Altered neural reward and loss processing and prediction error signalling in depression

Dysfunctional processing of reward and punishment may play an important role in depression. However, functional magnetic resonance imaging (fMRI) studies have shown heterogeneous results for reward processing in fronto-striatal regions. We examined neural responsivity associated with the processing of reward and loss during anticipation and receipt of incentives and related prediction error (PE) signalling in depressed individuals. Thirty medication-free depressed persons and 28 healthy controls performed an fMRI reward paradigm. Regions of interest analyses focused on neural responses during anticipation and receipt of gains and losses and related PE-signals. Additionally, we assessed the relationship between neural responsivity during gain/loss processing and hedonic capacity. When compared with healthy controls, depressed individuals showed reduced fronto-striatal activity during anticipation of gains and losses. The groups did not significantly differ in response to reward and loss outcomes. In depressed individuals, activity increases in the orbitofrontal cortex and nucleus accumbens during reward anticipation were associated with hedonic capacity. Depressed individuals showed an absence of reward-related PEs but encoded loss-related PEs in the ventral striatum. Depression seems to be linked to blunted responsivity in fronto-striatal regions associated with limited motivational responses for rewards and losses. Alterations in PE encoding might mirror blunted reward- and enhanced loss-related associative learning in depression.     

Mapping adolescent reward anticipation,receipt, and prediction error during the monetary incentive delay task

The functional neuroanatomy and connectivity of reward processing in adults are well documented, with relatively less research on adolescents, a notable gap given this developmental period's association with altered reward sensitivity. Here, a large sample (n = 1,510) of adolescents performed the monetary incentive delay (MID) task during functional magnetic resonance imaging. Probabilistic maps identified brain regions that were reliably responsive to reward anticipation and receipt, and to prediction errors derived from a computational model. Psychophysiological interactions analyses were used to examine functional connections throughout reward processing. Bilateral ventral striatum, pallidum, insula, thalamus, hippocampus, cingulate cortex, midbrain, motor area, and occipital areas were reliably activated during reward anticipation. Bilateral ventromedial prefrontal cortex and bilateral thalamus exhibited positive and negative activation, respectively, during reward receipt. Bilateral ventral striatum was reliably active following prediction errors. Previously, individual differences in the personality trait of sensation seeking were shown to be related to individual differences in sensitivity to reward outcome. Here, we found that sensation seeking scores were negatively correlated with right inferior frontal gyrus activity following reward prediction errors estimated using a computational model. Psychophysiological interactions demonstrated widespread cortical and subcortical connectivity during reward processing, including connectivity between reward‐related regions with motor areas and the salience network. Males had more activation in left putamen, right precuneus, and middle temporal gyrus during reward anticipation. In summary, we found that, in adolescents, different reward processing stages during the MID task were robustly associated with distinctive patterns of activation and of connectivity.     

Functional magnetic resonance imaging of reward prediction

PURPOSE OF REVIEW: Technical and conceptual advances in functional magnetic resonance imaging now allow visualization of real-time changes in oxygenation of deep subcortical regions, leading to rapid advances in scientific characterization of the neural substrates that underlie reward prediction in humans. RECENT FINDINGS: Neuroimaging research over the past year has focused on determining the necessary neural substrates for reward prediction. SUMMARY: While the orbitofrontal cortex has long been implicated in modality-specific reward representation, the ventral striatum (particularly the nucleus accumbens) may play a role in modality-independent representations of predicted reward. On the other hand, the mesial prefrontal cortex appears to play a role in representing reward prediction error and the dorsal caudate in linking reward to behavior. Theoretically, future studies will need to establish the specificity of these responses to reward versus punishment and anticipation versus outcome. Clinically, current findings suggest that patients can predict reward without a prefrontal cortex, but should experience difficulty correcting their behavior when reward predictions are violated.     

Neural dissociation of food- and money-related reward processing using an abstract incentive delay task

Food is an innate reward stimulus related to energy homeostasis and survival, whereas money is considered a more general reward stimulus that gains a rewarding value through learning experiences. Although the underlying neural processing for both modalities of reward has been investigated independently from one another, a more detailed investigation of neural similarities and/or differences between food and monetary reward is still missing. Here, we investigated the neural processing of food compared with monetary-related rewards in 27 healthy, normal-weight women using functional magnetic resonance imaging. We developed a task distinguishing between the anticipation and the receipt of either abstract food or monetary reward. Both tasks activated the ventral striatum during the expectation of a reward. Compared with money, greater food-related activations were observed in prefrontal, parietal and central midline structures during the anticipation and lateral orbitofrontal cortex (lOFC) during the receipt of food reward. Furthermore, during the receipt of food reward, brain activation in the secondary taste cortex was positively related to the body mass index. These results indicate that food-dependent activations encompass to a greater extent brain regions involved in self-control and self-reflection during the anticipation and phylogenetically older parts of the lOFC during the receipt of reward.     

The role of the human ventral striatum and the medial orbitofrontal cortex in the representation of reward magnitude - an activation likelihood estimation meta-analysis of neuroimaging studies of passive reward expectancy and outcome processing

Reward maximization is a core motivation of every organism. In humans, several brain regions have been implicated in the representation of reward magnitude. Still, it is unclear whether identical brain regions consistently play a role in reward prediction and its consumption. In this study we used coordinate-based ALE meta-analysis to determine the individual roles of the ventral striatum (vSTR) and the medial orbitofrontal cortex (mOFC/VMPFC) in the representation of reward in general and of reward magnitude in particular. Specifically, we wanted to assess commonalities and differences in regional brain activation during the passive anticipation and consumption of rewards. Two independent meta-analyses of neuroimaging data from the past decade revealed a general role for the vSTR in reward anticipation and consumption. This was the case particularly when the consumed rewards occurred unexpectedly or were uncertain. In contrast, for the mOFC/VMPFC the present meta-analytic data suggested a rather specific function in reward consumption as opposed to passive anticipation. Importantly, when considering only coordinates that compared different reward magnitudes, the same parts of the vSTR and the mOFC/VMPFC showed concordant responses across studies, although areas of coherence were regionally more confined. These meta-analytic data suggest that the vSTR may be involved in both prediction and consumption of salient rewards, and may also be sensitive to different reward magnitudes, while the mOFC/VMPFC may rather process the magnitude during reward receipt. Collectively, our meta-analytic data conform with the notion that these two brain regions may subserve different roles in processing of reward magnitude.     

Impact of aging on frontostriatal reward processing

Healthy aging is associated with a progressive decline across a range of cognitive functions. An important factor underlying this decline may be the age‐related impairment in stimulus–reward processing. Several studies have investigated age‐related effects, but compared young versus old subjects. This is the first study to investigate the effect of aging on brain activation during reward processing within a continuous segment of the adult life span. We scanned 49 healthy adults aged 40–70 years, using functional MRI. We adopted a simple reward task, which allowed separate evaluation of neural responses to reward anticipation and receipt. The effect of reward on performance accuracy and speed was not related to age, indicating that all subjects could perform the task correctly. We identified a whole‐brain significant age‐related decline of ventral striatum activation during reward anticipation as compared to neutral anticipation. Importantly, the specificity of this finding was underscored by the observation that there was no general decline in activation during anticipation. Activation in the ventral striatum increased with age during reward receipt as compared to receiving neutral outcome. Finally, activation in the ventromedial prefrontal cortex during outcome was not affected by age. Our data demonstrate that the typical shift in striatal activation from reward receipt to reward anticipation in young adults disappears with healthy aging. These changes are consistent the well‐ocumented age‐related decline of striatal dopamine availability, and may provide a stepping stone for further research of age‐related neurodegenerative diseases. Hum Brain Mapp 36:2305–2317, 2015. © 2015 Wiley Periodicals, Inc.     

Neuronal correlates of reward and loss in Cluster B personality disorders: a functional magnetic resonance imaging study

Decision making is guided by the likely consequences of behavioural choices. Neuronal correlates of financial reward have been described in a number of functional imaging studies in humans. Areas implicated in reward include ventral striatum, dopaminergic midbrain, amygdala and orbitofrontal cortex. Response to loss has not been as extensively studied but may involve prefrontal and medial temporal cortices. It has been proposed that increased sensitivity to reward and reduced sensitivity to punishment underlie some of the psychopathology in impulsive personality disordered individuals. However, few imaging studies using reinforcement tasks have been conducted in this group. In this fMRI study, we investigate the effects of positive (monetary reward) and negative (monetary loss) outcomes on BOLD responses in two target selection tasks. The experimental group comprised eight people with Cluster B (antisocial and borderline) personality disorder, whilst the control group contained fourteen healthy participants. A key finding was the absence of prefrontal responses and reduced BOLD signal in the subcortical reward system in the PD group during positive reinforcement. Impulsivity scores correlated negatively with prefrontal responses in the PD but not the control group during both, reward and loss. Our results suggest dysfunctional responses to rewarding and aversive stimuli in Cluster B personality disordered individuals but do not support the notion of hypersensitivity to reward and hyposensitivity to loss.     

Choice selection and reward anticipation: an fMRI study

We examined neural activations during decision-making using fMRI paired with the wheel of fortune task, a newly developed two-choice decision-making task with probabilistic monetary gains. In particular, we assessed the impact of high-reward/risk events relative to low-reward/risk events on neural activations during choice selection and during reward anticipation. Seventeen healthy adults completed the study. We found, in line with predictions, that (i) the selection phase predominantly recruited regions involved in visuo-spatial attention (occipito-parietal pathway), conflict (anterior cingulate), manipulation of quantities (parietal cortex), and preparation for action (premotor area), whereas the anticipation phase prominently recruited regions engaged in reward processes (ventral striatum); and (ii) high-reward/risk conditions relative to low-reward/risk conditions were associated with a greater neural response in ventral striatum during selection, though not during anticipation. Following an a priori ROI analysis focused on orbitofrontal cortex, we observed orbitofrontal cortex activation (BA 11 and 47) during selection (particularly to high-risk/reward options), and to a more limited degree, during anticipation. These findings support the notion that (1) distinct, although overlapping, pathways subserve the processes of selection and anticipation in a two-choice task of probabilistic monetary reward; (2) taking a risk and awaiting the consequence of a risky decision seem to affect neural activity differently in selection and anticipation; and thus (3) common structures, including the ventral striatum, are modulated differently by risk/reward during selection and anticipation.     

Distinct portions of anterior cingulate cortex and medial prefrontal cortex are activated by reward processing in separable phases of decision-making cognition.

BACKGROUND: Choosing between actions associated with uncertain rewards and punishments is mediated by neural circuitry encompassing the orbitofrontal cortex, anterior cingulate cortex (ACC), and striatum; however, the precise conditions under which these different components are activated during decision-making cognition remain uncertain. METHODS: Fourteen healthy volunteers completed an event-based functional magnetic resonance imaging protocol to investigate blood-oxygenation-level-dependent (BOLD) responses during independently modeled phases of choice cognition. In the "decision phase," participants decided which of two simultaneous visually presented gambles they wished to play for monetary reward. The gambles differed in their magnitude of gains, magnitude of losses, and the probabilities with which these outcomes were delivered. In the "outcome phase," the result of each choice was indicated on the visual display. RESULTS: In the decision phase, choices involving large gains were associated with increased BOLD responses in the pregenual ACC, paracingulate, and right posterior orbitolateral cortex compared with choices involving small gains. In the outcome phase, good outcomes were associated with increased BOLD responses in the posterior orbitomedial cortex, subcallosal ACC, and ventral striatum compared with negative outcomes. There was only limited overlap between reward-related activity in ACC and orbitofrontal cortex during the decision and outcome phases. CONCLUSIONS: Neural activity within the medial and lateral orbitofrontal cortex, pregenual ACC, and striatum mediate distinct representations of reward-related information that are deployed at different stages during a decision-making episode.     

Contextual interaction between novelty and reward processing within the mesolimbic system

Medial temporal lobe (MTL) dependent long-term memory for novel events is modulated by a circuitry that also responds to reward and includes the ventral striatum, dopaminergic midbrain, and medial orbitofrontal cortex (mOFC). This common neural network may reflect a functional link between novelty and reward whereby novelty motivates exploration in the search for rewards; a link also termed novelty "exploration bonus." We used fMRI in a scene encoding paradigm to investigate the interaction between novelty and reward with a focus on neural signals akin to an exploration bonus. As expected, reward related long-term memory for the scenes (after 24 hours) strongly correlated with activity of MTL, ventral striatum, and substantia nigra/ventral tegmental area (SN/VTA). Furthermore, the hippocampus showed a main effect of novelty, the striatum showed a main effect of reward, and the mOFC signalled both novelty and reward. An interaction between novelty and reward akin to an exploration bonus was found in the hippocampus. These data suggest that MTL novelty signals are interpreted in terms of their reward-predicting properties in the mOFC, which biases striatal reward responses. The striatum together with the SN/VTA then regulates MTL-dependent long-term memory formation and contextual exploration bonus signals in the hippocampus.     

Individual differences in sensitivity to reward and punishment and neural activity during reward and avoidance learning

In this functional neuroimaging study, we investigated neural activations during the process of learning to gain monetary rewards and to avoid monetary loss, and how these activations are modulated by individual differences in reward and punishment sensitivity. Healthy young volunteers performed a reinforcement learning task where they chose one of two fractal stimuli associated with monetary gain (reward trials) or avoidance of monetary loss (avoidance trials). Trait sensitivity to reward and punishment was assessed using the behavioral inhibition/activation scales (BIS/BAS). Functional neuroimaging results showed activation of the striatum during the anticipation and reception periods of reward trials. During avoidance trials, activation of the dorsal striatum and prefrontal regions was found. As expected, individual differences in reward sensitivity were positively associated with activation in the left and right ventral striatum during reward reception. Individual differences in sensitivity to punishment were negatively associated with activation in the left dorsal striatum during avoidance anticipation and also with activation in the right lateral orbitofrontal cortex during receiving monetary loss. These results suggest that learning to attain reward and learning to avoid loss are dependent on separable sets of neural regions whose activity is modulated by trait sensitivity to reward or punishment.     

Opposing BOLD responses to reciprocated and unreciprocated altruism in putative reward pathways

Mesencephalic dopamine neurons are believed to facilitate reward-dependent learning by computing errors in reward predictions. We used fMRI to test whether this system was activated as expected in response to errors in predictions about whether a social partner would reciprocate an act of altruism. Nineteen subjects received fMRI scans as they played a series of single-shot Prisoner's Dilemma games with partners who were outside the scanner. In both ventromedial prefrontal cortex and ventral striatum, reciprocated and unreciprocated cooperation were associated with positive and negative BOLD responses, respectively. Our results are consistent with the hypothesis that mesencephalic dopamine projection sites carry information about errors in reward prediction that allow us to learn who can and cannot be trusted to reciprocate favors.     

Attentional modulation of reward processing in the human brain

Although neural signals of reward anticipation have been studied extensively, the functional relationship between reward and attention has remained unclear: Neural signals implicated in reward processing could either reflect attentional biases towards motivationally salient stimuli, or proceed independently of attentional processes. Here, we sought to disentangle reward and attention‐related neural processes by independently modulating reward value and attentional task demands in a functional magnetic resonance imaging study in healthy human participants. During presentation of a visual reward cue that indicated whether monetary reward could be obtained in a subsequent reaction time task, participants either attended to the reward cue or performed an unrelated attention‐demanding task at two different levels of difficulty. In ventral striatum and ventral tegmental area, neural responses were modulated by reward anticipation irrespective of attentional demands, thus indicating attention‐independent processing of reward cues. By contrast, additive effects of reward and attention were observed in visual cortex. Critically, reward‐related activations in right anterior insula strongly depended on attention to the reward cue. Dynamic causal modelling revealed that the attentional modulation of reward processing in insular cortex was mediated by enhanced effective connectivity from ventral striatum to anterior insula. Our results provide evidence for distinct functional roles of the brain regions involved in the processing of reward‐indicating information: While subcortical structures signal the motivational salience of reward cues even when attention is fully engaged elsewhere, reward‐related responses in anterior insula depend on available attentional resources, likely reflecting the conscious evaluation of sensory information with respect to motivational value. Hum Brain Mapp 35:3036–3051, 2014. © 2013 Wiley Periodicals, Inc.     

Model-based learning and the contribution of the orbitofrontal cortex to the model-free world

Learning is proposed to occur when there is a discrepancy between reward prediction and reward receipt. At least two separate systems are thought to exist: one in which predictions are proposed to be based on model-free or cached values; and another in which predictions are model-based. A basic neural circuit for model-free reinforcement learning has already been described. In the model-free circuit the ventral striatum (VS) is thought to supply a common-currency reward prediction to midbrain dopamine neurons that compute prediction errors and drive learning. In a model-based system, predictions can include more information about an expected reward, such as its sensory attributes or current, unique value. This detailed prediction allows for both behavioral flexibility and learning driven by changes in sensory features of rewards alone. Recent evidence from animal learning and human imaging suggests that, in addition to model-free information, the VS also signals model-based information. Further, there is evidence that the orbitofrontal cortex (OFC) signals model-based information. Here we review these data and suggest that the OFC provides model-based information to this traditional model-free circuitry and offer possibilities as to how this interaction might occur.     

Fronto-striatal Dysfunction During Reward Processing in Unaffected Siblings of Schizophrenia Patients

Schizophrenia is a psychiatric disorder that is associated with impaired functioning of the fronto-striatal network, in particular during reward processing. However, it is unclear whether this dysfunction is related to the illness itself or whether it reflects a genetic vulnerability to develop schizophrenia. Here, we examined reward processing in unaffected siblings of schizophrenia patients using functional magnetic resonance imaging. Brain activity was measured during reward anticipation and reward outcome in 27 unaffected siblings of schizophrenia patients and 29 healthy volunteers using a modified monetary incentive delay task. Task performance was manipulated online so that all subjects won the same amount of money. Despite equal performance, siblings showed reduced activation in the ventral striatum, insula, and supplementary motor area (SMA) during reward anticipation compared to controls. Decreased ventral striatal activation in siblings was correlated with sub-clinical negative symptoms. During the outcome of reward, siblings showed increased activation in the ventral striatum and orbitofrontal cortex compared to controls. Our finding of decreased activity in the ventral striatum during reward anticipation and increased activity in this region during receiving reward may indicate impaired cue processing in siblings. This is consistent with the notion of dopamine dysfunction typically associated with schizophrenia. Since unaffected siblings share on average 50% of their genes with their ill relatives, these deficits may be related to the genetic vulnerability for schizophrenia.Key words: ventral striatum, orbitofrontal cortex, ventromedial prefrontal cortex, monetary incentive delay task, genetic vulnerability, cue processing     

Reward sensitivity modulates connectivity among reward brain areas during processing of anticipatory reward cues

Reward sensitivity, or the tendency to engage in motivated approach behavior in the presence of rewarding stimuli, may be a contributory factor for vulnerability to disinhibitory behaviors. Although evidence exists for a reward sensitivity‐related increased response in reward brain areas (i.e. nucleus accumbens or midbrain) during the processing of reward cues, it is unknown how this trait modulates brain connectivity, specifically the crucial coupling between the nucleus accumbens, the midbrain, and other reward‐related brain areas, including the medial orbitofrontal cortex and the amygdala. Here, we analysed the relationship between effective connectivity and personality in response to anticipatory reward cues. Forty‐four males performed an adaptation of the Monetary Incentive Delay Task and completed the Sensitivity to Reward scale. The results showed the modulation of reward sensitivity on both activity and functional connectivity (psychophysiological interaction) during the processing of incentive cues. Sensitivity to reward scores related to stronger activation in the nucleus accumbens and midbrain during the processing of reward cues. Psychophysiological interaction analyses revealed that midbrain–medial orbitofrontal cortex connectivity was negatively correlated with sensitivity to reward scores for high as compared with low incentive cues. Also, nucleus accumbens–amygdala connectivity correlated negatively with sensitivity to reward scores during reward anticipation. Our results suggest that high reward sensitivity‐related activation in reward brain areas may result from associated modulatory effects of other brain regions within the reward circuitry.     

Elevated cognitive control over reward processing in recovered female patients with anorexia nervosa

Background

Individuals with anorexia nervosa are thought to exert excessive self-control to inhibit primary drives.

Methods

This study used functional MRI (fMRI) to interrogate interactions between the neural correlates of cognitive control and motivational processes in the brain reward system during the anticipation of monetary reward and reward-related feedback. In order to avoid confounding effects of undernutrition, we studied female participants recovered from anorexia nervosa and closely matched healthy female controls. The fMRI analysis (including node-to-node functional connectivity) followed a region of interest approach based on models of the brain reward system and cognitive control regions implicated in anorexia nervosa: the ventral striatum, medial orbitofrontal cortex (mOFC) and dorsolateral prefrontal cortex (DLPFC).

Results

We included 30 recovered patients and 30 controls in our study. There were no behavioural differences and no differences in hemodynamic responses of the ventral striatum and the mOFC in the 2 phases of the task. However, relative to controls, recovered patients showed elevated DLPFC activity during the anticipation phase, failed to deactivate this region during the feedback phase and displayed greater functional coupling between the DLPFC and mOFC. Recovered patients also had stronger associations than controls between anticipation-related DLPFC responses and instrumental responding.

Limitations

The results we obtained using monetary stimuli might not generalize to other forms of reward.

Conclusion

Unaltered neural responses in ventral limbic reward networks but increased recruitment of and connectivity with lateral–frontal brain circuitry in recovered patients suggests an elevated degree of self-regulatory processes in response to rewarding stimuli. An imbalance between brain systems subserving bottom–up and top–down processes may be a trait marker of the disorder.     

Major depressive disorder is characterized by greater reward network activation to monetary than pleasant image rewards

Anhedonia, the loss of interest or pleasure in normally rewarding activities, is a hallmark feature of unipolar Major Depressive Disorder (MDD). A growing body of literature has identified frontostriatal dysfunction during reward anticipation and outcomes in MDD. However, no study to date has directly compared responses to different types of rewards such as pleasant images and monetary rewards in MDD. To investigate the neural responses to monetary and pleasant image rewards in MDD, a modified Monetary Incentive Delay task was used during functional magnetic resonance imaging to assess neural responses during anticipation and receipt of monetary and pleasant image rewards. Participants included nine adults with MDD and 13 affectively healthy controls. The MDD group showed lower activation than controls when anticipating monetary rewards in right orbitofrontal cortex and subcallosal cortex, and when anticipating pleasant image rewards in paracingulate and supplementary motor cortex. The MDD group had relatively greater activation in right putamen when anticipating monetary versus pleasant image rewards, relative to the control group. Results suggest reduced reward network activation in MDD when anticipating rewards, as well as relatively greater hypoactivation to pleasant image than monetary rewards.     

Dissociable neural responses in human reward systems.

Reward is one of the most important influences shaping behavior. Single-unit recording and lesion studies in experimental animals have implicated a number of regions in response to reinforcing stimuli, in particular regions of the extended limbic system and the ventral striatum. In this experiment, functional neuroimaging was used to assess neural response within human reward systems under different psychological contexts. Nine healthy volunteers were scanned using functional magnetic resonance imaging during the performance of a gambling task with financial rewards and penalties. We demonstrated neural sensitivity of midbrain and ventral striatal regions to financial rewards and hippocampal sensitivity to financial penalties. Furthermore, we show that neural responses in globus pallidus, thalamus, and subgenual cingulate were specific to high reward levels occurring in the context of increasing reward. Responses to both reward level in the context of increasing reward and penalty level in the context of increasing penalty were seen in caudate, insula, and ventral prefrontal cortex. These results demonstrate dissociable neural responses to rewards and penalties that are dependent on the psychological context in which they are experienced.     

Waiting to win: elevated striatal and orbitofrontal cortical activity during reward anticipation in euthymic bipolar disorder adults

Nusslock R, Almeida JRC, Forbes EE, Versace A, Frank E, LaBarbara EJ, Klein CR, Phillips ML. Waiting to win: elevated striatal and orbitofrontal cortical activity during reward anticipation in euthymic bipolar disorder adults. Bipolar Disord 2012: 14: 249–260. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Bipolar disorder may be characterized by a hypersensitivity to reward‐relevant stimuli, potentially underlying the emotional lability and dysregulation that characterizes the illness. In parallel, research highlights the predominant role of striatal and orbitofrontal cortical (OFC) regions in reward‐processing and approach‐related affect. We aimed to examine whether bipolar disorder, relative to healthy, participants displayed elevated activity in these regions during reward processing. Methods: Twenty‐one euthymic bipolar I disorder and 20 healthy control participants with no lifetime history of psychiatric disorder underwent functional magnetic resonance imaging (fMRI) scanning during a card‐guessing paradigm designed to examine reward‐related brain function to anticipation and receipt of monetary reward and loss. Data were collected using a 3T Siemens Trio scanner. Results: Region‐of‐interest analyses revealed that bipolar disorder participants displayed greater ventral striatal and right‐sided orbitofrontal [Brodmann area (BA) 11] activity during anticipation, but not outcome, of monetary reward relative to healthy controls (p < 0.05, corrected). Whole‐brain analyses indicated that bipolar disorder, relative to healthy, participants also displayed elevated left‐lateral OFC (BA 47) activity during reward anticipation (p < 0.05, corrected). Conclusions: Elevated ventral striatal and OFC activity during reward anticipation may represent a neural mechanism for predisposition to expansive mood and hypo/mania in response to reward‐relevant cues that characterizes bipolar disorder. Our findings contrast with research reporting blunted activity in the ventral striatum during reward processing in unipolar depressed individuals, relative to healthy controls. Examination of reward‐related neural activity in bipolar disorder is a promising research focus to facilitate identification of biological markers of the illness.