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

2021 ◽  
Vol 33 (5) ◽  
pp. 946-963
Author(s):  
Morgane Chassignolle ◽  
Ljubica Jovanovic ◽  
Catherine Schmidt-Mutter ◽  
Guillaume Behr ◽  
Anne Giersch ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Temporal Order ◽  
Reproduction Task ◽  
Healthy Human ◽  
Temporal Cues ◽  
Temporal Reproduction ◽  
Human Volunteers ◽  
Tyrosine Depletion ◽  
First Time ◽  
Temporal Order Judgments

Abstract 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

2013 ◽  
Vol 1 (1) ◽  
pp. 77-98 ◽  
Author(s):  
Jennifer T. Coull ◽  
Hye J. Hwang ◽  
Marco Leyton ◽  
Alain Dagher
Keyword(s):  
Healthy Volunteers ◽  
Time Interval ◽  
Motor Timing ◽  
Reproduction Task ◽  
Migration Effect ◽  
Temporal Reproduction ◽  
Testing Block ◽  
Paradoxical Effects ◽  
Tyrosine Depletion ◽  
Baseline Levels

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.

scholarly journals Single-Dose Safety and Pharmacokinetics of ST-246, a Novel Orthopoxvirus Egress Inhibitor

2008 ◽  
Vol 52 (5) ◽  
pp. 1721-1727 ◽  
Author(s):  
Robert Jordan ◽  
Deborah Tien ◽  
Tove' C. Bolken ◽  
Kevin F. Jones ◽  
Shanthakumar R. Tyavanagimatt ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Healthy Human ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Human Volunteers ◽  
Dose Study ◽  
Exposure Levels ◽  
Oral Doses ◽  
First Time ◽  
Single Ascending Dose Study

ABSTRACT ST-246 is a novel, potent orthopoxvirus egress inhibitor that is being developed to treat pathogenic orthopoxvirus infections of humans. This phase I, double-blind, randomized, placebo-controlled single ascending dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 in healthy human volunteers. ST-246 was administered in single oral doses of 500, 1,000, and 2,000 mg to fasting healthy volunteers and 1,000 mg to nonfasting healthy volunteers. ST-246 was generally well tolerated with no serious adverse events, and no subject was withdrawn from the study due to ST-246. The most commonly reported drug-related adverse event was neutropenia, which was found, upon further analysis, not to be treatment related. ST-246 was readily absorbed following oral administration with mean times to maximum concentration from 2 h to 3 h. Absorption was greater in nonfasting volunteers than in fasting volunteers. Administration of ST-246 resulted in exposure levels predicted to be sufficient for inhibiting orthopoxvirus replication compared to exposure levels in nonhuman primates in which ST-246 protected animals from lethal orthopoxvirus infection.

scholarly journals Development of an Innovative Berberine Food-Grade Formulation with an Ameliorated Absorption: In Vitro Evidence Confirmed by Healthy Human Volunteers Pharmacokinetic Study

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Giovanna Petrangolini ◽  
Fabrizio Corti ◽  
Massimo Ronchi ◽  
Lolita Arnoldi ◽  
Pietro Allegrini ◽  
...  
Keyword(s):  
Oral Administration ◽  
Healthy Volunteers ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Healthy Human ◽  
Food Grade ◽  
Dose Linearity ◽  
Human Volunteers ◽  
Intestinal Fluids

Objective. To evaluate in vitro solubility, bioaccessibility, and cytotoxic profile, together with a pharmacokinetic profile by oral administration to healthy volunteers of a novel food-grade berberine formulation (BBR-PP, i.e., berberine Phytosome®). Results. An in vitro increase of solubility in simulated gastric and intestinal fluids and an improved bioaccessibility at intestinal level along with a lower cytotoxicity with respect to berberine were observed with BBR-PP. The pharmacokinetic profile of the oral administration to healthy volunteers confirmed that berberine Phytosome® significantly ameliorated berberine absorption, in comparison to unformulated berberine, without any observed side effects. The berberine plasma concentrations observed with both doses of BBR-PP were significantly higher than those seen after unformulated berberine administration, starting from 45 min (free berberine) and 30 min (total berberine). Furthermore, BBR-PP improved berberine bioavailability (AUC) was significantly higher, around 10 times on molar basis and with observed dose linearity, compared to the unformulated berberine. Conclusion. These findings open new perspectives on the use of this healthy berberine formulation in metabolic discomforts.

scholarly journals Inter-individual differences in human brain structure and morphology link to variation in demographics and behavior

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Alberto Llera ◽  
Thomas Wolfers ◽  
Peter Mulders ◽  
Christian F Beckmann
Keyword(s):  
Individual Differences ◽  
Brain Function ◽  
Structural Features ◽  
Structural Variations ◽  
Healthy Human ◽  
Negative Spectrum ◽  
Human Volunteers ◽  
Wide Range ◽  
And Behavior ◽  
First Time

We perform a comprehensive integrative analysis of multiple structural MR-based brain features and find for the first-time strong evidence relating inter-individual brain structural variations to a wide range of demographic and behavioral variates across a large cohort of young healthy human volunteers. Our analyses reveal that a robust ‘positive-negative’ spectrum of behavioral and demographic variates, recently associated to covariation in brain function, can already be identified using only structural features, highlighting the importance of careful integration of structural features in any analysis of inter-individual differences in functional connectivity and downstream associations with behavioral/demographic variates.

Pharmacokinetics of Mephedrone and Its Metabolites in Whole Blood and Plasma after Controlled Intranasal Administration to Healthy Human Volunteers

2020 ◽  
Author(s):  
Joanna Czerwinska ◽  
Mark C Parkin ◽  
Claire George ◽  
Andrew T Kicman ◽  
Paul I Dargan ◽  
...  
Keyword(s):  
Whole Blood ◽  
Intranasal Administration ◽  
Plasma Samples ◽  
Healthy Human ◽  
Rapid Absorption ◽  
Plasma Distribution ◽  
Human Volunteers ◽  
Liquid Chromatography Tandem Mass ◽  
Synthetic Cathinone ◽  
First Time

Abstract Mephedrone is a popular synthetic cathinone, known for its psychostimulant effects. At present, there is no data available on the pharmacokinetics of mephedrone and its metabolites in concurrently collected whole blood and plasma samples after a controlled intranasal administration to healthy volunteers. In this study, six healthy male volunteers nasally insufflated 100 mg of pure mephedrone hydrochloride (Day 1). Whole blood and plasma samples were collected at different time points after the administration and were analyzed for the presence of mephedrone and its metabolites, dihydro-mephedrone (DHM), nor-mephedrone (NOR), hydroxytolyl-mephedrone (HYDROXY), 4-carboxy-mephedrone (4-CARBOXY) and dihydro-nor-mephedrone (DHNM), by validated liquid chromatography–tandem mass spectrometry methods. All analytes were detected in whole blood and plasma for 6 h post administration, with mephedrone and NOR also being detectable on Day 2 in some participants. 4-CARBOXY, followed by NOR, was the most abundant metabolite in both matrices. Compared to other psychostimulants, mephedrone showed rapid absorption (mean Tmax of 52.5 ± 20.7 min in plasma and 55.0 ± 18.2 min in whole blood) and elimination (mean t1/2 of 1.98 ± 0.30 h in plasma and 2.12 ± 0.33 h in whole blood). In addition, statistical analysis showed that median whole blood to plasma distribution ratios, reported here for the first time, were statistically different from 1 (unity) for mephedrone (median: 1.11), DHM (median: 1.30) and NOR (median: 0.765). It is hoped that the study will aid forensic and clinical toxicologists in detection, identification and interpretation of cases associated with mephedrone use.

scholarly journals No interaction between rivastigmine and citalopram on memory and novelty processing in healthy human volunteers

2018 ◽  
Vol 33 (2) ◽  
pp. 210-218
Author(s):  
PRA Heckman ◽  
A Blokland ◽  
A Sambeth
Keyword(s):  
Healthy Volunteers ◽  
Cognitive Functions ◽  
Animal Studies ◽  
Verbal Learning ◽  
Learning Task ◽  
Healthy Human ◽  
Delayed Recall ◽  
Human Volunteers ◽  
Novelty Processing ◽  
Verbal Learning Task

Background: Animal literature suggests an interaction between acetylcholine and serotonin on cognitive functions. Aims: The aim of the current study was to assess whether both neurotransmitters interact during memory and novelty processing in humans. Methods: We tested the interaction between acetylcholine and serotonin on cognitive functions in healthy volunteers by means of treatment with rivastigmine and citalopram, respectively. Results: The main result of the study showed that during the verbal learning task participants significantly recalled fewer words after citalopram treatment than after rivastigmine or placebo during both the immediate and delayed recall tasks. Rivastigmine was not able to reverse the impairing effect of citalopram. Conclusions: This finding is in line with previous studies in which we manipulated acetylcholine and serotonin in different manners. Taken together, these studies in humans do not support the notion from animal studies that these two neurotransmitters interact on cognitive functions.

Dichotic Temporal Order Judgments in Dyslexic and Nondyslexic Adults

2000 ◽  
Author(s):  
Harvey Babkoff ◽  
Elisheva Ben-Artzi ◽  
Leah Fostick
Keyword(s):  
Temporal Order ◽  
Temporal Order Judgments

Time changes: Temporal contexts support event segmentation in associative memory

2020 ◽  
Author(s):  
Vincent van de Ven ◽  
Moritz Jaeckels ◽  
Peter De Weerd
Keyword(s):  
Associative Memory ◽  
Temporal Order ◽  
Temporal Order Judgment ◽  
Temporal Context ◽  
Temporal Acuity ◽  
Event Segmentation ◽  
Standard Interval ◽  
Test Items ◽  
Time Changes ◽  
Temporal Order Judgments

We tend to mentally segment a series of events according to perceptual contextual changes, such that items from a shared context are more strongly associated in memory than items from different contexts. It is also known that temporal context provides a scaffold to structure experiences in memory, but its role in event segmentation has not been investigated. We adapted a previous paradigm, which was used to investigate event segmentation using visual contexts, to study the effects of changes in temporal contexts on event segmentation in associative memory. We presented lists of items in which the inter-stimulus intervals (ISIs) ranged across lists between 0.5 and 4 s in 0.5 s steps. After each set of six lists, participants judged which one of two test items were shown first (temporal order judgment) for items that were either drawn from the same list or from consecutive lists. Further, participants judged from memory whether the ISI associated to an item lasted longer than a standard interval (2.25s) that was not previously shown. Results showed faster responses for temporal order judgments when items were drawn from the same context, as opposed to items drawn from different contexts. Further, we found that participants were well able to provide temporal duration judgments based on recalled durations. Finally, we found temporal acuity, as estimated by psychometric curve fitting parameters of the recalled durations, correlated inversely with within-list temporal order judgments. These findings show that changes in temporal context support event segmentation in associative memory.

Sign in / Sign up

Export Citation Format

Share Document