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There has been considerable progress in recent years toward understanding the neuronal mechanisms mediating time perception. Notably, the striatum and its dopamine (DA) input from the ventral midbrain are considered to be central for timing on the scale of hundreds of milliseconds and seconds. The cholinergic interneurons (ChIs) of the striatum provide an extensive local innervation, which closely interacts with striatal DA afferents. Both neuronal systems have been shown to influence synaptic plasticity to shape the transfer of information through the striatum. Given their cooperative role in regulating striatal output pathways, DA and cholinergic inputs may have distinct but complementary roles in timing processes. Electrophysiological recordings from behaving animals have provided evidence that responses of midbrain DA neurons and striatal tonically active neurons (TANs), presumed ChIs, to motivationally relevant events are sensitive to the predicted time of these events; namely, changes in neuronal activity are reduced or absent at times when events are more expected, indicating that temporal aspects of prediction play an important role in the responsiveness of these two neuronal systems. Recently, new findings have further suggested that DA neurons and cholinergic TANs are both involved in the ability to keep track of the elapsed time. These two systems appear to work in parallel in initiating the timing process at the beginning of an interval to be timed. It therefore appears that DA and ChI signaling could participate in striatal processing that is crucial for the control of timing behavior.

As we interact with the external world, we judge magnitudes from sensory information. The estimation of magnitudes has been characterized in primates, yet it is largely unexplored in nonprimate species. Here, we use time interval reproduction to study rodent behavior and its neural correlates in the context of magnitude estimation. We show that gerbils display primate-like magnitude estimation characteristics in time reproduction. Most prominently their behavioral responses show a systematic overestimation of small stimuli and an underestimation of large stimuli, often referred to as regression effect. We investigated the underlying neural mechanisms by recording from medial prefrontal cortex and show that the majority of neurons respond either during the measurement or the reproduction of a time interval. Cells that are active during both phases display distinct response patterns. We categorize the neural responses into multiple types and demonstrate that only populations with mixed responses can encode the bias of the regression effect. These results help unveil the organizing neural principles of time reproduction and perhaps magnitude estimation in general.

Metacognition, the ability to know about one’s thought process, is self-referential. Here, we combined psychophysics and time-resolved neuroimaging to explore metacognitive inference on the accuracy of a self-generated behavior. Human participants generated a time interval and evaluated the signed magnitude of their temporal production. We show that both self-generation and self-evaluation relied on the power of beta oscillations (β; 15–40 Hz) with increases in early β power predictive of increases in duration. We characterized the dynamics of β power in a low-dimensional space (β state-space trajectories) as a function of timing and found that the more distinct trajectories, the more accurate metacognitive inferences were. These results suggest that β states instantiate an internal variable determining the fate of the timing network’s trajectory, possibly as release from inhibition. Altogether, our study describes oscillatory mechanisms for timing, suggesting that temporal metacognition relies on inferential processes of self-generated dynamics.

Behavioral flexibility requires the prefrontal cortex and striatum, but it is unclear if these structures play similar or distinct roles in adapting to novel circumstances. Here, we investigate neuronal ensembles in the medial frontal cortex (MFC) and the dorsomedial striatum (DMS) during one form of behavioral flexibility: learning a new temporal interval. We studied corticostriatal neuronal activity as rodents trained to respond after a 12-s fixed interval (FI12) learned to respond at a shorter 3-s fixed interval (FI3). On FI12 trials, we found that a key form of temporal processing—time-related ramping activity—decreased in the MFC but did not change in the DMS as animals learned to respond at a shorter interval. However, while MFC and DMS ramping was stable with successive days of two-interval performance, temporal decoding by DMS ensembles improved on FI3 trials. Finally, when comparing FI12 versus FI3 trials, we found that more DMS neurons than MFC neurons exhibited differential interval-related activity early in two-interval performance. These data suggest that the MFC and DMS play distinct roles during temporal learning and provide insight into corticostriatal circuits.

During Pavlovian aversive conditioning, a neutral conditioned stimulus (CS) becomes predictive of the time of arrival of an aversive unconditioned stimulus (US). Using a paradigm where animals had to discriminate between a CS+ (associated with a footshock) and a CS− (never associated with a footshock), we show that, early in training, dynamics of neuronal oscillations in an amygdalo–prefronto–striatal network are modified during the CS+ in a manner related to the CS–US time interval (30 or 10 s). This is the case despite a generalized high level of freezing to both CS+ and CS−. The local field potential oscillatory power was decreased between 12 and 30 Hz in the dorsomedial striatum (DMS) and increased between 55 and 95 Hz in the prelimbic cortex (PL), while the coherence between DMS, PL, and the basolateral amygdala was increased in the 3–6 Hz frequency range up to the expected time of US arrival only for the CS+ and not for the CS−. Changing the CS–US interval from 30 to 10 s shifted these changes in activity toward the newly learned duration. The results suggest a functional role of the amygdalo–prefronto–dorsostriatal network in encoding temporal information of Pavlovian associations independently of the behavioral output.

International audience; The processing of temporal intervals is essential to create causal maps and to predict future events so as to best adapt one's behavior. In this review, we explore the different brain activity patterns associated with processing durations and expressing temporally-adapted behavior in animals. We begin by describing succinctly some of the current models of the internal clock that can orient us in what to look for in brain activity. We then outline how durations can be decoded by single cell activity and which activity patterns could be associated with interval timing. We further point to similar patterns that have been observed at a more global level within brain areas (e.g. local field potentials) or, even, between these areas, that could represent another way of encoding duration or could constitute a necessary part for more complex temporal processing. Finally, we discuss to what extent neural data fit with internal clock models, and highlight improvements for experiments to obtain a more in-depth understanding of the brain's temporal encoding and processing.

The majority of studies in the field of timing and time perception have generally focused on sub- and supra-second time scales, specific behavioral processes, and/or discrete neuronal circuits. In an attempt to find common elements of interval timing from a broader perspective, we review the literature and highlight the need for cell and molecular studies that can delineate the neural mechanisms underlying temporal processing. Moreover, given the recent attention to the function of microtubule proteins and their potential contributions to learning and memory consolidation/re-consolidation, we propose that these proteins play key roles in coding temporal information in cerebellar Purkinje cells (PCs) and striatal medium spiny neurons (MSNs). The presence of microtubules at relevant neuronal sites, as well as their adaptability, dynamic structure, and longevity, makes them a suitable candidate for neural plasticity at both intra- and inter-cellular levels. As a consequence, microtubules appear capable of maintaining a temporal code or engram and thereby regulate the firing patterns of PCs and MSNs known to be involved in interval timing. This proposed mechanism would control the storage of temporal information triggered by postsynaptic activation of mGluR7. This, in turn, leads to alterations in microtubule dynamics through a “read-write” memory process involving alterations in microtubule dynamics and their hexagonal lattice structures involved in the molecular basis of temporal memory.

We recently found that when monkeys performed an oculomotor version of the time production task, the trial-by-trial latency of self-timed saccades was negatively correlated with pupil diameter just before the delay period ( Suzuki et al., 2016 ). Since pupil diameter has been shown to correlate with neuronal activity in the locus coeruleus, the level of noradrenaline (NA) in the brain might regulate the subjective passage of time. To examine this, we orally administered a selective noradrenaline reuptake inhibitor (reboxetine, 0.4–0.8 mg) when animals made a self-initiated memory-guided saccade >1 s following the appearance of a brief visual cue. We found that reboxetine delayed self-timed saccades, while the latency of visually triggered saccades remained unchanged. Because the changes in proportions and latencies of early impulsive saccades were comparable between conditions with and without drug administration, alteration of self-timing might not result from reduced impulsivity. We also assessed other behavioral parameters (saccade accuracy, velocity, and latency variance), but failed to find any drug effect except for the accuracy of visually triggered saccades in the high-dose condition, indicating that reboxetine specifically altered self-timing under our experimental conditions. Our results suggest that NA-related internal states may causally regulate temporal information processing in the brain.

The purpose of this study was to take a new approach in showing how the central nervous system might encode time at the supra-second level using recurrent neural nets (RNNs). This approach utilizes units with a delayed feedback, whose feedback weight determines the temporal properties of specific neurons in the network architecture. When these feedback neurons are coupled, they form a multilayered dynamical system that can be used to model temporal responses to steps of input in multidimensional systems. The timing network was implemented using separate recurrent "Go" and "No-Go" neural processing units to process an individual stimulus indicating the time of reward availability. Outputs from these distinct units on each time step are converted to a pulse reflecting a weighted sum of the separate Go and No-Go signals. This output pulse then drives an integrator unit, whose feedback weight and input weights shape the pulse distribution. This system was used to model empirical data from rodents performing in an instrumental "peak interval timing" task for two stimuli, Tone and Flash. For each of these stimuli, reward availability was signaled after different times from stimulus onset during training. Rodent performance was assessed on non-rewarded trials, following training, with each stimulus tested individually and simultaneously in a stimulus compound. The associated weights in the Go/No-Go network were trained using experimental data showing the mean distribution of bar press rates across an 80 s period in which a tone stimulus signaled reward after 5 s and a flash stimulus after 30 s from stimulus onset. Different Go/No-Go systems were used for each stimulus, but the weighted output of each fed into a final recurrent integrator unit, whose weights were unmodifiable. The recurrent neural net (RNN) model was implemented using Matlab and Matlab's machine learning tools were utilized to train the network using the data from non-rewarded trials. The neural net output accurately fit the temporal distribution of tone and flash-initiated bar press data. Furthermore, a "Temporal Averaging" effect was also obtained when the flash and tone stimuli were combined. These results indicated that the system combining tone and flash responses were not superposed as in a linear system, but that there was a non-linearity, which interacted between tone and flash. In order to achieve an accurate fit to the empirical averaging data it was necessary to implement non-linear "saliency functions" that limited the output signal of each stimulus to the final integrator when the other was co-present. The model suggests that the central nervous system encodes timing generation as a dynamical system whose timing properties are embedded in the connection weights of the system. In this way, event timing is coded similar to the way other sensory-motor systems, such as the vestibulo-ocular and optokinetic systems, which combine sensory inputs from the vestibular and visual systems to generate the temporal aspects of compensatory eye movements.

Previous research has shown that schizophrenia (SZ) patients exhibit impairments in interval timing. The cause of timing impairments in SZ remains unknown but may be explained by a dysfunction in the fronto-striatal circuits. Although the current literature includes extensive behavioral data on timing impairments, there is limited focus on the neural correlates of timing in SZ. The neuroimaging literature included in the current review reports hypoactivation in the dorsal-lateral prefrontal cortex (DLPFC), supplementary motor area (SMA) and the basal ganglia (BG). Timing deficits and deficits in attention and working memory (WM) in SZ are likely due to a dysfunction of dopamine (DA) and gamma-aminobutyric acid (GABA) neurotransmission in the cortico-striatal-thalamo-cortical circuits, which are highly implicated in executive functioning and motor preparation.

Objective: Clock variance is an important statistic in many clinical and developmental studies. Existing methods require a large number of trials for accurate clock variability assessment, which is problematic in studies using clinical or either young or aged participants. Furthermore, these existing methods often implicitly convolute clock and memory processes, making it difficult to disentangle whether the clock or memory system are driving the observed deviations. Here we assessed whether 20 repeated productions of a well-engrained interval (1 s), a task that does not incorporate memory updating nor the processing of feedback, could provide an accurate assessment of clock variability.Method: Sixty-eight undergraduate students completed two tasks: a 1-s production task in which they were asked to produce a 1-s duration by ending a tone by a keypress, and a multi-duration reproduction task. Durations presented in the reproduction task were tones lasting 1.17, 1.4 and 1.68 s. No feedback was presented in either task, and the order of presentation was counterbalanced between participants.Results: The observed central tendency in the reproduction task was better explained by models including the measures of clock variability derived from the 1-s production task than by models without it. Three clock variability measures were calculated for each participant [standard deviation, root mean squared residuals (RMSRs) from an estimated linear slope, and RMSR scaled by mean production duration]. The model including the scaled RMSR was preferred over the alternative models, and no notable effects of the order of task presentation were observed. These results suggest that: (1) measures of variability should account for drift; (2) the presentation of another timing task before a 1-s production task did not influence the assessment of the clock variability; and (3) the observed variability adheres to the scalar property and predicts temporal performance, and is thus a usable index of clock variability.Conclusion: This study shows that just 20 repeated productions of 1 s provide a reliable index of clock variability. As administering this task is fast and easy, it could prove to be useful in a large variety of developmental and clinical populations.

Individuals must predict future events to proactively guide their behavior. Predicting when events will occur is a critical component of these expectations. Temporal expectations are often generated based on individual cue-duration relationships. However, the durations associated with different environmental cues will often co-vary due to a common cause. We show that timing behavior may be calibrated based on this expected covariance, which we refer to as the ‘common cause hypothesis’. In five experiments using rats, we found that when the duration associated with one temporal cue changes, timed-responding to other cues shift in the same direction. Furthermore, training subjects that expecting covariance is not appropriate in a given situation blocks this effect. Finally, we confirmed that this transfer is context-dependent. These results reveal a novel principle that modulates timing behavior, which we predict will apply across a variety of magnitude-expectations.

Many organisms can time intervals flexibly on average with high accuracy but substantial variability between the trials. One of the core psychophysical features of interval timing functions relates to the signatures of this timing variability; for a given individual, the standard deviation of timed responses/time estimates is nearly proportional to their central tendency (scalar property). Many studies have aimed at elucidating the neural basis of interval timing based on the neurocomputational principles in a fashion that would explain the scalar property. Recent experimental evidence shows that there is indeed a specialized neural system for timekeeping. This system, referred to as the “time cells,” is composed of a group of neurons that fire sequentially as a function of elapsed time. Importantly, the time interval between consecutively firing time cell ensembles has been shown to increase with more elapsed time. However, when the subjective time is calculated by adding the distributions of time intervals between these sequentially firing time cell ensembles, the standard deviation would be compressed by the square root function. In light of this information the question becomes, “How should the signaling between the sequentially firing time cell ensembles be for the resulting variability to increase linearly with time as required by the scalar property?” We developed a simplified model of time cells that offers a mechanism for the synaptic communication of the sequentially firing neurons to address this ubiquitous property of interval timing. The model is composed of a single layer of time cells formulated in the form of integrate-and-fire neurons with feed-forward excitatory connections. The resulting behavior is simple neural wave activity. When this model is simulated with noisy conductances, the standard deviation of the time cell spike times increases proportionally to the mean of the spike-times. We demonstrate that this statistical property of the model outcomes is robustly observed even when the values of the key model parameters are varied., American University of the Middle East

The frontal cortex-basal ganglia circuit plays an important role in interval timing. We examined neuronal discharges in the dorsomedial and dorsolateral striatum (DMS and DLS) in rats performing a temporal categorization task and compared them with previously recorded neuronal activity in the medial prefrontal cortex (mPFC). All three structures conveyed significant temporal information, but striatal neurons seldom showed the prolonged, full-interval spanning ramping activity frequently observed in the mPFC. Instead, the majority fired briefly during sample intervals. Also, the precision of neural time decoding became progressively worse with increasing time duration in the mPFC, but not in the striatum. With the caveat that mPFC and striatal units were recorded from different animals, our results suggest that the striatum and mPFC convey temporal information via distinct neural processes.

It has previously been demonstrated that rats trained on the peak-interval procedure to associate two different cues with two different fixed interval schedules will generate a scalar peak function at an intermediate time when presented with the compound cue. This response pattern has been interpreted as resulting from the simultaneous retrieval of different temporal memories, and a consequential averaging process to resolve the ambiguity. In the present set of studies, we investigated the role that serotonin 1a receptors play in this process. In Experiment 1, rats were trained on a peak-interval procedure to associate the interoceptive states induced by saline and the 5-HT1a agonist, 8-OH-DPAT, with a 5 s or 20 s fixed-interval schedule signaled by the same tone cue (counter-balanced). While peak functions following administration of saline were centered at the appropriate time (5 s or 20 s), peak functions following administration of the agonist were centered around 7 s, irrespective of the reinforced time during training, suggesting agonist-induced disruption in selective temporal memory retrieval, resulting in increased ambiguity regarding the appropriate time at which to respond. In Experiment 2, rats were trained in a peak-interval procedure to associate a tone cue with a 10 s fixed interval and a light cue with a 20 s fixed interval. Administration of the 5-HT1a antagonist, WAY-100635, had no impact on timing when single cues were presented, but altered the intermediate, scalar, response to the stimulus compound, suggesting antagonist-induced disruption in the processes used to deal with temporal memory ambiguity. Together, these data suggest that manipulations of 5HT transmission at the 5-HT1a receptor cause changes in the temporal pattern of responding that are consistent with alterations in temporal memory processes and responses to temporal ambiguity.

The ability to flexibly adjust movement timing is important for everyday life. Although the basal ganglia and cerebellum have been implicated in monitoring of supra- and sub-second intervals, respectively, the underlying neuronal mechanism remains unclear. Here, we show that in monkeys trained to generate a self-initiated saccade at instructed timing following a visual cue, neurons in the caudate nucleus kept track of passage of time throughout the delay period, while those in the cerebellar dentate nucleus were recruited only during the last part of the delay period. Conversely, neuronal correlates of trial-by-trial variation of self-timing emerged earlier in the cerebellum than the striatum. Local inactivation of respective recording sites confirmed the difference in their relative contributions to supra- and sub-second intervals. These results suggest that the basal ganglia may measure elapsed time relative to the intended interval, while the cerebellum might be responsible for the fine adjustment of self-timing.

Motor sequence learning, planning and execution of goal-directed behaviors, and decision making rely on accurate time estimation and production of durations in the seconds-to-minutes range. The pathways involved in planning and execution of goal-directed behaviors include cortico-striato-thalamo-cortical circuitry modulated by dopaminergic inputs. A critical feature of interval timing is its scalar property, by which the precision of timing is proportional to the timed duration. We examined the role of medial prefrontal cortex (mPFC) in timing by evaluating the effect of its reversible inactivation on timing accuracy, timing precision and scalar timing. Rats were trained to time two durations in a peak-interval (PI) procedure. Reversible mPFC inactivation using GABA agonist muscimol resulted in decreased timing precision, with no effect on timing accuracy and scalar timing. These results are partly at odds with studies suggesting that ramping prefrontal activity is crucial to timing but closely match simulations with the Striatal Beat Frequency (SBF) model proposing that timing is coded by the coincidental activation of striatal neurons by cortical inputs. Computer simulations indicate that in SBF, gradual inactivation of cortical inputs results in a gradual decrease in timing precision with preservation of timing accuracy and scalar timing. Further studies are needed to differentiate between timing models based on coincidence detection and timing models based on ramping mPFC activity, and clarify whether mPFC is specifically involved in timing, or more generally involved in attention, working memory, or response selection/inhibition.

Temporal processing in the seconds-to-minutes range, known as interval timing, is a crucial cognitive function that requires activation of cortico-striatal circuits via dopaminergic–glutamatergic pathways. In humans, both children and adults with autism spectrum disorders (ASD) present alterations in their estimation of time intervals. At present, there are no records of interval timing studies in animal models of ASD. Hence, the objective of the present work was to evaluate interval timing in a mouse model of prenatal exposure to valproic acid (VPA) – a treatment used to induce human-like autistic features in rodent models. Animals were assessed for their ability to acquire timing responses in 15-s and 45-s peak-interval (PI) procedures. Our results indicate that both female and male mice prenatally exposed to VPA present decreased timing accuracy and precision compared to control groups, as well as deviations from the scalar property. Moreover, the observed timing deficits in male VPA mice were reversed after early social enrichment. Furthermore, catecholamine determination by HPLC-ED indicated significant differences in striatal dopaminergic, but not serotonergic, content in female and male VPA mice, consistent with previously identified alterations in dopamine metabolism in ASD. These deficits in temporal processing in a mouse model of autism complement previous results in humans, and provide a useful tool for further behavioral and pharmacological studies. Fil: Acosta, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina Fil: Campolongo, Marcos Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina Fil: Depino, Amaicha Mara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Golombek, Diego Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina Fil: Agostino, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina

International audience; Huntington disease (HD) is an autosomal dominantly inherited, progressive neurodegenerative disorder which is accompanied by executive dysfunctions and emotional alteration. The aim of the present study was to assess the impact of emotion/stress on on-going highly demanding cognitive tasks, i.e., temporal processing, as a function of age in BACHD rats (a "full length" model of HD). Middle-aged (4-6 months) and old (10-12 months) rats were first trained on a 2 vs. 8-s temporal discrimination task, and then exposed to a series of bisection tests under normal and stressful (10 mild unpredictable foot-shocks) conditions. The animals were then trained on a peak interval task, in which reinforced fixed-interval (FI) 30-s trials were randomly intermixed with non-reinforced probe trials. After training, the effect of stress upon time perception was again assessed. Sensitivity to foot-shocks was also assessed independently. The results show effects of both age and genotype, with largely greater effects in old BACHD animals. The older BACHD animals had impaired learning in both tasks, but reached equivalent levels of performance as WT animals at the end of training in the temporal discrimination task, while remaining impaired in the peak interval task. Whereas sensitivity to foot-shock did not differ between BACHD and WT rats, delivery of foot-shocks during the test sessions had a disruptive impact on temporal behavior in WT animals, an effect which increased with age. In contrast, BACHD rats, independent of age, did not show any significant disruption under stress. In conclusion, BACHD rats showed a disruption in temporal learning in late symptomatic animals. Age-related modification in stress-induced impairment of temporal control of behavior was also observed, an effect which was greatly reduced in BACHD animals, thus confirming previous results suggesting reduced emotional reactivity in HD animals. The results suggest a staggered onset in cognitive and emotional alterations in HD, with emotional alteration being the earliest, possibly related to different time courses of degeneration in cortico-striatal and amygdala circuits.

Recent work shows that putamen-originating beta power oscillations serve as a carrier for temporal information during tapping tasks, with higher beta power associated with longer temporal reproductions. However, given the nature of tapping tasks, it is difficult to determine whether beta power dynamics observed in these tasks are linked to the generation or execution of motor programs or to the internal representation of time. To assess whether recent findings in animals generalize to human studies we reanalyzed existing EEG data of participants who estimated a 2.5 s time interval with self-paced onset and offset keypresses. The results showed that the trial-to-trial beta power measured after the onset predicts the produced duration, such that higher beta power indexes longer produced durations. Moreover, although beta power measured before the first key-press also influenced the estimated interval, it did so independently from post-first-keypress beta power. These results suggest that initial motor inhibition plays an important role in interval production, and that this inhibition can be interpreted as a biased starting point of the decision processes involved in time estimation. (C) 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory–motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing., Highlights • High density EEG investigation in patients with PD before and after STN-DBS surgery • Resting state EEG: altered spectral composition following STN-DBS • Rhythmic auditory stimulation (RAS): absence of pre-stimulus beta activity in PD • Fast RAS: normalization of beta (13–30 Hz) activities by L-DOPA and STN-DBS • Altered beta modulation profile may contribute to timekeeping deficits in PD.

Drosophila melanogaster is an invaluable model organism for the study of basic neuroscience. Using two previously characterized mating behaviours (Longer- and Shorter-Mating Duration), this research aims to further our knowledge of the neural circuit involved in each, and shed light on the mechanism by which four SIFamide producing neurons are involved in both. We also seek to investigate the involvement of core circadian clock genes in interval timing mechanisms. To do so, we investigated the populations of SIFamide receptor expressing neurons necessary for each behaviour and studied the contribution of circadian clock genes within the SIFamide signalling pathway. Our main experimental approach consisted of population specific knock-downs of the SIFamide receptor, the impact of which was assessed using a simple behavioural assay. This approach was complemented by rescue experiments and feminization of neurons. Finally, our investigation of the circadian clock was mediated by circadian gene knock-downs in SIFamide expressing neurons. Our results show that SIFamide signalling for each mating behaviour is mediated by segregated signalling to different, non male-specific SIFamide receptor expressing neuronal populations. We further demonstrate that SIFamide expressing neurons are not involved in the interval timing mechanism of these mating behaviours via core circadian gene contribution. This work presents preliminary results towards the investigation of a novel model of decision-making via neuronal signalling.

This editorial serves a number of purposes. First, it aims at summarizing and discussing 33 accepted contributions to the special issue “The evolution of rhythm cognition: Timing in music and speech.” The major focus of the issue is the cognitive neuroscience of rhythm, intended as a neurobehavioral trait undergoing an evolutionary process. Second, this editorial provides the interested reader with a guide to navigate the interdisciplinary contributions to this special issue. For this purpose, we have compiled Table 1, where methods, topics, and study species are summarized and related across contributions. Third, we also briefly highlight research relevant to the evolution of rhythm that has appeared in other journals while this special issue was compiled. Altogether, this editorial constitutes a summary of rhythm research in music and speech spanning two years, from mid-2015 until mid-2017.

Cardiac signals reflect the function of the autonomic nervous system and have previously been associated with a range of self-regulatory behaviours such as emotion regulation and memory recall. It is unknown whether cardiac signals may also be associated with self-regulation in the temporal domain, in particular impulsivity. We assessed both decision impulsivity (temporal discounting) and time perception impulsivity (duration reproduction) in 120 participants while they underwent electrocardiography in order to test whether cardiac signals were related to these two aspects of impulsivity. We found that over the entire period of task performance, individuals with higher heart rates had a tendency toward lower discount rates, supporting previous research that has associated sympathetic responses with decreased impulsivity. We also found that low-frequency components of heart rate variability were associated with a less accurate perception of time, suggesting that time perception may be modulated by autonomic nervous system function. Overall, these findings constitute preliminary evidence that autonomic function plays an important role in both decision impulsivity and time perception.

Thalamic chronotaraxis is an isolated disorientation of time caused by the damage of thalamus, especially the mediodorsal nucleus. We performed interval timing trials on a patient with this phenomenon. Based on the results of those trials and compared to the previous reports, thalamic chronotaraxis of our case might be due to the disfunction of the dorsolateral prefrontal cortex caused by the right thalamic infarction. Keywords: Thalamic chronotaraxis, Interval timing, Mediodorsal nucleus of the thalamus, Dorsolateral prefrontal cortex

The dopamine clock hypothesis suggests that the dopamine level determines the speed of the hypothetical internal clock. However, dopaminergic function has also been implicated for motivation and thus the effect of dopaminergic manipulations on timing behavior might also be independently mediated by altered motivational state. Studies that investigated the effect of motivational manipulations on peak responding are reviewed in this paper. The majority of these studies show that a higher reward magnitude leads to a leftward shift, whereas reward devaluation leads to a rightward shift in the initiation of timed anticipatory behavior, typically in the absence of an effect on the timing of response termination. Similar behavioral effects are also present in a number of studies that investigated the effect of dopamine agonists and dopamine-related genetic factors on peak responding. These results can be readily accounted for by independent modulation of decision-thresholds for the initiation and termination of timed responding., FP7 Marie Curie; Scientific and Technological Research Council of Turkey (TÜBİTAK); The Science Academy BAGEP Grant

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 6.5s. 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; 3mg/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 (0.03mg/kg SC) but was unaffected by SB-242,084 (0.1mg/kg SC). Similar to DOI, the selective 5-HT2A agonist 25CN-NBOH (6mg/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.

This review outlines the basic psychological and neurobiological processes associated with age-related distortions in timing and time perception in the hundredths of milliseconds-to-minutes range. The difficulty in separating indirect effects of impairments in attention and memory from direct effects on timing mechanisms is addressed. The main premise is that normal aging is commonly associated with increased noise and temporal uncertainty as a result of impairments in attention and memory as well as the possible reduction in the accuracy and precision of a central timing mechanism supported by dopamine-glutamate interactions in cortico-striatal circuits. Pertinent to these findings, potential interventions that may reduce the likelihood of observing age-related declines in timing are discussed. Bayesian optimization models are able to account for the adaptive changes observed in time perception by assuming that older adults are more likely to base their temporal judgments on statistical inferences derived from multiple trials than on a single trial's clock reading, which is more susceptible to distortion. We propose that the timing functions assigned to the age-sensitive fronto-striatal network can be subserved by other neural networks typically associated with finely-tuned perceptuo-motor adjustments, through degeneracy principles (different structures serving a common function).

Existing evidence suggests that interval timing, processing of temporal information in the hundredth of milliseconds-to-minutes range, recruits broad brain regions such as cortico-striatal circuits via dopaminergic-glutamatergic pathways. In this review, we summarize recent findings on the neurobiological basis of interval timing with a special focus on dopaminergic modulations of temporal information. Two properties of interval timing - accuracy and precision - are used to examine recent results from manipulations of dopaminergic signaling and the resulting distortions in temporal processing. Fil: Agostino, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina Fil: Cheng, Ruey-Kuang. Institute Of Molecular And Cellular Biology A*star; Singapur

Organizing movements in time is a critical and highly conserved feature of mammalian behavior. Temporal control of action requires corticostriatal networks. We investigate these networks in rodents using a two-interval timing task while recording local field potentials in medial frontal cortex or dorsomedial striatum. Consistent with prior work, we found cue-triggered delta (1-4 Hz) and theta activity (4-8 Hz) primarily in rodent medial frontal cortex. We observed delta activity across temporal intervals in medial frontal cortex and dorsomedial striatum. Rewarded responses were associated with increased delta activity in medial frontal cortex. Activity in theta bands in medial frontal cortex and delta bands in the striatum was linked with the timing of responses. These data suggest both delta and theta activity in frontostriatal networks are modulated during interval timing and that activity in these bands may be involved in the temporal control of action.

Judgments of physical stimuli show characteristic biases; relatively small stimuli are overestimated whereas relatively large stimuli are underestimated (regression effect). Such biases likely result from a strategy that seeks to minimize errors given noisy estimates about stimuli that itself are drawn from a distribution, i.e., the statistics of the environment. While being conceptually well described, it is unclear how such a strategy could be implemented neurally. The present paper aims towards answering this question. A theoretical approach is introduced that describes magnitude estimation as two successive stages of noisy (neural) integration. Both stages are linked by a reference memory that is updated with every new stimulus. The model reproduces the behavioral characteristics of magnitude estimation and makes several experimentally testable predictions. Moreover, the model identifies the regression effect as a means of minimizing estimation errors and explains how this optimality strategy depends on the subject's discrimination abilities and on the stimulus statistics. The latter influence predicts another property of magnitude estimation, the so-called range effect. Beyond being successful in describing decision-making, the present work suggests that noisy integration may also be important in processing magnitudes.

Timing is a fundamental and highly conserved mammalian capability, yet the underlying neural mechanisms are widely debated. Ramping activity of single neurons that gradually increase or decrease activity to encode the passage of time has been speculated to predict a behaviorally relevant temporal event. Cue-evoked low-frequency activity has also been implicated in temporal processing. Ramping activity and low-frequency oscillations occur throughout the brain and could indicate a network-based approach to timing. Temporal processing requires cognitive mechanisms of working memory, attention, and reasoning, which are dysfunctional in neuropsychiatric disease. Therefore, timing tasks could be used to probe cognition in animals with disease phenotypes. The medial frontal cortex and cerebellum are involved in cognition. Cerebellar stimulation has been shown to influence medial frontal activity and improve cognition in schizophrenia. However, the mechanism underlying the efficacy of cerebellar stimulation is unknown. Here, we discuss how timing tasks can be used to probe cerebellar interactions with the frontal cortex and the therapeutic potential of cerebellar stimulation. The goal of this theory and hypothesis manuscript is threefold. First, we will summarize evidence indicating that in addition to motor learning, timing tasks involve cognitive processes that are present within both the cerebellum and medial frontal cortex. Second, we propose methodologies to investigate the connections between these areas in patients with Parkinson’s disease, autism, and schizophrenia. Lastly, we hypothesize that cerebellar transcranial stimulation may rescue medial frontal ramping activity, theta oscillations, and timing abnormalities, thereby restoring executive function in diseases of impaired cognition. This hypothesis could inspire the use of timing tasks as biomarkers for neuronal and cognitive abnormalities in neuropsychiatric disease and promote the therapeutic potential of the cerebellum in diseases of impaired cognition.

Medial frontal cortical (MFC) dopamine is essential for the organization of behavior in time. Our prior work indicates that blocking D1 dopamine receptors (D1DR) attenuates temporal processing and low-frequency oscillations by MFC neuronal networks. Here we investigate the effects of focal infusion of the D1DR agonist SKF82958 into MFC during interval timing. MFC D1DR agonist infusion impaired interval timing performance without changing overall firing rates of MFC neurons. MFC ramping patterns of neuronal activity that reflect temporal processing were attenuated following infusion of MFC D1DR agonist. MFC D1DR agonist infusion also altered MFC field potentials by enhancing delta activity between 1 and 4 Hz and attenuating alpha activity between 8 and 15 Hz. These data support the idea that the influence of D1-dopamine signals on frontal neuronal activity adheres to a U-shaped curve, and that cognition requires optimal levels of dopamine in frontal cortex.

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.

The striatum is an input structure of the basal ganglia implicated in several time-dependent functions including reinforcement learning, decision making, and interval timing. To determine whether striatal ensembles drive subjects' judgments of duration, we manipulated and recorded from striatal neurons in rats performing a duration categorization psychophysical task. We found that the dynamics of striatal neurons predicted duration judgments, and that simultaneously recorded ensembles could judge duration as well as the animal. Furthermore, striatal neurons were necessary for duration judgments, as muscimol infusions produced a specific impairment in animals' duration sensitivity. Lastly, we show that time as encoded by striatal populations ran faster or slower when rats judged a duration as longer or shorter, respectively. These results demonstrate that the speed with which striatal population state changes supports the fundamental ability of animals to judge the passage of time. DOI: http://dx.doi.org/10.7554/eLife.11386.001, eLife digest You know someone is a good cook from their rice - grains must be well cooked, but not to the point of being mushy. Despite consistently using the same pot and stove, we, however, will sometimes overcook it. It is as if our inner sense of time itself is variable. What is it about the brain that explains this variability in time estimation and indeed our ability to estimate time in the first place? One issue the brain must confront in order to estimate time is that individual brain cells typically fire in bursts that last for tens of milliseconds. So how does the brain use this short-lived activity to track minutes and hours? One possibility is that individual neurons in a given brain region are programmed to fire at different points in time. The overall firing pattern of a group of neurons will therefore change in a predictable way as time passes. Gouvêa, Monteiro et al. found such predictably changing patterns of activity in the striatum of rats trained to estimate and categorize the duration of time intervals as longer or shorter than 1.5 seconds. Interestingly, when rats mistakenly categorized a short interval as a long one, population activity had travelled farther down its path than it would normally (and vice-versa for long intervals incorrectly categorized as short), suggesting that variability in subjective estimates of the passage of time might arise from variability in the speed of a changing pattern of activity across groups of neurons. As further evidence for the involvement of the striatum, inactivating the structure impaired the rats’ ability to correctly classify even the longest and shortest interval durations. The next challenge is to determine exactly how the striatum generates these time-keeping signals, at which stage variability originates, and how the brain regions that the striatum signals to use them to control an animal’s behavior. DOI: http://dx.doi.org/10.7554/eLife.11386.002

Although perceiving the passage of time is a basic building block of cognitive processes and behavior such as expecting relevant events to happen, the neural underpinnings of interval timing are not well-understood as yet (van Wassenhove, 2009; Allman and Meck, 2012; Merchant et al., 2013). From the neurobiological point of view, it has been established that dopamine impacts interval timing (e.g., Meck, 1986, 1996; Allman and Meck, 2012). However, a link between pharmacological manipulations and their impact on neurophysiological signals has been rarely investigated. The leading neurobiologically plausible model of interval timing that considers both components is the Striatal Beat Frequency (SBF) model (Mattel and Meck, 2004; Buhusi and Meck, 2005; van Rijn et al., 2014). The SBF model relies on the neuromodulatory dynamics of the thalamo-cortico-striatal loops. Although currently most of the interactions in the SBF model are assumed to be unidirectional, Mattel and Meck (2004) also acknowledged the possibility of feedback from the cortex to the neurons in the VTA as well as from striatal neurons to both the cortex and the substantia nigra pars compacta. These potential feedback mechanisms are unaddressed in the SBF model. However, their implementation would allow for more accurate description of clock speed and memory updating mechanisms on a trial to trial basis (W. Meck, personal communication, May 15, 2015). Nevertheless, the SBF assumes that time is coded by the coincidental activation of striatal spiny neurons with cortical oscillators (CO). Numerical implementations of the SBF model utilizes the phase, or amplitude, of the CO that are envisioned to oscillate at various frequencies giving rise to different amplitude patterns over time as illustrated in Figure ​Figure1.1. Hence, at a given time point a specific amplitude pattern of the CO can be encoded by striatal spiny neurons. Crucially, the SBF model assumes that, at the onset of the to-be-timed interval, the phases of CO are reset by a burst of dopaminergic input from the ventral tegmental area (VTA, Mattel and Meck, 2004). Further, the SBF model contends that the initial dopamine-triggered phase-resetting of CO by VTA plays the role of a “start-gun” that initiates timing. This “start-gun” signal forces a whole set of CO to start from the same phase, allowing for coincidence detection to read the state of CO, and code for a particular duration over multiple trials. Importantly, the more accurate the phase-reset at the onset of the to-be-timed interval—that is, the proportion of CO that is reset to the same phase—the larger the phase synchronization and the oscillatory power of ongoing oscillations (Canavier, 2015), and as such reduces variability in memory representation of to-be-timed interval (see Figure ​Figure1;1; Ng et al., 2011). Within this framework more precise phase reset should be associated with an increase in timing accuracy. Note that timing accuracy can be seen as a peak latency of a response distribution, or kurtosis of a response distribution. According to the SBF model the peak latency and kurtosis of response distribution can be accounted for by different features of the model. The peak latency is modulated by frequency range of CO whereas kurtosis is accounted for by accuracy of initial phase reset (Oprisan and Buhusi, 2014). As such the width shows consistency of memory representation estimated over a number of trials. What is referred to here is the accuracy as the width of the response distribution that is associated to initial reset in terms of the SBF model. Therefore, the width of the response distribution should be affected by consistency of phase reset. However, such covariation between the precision of the “start-gun” represented by the modulation of oscillatory synchrony in any neural population and timing accuracy has not yet been tested directly.

Short-term interval timing i.e., perception and action relating to durations in the seconds range, has been suggested to display time-of-day as well as wake dependent fluctuations due to circadian and sleep-homeostatic changes to the rate at which an underlying pacemaker emits pulses; pertinent human data being relatively sparse and lacking in consistency however, the phenomenon remains elusive and its mechanism poorly understood. To better characterize the putative circadian and sleep-homeostatic effects on interval timing and to assess the ability of a pacemaker-based mechanism to account for the data, we measured timing performance in eighteen young healthy male subjects across two epochs of sustained wakefulness of 38.67 h each, conducted prior to (under entrained conditions) and following (under free-running conditions) a 28 h sleep-wake schedule, using the methods of duration estimation and duration production on target intervals of 10 and 40 s. Our findings of opposing oscillatory time courses across both epochs of sustained wakefulness that combine with increasing and, respectively, decreasing, saturating exponential change for the tasks of estimation and production are consistent with the hypothesis that a pacemaker emitting pulses at a rate controlled by the circadian oscillator and increasing with time awake determines human short-term interval timing; the duration-specificity of this pattern is interpreted as reflecting challenges to maintaining stable attention to the task that progressively increase with stimulus magnitude and thereby moderate the effects of pacemaker-rate changes on overt behavior.

The active place avoidance task is a dry-arena task used to assess spatial navigation and memory in rodents. In this task, a subject is put on a rotating circular arena and avoids an invisible sector that is stable in relation to the room. Rotation of the arena means that the subject’s avoidance must be active, otherwise the subject will be moved in the to-be-avoided sector by the rotation of the arena and a slight electric shock will be administered. The present experiment explored the effect of variable arena rotation speed on the ability to avoid the to-be-avoided sector. Subjects in a group with variable arena rotation speed learned to avoid the sector with the same speed and attained the same avoidance ability as rats in a group with a stable arena rotation speed. Only a slight difference in preferred position within the room was found between the two groups. No difference was found between the two groups in the dark phase, where subjects could not use orientation cues in the room. Only one rat was able to learn the avoidance of the to-be-avoided sector in this phase. The results of the experiment suggest that idiothetic orientation and interval timing are not crucial for learning avoidance of the to-be-avoided sector. However, idiothetic orientation might be sufficient for avoiding the sector in the dark.

Processing of time intervals in short tem-poral ranges, typically in sub- and supra-second intervals, is vital for the survivalof primates and humans. Research evi-dence has already shown that the process-ing of sub- and supra-second intervals issubserved by different neural mechanisms(Buhusi and Meck, 2005). In the domainof time perception, one outstanding sci-entific question remains to be solved iswhether the interval processing is imple-mented by a central clock (supra-sensory)or specific clock (neural state-specific)representation (Ivry and Schlerf, 2008).Gupta (2014) initiated theoretical explo-rations by introducing different types ofneuronal oscillators, with three key com-ponents:pacemakerneurons,tonicinputs,and synchronized excitation/inhibition ofinter-connected neurons (Gupta, 2014).Gupta further featured three characteris-ticfactorsinanintegrated model:(1).Theencoding of the time interval is reflectedby frequency modulated neuronal spikesor spikebursts affiliated with thetemporalpoints of a given interval. (2). Our brainembraces active calibration mechanismsamong multiple oscillators and modularconnections, which could to a large extentpitagainstthelossofintervaltimingfunc-tions of the brain. (3). The neuronal oscil-lators have solid foundations in neuralsubstrates that typically characterize sen-sorimotor timing, from the changes ofmembrane potential to the functioningof high-level brain structures (Teki et al.,2011; Santos et al., 2014).The concept of the building block for“neural oscillators” in Gupta (2014) inessence could be extended and interpretedin different contexts: Firstly, the “neu-ronaltemporalunits”in, Gupta (2014)in contrast to the traditional “pacemaker-accumulator” model (Treisman, 1963;Treisman et al., 1990, 1994; Wittmann,1999), is a machinery device (inherent inthebrain)thatprocessesthetimeinforma-tion. Secondly, the “oscillators” entail the“modular” nature of neuronal clocks, byemphasizing the correspondence betweenneural substrates in temporal bindingsbetween different sensory events. In thisway and from a broad perspective, thismodel dovetails the tenets of “intrin-sic model” (Ivry and Schlerf, 2008), butallows mechanistic flexibility for the inter-actions between separate clocks. Thirdly,the oscillators could demonstrate higher-level ensemble neuronal activities (butwere relatively less addressed in cur-rentmodel),includingoscillatorygamma-band responses (Herrmann et al., 2004;Tallon-Baudry and Bertrand, 1999).Movement is the expressed time (Tekiet al., 2011). The Theoretical modelfor Gupta (2014) stems from the com-mon setting of “movement control” butencourages more potential investigationstocome.Forexample,itcouldbeextendedand validated in other timing scenarios—go beyond the area of motor control—todemonstrate its robustness. Moreover, atypicalfunctionofhumantimingsystemisto predict the imminent events and hencemake efficient perceptual decision mak-ing. The current oscillation model leavesmuch room to be improved by revealinghowtheoscillatorscouldworkdirectlyinaframework of predictive coding. This pre-dictivecodingissomehowfreeoffeedbackprocesses as assumed in Gupta (2014).Furthermore, a high-level processing ofrhythm/periodicity-based upon the infor-mation of sub- or supra-second intervals,might mobilizepopulation/ensemble neu-ronal coding as well as impose more com-plexinter-connections/overlappings ofthesupposed neuronal temporal units (withmultiple neuronal feedback loops). WhatGupta (2014) proposed essentially indi-cated a potential panorama of neuraloscillators that could address the com-plexity of timing behavior. However,how many (levels of) oscillators areneeded to elucidate those timing behav-iors and how local lateral excitatory con-nectivity (Gavornik and Shouval, 2011),interacting with the global (stochastic)processingofbeattiming,warrantsfurtherexplorations.

Beta-band oscillations in basal ganglia-cortical loops have been shown to be linked to motor function in both healthy and pathological states (Brown, 2007; Engel and Fries, 2010). As well as coordinating motor activity, for instance when we synchronize our movements to a beat, the basal ganglia including the putamen and the caudate are said to contain specialized timekeeping mechanisms for perceptual timing (Buhusi and Meck, 2005). However, the exact neurophysiological role of beta-band oscillatory activity in the striatum in interval timing is not yet known. In a recent study published in The Journal of Neuroscience, Bartolo et al. (2014) examined the role of beta oscillations in interval timing by directly recording from the putamen in macaques during a rhythmic synchronization task. In this paradigm, a metronome is used to establish an isochronous beat (synchronization phase) and the variability in the subsequent taps produced by the subject after the metronome is turned off (continuation phase) is evaluated as an index of internal timing behavior. Single-unit as well as local field potential (LFP) activity in the putamen in the beta and gamma range was analyzed to determine the neural correlates of interval timing. They found that LFPs in the beta band exhibit interval tuning and showed a preference for intervals with duration around 800 ms, similar to the preferred duration observed in medial premotor cortex neurons (Merchant et al., 2013). They also reported tuning for serial order (or the task phases): LFPs in the beta band showed preferential tuning for the continuation phase that relies on internal timing whilst gamma band LFPs showed a bias toward the synchronization phase that depends on precise sensory coding. Another significant result suggests that beta oscillations are coherent at large electrode distances within the putamen that may reflect functional coordination across several areas of the putamen, and possibly the wider sensorimotor network for temporal processing. On the other hand, gamma oscillations showed small coherence associated most likely with local stimulus processing. The present study and previous work from this group (Merchant et al., 2011, 2013) are based on an arduous methodological approach where macaques are trained to perform complex tapping tasks based on sequences of intervals rather than single isolated intervals and disambiguating stimulus-related neural activity from movement-related responses (Perez et al., 2013). Natural acoustic signals consist of sequences of time intervals, and it is important not only to encode the duration of individual sounds but also the serial order in which they are presented. The current study is the first to show evidence of both interval and serial order tuning in such sequences in the beta-band responses in the putamen. The present study only addresses internal timing in regular sequences and it is not yet known how temporal jitter would affect the putaminal beta-band activity. In irregular sequences, beta-band modulation may remain the same or change as a function of the amount of jitter. As natural sounds are rarely presented in a temporally regular context, future work needs to address how the brain perceives time in irregular sequences. Related to this question, Fujioka et al. (2012) used magnetoencephalography to examine the nature of beta-band responses in the auditory cortex during passive listening to regular and random sequences. They found that the beta desynchronization after stimulus onset did not vary with the regularity of the stimulus, but the subsequent beta rebound peaked just before the next sound onset only for the regular stimuli. Temporal processing in irregular sequences has been shown to be preferentially mediated by a network based in the cerebellum whilst timing in regular sequences is carried out by a striato-frontal network (Teki et al., 2011). The cerebellum is another key node of the temporal processing network (Ivry and Spencer, 2004) and recent theoretical models emphasize the involvement of both the cerebellum and the basal ganglia that are inter-connected with each other and the cortex through multiple synaptic pathways (Teki et al., 2012; Allman et al., 2014). Fujioka et al. (2012) demonstrated beta-band coherence between auditory and motor-related areas including the cerebellum but it remains to be investigated whether such functional coupling during interval timing is driven by the cerebellum, the basal ganglia, or by a different brain area that influences activity in both these core timing areas. Bartolo et al. (2014) only briefly mention predictive coding mechanisms in bottom-up (synchronization phase) and top-down (continuation phase) processing. Bastos et al. (2012) recently proposed a canonical microcircuit for predictive coding based on iterative message passing between bottom-up stimulus-driven processing (in the gamma range) by superficial cortical neurons and top-down coding of predictive signals by deep cortical cells (in the beta range). A predictive model can be invoked in the context of the present rhythmic synchronization task where tapping to the metronome during the synchronization phase helps establish an internal model of the timing between successive metronome pulses and subsequent taps following the removal of the metronome may be driven by predictive signals. The findings of preferential gamma modulation during the synchronization phase and beta modulation during the continuation phase ties in with such a predictive coding framework. A hierarchical model for predictive coding may be anatomically realizable even locally within the striatum where there is evidence of prediction error coding by the caudate nucleus and ventral striatum whilst the putamen encodes the prediction (Haruno and Kawato, 2006). This hypothesis is supported by functional magnetic resonance imaging data showing that the putamen is specifically involved in internal prediction of beats rather than detection of beats (Grahn and Rowe, 2013). In summary, this stimulating work on the role of putamen during internally driven timing behavior significantly adds to previous work by Merchant and colleagues based on recordings from medial premotor cortex (Merchant et al., 2011, 2013). It emphasizes the role of endogenous beta oscillations in the basal ganglia as a principal feature of interval timing in a regular, beat-based context. The study underlines the importance of local electrophysiological recordings in key areas of the animal brain to inform models of interval timing and rhythmic synchronization in humans (Teki et al., 2012) as well as non-human primates (Merchant and Honing, 2014).

International audience; Interval timing refers to the ability to perceive, estimate and discriminate durations in the range of seconds to minutes. Very little is currently known about the ontogeny of interval timing throughout development. On the other hand, even though the neural circuit sustaining interval timing is a matter of debate, the striatum has been suggested to be an important component of the system and its maturation occurs around the third post-natal (PN) week in rats. The global aim of the present study was to investigate interval timing abilities at an age for which striatum is not yet mature. We used odor fear conditioning, as it can be applied to very young animals. In odor fear conditioning, an odor is presented to the animal and a mild footshock is delivered after a fixed interval. Adult rats have been shown to learn the temporal relationships between the odor and the shock after a few associations. The first aim of the present study was to assess the activity of the striatum during odor fear conditioning using 2-Deoxyglucose autoradiography during development in rats. The data showed that although fear learning was displayed at all tested ages, activation of the striatum was observed in adults but not in juvenile animals. Next, we assessed the presence of evidence of interval timing in ages before and after the inclusion of the striatum into the fear conditioning circuit. We used an experimental setup allowing the simultaneous recording of freezing and respiration that have been demonstrated to be sensitive to interval timing in adult rats. This enabled the detection of duration-related temporal patterns for freezing and/or respiration curves in infants as young as 12 days PN during odor fear conditioning. This suggests that infants are able to encode time durations as well as and as quickly as adults while their striatum is not yet functional. Alternative networks possibly sustaining interval timing in infant rats are discussed.

The processing of time intervals in the sub- to supra-second range by the brain is critical for the interaction of primates with their surroundings in activities, such as foraging and hunting. For an accurate processing of time intervals by the brain, representation of physical time within neuronal circuits is necessary. I propose that time dimension of the physical surrounding is represented in the brain by different types of neuronal oscillators, generating spikes or spike bursts at regular intervals. The proposed oscillators include the pacemaker neurons, tonic inputs, and synchronized excitation and inhibition of inter-connected neurons. Oscillators, which are built inside various circuits of brain, help to form modular clocks, processing time intervals or other temporal characteristics specific to functions of a circuit. Relative or absolute duration is represented within neuronal oscillators by “neural temporal unit,” defined as the interval between regularly occurring spikes or spike bursts. Oscillator output is processed to produce changes in activities of neurons, named frequency modulator neuron, wired within a separate module, represented by the rate of change in frequency, and frequency of activities, proposed to encode time intervals. Inbuilt oscillators are calibrated by (a) feedback processes, (b) input of time intervals resulting from rhythmic external sensory stimulation, and (c) synchronous effects of feedback processes and evoked sensory activity. A single active clock is proposed per circuit, which is calibrated by one or more mechanisms. Multiple calibration mechanisms, inbuilt oscillators, and the presence of modular connections prevent a complete loss of interval timing functions of the brain.

Distortions of time perception are presented by a number of neuropsychiatric illnesses. Here we survey timing abilities in clinical populations with focal lesions in key brain structures recently implicated in human studies of timing. We also review timing performance in amnesic and traumatic brain injured patients in order to identify the nature of specific timing disorders in different brain damaged populations. We purposely analyzed the complex relationship between both cognitive and contextual factors involved in time estimation, as to characterize the correlation between timed and other cognitive behaviors in each group. We assume that interval timing is a solid construct to study cognitive dysfunctions following brain injury, as timing performance is a sensitive metric of information processing, while temporal cognition has the potential of influencing a wide range of cognitive processes. Moreover, temporal performance is a sensitive assay of damage to the underlying neural substrate after a brain insult. Further research in neurological and psychiatric patients will clarify whether time distortions are a manifestation of, or a mechanism for, cognitive and behavioral symptoms of neuropsychiatric disorders.

We propose a decomposition of the neurocognitive mechanisms that might underlie interval-based timing and rhythmic entrainment. Next to reviewing the concepts central to the definition of rhythmic entrainment, we discuss recent studies that suggest rhythmic entrainment to be specific to humans and a selected group of bird species, but, surprisingly, is not obvious in non-human primates. On the basis of these studies we propose the gradual audiomotor evolution hypothesis that suggests that humans fully share interval-based timing with other primates, but only partially share the ability of rhythmic entrainment (or beat-based timing). This hypothesis accommodates the fact that non-human primates (i.e., macaques) performance is comparable to humans in single interval tasks (such as interval reproduction, categorization, and interception), but show differences in multiple interval tasks (such as rhythmic entrainment, synchronization, and continuation). Furthermore, it is in line with the observation that macaques can, apparently, synchronize in the visual domain, but show less sensitivity in the auditory domain. And finally, while macaques are sensitive to interval-based timing and rhythmic grouping, the absence of a strong coupling between the auditory and motor system of non-human primates might be the reason why macaques cannot rhythmically entrain in the way humans do.

Patients with Parkinson’s disease (PD) have deficits in perceptual timing, or the perception and estimation of time. PD patients can also have cognitive symptoms, including deficits in executive functions such as working memory, planning, and visuospatial attention. Here, we discuss how PD-related cognitive symptoms contribute to timing deficits. Timing is influenced by signaling of the neurotransmitter dopamine in the striatum. Timing also involves the frontal cortex, which is dysfunctional in PD. Frontal cortex impairments in PD may influence memory subsystems as well as decision processes during timing tasks. These data suggest that timing may be a type of executive function. As such, timing can be used to study the neural circuitry of cognitive symptoms of PD as they can be studied in animal models. Performance of timing tasks also maybe a useful clinical biomarker of frontal as well as striatal dysfunction in PD.

International audience; Time perception is crucial to goal attainment in humans and other animals, and interval timing also guides fundamental animal behaviors. Accumulating evidence has made it clear that in associative learning, temporal relations between events are encoded, and a few studies suggest this temporal learning occurs very rapidly. Most of these studies, however, have used methodologies that do not permit investigating the emergence of this temporal learning. In the present study we monitored respiration, ultrasonic vocalization (USV) and freezing behavior in rats in order to perform fine-grain analysis of fear responses during odor fear conditioning. In this paradigm an initially neutral odor (the conditioned stimulus, CS) predicted the arrival of an aversive unconditioned stimulus (US, footshock) at a fixed 20-s time interval. We first investigated the development of a temporal pattern of responding related to CS-US interval duration. The data showed that during acquisition with odor-shock pairings, a temporal response pattern of respiration rate was observed. Changing the CS-US interval duration from 20-s to 30-s resulted in a shift of the temporal response pattern appropriate to the new duration thus demonstrating that the pattern reflected the learning of the CS-US interval. A temporal pattern was also observed during a retention test 24 h later for both respiration and freezing measures, suggesting that the animals had stored the interval duration in long-term memory. We then investigated the role of intra-amygdalar dopaminergic transmission in interval timing. For this purpose, the D1 dopaminergic receptors antagonist SCH23390 was infused in the basolateral amygdala before conditioning. This resulted in an alteration of timing behavior, as reflected in differential temporal patterns between groups observed in a 24 h retention test off drug. The present data suggest that D1 receptor dopaminergic transmission within the amygdala is involved in temporal processing.

It is debated whether sub-second timing is subserved by a centralized mechanism or by the intrinsic properties of task-related neural activity in specific modalities (Ivry and Schlerf, 2008). By using a temporal adaptation task, we investigated whether adapting to different time intervals conveyed through stimuli in different modalities (i.e., frames of a visual Ternus display, visual blinking discs, or auditory beeps) would affect the subsequent implicit perception of visual timing, i.e., inter-stimulus interval (ISI) between two frames in a Ternus display. The Ternus display can induce two percepts of apparent motion (AM), depending on the ISI between the two frames: “element motion” for short ISIs, in which the endmost disc is seen as moving back and forth while the middle disc at the overlapping or central position remains stationary; “group motion” for longer ISIs, in which both discs appear to move in a manner of lateral displacement as a whole. In Experiment 1, participants adapted to either the typical “element motion” (ISI = 50 ms) or the typical “group motion” (ISI = 200 ms). In Experiments 2 and 3, participants adapted to a time interval of 50 or 200 ms through observing a series of two paired blinking discs at the center of the screen (Experiment 2) or hearing a sequence of two paired beeps (with pitch 1000 Hz). In Experiment 4, participants adapted to sequences of paired beeps with either low pitches (500 Hz) or high pitches (5000 Hz). After adaptation in each trial, participants were presented with a Ternus probe in which the ISI between the two frames was equal to the transitional threshold of the two types of motions, as determined by a pretest. Results showed that adapting to the short time interval in all the situations led to more reports of “group motion” in the subsequent Ternus probes; adapting to the long time interval, however, caused no aftereffect for visual adaptation but significantly more reports of group motion for auditory adaptation. These findings, suggesting amodal representation for sub-second timing across modalities, are interpreted in the framework of temporal pacemaker model.

Accurate timing is an integral aspect of sensory and motor processes such as the perception of speech and music and the execution of skilled movement. Neuropsychological studies of time perception in patient groups and functional neuroimaging studies of timing in normal participants suggest common neural substrates for perceptual and motor timing. A timing system is implicated in core regions of the motor network such as the cerebellum, inferior olive, basal ganglia, pre-supplementary, and supplementary motor area, pre-motor cortex as well as higher-level areas such as the prefrontal cortex. In this article, we assess how distinct parts of the timing system subserve different aspects of perceptual timing. We previously established brain bases for absolute, duration-based timing and relative, beat-based timing in the olivocerebellar and striato-thalamo-cortical circuits respectively (Teki et al., 2011). However, neurophysiological and neuroanatomical studies provide a basis to suggest that timing functions of these circuits may not be independent. Here, we propose a unified model of time perception based on coordinated activity in the core striatal and olivocerebellar networks that are interconnected with each other and the cerebral cortex through multiple synaptic pathways. Timing in this unified model is proposed to involve serial beat-based striatal activation followed by absolute olivocerebellar timing mechanisms.

Sleep, circadian rhythms, and interval timing are evolutionary well-conserved functions that are widely shared throughout the animal kingdom. A crucial property of the brain is to make use of internal clock mechanisms (e.g., circadian) to locate events in time. From a neurobiological and computational point of view, clock mechanisms can be seen as strategies that involve information processing of internal biological states at different time scales ( Tucci, 2011 , Tucci et al., 2014 ). The coordination between temporal information processing and internal physiological responses maintains homeostasis in many biological domains. For example, sleep is a genetically and epigenetically regulated phenomenon that can be mathematically modelled by, at least, two fundamental processes, a homeostatic process and a circadian process. The homeostatic process of sleep depends on the previous wakefulness, representing the pressure for sleep since last sleep episode. The circadian process dictates the timing of sleep, it is a self-sustained periodic mechanism and it develops with approximately 24 hours, cell- autonomous, oscillations. Thus, the distribution of sleep over 24 hours results from the combination of these two processes. Moreover, the ability to understand and perform in time is also realised within seconds-to-minutes intervals (e.g., interval timing). Interval timing represents a cross-species crucial property of many cognitive processes; interestingly, this short timing ability varies with the time of day, and it has been shown that sleep enhances the consolidation of timing learning. Furthermore, we have observed that mouse performance is modulated by a sleep inertia-like effect (Maggi et al., 2014). To understand the interplay between sleep homeostasis, circadian biological rhythms and interval timing it is mandatory to address specific questions on the genetic and epigenetic regulatory mechanisms that are associated with these functions. To address these questions, I will present our recent work which has been focused in: (i) understanding whether monoallelic versus biallelic epigenetic mechanisms exert a specific role in sleep and sleep-related timing functions ( Lassi et al., 2012 , Tinarelli et al., 2014 ), (ii) understanding how circadian rhythms and sleep-wake mechanisms modulate various cognitive processes such as interval timing, temporal uncertainty and risk assessment, (iii) understanding whether clock genes regulate sleep homeostasis and cognitive timing, by investigating these functions in mouse clock mutants.

The duration bisection paradigm is a classic task used to examine how humans and other animals perceive time. Typically, participants first learn short and long anchor durations and are subsequently asked to classify probe durations as closer to the short or long anchor duration. However, the specific representations of time and the decision rules applied in this task remain the subject of debate. For example, researchers have questioned whether participants actually use representations of the short and long anchor durations in the decision process rather than merely a response threshold that is derived from those anchor durations. Electroencephalographic (EEG) measures, like the Contingent Negative Variation (CNV), can provide information about the perceptual and cognitive processes that occur between the onset of the timing stimulus and the motor response. The CNV has been implicated as an electrophysiological marker of interval timing processes such as temporal accumulation, representation of the target duration, and the decision that the target duration has been attained. Hence, we used the CNV to investigate which durations are involved in the bisection categorization decision. The CNV increased in amplitude up to the value of the short anchor, remained at a constant level until about the geometric mean of the short and long anchors, when it began to resolve. These results suggest that the short anchor and the geometric mean of the short and long anchors are critical target durations used in the bisection categorization decision process. In addition, larger mean N1-P2 amplitude differences were associated with larger amplitude CNVs, which may reflect how precisely a participant is able to initiate timing on each trial across a test session. Overall, the results demonstrate the value of using scalp-recorded EEG to address basic questions about interval timing.