Impaired time perception and motor timing in stimulant-dependent subjects

https://doi.org/10.1016/j.drugalcdep.2007.03.005Get rights and content

Abstract

Stimulant-dependent individuals (SDI) have abnormal brain metabolism and structural changes involving dopaminergic target areas important for the processing of time. These individuals are also more impulsive and impaired in working memory and attention. The current study tested whether SDI show altered temporal processing in relation to impulsivity or impaired prefrontal cortex functioning. We employed a series of timing tasks aimed to examine time processing from the milliseconds to multiple seconds range and assessed cognitive function in 15 male SDI and 15 stimulant-naïve individuals. A mediation analysis determined the degree to which impulsivity or executive dysfunctions contributed to group differences in time processing. SDI showed several abnormal time processing characteristics. SDI needed larger time differences for effective duration discrimination, particularly for intervals of around 1 s. SDI also accelerated finger tapping during a continuation period after a 1 Hz pacing stimulus was removed. In addition, SDI overestimated the duration of a relatively long time interval, an effect which was attributable to higher impulsivity. Taken together, these data show for the first time that SDI exhibit altered time processing in several domains, one which can be explained by increased impulsivity. Altered time processing in SDI could explain why SDI have difficulty delaying gratification.

Introduction

Cocaine- and amphetamine-like drugs are psychostimulants which alter the dopaminergic system, e.g. by blocking the dopamine transporter (White and Kalivas, 1998) or releasing of dopamine via reverse transport (Sulzer et al., 2005). Methamphetamine (METH), a compound structurally similar to amphetamine also affects the dopamine system, e.g. it leads to downregulation of striatal D2 dopamine receptors (Chang and Haning, 2006) and dopamine transporters in the striatum (McCann et al., 1998), orbitofrontal cortex, and dorsolateral prefrontal cortex (Sekine et al., 2003). Although cocaine and amphetamines have different pharmacodynamic properties, both substances reduce the availability of D2 receptors, which is thought to alter the individual's ability to perform reward-related behaviors (Volkow et al., 2001a).

The dopamine system and its target neural substrates, e.g. the striatum and the prefrontal cortex, are an important neural system for the modulation of time perception and the timing of motor acts. Patients with structural damage such as focal brain lesions to the frontal lobes (Kagerer et al., 2002, Nichelli et al., 1995, von Steinbüchel et al., 1999) or traumatic brain injury predominantly affecting frontal areas (Pouthas and Perbal, 2004) can show substantial impairments in the estimation of temporal intervals. Patients with Parkinson's disease, who have decreased dopaminergic function in the basal ganglia, show deficits in motor timing as well as in duration discrimination (Hellström et al., 1997, O’Boyle et al., 1996). Neuroimaging studies have shown that temporal processing is associated with activation in right prefrontal regions (Rao et al., 2001, Rubia et al., 1998, Rubia and Smith, 2004). Other neuroimaging studies of timing have implicated a fronto-striatal network as the neural basis of the internal clock (Cuoll et al., 2004, Hinton and Meck, 2004, Nenadic et al., 2003). Pharmacological studies on animals and humans support the general hypothesis that fronto-striatal circuits are critical for temporal processing. Dopamine antagonists (like haloperidol) that affect the meso-striatal dopamine system slow down the clock rate in healthy subjects (Rammsayer, 1989, Rammsayer, 1999) whereas timing behavior in animals and humans under the acute influence of METH can be interpreted as the result of speeding up the clock rate (Buhusi and Meck, 2002, Cevik, 2003, Mohs et al., 1980).

Functional neuroimaging and neuropsychological studies show that chronic stimulant users have significant brain activation changes in fronto-striatal regions that are associated with impairments in attention, working memory, and decision making (Fein et al., 2002, McKetin and Mattick, 1997, Nordahl et al., 2003, O’Malley et al., 1992, Paulus et al., 2003, Salo et al., 2005). Stimulant using individuals and stimulant-dependent individuals (SDI) show fundamental cognitive deficits and increased impulsivity when making decisions (Leland and Paulus, 2005, Fillmore and Rush, 2002, Paulus et al., 2002). Similar to other drug-dependent individuals, SDI show less self-control in decision making tasks as they discount future rewards more strongly than control subjects, that is, they tend to prefer smaller and sooner over larger but later rewards (Hoffman et al., 2006, Kirby and Petry, 2004). Overall, the prefrontal cortex is strongly involved in executive functions such as attention regulation, the control of behavior and thoughts, and planning for the future (Arnsten and Li, 2005). These complex cognitive functions are intimately related to impulse control and are impaired in substance abusing individuals (Cardinal et al., 2004, Evenden, 1999, Kirby and Petry, 2004, Monterosso et al., 2006).

Although several cognitive dysfunctions have been reported in stimulant-dependent individuals, it is not known whether these individuals have fundamental problems with temporal processing. An answer to this question would be important because many higher order cognitive functions are dependent on intact temporal processing (von Steinbüchel and Pöppel, 1993). Thus, this is the first study to assess temporal processing in patients with a dependence on substances that have a neurotoxic effect on the dopamine system in fronto-striatal areas of the brain. We hypothesized that SDI would be affected in the accuracy and precision of duration perception and the timing of their behavior. Accuracy refers to the mean error in performance resulting from the difference between the physical duration and the subjective estimate of duration. Precision refers to the prevention of constant errors over trials, assessed by the variance in performance. We were especially interested in whether we would find specific effects of chronic stimulant use depending on the time intervals involved. Different temporal processing mechanisms seem to be involved for different time scales (Buhusi and Meck, 2005, Mauk and Buonomano, 2004, Wittmann, 1999). Temporal integration windows of around 250–500 ms (Rammsayer, 1999, Wittmann et al., 2001), of around 1 s (Madison, 2001) and for intervals up to 2–3 s (Fraisse, 1984, Pöppel, 1997, Wittmann et al., 2007) have been postulated. To probe temporal processing at a variety of time scales, from the milliseconds range to the seconds range, a set of tasks was employed assessing duration discrimination, temporal reproduction, time estimation, and paced finger tapping.

Section snippets

Subjects

This study was approved by the University of California San Diego (UCSD) Institutional Review Board and all subjects provided written informed consent to participate. The SDI group consisted of 15 men meeting criteria for methamphetamine and/or cocaine dependence as determined by interview for DSM-IV diagnoses (SSAGA; Bucholz et al., 1994) and consensus of a team of experienced clinicians. The mean age of the SDI group was 42.3 ± 8.5 years (range: 22–52), with a mean of 12.9 ± 1.24 years of

Group differences

For the duration discrimination task, ANCOVAs revealed that stimulant users had a significantly higher Weber fraction (corresponding to a higher threshold) than controls at the 1000 ms interval duration [F(2, 27) = 9.292, p < 0.0025], but the two groups did not differ in the 100 ms condition [F(2, 27) = 0.361, p < 0.553] (see Table 1).

In the temporal reproduction task a significant difference in timing accuracy between the groups was only revealed for the 2000 ms duration interval [F(2, 27) = 9.500, p < 

Discussion

This investigation showed that stimulant-dependent subjects (SDI) show impairments in time perception and in sensorimotor timing. Moreover, these impairments are task-dependent and possibly specific for the duration of the intervals processed. The mediator models put forth here tested the hypothesis that (neuro)psychological dysfunctions might carry the effects as mediator variables between stimulant dependence status and temporal processing abilities. We found partial support for this

Acknowledgments

We would like to acknowledge the invaluable help of Heather Donovan and Mani Mortezaei. This work was supported by grants from NIDA (R01DA016663, R01DA018307) and from the Veterans Administration via a Merit Grant (MPP), and an NIH training grant (5T32MH18399). The Max Kade Foundation who supported M. Wittmann by a grant is also gratefully acknowledged.

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      Finally, impulsivity, a central construct in substance use and addictive disorders (e.g., Stephan et al., 2017), has been thoroughly associated with time perception (Paasche et al., 2018). Impulsive individuals tend to overestimate time, potentially due to an increased tempo of their pacemaker (i.e., leading to more pulses recorded within the same interval; Wittman et al., 2007). This proposal is further supported by studies showing that populations marked by heightened impulsivity (e.g., individuals with attention deficit/hyperactivity disorder, borderline personality disorder, or addictive disorder) tend to overestimate time duration (Stanford and Barratt, 1996).

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