Dopamine Precursor Depletion in Healthy Volunteers Impairs Processing of Duration but Not Temporal Order

Studies in animals and humans have implicated the neurotransmitter dopamine in duration processing. However, very few studies have examined dopamine's involvement in other forms of temporal processing such as temporal order judgments. In a randomized within-subject placebo-controlled design, we used acute phenylalanine/tyrosine depletion (APTD) to reduce availability of the dopamine precursors tyrosine and phenylalanine in healthy human volunteers. As compared to a nutritionally balanced drink, APTD significantly impaired the ability to accurately reproduce interval duration in a temporal reproduction task. In addition, and confirming previous findings, the direction of error differed as a function of individual differences in underlying dopamine function. Specifically, APTD caused participants with low baseline dopamine precursor availability to overestimate the elapse of time, whereas those with high dopamine availability underestimated time. In contrast to these effects on duration processing, there were no significant effects of APTD on the accuracy of discriminating the temporal order of visual stimuli. This pattern of results does not simply represent an effect of APTD on motor, rather than perceptual, measures of timing because APTD had no effect on participants' ability to use temporal cues to speed RT. Our results demonstrate, for the first time in healthy volunteers, a dopaminergic dissociation in judging metrical (duration) versus ordinal (temporal order) aspects of time.

Dopaminergic Modulation of Motor Timing in Healthy Volunteers Differs as a Function of Baseline DA Precursor Availability

Although numerous experiments in patients and animals implicate the dopamine (DA) system in timing, there are relatively few studies examining this effect in healthy volunteers. Moreover, the majority of these studies employed tasks of perceptual timing. We therefore investigated the DA modulation of motor timing in healthy volunteers using Acute Phenylalanine/Tyrosine Depletion (APTD), an amino-acid drink that reduces concentrations of the DA precursors tyrosine and phenylalanine. We also examined how APTD’s effects on timing might differ as a function of underlying DA function, as indexed by baseline levels of DA precursors. 18 healthy volunteers performed a Mixed Temporal Reproduction task, in which reproduction of five different sample durations (500 ms–1500 ms) were tested within a single testing block. Reproduction times conformed to Vierordt’s Law, such that the shortest durations were overestimated and the longest ones underestimated. Yet contrary to reported effects in Parkinson’s disease, we found no DA modulation of this ‘migration’ effect in our healthy volunteers. Instead, APTD produced systematic shifts in reproduction time across all durations. However, the direction of the shift differed according to individual differences in baseline levels of DA precursor availability. Specifically, APTD slowed reproduction times in participants with low baseline DA precursor levels whereas it speeded them in participants with high baseline levels. These apparently paradoxical effects can be reconciled in terms of the inverted U-shaped relationship between DA function and cognition. Finally, APTD had no effect on a test of temporal production in which participants were asked to provide spontaneous estimates of a one-second time interval. The differential effect of APTD on the reproduction versus production tasks suggests DA modulates the magnitude of the duration initially encoded into working memory, rather than clock-speed.