Proefschrift_Holstein

Chapter 8

humans ( chapter 3 and 4 ) is related to the baseline-dependency of these effects. Whereas the effect of reward on task switching in humans were only revealed when taking into account a baseline measure of dopamine signalling, in rodents the effects were revealed without accounting for individual differences. This discrepancy is possibly explained by the absence of genetic variation in rodents, caused by the inbred nature of laboratory animals. In chapter 7 we assessed the role of prefrontal modulation of striatal processing during motivated cognitive control and subsequent action selection. However, the effects of prefrontal stimulation on the processing of information about motivated cognitive control (without taking into account response switching) did not reach significance. One potential explanation for the effect may be related to the nature of the spiralling dopamine connections between the striatum and the midbrain (Ikeda et al., 2013). The striatum sends inhibitory (GABA-ergic) projections to the midbrain. These GABA-ergic connections inhibit the dopamine neurons that project back to the (‘next’ region) in the striatum ( figure 2.1 ). If we assume that distinct SNS projections originate from the ventral striatum, the anterior caudate nucleus, posterior caudate nucleus and putamen ( figure 2.1 ), then I would speculate that the inhibition caused by stimulation of the anterior prefrontal cortex (reflected by the decrease in reward-related BOLD response after prefrontal stimulation observed in chapter 7 ), decreased the inhibition of the projection from the anterior caudate nucleus to the section of the midbrain it projects to. This part of the midbrain (which in turn projects to the posterior caudate nucleus) will cause an increase in dopamine signalling in the posterior caudate nucleus (i.e. attenuating the inhibitory effect of TMS, masking any direct prefrontal modulation of the prefrontal stimulation). Crucially then, this increased signalling in the posterior caudate will increase the inhibition on the midbrain and will subsequently decrease dopamine release from the midbrain to the putamen (reflected by a decrease in BOLD response in the putamen during the integration of motivation, cognition and action in chapter 7 ). However, this idea is highly speculative and evidence to substantiate the projections assumed above is currently absent ( future research ). Future research Based on the combined evidence presented in chapter 3, 4, and 5 we propose a role for striatal dopamine in mediating motivated cognitive control. This claim can be assessed in a number of ways. First, direct measurements of dopamine signalling in the striatum, for example using voltammetry or microdialysis in rodents, should reveal increases in striatal dopamine signalling during motivated cognitive control. Second, age-related dopamine cell loss in the striatum, measured using molecular imaging (e.g. single photon emission computed tomography; SPECT) should be related to age-related changes in motivated cognitive control. This latter approach would parallel the way in which the relationship between motivated cognitive control and dopamine was previously established in Parkinson’s disease ( chapter 1: figure 1.2f (Aarts et al., 2012). Third, in addition to the results of NMDA lesions in chapter

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