Proefschrift_Holstein

Chapter 2

any effects dependent on the DAT1 are associated with the striatum. The previous observation that motivated cognitive control depends on striatal dopamine signalling ( chapter 1 ) was replicated in chapter 3 , by showing that the effect of reward on task switching depended on individual differences in the DAT1 genotype. Although the administration of bromocriptine affected task switching, it had no effect on the interaction between reward and task switching. Thus, the work in chapter 3 revealed a role for dopamine in motivated cognitive control. However, evidence for the involvement of dopamine D2 receptors in motivated cognitive control was not provided. Given previous evidence for a role of dopamine D1 and D2 receptors (Koch et al., 2000), or even combined dopamine D1 and D2 receptor stimulation (Ikemoto et al., 1997) in reward motivation, we aimed to manipulate the dopamine system in a more general manner in chapter 4 . To this end we administered the rewarded task- switching paradigm in patients with attention deficit hyperactivity disorder (ADHD) after intake and withdrawal of methylphenidate, a non-selective catecholamine reuptake blocker ( box 2.2b ), and compared their performance and brain activity to that of a group of subjects without ADHD. ADHD is a neuropsychiatric disorder with symptoms related to hyperactivity, inattention and/or impulsivity, which start in childhood (American Psychiatric Association, 1994, 2013). ADHD is not exclusively a childhood disorder, but it continues to affect`~2.5% of adults (Simon et al., 2009). Deficits in flexible, adaptive control have been reported in ADHD (Sonuga-Barke, 2003; Dibbets et al., 2010), but also in other neuropsychiatric disorders such as schizophrenia (Ravizza et al., 2010), Parkinson’s disease (Cools et al., 2001a), and obsessive compulsive disorder (OCD) (Meiran et al., 2011). Interestingly, deficits in these disorders are not restricted to the cognitive domain, but often extend to reward processing deficits, at least in ADHD (Plichta and Scheres, 2014), schizophrenia (Strauss et al., 2014) and OCD (Figee et al., 2010). Combined with the abundance of evidence above showing that motivation can indeed change cognitive processing, it is conceivable that at least some of these cognitive deficits may actually stem from deficits in the motivational domain. Previous work has indeed shown that motivation can improve cognitive control in children with ADHD (Konrad et al., 2000), but studies on motivated cognitive control are thus far absent in this group. Previous attempts to elucidate the neural mechanism underlying aberrant neural processing in ADHD often focused on deficits in dopamine signalling in the prefrontal cortex, but deficits in reward-related striatal dopamine have also been suggested in ADHD (Tripp and Wickens, 2009). We hypothesized that ADHD would be accompanied by aberrant integration of reward and cognitive neural signalling and that striatal dopamine would be involved in this process. Chapter 4 addresses this issue by assessing, in adults with ADHD compared with healthy individuals, how reward motivation can alter neural Clinical relevance: Neuropsychiatric deficits in motivated cognitive con- trol

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