The present study is the first to examine reward-related brain activity in bipolar euthymic participants and healthy controls during reward processing. Consistent with hypotheses, ROI analyses indicated that bipolar disorder participants showed greater ventral striatal activity and right-sided-OFC activity during anticipation, but not outcome, of monetary reward, relative to healthy controls. Wholebrain analyses indicated elevated left-lateral OFC activity among bipolar disorder participants during reward anticipation, relative to healthy controls. No difference in ventral striatal activity and OFC activity was observed between bipolar disorder and healthy control participants during loss-anticipation. All main findings were specific to the anticipation-period.
The ventral striatum is implicated in reward processing (11
) and there is growing evidence that dopamine plays an important role in ventral striatal-centered reward processing (14
). Dopaminergic abnormalities may therefore serve as the neurochemical basis for elevated ventral striatal activity in bipolar disorder. Elevated OFC activity has also been linked to reward processing, and Bermpohl and colleagues (16
) recently reported that bipolar manic patients displayed greater OFC activity during reward anticipation relative to healthy controls. We now show abnormally elevated OFC and ventral striatal activity during reward anticipation in bipolar disorder euthymic adults, and suggest that this may represent a neural mechanism for the elevated self-report and neurophysiological indices of reward sensitivity (6
) and approach-related behavior (5
) underlying vulnerability for hypo/mania in bipolar illness.
While control participants did not recruit the ventral striatum, they did recruit the left-lateral OFC during both reward and loss anticipation. Rodent studies suggest that the ventral striatum may encode both the value, or magnitude, and identity, or quality, of rewarding stimuli, while the OFC may be necessary for encoding the identity, but not the value, of reward (33
). This suggests that bipolar disorder and control participants may have employed different strategies during encoding of potential future reward during the anticipation-period, and that, unlike participants with bipolar disorder, control participants may have focused on encoding the identity rather than value of potential future reward. Accordingly, previous and present data suggest that ventral striatal hypersensitivity, together with elevated OFC activity to anticipation of reward-relevant cues, may be a key biological marker of bipolar disorder, potentially reflecting an underlying neural mechanism for abnormal processing of potential future reward, that in turn may predispose a person to hypo/mania. These patterns of abnormal neural activity may be a useful future biological target for novel interventions to help individuals with bipolar disorder develop strategies for effectively regulating their behavior in response to reward-relevant environmental events (34
Neuroimaging studies in unipolar depression reported abnormally reduced, as opposed to elevated, ventral striatal activity, versus healthy controls, during reward-related laboratory tasks (18
) and to positive emotional stimuli (37
). Together with our present findings, these findings suggest that unipolar depression and bipolar disorder may be characterized by differential patterns of abnormal ventral striatal activity during reward anticipation and receipt. It is important to note, however, that research on ventral striatal activity to reward cues in unipolar depression has typically examined participants in a depressive episode at the time of fMRI scanning. Future research is needed directly comparing euthymic bipolar and euthymic unipolar depressed individuals to determine whether ventral striatal activity during reward processing may yield state-independent biological markers to help distinguish the two disorders.
Rates of lifetime comorbidity reported in the present study were consistent with existing epidemiological research on lifetime comorbidity rates in bipolar disorder (23
). Importantly, bipolar disorder participants were free from alcohol/substance abuse or dependence for a minimum of seven months (range: 7 to 269 months), and we did not observe any significant relationships between a prior history of substance or alcohol abuse and ventral striatal or OFC activity during reward anticipation in participants with bipolar disorder. Further, individuals with substance use disorders have previously been shown to display decreased, rather than increased, ventral striatal activity during anticipation of non-drug related cues, such as monetary reward (39
). Thus, the elevated ventral striatal and OFC activity observed in the present study among bipolar disorder participants during reward anticipation is likely not attributable to alcohol/substance abuse or dependence.
There were limitations to the present study. Future studies are needed to examine mood state-independent versus mood state-dependent components of abnormally elevated neural activity during reward anticipation and receipt in bipolar disorder by comparing euthymic bipolar disorder participants with manic and/or depressed bipolar disorder. It will be important for this research to employ fMRI reward paradigms examining both the anticipation and receipt of reward, as well as omission of reward. This is particularly relevant given research suggesting that bipolar manic patients fail to show the previously reported pattern of decreased ventral striatal activation when an expected reward is omitted (40
). Second, future research is needed to examine whether elevated neural activity to reward cues is specific to bipolar disorder or indicative of more general motivational and/or regulatory deficits observed across multiple psychiatric disorders. Third, bipolar disorder participants were medicated at the time of study. We did not, however, observe any significant relationships between psychotropic or antipsychotic medication load, total number of psychotropic medications, or between any specific class of psychotropic medication, including dopaminergic-antidepressants or antipsychotic medications, and neural activity during reward anticipation in participants with bipolar disorder. Furthermore, removing individuals on dopaminergic-antidepressants did not alter the critical interaction in the ventral striatal ROI. Given that 12 of 21 bipolar disorder participants were taking antipsychotic medications at fMRI scanning, we did not have the statistical power to examine our a priori hypotheses excluding participants taking antipsychotic medications. Future studies, may wish to examine this issue. Lastly, we used one run of twenty-four trials for the fMRI reward paradigm given previous research indicating that this configuration is effective for assessing reward-related brain function and minimizing fatigue and habituation (18
). However, we cannot rule out the possibility that a larger number of trials could have produced group differences to other conditions or in other neural regions. Future research may wish to address this issue.
Abnormally elevated ventral striatal and OFC activity during reward anticipation is a potential neural basis for the observed hypersensitivity to reward-relevant stimuli in bipolar disorder. The possible dopaminergic basis of elevated ventral striatal activity in bipolar disorder has important implications for treatment choices and new treatment development for the illness. Future studies should aim to replicate our findings and examine the extent to which abnormally elevated ventral striatal and OFC activity during reward processing may serve as a potential biological marker of bipolar disorder. It will be important for this subsequent research to examine reward-related brain activity in individuals at heightened risk for bipolar disorder, but who have not yet developed the disorder. This will help determine whether abnormally elevated ventral striatal and OFC activity during reward processing represents a pre-existing vulnerability for bipolar disorder, or a consequence of having a bipolar episode.