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Review
A R T I C LE I N FO
AB S T R A C T
Article history:
environment is critical for behavioral success and subjective well being in everyday life.
Keywords:
interest to the assessment of impaired brain function in psychiatric patients. This article
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
fMRI
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
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Likelihood
7.2. Substance (ab)use disordersConclusions and outstanding questions . . . . . . . . . . . . . . . . . .
. . . . 165
. . . . 165
. . . . 166
. . . . 166
. . . . 167
. . . . 167
. . . . 168
. . . . 169
Likelihood
. . . . 171
. . . . 171
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8.
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-
. . . . . . . . . . . .
in MDDActivation
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . 176
Likelihood
. . . 178
. . . 178
. . . 179
. . . 180
. . . 180
. . . 180
2.
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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
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-
B RA I N RE SE A R CH RE V I EW S 59 ( 20 0 8 ) 1 6 41 8 4
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.
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6.1.
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)
B RA I N RE SE A R CH RE V I EW S 59 ( 20 0 8 ) 1 6 41 8 4
7.
169
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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 perception of craving-related stimuli
Passive viewing of sex-related stimuli
Decision-making in IGT
Passive perception of craving-related stimuli
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
Decision-making in IGT
Passive perception of craving-related stimuli
Verbal feedback
Craving for cocaine self-administration
Passive perception of craving-related stimuli
Activation decrease
Cocaine-related imagery
Interview about cocaine themes
Passive viewing of sex-related stimuli
Activation increase
Activation decrease
Activation increase
Verbal feedback
Decision-making in IGT
Cambridge Risk Task
Passive perception of craving-related stimuli
Activation increase
Activation decrease
Amygdala
Activation increase
Midbrain
Striatum7
Activation decrease
Activation increase
Activation increase
Reward evaluation
Verbal feedback
Passive perception of craving-related stimuli
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
Risinger et al. (2005)2
Franklin et al. (2007)4; Garavan et al. (2000)2;
McBride et al. (2006)4; Sell et al. (2000)5
Kilts et al. (2004)2
Wang et al. (1999)2
Garavan et al. (2000)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
Risinger et al. (2005)2
Martin-Soelch et al. (2001a)5
Bolla et al. (2003)2
Goldstein et al. (2007a)2;
Goldstein et al. (2007b)2
Martin-Soelch et al. (2001b)4
Bolla et al. (2005)3
Ersche et al. (2006)5
Bonson et al. (2002)2; Brody et al. (2002)4;
Franklin et al. (2007)4; Garavan et al. (2000)2;
Hermann et al. (2006)1; McBride et al. (2006)4 ;
Sell et al. (2000)5; Wrase et al. (2002)1
Risinger et al. (2005)2
McClernon et al. (2005)4
Goldstein et al. (2007b)2
Martin-Soelch et al. (2001a)5
Martin-Soelch et al. (2001a)5
Wrase et al. (2007b)1
Adinoff et al. (2003)2
Bonson et al. (2002)2
Garavan et al. (2000)2
Goldstein et al. (2007a)2
Martin-Soelch et al. (2001b)2
Bolla et al. (2003)2;
Bolla et al. (2005)3
Bonson et al. (2002)2; Franklin et al. (2007)4;
Schneider et al. (2001)1
Goldstein et al. (2007b)2
Martin-Soelch et al. (2001b)4
Franklin et al. (2007)4; Garavan et al. (2000)2;
Grsser et al. (2004)1; Heinz et al. (2004)1;
McBride et al. (2006)4; Wrase et al. (2002)1
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Table 1 (continued)
Region
Striatum7
Direction of
activation
Task
Activation increase
Cocaine-related imagery
Craving for cocaine-self-administration
Implicit perception of smoking-related stimuli
in a target detection task
Decision-making in IGT
Anticipation of monetary gain
Anticipation of monetary loss
Activation decrease
Study
Kilts et al. (2004)2
Risinger et al. (2005)2
McClernon et al. (2005)4
Bolla et al. (2003)2
Wrase et al. (2007b)1
Wrase et al. (2007b)1
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.
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
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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
Activation decrease
ACC5
Activation increase
Activation decrease
Mid cingulate
gyrus
PCC
Activation increase
Activation increase
Activation decrease
OFC
Activation increase
Activation decrease
LPFC6
Activation increase
Task
Activation decrease
Amygdala
Striatum7
Activation increase
Activation decrease
Activation increase
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
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
Abler et al. (2007a,b)3
Gotlib et al. (2005)2
Keedwell et al. (2005a)2
Kumari et al. (2003)4
Kumari et al. (2003)4
Kumari et al. (2003)4
Elliott et al. (2002)2
Fu et al. (2004)2
Keedwell et al. (2005b)2
Kumari et al. (2003)4
Keedwell et al. (2005b)2
Keedwell et al. (2005a)2
Schaefer et al. (2006)2
Kumari et al. (2003)4
Elliott et al. (2002)2
Keedwell et al. (2005a)2
Kumari et al. (2003)4
Elliott et al. (1998)2
Tremblay et al. (2005)2
Keedwell et al. (2005b)2
Abler et al. (2007a,b)3
Canli et al. (2004)2
Gotlib et al. (2005)2
Keedwell et al. (2005a)2;
Keedwell et al. (2005b)2
Gotlib et al. (2005)2
Keedwell et al. (2005a)2;
Keedwell et al. (2005b)2
Schaefer et al. (2006)2
Tremblay et al. (2005)2
Davidson et al. (2003a,b)2
Gotlieb et al. (2005)2
Siegle et al. (2002)1
Canli et al. (2004)2;
Siegle et al. (2002)1
Fu et al. (2004)2
Sheline et al. (2001)2
Abler et al. (2007a,b)3
Fu et al. (2004)2,
Surguladze et al. (2005)2
Sheline et al. (2001)2
Siegle et al. (2002)1
Canli et al. (2004)2
Fu et al. (2004)2
Surguladze et al. (2005)2
Kumari et al. (2003)4
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Table 2 (continued)
Region
Direction of activation
Striatum7
Activation decrease
Task
Study
Feedback per se
Positive monetary outcome (gain)
Pictures of social interaction
Emotional rating after challenge with dextroamphetamine
Positive words
Implicit processing of positive facial expressions
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.
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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
Activation decrease
Activation decrease
Activation increase
OFC
Activation increase
Activation decrease
LPFC4
Activation increase
Task
Cognitive generation of positive affect
Implicit processing of mild happy facial expressions
Decision-making/Risk-taking
Happy distractor words
Implicit and explicit processing of happy facial expressions
Cognitive generation of positive affect
Implicit processing of intense sad facial expressions
Explicit facial affect processing per se
Explicit facial affect processing per se
Explicit facial affect processing per se
Implicit and explicit processing of happy facial expressions
Cognitive generation of negative affect
Happy distractor words
Implicit facial affect processing per se
Implicit processing of mild sad facial expressions
Emotional words per se
Cognitive generation of affect per se
Happy distractor words
Cognitive generation of positive affect
Implicit and explicit processing of happy facial expressions
Implicit processing of mild happy expressions
Sad distractor words
Implicit processing of sad expressions
Cognitive generation of negative affect
Activation decrease
Midbrain
Activation increase
Activation decrease
Amygdala
Activation increase
Activation decrease
Striatum5
Activation increase
Activation decrease
Study
Malhi et al. (2004a)3;
Malhi et al. (2007)1
Lawrence et al. (2004)1,3
Rubinsztein et al. (2001)2
Elliott et al. (2004)2
Chen et al., (2006)3
Malhi et al. (2007)1
Lawrence et al. (2004)1,3
Lennox et al. (2004)2
Lennox et al. (2004)2
Lennox et al. (2004)2
Chen et al., (2006)3
Malhi et al. (2007)1
Elliott et al. (2004)2
Altshuler et al. (2005)2
Lawrence et al. (2004)1,3
Elliott et al. (2004)2
Malhi et al. (2005)1
Elliott et al. (2004)2
Malhi et al. (2004a3,b)2;
Malhi et al. (2007)1
Chen et al., (2006)3
Lawrence et al. (2004)1,3
Elliott et al. (2004)2
Lawrence et al. (2004)1,3
Malhi et al. (2004a3,b)2;
Malhi et al. (2007)1
Lawrence et al. (2004)1,3
Elliott et al. (2004)2
Rubinsztein et al. (2001)2
Yurgelun-Todd et al. (2000)1;
Lawrence et al. (2004)1,3
Lawrence et al. (2004)1,3
Mitchell et al. (2004)1
Chen et al., (2006)2,3
Lawrence et al. (2004)1,3
Altshuler et al. (2005)2
Malhi et al. (2004a)3
Lawrence et al. (2004)1,3
Yurgelun-Todd et al. (2000)1;
Lawrence et al. (2004)1,3
Lawrence et al. (2004)1,3
Lawrence et al. (2004)1,3
Mitchell et al. (2004)1
Lennox et al. (2004)2
Chen et al., (2006)3;
Lawrence et al. (2004)1,3
Malhi et al. (2004b)2
Chen et al., (2006)2,3;
Lawrence et al. (2004)1,3
Lawrence et al. (2004)1,3
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.
B RA I N RE SE A R CH RE V I EW S 59 ( 20 0 8 ) 1 6 41 8 4
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
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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
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
B RA I N RE SE A R CH RE V I EW S 59 ( 20 0 8 ) 1 6 41 8 4
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
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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
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
B RA I N RE SE A R CH RE V I EW S 59 ( 20 0 8 ) 1 6 41 8 4
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
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10.
Limitations of ALE
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