Thomas Rammsayer

Are There Dissociable Roles of the Mesostriatal and Mesolimbocortical Dopamine Systems on Temporal Information Processing in Humans

There is some experimental evidence suggesting that temporal processing of brief duration in the range of milliseconds is based on dopamine (DA)-dependent neural counting mechanisms, whereas processing of longer duration is cognitively mediated. To further elucidate the critical role of DA receptors of the D2 receptor family for temporal information processing in humans, the effects of the 3 mg of haloperidol, 300 mg of sulpiride, and 150 mg of remoxipride were studied in a placebo-controlled double-blind experiment. In addition, concomitant changes in cortical arousal as well as speed of information processing and motor execution were measured. Temporal processing of brief duration was significantly impaired by haloperidol (p < 0.01) but not by sulpiride and remoxipride, whereas processing of longer duration was adversely affected by haloperidol (p < 0.001) as well as remoxipride (p < 0.01) as compared to placebo. The pattern of results in combination with the different pharmacological profiles of the dopaminergic drugs applied in the present study suggests that temporal processing of brief duration is mediated by D2 receptor activity in the mesostriatal system and, thus, point to the basal ganglia as a neuroanatomical structure possibly involved in timing of brief duration. On the other hand, deteriorating effects of D2 receptor blockers on processing of longer duration appear to be due to DA-induced impairment of memory functions which may be mediated by the mesolimbocortical DA system.

Time estimation in schizophrenia : an fMRI study at adjusted levels of difficulty

fMRI was performed in nine male schizophrenia patients and 15 healthy male controls during an auditory time estimation (timing), a frequency (i.e. pitch) discrimination task, and rest. An adaptive psychophysical approach, the weighted up–down method, was used to adjust individual performance to a level of 75% probability for correct answers. Although performing on the same level of individual difficulty, schizophrenia patients revealed less activations in prefrontal cortex and caudate nucleus, comparing time vs rest. Timing specific differences (i.e. timing vs pitch) between patients and controls were found in the posterior putamen, anterior thalamus, and right medial prefrontal cortex, with patients showing relative hypoactivity. Impairment in time estimation in schizophrenia might be mediated by specific fronto-thalamo-striatal dysfunction.

On dopaminergic modulation of temporal information processing

Temporal processing of durations in the range of seconds or more (i.e. time estimation) is cognitively mediated, whereas processing of brief durations in the range of milliseconds (i.e. time perception) appears to be beyond cognitive control and based on neural counting mechanisms. Although there is some evidence from animal and human studies suggesting that the internal timing mechanism underlying time perception is modulated by the effective level of brain dopamine, the findings are not conclusive. Therefore, the effects of pharmacologically induced changes in D2 receptor activity on temporal information processing were evaluated. In a double-blind design, either 3 mg of haloperidol, 150 mg of remoxipride, or placebo were administered in a single oral dose. Performance on time estimation was significantly impaired by both haloperidol and remoxipride as compared with placebo. Both drugs obviously affected cognitive mechanisms underlying temporal processing of durations in the range of seconds. On the other hand, only haloperidol produced a significant decrease in performance on time perception as compared with placebo and remoxipride, whereas the remoxipride and placebo groups did not differ significantly. The differential effects of haloperidol and remoxipride on performance on time perception suggest that D2 receptor activity in the basal ganglia may play a critical role in timing of brief durations in the range of milliseconds.

Temporal discrimination in schizophrenic and affective disorders: Evidence for a dopamine-dependent internal clock

Performance in temporal discrimination of time intervals in the range of milliseconds was compared in 80 healthy subjects, 27 patients with schizophrenic disorders, 33 patients with major depression, 21 patients with dysthymic disorders. For schizophrenic patients as well as for patients with major depression, pronounced deficits in duration discrimination could be demonstrated as compared to the healthy control group (p less than .01). Patients with dysthymic disorders and schizophrenic patients differed significantly from the melancholic group (p less than .01 and p less than .05, respectively). The results are discussed on the basis of the assumption of an internal clock, implying that the clock rate is highest and therefore temporal resolution is best with healthy subjects. With psychiatric patients performance in temporal discrimination was impaired to a slowing down in clock rate and thus decreased temporal resolution. There is strong evidence that changes in clock rate depend on the effective level of dopamine. This leads to the conclusion that temporal discrimination thresholds may be seen as an indicator for deviations from the optimal level of dopaminergic activity in psychiatric patients. In addition, possible effects due to age and medication are discussed.

Impaired Temporal Discrimination in Parkinson's Disease: Temporal Processing of Brief Durations as an Indicator of Degeneration of Dopaminergic Neurons in the Basal Ganglia

Recent findings suggest that temporal processing of brief durations is a function of dopaminergic neurotransmission in the basal ganglia. Furthermore, there is preliminary evidence of abnormal timing functions in patients suffering from idiopathic Parkinsons disease (PD). In the present study, temporal discrimination of intervals in the range of milliseconds was investigated in 20 PD patients and 20 healthy controls matched for sex and age. Temporal discrimination was significantly impaired in PD patients as compared to healthy controls. For PD patients, additional correlational analyses did not yield any significant relationship between performance on temporal processing and degree of motor impairment or illness duration. However, impairment in temporal processing was associated with dosage of L-dopa substitution and self-rated feelings of depression. The overall pattern of results suggests that deficits in temporal information processing observed in PD patients may represent a trait marker of vulnerability to decreasing levels of dopaminergic activity in the basal ganglia rather than a state-dependent indicator of the acute clinical symptomatology.

Effects of practice and signal energy on duration discrimination of brief auditory intervals

In Experiment 1, the proposition that duration discrimination of filled auditory intervals is based on temporal information rather than on energy-dependent cues was tested in 64 naive subjects. The subjects were presented with two auditory stimuli at different levels of intensity within one trial, and had to decide which of the two was longer in duration. An adaptive psychophysical procedure was used. As a measure of performance, difference threshold estimates in relation to a 50-msec standard interval were computed. Duration discrimination showed no effect of energy values, indicating that the subjects’ discrimination was independent of stimulus intensity. The goal of Experiments 2A and 2B was to investigate the effects of practice on duration discrimination which, in addition, may provide an indirect test for the potential use of energy-dependent cues. Effects of practice on duration discrimination of filled (Experiment 2 A) and empty (Experiment 2B) intervals were studied in 6 subjects in each case, over 20 testing sessions. An adaptive psychophysical procedure that was similar to the one used in Experiment 1 was applied. Neither short-term effects of practice based on the first five testing sessions, nor long-term effects of practice based on the means of 4 consecutive weeks, could be demonstrated. The results of the present study suggest that duration discrimination of brief auditory intervals is based on temporal information and not on stimulus energy. Furthermore, implications for the notion of a very basic bio-logical timing mechanism underlying temporal processing of brief auditory intervals in the range of milliseconds are discussed.

Is there a common dopaminergic basis of time perception and reaction time

The effects of 3 mg haloperidol and 125 mg Madopar on duration discrimination (DD) as well as reaction times were tested in a placebo-controlled, double-blind crossover study with 24 healthy male volunteers. Performance in DD was significantly impaired under haloperidol compared to placebo as well as to Madopar. No changes could be demonstrated for Madopar compared to placebo. Similar results were obtained for measures of reaction time. Significant negative correlations between individual changes in DD and measures of reaction time under each drug condition revealed that subjects with drug-induced impairment in DD also show an increase in reaction times. The nearly identical patterns of drug-induced changes in DD and measures of reaction time may be interpreted in terms of a common neural basis.

SEX DIFFERENCES IN TIME PERCEPTION

In an experiment on discrimination of duration of auditory stimuli in the range of milliseconds 16 men and 16 women were tested. Men scored better than women in discrimination of duration as well as in required session time. These results were discussed in terms of the assumption of a neurotransmitter-related internal clock and with respect to sex differences in reaction time.

Pharmacologic properties of the internal clock underlying time perception in humans

Performance on temporal discrimination of time intervals in the range of milliseconds is interpreted by the assumption of an internal clock; the higher the clock rate the better the temporal resolution of the internal clock will be, which is equivalent to more accuracy in timing of brief intervals. Although there is some evidence from animal and human studies suggesting that the clock rate depends on the effective level of brain dopamine (DA), the findings are not conclusive. Therefore, an alternative interpretation of the pharmacologic properties of the internal clock has been introduced. According to this interpretation, the internal timing mechanism can be seen as a biological rhythm that is susceptible to chronomutagenic agents, i.e., pharmacologic compounds that are able to produce an alteration in the period of a biological rhythm. To elucidate the pharmacologic properties of the internal timing mechanism, in a double-blind study either 1750 mg of the DA antagonist alpha-methyl-p-tyrosine (AMPT), 0.65 g/kg ethanol which possesses chronomutagenic effects, or placebo were applied to 80 male subjects. As measures of performance, difference threshold estimates in relation to a 50- and a 1,000-ms standard interval and respective response latencies were computed. Furthermore, urinary levels of DA, DOPAC, and HVA were quantified by HPLC analysis. Although AMPT treatment resulted in a pronounced reduction of more than 50% for DA, DOPAC, and HVA, temporal discrimination was not affected. On the other hand, ethanol induced a significant impairment in performance on temporal discrimination in the range of milliseconds as compared to placebo. Neither temporal discrimination in the range of seconds nor response latencies were affected by the drugs applied in this experiment. Our findings suggest that the internal timing mechanism underlying temporal discrimination of intervals in the range of milliseconds is independent of the effective level of brain DA. More likely, pharmacologically induced changes in clock rate appear to depend on the chronomutagenic effects of the drug applied. Furthermore, the absence of ethanol-induced changes in performance on temporal discrimination of longer intervals in the range of seconds supports the assumption of two distinct timing mechanisms underlying temporal discrimination in the millisecond and second range.

A neurochemical model underlying differences in reaction times between introverts and extraverts

Abstract Based on a model for action of the mesostriatal dopamine (DA) system the assumption is made that DA activity modulates the threshold for behavioral responses to sensory input. This modulating function of DA activity on the transmission of sensory input into motor output is most likely reflected in reaction time tasks. This study attempted to relate a model of DA activition of differences in reaction times between introverts and extraverts. Experiment 1 addressed the question of whether haloperidol-induced deviations from the psysiological level of DA activity would differentially affect reaction times of extraverts and introverts. The DA receptor blocker haloperidol caused a marked impairment in reaction time performance in both, extraverts and introverts, but no relationship between Extraversion and reaction time performance was found. In Experiment 2, biosynthesis of DA, as measured by biochemical analysis of urine samples, was significantly reduced by alpha- p -tyrosine (AMPT). Although there were no differences in DA activity between extraverts and introverts after treatment with AMPT, reaction time performance was markedly decreased in introverts, but not in extraverts, as compared to the respective placebo groups. The outcome of the two experiments suggests individual differences between extraverts and introverts in responsivity to experimentally induced changes in DA activity. Introverts appear to be more sensitive to changes in DA activity than activity than extraverts whereas the latter can be characterized by more effective neuronal compensatory mechanisms for maintaining homeostasis in neurotransmission. Furthermore, responsivity to changes in DA activity seems to be mediated by up-regulation of postsynaptic receptors.