The spatial properties of adaptation-induced distance compression.

Exposure to a dynamic texture reduces the perceived separation between objects, altering the mapping between physical relations in the environment and their neural representations. Here we investigated the spatial tuning and spatial frame of reference of this aftereffect to understand the stage(s) of processing where adaptation-induced changes occur. In Experiment 1, we measured apparent separation at different positions relative to the adapted area, revealing a strong but tightly tuned compression effect. We next tested the spatial frame of reference of the effect, either by introducing a gaze shift between adaptation and test phase (Experiment 2) or by decoupling the spatial selectivity of adaptation in retinotopic and world-centered coordinates (Experiment 3). Results across the two experiments indicated that both retinotopic and world-centered adaptation effects can occur independently. Spatial attention to the location of the adaptor alone could not account for the world-centered transfer we observed, and retinotopic adaptation did not transfer to world-centered coordinates after a saccade (Experiment 4). Finally, we found that aftereffects in different reference frames have a similar, narrow spatial tuning profile (Experiment 5). Together, our results suggest that the neural representation of local separation resides early in the visual cortex, but it can also be modulated by activity in higher visual areas.

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.

Contrasting contributions of movement onset and duration to self-evaluation of sensorimotor timing performance.

Movement execution is not always optimal. Understanding how humans evaluate their own motor decisions can give us insights into their suboptimality. Here, we investigated how humans time the action of synchronizing an arm movement with a predictable visual event and how well they can evaluate the outcome of this action. On each trial, participants had to decide when to start (reaction time) and for how long to move (movement duration) to reach a target on time. After each trial, participants judged the confidence they had that their performance on that trial was better than average. We found that participants mostly varied their reaction time, keeping the average movement duration short and relatively constant across conditions. Interestingly, confidence judgements reflected deviations from the planned reaction time and were not related to planned movement duration. In two other experiments, we replicated these results in conditions where the contribution of sensory uncertainty was reduced. In contrast to confidence judgements, when asked to make an explicit estimation of their temporal error, participants' estimates were related in a similar manner to both reaction time and movement duration. In summary, humans control the timing of their actions primarily by adjusting the delay to initiate the action, and they estimate their confidence in their action from the difference between the planned and executed movement onset. Our results highlight the critical role of the internal model for the self-evaluation of one's motor performance.

Timing in the absence of a clock reset.

Prominent models of time perception assume a reset of the timing mechanism with an explicit onset of the interval to be timed. Here we investigated the accuracy and precision of temporal estimations when the duration does not have such an explicit onset. Participants were tracking a disc moving on a circular path with varying speeds, and estimated the duration of one full revolution before the stimulus stopped. The onset of that revolution was either cued (explicit), or undetermined until the stimulus stopped (implicit). Reproduced duration was overestimated for short and underestimated for long durations, and variability of the estimates scaled with the duration in both temporal conditions. However, the bias was more pronounced in the implicit condition. In addition, if the stimulus path was partially occluded, duration of the occluded motion was correctly estimated. In a second experiment, we compared the precision in the explicit and implicit conditions by asking participants to discriminate the duration of one revolution before the stimulus stopped to that of a static stimulus presentation in a forced-choice task. Sensitivity of discrimination was worse in the implicit onset condition, but surprisingly, still comparable to the explicit condition. In summary, the estimates follow principles described in prospective timing paradigms, although not knowing beforehand when to start timing decreases sensitivity of temporal estimations. Since in naturalistic contexts, we often do not know in advance which durations might be relevant to estimate, the simple task presented here could become a valuable tool for testing models of temporal estimation.

Practical Aspects of Monitoring of Antiplatelet Therapy.

Despite the application of new antiplatelet drugs (prasugrel and ticagrelor), dual antiplatelet therapy with clopidogrel and aspirin remains the standard for patients with acute coronary syndrome undergoing percutaneous coronary intervention, especially in countries of low socioeconomic status. Regardless of the proven benefits, numerous studies have shown that certain groups of patients who receive standard doses of clopidogrel and aspirin do not respond adequately, and many of them also exhibit adverse cardiovascular events. Studies have shown that the risk of stent thrombosis and ischemic complications is higher in patients with: acute coronary syndrome, diabetes mellitus, thrombocytosis, reduced systolic function of the left ventricle with ejection fraction less than 30%, presence of multiple stents, longer and thinner stents, and renal failure. In these patients it is particularly important to assess the response to clopidogrel and selecting adequate antiplatelet therapy; this provides an impetus for platelet function tests. The second especially significant group to target for laboratory evaluation includes patients with increased risk of bleeding, such as elderly patients, patients with low body weight, anemia, thrombocytopenia, renal failure, past or current ventricular or duodenal ulcer, coagulopathy, or liver disease. The third important application of platelet function tests entails the preparation and evaluation of the time for surgical interventions or invasive diagnostic procedures in patients on antiplatelet therapy. These tests can also be helpful for monitoring the effects of therapy of bleeding due to platelet dysfunction. For high-risk patients the careful selection of optimal antiplatelet drug(s) on the basis of estimated individual risk of thrombosis and bleeding, pharmacodynamic characteristics of each drug, and patient̀s comorbidity remains essential.

Strong perceptual consequences of low-level visual predictions: A new illusion.

Predicting information is considered to be an efficient strategy to minimise processing costs by exploiting regularities in the environment, and to allow for adaptation in case of irregularities, i.e. prediction errors. How such errors impact conscious perception is unclear, especially when predictions concern elementary visual features. Here we present results from a novel experimental approach allowing us to investigate the perceptual consequences of violated low-level predictions about moving objects. Observers were presented with two squares moving towards each other with a constant speed, and reported whether they were in contact or not before they disappeared. A compelling illusion of a gap between the squares occurred when the leading edges of those squares contacted briefly. The apparent gap was larger than a physical and stable separation of 2.6 min of arc between the squares. The illusion disappeared only when the contact did not violate extrapolations of the contrast edge between the moving object and the background. The pattern of results is consistent with an early locus of the effect and cannot be explained by decisional biases, guesses, top-down, attentional or masking effects. We suggest that violations of the contrast edge extrapolation in the direction of motion have strong perceptual consequences.

The processing of subthreshold visual temporal order is transitory and motivation-dependent.

Processing a sequence of events is different from encoding the relative order of the elements composing the sequence. Whether order processing arises automatically from the sequential processing of events is yet unknown, however the literature suggests that order processing can occur at an automatic level when the order of stimuli is not detected consciously. In the present study, we aimed to investigate the question of automatic order processing in a difficult visual task where participants identified one among two possible target luminances. The luminance of the targets was contingent on the order of presentation of two visual cues separated by a subthreshold asynchrony. Participants' performance was compared to that in a control condition where the cues were presented synchronously. In a first experiment, participants' performance benefited from the use of subthreshold order information compared to the control condition, however this facilitation effect was transient and disappeared over the course of the experiment. In a second experiment, we investigated and confirmed the role of motivation, via a monetary incentive, on the previously observed effect. Taken together, our results suggest that the processing of temporal order of sub-threshold asynchronies is possible, although fragile and likely dependent on task requirements.

Dopamine precursor depletion affects performance and confidence judgements when events are timed from an explicit, but not an implicit onset.

Dopamine affects processing of temporal information, but most previous work has tested its role in prospective tasks, where participants know in advance when the event to be timed starts. However, we are often exposed to events whose onset we do not know in advance. We can evaluate their duration after they have elapsed, but mechanisms underlying this ability are still elusive. Here we contrasted effects of acute phenylalanine and tyrosine depletion (APTD) on both forms of timing in healthy volunteers, in a within-subject, placebo-controlled design. Participants were presented with a disc moving around a circular path and asked to reproduce the duration of one full revolution and to judge their confidence in performance. The onset of the revolution was either known in advance (explicit onset) or revealed only at the end of the trial (implicit onset). We found that APTD shortened reproduced durations in the explicit onset task but had no effect on temporal performance in the implicit onset task. This dissociation is corroborated by effects of APTD on confidence judgements in the explicit task only. Our findings suggest that dopamine has a specific role in prospective encoding of temporal intervals, rather than the processing of temporal information in general.

Confidence at the limits of human nested cognition.

Metacognition is the ability to weigh the quality of our own cognition, such as the confidence that our perceptual decisions are correct. Here we ask whether metacognitive performance can itself be evaluated or else metacognition is the ultimate reflective human faculty. Building upon a classic visual perception task, we show that human observers are able to produce nested, above-chance judgements on the quality of their decisions at least up to the fourth order (i.e. meta-meta-meta-cognition). A computational model can account for this nested cognitive ability if evidence has a high-resolution representation, and if there are two kinds of noise, including recursive evidence degradation. The existence of fourth-order sensitivity suggests that the neural mechanisms responsible for second-order metacognition can be flexibly generalized to evaluate any cognitive process, including metacognitive evaluations themselves. We define the theoretical and practical limits of nested cognition and discuss how this approach paves the way for a better understanding of human self-regulation.

The Blursday database as a resource to study subjective temporalities during COVID-19.

The COVID-19 pandemic and associated lockdowns triggered worldwide changes in the daily routines of human experience. The Blursday database provides repeated measures of subjective time and related processes from participants in nine countries tested on 14 questionnaires and 15 behavioural tasks during the COVID-19 pandemic. A total of 2,840 participants completed at least one task, and 439 participants completed all tasks in the first session. The database and all data collection tools are accessible to researchers for studying the effects of social isolation on temporal information processing, time perspective, decision-making, sleep, metacognition, attention, memory, self-perception and mindfulness. Blursday includes quantitative statistics such as sleep patterns, personality traits, psychological well-being and lockdown indices. The database provides quantitative insights on the effects of lockdown (stringency and mobility) and subjective confinement on time perception (duration, passage of time and temporal distances). Perceived isolation affects time perception, and we report an inter-individual central tendency effect in retrospective duration estimation.

Events are perceived earlier in peripheral vision.

Visual perception is not instantaneous. It takes a few milliseconds for light to be transduced in photoreceptors and tens of milliseconds more for neuronal spikes to occur at successive levels of the visual hierarchy. Moreover, the latency of responses varies across the visual field and the cortical hierarchy. In peripheral compared to central vision, the impulse response of primates' ganglion cells has a higher peak occurring at shorter latency [1], and yet humans' primary visual cortex is activated later [2]. The diversity of these physiological results makes it difficult to predict when is the perceived present [3], especially when events are presented across the visual field. This question cannot be directly addressed with paradigms traditionally used to investigate perceptual latencies. In particular, response times are not suitable because they are influenced by decisional mechanisms, motor-related processing or compensatory mechanisms [4,5]. Likewise, temporal order judgements between foveal and peripheral stimuli are not suitable because humans overweigh foveal information when making perceptual decisions [6]. Here we explicitly asked participants to estimate when a stimulus is perceived within a fixed duration temporal interval, rather than relative to another stimulus presented in its near temporal proximity. We show that the perceived time of a visual event depends on its position in the visual field. We find a large bias to report events earlier when they were presented in the periphery.

Temporal context affects the perceived time of visual events.

We investigated whether the moment at which an event is perceived depends on its temporal context. Participants learned a mapping between time and space by watching the hand of a clock rotating a full revolution in a fixed duration. Then the hand was removed, and a target disc was flashed within a fixed-interval duration. Participants were to indicate where the hand would have been at the time of the target. In three separate experiments, we estimated the disruption from a distractor disc that was presented before or after the target disc, with a variable time between them. The target was either revealed at the end of the trial or cued beforehand, and in the latter case, was cued by either color or temporal order. We found an attraction to the presentation time of the distractor when both events were attended equally (target revealed at the end). When the target was cued beforehand, the reported time was under- or overestimated, depending on whether the nature of distractor had to be decoded (precued by color) or not (precued by order). In summary, the perceived time of an event is always affected by other events in temporal proximity, but the nature of this effect depends on how each event is attended.

When an Event Is Perceived Depends on Where We Attend.

Does the moment when an event is perceived depends on where it is presented? To measure when participants perceived events, they were first familiarized with trial duration, by watching the hand of a clock rotating. Then, the hand was removed, and stimuli were presented at a random time from the trial onset. Participants indicated the location where the hand would have been when the stimulus was presented. The stimuli's eccentricity, the appearance, and location of the spatial features of the clock were varied. The targets were reported earlier if they were presented in spatial proximity to the clock outline, even when it was not presented during the trial. The effect was replicated with stimuli presented at the same distance from fixation but at different distances from the spatial features. In summary, the time of an event is perceived earlier if it is presented near attended features in the visual scene.

Is the Ebbinghaus illusion a size contrast illusion?

The Ebbinghaus illusion, in which a central target surrounded by larger context figures looks smaller than when surrounded by smaller context figures, is usually classified as a size contrast illusion. Thus "size contrast" is the dominant account of this effect. However, according to an alternative "contour interaction" account this phenomenon has little to do with size contrast but is rather caused by distance-dependent attractive and repulsive interactions between neural representation of contours. Here evidence is presented against the size contrast account and consistent with the contour interaction account. Experiment 1 was a control study confirming that the illusion can be obtained using displays consisting only of squares, which are more convenient to manipulate than the standardly used circles. In Experiment 2, the standard configuration involving small context figures surrounding the target was compared to a novel configuration, which involved many "spread" small context figures. The illusory effect of the standard context was stronger than the illusory effect of the spread context, in accord with the prediction of the contour interaction account, and contrary to the prediction of the size contrast account. In Experiment 3 two novel configurations were used, based on standard and spread contexts. The results were in accord with the prediction of the contour interaction account, whereas the size contrast account had no prediction because the stimuli did not involve conventional size contrast. Additional aspects of the stimuli and an account of the illusion based on a perspective interpretation are also discussed.

Dabigatran - Metabolism, Pharmacologic Properties and Drug Interactions.

BACKGROUND: The superiority of dabigatran has been well proven in the standard dosing regimen in prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and extended venous thromboembolism (VTE) treatment. Dabigatran, an anticoagulant with a good safety profile, reduces intracranial bleeding in patients with atrial fibrillation and decreases major and clinically relevant non-major bleeding in acute VTE treatment. However, several important clinical issues are not fully covered by currently available directions with regard to dabigatran administration. The prominent one is reflected in the fact that dynamic impairment in renal function due to dehydratation may lead to haemorragic complications on the one hand, while on the other hand glomerular hyperfiltration may be a possible cause of dabigatran subdosing, hence reducing the drug's efficacy. Furthermore, limitations of the Cockcroft-Gault formula, considered a standard equation for assessing the renal function, may imply that other calculations are likely to obtain more accurate estimates of the kidney function in specific patient populations. Method and Conclusions: Although not routinely recommended, a possibility of monitoring dabigatran in special clinical settings adds to optimization of its dosage regimens, timely perioperative care and administration of urgently demanded thrombolytic therapy, therefore significantly improving this drug's safety profile. Despite the fact that dabigatran has fewer reported interactions with drugs, food constituents, and dietary supplements, certain interactions still remain, requiring considerable caution, notably in elderly, high bleeding risk patients, patients with decreased renal function and those on complex drug regimens. Additionally, upon approval of idarucizumab, an antidote to dabigatran solution, hitherto being a major safety concern, has been finally reached, which plays a vital role in life-threatening bleeding and emergency interventions and surgery.

[Contribution of novel anticoagulants fondaparinux and dabigatran to venous thromboembolism prevention].

The data that episodes and sequels of venous thromboembolism (VTE) are recorded in a significant percentage of patients receiving standard anticoagulants as VTE prophylaxis (unfractionated, low-molecular-weight heparin and vitamin K inhibitors) as well as the fact that these drugs have significant limitations and that they may cause serious side-effects in some patients indicate the need for the introduction of new anticoagulant drugs. Fondaparinux, a selective inhibitor of Factor Xa, administered following major orthopedic surgeries having a high risk for the development of VTE, is more efficient than enoxaparin sodium used in European and North-American approved doses. The increased incidence of major bleeding (excluding fatal) due to fondaparinux could be perhaps lowered by dosage reduction in patients with a mildly decreased creatinine clearance. Dabigatran, a peroral direct thrombin inhibitor, administered for VIE prophylaxis in elective hip and knee surgery, showed in to date studies the efficacv comparable (if dabiqatran is given in both dosage regimes of 150 mg and 220 mg daily) or superior (if dabigatran is given at a dose of 220 mg daily) to enoxaparin administered in European-approved doses, while North American-approved doses of enoxaparin were superior than dabigatran in VTE reduction. No significant differences in bleeding rates were determined in any of the study groups. We consider that the introduction of new anticoagulants, including fondaparinux and dabigatran, will contribute to the establishment of a better safety profile and efficacy, and will also enable adequate therapy individualization for each patient depending on his/hers clinical characteristics. The introduction of novel peroral anticoagulants will, inter alia, significantly contribute to improvement in the quality of life, release the patient from numerous limitations in nutrition, interreaction, frequent laboratory monitoring, and also significantly improve therapeutic predictability.

[Contemporary approach to primary prophylaxis of venous thromboembolism regarding the impact of risk factors on anticoagulation therapy duration].

Adequate thromboprophylaxis primarily requires timely detection of reversible and irreversible risk factors of venous thromboembolism (VTE) and their categorization. It is important to note that the highest percentage ofVTE episodes occur in non-surgical (medical) patients and that VTE develops in a large number of surgical patients upon hospital discharge; this emphasizes the need for adequate VTE prevention in inflammatory diseases, acute medical illness and other medical diseases as well as for prolonging and optimizing the anticoagulant regimen after surgical intervention in the primary VTE prophylaxis. As almost completely unrecognized and neglected major risk factors of VTE in clinical practice, we particularly point out the chronic obstructive pulmonary disease (COPD) and heart failure, especially in NYHA functional class III and IV patients with significantly reduced left heart ventricle. It is necessary to raise clinicians' awareness of a potential danger from wrongly and one-sidedly interpreted dyspnea and coughing signs in patients with COPD as typical symptoms of basic respiratory disease as well as from ascribing the signs of disease aggravation in heart failure patients exclusively to cardial status worsening, neglecting the possibility of having unrecognized and untreated pulmonary embolism at issue. Contemporary way of life enhances the development of new VTE risk factors such as traveler's thrombosis, in particular during long-haul flights as well as in individuals sitting at a computer for prolonged periods (e-thrombosis). Determining and recognizing VTE risk factors, especially those formerly neglected nonsurgical ones and simultaneous presence of multiple risk factors within a given period is required for defining an adequate anticoagulant regimen in primary VTE prophylaxis for surgical and non-surgical (medical) patients.