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.

Stable multiday recordings from the dorsolateral prefrontal cortex of 2 monkeys performing 2 Go/NoGo visual-discrimination tasks (one requiring well-learned responses, the other requiring learning) demonstrate that the majority of prefrontal neurons were "functionally stable". Recordings were made using a series of removable microdrives, each implanted for 3-6 mo, housing independently mobile electrodes. Action potential waveforms of 94 neurons were stable over 2-9 days; 66/94 (70%) of these cells responded each day, 22/94 (23%) never responded significantly, and 6/94 (6%) responded one day but not the next. Of 66 responsive neurons, 55 were selective for either Go or NoGo trials, individual stimuli, or eye movements. This selectivity was functionally stable (i.e., maintained) for 46/55 neurons across all recording days. Functional stability was also noted in terms of response strength (baseline firing rates compared with poststimulation firing rates) and event-related response timing. Two neurons with consistent responses in familiar testing conditions responded flexibly when the monkeys learned to make correct responses to novel stimuli. We conclude that the majority of prefrontal neurons were functionally stable during the performance of well-learned tasks. Such stability may be a general property of prefrontal neurons, given that neurons with 4 different types of task selectivity were found to be functionally stable. Conceptually similar studies based on long-term recordings in other cortical regions reached similar conclusions, suggesting that neurons throughout the brain are functionally stable.

After few seconds, a figure steadily presented in peripheral vision becomes perceptually filled-in by its background, as if it "disappeared". We report that directing attention to the color, shape, or location of a figure increased the probability of perceiving filling-in compared to unattended figures, without modifying the time required for filling-in. This effect could be augmented by boosting attention. Furthermore, the frequency distribution of filling-in response times for attended figures could be predicted by multiplying the frequencies of response times for unattended figures with a constant. We propose that, after failure of figure-ground segregation, the neural interpolation processes that produce perceptual filling-in are enhanced in attended figure regions. As filling-in processes are involved in surface perception, the present study demonstrates that even very early visual processes are subject to modulation by cognitive factors.

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