The main finding of our study is that tonic dopaminergic stimulation with DAs in PD patients specifically diminished reward processing in the lateral OFC by relatively increasing activity during negative errors of reward prediction. To our knowledge, this represents the first empirical evidence that DAs may abate negative reinforcement in feedback-based learning by preventing phasic decreases in synaptic activity that occurs with negative errors of reward prediction. Critically, this finding was drug specific, as it was not observed after LD administration—which instead is believed to enhance pulsatile stimulation of dopaminergic receptors. This notion concurs with a specifically increased risk to develop PG in DA-treated PD patients (Voon et al, 2006
; Pontone et al, 2006
; Weintraub et al, 2008
Our observation is in line with current theoretical models and empirical data of dopamine-dependent reinforcement learning (Frank et al, 2004
; Cools et al, 2006
). Unmedicated PD patients showed impaired feedback-based learning in various tasks (Frank et al, 2004
; Shohamy et al, 2004
; Cools et al, 2006
). Although some findings indicate that unmedicated patients may be specifically impaired in learning from positive feedback (Frank et al, 2004
; Cools et al, 2006
), empirical evidence for a detrimental effect of dopamine replacement therapy in negative feedback learning seems more consistent (Cools et al, 2006
; Frank et al, 2007
). According to the computational model proposed by Frank and colleagues, phasic bursts of dopamine after unexpected rewards exert a positive reinforcing effect by stimulating D1 receptors (Frank et al, 2004
). Conversely, unexpected punishments or withheld rewards lead to negative reinforcement by transient reduction in D2 signaling. Persisting tonic stimulation of dopamine receptors—as with DA medication—could therefore enhance D1-mediated effects (eg positive reinforcement). On the other hand, it could prevent pauses in D2 signaling and consequently impair negative feedback learning. Our results point toward a greater effect of the latter, which may well be explained by the D2/D3 selectivity of pramipexole (Seeman, 2007
). In fact, outcome-induced activation in the OFC was higher with DA and the boosting effect seemed greater for unexpected losses than for unexpected gains, thereby diminishing correlation with RPE values. However, the fact that our paradigm is different from the one used in the studies of Frank and coworkers represents an important caveat (Frank et al, 2004
). Moreover, an alternative theoretical consideration is that tonic stimulation of presynaptic autoreceptors may reduce correlation with RPE values by suppressing firing of midbrain dopaminergic neurons.
Our results point toward a relative preservation of reward processing in unmedicated PD patients, whereas LD and DA both diminished reward processing in the ventral striatum and OFC. This corroborates the view that with dopamine replacement therapy, restoration of dopamine levels in the motor part of the striatum (dorsal putamen) might also come with detrimental overdosing of more cognitive (dorso-medial caudate) and limbic (ventral striatum, nucleus accumbens) parts (Swainson et al, 2000
; Cools et al, 2001
; Cools, 2006
Could neuronal activity before the outcome have influenced neuronal processing of the RPE values in different medication states? In young healthy subjects, one would indeed expect a relationship of ventral striatal activity during anticipation and reward prediction value. It should be noted, however, that this effect is much more subtle than the relationship with RPE (Yacubian et al, 2006
). In a preliminary analysis of our data, we could not find such a relationship in any of the pharmacological conditions (OFF, LD, DA). In fact, one might not assume this relationship to be maintained in PD. A recent neuroimaging study in PD patients after withdrawal of medication, elderly and young healthy controls showed that though RPE processing seems relatively preserved, PD patients and elderly controls show a markedly impaired reward prediction signal (Schott et al, 2007
). Given the subtle nature of this relationship in young participants, the relative loss of this relationship in elderly and PD patients, and the lack of such a relationship in our study, we assume that a putative influence can only be of negligible quantity.
This study may also bear important implications for pathological gamblers without PD. Reuter et al (2005)
found that the difference in ventral striatal activation after positive vs
negative financial feedback was diminished in pathological gamblers relative to healthy controls. As the authors pointed out, it remains to be elucidated, how much this finding stems from blunted response to gains, or from augmented responses to losses. Our findings raise the question of whether PG may be associated with an impaired capacity of the OFC to guide behavior when facing negative consequences.
As outlined in the introduction, there are two main reasons to compare our findings with those in drug addiction. First, current diagnostic criteria of PG and drug addiction overlap (American Psychiatric Association, 1994
). Second, several recent functional imaging studies on substance addiction have underlined the critical role of mesolimbic dopaminergic pathways (Garavan et al, 2000
; Volkow et al, 2004
; Goldstein et al, 2007
). In the addict, the value that is attributed to certain events or cues seems to be altered (Garavan et al, 2000
; Ahmed et al, 2002
; Grigson and Twining, 2002
). There is substantial evidence that the OFC mediates subjective value attribution and is an integral part in adaptive decision making (Tremblay and Schultz, 1999
; Knutson et al, 2000
; Breiter et al, 2001
; Elliott et al, 2003
; Valentin et al, 2007
). Indeed, a recent activation study in cocaine users confirmed the involvement of the lateral OFC in deficient attribution of feedback values (Goldstein et al, 2007
). Control subjects valued high wins more than low wins, whereas over half of the cocaine-addicted subjects valued all wins equally. This finding was significantly correlated with high, unmodulated activations to money in the lateral OFC. Our results suggest that DAs in PD patients shift the lateral OFC toward high, unmodulated activations after financial feedback—a finding that strikingly resembles those made in cocaine addicts.
Although DA-mediated effects on lateral OFC function were associated with relative changes in risk taking in the offline task, pramipexole administration had no measurable direct effect on behavior, replicating earlier findings in young healthy volunteers (Hamidovic et al, 2008
). In other words, neuronal effects of DAs may not be strong enough to actually alter behavior in every individual. But what happens, if this pharmacological trigger interacts with an individual vulnerability? Reduced availability of striatal D2 receptors is a trait that has been associated with drug addiction (Volkow et al, 1997
). Interestingly, we recently found that reduced availability of striatal D2 receptors also distinguishes PD patients with PG from PD patients without PG (Steeves et al, 2009
). One may speculate that in individuals with reduced D2 receptor density, the interference of DAs with D2-mediated negative feedback learning could be amplified. However, one cannot rule out that the individual vulnerability to develop behavioral addictions also stems from neurobehavioral mechanisms that are not related to mesolimbic dopamine. In the absence of an external task (ie freely fluctuating brain activity), PD patients experiencing heavy PG symptoms at the time of study showed increased brain perfusion in dopaminergic mesolimbic structures, but also in the insula, the hippocampus, and the amygdala (Cilia et al, 2008
). More studies are needed in this area to distinguish traits that predict vulnerability from an abnormal neurobehavioral pattern that may evolve once PG consolidates as a behavior.
In sum, we provide some evidence that tonic stimulation of frontal dopamine receptors may impair physiologic (specifically negative) reinforcement value attribution by preventing decreases of cortical synaptic activity that occurs with negative feedback. Our findings raise the question, whether PG may in part stem from an impaired capacity of the OFC to guide behavior when facing negative consequences.
However, there are several limitations of our study that may challenge our conclusion. First, given that the findings in our study represent a generic pharmacological mechanism, it may not be the only trigger for PG in vulnerable patients with PD. Second, with fMRI, we measured change in blood oxygenation. Although this may serve as an index of synaptic activity, this study does not investigate frontal dopamine receptors directly (eg through use of radioligands targeting dopamine receptors) and therefore, we cannot draw any specific conclusion on the neurotransmitters involved. Third, we investigated performance-independent feedback processing. Although we were able to indirectly link findings with offline risk-taking scores, we did not gather any more direct evidence of the behavioral importance of DA-induced lateral OFC dysfunction. Further limitations are the relatively small sample size and the risk of circular relationships with potentially nonindependent measures (Kriegeskorte et al, 2009
). Future studies may be able to directly elucidate the role of frontal dopaminergic transmission in negative feedback learning and to assess pharmacological interference with DAs or specific deficits in pathological gamblers.