Individual differences in set-shifting and levodopa responsiveness in Parkinson's disease

Perseveration (PE) and learned irrelevance (LI) are two distinct processes that shape attentional set-shifting in Parkinson's disease (PD). Whether LI and PE are dopamine-dependent remains unclear. We investigated whether PE and LI may be dissociated in early PD and whether these switch conditions are associated with an individual motor response to levodopa. Fifty patients with early idiopathic PD (Hoehn-Yahr I-II) were assessed OFF and ON levodopa in a counterbalanced crossover design, and 50 age- and sex-matched controls completed the same computerized LI/PE explicit-rule task twice. Log-transformed reaction time (RT) and accuracy were modelled using linear mixed effect models adjusted for global cognition, verbal fluency, and executive function, with within-PD models additionally testing period-adjusted. We also explored the addition of patients' motor response OFF versus ON levodopa, quantified as change in UPDRS-III, as a moderator variable. Overall, LI incurred the largest RT cost in both PD and controls, whereas PE was tied to a smaller but reliable cost. Levodopa status did not affect switching costs at the PD group level, whereas OFF medication patients did not differ from controls after adjustment for cognitive covariates. In exploratory analyses, a larger motor response to levodopa was associated with greater overall ON-state slowing (PE, p = .031; LI, p = .027). However, the effect size was small and only partly robust in sensitivity analyses, which requires further validation. Taken together, in early, cognitively preserved PD, PE and LI are characterized with partly separable behavioural profiles, though on average, levodopa did not alter switching costs. Individual motor improvement after dopaminergic treatment may be linked to shifting performance variability, but this requires further study and clarification.