Neurobehavioral Mechanisms of Temporal Processing Deficits in Parkinson's Disease

et al. (2011) Neurobehavioral Mechanisms of Temporal Processing Deficits in Parkinson's Disease. PLoS ONE 6(2): e17461. doi:10.1371/journal.pone.0017461 Neurobehavioral Mechanisms of Temporal Processing Deficits in Parkinson's Disease Deborah L. Harrington 0 Gabriel N. Castillo 0 Paul A. Greenberg 0 David D. Song 0 Stephanie Lessig 0 Roland R. Lee 0 Stephen M. Rao 0 Paul Gribble, The University of Western Ontario, Canada 0 1 Research, Neurology, and Radiology Services, Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America, 2 Department of Radiology, University of California San Diego, San Diego, California, United States of America, 3 Department of Neurosciences, University of California San Diego, San Diego, California, United States of America, 4 Neurological Institute, Cleveland Clinic , Cleveland, Ohio , United States of America 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. - Funding: This research was supported by grants from the Department of Veterans Affairs (1IOICX000146-01and B5015R), the NIH (NS040068), and the Office of Naval Research (N00141010072). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Timing is a process that helps structure perception, cognition and movement. Prevailing models emphasize the role of the striatum and dopamine (DA) neurotransmission [1,2] in regulating an internal clock that generates pulses and an accumulator that counts pulses, thereby representing perceived duration. The experience of time, however, can be dilated or compressed by working memory (WM), attention, and decisional processes [3], which are cortically driven. Thus, timing emerges from interactions among multiple processes that are intertwined. When timing is disentangled from other processes, the striatum is closely linked to timing, whereas the supplementary motor area (SMA) and the middle-frontal and inferior parietal cortices are more associated with WM and executive processes, respectively [4]. The basal ganglias role in timing is particularly relevant to individuals with Parkinsons disease (PD), who exhibit temporal processing deficits [512]. Timing deficits may contribute to the breakdown in the spatiotemporal patterning of movements in PD, which benefit from external rhythmic sensory-cueing [13]. The neuronal sources of timing impairments in PD and their response to DA therapy are not well understood. Whether DA therapy improves timing deficits is controversial [912,1416]. To date, three fMRI and one PET study of timing have been conducted in PD [1619]. Only two of these studies examined the effect of DA treatment [16,19], and all studied timed movements, so that it was not possible to distinguish abnormal activation in systems classically associated with motor-control (i.e., basal ganglia, cerebellum) from activity related to temporal processing. The present study addressed these issues by testing PD participants on and off their DA therapy as they underwent fMRI while performing a time-perception task. In this task, a standard interval (SI) and a comparison interval (CI) were successively encoded, followed by a decision about their relative duration. To identify neural systems related to different components of temporal processing, we separated brain activation associated with encoding the SI and holding it in WM from activation associated with encoding the CI and making a decision. We reasoned that the encoding phase would emphasize timekeeping, but also WM maintenance. Whereas the decision phase engages timekeeping as well, executive processes involved in updating WM and comparing information is also emphasized during this period [4,20,21]. We predicted that abnormal basal ganglia activation in PD would be seen during both phases if the striatum is critical for timekeeping. As SMA dysfunction is common in PD, we also expected abnormal activation during both phases if the SMA plays a key role in timekeeping [22]. Finally, we predicted abnormal middle-frontal cortex activation during the decision, but not the encoding phase if executive difficulties [23,24] contribute to timing deficits in PD. To determine if the cognitivecontrol systems emphasized by the two phases respond differently to DA therapy [25], we studied the effects of medication on brain activation and on striatal interactions with the cortex and cerebellum (i.e., effective connectivity). Though DA therapy was expected to improve striatal function, its effects on key cortical regions that support time perception (e.g., SMA, middle-frontal and inferiorparietal cortex) are unclear as this has not been previously studied. Participants and Proc (...truncated)