Proefschrift_Holstein

General discussion

ADHDwho take methylphenidate on a daily basis and who refrained from taking their normal medication prior to the experimental session. When comparing this to drug administration studies in non-medicated subjects, the long term effect of methylphenidate should be taken into account. For example, it has been suggested that long-term use of methylphenidate may – among other things – decrease excessive reward-related signalling in the striatum (Seeman and Madras, 1998; Robbins, 2002). It remains unclear from chapter 4 to what extent the effects in the ADHD patients after medication withdrawal reflect deficits related to ADHD, or to long term effect of methylphenidate use. Another limitation of the work in chapter 4 is that it failed to reveal clear behavioural effects, i.e. it remains unclear how the change in striatal signalling would affect behaviour. The results in chapter 5 speak to opposite effects of dopamine on cognitive focusing (task repetition) and cognitive flexibility (task switching). However, cognitive flexibility and stability were not formally manipulated in this study. Moreover given the age-related degeneration of dopamine neurons, and the opposite effects of reward on task switching and repeat trials, it is reasonable to speculate that dopamine mediated these opposite reward-related effects on cognitive control. However, future work should test this hypothesis ( future research ). In chapter 6 I present a novel rodent paradigm allowing the independent manipulation of reward motivation and cognitive control, enabling the assessment of the interaction between reward and task switching. Although this paradigm parallels the paradigm used in human subjects ( box 2.3 ), at least two differences should be considered when comparing the results between species. First, whereas the size of the reward varied on a trial-by-trial basis in the human version, the rodents performed the task-switching paradigm in separate high and low reward blocks. However, similar block-designs have been used in humans to reveal motivation–cognition interactions (Locke and Braver, 2008; Kouneiher et al., 2009), although not with the rewarded task-switching paradigm. It is therefore unlikely that these differences in trial-by-trial fluctuations in reward expectancy will have dissociable effects on task-switching behaviour. Second, the trial duration in the rodent paradigm is much larger than that in the human paradigm: The animals were presented with the task cue for one minute and were then given another minute to press the levers during the presentation of the target, whereas these events lasted merely a second in the human paradigm. As a consequence, the time between the task cue and the target was much shorter in the human version of the paradigm than it was in the rodent paradigm (i.e. 400ms instead of 1 minute). Longer cue-target intervals in humans are known to decrease the switch cost (Meiran et al., 2000). Moreover, situations in real-life often require instantaneous decisions and the need for lengthy preparation times can be detrimental for survival. In the future it is thus advisable to reduce the the cue-target interval. The large cue-target interval in chapter 6 may potentially account for a switch benefit in the high reward condition, and a non-significant switch cost in the low reward condition: If increasing the cue-target interval will increase the difficulty of switching, animals may well show the same pattern of results as that observed in the 9R subjects in the healthy population. One additional question that is raised when comparing the results in rodents to those in

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