Cooperation based on reciprocal altruism has evolved in only a small number of species, yet it constitutes the core behavioral principle of human social life. The iterated Prisoner's Dilemma Game has been used to model this form of cooperation. We used fMRI to scan 36 women as they played an iterated Prisoner's Dilemma Game with another woman to investigate the neurobiological basis of cooperative social behavior. Mutual cooperation was associated with consistent activation in brain areas that have been linked with reward processing: nucleus accumbens, the caudate nucleus, ventromedial frontal/orbitofrontal cortex, and rostral anterior cingulate cortex. We propose that activation of this neural network positively reinforces reciprocal altruism, thereby motivating subjects to resist the temptation to selfishly accept but not reciprocate favors.

Certain classes of stimuli, such as food and drugs, are highly effective in activating reward regions. We show in humans that activity in these regions can be modulated by the predictability of the sequenced delivery of two mildly pleasurable stimuli, orally delivered fruit juice and water. Using functional magnetic resonance imaging, the activity for rewarding stimuli in both the nucleus accumbens and medial orbitofrontal cortex was greatest when the stimuli were unpredictable. Moreover, the subjects' stated preference for either juice or water was not directly correlated with activity in reward regions but instead was correlated with activity in sensorimotor cortex. For pleasurable stimuli, these findings suggest that predictability modulates the response of human reward regions, and subjective preference can be dissociated from this response.

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Context Inflammatory cytokines or cytokine inducers can alter basal ganglia activity, including reducing responsiveness to rewarding stimuli that may be mediated by cytokine effects on dopamine function. Objectives To determine whether long-term administration of the inflammatory cytokine interferon alfa reduces the basal ganglia response to reward and whether such changes are associated with decreased presynaptic striatal dopamine function and altered behavior. Design Cross-sectional and longitudinal studies. Setting Outpatient research unit and neuroimaging facilities at Emory University, Atlanta, Georgia. Patients Medically stable adults with chronic hepatitis C virus (HCV) infection eligible for interferon alfa treatment. Main Outcome Measures Neural activity in the ventral striatum during a hedonic reward task as measured by functional magnetic resonance imaging, uptake and turnover of radiolabeled fluorodopa F 18 (18F-dopa) in caudate and putamen using positron emission tomography, and interferon alfa–induced depression, anhedonia, fatigue, and neurotoxicity. Results Patients with HCV receiving interferon alfa for 4 to 6 weeks (n=14) exhibited significantly reduced bilateral activation of the ventral striatum in the win vs lose condition of a gambling task compared with patients with HCV awaiting interferon alfa treatment (n=14). Reduced activation of the ventral striatum was, in turn, significantly correlated with anhedonia, depression, and fatigue. In a separate longitudinal study, patients with HCV treated with interferon alfa for 4 to 6 weeks (n=12) exhibited significantly increased 18F-dopa uptake and decreased 18F-dopa turnover in caudate and putamen and in the same ventral striatal regions identified in the functional magnetic resonance imaging study. Baseline and percentage change in 18F-dopa uptake and turnover were correlated with behavioral alterations, including depression, fatigue, and neurotoxicity, during interferon alfa administration. Conclusions These data replicate and extend findings that inflammatory stimuli, including inflammatory cytokines, such as interferon alfa, alter basal ganglia activity and behavior in association with significant changes in presynaptic striatal dopamine function consistent with decreased dopamine synthesis or release.

The mesolimbic dopaminergic system has long been known to be involved in the processing of rewarding stimuli, although recent evidence from animal research has suggested a more specific role of signaling errors in the prediction of rewards. We tested this hypothesis in humans, using functional magnetic resonance imaging (fMRI) and an operant conditioning paradigm for the discrete delivery of small quantities of fruit juice, along with a control experiment in which juice was substituted with a neutral visual stimulus. A local estimation of the activity in the ventral striatum showed a significant differentiation when the juice was withheld at the expected time of delivery; this finding was not replicated in the case of visual stimulation, providing evidence for time-locked processing of reward prediction errors in human ventral striatum.