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Nicotinic acetylcholine receptors are thought to be associated with a wide range of phenomena, such as movement, learning, memory, attention, and addiction. However, the causal relationship between nicotinic receptor activity and behavior remains unclear. Contrary to the studies that examined the functions of muscarinic acetylcholine receptors, the role of the nicotinic acetylcholine receptors on behavior has not been examined as extensively. Here, we examined the effects of intraperitoneal injection of mecamylamine, a nicotinic acetylcholine receptor antagonist, on the performance of male mice in a head-fixed temporal conditioning task and a free-moving open-field task. The head-fixed experimental setup allowed us to record and precisely quantify the licking response while the mice performed the behavioral task with no external cues. In addition, by combining the utility of the head-fixed experimental design with computer vision analysis based on deep learning algorithms, we succeeded in quantifying the eyelid size of awake mice. In the temporal conditioning task, we delivered a 10% sucrose solution every 10 s using a blunt-tipped needle placed within the licking distance of the mice. After the training, the mice showed increased anticipatory licking toward the timing of sucrose delivery, suggesting that the mice could predict the timing of the reward. Systemic injection of mecamylamine decreased licking behavior and caused eye closure but had no effect on learned conditioned predictive behavior in the head-fixed temporal conditioning task. In addition, the injection of mecamylamine decreased spontaneous locomotor activity in a dose-dependent manner in the free-moving open-field task. The results in the open-field experiments further revealed that the effect of mecamylamine on fecal output and urination, suggesting the effects on autonomic activities. Our achievement of successful eyelid size recording has potential as a useful approach in initial screening for drug discovery. Our study paves a way forward to understanding the role of nicotinic acetylcholine receptors on learning and behavior.

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The dynamics of the environment where we live in and the interaction with it, predicting events, provided strong evolutionary pressures for the brain functioning to process temporal information and generate timed responses. As a result, the human brain is able to process temporal information and generate temporal patterns. Despite the clear importance of temporal processing to cognition, learning, communication and sensory, motor and emotional processing, the basal mechanisms of how animals differentiate simple intervals or provide timed responses are still under debate. The lesson we learned from the last decade of research in neuroscience is that functional and structural brain connectivity matter. Specifically, it has been accepted that the organization of the brain in interacting segregated networks enables its function. In this paper we delineate the route to a promising approach for investigating timing mechanisms. We illustrate how novel insight into timing mechanisms can come by investigating brain functioning as a multi-layer dynamical network whose clustered dynamics is bound to report the presence of metastable states. We anticipate that metastable dynamics underlie the real-time coordination necessary for the brain's dynamic functioning associated to time perception. This new point of view will help further clarifying mechanisms of neuropsychiatric disorders.

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Objective: Basic temporal dysfunctions have been described in patients with schizophrenia, which may impact their ability to connect and synchronize with the outer world. The present study was conducted with the aim to distinguish between interval timing and synchronization difficulties and more generally the spatial-temporal organization disturbances for voluntary actions. A new sensorimotor synchronization task was developed to test these abilities. Method: Twenty-four chronic schizophrenia patients matched with 27 controls performed a spatial-tapping task in which finger taps were to be produced in synchrony with a regular metronome to six visual targets presented around a virtual circle on a tactile screen. Isochronous (time intervals of 500 ms) and non-isochronous auditory sequences (alternated time intervals of 300/600 ms) were presented. The capacity to produce time intervals accurately versus the ability to synchronize own actions (tap) with external events (tone) were measured. Results: Patients with schizophrenia were able to produce the tapping patterns of both isochronous and non-isochronous auditory sequences as accurately as controls producing inter-response intervals close to the expected interval of 500 and 900 ms, respectively. However, the synchronization performances revealed significantly more positive asynchrony means (but similar variances) in the patient group than in the control group for both types of auditory sequences. Conclusion: The patterns of results suggest that patients with schizophrenia are able to perceive and produce both simple and complex sequences of time intervals but are impaired in the ability to synchronize their actions with external events. These findings suggest a specific deficit in predictive timing, which may be at the core of early symptoms previously described in schizophrenia.

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For years, phenomenological psychiatry has proposed that distortions of the temporal structure of consciousness contribute to the abnormal experiences described before schizophrenia emerges, and may relate to basic disturbances in consciousness of the self. However, considering that temporality refers mainly to an implicit aspect of our relationship with the world, disturbances in the temporal structure of consciousness remain difficult to access. Nonetheless, previous studies have shown a correlation between self disorders and the automatic ability to expect an event in time, suggesting timing is a key issue for the psychopathology of schizophrenia. Timing disorders may represent a target for cognitive remediation, but this requires that disorders can be demonstrated at an individual level. Since cognitive impairments in patients with schizophrenia are discrete, and there is no standardized timing exploration, we focused on timing impairments suggested to be related to self disorders. We present the case report of AF, a 22 year old man suffering from schizophrenia, with no antipsychotic intake. Although AF shows few positive and negative symptoms and has a normal neurocognitive assessment, he shows a high level of disturbance of Minimal Self Disorders (SDs) (assessed with the EASE scale). Moreover, AF has a rare ability to describe his self and time difficulties. An objective assessment of timing ability (variable foreperiod task) confirmed that AF had temporal impairments similar to those previously described in patients, i.e., a preserved ability to distinguish time intervals, but a difficulty to benefit from the passage of time to expect a visual stimulus. He presents additional difficulties in benefitting from temporal cues and adapting to changes in time delays. The impairments were ample enough to yield significant effects with analyses at the individual level. Although causal relationships between subjective and objective impairments cannot be established, the results show that exploring timing deficits at the individual level is possible in patients with schizophrenia. Besides, the results are consistent with hypotheses relating minimal self disorders (SDs) to timing difficulties. They suggest that both subjective and objective timing investigations should be developed further so that their use at an individual level can be generalized in clinical practice.

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OBJECTIVES: Precise temporal performance is crucial for several complex tasks. Time estimation in the second-to-minutes range-known as interval timing-involves the interaction of the basal ganglia and the prefrontal cortex via dopaminergic-glutamatergic pathways. Patients with Huntington's disease (HD) present deficits in cognitive and motor functions that require fine control of temporal processing. The objective of the present work was to assess temporal cognition through a peak-interval time (PI) production task in patients with HD and its potential correlation with the Unified Huntington's Disease Rating Scale (UHDRS). MATERIALS AND METHODS: Patients with molecular diagnosis of HD and controls matched by age, sex and educational level (n=18/group) were tested for interval timing in short- (3 seconds), medium- (6 seconds) and long (12 seconds)-duration stimuli. RESULTS: Significant differences were observed in the PI task, with worse performance in HD compared to controls. Patients underestimated real time (left-shifted Peak location) for 6- and 12-second intervals (P<.05) and presented decreased temporal precision for all the intervals evaluated (P<.01). Importantly, a significant correlation was found between time performance and the UHDRS (P<.01). Patients' responses also deviated from the scalar property. CONCLUSIONS: Our results contribute to support that timing functions are impaired in HD in correlation with clinical deterioration. Recordings of cognitive performance related to timing could be a potential useful tool to measure the neurodegenerative progression of movement disorder-related pathologies.

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The subjective representation of "time" is critical for cognitive tasks but also for several motor activities. The neural network supporting motor timing comprises: lateral cerebellum, basal ganglia, sensorimotor and prefrontal cortical areas. Basal ganglia and associated cortical areas act as a hypothetical "internal clock" that beats the rhythm when the movement is internally generated. When timing information is processed to make predictions on the outcome of a subjective or externally perceived motor act, cerebellar processing and outflow pathways appear to be primarily involved. Clinical and experimental evidence on time processing and motor control points to a dysfunction of the neural networks involving basal ganglia and cerebellum in movement disorders. In some cases, temporal processing deficits could directly contribute to core motor features of the movement disorder, as in the case of bradykinesia in Parkinson's disease. For other movement disorders, the relationship between abnormal time processing and motor performance is less obvious and requires further investigation, as in the reduced accuracy in predicting the temporal outcome of a motor act in dystonia. We aim to review the literature on time processing and motor control in Parkinson's disease, dystonia, Huntington's disease, and Tourette syndrome, integrating the available findings with current pathophysiological models; we will highlight the areas in which future explorations are warranted, as well as the aspects of time processing in motor control that present translational aspects in future rehabilitation strategies. The subjective representation of "time" is critical for cognitive tasks but also for motor activities. Recently, greater attention has been devoted to improve our understanding of how temporal information becomes integrated within the mechanisms of motor control. Experimental evidence recognizes time processing in motor control as a complex neural function supported by diffuse cerebral networks including cortical areas, cerebellum, and other subcortical structures (Ivry and Spencer, 2004; Coull and Nobre, 2008). Timing is an essential component of motor control primarily within two types of motor tasks: (i) when producing sequential rhythmic movements or sustained movements of a definite duration (explicit timing); (ii) when the temporal information is used implicitly, such as when coordinating our movements to those of moving objects or individuals within the external environment (implicit timing). In this review, we will provide a brief description of the neural network supporting motor timing focusing only on instrumental information to explain the link between timing and motor control in movement disorders. Then we will review available data on motor timing in Parkinson's disease, dystonia, Huntington's disease, and Tourette syndrome, and discuss how this body of evidence integrates with the available information on the pathophysiology of these movement disorders. Finally, we will discuss the translational aspects of the explored neural mechanisms with respect to future rehabilitation strategies.

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Discriminative fear conditioning requires learning to dissociate between safety cues and cues that predict negative outcomes yet little is known about what processes contribute to discriminative fear learning. According to attentional models of time perception, processes that distract from timing result in temporal underestimation. If discriminative fear learning only requires learning what cues predict what outcomes, and threatening stimuli distract attention from timing, then better discriminative fear learning should predict greater temporal distortion on threat trials. Alternatively, if discriminative fear learning also reflects a more accurate perceptual experience of time in threatening contexts, discriminative fear learning scores would predict less temporal distortion on threat trials, as time is perceived more veridically. Healthy young adults completed discriminative fear conditioning in which they learned to associate one stimulus (CS+) with aversive electrical stimulation and another stimulus (CS-) with non-aversive tactile stimulation and then an ordinal comparison timing task during which CSs were presented as task-irrelevant distractors Consistent with predictions, we found an overall temporal underestimation bias on CS+ relative to CS- trials. Differential skin conductance responses to the CS+ versus the CS- during conditioning served as a physiological index of discriminative fear conditioning and this measure predicted the magnitude of the underestimation bias, such that individuals exhibiting greater discriminative fear conditioning showed less underestimation on CS+ versus CS- trials. These results are discussed with respect to the nature of discriminative fear learning and the relationship between temporal distortions and maladaptive threat processing in anxiety.

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The most popular tasks with which to investigate the perception of subjective synchrony are the temporal order judgment (TOJ) and the simultaneity judgment (SJ). Here, we discuss a complementary approach-a dual-presentation (2x) SJ task-and focus on appropriate analysis methods for a theoretically desirable "roving" design. Two stimulus pairs are presented on each trial and the observer must select the most synchronous. To demonstrate this approach, in Experiment 1 we tested the 2xSJ task alongside TOJ, SJ, and simple reaction-time (RT) tasks using audiovisual stimuli. We interpret responses from each task using detection-theoretic models, which assume variable arrival times for sensory signals at critical brain structures for timing perception. All tasks provide similar estimates of the point of subjective simultaneity (PSS) on average, and PSS estimates from some tasks were correlated on an individual basis. The 2xSJ task produced lower and more stable estimates of model-based (and thus comparable) sensory/decision noise than the TOJ. In Experiment 2 we obtained similar results using RT, TOJ, ternary, and 2xSJ tasks for all combinations of auditory, visual, and tactile stimuli. In Experiment 3 we investigated attentional prior entry, using both TOJs and 2xSJs. We found that estimates of prior-entry magnitude correlated across these tasks. Overall, our study establishes the practicality of the roving dual-presentation SJ task, but also illustrates the additional complexity of the procedure. We consider ways in which this task might complement more traditional procedures, particularly when it is important to estimate both PSS and sensory/decisional noise.

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The ability to time intervals confers organisms, including humans, with many remarkable capabilities. A common method for studying interval timing is classification, in which a subject must indicate whether a given probe duration is nearer a previously learned short or long reference interval. This task is designed to reveal the probe duration that is equally likely to be labeled as short or long, known as the temporal bisection point. Studies have found that this bisection point is influenced by a variety of factors including the ratio of the target intervals, the spacing of the probe durations, the modalities of the stimuli, the attentional load, and the inter-trial duration. While several of these factors are thought to be mediated by memory effects, the prototypical classification task affords no opportunity to measure these memory effects directly. Here, we present a novel bisection task, termed the "Bisection by Classification and Production" (BiCaP) task, in which classification trials are interleaved with trials in which subjects must produce either the short or long referents or their midpoint. Using this method, we found a significant correlation between the means of the remembered referents and the bisection points for both classification and production trials. We then cross-validated the bisection points for production and classification trials by showing that they were not statistically differentiable. In addition to these population-level effects, we found within-subject evidence for co-variation across a session between the production bisection points and the means of the remembered referents. Finally, by using two sets of referent durations, we showed that only memory bias-corrected measures were consistent with a previously reported effect in which the ratio of the referents affects the location of the bisection point. These results suggest that memory effects should be considered in temporal tasks.

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It has been shown that prior experience with a task improves temporal prediction, even when the amount of prior experience with the task is often limited. The present study targeted the role of extensive training on temporal prediction. Expert and intermediate runners had to predict the time of a 5 km running competition. Furthermore, after the race's completion, participants had to estimate their running time so that it could be compared with the predicted time. Results show that expert runners were more accurate than intermediate runners for both predicting and estimating their running time. Furthermore, only expert runners had an estimation that was more accurate than their initial prediction. The results confirm the role of prior task experience in both temporal prediction and estimation.

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Interval timing and working memory are critical components of cognition that are supported by neural oscillations in prefrontal-striatal-hippocampal circuits. In this review, the properties of interval timing and working memory are explored in terms of behavioral, anatomical, pharmacological, and neurophysiological findings. We then describe the various neurobiological theories that have been developed to explain these cognitive processes - largely independent of each other. Following this, a coupled excitatory - inhibitory oscillation (EIO) model of temporal processing is proposed to address the shared oscillatory properties of interval timing and working memory. Using this integrative approach, we describe a hybrid model explaining how interval timing and working memory can originate from the same oscillatory processes, but differ in terms of which dimension of the neural oscillation is utilized for the extraction of item, temporal order, and duration information. This extension of the striatal beat-frequency (SBF) model of interval timing (Matell and Meck, 2000, 2004) is based on prefrontal-striatal-hippocampal circuit dynamics and has direct relevance to the pathophysiological distortions observed in time perception and working memory in a variety of psychiatric and neurological conditions.

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Duration discrimination within the seconds-to-minutes range, known as interval timing, involves the interaction of cortico-striatal circuits via dopaminergic-glutamatergic pathways. Besides interval timing, most (if not all) organisms exhibit circadian rhythms in physiological, metabolic and behavioral functions with periods close to 24 h. We have previously reported that both circadian disruption and desynchronization impaired interval timing in mice. In this work we studied the involvement of dopamine (DA) signaling in the interaction between circadian and interval timing. We report that daily injections of levodopa improved timing performance in the peak-interval procedure in C57BL/6 mice with circadian disruptions, suggesting that a daily increase of DA is necessary for an accurate performance in the timing task. Moreover, striatal DA levels measured by reverse-phase high-pressure liquid chromatography indicated a daily rhythm under light/dark conditions. This daily variation was affected by inducing circadian disruption under constant light (LL). We also demonstrated a daily oscillation in tyrosine hydroxylase levels, DA turnover (3,4-dihydroxyphenylacetic acid/DA levels), and both mRNA and protein levels of the circadian component Period2 (Per2) in the striatum and substantia nigra, two brain areas relevant for interval timing. None of these oscillations persisted under LL conditions. We suggest that the lack of DA rhythmicity in the striatum under LL - probably regulated by Per2 - could be responsible for impaired performance in the timing task. Our findings add further support to the notion that circadian and interval timing share some common processes, interacting at the level of the dopaminergic system.

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Variations in both pitch and time are important in conveying meaning through speech and music, however, research is scant on perceptual interactions between these two domains. Using an ordinal comparison procedure, we explored how different pitch levels of flanker tones influenced the perceived duration of empty interstimulus intervals (ISIs). Participants heard monotonic, isochronous tone sequences (ISIs of 300, 600, or 1200 ms) composed of either one or five standard ISIs flanked by 500 Hz tones, followed by a final interval (FI) flanked by tones of either the same (500 Hz), higher (625 Hz), or lower (400 Hz) pitch. The FI varied in duration around the standard ISI duration. Participants were asked to determine if the FI was longer or shorter in duration than the preceding intervals. We found that an increase in FI flanker tone pitch level led to the underestimation of FI durations while a decrease in FI flanker tone pitch led to the overestimation of FI durations. The magnitude of these pitch-level effects decreased as the duration of the standard interval was increased, suggesting that the effect was driven by differences in mode-switch latencies to start/stop timing. Temporal context (One vs. Five Standard ISIs) did not have a consistent effect on performance. We propose that the interaction between pitch and time may have important consequences in understanding the ways in which meaning and emotion are communicated.

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Cholinergic neurons in the basal forebrain innervate discrete regions of the cortical mantle, bestowing the cholinergic system with the potential to dynamically modulate sub-regions of the cortex according to behavioral demands. Cortical cholinergic activity has been shown to facilitate learning and modulate attention. Experiments addressing these issues have primarily focused on widespread cholinergic depletions, extending to areas involved in general cognitive processes and sleep cycle regulation, making a definitive interpretation of the behavioral role of cholinergic projections difficult. Furthermore, a review of the electrophysiological literature suggests that cholinergic modulation is particularly important in representing the fine temporal details of stimuli, an issue rarely addressed in behavioral experimentation. The goal of this work is to understand the role of cholinergic projections, specific to the sensory cortices, in learning to discriminate fine differences in the temporal structure of stimuli. A novel visual Go/No-Go task was developed to assess the ability of rats to learn to discriminate fine differences in the temporal structure of visual stimuli (lights flashing at various frequencies). The cholinergic contribution to this task was examined by selective reduction of acetylcholine projections to visual cortex (VCx) (using 192 IgG-saporin), either before or after discrimination training. We find that in the face of compromised cholinergic input to the VCx, the rats' ability to learn to perform fine discriminations is impaired, whereas their ability to perform previously learned discriminations remains unaffected. These results suggest that acetylcholine serves the role of facilitating plastic changes in the sensory cortices that are necessary for an animal to refine its sensitivity to the temporal characteristics of relevant stimuli.

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Time-based decision-making in peak-interval timing procedures involves the setting of response thresholds for the initiation ("Start") and termination ("Stop") of a response sequence that is centered on a target duration. Using intracerebral infusions of the protein synthesis inhibitor anisomycin, we report that the acquisition of the "Start" response depends on normal functioning (including protein synthesis) in the dorsal striatum (DS), but not the ventral striatum (VS). Conversely, disruption of the VS, but not the DS, impairs the acquisition of the "Stop" response. We hypothesize that the dorsal and ventral regions of the striatum function as a competitive neural network that encodes the temporal boundaries marking the beginning and end of a timed response sequence.

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The relation between the contingent negative variation (CNV) and time estimation is evaluated in terms of temporal accumulation and preparation processes. The conclusion is that the CNV as measured from the electroencephalogram (EEG) recorded at fronto-central and parietal-central areas is not a direct reflection of the underlying interval timing mechanism(s), but more likely represents a time-based response preparation/decision-making process.