Single-dose Levodopa Administration and Aging Independently Disrupt Time Production

We tested the hypothesis that age-related time production deficits are dopamine-mediated. The experiment was conducted double-blind, and with random assignment of 32 healthy aged and 32 healthy young participants to either inert placebo or levodopa (200 mg) groups. The procedure included training participants to produce two target time intervals (6 and 17 sec) in separate blocks, drug/placebo administration, a 1-hr delay, and then delayed free-recall time production retesting without feedback. Participants also performed a speeded choice reaction time (RT) task, as a control for potential dopaminergic and aging effects on attention and psychomotor speed. Results indicate that during retesting, aged participants show duration-dependent timing errors that are larger than those shown by the young participants. Levodopa administration yielded lengthened time production of both target intervals. The aging and levodopa effects did not interact. Also, aging slowed RT and increased RT variability, but levodopa had no effect on the RT. These results suggest that at this dosage and under these specific conditions, timing is dopamine-mediated but the effect of aging on time production is not. Moreover, the levodopa timing effect cannot be attributed to the effects of dopaminergic function on psychomotor speed

Modulation of Human Time Processing by Subthalamic Deep Brain Stimulation

Timing in the range of seconds referred to as interval timing is crucial for cognitive operations and conscious time processing. According to recent models of interval timing basal ganglia (BG) oscillatory loops are involved in time interval recognition. Parkinsońs disease (PD) is a typical disease of the basal ganglia that shows distortions in interval timing. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a powerful treatment of PD which modulates motor and cognitive functions depending on stimulation frequency by affecting subcortical-cortical oscillatory loops. Thus, for the understanding of BG-involvement in interval timing it is of interest whether STN-DBS can modulate timing in a frequency dependent manner by interference with oscillatory time recognition processes. We examined production and reproduction of 5 and 15 second intervals and millisecond timing in a double blind, randomised, within-subject repeated-measures design of 12 PD-patients applying no, 10-Hz- and ≥130-Hz-STN-DBS compared to healthy controls. We found under(re-)production of the 15-second interval and a significant enhancement of this under(re-)production by 10-Hz-stimulation compared to no stimulation, ≥130-Hz-STN-DBS and controls. Milliseconds timing was not affected. We provide first evidence for a frequency-specific modulatory effect of STN-DBS on interval timing. Our results corroborate the involvement of BG in general and of the STN in particular in the cognitive representation of time intervals in the range of multiple seconds

Dorsal hippocampal involvement in conditioned-response timing and maintenance of temporal information in the absence of the CS

Involvement of the dorsal hippocampus (DHPC) in conditioned-response timing and maintaining temporal information across time gaps was examined in an appetitive Pavlovian conditioning task, in which rats with sham and DHPC lesions were first conditioned to a 15-s visual cue. After acquisition, the subjects received a series of non-reinforced test trials, on which the visual cue was extended (45 s) and gaps of different duration, 0.5, 2.5, and 7.5 s, interrupted the early portion of the cue. Dorsal hippocampal-lesioned subjects underestimated the target duration of 15 s and showed broader response distributions than the control subjects on the no-gap trials in the first few blocks of test, but the accuracy and precision of their timing reached the level of that of the control subjects by the last block. On the gap trials, the DHPC-lesioned subjects showed greater rightward shifts in response distributions than the control subjects. We discussed these lesion effects in terms of temporal versus non-temporal processing (response inhibition, generalisation decrement, and inhibitory conditioning)

Neurobehavioral Mechanisms of Temporal Processing Deficits in Parkinson's Disease

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.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.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

The effects of aging on time reproduction in delayed free-recall

The experiments presented here demonstrate that normal aging ampliWes diVerences in time production occurring in delayed freerecall testing. Experiment 1 compared the time production ability of two healthy aged groups as well as college-aged participants. During the test session, which followed a 24-h delay and omitted all feedback and examples of the two target intervals, the two groups of aged participants’ over-produced a 6 s interval. This eVect is similar in form to errors shown by young participants, but twice the magnitude. Productions of a 17 s interval were generally accurate overall. However, further analysis indicated that the majority of aged participants over-produced the 17 s interval while a minority greatly under-produced the 17 s interval. Furthermore, aged participants showed violations of the scalar property of timing variability in the training session, while in the test session, only those who under-produced the 17 s interval showed this tendency. In contrast, training session performance was good for all participants. Experiments 2 and 3 investigated the ability of the participants in Experiment 1 to reproduce the length of a line from memory, under conditions analogous to those of the time production experiments. These experiments provided tests of the speciWcity of the errors observed in Experiment 1. Performance in the older participants was accurate, if more variable, compared to the young participants, in contrast to the time production results, indicating that production inaccuracy in free-recall is speciWc to interval timing in the current context

Scalar expectancy theory and peak-interval timing in humans

The properties of the internal clock, temporal memory, and decision processes used to time short durations were investigated. The peak-interval procedure was used to evaluate the timing of 8-, 12-, and 21-s intervals, and analyses were conducted on the mean response functions and on individual trials. A distractor task prevented counting, and visual feedback on accuracy and precision was provided after each trial. Mean response distributions were (a) centered at the appropriate real-time criteria, (b) highly symmetrical, and (c) scalar in their variability. Analysis of individual trials indicated more memory variability relative to response threshold variability. Taken together, these results demonstrate that humans show the same qualitative timing properties that other animals do, but with some quantitative differences