or the amygdala)
to positive valent emotional stimuli and monetary outcome
was found to be diminished in many previous studies on MDD
(e.g., Canli et al., 2004, Elliott et al., 2002; Knutson et al., in
press). It became obvious that the lacking emotional input
from the amygdala and associated regions supposedly also
compromised sensory processing regions that similarly
exhibited a bias against positive stimuli (Surguladze et al.,
2005; see also Vuilleumier and Pourtois, 2006). The bias thereby appeared to be directly associated to depression severity or
the degree of anhedonia (Keedwell et al., 2005a,b; Surguladze
et al., 2005), which again suggested that these alterations also
reflected another state-marker of depression.
However, some studies also reported an increase in
activation to implicit processing of happy facial expressions
(Gottlib et al., 2005) and pictures (Abler et al., 2007a,b), in the
direct comparison of happy and neutral autobiographical
prompts intended to induce a mood state (Keedwell et al.,
2005a) or during anticipation of a potential monetary gain
(Knutson et al., in press), when compared to activation in
healthy controls or activity evoked by neutral stimulation.
These stimuli affected different parts of the regions that also
responded to negative stimulation (e.g., the anterior cingulate
cortex and the amygdala; see also Table 2). Partly discrepant
findings may thereby be directly assigned to differential
salience levels of the stimulus material used. One may assume
that especially positive emotional words (e.g., Canli et al., 2004)
were not salient enough to evoke an emotional response in the
depressive state, while emotional facial displays (Gottlib et al.,
2005) with a closer relation to the underlying neural circuitry,
outcome-uncertainty during anticipation (Knutson et al., in
press), or positive autobiographical prompts (Keedwell et al.,
2005a,b) with a direct linkage to the individual's personal
emotional experiences, instead may have been perceived as
highly salient and were therefore supposedly more deeply
processed leading to the observed increase in activation.
In contrast to patients with MDD, bipolar patients being in
the manic phase exhibited no such bias for negative valent
stimuli, but either showed an impaired recognition of negative
facial affect, an increased responsiveness to positive stimuli or
exhibited a general disability to process emotional stimuli at
all, which was also expressed in the neural response pattern
(cf., Table 3 and Supplementary Table 5). For example, patients
in the manic state exhibited a reduced sensitivity for rewardrelated and motivationally salient information, which was
accompanied by a decreased behavioral sensitivity for differences in reward value and a lack of relative activational
increase in the nucleus accumbens during both reward
178
anticipation and receipt when compared to expectation and

receipt of no reward (Abler et al., 2007b). In addition, patients
with bipolar mania rated sad facial expressions as less intense
then healthy controls (e.g., Lennox et al., 2004). Concurrently,
these patients showed an attenuation of activation in the
subgenual ACC and the bilateral amygdalae, which was
accompanied by an increased activation in the posterior cingulate and the posterior insula when compared to healthy controls, but at the same time they showed an unaltered neural
response to happy facial expressions (Lennox et al., 2004). In
another study, evidence was found for a positive affective
bias in manic patients showing an enhanced ventral and
medial prefrontal response to positive emotional distractors
(Elliott et al., 2004). The same patients, however, lacked a
differential response to happy and sad targets, which may be
assigned to both a general bias in emotional processing and a
heightened distractibility observed during mania that could
have impaired processing of explicit targets and may have
instead increased responses to emotional distractors (Elliott
et al., 2004). Considering that these effects were mediated by
distinct functional regions when compared to patients with
MDD performing the same task as indicated by the results from
3 previous studies (Elliott et al., 2002; 2004; Lawrence et al.,
2004), the pathophysiological basis of altered processing of
emotional stimuli appears to differ in these two disorders. In
the depressive and euthymic state of BD, patients partly
showed unique responses to both negative and positive facial
expressions when compared to MDD patients (Lawrence et al.,
2004), although overlapping changes in activation patterns
could also be observed (e.g., the hippocampal response to mild
sadness correlated with depression severity; Lawrence et al.,
2004). This led to the question on whether some alterations
occurring in both MDD and BD were actually trait markers of
the disease and therefore independent of mood state. In
patients with severe MDD there is already evidence for statedependency of some neural deficits, in that for instance the
hyperactivation of the amygdala and the striatum in response
to sad faces receded in the state of remission (Fu et al., 2004).
Similarly, in bipolar patients hyperactivation of subcortical
regions in both depressed bipolar patients when processing
happy and fearful faces (Lawrence et al., 2004) and in hypomanic patients in response to negative stimuli (Malhi et al.,
2004b) supposedly represented a specific marker for BD in the
acute state, which apparently disappeared in euthymic
patients (Malhi et al., 2005, 2007). In addition, some studies
were already able to show similar activations when comparing
different BD patients in the depressive and in the manic state
(e.g., Chen et al., 2006), providing indications for functional
trait markers in BD. Still, to date further evidence from
different phases of BD observed in the same patients remains
to be acquired.
8.1.
Regional distribution of activation associated with
mood-congruent processing in MDDActivation Likelihood
Estimation
The results from the ALE meta-analysis indicated that the bias
towards mood-congruent or negative stimulation may be
mediated by a network that comprises parts of the mesolimbic
reward system (striatum and pregenual ACC), but also
includes regions involved in cognitive and sensory processing

(see Table 4B; Fig. 3B). The highest ALE value in regions of the
reward system was observed in the left striatum with a cluster
extent of 1136mm3 followed by one cluster in the right
pregenual ACC and 2 further clusters in the left striatum. In
addition, we also observed clusters in the left thalamus and
subthalamic nucleus, the left insula adjacent to the posterior
OFC, the left middle frontal gyrus, left inferior parietal lobe,
left inferior temporal cortex as well as the right lingual gyrus.
These results in part confirm the observation from the
systematic review (Table 2) and indicate that some of the
regions, which contribute in the attribution of motivational
salience and goal-directed behavior in the healthy brain, may
be biased towards negative stimulation in MDD. In addition,
attentional and sensory processing areas also showed concordant hyperactivation for negative stimulation in patients in
the depressive state. Surprisingly, the ALE meta-analysis
found no evidence for a dysfunction of the relevance detector
amygdala during mood-congruent stimulation, albeit 3 studies reported an increased amygdala response during negative
stimulation (Fu et al., 2004; Surguladze et al., 2005; Abler et al.,
2007a,b; see also Sheline et al., 2001 and Siegle et al., 2002, who
also reported activation in the amygdala, but did not report
peak coordinates). However, one has to be aware of the fact
that the limited number of peaks included in the analysis
(<100) as well as variations in depression severity of patients
assessed by different studies could have severely affected the
present results. The meta-analytic results may thus only
provide initial evidence that in MDD the observable bias in
salience attribution may in part be associated with disturbances within the mesolimbic dopaminergic system, but may
also be related to a dysfunctional attentional control system.
Future research is definitely necessary to provide a broader
data base that allows one to achieve more conclusive results.
8.2.
Mood disordersConclusions and outstanding
questions
Mood disorders may be best characterized by an overall
disturbed ability to process motivationally relevant stimuli
in a context-appropriate way (i.e., according to their objective'
affective valence). Depending on current mood state, some
patients exhibited a kind of motivational blindness for moodincongruent stimuli that was associated with decreased
activity in brain regions involved in emotional salience
attribution and sometimes even in regions of general stimulus
processing, while mood-congruent stimulation in most
patients led to enhanced activation in similar brain regions
(see Table 4B). Important to note, it could be ruled out that
these differences in neural response patterns were simply a
function of decreased effort or task engagement, as they were
both evident during implicit and explicit perception of
emotional stimulation (especially facial expressions) and
also occurred in patients with normal behavioral performance
(e.g., Epstein et al., 2006). It nevertheless remains to be further
elucidated, how the observed neural deficits may affect those
stages of the decision-making process, that rely on unequivocal affective signals as guidance for adaptive behavioral
choice (e.g., reward-related reversals or the decision for the
advantageous deck in the IGT). Patients with BD have already
been reported to show a lack of inhibitory control, supposedly

due to an insufficient integration of negative affective signals
into behavioral choice leading to overall disadvantageous
behavior (Christodoulou et al., 2006). In addition, patients with
MDD showed normal performance in the IGT, when advantageous decks provided immediate large punishment, and even
larger future reward, but were significantly impaired in the
normal version of the IGT with low immediate reward
followed by even lower punishment in advantageous decks
(Must et al., 2006). This observation indicated that depressives
were supposedly only able to use reward feedback in an
adaptive way, if it was (1.) considerable high, (2.) infrequent
and (3.) also highly variable in value, which opens new
perspectives for future research in depression. Accordingly,
the impairment in processing of positive valent stimuli could
have simply been a function of salience level and not of a
general impairment in processing of positive or affective
stimuli per se, which means that depressives should supposedly be still able to process positive stimuli, but only at high
salience levels.
9.
General conclusion
Context-sensitive reward processing and adaptive decisionmaking require the intact interplay between various cortical
and subcortical regions that form the brain's reward circuit.
Disturbances within this network have been reported in all of
the psychiatric disorders reviewed above, even in patients
without overt behavioral deficits. Both patients with substance dependence and mood disorders thereby showed a
more or less consistent motivational bias towards certain
stimulus categories (in mood disorders depending on current
mood state) that also affected the neural response in the
relevance detectors' amygdala and OFC as well as in other
regions of the brain's reward system. In addiction, regions of
the reward system that most consistently showed a motivational bias towards the drug of abuse appeared to be the ACC,
the striatum, the amygdala and the OFC (Table 4A), while in
MDD there was evidence for concordant activity in mesolimbic
sites of the dopaminergic system during processing of moodcongruent or negative stimuli across the studies reviewed
(Table 4B). Still, when considering the results of the systematic
review of studies on MDD (Table 2) it cannot be ruled out that
other regions like the relevance detector amygdala may also
be important in a mechanism that leads to the observed bias
in salience attribution during the depressive state.
Nevertheless, despite some similarities in the neural
responses to biased stimuli (e.g., the observation of
increased mesocorticolimbic responses to drug stimuli in
addiction or sad/negative stimulation in MDD; see also Fig. 3),
the underlying neural mechanisms may be different. In
particular studies that did not exclusively assess activation
differences in patient populations, but also examined the
underlying neurotransmitter systems in humans provide
further evidence on pathophysiological (and maybe even
etiological) differences between these disorders. In addiction,
most drugs have shown to trigger a phasic increase in
dopamine release in the wanting system of the brain. It
has been proposed that this increase may produce a false,
179
fixed reward prediction error in dopamine neurons (Redish et

al., 2004), which leads to a sensitization of certain drug effects,
by increasing the relative reward value of drugs and drugrelated stimuli through a simple Pavlovian stimulusstimulus
association learning in the OFC and associated areas like the
nucleus accumbens (Robinson and Berridge, 2003). In combination with a significant reduction of dopamine receptor
density or lowered presynaptic dopamine production and
release (e.g., Heinz et al., 2004; Chang and Haning, 2006), this
could significantly contribute to the overvaluing of drugrelated stimuli, leading to a persistence of neural cravingresponses' even in the state of abstinence and may thus also
impair the ability to adequately respond to drug-unrelated
reward (Wrase et al., 2007b). Conversely, in mood disorders, the
motivational bias appears to depend on current mood state in
favor of mood-congruent stimulation, and there are only few
indications for neural deficits that persisted over different
states. The underlying mechanism leading to this bias may at
least in part be assigned to external stressors leading to
increases in cortisol and norepinephrine levels affecting
activation of the amygdala and other reward-sensitive regions
(Drevets, 2001). The loss of pleasure and motivational drive
during the state of depression, which may be partly related to
an underlying dysfunction of regions sensitive to dopaminergic modulation (e.g. Willner et al., 2005; Nutt et al., 2007; see
also Willner, 2002), may further be assumed to lead to a
reduced responsiveness to salient stimuli in general, which
would favor those stimuli that have a per se higher salience
level and importance due to their direct relevance for the
organism's survival, namely fear- or threat-related cues,
especially when displayed in human facial expressions. In
healthy humans, the extent of dopamine transmission has
shown to be maximal during processing of salient reward (Zald
et al., 2004), and activations in regions like the striatum
increased with rising salience, even outside of the reward
context (Zink et al., 2006). Conversely during the state of mania,
it may be possible that the assumed hyperdopaminergic state
could have increased the noise in the reward system, which
could lead to an overall inability to focus on relevant emotional
events at all (see also Juckel et al., 2006, who found evidence for
such a process taking place in never-medicated schizophrenics).
A combination of functional neuroimaging methods (fMRI and
PET) and pharmacological challenge of selective neurotransmitter systems may thus represent one promising route for
future neuropsychiatric research, as indicated by recent
findings in healthy controls (e.g., Pessiglione et al., 2006) and
in patients with MDD (Tremblay et al. 2005).
In the direct comparison of disorders, it will further be
necessary to unify experimental approaches to achieve a
better discriminatory power regarding disorder-specific
alterations in neurophysiologic processes. This means that
future research will certainly gain from the examination of
different patient populations with similar and not only
disease-specific experimental paradigms and will thus allow
a more fundamental understanding of the underlying pathophysiology. So far most neuroimaging studies in substance
abuse presented either drug-related and neutral stimuli in
passive viewing tasks or used monetary reward and thus
mainly assessed responses during the state of craving or the
actual reception of positive feedback contingent on a manual
180
response. Conversely, in mood disorders subjects rather

performed emotional evaluation tasks, which allowed direct
comparisons between neural responses to happy and sad
stimulation. Emotional content was thereby often conveyed
through facial displays, which makes it possible that the
pathophysiological role of the amygdala in depression has
simply been overestimated, when compared to other disorders, because also in healthy humans this region plays a
superior role in processing of emotional faces (Vuilleumier
and Pourtois, 2006). The future use of similar, if not identical
behavioral paradigms from fundamental research may have
the overall advantage that it allows a clear differentiation of
disorder-specific aberrations in brain function.
10.
Limitations of ALE
ALE provides a useful tool that has many advantages over

label-based reviews (see Laird et al., 2005b for a detailed
discussion), but nevertheless suffers from some potential
limitations that have not been overcome yet. For instance, ALE
neither provides a weighting factor for the number of subjects
in each study nor for the different voxel heights (z-values) and
spatial extents of clusters in the studies included as data basis.
In addition, this method does not account for the proportion of
studies that activate in a certain region, but instead looks for
correspondence in the clustering of peaks regardless of
whether a certain cluster comprises only foci from a single
study (Wager et al., 2007). We have tried to overcome this
problem by selecting only peaks with the highest statistical
significance from a subset of neighboring peaks and by
restricting the analysis to one relevant contrast per study
(see above). Still, one cannot rule out that for example the 27
foci from the study by Fu et al. (2004) may have contributed
disproportionally to the results of the ALE meta-analysis on
MDD, albeit reported peaks in that particular study were
distributed across the entire brain. Different meta-analytic
approaches will always suffer from one or the other limitation
(see Laird et al., 2005a; Wager et al., 2007) and thus metaanalytic results always need to be treated with care.
Appendix A. Supplementary data

Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.brainresrev.2008.07.004.
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B RA I N R E SE A R CH RE V I EW S 59 ( 20 0 8 ) 1 6 41 8 4

Functional neuroimaging of reward processing and

The adequate integration of reward- and decision-related information provided by the

Accepted 11 July 2008

Available online 21 July 2008

Functional neuroimaging research has already presented a comprehensive picture on affective

Substance abuse disorder

an outline on the neural mechanisms guiding context-adequate reward processing and

decision-making processes in the healthy brain, and also addresses pathophysiological

Corresponding author. Fax: +49 551 39 2798.

Mood disordersChanges in motivational relevance and affective processing . . . . . .

nections with other experimental approaches (e.g., psychopharmacological research).

Learning to predict reward

The prospective organization of goal-directed behavior requires

establishment of stimulusresponse(reward) contingencies,

represent the current motivational value of available rewards,

biological basis of the concepts of motivation and pleasure

Implications for psychiatric disorders

Overt behavioral impairments of motivational and affective

and help to guide adaptive behavioral adjustments in response

paradigm and 2 studies employed a mood-provocation task).

Activation likelihood estimation (ALE)

compared to a neutral control condition and/or showed a

Substance (ab)use disorders

Addiction may be best described as a pathology of incentive

Passive perception of craving-related stimuli

Craving for cocaine self-administration

Craving for cocaine self-administration

Passive perception of craving-related stimuli

and striatum as well as of sensory processing regions during

the right anterior OFC, which positively correlated with task

Expectation of negative pictures

Emotional rating after challenge with

Implicit processing of sad facial expressions

Pictures of social interaction

Elliott et al. (1998)2

replicated finding is that patients showed a motivational bias

striatum (see also Hyman et al., 2006). It should therefore be

Mid cingulate gyrus

Implicit and explicit processing of fearful facial expressions

(A) Regional concordance in hyperactivation related to

stimulation by drug-cues in addiction

(B) Regional concordance in hyperactivation related to negative stimuli in MDD

Fig. 3 ALE maps for cue-related hyperactivation in

al., 2002; Surguladze et al., 2005) also showed an affective bias

anticipation and receipt when compared to expectation and

includes regions involved in cognitive and sensory processing

been reported to show a lack of inhibitory control, supposedly

fixed reward prediction error in dopamine neurons (Redish et

response. Conversely, in mood disorders subjects rather

ALE provides a useful tool that has many advantages over

Appendix A. Supplementary data

Chang, L., Haning, W., 2006. Insights from recent positron

from functional magnetic resonance imaging studies in

monetary gradients is associated with frontolimbic activation

generation of affect in bipolar depression: an fMRI study.

emotional faces in depressed subjects resolves with

Wager, T.D., Lindquist, M., Kaplan, L., 2007. Meta-analysis of

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