Neurobehavioral Mechanisms of Temporal Processing Deficits in Parkinson's Disease.

Background: Parkinson'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/Findings: The 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/Significance: Our 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. [ABSTRACT FROM AUTHOR]