All of these models commonly propose that, in early PD patients, the withdrawal of dopaminergic medication has a detrimental effect on cognitive functions associated with the dorsolateral loop, and a beneficial effect on the cognitive functions associated with the MLN8237 clinical trial orbital loop; this pattern has been recently

confirmed and better specified by a study that matched Inhibitors,research,lifescience,medical behavioral performances of PD patients ‘on’ and ‘off’ dopaminergic drugs and fMRI findings in healthy subjects in a simple selection task [MacDonald et al. 2011]. Findings confirmed that ventral striatum and the related orbital frontostriatal circuit is involved in learning new stimulus–stimulus

associations and its functioning Inhibitors,research,lifescience,medical is impaired in early PD stages by dopaminergic drugs; on the other hand, dorsal striatum and the related dorsolateral frontostriatal circuit is involved in the assimilation of new and relevant information for the production of more accurate selections, for example shifting attention to more salient stimuli, and its functioning is enhanced in early PD stages by dopaminergic drugs. This double dissociation involving cognitive effects of dopaminergic drugs Inhibitors,research,lifescience,medical is therefore evident when directly comparing patients ‘on’ and ‘off’ dopaminergic medication and was first suggested by the ‘dopamine overdose hypothesis’ [Gotham et al. 1986, 1988], stating that the administration of dopaminergic medication to early PD patients may replete dopamine-depleted circuits (including the dorsal striatum), thus improving Inhibitors,research,lifescience,medical performances in

tasks related to the dorsolateral loop while ‘overdosing’ relatively intact circuits (including the orbital loop). As levodopa mainly elevates dopamine levels Inhibitors,research,lifescience,medical in the striatum [Hornykiewicz, 1974; Maruyama et al. 1996], these differential effects are likely due to opposing effects of levodopa in the dorsal and the ventral striatum, which are connected to different cortical areas via segregated frontostriatal loops [Alexander et al. 1986]. Calpain The neurocomputational model of frontostriatal circuitry functioning in PD [Frank et al. 2004] proposed that basal ganglia modulate the selection of actions under consideration in the PFC. Two main projection pathways from the striatum travel up to the cortex through the thalamus via different basal ganglia output structures. The subthalamic nucleus provides a self-adaptive, dynamic control signal that temporarily prevents the execution of any response, depending on decision conflict [Frank, 2006]. The direct frontostriatal ‘orbital’ pathway is excitatory and the indirect frontostriatal ‘orbital’ pathway is inhibitory.