We demonstrate a pharmacological manipulation of risk taking in a susceptible population of subjects with ICD with underlying vulnerability such as problem gambling or compulsive shopping. Compared to Parkinson's; disease controls, patients with ICD demonstrate an overall bias towards riskier choices in the ‘Gain’ relative to ‘Loss’ condition associated with lower correlation between risk and neural activity in the orbitofrontal cortex and anterior cingulate. As expected, all subjects showed a general sensitivity to increasing risk, choosing to gamble less as the ‘Gamble Risk’ (the range of possible outcomes) increased. In particular, dopamine agonists in patients with ICD enhanced sensitivity to ‘Gamble Risk’ with an opposite effect in Parkinson's; disease controls, promoting a bias towards increased risk-taking for gambles at equivalent low-risk levels, compared to OFF dopamine agonists and Parkinson's; disease controls. Compared to Parkinson's; disease controls, dopamine agonists in patients with ICD were also associated with lower ventral striatal activity to Gamble Risk. Thus, overall patients with ICD have an increased risk-taking bias compared to Parkinson's; disease controls when there is only the prospect of gain but not where there are both prospects of gain and loss. Crucially, all subjects (both ICD and Parkinson's; disease controls) showed a general sensitivity to increasing risk, choosing to gamble less as the ‘Gamble Risk’ increased. Taken together, this suggests that rather than a sensitivity to a specific effect of loss or a non-specific decreased sensitivity to risk, patients with ICD have a specific change in attitude to risky situations. Dopamine agonists appear to alter a pre-potent or unconscious bias towards ‘Gamble Risk’ rather than simply affecting conscious risk estimation or evaluation, moreover with a potentially opposite effect in ICD and Parkinson's; disease controls (i.e. dependent on underlying vulnerability).
We have previously demonstrated that patients with ICD ON dopamine agonists compared to OFF dopamine agonists learn faster from gain outcomes using a probabilistic reward learning task along with greater ventral striatal activity to unexpected rewards (Voon et al., 2010a
). Patients with ICD ON dopamine agonists compared to OFF dopamine agonists also make more impulsive choices, preferring smaller immediate rewards over larger delayed rewards, and make faster decisions during high conflict choices (Voon et al., 2010b
). These studies focused on learning from outcomes and assessment of impulsivity. Our current findings suggest a potential mechanism whereby dopamine agonists may influence risk-taking choices leading towards pathological behaviours. As the current risk task is not associated with outcomes, these findings focus on risk anticipation without the influence of gain or loss outcomes and the consequent effects of dopamine on outcome prediction error. The neural findings concur with a recent study demonstrating that medicated patients with Parkinson's; disease with ICDs compared to medicated patients with Parkinson's; disease without ICDs have lower ventral striatal activity in the Balloon Analogue Risk Task (Rao et al., 2010
), a measure of ambiguity in which the probability is not explicitly known. The authors did not demonstrate any behavioural difference between groups and subjects were only evaluated on medication. Similarly, in a task assessing impulsive choice, with dopamine agonists manipulation, patients with ICD ON compared to OFF dopamine agonists relative to Parkinson's; disease controls had a trend towards a higher indifference point when choosing between a varying deterministic choice versus a fixed probabilistic choice (P
= 0.35 of gaining $0.30) with real-time feedback compared to OFF dopamine agonists (Voon et al., 2010b
). This study focused on impulsive choice with feedback and was not designed to evaluate risk; the calculation of the single indifference point was used as a baseline measure to control for the effects of probabilistic learning. A behavioural study assessing patients with Parkinson's; disease on medications (levodopa and dopamine agonists) with and without pathological gambling along with compulsive medication use demonstrated impairment in the Iowa Gambling Task but not the Game of Dice Task, suggesting impairment in decisions under ambiguity but not risk (Rossi et al., 2010
). Another behavioural study did not demonstrate an effect of levodopa manipulation on a risk-taking task in patients with Parkinson's; disease with mixed ICD symptoms compared to OFF levodopa (Djamshidian et al., 2010
). A subanalysis of the pathological gambling group compared to the control group did demonstrate a difference between groups. The study assessed the effects of levodopa rather than dopamine agonists on mixed gambles with both gains and losses and did not include an imaging arm. These current findings uniquely evaluate the effect of specific manipulation of dopamine agonists on behavioural risk assessment, with simultaneous measurement of functional MRI BOLD activity, and furthermore assessed the influence of degree of risk anticipation without feedback along with separation of the gain and loss components of the task.
Dopamine agonists in patients with ICD appear behaviourally to not only enhance risk sensitivity but also promote baseline risk-taking. Neurally, this is associated with lower ventral striatal activity to ‘Gamble Risk’. The ventral striatum is implicated in tracking risk and ventral striatal activity commonly increases with increasing risk (Preuschoff et al., 2006
). The lower activity in our study suggests that rather than tracking risk per se
, dopamine agonists may decrease the coupling of ventral striatal evaluation of risk in patients with ICD, and lead to an altered evaluation of the presented gambles. According to the hypothesis of an inverted U-shaped function of dopaminergic activity, if baseline dopaminergic activity in the ventral striatum is elevated in patients with ICD, then additional dopaminergic activity may further shift function along the curve and impair ventral striatal function (Cools, 2006
). A PET study using 11
C-raclopride suggests a potential finding of elevated dopaminergic activity at baseline in patients with ICD (Steeves et al., 2009
). Tonic dopamine has also been implicated in representation of risk as measured using variance (Fiorillo et al., 2003
). Thus, one possible interpretation may be that dopaminergic modulation may influence risk-taking through the encoding of uncertainty via the midbrain dopaminergic neurons. Tonic dopamine has also been implicated in motivation (Niv et al., 2007
), which was not evaluated in this task. In healthy volunteers, levodopa increases risk-taking choices in subjects with a DRD4 polymorphism with at least one copy of a 7-repeat allele (Eisenegger et al., 2010
). Further studies may shed light on whether genetic polymorphisms may mediate risk taking behaviours in the ICD population.
We further demonstrate that patients with ICD make more risky choices to gambles without the specific effect of loss aversion accompanied by lower orbitofrontal and anterior cingulate activity. The orbitofrontal cortex and anterior cingulate are also commonly implicated in tracking risk and value (Critchley et al., 2001
; Tobler et al., 2007
). Again, our findings suggest that in patients with ICD, neural tracking of risk in the orbitofrontal cortex and anterior cingulate is decreased leading to a bias towards risky choices in the ‘Gain’ condition. The finding is consistent with a recent study demonstrating that dopamine agonists are associated with an inhibition of orbitofrontal cortex activity in patients with ICD (van Eimeren et al., 2010
). The lower effect size in neural activity can also be interpreted as greater signal to noise, which is also consistent with a lower correlation between risk and neural activity.
We also show that dopamine agonists are associated with greater risk-taking and greater anterior insular activity, specifically in mixed gambles with the prospect of gain or loss as compared to risk taking with only the prospect of gains. The anterior insula tracks risk, risk prediction (Preuschoff et al., 2008
) and is also implicated in the representation of negative states including loss anticipation, pain and loss prediction error (Seymour et al., 2005
; Craig, 2009
). Since gamble risk is objectively similar in both conditions, the difference in anterior insular activity must reflect either the different representation of subjective risk or a specific feature of the gamble such as the probability of a loss. ‘Loss’ aversion is one mechanism believed to underlie an increase in risk-taking behaviour in the context of loss. Thus, dopamine agonists may increase anticipatory loss aversion represented by greater anterior insular activity leading towards greater risk-taking behaviour. However, as patients with ICD were more risk-seeking in the ‘Gain’ but not the ‘Loss’ condition, this dopamine agonist effect, while intriguing, is unlikely to be driving risk-taking in patients with ICD.