Dopamine Treatment and Cognitive Functioning in Individuals with Parkinson’s Disease: The “Cognitive Flexibility” Hypothesis Seems to Work

Abstract

Background. Previous data suggest that (i) dopamine modulates the ability to implement nonroutine schemata and update operations (flexibility processes) and that (ii) dopamine-related improvement may be related to baseline dopamine levels in target pathways (inverted U-shaped hypothesis). Objective. To investigate above hypotheses in individuals with Parkinson's disease (PD). Methods. Twenty PD patients were administered tasks varying as to flexibility load in two treatment conditions: (i) “off” condition, about 18 hours after dopamine dose and (ii) “on” condition, after dopamine administration. PD patients were separated into two groups: low performers (i.e., performance on Digit Span Backward below the sample mean) and high performers (i.e., performance above the mean). Twenty healthy individuals performed the tasks in two sessions without taking drugs. Results. Passing from the “off” to the “on” state, only low performer PD patients significantly improved their performance on high-flexibility measures (interference condition of the Stroop test; P < 0.05); no significant effect was found on low-flexibility tasks. Conclusions. These findings document that high-flexibility processes are sensitive to dopamine neuromodulation in the early phases of PD. This is in line with the hypothesis that striatal dopamine pathways, affected early by PD, are precociously implicated in the expression of cognitive disorders in these individuals.

Nigral proteasome inhibition in mice leads to motor and non-motor deficits and increased expression of Ser129 phosphorylated α-synuclein

“…The decreases in turn angle and meander indicated that lesioned mice generated less random movement, and tended to follow more straight sequences. These results are consistent with the modulating role played by striatal DA in controlling cognitive flexibility (Costa et al, 2014 ; Darvas et al, 2014 ).…”

Dissociable Effects of Dopamine on the Initial Capture and the Reactive Inhibition of Impulsive Actions in Parkinson's Disease

“…The possibility that the inverted U-shaped curve applies to a more fine-grained interaction between levodopa and agonist medication could not be directly addressed in the current study, but certainly warrants future attention. Thus, based on the current findings, inhibitory control of action impulses is not easily reconciled with a similar dopamine–performance curve observed in studies of working memory, probabilistic learning, and other cognitive control processes (Costa et al, 2014; Cools & D'Esposito, 2011; Cools, Barker, Sahakian, & Robbins, 2001; Swainson et al, 2000; Gotham, Brown, & Marsden, 1988). However, our behavioral findings allow limited interpretation, and PET imaging would be required to provide more conclusive statements about the relation between individual differences in baseline DA and inhibitory control.…”

A pilot study on the effect of cognitive training on BDNF serum levels in individuals with Parkinson’s disease

“…Thus, there may be fundamental differences in the functional effects of different dopaminergic drugs. At this regard, some data on healthy subjects and PD patients suggest that phasic D2 activity would be critical for allowing the flexible modification of mental representations (cognitive flexibility) whereas tonic D1 activity could sustain the ability to retain stable representations in the face of incoming information ( Cohen et al, 2002 ; Frank, 2005 ; Costa et al, 2009 , 2014b ; Cools and D’Esposito, 2011 ). Coherently with this view, the hypothesis was advanced that, in the early stages of PD, dopamine efficacy on cognitive operations might be related to the regional distribution of dopamine receptors dysfunctioning.…”