Reward mechanisms in the brain and their role in dependence: evidence from neurophysiological and neuroimaging studies

This article reviews neuronal activity related to reward processing in primate and human brains. In the primate brain, neurophysiological methods provide a differentiated view of reward processing in a limited number of brain structures. Dopamine neurons respond to unpredictable rewards and produce a global reinforcement signal. Some neurons in the striatum also react to the expectation and detection of reward. Other striatal neurons show reward-related activities related to the preparation, initiation and execution of movement. Orbitofrontal neurons discriminate among different rewards and code reward preferences. In the human brain, regions belonging to a meso-striatal and meso-corticolimbic loop respond to reinforcement stimuli in control subjects. These observations corroborate results obtained in primates. Additionally, reward induces activation in regions specific to task performance. Our results also show a similar pattern of reward-related activation in nicotine and opiate addicts. Thus, in contrast to healthy subjects, typical reward-related regions respond in addicts to monetary reward but not to nonmonetary reinforcement. Reduced activation in performance-related regions is also observed in both groups of dependent subjects. The results of animal and human studies suggest that dopamine and dopamine-related regions are associated with the integration of motivational information and movement execution. Dopamine-related pathological disorders can be associated with movement disorders, such as Parkinson’s disease or with false motivational attributions such as drug dependence.     

Reduced reward processing in the brains of Parkinsonian patients

Regional cerebral blood flow (rCBF) in healthy controls and non-demented, non-depressed Parkinsonian patients was measured using H2(15)O PET while subjects performed a prelearned pattern recognition task with delayed response. To investigate differences between the two groups in response to reward, the experimental design consisted of three reinforcement conditions: no reinforcement consisting of nonsense feedback, positive symbolic reinforcement and monetary reward. In the controls, monetary reward activated bilaterally the striatum and anterior cingulate gyrus, as well as unilaterally the left cerebellum, midbrain and medial frontal gyrus. Symbolic reinforcement revealed a similar pattern of activation, except that the striatum and left midbrain showed no activation. The Parkinsonian patients responded to monetary reward with increased activation bilaterally in the cerebellum, medial frontal gyrus, and anterior cingulate gyrus as well as unilaterally in the right fusiform gyrus and midbrain and left caudate nucleus and precentral gyrus. Symbolic reinforcement induced significantly increased rCBF in the right cerebellum only. Compared with symbolic reinforcement, monetary reward produced extended activation of temporoparietal association cortex. The pattern observed in the controls demonstrates the role in reward processing of dopaminergic mesolimbic pathways in the healthy human brain, whereas the pattern in the Parkinsonian patients suggests the involvement of compensatory cortical loops in the diseased brain.     

Neural activity related to the processing of increasing monetary reward in smokers and nonsmokers

This study investigated the processing of increasing monetary reward in nonsmoking and smoking subjects. The choice of the subject populations has been motivated by the observation of differences between nonsmokers and smokers in response to rewarding stimuli in a previous study. Subjects performed a pattern recognition task with delayed response, while rCBF was measured with [H215O] PET. Correct responses to the task were reinforced with three different amounts of monetary reward. The subjects received the sum of the rewards at the end of the experiment. The results show that a cortico-subcortical loop, including the dorsolateral prefrontal cortex, the orbitofrontal cortex, the cingulate gyrus and the thalamus is involved in processing increasing monetary reward. Furthermore, the striatal response differentiates nonsmokers from smokers. Thus, we found significant correlations between rCBF increases in striatum and increasing monetary reward and between striatal rCBF increases and mood in nonsmokers, but not in smokers. Moreover, no significant mood changes among the different monetary rewards could be observed in smokers. We infer that the response of the striatum to reward is related to changes in subjective feelings. The differences between smokers and nonsmokers confirm our previous conclusions that the association between blood flow, performance, mood and amount of reward is more direct in nonsmokers.     

Mesolimbic recruitment by nondrug rewards in detoxified alcoholics: effort anticipation, reward anticipation, and reward delivery

Aberrant sensitivity of incentive neurocircuitry to nondrug rewards has been suggested as either a risk factor for or consequence of drug addiction. Using functional magnetic resonance imaging, we tested whether alcohol‐dependent patients (ADP: n = 29) showed altered recruitment of ventral striatal (VS) incentive neurocircuitry compared to controls (n = 23) by: (1) cues to respond for monetary rewards, (2) post‐response anticipation of rewards, or (3) delivery of rewards. Using an instrumental task with two‐stage presentation of reward‐predictive information, subjects saw cues signaling opportunities to win Aberrant sensitivity of incentive neurocircuitry to nondrug rewards has been suggested as either a risk factor for or consequence of drug addiction. Using functional magnetic resonance imaging, we tested whether alcohol‐dependent patients (ADP: n = 29) showed altered recruitment of ventral striatal (VS) incentive neurocircuitry compared to controls (n = 23) by: (1) cues to respond for monetary rewards, (2) post‐response anticipation of rewards, or (3) delivery of rewards. Using an instrumental task with two‐stage presentation of reward‐predictive information, subjects saw cues signaling opportunities to win Aberrant sensitivity of incentive neurocircuitry to nondrug rewards has been suggested as either a risk factor for or consequence of drug addiction. Using functional magnetic resonance imaging, we tested whether alcohol-dependent patients (ADP: n = 29) showed altered recruitment of ventral striatal (VS) incentive neurocircuitry compared to controls (n = 23) by: (1) cues to respond for monetary rewards, (2) post-response anticipation of rewards, or (3) delivery of rewards. Using an instrumental task with two-stage presentation of reward-predictive information, subjects saw cues signaling opportunities to win $0, $1, or $10 for responding to a target. Following this response, subjects were notified whether their success would be indicated by a lexical notification (“Hit?”) or by delivery of a monetary reward (“Win?”). After a variable interval, subjects then viewed the trial outcome. We found no significant group differences in voxelwise activation by task contrasts, or in signal change extracted from VS. Both ADP and controls showed significant VS and other limbic recruitment by pre-response reward anticipation. In addition, controls also showed VS recruitment by post-response reward-anticipation, and ADP had appreciable subthreshold VS activation. Both groups also showed similar mesolimbic responses to reward deliveries. Across all subjects, a questionnaire measure of “hot” impulsivity correlated with VS recruitment by post-response anticipation of low rewards and with VS recruitment by delivery of low rewards. These findings indicate that incentive-motivational processing of nondrug rewards is substantially maintained in recovering alcoholics, and that reward-elicited VS recruitment correlates more with individual differences in trait impulsivity irrespective of addiction.     

The rewarding value of good motor performance in the context of monetary incentives

Whether an agent receives positive task feedback or a monetary reward, neural activity in their striatum increases. In the latter case striatal activity reflects extrinsic reward processing, while in the former, striatal activity reflects the intrinsically rewarding effects of performing well. There can be a "hidden cost of reward", which is a detrimental effect of extrinsic on intrinsic reward value. This raises the question how these two types of reward interact. To address this, we applied a monetary incentive delay task: in all trials participants received feedback depending on their performance. In half of the trials they could additionally receive monetary reward if they performed well. This resulted in high performance trials, which were monetarily rewarded and high performance trials that were not. This made it possible to dissociate the neural correlates of performance feedback from the neural correlates of monetary reward that comes with high performance. Performance feedback alone elicits activation increases in the ventral striatum. This activation increases due to additional monetary reward. Neural response in the dorsal striatum on the other hand is only significantly increased by feedback when a monetary incentive is present. The quality of performance does not significantly influence dorsal striatum activity. In conclusion, our results indicate that the dorsal striatum is primarily sensitive to optional or actually received external rewards, whereas the ventral striatum may be coding intrinsic reward due to positive performance feedback. Thus the ventral striatum is suggested to be involved in the processing of intrinsically motivated behavior.     

Lateralization and gender differences in the dopaminergic response to unpredictable reward in the human ventral striatum

Electrophysiological studies have shown that mesostriatal dopamine (DA) neurons increase activity in response to unpredicted rewards. With respect to other functions of the mesostriatal dopaminergic system, dopamine’s actions show prominent laterality effects. Whether changes in DA transmission elicited by rewards also are lateralized, however, has not been investigated. Using [¹¹C]raclopride‐PET to assess the striatal DA response to unpredictable monetary rewards, we hypothesized that such rewards would induce an asymmetric reduction in [¹¹C]raclopride binding in the ventral striatum, reflecting lateralization of endogenous dopamine release. In 24 healthy volunteers, differences in the regional D_2/3 receptor binding potential (ΔBP) between an unpredictable reward condition and a sensorimotor control condition were measured using the bolus‐plus‐constant‐infusion [¹¹C]raclopride method. During the reward condition subjects randomly received monetary awards while performing a ‘slot‐machine’ task. The ΔBP between conditions was assessed in striatal regions‐of‐interest and compared between left and right sides. We found a significant condition × lateralization interaction in the ventral striatum. A significant reduction in binding potential (BP_ND) in the reward condition vs. the control condition was found only in the right ventral striatum, and the ΔBP was greater in the right than the left ventral striatum. Unexpectedly, these laterality effects appeared to be partly accounted for by gender differences, as our data showed a significant bilateral BP_ND reduction in women while in men the reduction reached significance only in the right ventral striatum. These data suggest that DA release in response to unpredictable reward is lateralized in the human ventral striatum, particularly in males.     

Effects of emotional preferences on value-based decision-making are mediated by mentalizing and not reward networks

Real-world decision-making often involves social considerations. Consequently, the social value of stimuli can induce preferences in choice behavior. However, it is unknown how financial and social values are integrated in the brain. Here, we investigated how smiling and angry face stimuli interacted with financial reward feedback in a stochastically rewarded decision-making task. Subjects reliably preferred the smiling faces despite equivalent reward feedback, demonstrating a socially driven bias. We fit a Bayesian reinforcement learning model to factor the effects of financial rewards and emotion preferences in individual subjects, and regressed model predictions on the trial-by-trial fMRI signal. Activity in the subcallosal cingulate and the ventral striatum, both involved in reward learning, correlated with financial reward feedback, whereas the differential contribution of social value activated dorsal temporo-parietal junction and dorsal anterior cingulate cortex, previously proposed as components of a mentalizing network. We conclude that the impact of social stimuli on value-based decision processes is mediated by effects in brain regions partially separable from classical reward circuitry.     

Anticipation of monetary and social reward differently activates mesolimbic brain structures in men and women

Motivation for goal-directed behaviour largely depends on the expected value of the anticipated reward. The aim of the present study was to examine how different levels of reward value are coded in the brain for two common forms of human reward: money and social approval. To account for gender differences 16 male and 16 female participants performed an incentive delay task expecting to win either money or positive social feedback. fMRI recording during the anticipation phase revealed proportional activation of neural structures constituting the human reward system for increasing levels of reward, independent of incentive type. However, in men activation in the prospect of monetary rewards encompassed a wide network of mesolimbic brain regions compared to only limited activation for social rewards. In contrast, in women, anticipation of either incentive type activated identical brain regions. Our findings represent an important step towards a better understanding of motivated behaviour by taking into account individual differences in reward valuation.     

The neural basis of addiction: a pathology of motivation and choice

OBJECTIVE: A primary behavioral pathology in drug addiction is the overpowering motivational strength and decreased ability to control the desire to obtain drugs. In this review the authors explore how advances in neurobiology are approaching an understanding of the cellular and circuitry underpinnings of addiction, and they describe the novel pharmacotherapeutic targets emerging from this understanding. METHOD: Findings from neuroimaging of addicts are integrated with cellular studies in animal models of drug seeking. RESULTS: While dopamine is critical for acute reward and initiation of addiction, end-stage addiction results primarily from cellular adaptations in anterior cingulate and orbitofrontal glutamatergic projections to the nucleus accumbens. Pathophysiological plasticity in excitatory transmission reduces the capacity of the prefrontal cortex to initiate behaviors in response to biological rewards and to provide executive control over drug seeking. Simultaneously, the prefrontal cortex is hyperresponsive to stimuli predicting drug availability, resulting in supraphysiological glutamatergic drive in the nucleus accumbens, where excitatory synapses have a reduced capacity to regulate neurotransmission. CONCLUSIONS: Cellular adaptations in prefrontal glutamatergic innervation of the accumbens promote the compulsive character of drug seeking in addicts by decreasing the value of natural rewards, diminishing cognitive control (choice), and enhancing glutamatergic drive in response to drug-associated stimuli.     

Neural response to monetary and social feedback demonstrates differential associations with depression and social anxiety

An aberrant neural response to rewards has been linked to both depression and social anxiety. Most studies have focused on the neural response to monetary rewards, and few have tested different modalities of reward (e.g. social) that are more salient to particular forms of psychopathology. In addition, most studies contain critical confounds, including contrasting positive and negative feedback and failing to disentangle being correct from obtaining positive feedback. In the present study, 204 participants underwent electroencephalography during monetary and social feedback tasks that were matched in trial structure, timing and feedback stimuli. The reward positivity (RewP) was measured in response to correctly identifying stimuli that resulted in monetary win, monetary loss, social like or social dislike feedback. All monetary and social tasks elicited a RewP, which were positively correlated. Across all tasks, the RewP was negatively associated with depression and positively associated with social anxiety. The RewP to social dislike feedback, independent of monetary and social like feedback, was also associated with social anxiety. The present study suggests that a domain-general neural response to correct feedback demonstrates a differential association with depression and social anxiety, but a domain-specific neural response to social dislike feedback is uniquely associated with social anxiety.     

Dopamine and reward: The anhedonia hypothesis 30 years on

The anhedonia hypothesis — that brain dopamine plays a critical role in the subjective pleasure associated with positive rewards — was intended to draw the attention of psychiatrists to the growing evidence that dopamine plays a critical role in the objective reinforcement and incentive motivation associated with food and water, brain stimulation reward, and psychomotor stimulant and opiate reward. The hypothesis called to attention the apparent paradox that neuroleptics, drugs used to treat a condition involving anhedonia (schizophrenia), attenuated in laboratory animals the positive reinforcement that we normally associate with pleasure. The hypothesis held only brief interest for psychiatrists, who pointed out that the animal studies reflected acute actions of neuroleptics whereas the treatment of schizophrenia appears to result from neuroadaptations to chronic neuroleptic administration, and that it is the positive symptoms of schizophrenia that neuroleptics alleviate, rather than the negative symptoms that include anhedonia. Perhaps for these reasons, the hypothesis has had minimal impact in the psychiatric literature. Despite its limited heuristic value for the understanding of schizophrenia, however, the anhedonia hypothesis has had major impact on biological theories of reinforcement, motivation, and addiction. Brain dopamine plays a very important role in reinforcement of response habits, conditioned preferences, and synaptic plasticity in cellular models of learning and memory. The notion that dopamine plays a dominant role in reinforcement is fundamental to the psychomotor stimulant theory of addiction, to most neuroadaptation theories of addiction, and to current theories of conditioned reinforcement and reward prediction. Properly understood, it is also fundamental to recent theories of incentive motivation.     

Influences of social reward experience on behavioral responses to drugs of abuse: Review of shared and divergent neural plasticity mechanisms for sexual reward and drugs of abuse

Different factors influence the development of drug addiction in humans, including social reward experiences. In animals, experience with social rewards, such as sexual behavior, pair bonding, social and environmental enrichment, can be protective. However, loss or lack of social rewards can lead to a vulnerability to drug-seeking behavior. The effects of social reward experience on drug-seeking behavior are associated with changes in the neural pathways that control drug-related behavior. This review will provide an introduction and overview of the mesolimbic pathway and the influence of social reward experience on drug-seeking behavior in rodents. Moreover, the research from our laboratory on effects of sexual experience and loss of sex reward on psychostimulant and opiate reward will be reviewed. Finally, we will review current knowledge of the neural mechanisms that underlie these interactions. Investigations of the neural underpinnings by which social and drug rewards interact contribute to improved understanding of the neural basis of vulnerability for drug addiction and reward-related behaviors in general.     

The novelty exploration bonus and its attentional modulation

We hypothesized that novel stimuli represent salient learning signals that can motivate ‘exploration’ in search for potential rewards. In computational theories of reinforcement learning, this is referred to as the novelty ‘exploration bonus’ for rewards. If true, stimulus novelty should enhance the reward anticipation signals in brain areas that are part of dopaminergic circuitry and thereby reduce responses to reward outcomes. We investigated this hypothesis in two fMRI experiments. Images of complex natural scenes predicted monetary reward or a neutral outcome by virtue of depicting either indoor or outdoor scenes. Half of the reward-predicting and neutral images had been familiarized the day before, the other half were novel. In experiment 1, subjects indicated whether images were novel or familiar, whereas in experiment 2, they explicitly decided whether or not images predicted reward by depicting indoor or outdoor scenes. Novelty led to the hypothesized enhancement of mesolimbic reward prediction responses and concomitant reduction of mesolimbic responses to reward outcomes. However, this effect was strongly task-dependent and occurred only in experiment 2, when the reward-predicting property of each image was attended. Recognition memory for the novel and familiar stimuli (after 24 h) was enhanced by reward anticipation in both tasks. These findings are compatible with the proposition that novelty can act as a bonus for rewards under conditions when rewards are explicitly attended, thus biasing the organism towards reward anticipation and providing a motivational signal for exploration.     

Neural evidence for enhanced error detection in major depressive disorder

OBJECTIVE: Anomalies in error processing have been implicated in the etiology and maintenance of major depressive disorder. In particular, depressed individuals exhibit heightened sensitivity to error-related information and negative environmental cues, along with reduced responsivity to positive reinforcers. The authors examined the neural activation associated with error processing in individuals diagnosed with and without major depression and the sensitivity of these processes to modulation by monetary task contingencies. METHOD: The error-related negativity and error-related positivity components of the event-related potential were used to characterize error monitoring in individuals with major depressive disorder and the degree to which these processes are sensitive to modulation by monetary reinforcement. Nondepressed comparison subjects (N=17) and depressed individuals (N=18) performed a flanker task under two external motivation conditions (i.e., monetary reward for correct responses and monetary loss for incorrect responses) and a nonmonetary condition. After each response, accuracy feedback was provided. The error-related negativity component assessed the degree of anomaly in initial error detection, and the error positivity component indexed recognition of errors. RESULTS: Across all conditions, the depressed participants exhibited greater amplitude of the error-related negativity component, relative to the comparison subjects, and equivalent error positivity amplitude. In addition, the two groups showed differential modulation by task incentives in both components. CONCLUSIONS: These data implicate exaggerated early error-detection processes in the etiology and maintenance of major depressive disorder. Such processes may then recruit excessive neural and cognitive resources that manifest as symptoms of depression.     

Human oscillatory activity associated to reward processing in a gambling task

Previous event-related brain potential (ERP) studies have identified a medial frontal negativity (MFN) in response to negative feedback or monetary losses. In contrast, no EEG correlates have been identified related to the processing of monetary gains or positive feedback. This result is puzzling considering the large number of brain regions involved in the processing of rewards. In the present study we used a gambling task to investigate this issue with trial-by-trial wavelet-based time-frequency analysis of the electroencephalographic signal recorded non-invasively in healthy humans. Using this analysis a mediofrontal oscillatory component in the beta range was identified which was associated to monetary gains. In addition, standard time-domain ERP analysis showed an MFN for losses that was associated with an increase in theta power in the time-frequency analysis. We propose that the reward-related beta oscillatory activity signifies the functional coupling of distributed brain regions involved in reward processing.     

Neural substrates of opiate reinforcement

1. 1. A major component of opiate reward is derived from a drug action in the ventral tegmental area: (a) rats quickly learn to self-administer morphine directly into the ventral tegmentum, (b) intracranial self-administration into other brain sites is not quickly learned, and (c) narcotic antagonist microinjections into the ventral tegmentum attenuate reward from intravenous heroin infusions.

2. 2. At least one component of opiate reward is dependent on a dopaminergic system: (a) electrophysiological and neurochemical indices suggest that opiates activate ventral tegmental dopaminergic neurons, (b) ventral tegmental opiate infusions are behaviorally activating producing contralateral rotation that is blocked by neuroleptics, (c) reward from heroin is blocked by neuroleptics, and (d) reward from heroin is attenuated by dopamine-depleting lesions of the ventral tegmental system.

3. 3. Brain sites involved in the production of physical dependence on opiates are anatomically distinct from those initiating the acutely rewarding action of opiates.

4. 4. It is theoretically viable that opiates derive their reinforcing impact from a combination of positive and negative reinforcement processes: (a) the neural substrate for the positive reinforcing action probably involves a ventral tegmental dopamine system important in appetitive motivation, and (b) the neural substrate for the negative reinforcing action may involve a periventricular gray system that is independent of the system which mediates the acutely rewarding property of opiates.

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.     

Measurement of reinforcement in depression: a pilot study

We tested whether performance on a progressive ratio schedule of reinforcement with increasing magnitudes of monetary reward could be used as a behavioral measure of response to reinforcement during depression. Performance on the task was recorded before, during and after treatment of depression in six melancholic patients. The amount of money earned and the number of responses to obtain money during the task increased in the three subjects who improved with treatment but did not increase in three subjects who did not improve. In addition, the degree to which responses increased with increasing monetary reward became greater in two of the three subjects who improved but in none of the subjects who did not improve. Methodological liabilities (e.g., the small sample size and absence of a control group) may limit the validity of our findings. Our results do suggest performance of the task may be an objective measure of response to reinforcement that could be used in both basic and clinical research on depression.     

Enhanced reward sensitivity and decreased loss sensitivity in Internet addicts: An fMRI study during a guessing task

As the world’s fastest growing “addiction”, Internet addiction should be studied to unravel the potential heterogeneity. The present study is set to examine reward and punishment processing in Internet addicts as compared to healthy controls while they subjectively experience monetary gain and loss during the performance of a guessing task. The results showed that Internet addicts associated with increased activation in orbitofrontal cortex in gain trials and decreased anterior cingulate activation in loss trials than normal controls. The results suggested that Internet addicts have enhanced reward sensitivity and decreased loss sensitivity than normal comparisons.     

Blunted reward responsiveness in remitted depression

Major depressive disorder has been associated with blunted responsiveness to rewards, but inconsistencies exist whether such abnormalities persist after complete remission. To address this issue, across two independent studies, 47 adults with remitted major depressive disorder (rMDD) and 37 healthy controls completed a Probabilistic Reward Task, which used a differential reinforcement schedule of social or monetary feedback to examine reward responsiveness (i.e., ability to modulate behavior as a function of reinforcement history). Relative to controls, adults with rMDD showed blunted reward responsiveness. Importantly, a history of depression predicted reduced reward learning above and beyond residual depressive (including anhedonic) symptoms and perceived stress. Findings indicate that blunted reward responsiveness endures even when adults are in remission and might be a trait-related abnormality in MDD. More research is warranted to investigate if blunted reward responsiveness may predict future depressive episodes and whether targeting reward-related deficits may prevent the re-occurrence of the disorder.