The effect of Parkinson's disease on time estimation as a function of stimulus duration range and modality

The present research sought to investigate the role of the basal ganglia in timing of sub- and supra-second intervals via an examination of the ability of people with Parkinson's disease (PD) to make temporal judgments in two ranges, 100-500 ms, and 1-5 s. Eighteen non-demented medicated patients with PD were compared with 14 matched controls on a duration-bisection task in which participants were required to discriminate auditory and visual signal durations within each time range. Results showed that patients with PD exhibited more variable duration judgments across both signal modality and duration range than controls, although closer analyses confirmed a timing deficit in the longer duration range only. The findings presented here suggest the bisection procedure may be a useful tool in identifying timing impairments in PD and, more generally, reaffirm the hypothesised role of the basal ganglia in temporal perception at the level of the attentionally mediated internal clock as well as memory retrieval and/or decision-making processes.     

Effects of internal clock and memory disorders on duration reproductions and duration productions in patients with Parkinson's disease

Patients with Parkinson's disease (PD) exhibit deficits in perceptual and motor timing as well as impairments in memory and attentional processes that are related to dysfunction of dopaminergic systems in the basal ganglia. The aim of the present study was to assess the relationships existing between impaired duration judgments and defective memory and attention in PD patients. We compared time performance of medicated PD patients and control subjects on a duration reproduction task that is highly memory-dependent, and on a duration production task that could reveal effects of changes in the speed of internal time-keeping mechanisms. Each task was performed in a control counting condition and in a condition requiring divided attention between the temporal task and a concurrent reading task. Moreover, PD patients and control subjects were assessed on memory and attention using a battery of neuropsychological tests. The results revealed that in the concurrent reading condition of the reproduction task, duration judgments tended to be more variable in PD patients than in control subjects. Moreover, variability of duration reproductions was correlated with both measures of memory and of disease severity. In the concurrent reading condition of the production task, duration judgments were significantly shorter in PD patients than in control subjects, and accuracy of duration productions was correlated with scores on sub-tests of short-term memory. The findings suggest that the administration of dopamine did not entirely remove the memory deficits in PD patients. Moreover, DA treatment would have abnormally accelerated the rate of the internal clock leading to shorter duration productions in PD patients. The whole results indicate that dopamine administration in patients might have overshadowed the slowing rate of the internal clock usually reported in non medicated PD patients, without entirely restoring all of the memory functions.     

时间认知神经科学研究进展

当前对时间认知的脑机制探讨有三个模型：特异化计时模型、分布网络模型和定域计时模型。在这些模型的框架下,时间认知的神经心理学研究集中探讨了小脑、基底神经节、前额叶在时间信息加工中的作用和大脑两半球在时间认知中的不对称性。小脑作为内部计时系统对时间控制具有重要作用,在周期性动作任务中,小脑对不连续动作计时具有特异性。基底神经节在时间加工任务中与小脑存在明显的作用分离,其具体机制还有待深入研究。前额叶的计时功能可能与注意和工作记忆对时间信息的获得、维持和组织有关。此外,还发现大脑右半球与时问信息的加工关系密切。     

Executive functioning and processing speed in age-related differences in time estimation: a comparison of young,old, and very old adults

Age-related differences in time estimation were examined by comparing the temporal performance of young, young–old, and old–old adults, in relation to two major theories of cognitive aging: executive decline and cognitive slowing. We tested the hypothesis that processing speed and executive function are differentially involved in timing depending on the temporal task used. We also tested the assumption of greater age-related effects in time estimation in old–old participants. Participants performed two standard temporal tasks: duration production and duration reproduction. They also completed tests measuring executive function and processing speed. Findings supported the view that executive function is the best mediator of reproduction performance and inversely that processing speed is the best mediator of production performance. They also showed that young–old participants provide relatively accurate temporal judgments compared to old–old participants. These findings are discussed in terms of compensation mechanisms in aging.     

Effects of noradrenergic activity on temporal information processing in humans

Temporal processing of durations in the range of seconds or more is mediated by working-memory mechanisms whereas processing of brief durations in the range of milliseconds appears to be beyond cognitive control and modulated by dopaminergic activity in the basal ganglia. In the present study, the effects of the selective noradrenaline reuptake inhibitor reboxetine on temporal information processing were evaluated. In a double-blind crossover design, either placebo or 2 or 4 mg of reboxetine were administered to 24 healthy male volunteers. Performance on temporal discrimination of longer durations, as indicated by 75%-difference thresholds in relation to a 1,000-ms standard interval, was significantly improved by 2 mg of reboxetine as compared to placebo, whereas the improvement observed with the 4-mg dose just failed to reach statistical significance. There was, however, no effect of reboxetine on temporal discrimination of extremely brief durations, as indicated by threshold values in relation to a 50-ms standard interval. Findings provided additional evidence for the notion that temporal processing of durations in the range of seconds is based on working-memory processes including aspects of directed attention. In timing of brief durations in the range of milliseconds, however, noradrenergic activity didnot seem to play a critical role.     

The effects of clinical motor variables and medication dosage on working memory in Parkinson’s disease

In this study, we investigate the interrelationship between clinical variables and working memory (WM) in Parkinson’s disease (PD). Specifically, the aim of the study was to investigate the relationship between disease duration, dopaminergic medication dosage, and motor disability (UPDRS score) with WM in individuals with PD. Accordingly, we recruited three groups of subjects: unmedicated PD patients, medicated PD patients, and healthy controls. All subjects were tested on three WM tasks: short-delay WM, long-delay WM, and the n-back task. Further, PD encompasses a spectrum that can be classified either into akinesia/rigidity or resting tremor as the predominant motor presentation of the disease. In addition to studying medication effects, we tested WM performance in tremor-dominant and akinesia-dominant patients. We further correlated WM performance with disease duration and medication dosage. We found no difference between medicated and unmedicated patients in the short-delay WM task, but medicated patients outperformed unmedicated patients in the long-delay WM and n-back tasks. Interestingly, we also found that akinesia-dominant patients were more impaired than tremor-dominant patients at various WM measures, which is in agreement with prior studies of the relationship between akinesia symptom and basal ganglia dysfunction. Moreover, the results show that disease duration inversely correlates with more demanding WM tasks (long-delay WM and n-back tasks), but medication dosage positively correlates with demanding WM performance. In sum, our results show that WM impairment in PD patients depend on cognitive domain (simple vs. demanding WM task), subtype of PD patients (tremor- vs. akinesia-dominant), as well as disease duration and medication dosage. Our results have implications for the interrelationship between motor and cognitive processes in PD, and for understanding the role of cognitive training in treating motor symptoms in PD.     

时间认知的脑机制研究

从神经心理学和脑成像2个领域综述了有关时间认知脑机制的研究。神经心理学及脑损伤的研究结果表明小脑可能与内部时钟功能有关,前额叶可能调节时间认知中的注意过程。PET和fMRI脑成象研究结果显示,基底神经节、小脑和前额叶在所有的计时作业中都被激活。ERP的研究结果还证实,时间信息加工和非时间信息加工存在时间历程上的差异,并且时间信息加工还存在的显著半球优势效应。因此基底神经节、小脑和前额叶可能是时间认知的主要脑机制,但由于研究材料、方法和程序的不同,大脑皮层的广泛区域都有可能参与时间信息的加工。     

工作记忆对时间加工的影响

非时间信息加工与时间加工的关系是复杂的, 存在双向干扰或单向干扰, 结果的不一致与任务所需的注意资源及工作记忆都有关。工作记忆的中央执行系统在时间加工中起主要作用, 同时进行的非时间任务对中央执行功能的需求越多, 两种任务之间的干扰程度越大。语言环和视空间模板对时间加工的影响与非时间信息的类型有关。工作记忆作为一个整体以工作记忆容量为指标, 计时成绩也表现出与工作记忆容量有关的年龄、智力等方面的差异。时间加工和工作记忆在额叶、顶叶、基底神经节等皮质存在共同的神经机制。未来应该丰富工作记忆的研究内容, 结合时间加工的分段性探讨工作记忆影响时间加工的具体进程及神经机制, 并力求在应用方面取得一定的成果。     

Dissecting the clock: understanding the mechanisms of timing across tasks and temporal intervals

Currently, it is unclear what model of timing best describes temporal processing across millisecond and second timescales in tasks with different response requirements. In the present set of experiments, we assessed whether the popular dedicated scalar model of timing accounts for performance across a restricted timescale surrounding the 1-second duration for different tasks. The first two experiments evaluate whether temporal variability scales proportionally with the timed duration within temporal reproduction. The third experiment compares timing across millisecond and second timescales using temporal reproduction and discrimination tasks designed with parallel structures. The data exhibit violations of the assumptions of a single scalar timekeeper across millisecond and second timescales within temporal reproduction; these violations are less apparent for temporal discrimination. The finding of differences across tasks suggests that task demands influence the mechanisms that are engaged for keeping time.     

Neuropharmacological Evidence for Different Timing Mechanisms in Humans

Temporal processing of intervals in the range of seconds or more is cognitively mediated, whereas processing of brief durations below 500 msec appears to be based on brain mechanisms outside cognitive control. To elucidate the critical role of various neurotransmitters in timing processes in humans, the effects of 3 mg of haloperidol, a dopamine receptor antagonist, 11 mg of the benzodiazepine midazolam, and 1 mg of scopolamine, a cholinergic receptor antagonist, were compared in a placebo-controlled double-blind experiment. In addition, changes in cortical arousal, semantic memory, and cognitive and motor skill acquisition were assessed. Temporal processing of long durations was significantly impaired by haloperiodol and midazolam, whereas processing of extremely brief intervals was only affected by haloperidol. The overall pattern of results supports the notion that temporal processing of longer intervals is mediated by working-memory functions and, therefore, any pharmacological treatment, irrespective of the neurotransmitter system involved, that produces a deterioration of working memory, may interfere with temporal processing of longer intervals. Temporal processing of intervals in the range of milliseconds appears to depend on the effective level of dopaminergic activity in the basal ganglia.     

Effects of focal basal ganglia lesions on timing and force control

Studies of basal ganglia dysfunction in humans have generally involved patients with degenerative disorders, notably Parkinson's disease. In many instances, the performance of these patients is compared to that of patients with focal lesions of other brain structures such as the cerebellum. In the present report, we studied the performance of patients with focal basal ganglia lesions on three fundamental motor tasks. The patients all had suffered unilateral damage in the striatum and were tested in the chronic state. The first task required the participants to tap with their index finger as fast as possible; this test provided a simple assessment of motor competence. Compared to controls, the maximum tapping rate was lower for the patients when tapping with their contralesional limb, although the deficit was not severe. The second and third tasks were designed to assess timing and force control, two functions that have been associated with basal ganglia function. The patients performed similar to controls on both tasks and showed no evidence of impairment when using their contralesional limb compared to their ipsilesional limb. The results indicate that unilateral basal ganglia lesions tend to produce minor motor problems in force control, and fail to support the hypothesized role of the basal ganglia in timing.     

Time processing in children with Tourette’s syndrome

Background

Tourette syndrome (TS) is characterized by dysfunctional connectivity between prefrontal cortex and sub-cortical structures, and altered meso-cortical and/or meso-striatal dopamine release. Since time processing is also regulated by fronto-striatal circuits and modulated by dopaminergic transmission, we hypothesized that time processing is abnormal in TS.

Methods

We compared time processing abilities between nine children with TS-only (i.e. without major psychiatric comorbidities) and 10 age-matched healthy children, employing a time reproduction task in which subjects actively reproduce different temporal intervals, and a time comparison task in which subjects judge whether a test interval is longer or shorter than a reference interval. IQ, sustained and divided attention, and working memory were assessed in both groups using the Leiter International Performance Scale-Revised, and the Digit Span sub-test of the WISC-R.

Results

Children with TS-only reproduced in an overestimated fashion over-second, but not sub-second, time intervals. The precision of over-second intervals reproduction correlated with tic severity, in that the lower the tic severity, the closer the reproduction of over-second time intervals to their real duration. Time reproduction performance did not significantly correlate with IQ, attention and working memory measures in both groups. No differences between groups were documented in the time comparison task.

Conclusions

The improvement of time processing in children with TS-only seems specific for the over-second range of intervals, consistent with an enhancement in the ‘cognitively controlled’ timing system, which mainly processes longer duration intervals, and depends upon dysfunctional connectivity between the basal ganglia and the dorso-lateral prefrontal cortex. The absence of between-group differences on time comparison, moreover, suggests that TS patients manifest a selective improvement of ‘motor’ timing abilities, rather than of perceptual time abilities. Our data also support an enhancement of cognitive control processes in TS children, probably facilitated by effortful tic suppression.     

Temporal order in memory and interval timing: an interference analysis

The effect of varying load in memory tasks performed during a time interval production was examined. In a first experiment, increasing load in memory search for temporal order affected concurrent time production more strongly than varying load in a spatial memory task of equivalent difficulty. This result suggests that timing uses some specific resources also required in processing temporal order in memory, resources that would not be used in the spatial memory task. A second experiment showed that the interference between time production and memory search involving temporal order was stronger when, during the timing task, a decision was made on the temporal position of a memory item, than when information on temporal order was retained throughout the interval to be produced. These results underscore the importance of considering the specific resources and processes involved when the interference between timing and concurrent non-temporal tasks is analyzed.     

No evidence for qualitative differences in the processing of short and long temporal intervals

Several lines of research suggest that two distinct timing mechanisms are involved in temporal information processing: a sensory mechanism for processing of durations in the range of milliseconds and a cognitively controlled mechanism for processing of longer durations. The present study employed a dual-task approach and a sensory interference paradigm to further elucidate the distinct timing hypothesis. Experiment 1 used mental arithmetic as a nontemporal secondary task, Experiment 2 a memory search task, and Experiment 3 a visuospatial memory task. In Experiment 4, a loudness manipulation was applied. Mental arithmetic and loudness manipulation affected temporal discrimination of both brief and long intervals, whereas the two remaining tasks did not influence timing performance. Observed differences in interference patterns may be explained by some tasks being more difficult than others. The overall pattern of results argues against two qualitatively distinct timing mechanisms, but is consistent with attention-based cognitive models of human timing.     

Comparison of patients with Parkinson's disease or cerebellar lesions in the production of periodic movements involving event-based or emergent timing

We have hypothesized a distinction between the processes required to control the timing of different classes of periodic movements. In one class, salient events mark successive cycles. For these movements, we hypothesize that the temporal goal is a requisite component of the task representation, what we refer to as event-based timing. In the other class, the successive cycles are produced continuously. For these movements, alternative control strategies can optimize performance, allowing timing to be emergent. In a previous study, patients with cerebellar lesions were found to be selectively impaired on event-based timing tasks; they were unimpaired on a continuously produced task. In the present study, patients with Parkinson's disease were tested on repetitive movement tasks in which timing was either event-based or emergent. Temporal variability on either type of task did not differ between on- and off-medication sessions for the Parkinson's patients nor did patient performance differ from that of controls. These results suggest that the basal ganglia play a minimal role in movement timing and that impairments on event-based timing tasks are specific to cerebellar damage.     

Time estimation: does the reference memory mediate the effect of knowledge of results?

This study presents evidence for the role of knowledge of results (KR) in the estimation of medium time intervals (4-12 s durations). Experiment 1 tested the hypothesis that KR operates at the same stage of temporal processing as attention. The absence of an interaction of attention and KR is taken as evidence against this hypothesis. Experiments 2 and 3 further studied the effects of KR in a reproduction and a production task, respectively. The effects of KR were small in the reproduction and substantial in the production task. The results are interpreted in terms of a clock-based timing model and the findings taken together converge on the interpretation that KR affects the reference memory (RM), rather than the other components of the model.     

Time perception in severe traumatic brain injury patients: A study comparing different methodologies

In this study, we investigated time perception in patients with traumatic brain injury (TBI). Fifteen TBI patients and 15 matched healthy controls participated in the study. Participants were tested with durations above and below 1 s on three different temporal tasks that involved time reproduction, production, and discrimination tasks. Data variables analyzed included amount of errors, relative errors, and coefficient of variation. Both groups completed a neuropsychological battery that included measures of attention, working memory, and executive functions. Results revealed significant differences between groups on the time reproduction and discrimination tasks, whereas groups showed similar performance on the time production task. Correlation analyses showed involvement of attention, working memory and executive functions on the time reproduction and time discrimination tasks, but there was no involvement on the time production task. These findings suggest that TBI does not impact specific temporal function. Rather, impairments in attention, working memory and executive function abilities may explain lower temporal performance in people with TBI.     

Stimulus timing by people with Parkinson's disease

Previous literature suggests that Parkinson’s disease is marked by deficits in timed behaviour. However, the majority of studies of central timing mechanisms in patients with Parkinson’s disease have used timing tasks with a motor component. Since the motor abnormalities are a defining feature of the condition, the status of timing in Parkinson’s disease remains uncertain. Data are reported from patients with mild to moderate Parkinson’s disease (both on and off medication) and age- and IQ-matched controls on a range of stimulus timing tasks without counting. Tasks used were temporal generalization, bisection, threshold determination, verbal estimation, and a memory for duration task. Performance of patients was generally “normal” on all tasks, but significant differences from performance of controls were found on the memory for duration task. Among the “normal” effects noted were arithmetic mean bisection, asymmetric temporal generalization gradients, and subjective shortening on the memory for duration task. The results suggest (a) that some previous reports of timing “deficits” in Parkinson’s patients were possibly due to the use of tasks requiring a timed manual response and (b) small differences between patients and controls may be found on tasks where two stimuli are presented on each trial, whether patients are on medication or off it.     

Timing recalibration in childhood Tourette syndrome associated with persistent pimozide treatment

In this study, we have tested the effects of the dopamine D₂ receptor blocker pimozide on timing performance in patients with Tourette syndrome (TS). Nine children with TS were tested off‐medication and following 3 months of daily treatment with pimozide. Subjects completed a time reproduction and a time production task using supra‐second temporal intervals. We show that pimozide improves motor timing performance by reducing the patients' variability in reproducing the duration of visual stimuli. On the other hand, this medication has no effect on the reproduction accuracy and on both variability and accuracy of the performance on the time production task. Our results suggest that pimozide might have improved motor timing variability as a result of its beneficial side effect on endogenous dopamine levels (i.e., normalization).     

Sensorimotor Impairment of Speech and Hand Movement Timing Processing in Parkinson’s Disease

Models of motor control have highlighted the role of temporal predictive mechanisms in sensorimotor processing of speech and limb movement timing. We investigated how these mechanisms are affected in Parkinson’s disease (PD) while patients performed speech and hand motor reaction time tasks in response to sensory stimuli with predictable and unpredictable temporal dynamics. Results showed slower motor reaction times in PD vs. control in response to temporally predictable, but not unpredictable stimuli. This effect was driven by faster motor responses to predictable stimuli in control subjects; however, no such effect was observed in the PD group. These findings indicated the relationship between PD pathology and sensorimotor deficits in temporal predictive mechanisms of timing processing during speech production and hand movement.