Incentive motivational salience and the human brain

Abstract

In this paper the concept of incentive motivational salience is briefly described, pioneering studies on the subject of the mesolimbic motivational system are reviewed, and studies we have been involved in conducting which elaborate on this subject are discussed. In particular, we aim to show that the mesolimbic motivational system is recruited as a reaction to primary and secondary reinforcers as a function of salience, that is independent of valence. Furthermore, studies showing that both psychological and pharmacological interventions can affect the function of the mesolimbic motivational system and how its' dysfunction is related to psychopathological phenomena with an emphasis on psychosis are discussed.

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Restorative Neurology and Neuroscience 32 (2014) 141–147
DOI 10.3233/RNN-139006
IOS Press
141
Incentive motivational salience and the
human brain
Jimmy Jensen and Henrik Walter∗
Department of Psychiatry and Psychotherapy, Charit´e Universit¨atsmedizin, Berlin, Germany
Abstract. In this paper the concept of incentive motivational salience is briefly described, pioneering studies on the subject of
the mesolimbic motivational system are reviewed, and studies we have been involved in conducting which elaborate on this
subject are discussed. In particular, we aim to show that the mesolimbic motivational system is recruited as a reaction to primary
and secondary reinforcers as a function of salience, that is independent of valence. Furthermore, studies showing that both
psychological and pharmacological interventions can affect the function of the mesolimbic motivational system and how its’
dysfunction is related to psychopathological phenomena with an emphasis on psychosis are discussed.
Keywords: Motivation, salience, ventral striatum, imaging, schizophrenia
1. Background
Three of the most basic psychological components
of motivation are the subjective experience of stim-
uli, the incentive motivational salience of stimuli and
the learning of predictive associations (Berridge &
Robinson, 2003). While these motivational processes
are seamlessly integrated, it is possible to dissociate
them and investigate them experimentally (Berridge &
Robinson, 1998). One aim for affective neuroscience
is to identify these psychological components of moti-
vation and their neurobiological underpinnings.
Human neuroimaging studies have found various
stimuli to recruit the brain’s motivational systems, both
rewarding such as money and taste reward (Knutson
et al., 2001; O’Doherty et al., 2002) as well as pun-
ishing stimuli such as pain (Seymour et al., 2004).
Many regions of the brain are activated by motiva-
tional processes including the orbitofrontal cortex,
the anterior insula and anterior cingulate in addition
∗Corresponding author: Henrik Walter, M.D., Ph.D., Depart-
ment of Psychiatry and Psychotherapy, Charit´
e Universit¨
atsmedizin
Berlin, Campus Mitte, Charit´
eplatz 1, D-10117 Berlin, Germany.
Tel.: +49 30450517141; Fax: +49 30450517921; E-mail: Henrik.
Walter@charite.de.
to more sub-cortical structures such as the ventral
striatum, amygdala and the mesolimbic dopaminer-
gic projections. In the area of motivation, where most
studies have focused on reward, functional magnetic
resonance imaging (fMRI) has demonstrated reliable
recruitment of the mesolimbic-mesocortical systems
(Abler et al., 2005a) in healthy controls, for example,
(Knutson et al., 2001; O’Doherty et al., 2002).
It has been suggested that processes involving
dopamine signalling may mediate the motivational
salience of environmental stimuli and their associ-
ations (Berridge & Robinson, 1998). Studies have
shown that the dopaminergic mesolimbic system is
involved in motivation, for both appetitive (Wise et al.,
1978) and aversive events (Salamone, 1994). It has also
been found that dopamine signalling often precedes
hedonic experience which suggests that dopamine is
involved in the motivational prediction of rewarding
events (Schultz, 2002). The subjective feelings asso-
ciated with such motivational events belong to the
concept of affect and thus are considered separate from
motivational incentive salience (Berridge & Robinson,
1998). Incentive salience is a specific form of associa-
tive reward and punishment learning mediated by the
mesolimbic system. Incentive salience integrates the
0922-6028/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

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142 J. Jensen and H. Walter / Incentive motivational salience
current neurobiological state and previously learned
associations about the motivational cue (Berridge,
2012). The mesolimbic system is thus involved in
detecting new incentives in the environment, in pro-
moting learning about those and their associations, and
in driving goal-directed behaviour.
In this non-exhaustive review focussing on human
functional imaging studies we have been involved
in conducting, the mesolimbic system will be dis-
cussed as a motivational incentive salience system
that responds to motivational stimuli regardless of
valence. We will discuss how the motivational incen-
tive salience system can be affected by psychological
and pharmacological interventions and will present
some clinical implications of its’ dysfunction.
2. Learning and motivation
Associative motivational learning often refers to
pavlovian conditioning where a stimulus gains signifi-
cance due to its association to a reward or a punishment.
The ventral striatum has a dual role in represent-
ing motivation since it is recruited both during affect
and motivational incentive processes. However, deplet-
ing dopaminergic signalling to this region changes
the motivational incentive process without changing
the affect (Berridge & Robinson, 1998). Thus, when
it comes to prediction of motivational salience, the
ventral striatum, centrally located in the mesolimbic
system, has been of central importance. The ventral
striatum has been suggested to be an interphase from
motivation to action (Mogenson et al., 1993).
Initially, human neuroimaging studies found that the
mesolimbic system was mainly involved in the pro-
cessing of positive rewards. The ventral striatum in
particular was found to be activated in anticipation
of a reward and importantly, the magnitude of the
reward correlated with the activation strength (Knutson
et al., 2001). In a within-subject study a signifi-
cant correlation between dopamine release (measured
using displacement positron emission tomography)
and functional blood-oxygen level dependent activa-
tion in the ventral striatum was shown using a monetary
incentive delay paradigm (Schott et al., 2008).
Furthermore, research has taken the ventral striatum
beyond primary and secondary rewards, where it has
been shown to be recruited not only in anticipation
of primary or secondary rewards, but also to signal
learned incentives of wealth and social dominance. In
a study taking on an evolutionary perspective, Erk and
colleagues (2002) found that in healthy young men
viewing stimuli that signalled high status (sports cars)
activated the ventral striatum more than other cate-
gories of cars. This type of stimulus can be seen as
a cognitive incentive which is known to the subject by
learning, expected to be pleasant or associated with
pleasant attributes, subjectively desired and should,
therefore, be gained. Thus, the ventral striatum is
recruited in association with primary rewards such
as juice squirts (O’Doherty et al., 2002), secondary
rewards such as money (Knutson et al., 2001) and even
stimuli that have been learned to be associated with
attributes such as wealth and power (Erk et al., 2002).
In a series of event-related fMRI experiments in
healthy controls using paradigms based on classical
pavlovian conditioning (mild electrical shocks were
used as aversive stimuli), activations in the mesolim-
bic motivational system in the anticipation of aversive
stimuli were found (Jensen et al., 2003). Further, it was
demonstrated that activation of the mesolimbic motiva-
tional system was time-linked to conditioned aversive
stimuli suggesting that the activation was a direct con-
sequence of the processing of the aversive stimuli, as
opposed to the relief experienced upon its termina-
tion (Jensen et al., 2003). In addition, the activation of
the ventral striatum was present regardless of whether
there was an opportunity to avoid the shock or not.
If the role of the ventral striatum is primarily moti-
vational salience coding, valence must be represented
elsewhere. In a subsequent study, both appetitive
(money) and aversive (electrical stimulations) motiva-
tional stimuli were used in the same session (Jensen et
al., 2007). It was shown that positive stimuli primarily
recruited the medial orbitofrontal cortex when com-
pared to negative stimuli; the reverse contrast showed
activation in more lateral regions, especially the right
anterior insula. Although this study used different rein-
forcer modalities, the results implicate the orbitofrontal
cortex in the coding of valence. These findings support
a medial-lateral distinction for positive and negative
events as has been previously suggested (Kringelbach,
2005). It has been proposed that the orbitofrontal cor-
tex guides behavior based on the anticipated value of
different actions (Rolls et al., 2003), which in turn
suggests that the affective value of a stimulus is repre-
sented in this region and that dissociable regions of the
human orbitofrontal cortex correlate with subjective
pleasantness and unpleasantness ratings of emotional
stimuli.

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J. Jensen and H. Walter / Incentive motivational salience 143
To test the reward prediction-error model demon-
strated in animals (Schultz, 2002), computational
models based on the events in the animal behavioural
paradigms were used to obtain a theoretical estimate of
motivational prediction-error signalling (Jensen et al.,
2007). This quantitative estimate of prediction-error
signalling, derived from the behavioural paradigm,
was then correlated with brain activity measured with
event-related fMRI. A central role for the ventral
striatum was confirmed in the processing of motiva-
tional events, whether they were appetitive or aversive.
Further, it was demonstrated that the BOLD fMRI
signal showed deviations consistent with the theoreti-
cal models of learning prediction-error (Jensen et al.,
2007). Thus, these findings raise the possibility that
motivational-salience prediction-error, as opposed to
reward prediction error, may better characterize how
the BOLD signals change in the ventral striatum.
An important aspect of this line of research, how-
ever, is what happens at omission of the reward. In
a study using a monetary incentive delay paradigm
it was found a decrease in the ventral striatal activa-
tion to omissions as compared to receipts of reward in
the outcome phase as predicted by the formal learn-
ing theory mentioned above (Abler et al., 2005b). In a
parametric follow up study (Abler et al., 2006), it was
shown that ventral striatal activation correlated with the
prediction-error both when receiving a reward (more
striatal activation with lower prior reward probability
in the anticipation phase) as well as when a reward
was omitted (lower striatal activation with higher prior
reward probability in the anticipation phase). Thus,
in addition to rewarding events, the ventral striatum
is robustly involved in the association with aversive
events (omission of expected rewards). However, since
all studies using different types of aversive events were
fMRI-studies, the role dopamine plays can only be
indirectly inferred. In fact, ventral striatal activation in
response to rewarding and punishing event may depend
on different neurotransmitter system inputs.
Since the brain consists of dynamic distributed net-
works, the focus on single regions and structures in the
hypothesis-driven studies reviewed above is an over-
simplification. In a study on appetitive conditioning
using monetary rewards and a multivariate approach
(Diaconescu et al., 2011), increased BOLD activity
across several brain regions was found in the bilat-
eral cerebellum, right thalamus, right ventral striatum,
bilateral putamen, left globus pallidus, right hippocam-
pus, bilateral anterior cingulate, right parahippocampal
gyrus, occipital regions, cuneus, and in the lingual
gyrus. In addition, frontal regions including bilateral
superior frontal gyrus, left medial PFC and middle
frontal gyrus were more active when comparing a
neutral stimulus associated with a possible reward
to another neutral stimulus without rewarding conse-
quences. Since the ventral striatum is a critical node it
was used as a seed in a functional connectivity analysis.
It was found to correlate with activations in the sub-
stantia nigra, dorsal striatum, anterior cingulate cortex,
hippocampus and prefrontal cortices such as OFC,
middle frontal gyrus and inferior frontal gyrus. These
findings clearly show that many more brain regions are
involved in the processing of rewarding stimuli than
just the ventral striatum and the OFC.
3. Challenging the motivational system in
healthy subjects
3.1. Effects of psychological intervention
Emotion regulation strategies have been shown to
be able to modulate neural activations in the striatum
and peripheral physiological underpinnings of both
aversive emotional processing (Goldin et al., 2008;
Ochsner & Gross, 2005; Walter et al., 2009b) and
the expectation of reward (Delgado et al., 2008). It
has been demonstrated that explicit cognitive strate-
gies such as reappraisal can affect striatal activation
(Staudinger et al., 2009). In this study a monetary
incentive delay task was used and subjects were
instructed to either allow all upcoming feelings or to
distance (detach) themselves from their feelings. It
was shown that a region in the right fronto-parietal
network consisting of parts of the anterior cingulate,
lateral orbitofrontal cortex and the temporo-parietal
junction was activated when cognitive reappraisal was
used. Self-reported reappraisal success correlated with
the activation of the anterior cingulate cortex and
the lateral orbitofrontal cortex. Successful reappraisal
decreased ventral striatum activation during reward
expectation epochs. Furthermore, it was shown that
reappraisal also influenced coding of prediction-error
in the outcome period. In a subsequent follow-up study
using a similar paradigm, Staudinger and colleagues
investigated whether cognitive reappraisal affects the
connectivity between frontal regions and the striatum
(Staudinger et al., 2011). It was found that cogni-
tive reappraisal was subjectively effective, lowered

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144 J. Jensen and H. Walter / Incentive motivational salience
motivational salience as indicated by slowing reac-
tion times to larger rewards, and attenuated activation
in striatal regions (putamen). Moreover, functional
connectivity between the striatum and prefrontal
regions was altered by cognitive reappraisal. Correla-
tion analyses with behaviour suggested that prefrontal
activation during reappraisal does influence motiva-
tion by affecting motor preparation in anticipation of
rewards resulting in decreased motivation (indicated
by increased reaction times) to obtain a high reward.
3.2. Effects of pharmacological intervention
Pharmacological fMRI has the potential to test trans-
mitter models of disorders, predict the response to
pharmacological treatments and to support the devel-
opment of novel compounds in neuropsychiatry. In a
pharmacological double blind, between-subjects study
acute doses of amphetamine, haloperidol or placebo
were administered to healthy subjects during an aver-
sive conditioning paradigm using fMRI (Menon et al.,
2007). The results suggested that the ventral stria-
tum was active in response to salient stimuli and
altering dopamine transmission by acute drug admin-
istration affected the activity in this region. Further,
amphetamine gave rise to a higher correlation with a
model predicted by formal learning theory compared to
placebo and haloperidol. Using an atypical neuroleptic
(olanzapine) it was found that ventral striatal activa-
tion to high rewards was reduced compared to placebo
(Abler et al., 2007). Additionally,the usual acceleration
of reaction times in higher compared to lower reward
trials was reduced compared to placebo, indicating that
olanzapine reduced motivation to obtain an reward.
Using the same data set as Menon et al. (2007) in
a multivariate approach (Diaconescu et al., 2010), it
was demonstrated that the participants in the placebo
group showed increased BOLD activity across dif-
ferent brain regions such as the left ventral striatum,
amygdala, insula, bilateral middle and superior tempo-
ral cortices, and the bilateral medial PFC in response to
a neutral stimulus associated with an electrical shock.
Again, the ventral striatum has previously been asso-
ciated with motivational learning in response to both
appetitive and aversive stimuli, while amygdala and
insula activity have been more associated with antici-
pation of aversive, noxious events per se (Seymour et
al., 2004). Since the electrical shocks were delivered
to the left index finger, activity localized to the pri-
mary somatosensory area contralateral to the site of
stimulation may relate to the anticipation of the aver-
sive stimulus. This study also adds evidence to the
discussion as to whether dopamine is involved in aver-
sive processes.
To investigate functional connectivity in the pharma-
cological challenge study, seeds were extracted from
bilateral ventral striatum and amygdala due to their
involvement in motivational salience (Diaconescu et
al., 2010). In the placebo group, the right ventral
tegmental area, bilateral caudate, right parahippocam-
pal gyrus, left inferior lobule, bilateral postcentral
gyrus, bilateral middle frontal, orbitofrontal and ven-
tromedial prefrontal cortices activities correlated with
the seed. In response to the salient versus non-
salient stimuli condition, dopamine modulation via
amphetamine was associated with reduced task dif-
ferences and functional connectivity for both stimuli
between the left ventral striatum seed and regions such
as ventral tegmental area, right caudate, left amygdala,
left middle frontal gyrus and bilateral ventromedial
prefrontal cortex. Blocking dopamine transmission via
haloperidol was associated with a different network
which was connected to the amygdala seed: right
insula, left anterior cingulate cortex, bilateral inferior
parietal lobule, precuneus, post-central gyrus, middle
frontal gyrus and supplementary motor area compar-
ing the salient stimuli to the non-salient stimuli. Since
dopamine agonists and antagonists do not deliver the
same activation patterns, it is suggested that this neuro-
transmitter codes for motivational salience rather than
reward only.
4. Motivational salience system in patients
with schizophrenia
Several studies using Positron Emission Tomog-
raphy have found that patients with schizophrenia
suffering from a psychotic episode show a height-
ened synthesis of dopamine, for example (Reith et al.,
1994) and an increased level of synaptic dopamine, for
example (Abi-Dargham et al., 2000) in the mesolimbic
motivational system. Schizophrenia, one of the most
severe psychiatric disorders, is characterized by posi-
tive symptoms such as hallucinations and delusions, as
well as by negative symptoms like anhedonia, apathy,
and lack of motivation and social interaction. It has
been hypothesized that a dysfunctional motivational
system could explain several aspects of the symptoma-
tology in schizophrenia.

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J. Jensen and H. Walter / Incentive motivational salience 145
A recent influential theory hypothesized that
increased chaotic activity of the mesolimbic motiva-
tional salience system in patients with schizophrenia
results in attribution of aberrant salience where
salience thus is attributed to irrelevant stimuli (Heinz
& Schlagenhauf, 2010; Kapur, 2003). According
to this hypothesis dopamine is mediating motiva-
tional salience of internally and externally generated
representations. A dysregulated hyperdopaminergic
mesolimbic motivational system leads to an aberrant
assignment of salience to these representations. To be
able to explain these aberrantly salient representations
delusions are formed for the external events and hallu-
cinations for the internal events (Kapur, 2003).
Studies by Juckel, Schlagenhauf, Heinz and collabo-
ratorsfoundthatunmedicatedpatientswithschizophre-
nia displayed a striatal dysfunction during a similar
monetary incentive delay paradigm as reviewed above
(Juckel et al., 2006b). They showed also that patients
treated with typical medication showed blunted reward
activations compared to patients treated with atyp-
ical medication (Juckel et al., 2006a). The same
group also demonstrated that drug-free patients with
schizophrenia show impaired processing of reward and
loss-avoidance and have reduced connectivity between
the ventral striatum and medial prefrontal cortex that
both are prominent parts of the mesolimbic reward sys-
tem (Schlagenhauf et al., 2009).
Murray and collaborators (Murray et al., 2008)
undertook a study of first-episode psychosis patients
using an event-related reward fMRI paradigm. They
found a disruption in reward prediction among the
patients and abnormal activations in dopaminergic
regions, such as ventral tegmental area/substantia nigra
and the striatum. They also showed that patients had
difficulties in discriminating between motivationally
salient and neutral stimuli.
Studying reward functions in patients with psychosis
on atypical medication (with varying magnitude),
showed that both patients and controls activated the
ventral striatum in anticipation of reward (Walter et
al., 2009a). Also, both groups showed an encoding of
prediction error in the ventral striatum although the
steepness of the correlation between prediction error
and ventral striatal activation was significantly smaller
in the patient group. Whereas controls showed signif-
icantly more increasing anterior cingulate activation
to increasing rewards, this was not found in patients
which instead showed a negative correlation with pos-
itive symptoms in this region. Furthermore, it was
found, as in a previous study (Abler et al., 2005), that
during outcome salience was encoded in the right infe-
rior frontal cortex showing a u-shaped activation with
highest values for high omissions and high rewards.
To test if the ventrolateral prefrontal cortex (VLPFC)
coding of salience could be replicated, four studies of
the same group were reanalysed (Walter et al., 2010).
Indeed the u-shaped salience function in the outcome
period could be replicated in four independent sam-
ples of healthy controls groups independently of the
reward parameter, that is, for reward magnitude as
well as reward probability (Abler et al., 2007, 2008,
2009, 2006). Furthermore, the aberrant assignment of
salience in the VLPFC was replicated in another group
of patients with schizophrenia (Walter et al., 2009a).
In both patient studies (Abler et al., 2008; Walter et
al., 2009a), negative symptoms were correlated with
activation in the VLPFC.
In another study using appetitive conditioning with
monetary reward (Diaconescu et al., 2011), it was
found that patients did neither differentiate between
salient and non-salient events as measured with
psychophysiological measures, nor did they report
increased happiness to the salient stimuli as healthy
controls did. The healthy subjects displayed increased
effective connectivity from the ventral striatum to the
orbitofrontal cortex in salient compared to the non-
salient conditions. The patients, however, displayed
increased connectivity from the striatum to hippocam-
pus and prefrontal regions in the non-salient compared
to the salient condition. Increased activity and effective
connectivity in response to the non-salient conditions
in patients with schizophrenia support the aberrant
assignment of salience hypothesis.
The findings from reward studies have been
enhanced with data that suggest that patients with
schizophrenia, when exposed to neutral stimuli in a
threatening situation, have an impaired ability to distin-
guish between neutral stimuli and stimuli truly linked
to danger (Jensen et al., 2008). Thus, the behavioral
results here were very similar to the results obtained
in the appetitive conditioning experiment discussed in
the previous paragraph and show a similar pattern to
studies where subjects were administered dopamine
agonists. Further, the neutral stimulus was associated
with significant conditioned brain activations among
the patients, an abnormality that was accompanied
by abnormal autonomic physiological responses and
deviant explicit learning. It has been suggested that
activations of the ventral striatum normally mediate

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146 J. Jensen and H. Walter / Incentive motivational salience
Table 1
Summary of incentive motivational salience and the human brain
with some example references
Activation of the mesolimbic motivational system in anticipation of
- Primary rewards (O’Doherty et al., 2002)
- Primary punishments (Jensen et al., 2003)
- Secondary rewards (Erk et al., 2002)
Challenging the mesolimbic motivational system with
- Psychological intervention (Staudinger et al., 2009)
- Pharmacological intervention (Menon et al., 2007)
Dysfunction of the mesolimbic motivational system in
- Schizophrenia (Jensen et al., 2008; Juckel et al., 2006b;
Walter et al., 2009a)
the incentive motivational salience of environmental
stimuli (Jensen et al., 2003; Zink et al., 2006) and thus
the stronger responses to the neutral stimulus among
patients may reflect an aberrant attribution of moti-
vational salience to items considered to be neutral in
healthy subjects (Kapur, 2003). As a result, stimuli that
are neutral and innocuous among healthy controls may
gain a status as motivationally salient among patients
with schizophrenia.
5. Summary
In summary (see Table 1 for an overview), we have
reviewed some of the original and pioneering stud-
ies on the subject of the mesolimbic motivational
system, in particular the ventral striatum, and demon-
strated how studies we have been involved in fit with
and extend this pre-existing literature. These studies
suggest that the mesolimbic motivational system is
recruited in response to primary and secondary rein-
forcers regardless of valence, i.e., for positive as well
as negative events. This is compatible with the idea
that it is crucial for indicating salience. Activation of
the mesolimbic motivational system can be influenced
by cognitive processes (probably via the prefrontal
cortex) and is sensitive to pharmacological challenges
using dopamine antagonists and agonists. Patients with
schizophrenia show aberrant salience coding for both
negative and positive stimuli. Finally, other regions
beyond the ventral striatum and the OFC contribute
to coding salience, in particular the right ventrolateral
prefrontal cortex.
Acknowledgments
We would like to thank all our collaborators in the
studies reviewed in this paper.
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