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Animals often engage in representationally guided goal-directed behaviors. These behaviors are thus also subjected to representational uncertainty (e.g. timing uncertainty during waiting), which has been previously shown to adaptively guide behaviors normatively. These observations raise the question of whether non-human animals can track the direction and magnitude of their timing errors (i.e. temporal error monitoring). Only a few studies have investigated this question without addressing the key components of temporal error monitoring (e.g. due to differential reinforcement of metacognitive judgments and primary task representation). We conducted the critical test of temporal error monitoring in mice by developing a novel behavioral task that involved temporal production that exponentially favored temporal accuracy and minimized the contribution of sensorimotor noise. The response rate for an upcoming probabilistic reward following the timing performance was used as a proxy for confidence. We found that mice exhibited high reward expectancy after accurate and low reward expectancy after inaccurate timing performance. The reward expectancy decreased as a function of deviations from the target interval for the short and long reproductions; pointing to the symmetrical sensitivity of metacognition to shorter/longer than target responses. These findings suggest a complete temporal error monitoring ability for mice with human-like metacognitive features. [ABSTRACT FROM AUTHOR]

In interval reproduction tasks, animals must remember the event starting the interval and anticipate the time of the planned response to terminate the interval. The interval reproduction task thus allows for studying both memory for the past and anticipation of the future. We analyzed previously published recordings from the rodent medial prefrontal cortex [J. Henke et al., eLife 10, e71612 (2021)] during an interval reproduction task and identified two cell groups by modeling their temporal receptive fields using hierarchical Bayesian models. The firing in the "past cells" group peaked at the start of the interval and relaxed exponentially back to baseline. The firing in the "future cells" group increased exponentially and peaked right before the planned action at the end of the interval. Contrary to the previous assumption that timing information in the brain has one or two time scales for a given interval, we found strong evidence for a continuous distribution of the exponential rate constants for both past and future cell populations. The real Laplace transformation of time predicts exponential firing with a continuous distribution of rate constants across the population. Therefore, the firing pattern of the past cells can be identified with the Laplace transform of time since the past event while the firing pattern of the future cells can be identified with the Laplace transform of time until the planned future event. [ABSTRACT FROM AUTHOR]

Consciousness requires subjective experience in the "now." Establishing "now," however, necessitates temporal processing. In the current article, we review one method of altering consciousness, anaesthetic drug administration, and its effects on perceived duration. We searched PubMed, PsycInfo, and ScienceDirect databases, and article reference sections, for combinations of anaesthetic drugs and time perception tasks, finding a total of 36 articles which met our inclusion criteria. We categorised these articles with regard to whether they altered the felt passage of time, short or long interval timing, or were motor timing tasks. We found that various drugs alter the perceived passage of time; ketamine makes time subjectively slow down while GABAergic drugs make time subjectively speed up. At a short interval there is little established evidence of a shift in time perception, though temporal estimates appear more variable. Similarly, when asked to use time to optimise responses (i.e., in motor timing tasks), various anaesthetic agents make timing more variable. Longer durations are estimated as lasting longer than their objective duration, though there is some variation across articles in this regard. We conclude by proposing further experiments to examine time perception under altered states of consciousness and ask whether it is possible to perceive the passage of time of events which do not necessarily reach the level of conscious perception. The variety of methods used raises the need for more systematic investigations of time perception under anaesthesia. We encourage future investigations into the overlap of consciousness and time perception to advance both fields. [ABSTRACT FROM AUTHOR]

Prior studies have documented the role of the striatum and its dopaminergic input in time processing, but the contribution of local striatal cholinergic innervation has not been specifically investigated. To address this issue, we recorded the activity of tonically active neurons (TANs), thought to be cholinergic interneurons in the striatum, in two male macaques performing self‐initiated movements after specified intervals in the seconds range have elapsed. The behavioral data showed that movement timing was adjusted according to the temporal requirements. About one‐third of all recorded TANs displayed brief depressions in firing in response to the cue that indicates the interval duration, and the strength of these modulations was, in some instances, related to the timing of movement. The rewarding outcome of actions also impacted TAN activity, as reflected by stronger responses to the cue paralleled by weaker responses to reward when monkeys performed correctly timed movements over consecutive trials. It therefore appears that TAN responses may act as a start signal for keeping track of time and reward prediction could be incorporated in this signaling function. We conclude that the role of the striatal cholinergic TAN system in time processing is embedded in predicting rewarding outcomes during timing behavior. [ABSTRACT FROM AUTHOR]

The roles of brain asymmetry in Drosophila are diverse, encompassing the regulation of behavior, the creation of memory, neurodevelopment, and evolution. A comprehensive examination of the Drosophila brain has the potential to enhance our understanding of the functional significance of brain asymmetry in cognitive and behavioral processes, as well as its role in evolutionary perspectives. This study explores the influence of brain asymmetry on interval timing behaviors in Drosophila, with a specific focus on the asymmetric body (AB) structure. Despite being bilaterally symmetric, the AB exhibits functional asymmetry and is located within the central complex of the fly brain. Interval timing behaviors, such as rival-induced prolonged mating duration: longer mating duration behavior (LMD) and sexual experience-mediated shorter mating duration behavior (SMD), are essential for Drosophila. We utilize genetic manipulations to selectively activate or inhibit AB neurons and evaluates their impact on LMD and SMD behaviors. The results indicate that specific populations of AB neurons play unique roles in orchestrating these interval timing behaviors. Notably, inhibiting GAL4R38D01-labeled AB neurons disrupts both LMD and SMD, while GAL4R42C09 neuron inhibition affects only LMD. Moreover, hyperexcitation of GAL4R72A10-labeled AB neurons perturbs SMD. Our study identifies NetrinB (NetB) and Abdominal-B (Abd-B) are important genes for AB neurons in LMD and highlights the role of 5-HT1B neurons in generating LMD through peptidergic Pigment-dispersing factor (PDF) signaling. In summary, this study underscores the importance of AB neuron asymmetry in mediating interval timing behaviors and provides insights into the underlying mechanisms of memory formation and function in Drosophila. [ABSTRACT FROM AUTHOR]

Simple Summary: Intraperitoneal (IP) administration of Paclitaxel (PTX) is a logical approach for treating peritoneal metastases (PMs), as it allows direct drug infiltration into PMs, providing prolonged exposure at high concentrations with minimal systemic side effects. However, the optimal timing for combining intravenous (IV) and IP administration remains uncertain. This study demonstrated that IP administration of PTX resulted in higher concentrations of PTX in peritoneal tumors, as well as increased levels of intravenously administered Carboplatin (CBDCA) when given four days after PTX administration. These findings suggest that IP PTX may enhance the efficacy of subsequent systemic chemotherapy. Therefore, staggered and repeated systemic chemotherapy following IP PTX appears to be a highly effective strategy for managing PMs. Despite advances in systemic chemotherapy, patients with gastric cancer (GC) and peritoneal metastases (PMs) continue to have poor prognoses. Intraperitoneal (IP) administration of Paclitaxel (PTX) combined with systemic chemotherapy shows promise in treating PMs from GC. However, methods of drug administration need to be optimized to maximize efficacy. In this study, we utilized a mouse model with PMs derived from a human GC cell line, administering PTX either IP or intravenously (IV), and Carboplatin (CBDCA) IV 0, 1, and 4 days after PTX administration. The PMs were resected 30 min later, and concentrations of PTX and CBDCA in resected tumors were measured using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results indicated that PTX concentrations were higher with IP administration than with IV administration, with significant differences observed on days 0 and 1. CBDCA concentrations 4 days post-IP PTX administration were higher than with simultaneous IV PTX administration. These findings suggest that IP PTX administration enhances CBDCA concentration in peritoneal tumors. Therefore, sequential IV administration of anti-cancer drugs appears more effective than simultaneous administration with IP PTX, a strategy that may improve prognoses for patients with PMs. [ABSTRACT FROM AUTHOR]

Abstract Animals often engage in representationally guided goal-directed behaviors. These behaviors are thus also subjected to representational uncertainty (e.g. timing uncertainty during waiting), which has been previously shown to adaptively guide behaviors normatively. These observations raise the question of whether non-human animals can track the direction and magnitude of their timing errors (i.e. temporal error monitoring). Only a few studies have investigated this question without addressing the key components of temporal error monitoring (e.g. due to differential reinforcement of metacognitive judgments and primary task representation). We conducted the critical test of temporal error monitoring in mice by developing a novel behavioral task that involved temporal production that exponentially favored temporal accuracy and minimized the contribution of sensorimotor noise. The response rate for an upcoming probabilistic reward following the timing performance was used as a proxy for confidence. We found that mice exhibited high reward expectancy after accurate and low reward expectancy after inaccurate timing performance. The reward expectancy decreased as a function of deviations from the target interval for the short and long reproductions; pointing to the symmetrical sensitivity of metacognition to shorter/longer than target responses. These findings suggest a complete temporal error monitoring ability for mice with human-like metacognitive features.

Adverse early life experiences can have remarkably enduring negative consequences on mental health, with numerous, varied psychiatric conditions sharing this developmental origin. Yet, the mechanisms linking adverse experiences to these conditions remain poorly understood. Here, we draw on a principled model of interval timing to propose that statistically optimal adaptation of temporal representations to an unpredictable early life environment can produce key characteristics of anhedonia, a transdiagnostic symptom associated with affective disorders like depression and anxiety. The core observation is that early temporal unpredictability produces broader, more imprecise temporal expectations. As a result, reward anticipation is diminished, and associative learning is slowed. When agents with such representations are later introduced to more stable environments, they demonstrate a negativity bias, responding more to the omission of reward than its receipt. Increased encoding of negative events has been proposed to contribute to disorders with anhedonia as a symptom. We then examined how unpredictability interacts with another form of adversity, low reward availability. We found that unpredictability's effect was most strongly felt in richer environments, potentially leading to categorically different phenotypic expressions. In sum, our formalization suggests a single mechanism can help to link early life adversity to a range of behaviors associated with anhedonia, and offers novel insights into the interactive impacts of multiple adversities.

The present study aimed to examine the effect of cholinergic interneuron lesions in the dorsal striatum on duration‐memory formation. Cholinergic interneurons in the dorsal striatum may be involved in the formation of duration memory since they are among the main inputs to the dorsal striatal muscarinic acetylcholine‐1 receptors, which play a role in the consolidation of duration memory. Rats were sufficiently trained using a peak‐interval 20 s procedure and then infused with anti‐choline acetyltransferase–saporin into the dorsal striatum to cause selective ablation of cholinergic interneurons. To make the rats acquire new duration‐memories, we trained them with a peak interval 40 s after lesion. Before lesion, the peak times (an index of duration memory) for sham‐lesioned and lesioned groups were similar at approximately 20 s. In the peak interval 40 s session, the peak times for the sham‐lesioned and lesioned groups were approximately 30 and 20 s, respectively. After additional peak interval 40 s sessions, the peak times of both groups were shifted to approximately 40 s. Those results suggest that the cholinergic interneuron lesion delayed new duration‐memory acquisition. Subsequent experiments showed that cholinergic interneuron lesions did not retard the shift of peak time to the original target time (20 s). Following experiment without changing the target time after lesion showed that cholinergic interneuron lesions did not change their peak times. Our findings suggest that cholinergic interneurons in the dorsal striatum are involved in new duration‐memory acquisition but not in the utilization of already acquired duration memory and interval timing. [ABSTRACT FROM AUTHOR]

Abstract Prior studies have documented the role of the striatum and its dopaminergic input in time processing, but the contribution of local striatal cholinergic innervation has not been specifically investigated. To address this issue, we recorded the activity of tonically active neurons (TANs), thought to be cholinergic interneurons in the striatum, in two male macaques performing self‐initiated movements after specified intervals in the seconds range have elapsed. The behavioral data showed that movement timing was adjusted according to the temporal requirements. About one‐third of all recorded TANs displayed brief depressions in firing in response to the cue that indicates the interval duration, and the strength of these modulations was, in some instances, related to the timing of movement. The rewarding outcome of actions also impacted TAN activity, as reflected by stronger responses to the cue paralleled by weaker responses to reward when monkeys performed correctly timed movements over consecutive trials. It therefore appears that TAN responses may act as a start signal for keeping track of time and reward prediction could be incorporated in this signaling function. We conclude that the role of the striatal cholinergic TAN system in time processing is embedded in predicting rewarding outcomes during timing behavior.

Associative learning and memory, i.e., learning and remembering the associations between environmental stimuli, self-generated actions, and outcomes such as rewards or punishments, are critical for the well-being of animals. Hence, the neural mechanisms underlying these processes are extensively studied using behavioral tasks in laboratory animals. Traditionally, these tasks have been controlled using commercial hardware and software, which limits scalability and accessibility due to their cost. More recently, due to the revolution in microcontrollers or microcomputers, several general-purpose and open-source solutions have been advanced for controlling neuroscientific behavioral tasks. While these solutions have great strength due to their flexibility and general-purpose nature, for the same reasons, they suffer from some disadvantages including the need for considerable programming expertise, limited online visualization, or slower than optimal response latencies for any specific task. Here, to mitigate these concerns, we present an open-source behavior controller for associative learning and memory (B-CALM). B-CALM provides an integrated suite that can control a host of associative learning and memory behaviors. As proof of principle for its applicability, we show data from head-fixed mice learning Pavlovian conditioning, operant conditioning, discrimination learning, as well as a timing task and a choice task. These can be run directly from a user-friendly graphical user interface (GUI) written in MATLAB that controls many independently running Arduino Mega microcontrollers in parallel (one per behavior box). In sum, B-CALM will enable researchers to execute a wide variety of associative learning and memory tasks in a scalable, accurate, and user-friendly manner. [ABSTRACT FROM AUTHOR]

ABSTRACTPerception and production of second-level temporal intervals are critical in several behavioral and cognitive processes, including adaptive anticipation, motor control, and social communication. These processes are impaired in several neurological and psychological disorders, such as Parkinson’s disease and attention-deficit hyperactivity disorder. Although evidence indicates that second-level interval timing exhibit circadian patterns, it remains unclear whether the core clock machinery controls the circadian pattern of interval timing. To investigate the role of core clock molecules in interval timing capacity, we devised a behavioral assay called the interval timing task to examine prospective motor interval timing ability. In this task, the mouse produces two separate nose pokes in a pretrained second-level interval to obtain a sucrose solution as a reward. We discovered that interval perception in wild-type mice displayed a circadian pattern, with the best performance observed during the late active phase. To investigate whether the core molecular clock is involved in the circadian control of interval timing, we employed Bmal1 knockout mice (BKO) in the interval timing task. The interval production of BKO did not display any difference between early and late active phase, without reaching the optimal interval production level observed in wild-type. In summary, we report that the core clock gene Bmal1 is required for the optimal performance of prospective motor timing typically observed during the late part of the active period.

Adverse early life experiences can have remarkably enduring negative consequences on mental health, with numerous, varied psychiatric conditions sharing this developmental origin. Yet, the mechanisms linking adverse experiences to these conditions remain poorly understood. Here, we draw on a principled model of interval timing to propose that statistically optimal adaptation of temporal representations to an unpredictable early life environment can produce key characteristics of anhedonia, a transdiagnostic symptom associated with affective disorders like depression and anxiety. The core observation is that early temporal unpredictability produces broader, more imprecise temporal expectations. As a result, reward anticipation is diminished, and associative learning is slowed. When agents with such representations are later introduced to more stable environments, they demonstrate a negativity bias, responding more to the omission of reward than its receipt. Increased encoding of negative events has been proposed to contribute to disorders with anhedonia as a symptom. We then examined how unpredictability interacts with another form of adversity, low reward availability. We found that unpredictability's effect was most strongly felt in richer environments, potentially leading to categorically different phenotypic expressions. In sum, our formalization suggests a single mechanism can help to link early life adversity to a range of behaviors associated with anhedonia, and offers novel insights into the interactive impacts of multiple adversities. Harhen and Bornstein extend a reinforcement learning model of interval timing to demonstrate that statistically rational adaptation to an unpredictable early life environment can give rise to a variety of presumed maladaptive behaviors that define anhedonia. They then use this model to test whether distinct forms of early life adversity exert unique impacts on learning. They find that these forms of adversity interact non‐additively, running counter to a core assumption of the widely used 'cumulative risk' approach of measuring adversity. [ABSTRACT FROM AUTHOR]

Interval timing refers to the ability to perceive and remember intervals in the seconds to minutes range. Our contemporary understanding of interval timing is derived from relatively small-scale, isolated studies that investigate a limited range of intervals with a small sample size, usually based on a single task. Consequently, the conclusions drawn from individual studies are not readily generalizable to other tasks, conditions, and task parameters. The current paper presents a live database that presents raw data from interval timing studies (currently composed of 68 datasets from eight different tasks incorporating various interval and temporal order judgments) with an online graphical user interface to easily select, compile, and download the data organized in a standard format. The Timing Database aims to promote and cultivate key and novel analyses of our timing ability by making published and future datasets accessible as open-source resources for the entire research community. In the current paper, we showcase the use of the database by testing various core ideas based on data compiled across studies (i.e., temporal accuracy, scalar property, location of the point of subjective equality, malleability of timing precision). The Timing Database will serve as the repository for interval timing studies through the submission of new datasets. [ABSTRACT FROM AUTHOR]

The relationship between working memory and time perception has been typically investigated using dual-task paradigms (e.g., testing timing performance during a concurrent task). To our knowledge, none of these studies used time intervals as the target stimulus to be remembered. The current study investigated the working memory for time intervals by asking participants to reproduce durations they experienced at different orders in a series of experienced intervals (n-back task). One of the experiments was conducted online and the other one in the lab setting. Results showed a central tendency bias and additive elongation of time reproductions with increasing working memory load. Our results also showed that participants assigned different weights to experienced intervals based on their order of presentation (higher weight to the target interval). We conclude that the recall of intervals from working memory under high cognitive load leads to a central tendency effect, which is known to be induced by the temporal context and present particularly in aging and in those with Parkinson's disease. [ABSTRACT FROM AUTHOR]

Impulsive choice is preference for a smaller-sooner (SS) outcome over a larger-later (LL) outcome when LL choices result in greater reinforcement maximization. Delay discounting is a model of impulsive choice that describes the decaying value of a reinforcer over time, with impulsive choice evident when the empirical choice-delay function is steep. Steep discounting is correlated with multiple diseases and disorders. Thus, understanding the processes underlying impulsive choice is a popular topic for investigation. Experimental research has explored the conditions that moderate impulsive choice, and quantitative models of impulsive choice have been developed that elegantly represent the underlying processes. This review spotlights experimental research in impulsive choice covering human and nonhuman animals across the domains of learning, motivation, and cognition. Contemporary models of delay discounting designed to explain the underlying mechanisms of impulsive choice are discussed. These models focus on potential candidate mechanisms, which include perception, delay and/or reinforcer sensitivity, reinforcement maximization, motivation, and cognitive systems. Although the models collectively explain multiple mechanistic phenomena, there are several cognitive processes, such as attention and working memory, that are overlooked. Future research and model development should focus on bridging the gap between quantitative models and empirical phenomena. [ABSTRACT FROM AUTHOR]

Introduction: An accurate sense of time is crucial in flexible sensorimotor control and other cognitive functions. However, it remains unknown how multiple timing computations in different contexts interact to shape our behavior. Methods: We asked 41 healthy human subjects to perform timing tasks that differed in the sensorimotor domain (sensory timing vs. motor timing) and effector (hand vs. saccadic eye movement). To understand how these different behavioral contexts contribute to timing behavior, we applied a three-stage Bayesian model to behavioral data. Results: Our results demonstrate that the Bayesian model for each effector could not describe bias in the other effector. Similarly, in each task the model-predicted data could not describe bias in the other task. These findings suggest that the measurement stage of interval timing is context-specific in the sensorimotor and effector domains. We also showed that temporal precision is context-invariant in the effector domain, unlike temporal accuracy. Discussion: This combination of context-specific and context-invariant computations across sensorimotor and effector domains suggests overlapping and distributed computations as the underlying mechanism of timing in different contexts. [ABSTRACT FROM AUTHOR]

It is commonly known—and previous studies have indicated—that time appears to last longer during unpleasant situations. This study examined whether a reciprocal statement can be made—that is, whether changes in the perception of time can influence our judgment (or rating) of a negative event. We used a temporal illusion method (Pomares et al. Pain 152, 230–234, 2011) to induce distortions in the perception of time. Two stimuli were presented for a constant time: a full clock, which stayed on the screen until its clock hand completed a full rotation (360°); and a short clock, in which the clock hand moved just three-quarters of the way (270°), thus suggesting a reduced interval duration. However, both stimuli were shown for the same amount of time. We specifically investigated (a) whether we could induce a temporal illusion with this simple visual manipulation, and (b) whether this illusion could change participants' ratings of a painful stimulus. In Experiment I (n = 22), to answer (a) above, participants were asked to reproduce the duration in which the different clocks were presented. In Experiment II (n = 30), a painful thermal stimulation was applied on participants' hands while the clocks were shown. Participants were asked to rate the perceived intensity of their pain, and to reproduce its duration. Results showed that, for both experiments, participants reproduced a longer interval after watching the full clock compared with the short clock, confirming that the clock manipulation was able to induce a temporal illusion. Furthermore, the second experiment showed that participants rated the thermal stimuli as less painful when delivered with the short clock than with the full clock. These findings suggest that temporal distortions can modulate the experience of pain. [ABSTRACT FROM AUTHOR]

Prior research suggests that interval timing performance is sensitive to reinforcer devaluation effects and to the rate of competing sources of reinforcement. The present study sought to replicate and account for these findings in rats. A self-paced concurrent fixed-interval (FI) random-ratio (RR) schedule of reinforcement was implemented in which the FI requirement varied across training conditions (12, 24, 48 s). The RR requirement—which imposed an opportunity cost to responding on the FI component—was adjusted so that it took about twice the FI requirement, on average, to complete it. Probe reinforcer devaluation (prefeeding) sessions were conducted at the end of each condition. To assess the effect of contextual reinforcement on timing performance, the RR requirement was removed before the end of the experiment. Consistent with prior findings, performance on the FI component tracked schedule requirement and displayed scalar invariance; the removal of the RR component yielded more premature FI responses. For some rats, prefeeding reduced the number of trials initiated without affecting timing performance; for other rats, prefeeding delayed responding on the FI component but had a weaker effect on trial initiation. These results support the notion that timing and motivational processes are separable, suggesting novel explanations for ostensible motivational effects on timing performance. [ABSTRACT FROM AUTHOR]

Important characteristics of the environment can be represented in the temporal pattern of sensory stimulation. In two experiments, we compared accuracy of temporal processing by different modalities. Experiment 1 examined binary categorization of rate for visual (V) or vibrotactile (T) stimulus pulses presented at either 4 or 6 Hz. Inter-pulse intervals were either constant or variable, perturbed by random Gaussian variates. Subjects categorized the rate of T pulse sequences more accurately than V sequences. In V conditions only, subjects disproportionately tended to mis-categorize 4-Hz pulse rates, for all but the most variable sequences. In Experiment 2, we compared gap detection thresholds across modalities, using the same V and T pulses from Experiment 1, as well as with bimodal (VT) pulses. Visual gap detection thresholds were larger (3 × ) than tactile thresholds. Additionally, performance with VT stimuli seemed to be nearly completely dominated by their T components. Together, these results suggest (i) that vibrotactile temporal acuity surpasses visual temporal acuity, and (ii) that vibrotactile stimulation has considerable, untapped potential to convey temporal information like that needed for eyes-free alerting signals. [ABSTRACT FROM AUTHOR]

IntroductionAn accurate sense of time is crucial in flexible sensorimotor control and other cognitive functions. However, it remains unknown how multiple timing computations in different contexts interact to shape our behavior.MethodsWe asked 41 healthy human subjects to perform timing tasks that differed in the sensorimotor domain (sensory timing vs. motor timing) and effector (hand vs. saccadic eye movement). To understand how these different behavioral contexts contribute to timing behavior, we applied a three-stage Bayesian model to behavioral data.ResultsOur results demonstrate that the Bayesian model for each effector could not describe bias in the other effector. Similarly, in each task the model-predicted data could not describe bias in the other task. These findings suggest that the measurement stage of interval timing is context-specific in the sensorimotor and effector domains. We also showed that temporal precision is context-invariant in the effector domain, unlike temporal accuracy.DiscussionThis combination of context-specific and context-invariant computations across sensorimotor and effector domains suggests overlapping and distributed computations as the underlying mechanism of timing in different contexts.

Bayesian models of perception posit that percepts result from the optimal integration of new sensory information and prior expectations. In turn, prominent models of perceptual disturbances in psychosis frame hallucination-like phenomena as percepts excessively biased toward perceptual prior expectations. Despite mounting support for this notion, whether this hallucination-related prior bias results secondarily from imprecise sensory representations at early processing stages or directly from alterations in perceptual priors—both suggested candidates potentially consistent with Bayesian models—remains to be tested. Using modified interval timing paradigms designed to arbitrate between these alternative hypotheses, we show in human participants (16 females and 24 males) from a nonclinical population that hallucination proneness correlates with a circumscribed form of prior bias that reflects selective differences in weighting of contextual prior variance, a prior bias that is unrelated to the effect of sensory noise and to a separate index of sensory resolution. Our results thus suggest distinct mechanisms underlying prior biases in perceptual inference and favor the notion that hallucination proneness could reflect direct alterations in the representation or use of perceptual priors independent of sensory noise. [ABSTRACT FROM AUTHOR]

Animals learn multiple spatiotemporal contingencies and organize their anticipatory responses accordingly. The representational/computational capacity that underlies such spatiotemporally guided behaviors is not fully understood. To this end, we investigated whether mice make temporal inferences of novel locations based on previously learned spatiotemporal contingencies. We trained 18 C57BL/6J mice to anticipate reward after three different intervals at three different locations and tested their temporal expectations of a reward at five locations simultaneously, including two locations that were not previously associated with reward delivery but adjacent to the previously trained locations. If mice made spatiotemporal inferences, they were expected to interpolate between duration pairs associated with previously reinforced hoppers surrounding the novel hopper. We found that the maximal response rate at the novel locations indeed fell between the two intervals reinforced at the surrounding hoppers. We argue that this pattern of responding might be underlain by spatially constrained Bayesian computations. [ABSTRACT FROM AUTHOR]

Perception and production of second-level temporal intervals are critical in several behavioral and cognitive processes, including adaptive anticipation, motor control, and social communication. These processes are impaired in several neurological and psychological disorders, such as Parkinson's disease and attention-deficit hyperactivity disorder. Although evidence indicates that second-level interval timing exhibit circadian patterns, it remains unclear whether the core clock machinery controls the circadian pattern of interval timing. To investigate the role of core clock molecules in interval timing capacity, we devised a behavioral assay called the interval timing task to examine prospective motor interval timing ability. In this task, the mouse produces two separate nose pokes in a pretrained second-level interval to obtain a sucrose solution as a reward. We discovered that interval perception in wild-type mice displayed a circadian pattern, with the best performance observed during the late active phase. To investigate whether the core molecular clock is involved in the circadian control of interval timing, we employed Bmal1 knockout mice (BKO) in the interval timing task. The interval production of BKO did not display any difference between early and late active phase, without reaching the optimal interval production level observed in wild-type. In summary, we report that the core clock gene Bmal1 is required for the optimal performance of prospective motor timing typically observed during the late part of the active period. [ABSTRACT FROM AUTHOR]

A growing collection of observations has demonstrated the presence of multiple neural oscillations participating in human temporal cognition and psychiatric pathologies such as depression and anxiety. However, there remains a gap in the literature regarding the specific roles of these neural oscillations during interval timing, and how these oscillatory activities might vary with the different levels of mental health. The current study examined the participation of the frontal midline theta and occipital alpha oscillations, both of which are prevalent cortical oscillatory markers frequently reported in working memory and time perception paradigms. Participants performed a time reproduction task in the sub- (400, 600, 800 ms) and supra-second timescales (1600, 1800, 2000 ms) while undergoing scalp EEG recordings. Anxiety and depression levels were measured via self-report mental health inventories. Time–frequency analysis of scalp EEG revealed that both frontal midline and occipital alpha oscillations were engaged during the encoding of the durations. Furthermore, we observed that the correlational relationship between frontal midline theta power and the reproduction performance in the sub-second range was modulated by state anxiety. In contrast, the correlational relationship between occipital alpha and the reproduction performance of supra-second intervals was modulated by depression and trait anxiety. The results offer insights on how alpha and theta oscillations differentially play a role in interval timing and how mental health further differentially relates these neural oscillations to sub- and supra-second timescales. [ABSTRACT FROM AUTHOR]

Biological timing (including circadian and interval timing) has mainly focused on rigorously controlled laboratory experiments. There are relatively few studies looking into interval timing behaviors in the wild, which could be understandable due to the complexity of the experimental design but are definitely needed in order to comprehend the adaptive value of such behavior. In this opinion paper we review some of the literature regarding timing observations under field conditions, including reports from birds and mammals, and propose a call-to-action to think about the need of a more naturalistic interpretation of time production and perception, as well as the advantage of designing more 'natural' settings in the laboratory. [ABSTRACT FROM AUTHOR]

Many conventional interval timing tasks do not contain asymmetric cost (loss) functions and thereby favor high temporal accuracy. On the other hand, asymmetric cost functions that differentially penalize/reinforce the early or late responses result in adaptive biases (shift) in timed responses due to timing uncertainty. Consequently, optimal performance in these tasks entails the normative parametrization of adaptive timing biases by the level of timing uncertainty. Differential reinforcement of response duration (DRRD) is one of these tasks that require mice to actively respond (e.g., continuously depressing a lever) for a minimum amount of time to be reinforced. The active production of a time interval by mice in DRRD differentiates this task from the differential reinforcement of low rates of responding (DRL) task as a passive waiting task that was used in earlier studies to investigate the optimality of adaptive biases in timing behavior. We tested 21 Th-Cre male mice (9 weeks old) in a DRRD task with a minimum requirement of 2 s. Mean response durations were positively biased (longer than the minimum requirement), and the extent of bias was predicted by the level of endogenous timing uncertainty. Mice nearly maximized the reward rate in this task. These results contribute to the accumulating evidence supporting optimal temporal risk assessment in non-human animals. [ABSTRACT FROM AUTHOR]

Many species, including humans, show both accurate timing − appropriate time estimation in the seconds to minutes range − and scalar timing − time estimation error varies linearly with estimated duration. Behavioral paradigms aimed at investigating interval timing are expected to evaluate these dissociable characteristics of timing. However, when evaluating interval timing in models of neuropsychiatric disease, researchers are confronted with a lack of adequate studies about the parent (background) strains, since accuracy and scalar timing have only been demonstrated for the C57BL/6 strain of mice (Buhusi, Aziz, Winslow, Carter, Swearingen, & Buhusi (2009) Behav. Neurosci., 123 , 1102–1113). We used a peak-interval (PI) procedure with three intervals − a protocol in which other species, including humans, demonstrate accurate, scalar timing − to evaluate timing accuracy and scalar timing in three strains of mice frequently used in genetic and behavioral studies: 129, Swiss-Webster (SW), and C57BL/6. C57BL/6 mice showed accurate, scalar timing, while 129 and SW mice showed departures from accuracy and/or scalar timing. Results suggest that the genetic background/strain of the mouse is a critical variable for studies investigating interval timing in genetically engineered mice. Our study validates the PI procedure with multiple intervals as a proper technique, and the C57BL/6 strain as the most suitable genetic background to date for behavioral investigations of interval timing in genetically engineered mice modeling human disorders. In contrast, studies using mice in 129, SW, or mixed-background strains should be interpreted with caution, and thorough investigations of accuracy and scalar timing should be conducted before a less studied strain of mouse is considered for use in timing studies. [ABSTRACT FROM AUTHOR]

The Striatal Beat Frequency (SBF) model of interval timing uses many neural oscillators, presumably located in the frontal cortex (FC), to produce beats at a specific criterion time T c. The coincidence detection produces the beats in the basal ganglia spiny neurons by comparing the current state of the FC neural oscillators against the long-term memory values stored at reinforcement time T c. The neurobiologically realistic SBF model has been previously used for producing precise and scalar timing in the presence of noise. Here we simplified the SBF model to gain insight into the resource allocation problem in interval timing networks. Specifically, we used a noise-free SBF model to explore the lower limits of the number of neural oscillators required for producing accurate timing. Using abstract sine-wave neural oscillators in the SBF-sin model, we found that the lower limit of the number of oscillators needed is proportional to the criterion time T c and the frequency span (f max − f min) of the FC neural oscillators. Using biophysically realistic Morris–Lecar model neurons in the SBF-ML model, the lower bound increased by one to two orders of magnitude compared to the SBF-sin model. [ABSTRACT FROM AUTHOR]

One of the major challenges for computational models of timing and time perception is to identify a neurobiological plausible implementation that predicts various behavioral properties, including the scalar property and retrospective timing. The available timing models primarily focus on the scalar property and prospective timing, while virtually ignoring the computational accessibility. Here, we first selectively review timing models based on ramping activity, oscillatory pattern, and time cells, and discuss potential challenges for the existing models. We then propose a multifrequency oscillatory model that offers computational accessibility, which could account for a much broader range of timing features, including both retrospective and prospective timing. [ABSTRACT FROM AUTHOR]

The major tenets of beat-frequency/coincidence-detection models of reward-related timing are reviewed in light of recent behavioral and neurobiological findings. This includes the emphasis on a core timing network embedded in the motor system that is comprised of a corticothalamic-basal ganglia circuit. Therein, a central hub provides timing pulses (i.e., predictive signals) to the entire brain, including a set of distributed satellite regions in the cerebellum, cortex, amygdala, and hippocampus that are selectively engaged in timing in a manner that is more dependent upon the specific sensory, behavioral, and contextual requirements of the task. Oscillation/coincidence-detection models also emphasize the importance of a tuned 'perception' learning and memory system whereby target durations are detected by striatal networks of medium spiny neurons (MSNs) through the coincidental activation of different neural populations, typically utilizing patterns of oscillatory input from the cortex and thalamus or derivations thereof (e.g., population coding) as a time base. The measure of success of beat-frequency/coincidence-detection accounts, such as the Striatal Beat-Frequency model of reward-related timing (SBF), is their ability to accommodate new experimental findings while maintaining their original framework, thereby making testable experimental predictions concerning diagnosis and treatment of issues related to a variety of dopamine-dependent basal ganglia disorders, including Huntington's and Parkinson's disease. [ABSTRACT FROM AUTHOR]

Estimates of the duration of time intervals and other magnitudes exhibit characteristic biases that likely result from error minimization strategies. To investigate such phenomena, magnitude reproduction tasks are used with humans and other primates. However, such behavioral tasks do not exist for rodents, one of the most important animal orders for neuroscience. We, therefore, developed a time reproduction task that can be used with rodents. It involves an animal reproducing the duration of a timed visual stimulus by walking along a corridor. The task was implemented in virtual reality, which allowed us to ensure that the animals were actually estimating time. The hallway did not contain prominent spatial cues and movement could be de-correlated from optic flow, such that the animals could not learn a mapping between stimulus duration and covered distance. We tested the reproduction of durations of several seconds in three different stimulus ranges. The gerbils reproduced the durations with a precision similar to experiments on humans. Their time reproductions also exhibited the characteristic biases of magnitude estimation experiments. These results demonstrate that our behavioral paradigm provides a means to study time reproduction in rodents. [ABSTRACT FROM AUTHOR]

In interval reproduction tasks, animals must remember the event starting the interval and anticipate the time of the planned response to terminate the interval. The interval reproduction task thus allows for studying both memory for the past and anticipation of the future. We analyzed previously published recordings from the rodent medial prefrontal cortex [J. Henke et al. , eLife 10 , e71612 (2021)] during an interval reproduction task and identified two cell groups by modeling their temporal receptive fields using hierarchical Bayesian models. The firing in the "past cells" group peaked at the start of the interval and relaxed exponentially back to baseline. The firing in the "future cells" group increased exponentially and peaked right before the planned action at the end of the interval. Contrary to the previous assumption that timing information in the brain has one or two time scales for a given interval, we found strong evidence for a continuous distribution of the exponential rate constants for both past and future cell populations. The real Laplace transformation of time predicts exponential firing with a continuous distribution of rate constants across the population. Therefore, the firing pattern of the past cells can be identified with the Laplace transform of time since the past event while the firing pattern of the future cells can be identified with the Laplace transform of time until the planned future event., Competing Interests: Competing interests statement:M.W.H. is a cofounder of Cognitive Scientific AI, Inc., which could conceivably benefit indirectly from this publication.

Estimates of the duration of time intervals and other magnitudes exhibit characteristic biases that likely result from error minimization strategies. To investigate such phenomena, magnitude reproduction tasks are used with humans and other primates. However, such behavioral tasks do not exist for rodents, one of the most important animal orders for neuroscience. We, therefore, developed a time reproduction task that can be used with rodents. It involves an animal reproducing the duration of a timed visual stimulus by walking along a corridor. The task was implemented in virtual reality, which allowed us to ensure that the animals were actually estimating time. The hallway did not contain prominent spatial cues and movement could be de-correlated from optic flow, such that the animals could not learn a mapping between stimulus duration and covered distance. We tested the reproduction of durations of several seconds in three different stimulus ranges. The gerbils reproduced the durations with a precision similar to experiments on humans. Their time reproductions also exhibited the characteristic biases of magnitude estimation experiments. These results demonstrate that our behavioral paradigm provides a means to study time reproduction in rodents.

Gait abnormalities and cognitive dysfunction are common in patients with Parkinson's disease (PD) and get worse with disease progression. Recent evidence has suggested a strong relationship between gait abnormalities and cognitive dysfunction in PD patients and impaired cognitive control could be one of the causes for abnormal gait patterns. However, the pathophysiological mechanisms of cognitive dysfunction in PD patients with gait problems are unclear. Here, we collected scalp electroencephalography (EEG) signals during a 7-s interval timing task to investigate the cortical mechanisms of cognitive dysfunction in PD patients with (PDFOG +, n = 34) and without (PDFOG–, n = 37) freezing of gait, as well as control subjects (n = 37). Results showed that the PDFOG + group exhibited the lowest maximum response density at around 7 s compared to PDFOG– and control groups, and this response density peak correlated with gait abnormalities as measured by FOG scores. EEG data demonstrated that PDFOG + had decreased midfrontal delta-band power at the onset of the target cue, which was also correlated with maximum response density and FOG scores. In addition, our classifier performed better at discriminating PDFOG + from PDFOG– and controls with an area under the curve of 0.93 when midfrontal delta power was chosen as a feature. These findings suggest that abnormal midfrontal activity in PDFOG + is related to cognitive dysfunction and describe the mechanistic relationship between cognitive and gait functions in PDFOG +. Overall, these results could advance the development of novel biosignatures and brain stimulation approaches for PDFOG +. [ABSTRACT FROM AUTHOR]

It is well known that, all things being equal, the accuracy ofmammalian timing and memory decays gradually with the pas-sage of time. The gradual decay of temporal accuracy is alsoobserved in single-unit neural recordings. Here we review re-cent modeling work describing a specific mechanism for tim-ing and memory and relevant neural data. The model describesa neural mechanism that can give rise to a logarithmically com-pressed representation of the recent past. We examine the spe-cific predictions of the model, in particular that the elapse oftime is represented by sequentially activated cells which firefor a circumscribed period of time. Such cells, called timecells, have been observed in neural recordings from severalbrain regions in multiple species. As predicted by the model,the cells show accuracy that decreases with time.

A classic effect in the timing field is that “sounds are judgedlonger than lights” (Goldstone, Boardman & Lhamon, 1959).Recently, judgements for tactile durations have been found tofall between the two (Jones, Poliakoff & Wells, 2009). Thesemodality differences are commonly interpreted within scalartiming theory as the work of a central pacemaker which runsfaster for sounds, then vibrations, and slowest for lights(Wearden, Edwards, Fakhri & Percival, 1998). Weinvestigated whether verbal estimates and temporal differencethresholds are correlated within each modality, but found thisnot to be the case. This suggests that differences in pacemakerspeed may not be the main driver for modality differences inthresholds. In addition, we investigated sensory bias as analternative to the pacemaker explanation, but this was foundnot to correlate with modality differences in timing.

Recurrent neural networks of spiking neurons can exhibit long lasting and even persistent activity. Such networks are often not robust and exhibit spike and firing rate statistics that are inconsistent with experimental observations. In order to overcome this problem most previous models had to assume that recurrent connections are dominated by slower NMDA type excitatory receptors. Usually, the single neurons within these networks are very simple leaky integrate and fire neurons or other low dimensional model neurons. However real neurons are much more complex, and exhibit a plethora of active conductances which are recruited both at the sub and supra threshold regimes. Here we show that by including a small number of additional active conductances we can produce recurrent networks that are both more robust and exhibit firing-rate statistics that are more consistent with experimental results. We show that this holds both for bi-stable recurrent networks, which are thought to underlie working memory and for slowly decaying networks which might underlie the estimation of interval timing. We also show that by including these conductances, such networks can be trained to using a simple learning rule to predict temporal intervals that are an order of magnitude larger than those that can be trained in networks of leaky integrate and fire neurons [ABSTRACT FROM AUTHOR]

Timing deficits are observed in patients with schizophrenia. Serotonergic hallucinogens can also alter the subjective experience of time. Characterizing the mechanism through which the serotonergic system regulates timing will increase our understanding of the linkage between serotonin (5-HT) and schizophrenia, and will provide insight into the mechanism of action of hallucinogens. We investigated whether interval timing in mice is altered by hallucinogens and other 5-HT2 receptor ligands. C57BL/6J mice were trained to perform a discrete-trials temporal discrimination task. In the discrete-trials task, mice were presented with two levers after a variable interval. Responding on lever A was reinforced if the interval was 6.5 s. A 2-parameter logistic function was fitted to the proportional choice for lever B (%B responding), yielding estimates of the indifference point (T50) and the Weber fraction (a measure of timing precision). The 5-HT2A antagonist M100907 increased T50, whereas the 5-HT2C antagonist SB-242,084 reduced T50. The results indicate that 5-HT2A and 5-HT2C receptors have countervailing effects on the speed of the internal pacemaker. The hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI; 3 mg/kg IP), a 5-HT2 agonist, flattened the response curve at long stimulus intervals and shifted it to the right, causing both T50 and the Weber fraction to increase. The effect of DOI was antagonized by M100907 (0.03 mg/kg SC) but was unaffected by SB-242,084 (0.1 mg/kg SC). Similar to DOI, the selective 5-HT2A agonist 25CN-NBOH (6 mg/kg SC) reduced %B responding at long stimulus intervals, and increased T50 and the Weber fraction. These results demonstrate that hallucinogens alter temporal perception in mice, effects that are mediated by the 5-HT2A receptor. It appears that 5-HT regulates temporal perception, suggesting that altered serotonergic signaling may contribute to the timing deficits observed in schizophrenia and other psychiatric disorders.

Pain has not only sensory, but also emotional and cognitive, components. Some studies have explored the effect of pain on time perception, but the results remain controversial. Whether individual pain-related emotional and cognitive factors play roles in this process should also be explored. In this study, we investigated the effect of electrical stimulation–induced pain on interval timing using a temporal bisection task. During each task session, subjects received one of five types of stimulation randomly: no stimulus and 100 and 300 ms of non-painful and painful stimulation. Pain-related emotional and cognitive factors were measured using a series of questionnaires. The proportion of "long" judgments of a 1,200-ms visual stimulus duration was significantly smaller with 300 ms painful stimulation than with no stimulus (P < 0.0001) and 100 ms (P < 0.0001) and 300 ms (P = 0.021) non-painful stimulation. The point of subjective equality (PSE) did not differ among sessions, but the average Weber fraction (WF) was higher for painful sessions than for no-stimulus session (P = 0.022). The pain fear score correlated positively with the PSE under 100 ms non-painful (P = 0.031) and painful (P = 0.002) and 300 ms painful (P = 0.006) stimulation. Pain catastrophizing and pain anxiety scores correlated significantly with the WF under no stimulus (P = 0.005) and 100 ms non-painful stimulation (P = 0.027), respectively. These results suggest that electrical stimulation–induced pain affects temporal sensitivity, and that pain-related emotional and cognitive factors are associated with the processing of time perception. [ABSTRACT FROM AUTHOR]