Neurobehavioral Mechanisms of Temporal Processing Deficits in Parkinson's Disease

Abstract

BackgroundParkinson's disease (PD) disrupts temporal processing, but the neuronal sources of deficits and their response to dopamine (DA) therapy are not understood. Though the striatum and DA transmission are thought to be essential for timekeeping, potential working memory (WM) and executive problems could also disrupt timing.Methodology/FindingsThe present study addressed these issues by testing controls and PD volunteers ‘on’ and ‘off’ DA therapy as they underwent fMRI while performing a time-perception task. To distinguish systems associated with abnormalities in temporal and non-temporal processes, we separated brain activity during encoding and decision-making phases of a trial. Whereas both phases involved timekeeping, the encoding and decision phases emphasized WM and executive processes, respectively. The methods enabled exploration of both the amplitude and temporal dynamics of neural activity. First, we found that time-perception deficits were associated with striatal, cortical, and cerebellar dysfunction. Unlike studies of timed movement, our results could not be attributed to traditional roles of the striatum and cerebellum in movement. Second, for the first time we identified temporal and non-temporal sources of impaired time perception. Striatal dysfunction was found during both phases consistent with its role in timekeeping. Activation was also abnormal in a WM network (middle-frontal and parietal cortex, lateral cerebellum) during encoding and a network that modulates executive and memory functions (parahippocampus, posterior cingulate) during decision making. Third, hypoactivation typified neuronal dysfunction in PD, but was sometimes characterized by abnormal temporal dynamics (e.g., lagged, prolonged) that were not due to longer response times. Finally, DA therapy did not alleviate timing deficits.Conclusions/SignificanceOur findings indicate that impaired timing in PD arises from nigrostriatal and mesocortical dysfunction in systems that mediate temporal and non-temporal control-processes. However, time perception impairments were not improved by DA treatment, likely due to inadequate restoration of neuronal activity and perhaps corticostriatal effective-connectivity.

Prefrontal D1 dopamine signaling is required for temporal control

“…One such disease, Parkinson disease, involves cognitive dysfunction (37) that can manifest as a dysexecutive syndrome (38) with impaired temporal control (9). Although temporal processing and executive function in Parkinson disease can be heterogeneous (37,39), impairment in these processes in Parkinson disease is likely related to dysfunctional mesocortical networks (12,18,40). The present study provides data demonstrating that prefrontal dopamine is crucial to timing, and that stimulation of D1 systems in prefrontal cortex can facilitate temporal control.…”

Motor Timing Deficits in Sequential Movements in Parkinson Disease Are Related to Action Planning: A Motor Imagery Study

“…Thus, we can only assume that PD patients have deficit in planning the temporal features of sequential finger movements when the interval between two successive movements is supra-second, but we cannot discern whether this represents a distorted mental representation of time or, rather, defective spatio-temporal integration during motor planning. The data present in the literature so far support both interpretations, showing that PD patients are impaired in pure time processing tasks [56,57], but also in sensorimotor integration processes [58,59]. However an ad hoc study designed to correlate perceptual timing with motor planning ability in patients with PD might be useful to shed more light on the function of basal ganglia and interconnected cortical areas on this issue.…”

The vulnerable ventral tegmental area in Parkinson’s disease

“…Though several studies have reported improvements in cognition in PD patients while on dopamine replacement therapy (e.g. levodopa) when compared to off treatment [37,38], these results are not consistent [39], supporting the notion that PD is a complex disease. In the literature reported here, only one study provided information on non-motor symptoms: two patients had intellectual impairment and only one subject presented with hallucinations [22].…”