Neuropharmacology of timing and time perception

doi:10.1016/0926-6410(96)00009-2

Cognitive Brain Research

Volume 3, Issues 3–4, June 1996, Pages 227-242

https://doi.org/10.1016/0926-6410(96)00009-2 Get rights and content

Abstract

Time is a guiding force in the behavior of all organisms. For both a rat in an experimental setting (e.g. Skinner box) trying to predict when reinforcement will be delivered and a human in a restaurant waiting for his dinner to be served an accurate perception of time is an important determinant of behavior. Recent research has used a combination of pharmacological and behavioral manipulations to gain a fuller understanding of how temporal information is processed. A psychological model of duration discrimination that differentiates the speed of an internal clock used for the registration of current sensory input from the speed of the memory-storage process used for the representation of the durations of prior stimulus events has proven useful in integrating these findings. Current pharmacological research suggests that different stages of temporal processing may involve separate brain regions and be modified by different neurotransmitter systems. For example, the internal clock used to time durations in the seconds-to-minutes range appears linked to dopamine (DA) function in the basal ganglia, while temporal memory and attentional mechanisms appear linked to acetylcholine (ACh) function in the frontal cortex. These two systems are connected by frontal-striatal loops, thus allowing for the completion of the timing sequences involved in duration discrimination.

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The dopaminergic (DA) system is an important neural system for the modulation of time perception and the timing of motor actions. Dysregulation of the DA system is related to chronic use of stimulant drugs, which lead, among others, to executive dysfunctions. Little is known instead about the potential deficiencies in temporal processing of stimulant-dependent individuals. The present study aimed to investigate temporal processing using a time bisection task with different temporal intervals in chronic cocaine users undergoing repetitive transcranial magnetic stimulation (rTMS).
Study 1: A time bisection task with short temporal intervals range (480/1920 ms) was administered to 18 cocaine use disorder (CocUD) patients and 20 healthy control before and after the intensive phase of rTMS treatment (5 days apart). Study 2: 22 CocUD participants and 23 control participants completed two temporal tasks (time bisection and time reproduction) with long temporal intervals range (1200/2640 ms) at baseline and immediately after the intensive phase of rTMS treatment.
Study 1: A shift in the psychometric function consistent with temporal overestimation in CocUD patients compared to controls was observed. However, no temporal impairment in CocUD patients at test session was found. Study 2: The analysis of temporal variability indices showed a significant difference between groups at baseline but not at Day 5 due to a significant difference between time points only in the CocUD group.
This study report a temporal overestimation in CocUD patients and a temporal variability reduction after an rTMS protocol in CocUD patients.
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Previous studies show that the right hemisphere is involved in time processing, and that damage to the right hemisphere is associated with a tendency to perceive time intervals as shorter than they are, and to reproduce time intervals as longer than they are. Whether time processing deficits following right hemisphere damage are related and what is their neurocognitive basis is unclear. In this study, right brain damaged (RBD) patients, left brain damaged (LBD) patients, and healthy controls underwent a time bisection task and a time reproduction task involving time intervals varying between each other by milliseconds (short durations) or seconds (long durations). The results show that in the time bisection task RBD patients underestimated time intervals compared to LBD patients and healthy controls, while they reproduced time intervals as longer than they are. Time underestimation and over-reproduction in RBD patients applied to short but not long time intervals, and were correlated. Voxel-based lesion-symptom mapping (VLSM) showed that time underestimation was associated with lesions to a right cortico-subcortical network involving the insula and inferior frontal gyrus. A small portion of this network was also associated with time over-reproduction. Our findings are consistent with a slowdown of an ‘internal clock’ timing mechanism following right brain damage, which likely underlies both the underestimation and the over-reproduction of time intervals, and their (overlapping) neural bases.
The Functional Brain Network of Subcortical and Cortical Regions Underlying Time Estimation: An Functional MRI Study
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Time estimation is fundamental for human survival. There have been increasing studies suggesting that distributed brain regions, such as the basal ganglia, cerebellum and the parietal cortex, may contribute to a dedicated neural mechanism of time estimation. However, evidence on the specific function of the subcortical and cortical brain regions and the interplay of them is scare. In this work, we explored how the subcortical and cortical networks function in time estimation during a time reproduction task using functional MRI (fMRI). Thirty healthy participants performed the time reproduction task in both auditory and visual modalities. Results showed that time estimation in visual and auditory modality recruited a subcortical-cortical brain network including the left caudate, left cerebellum, and right precuneus. Besides, the superior temporal gyrus (STG) was found essential in the difference between time estimation in visual and auditory modality. Using psychophysiological interaction (PPI) analysis, we observed an increase in the connection between left caudate and left precuneus using the left caudate as the seed region in temporal reproduction task than control task. This suggested that the left caudate is the key region connecting and transmitting information to other brain regions in the dedicated brain network of time estimation.
The neural representation of time distributed across multiple brain regions differs between implicit and explicit time demands
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Animals appear to possess an internal timer during action, based on the passage of time. However, the neural underpinnings of the perception of time, ranging from seconds to minutes, remain unclear. Herein, we considered the neural representation of time based on mounting evidence on the neural correlates of time perception. The passage of time in the brain is represented by two types of neural encoding as follows: (i) the modulation of firing rates in single neurons and (ii) the sequential activity in neural ensembles. Time-dependent neural activity reflects the relative time rather than the absolute time, similar to a clock. They emerge in multiple regions, including the hippocampus, medial and lateral entorhinal cortices, medial prefrontal cortex, and dorsal striatum. Moreover, they involve different brain regions, depending on an implicit or explicit event duration. Thus, the two types of internal timers distributed across multiple brain regions simultaneously engage in time perception, in response to implicit or explicit time demands.
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Citation Excerpt :
This possibility is in line with previous work showing reduced impulsive choice following time-based interventions without improvements in interval timing itself [31,59]. Indeed, dopamine signaling, through its participation with glutamate, greatly facilitates subjective time estimation with increases or decreases in dopamine signaling producing overestimation or underestimation of subjective duration, respectively, in interval timing tasks [44,47]. Serotonin, rather than being a necessary component of neural timing systems [37], appears to play more general role in response inhibition or “waiting” behavior [11,43].
Many studies support the hypothesis that time-based interventions reduce impulsive behavior in rodents. However, few studies have directly assessed 1) how such interventions affect impulsive action rather than impulsive choice, 2) if intervention effects differ by sex, and 3) how time-based interventions affect neurochemistry in regions mediating decision-making and reward. Thus, we assessed how a fixed-interval (FI) intervention initiated during late adolescence and extending into adulthood affected dopaminergic and serotonergic analytes in the frontal cortex and striatum and subsequent impulsive action in adult male and female mice. Beginning on postnatal day (PND) 45, mice were either trained on a progressive series of FI schedules (FI 20, 40, & 60 s) or remained in the home cage. Following the intervention, increases in striatal serotonergic analytes were found in FI-exposed males and females (n = 8/sex/group) with few changes found in the frontal cortex. Impulsive action was assessed in the remaining mice (n = 10/sex/group) using a fixed-ratio waiting-for-reward (FR-wait) task in which completion of an FR-25 component initiated a “free” pellet component in which pellets were delivered at increasing intervals according to a fixed delay increment that varied across sessions. Responses reset the additive delay and initiated a new FR-25 component. FI-exposed males, but not females, showed fewer delay resets and no-wait resets relative to control mice. Importantly, FI-exposure did not affect discrimination reversal performance in either sex. These data suggest that time-based interventions may reduce impulsive action in addition to impulsive choice perhaps with increased male sensitivity. Additionally, time-based interventions appear to operate through striatal serotonergic augmentation.
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Neuropharmacology of timing and time perception

Abstract

Physiol. Behav.

Pharm. Biochem. Behav.

TINS

Brain Res.

Eur. J. Pharmacol.

Learn. Motiv.

Cognition

Trends Neurosci.

Brain Res.

Eur. J. Pharmacol.

Brain Res.

Brain Res. Rev.

Brain Res.

Behav. Brain Res.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Behav. Brain Res.

Learn. Motiv.

Eur. J. Pharmacol.

TINS

Cogn. Brain Res.

Neuropsychologia

Brain Res.

Neuropsychologia

Trends. Pharmacol. Sci.

Neurosci. Lett.

Behav. Brain Res.

Depletion of dopamine in the caudate nucleus but not in nucleus accumbens impairs reaction-time performance in rats

J. Neurosci.

Time estimation at reduced body temperature

Am. J. Psychol.

The cholinergic hypothesis of geriatric memory dysfunction

Science

The cholinergic hypothesis: a historical overview, current perspective, an d future directions

Choline and cholinergic neurons

Science

A detailed analysis of the effects of d-amphetamine on behavior under fixed interval schedules

J. Exp. Anal. Behav.

The NMDA antagonist MK-801 causesmarked locomotor stimulation in monoamine-depleted mice

J. Neural Trans.

Dendritic release of dopamine in the substantia nigra

Nature

Properties of the internal clock

Application of scalar timing theory to individual trials

J. Exp. Psychol. Anim. Behav.

Lasting consequences of bilateral medial temporal lobectomy: clinical course in experimental findings in H.M.

Neurology

Methadone-induced attenuation of the effects of D9-tetrahydrocannabinol on temporal discrimination in pigeons

J. Pharmacol. Exp. Ther.

Parametric analysis of brain stimulation reward in the rat. II. Temporal summation in the reward system

J. Comp. Physiol. Psychol.

Parametric analysis of brain stimulation reward in the rat. III. Effect of performance variables on the reward summation function

J. Comp. Physiol. Psychol.

Muscular rigidity and delineation of a dopamine specific neostratial subregion EMG activity in rats

Brain Res.

Chronic levodopa treatment alters basal and dopamine agonist-stimulated cerebral glucose utilization

J. Neurosci.

Perception and estimation of time

Annu. Rev. Psychol.

The Prefrontal Cortex: Anatomy, Physiology and Neuropsychology of the Frontal Lobe

Dynamic utilization of GABA in substantia nigra: regulation by dopamine and GABA in the striatum, and its clinical and behavioral implications

Mol. Cell Biochem.

D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons

Science

Scalar expectancy theory and Weber's law in animal timing

Psychol. Rev.

Methadone-induced attenuation of the effects of D⁹-tetrahydrocannabinol on temporal discrimination in pigeons