Rodents monitor their error in self-generated duration on a single trial basis

A fundamental question in neuroscience is what type of internal representation leads to complex, adaptive behavior. When faced with a deadline, individuals’ behavior suggests that they represent the mean and the uncertainty of an internal timer to make near-optimal, time-dependent decisions. Whether this ability relies on simple trial-and-error adjustments or whether it involves richer representations is unknown. Richer representations suggest a possibility of error monitoring, that is, the ability for an individual to assess its internal representation of the world and estimate discrepancy in the absence of external feedback. While rodents show timing behavior, whether they can represent and report temporal errors in their own produced duration on a single-trial basis is unknown. We designed a paradigm requiring rats to produce a target time interval and, subsequently, evaluate its error. Rats received a reward in a given location depending on the magnitude of their timing errors. During the test trials, rats had to choose a port corresponding to the error magnitude of their just-produced duration to receive a reward. High-choice accuracy demonstrates that rats kept track of the values of the timing variables on which they based their decision. Additionally, the rats kept a representation of the mapping between those timing values and the target value, as well as the history of the reinforcements. These findings demonstrate error-monitoring abilities in evaluating self-generated timing in rodents. Together, these findings suggest an explicit representation of produced duration and the possibility to evaluate its relation to the desired target duration.

In neuroscience, a fundamental question is how rich the internal representation of an individual’s experience must be to yield adaptive behavior. Let us consider a hungry individual in need of finding food fast: The individual may adopt a trial-and-error foraging strategy to maximize reward but may also, to maximize its efficiency, represent rich experiential variables, such as how much time it takes to reach a source of food. Both representing elapsed time and monitoring its inherent uncertainty plays an important role in adaptive behavior, learning, and decision making (1). When representing these variables, the sources of uncertainty are both exogenous (stimuli driven) and endogenous (neural implementation). The mapping of exogenous sources of temporal uncertainty has been well described in timing behavior: For instance, mice can adjust their behaviors to the width of the distribution of temporal intervals provided through external stimuli (2). On the other hand, the endogenous sources of uncertainty for time perception are less understood and more difficult to address.Evidence that animals are sensitive and have access to the internal uncertainty of elapsed time comes from a task in which the individual must produce a required target duration using a lever press or a key press (1, 3, 4). In a task in which individuals must produce an interval of fixed duration to obtain a reward (Fig. 1A), a plausible strategy to maximize reward would be to set the produced duration to be longer than the required target duration so as to allow a margin of error [internal target duration; (5)]. This is because the larger an individual’s representational uncertainty, the larger the margin of error to maximize the reward. Consistent with this, studies have shown that the magnitude of error in produced intervals varies with the magnitude of temporal uncertainties (6, 7), and participants with larger temporal uncertainty set larger margins of errors [Fig. 1B and SI Appendix, Fig. S2; (1, 7)]. The observed optimization of timing behavior begs the question of how rich the representation of elapsed time must be.Open in a separate windowFig. 1.The TP task and error-monitoring protocol. (A) Schematic of a box arrangement with a lever available in the middle of the panel and reward ports on the left and right side of the lever. Reward availability was signaled by the port lit, depicted by the lightbulbs. Reward delivery was triggered by rats’ nose poke in the reward port. Depending on the group assignment, rats had to either hold the lever pressed for a minimum of 3.2 s (HOLD group) or press the lever twice with a minimal delay (3.2 s) between two presses (PRESS group). (B) TP performance, in error-monitoring test sessions, follows Weber’s law for both groups, with signatures of optimality. (Upper) Probability density functions over TPs for each individual rat in HOLD (blue) and PRESS (red) groups. Thresholds Θ (blue and red dashed lines for HOLD and PRESS groups, respectively) are plotted for each individual. (Bottom Left) Average probability density functions over TPs for HOLD and PRESS groups superimposed. Note the distribution shift and width shrinkage for HOLD group. (Bottom Right) For each rat, µ(TP) is plotted against σ(TP). Both at the individual and at the group level the PRESS rats showed larger µ(TP) and σ(TP), visible as an upward right shift of the red curve. This pattern indicates that rats make their choices optimally, taking into account their level of TP variability. The results hold within each rat and across sessions (SI Appendix, Fig. S3). (C) Schematic depiction of how rewards were assigned to specific parts of TP distribution. Green color is used for “small error” (SE) trials and orange color for “large error” (LE) trials. Red color indicates TPs that were out of reward range. The arrows indicate probabilistic assignment of TP type (SE or LE) to left and right ports, on training trials. On test trials, the food–port assignments remained, but both ports were available and, thus, the amount of reward was driven by the rat’s choice. (D) Schematic of a trial structure. From the top to bottom, the succession of task events is depicted. They alternate along TP axis (color bar with red, green, and orange) and show different scenarios that are determined by the rats’ performance on TP in single trials. ITI is the last event in a single-trial sequence.A trial-and-error strategy would predict that near-optimal behavior can be parsimoniously explained by adaptation so that timing behavior would fluctuate around the required duration. The representational view would predict that uncertainty and trial-to-trial errors are experiential variables used by the animals to monitor their timing behavior.To settle the question of whether rodents can monitor their timing errors relative to their target on a trial-by-trial basis, we developed a task inspired by human work. Humans required to generate a time interval can also reliably report the magnitude of their errors and their sign (8) (i.e., they can evaluate by how much [magnitude] their generated duration was too short or too long [sign], with respect to the target duration). Humans can also report how confident they are in their timing behavior (9). We tested here these temporal cognitive abilities in rats, which were required to produce a time interval and correctly report, in order to obtain a reward, the magnitude of their timing errors on some test trials. We show that rats correctly reported the magnitude of their timing error, suggesting that their timing behavior uses explicit representations of time intervals together with their uncertainty around the internal target duration.     

Temporal perturbations cause movement-context independent but modality specific sensorimotor adaptation

Complex, goal-directed and time-critical movements require the processing of temporal features in sensory information as well as the fine-tuned temporal interplay of several effectors. Temporal estimates used to produce such behavior may thus be obtained through perceptual or motor processes. To disentangle the two options, we tested whether adaptation to a temporal perturbation in an interval reproduction task transfers to interval reproduction tasks with varying sensory information (visual appearance of targets, modality, and virtual reality [VR] environment or real-world) or varying movement types (continuous arm movements or brief clicking movements). Halfway through the experiments we introduced a temporal perturbation, such that continuous pointing movements were artificially slowed down in VR, causing participants to adapt their behavior to sustain performance. In four experiments, we found that sensorimotor adaptation to temporal perturbations is independent of environment context and movement type, but modality specific. Our findings suggest that motor errors induced by temporal sensorimotor adaptation affect the modality specific perceptual processing of temporal estimates.     

终末期肾脏病患者的透析时机及其评价方法

透析时机是影响终末期肾脏病患者预后的独立危险因素,但目前关于终末期肾脏病患者的透析时机尚无定论.国内外研究以eGFR或Ccr界定早晚透析,但其与终末期肾脏病患者临床结局的关系结论不一.目前指南推荐的透析时机为eGFR或Ccr结合临床症状或体征.因诸多因素影响透析时机,所以需要进一步探索应用多因素评价透析时机的定量方法,...     

���ǹ��۲�ͬ����ʱ�������󲢷�֢��ϵ�о�

目的探讨下颌骨骨折不同手术时机与术后并发症的关系。方法回顾2007--2012年济南市第五人民医院口腔科收治的下颌骨骨折患者61例,按伤后手术时机的不同将患者依次分类,观察各患者术后感染、骨折畸形愈合和骨折不愈合的发生情况,数据采用Logistical回归分析和方差分析。结果61例患者中有5例出现术后并发症,无骨折不愈合病例。Logistical回归分析得知延迟手术对全部并发症的相对危险度为0．61（P=0．12）,对感染的相对危险度为0．82（P=0．39）,对骨折畸形愈合的相对危险度为0．61（P=0．12）;各组并发症发生与否的手术时机差异无统计学意义（P〉0．05）。结论下颌骨骨折的手术时机与术后并发症的发生无明显关联。     

Biophysical modeling of neural plasticity induced by transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is a widely used noninvasive brain stimulation method capable of inducing plastic reorganisation of cortical circuits in humans. Changes in neural activity following TMS are often attributed to synaptic plasticity via process of long-term potentiation and depression (LTP/LTD). However, the precise way in which synaptic processes such as LTP/LTD modulate the activity of large populations of neurons, as stimulated en masse by TMS, are unclear. The recent development of biophysical models, which incorporate the physiological properties of TMS-induced plasticity mathematically, provide an excellent framework for reconciling synaptic and macroscopic plasticity. This article overviews the TMS paradigms used to induce plasticity, and their limitations. It then describes the development of biophysically-based numerical models of the mechanisms underlying LTP/LTD on population-level neuronal activity, and the application of these models to TMS plasticity paradigms, including theta burst and paired associative stimulation. Finally, it outlines how modeling can complement experimental work to improve mechanistic understandings and optimize outcomes of TMS-induced plasticity.     

Keeping with the beat: movement trajectories contribute to movement timing

Previous studies of paced repetitive movements with respect to an external beat have either emphasised (a) the form of movement trajectories or (b) timing errors made with respect to the external beat. The question of what kinds of movement trajectories assist timing accuracy has not previously been addressed. In an experiment involving synchronisation or syncopation with an external auditory metronome we show that the nervous system produces trajectories that are asymmetric with respect to time and velocity in the out and return phases of the repeating movement cycle. This asymmetry is task specific and is independent of motor implementation details (finger flexion vs. extension). Additionally, we found that timed trajectories are less smooth (higher mean squared jerk) than unpaced ones. The degree of asymmetry in the flexion and extension movement times is positively correlated with timing accuracy. Negative correlations were observed between synchronisation timing error and the movement time of the ensuing return phase, suggesting that late arrival of the finger is compensated by a shorter return phase and conversely for early arrival. We suggest that movement asymmetry in repetitive timing tasks helps satisfy requirements of precision and accuracy relative to a target event.     

Management and outcome challenges in newborns with gastroschisis: A 6-year retrospective French study

Objective: To identify the gestational age (GA) at which risk of mortality and severe outcome was minimized comparing preterm delivery and expectant management.

Methods: Retrospective study performed between 2009 and 2014 of newborns with gastroschisis in three large French level III neonatal intensive care units. Each department followed two distinct strategies: elective delivery at 35 weeks’ GA and a delayed approach.

Results: We included 69 gastroschisis cases. The lengths of stay lasting more than 60 days were significantly greater in the planned delivery group than in the expectant approach group (18/30 (60%) vs. 8/39 (20.5%), p?=?0.001). Gastroschisis cases receiving antenatal corticoids during the last two weeks of gestation required significantly less surgeries during their initial stay (p?=?0.003) as well as shorter parenteral feedings (p?=?0.002). A multivariate logistic regression showed that a GA of less than 36 weeks’ GA was is a pejorative factor for a stay above 60 days, regardless of whether it was a simple or complex gastroschisis, (OR=?3.8; p?=?0.021). A complex gastroschisis was a risk factor for significantly longer parenteral feedings, regardless of the center where patient is treated (Beta = ?0.3, p?=?0.035).

Conclusions: Future research should focus on decisions about delivery timing by incorporating risk of neonatal morbidity.