Perseveration and choice in Parkinson's disease: the impact of progressive frontostriatal dysfunction on action decisions

Abstract

We have previously shown that patients with Parkinson's disease (PD) perseverate in their choice of action relative to healthy controls, and that this is affected by dopaminergic medication (Hughes LE, Barker RA, Owen AM, Rowe JB. 2010. Parkinson's disease and healthy aging: Independent and interacting effects on action selection. Hum Brain Mapp. 31:1886-1899). To understand further the neural basis of these phenomena, we used a new task that manipulated the options to repeat responses. Seventeen patients with idiopathic PD were studied both "on" and "off" dopaminergic medication and 18 healthy adults were scanned twice as controls. All subjects performed a right-handed 3-choice button press task, which controlled the availability of repeatable responses. The frequency of choosing to repeat a response (a form of perseveration) in patients was related to dopamine therapy and disease severity as a "U-shaped" function. For repetitive trials, this "U-shaped" relationship was also reflected in the BOLD response in the caudate nuclei and ventrolateral prefrontal cortex. Our results support a U-shaped model of optimized cortico-striatal circuit function and clearly demonstrate that flexibility in response choice is modulated by an interaction of dopamine and disease severity.

Keywords: Action-selection; Caudate; Ventrolateral prefrontal cortex; fMRI; “U-shaped” function.

Figure 1.

The 3-choice action-selection task. The first and last trial in this example sequence are types of specified trials, in which the finger to press is indicated by a black opaque circle. The second and third are examples of action-selection trials in which the subject can select any 1 of the 3 options highlighted by the black circles. In the second trial illustrated, there is the option to repeat a response. A repeat action-selection trial would occur if in the second trial the index finger is selected. Conversely, if in the second trial the ring finger was selected, this would be a “repeat-reject” trial, since the repetition was available but not used. A non-repeat action-selection trial would occur in trial 3, if in the second trial the index finger was selected, as this option is not available in trial 3.

Figure 2.

(A) Reaction times for repeat, repeat-reject and non-repeat trials in the specified and action-selection conditions for patients and controls. Patient reaction times are slower than for controls, and their repeat trials are faster than the trials in which an alternative response was selected. (B) The proportion of repetitive responses (in trials where a repetition was available). At chance, repetitions should be ∼0.33. When “on” dopaminergic medication, patients with less disease severity (lower UPDRS) made more repetitions and this decreased with advancing disease. In contrast, patients “off” medication show a trend of increasing repetitions with increasing disease severity. (C) The difference in patients' repetition rates between sessions (proportion of repetitions when “off” minus proportion when “on”) as a function of disease severity, demonstrating the change in repetition when patients are withdrawn from medication. Patients who have lower UPDRS scores when “on” have a larger reduction in repetition rates when withdrawn from their medication. As UPDRS increases the difference in repetition rates between sessions decreases. At approximately an UPDRS “on” score of 11 points, the change in repetition rates starts to increase, such that those patients who have high UPDRS when “on” have increased repetition rates when withdrawn from medication.

Figure 3.

(A) fMRI activity for all action-selection trials compared with all specified trials for all subjects. Activity is within a broad bilateral frontoparietal network. (P < 0.05 FWE cluster correction.) (B to D) Repetition of responses in patients “on” and “off” medication. (B) BOLD activity in the caudate nucleus for repeat action-selection trials versus repeat-specified trials. The activity for patients was linearly related to the UPDRS score (cluster-level FWE P < 0.05). (C) The plot of peak voxels within the caudate (xyz = −14 −12 22) depicts this linear relationship. There is a decrease in BOLD activity with increasing UPDRS in patients “on” medication and an increase in activity with increasing UPDRS in patients “off” medication. (D) BOLD response (red) in ventrolateral PFC for an interaction between repeat action-selection trials versus repeat-specified trials and non-repeat action–selection trials versus non-repeat–specified trials. The activity was significant within a mask of the PFC (blue) (peak voxels FWE P < 0.05). (E) The plot of peak voxels within the ventrolateral PFC (xyz = 42, 38, 6) depicts the interaction of BOLD with UPDRS for both trial types: when repeating actions (black diamonds) patients “on” medication have decreasing activity as UPDRS increases, while patients “off” medication have increasing activity with UPDRS. In non-repeat trials (grey diamonds), the reverse pattern is observed.