Proefschrift_Holstein

General discussion

carrying the 9R allele, but had no effect in those homozygous for the 10R allele. These results strengthen the evidence for a causal role for dopamine in motivated cognitive control and they reveal differences in striatal dopamine signalling between patients with ADHD and subjects without ADHD during motivated cognitive control. The effects observed in chapter 4 seemat odds with those observed in healthy subjects ( chapter 3 and (Aarts et al., 2010)). In healthy young adults who carry the 9R allele, reward previously increased the task-switch related signal in the caudate nucleus (Aarts et al., 2010). In addition, reward anticipation had a beneficial effect on task switching performance in young healthy adults ( chapter 3) . By contrast, in the healthy control group in chapter 4 , we did not observe any evidence for an effect of reward on task switching, either in terms of neural signalling or behaviour. In patients with ADHD who carry the 9R allele of the DAT1 genotype, we observed that reward motivation increased the task-switch related signal in the striatum (i.e. the caudate nucleus), as it previously did in young healthy subjects (Aarts et al., 2010). In addition, (if anything) reward had a detrimental effect on task switching in these patients. Thus, the neural signal in the ADHD patients was in line with that observed previously in young healthy subjects, but to our surprise, in the healthy control group in chapter 4 , we did not replicate previous work showing that the integration between reward and cognitive control was associated with a DAT1 genotype-dependent change in behaviour ( chapter 3 ) and striatal signalling (Aarts et al., 2010). One potential explanation for this discrepancy is related to the age of the participants: Whereas the subjects in the healthy control group in the ADHD study were ~38 years old, subjects in the other studies were younger (~22 years old). Striatal dopamine levels decrease dramatically across the lifespan, starting in early adulthood (from ~20 years onwards) (Volkow et al., 1996a; Bäckman et al., 2000; Backman and Farde, 2001). If striatal dopamine is indeed crucial for successful motivation-cognition integration, deficits in motivated cognition should be evident with increasing age. ADHD has been associated with a developmental delay, resulting from dysfunctional nigrostriatal dopamine projections (Sagvolden et al., 2005). Such a developmental delay may explain the observation of an effect of reward on task switching in patients, but not in age-matched healthy controls. The questions remains however why this increased signalling in the 9R ADHD group is not associated with beneficial effects on behaviour, and why they – if anything – are even behaviourally impaired when integrating reward and task-switching signals. In chapter 5 we assessed whether any evidence for age-related changes in the motivational enhancement of cognitive control could be revealed. To this end we analyzed data from subjects ranging from14 to 69 years oldwho performed the rewarded task-switching paradigm and we observed that increasing age was indeed associated with less flexible adaptation to changing task demands. Specifically, the younger group showed reward-related behaviour that depended on the cognitive condition (i.e. whether a task repetition or a task switch was required), whereas the older group did not show any reward-related change in cognitive control. Based on previous imaging work which revealed decreases in dopamine neurons with increasing age, we speculate that the age-related effects observed in chapter 5 are due

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