Embodying Time in the Brain: A Multi-Dimensional Neuroimaging Meta-Analysis of 95 Duration Processing Studies.

Time is an omnipresent aspect of almost everything we experience internally or in the external world. The experience of time occurs through such an extensive set of contextual factors that, after decades of research, a unified understanding of its neural substrates is still elusive. In this study, following the recent best-practice guidelines, we conducted a coordinate-based meta-analysis of 95 carefully-selected neuroimaging papers of duration processing. We categorized the included papers into 14 classes of temporal features according to six categorical dimensions. Then, using the activation likelihood estimation (ALE) technique we investigated the convergent activation patterns of each class with a cluster-level family-wise error correction at p < 0.05. The regions most consistently activated across the various timing contexts were the pre-SMA and bilateral insula, consistent with an embodied theory of timing in which abstract representations of duration are rooted in sensorimotor and interoceptive experience, respectively. Moreover, class-specific patterns of activation could be roughly divided according to whether participants were timing auditory sequential stimuli, which additionally activated the dorsal striatum and SMA-proper, or visual single interval stimuli, which additionally activated the right middle frontal and inferior parietal cortices. We conclude that temporal cognition is so entangled with our everyday experience that timing stereotypically common combinations of stimulus characteristics reactivates the sensorimotor systems with which they were first experienced.

The Motor of Time: Coupling Action to Temporally Predictable Events Heightens Perception.

Timing and motor function share neural circuits and dynamics, which underpin their close and synergistic relationship. For instance, the temporal predictability of a sensory event optimizes motor responses to that event. Knowing when an event is likely to occur lowers response thresholds, leading to faster and more efficient motor behavior though in situations of response conflict can induce impulsive and inappropriate responding. In turn, through a process of active sensing, coupling action to temporally predictable sensory input enhances perceptual processing. Action not only hones perception of the event's onset or duration, but also boosts sensory processing of its non-temporal features such as pitch or shape. The effects of temporal predictability on motor behavior and sensory processing involve motor and left parietal cortices and are mediated by changes in delta and beta oscillations in motor areas of the brain.

Time for Action: Neural Basis of the Costs and Benefits of Temporal Predictability for Competing Response Choices.

The brain can anticipate the time of imminent events to optimize sensorimotor processing. Yet, there can be behavioral costs of temporal predictability under situations of response conflict. Here, we sought to identify the neural basis of these costs and benefits by examining motor control processes in a combined EEG-EMG study. We recorded electrophysiological markers of response activation and inhibition over motor cortex when the onset-time of visual targets could be predicted, or not, and when responses necessitated conflict resolution, or not. If stimuli were temporally predictable but evoked conflicting responses, we observed increased intertrial consistency in the delta range over the motor cortex involved in response implementation, perhaps reflecting increased response difficulty. More importantly, temporal predictability differentially modulated motor cortex activity as a function of response conflict before the response was even initiated. This effect occurred in the hemisphere ipsilateral to the response, which is involved in inhibiting unwanted actions. If target features all triggered the same response, temporal predictability increased cortical inhibition of the incorrect response hand. Conversely, if different target features triggered two conflicting responses, temporal predictability decreased inhibition of the incorrect, yet prepotent, response. This dissociation reconciles the well-established behavioral benefits of temporal predictability for nonconflicting responses as well as its costs for conflicting ones by providing an elegant mechanism that operates selectively over the motor cortex involved in suppressing inappropriate actions just before response initiation. Taken together, our results demonstrate that temporal information differentially guides motor activity depending on response choice complexity.

Don't Stop Me Now: Neural Underpinnings of Increased Impulsivity to Temporally Predictable Events.

Although the benefit of temporal predictability for behavior is long-established, recent studies provide evidence that knowing when an important event will occur comes at the cost of greater impulsivity. Here, we investigated the neural basis of inhibiting actions to temporally predictable targets using an EEG-EMG method. In our temporally cued version of the stop-signal paradigm (two-choice task), participants used temporal information delivered by a symbolic cue to speed their responses to the target. In a quarter of the trials, an auditory signal indicated that participants had to inhibit their actions. Behavioral results showed that although temporal cues speeded RTs, they also impaired the ability to stop actions as indexed by longer stop-signal reaction time. In line with behavioral benefits of temporal predictability, EEG data demonstrated that acting at temporally predictable moments facilitated response selection at the cortical level (reduced frontocentral negativity just before the response). Likewise, activity of the motor cortex involved in suppression of incorrect response hand was stronger for temporally predictable events. Thus, by keeping an incorrect response in check, temporal predictability likely enabled faster implementation of the correct response. Importantly, there was no effect of temporal cues on the EMG-derived index of online, within-trial inhibition of subthreshold impulses. This result shows that although participants were more prone to execute a fast response to temporally predictable targets, their inhibitory control was, in fact, unaffected by temporal cues. Altogether, our results demonstrate that greater impulsivity when responding to temporally predictable events is paralleled by enhanced neural motor processes involved in response selection and implementation rather than impaired inhibitory control.

Dopamine Precursor Depletion in Healthy Volunteers Impairs Processing of Duration but Not Temporal Order.

Studies in animals and humans have implicated the neurotransmitter dopamine in duration processing. However, very few studies have examined dopamine's involvement in other forms of temporal processing such as temporal order judgments. In a randomized within-subject placebo-controlled design, we used acute phenylalanine/tyrosine depletion (APTD) to reduce availability of the dopamine precursors tyrosine and phenylalanine in healthy human volunteers. As compared to a nutritionally balanced drink, APTD significantly impaired the ability to accurately reproduce interval duration in a temporal reproduction task. In addition, and confirming previous findings, the direction of error differed as a function of individual differences in underlying dopamine function. Specifically, APTD caused participants with low baseline dopamine precursor availability to overestimate the elapse of time, whereas those with high dopamine availability underestimated time. In contrast to these effects on duration processing, there were no significant effects of APTD on the accuracy of discriminating the temporal order of visual stimuli. This pattern of results does not simply represent an effect of APTD on motor, rather than perceptual, measures of timing because APTD had no effect on participants' ability to use temporal cues to speed RT. Our results demonstrate, for the first time in healthy volunteers, a dopaminergic dissociation in judging metrical (duration) versus ordinal (temporal order) aspects of time.

Dopamine Signaling Modulates the Stability and Integration of Intrinsic Brain Networks.

Dopaminergic projections are hypothesized to stabilize neural signaling and neural representations, but how they shape regional information processing and large-scale network interactions remains unclear. Here we investigated effects of lowered dopamine levels on within-region temporal signal variability (measured by sample entropy) and between-region functional connectivity (measured by pairwise temporal correlations) in the healthy brain at rest. The acute phenylalanine and tyrosine depletion (APTD) method was used to decrease dopamine synthesis in 51 healthy participants who underwent resting-state functional MRI (fMRI) scanning. Functional connectivity and regional signal variability were estimated for each participant. Multivariate partial least squares (PLS) analysis was used to statistically assess changes in signal variability following APTD as compared with the balanced control treatment. The analysis captured a pattern of increased regional signal variability following dopamine depletion. Changes in hemodynamic signal variability were concomitant with changes in functional connectivity, such that nodes with greatest increase in signal variability following dopamine depletion also experienced greatest decrease in functional connectivity. Our results suggest that dopamine may act to stabilize neural signaling, particularly in networks related to motor function and orienting attention towards behaviorally-relevant stimuli. Moreover, dopamine-dependent signal variability is critically associated with functional embedding of individual areas in large-scale networks.

The beneficial effect of synchronized action on motor and perceptual timing in children.

We examined the role of action in motor and perceptual timing across development. Adults and children aged 5 or 8 years old learned the duration of a rhythmic interval with or without concurrent action. We compared the effects of sensorimotor versus visual learning on subsequent timing behaviour in three different tasks: rhythm reproduction (Experiment 1), rhythm discrimination (Experiment 2) and interval discrimination (Experiment 3). Sensorimotor learning consisted of sensorimotor synchronization (tapping) to an isochronous visual rhythmic stimulus (ISI = 800 ms), whereas visual learning consisted of simply observing this rhythmic stimulus. Results confirmed our hypothesis that synchronized action during learning systematically benefitted subsequent timing performance, particularly for younger children. Action-related improvements in accuracy were observed for both motor and perceptual timing in 5 years olds and for perceptual timing in the two older age groups. Benefits on perceptual timing tasks indicate that action shapes the cognitive representation of interval duration. Moreover, correlations with neuropsychological scores indicated that while timing performance in the visual learning condition depended on motor and memory capacity, sensorimotor learning facilitated an accurate representation of time independently of individual differences in motor and memory skill. Overall, our findings support the idea that action helps children to construct an independent and flexible representation of time, which leads to coupled sensorimotor coding for action and time.

Dissociating Bottom-Up and Top-Down Mechanisms in the Cortico-Limbic System during Emotion Processing.

The cortico-limbic system is critically involved in emotional responses and resulting adaptive behaviors. Within this circuit, complementary regions are believed to be involved in either the appraisal or the regulation of affective state. However, the respective contribution of these bottom-up and top-down mechanisms during emotion processing remains to be clarified. We used a new functional magnetic resonance imaging (fMRI) paradigm varying 3 parameters: emotional valence, emotional congruency, and allocation of attention, to distinguish the functional variation in activity and connectivity between amygdala, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). Bottom-up appraisal of negative compared with positive stimuli led to a greater amygdala response and stronger functional interaction between amygdala and both dorsal ACC and DLPFC. Top-down resolution of emotional conflict was associated with increased activity within ACC and higher functional connectivity between this structure, and both the amygdala and DLPFC. Finally, increased top-down attentional control caused greater engagement of the DLPFC, accompanied by increased connectivity between DLPFC and dorsal ACC. This novel task provides an efficient tool for exploring bottom-up and top-down processes underlying emotion and may be particularly helpful for investigating the neurofunctional underpinnings of psychiatric disorders.

Differential roles for parietal and frontal cortices in fixed versus evolving temporal expectations: Dissociating prior from posterior temporal probabilities with fMRI.

The ability to predict when an event will occur allows us to respond optimally to that event. Temporal predictability can be either fixed (prior probability) or evolving (posterior probability), in which case it is dynamically updated as a function of the elapse of time itself ("hazard function"). We used fMRI to identify the brain regions involved in either form of temporal prediction, within a single experimental paradigm. Participants performed a cued reaction time (RT) task, in which the target appeared after one of four intervals ("foreperiods") that was either predictable (temporal condition) or variable (neutral condition). As expected, RTs were faster in temporal versus neutral conditions, indicating the behavioural benefit of fixed temporal predictability. RTs also got faster as a function of foreperiod in the neutral, but not temporal, condition, reflecting the evolving temporal predictability of the hazard function. We confirmed that left inferior parietal cortex was preferentially activated by the fixed temporal predictability of temporal (versus neutral) cues. Then, by directly comparing how activity varied as a function of foreperiod in the neutral versus time conditions, we identified the neural substrates of the changes in temporal probability defined by the hazard function, while simultaneously controlling for changes related simply to the elapse of time itself. Whole-brain fMRI analyses (independently confirmed by anatomically guided ROI analyses) showed that activity in left inferior parietal cortex tracked the evolving temporal probabilities of the hazard function. ROI analysis further revealed a similar role for right inferior frontal cortex. Our data highlight a key role for left parietal cortex in instantiating the behavioural benefits of temporal predictability, whether predictions are fixed or dynamically evolving.

Distinct developmental trajectories for explicit and implicit timing.

Adults and children aged 5 and 8years were given explicit and implicit timing tasks. These tasks were based on the same temporal representation (the temporal interval between two signals), but in the explicit task participants received overt instructions to judge the duration of the interval, whereas in the implicit task they did not receive any temporal instructions and were asked only to press as quickly as possible after the second signal. In addition, participants' cognitive capacities were assessed with different neuropsychological tests. The results showed that temporal variability (i.e., the spread of performance around the reference interval) decreased as a function of age in the explicit task, being higher in the 5-year-olds than in the 8-year-olds and adults. The higher variability in the youngest children was directly linked to their limited cognitive capacity. By contrast, temporal variability in the implicit timing task remained constant across the different age groups and was unrelated to cognitive capacity. Processing of time, therefore, was independent of age in the implicit task but changed with age in the explicit task, thereby demonstrating distinct developmental trajectories for explicit and implicit timing.

SMA Selectively Codes the Active Accumulation of Temporal, Not Spatial, Magnitude.

Estimating duration depends on the sequential integration (accumulation) of temporal information in working memory. Using fMRI, we directly compared the accumulation of information in temporal versus spatial domains. Participants estimated either the duration or distance of the dynamic trajectory of a moving dot or, in a control condition, a static line stimulus. Comparing the duration versus distance of static lines activated an extensive cortico-striatal network. By contrast, comparing the duration versus distance of dynamic trajectories, both of which required sequential integration of information, activated SMA alone. Indeed, activity in SMA, as well as right inferior occipital cortex, increased parametrically as a function of stimulus duration and also correlated with individual differences in the propensity to overestimate stimulus duration. By contrast, activity in primary visual cortex increased parametrically as a function of stimulus distance. Crucially, a direct comparison of the parametric responses to duration versus distance revealed that activity in SMA increased incrementally as a function of stimulus duration but not as a function of stimulus distance. Collectively, our results indicate that SMA responds to the active accumulation of information selectively in the temporal domain.

Effect of trait anxiety on prefrontal control mechanisms during emotional conflict.

Converging evidence points to a link between anxiety proneness and altered emotional functioning, including threat-related biases in selective attention and higher susceptibility to emotionally ambiguous stimuli. However, during these complex emotional situations, it remains unclear how trait anxiety affects the engagement of the prefrontal emotional control system and particularly the anterior cingulate cortex (ACC), a core region at the intersection of the limbic and prefrontal systems. Using an emotional conflict task and functional magnetic resonance imaging (fMRI), we investigated in healthy subjects the relations between trait anxiety and both regional activity and functional connectivity (psychophysiological interaction) of the ACC. Higher levels of anxiety were associated with stronger task-related activation in ACC but with reduced functional connectivity between ACC and lateral prefrontal cortex (LPFC). These results support the hypothesis that when one is faced with emotionally incompatible information, anxiety leads to inefficient high-order control, characterized by insufficient ACC-LPFC functional coupling and increases, possibly compensatory, in activation of ACC. Our findings provide a deeper understanding of the pathophysiology of the neural circuitry underlying anxiety and may offer potential treatment markers for anxiety disorders.

Metrical rhythm implicitly orients attention in time as indexed by improved target detection and left inferior parietal activation.

When we direct attentional resources to a certain point in time, expectation and preparedness is heightened and behavior is, as a result, more efficient. This future-oriented attending can be guided either voluntarily, by externally defined cues, or implicitly, by perceived temporal regularities. Inspired by dynamic attending theory, our aim was to study the extent to which metrical structure, with its beats of greater or lesser relative strength, modulates attention implicitly over time and to uncover the neural circuits underlying this process of dynamic attending. We used fMRI to investigate whether auditory meter generated temporal expectancies and, consequently, how it affected processing of auditory and visual targets. Participants listened to a continuous auditory metrical sequence and pressed a button whenever an auditory or visual target was presented. The independent variable was the time of target presentation with respect to the metrical structure of the sequence. Participants' RTs to targets occurring on strong metrical positions were significantly faster than responses to events falling on weak metrical positions. Events falling on strong beats were accompanied by increased activation of the left inferior parietal cortex, a region crucial for orienting attention in time, and, by greater functional connectivity between the left inferior parietal cortex and the visual and auditory cortices, the SMA and the cerebellum. These results support the predictions of the dynamic attending theory that metrical structure with its relative strong and weak beats modulates attentional resources over time and, in turn, affects the functioning of both perceptual and motor preparatory systems.

Getting the timing right: experimental protocols for investigating time with functional neuroimaging and psychopharmacology.

Functional Magnetic Resonance Imaging (fMRI) is an effective tool for identifying brain areas and networks implicated in human timing. But fMRI is not just a phrenological tool: by careful design, fMRI can be used to disentangle discrete components of a timing task and control for the underlying cognitive processes (e.g. sustained attention and WM updating) that are critical for estimating stimulus duration in the range of hundreds of milliseconds to seconds. Moreover, the use of parametric designs and correlational analyses allows us to better understand not just where, but also how, the brain processes temporal information. In addition, by combining fMRI with psychopharmacological manipulation, we can begin to uncover the complex relationship between cognition, neurochemistry and anatomy in the healthy human brain. This chapter provides an overview of some of the key findings in the functional imaging literature of both duration estimation and temporal prediction, and outlines techniques that can be used to allow timing-related activations to be interpreted more unambiguously. In our own studies, we have found that estimating event duration, whether that estimate is provided by a motor response or a perceptual discrimination, typically recruits basal ganglia, SMA and right inferior frontal cortex, and can be modulated by dopaminergic activity in these areas. By contrast, orienting attention to predictable moments in time in order to optimize behaviour, whether that is to speed motor responding or improve perceptual accuracy, recruits left inferior parietal cortex.

Dopamine precursor depletion impairs timing in healthy volunteers by attenuating activity in putamen and supplementary motor area.

Neuropsychological investigations of patients with Parkinson's disease, schizophrenia, or attention deficit disorder converge with psychopharmacological studies in animals and healthy volunteers to implicate dopamine (DA) pathways in timing. In parallel, single-cell recording and functional neuroimaging studies have highlighted the importance of basal ganglia, prefrontal cortex, and supplementary motor area (SMA) for timing. In a placebo-controlled, within-subject design, we combined event-related functional magnetic resonance imaging with a DA manipulation (acute phenylalanine/tyrosine depletion; APTD) in healthy volunteers to pinpoint the neuroanatomical and functional substrates of the DA modulation of timing. Behaviorally, APTD selectively impaired accuracy of perceptual timing, with no effect on performance of a color-control task matched for difficulty, working memory (WM), and attentional demands. Neurally, APTD attenuated timing-specific activity in the putamen and SMA. Notably, APTD-induced decreases in brain activity were directly correlated to APTD-induced impairments in timing performance. Moreover, APTD modulated timing-specific activity selectively during initial storage of the sample duration, but had no effect during its subsequent retrieval or comparison to a probe. Our results do not simply reflect DA modulation of WM since the color task controlled for the WM updating process necessary for timing of durations in the seconds range. Moreover, preliminary evidence indicated APTD effects on putamen and SMA were greater for subsecond (540 ms) than suprasecond (1080 ms) durations, when WM demands would actually be lower. Instead, we show for the first time in healthy humans that DA manipulation perturbs timing by attenuating the activity in putamen and SMA that mediates initial storage of temporal information into WM.

A transcranial magnetic stimulation study on the role of the left intraparietal sulcus in temporal orienting of attention.

Adaptive behavior requires the ability to orient attention to the moment in time at which a relevant event is likely to occur. Temporal orienting of attention has been consistently associated with activation of the left intraparietal sulcus (IPS) in prior fMRI studies. However, a direct test of its causal involvement in temporal orienting is still lacking. The present study tackled this issue by transiently perturbing left IPS activity with either online (Experiment 1) or offline (Experiment 2) transcranial magnetic stimulation (TMS). In both experiments, participants performed a temporal orienting task, alternating between blocks in which a temporal cue predicted when a subsequent target would appear and blocks in which a neutral cue provided no information about target timing. In Experiment 1 we used an online TMS protocol, aiming to interfere specifically with cue-related temporal processes, whereas in Experiment 2 we employed an offline protocol whereby participants performed the temporal orienting task before and after receiving TMS. The right IPS and/or the vertex were stimulated as active control regions. While results replicated the canonical pattern of temporal orienting effects on reaction time, with faster responses for temporal than neutral trials, these effects were not modulated by TMS over the left IPS (as compared to the right IPS and/or vertex regions) regardless of the online or offline protocol used. Overall, these findings challenge the causal role of the left IPS in temporal orienting of attention inviting further research on its underlying neural substrates.

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

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

Neural substrates of mounting temporal expectation.

A new primer gives a cognitive and neuroanatomical perspective on how timing and expectation are represented in the human brain.

Space-Time Congruency Effects Using Eye Movements During Processing of Past- and Future-Related Words.

In Western cultures where people read and write from left to right, time is represented along a spatial continuum that goes from left to right (past to future), known as the mental timeline (MTL). In language, this MTL was supported by space-time congruency effects: People are faster to make lexical decisions to words conveying past or future information when left/right manual responses are compatible with the MTL. Alternatively, in cultures where people read from right to left, space-time congruency effects go in the opposite direction. Such cross-cultural differences suggest that repeated writing and reading dynamic movements are critically involved in the spatial representation of time. In most experiments on the space-time congruency effect, participants use their hand for responding, an effector that is associated to the directionality of writing. To investigate the role of the directionality of reading in the space-time congruency effect, we asked participants to make lateralized eye movements (left or right saccades) to indicate whether stimuli were real words or not (lexical decision). Eye movement responses were slower and higher in amplitude for responses incompatible with the direction of the MTL. These results reinforce the claim that repeated directional reading and writing movements promote the embodiment of time-related words.

Embodied time: Effect of reading expertise on the spatial representation of past and future.

How do people grasp the abstract concept of time? It has been argued that abstract concepts, such as future and past, are grounded in sensorimotor experience. When responses to words that refer to the past or the future are either spatially compatible or incompatible with a left-to-right timeline, a space-time congruency effect is observed. In the present study, we investigated whether reading expertise determines the strength of the space-time congruency effect, which would suggest that learning to read and write drives the effect. Using a temporal categorization task, we compared two types of space-time congruency effects, one where spatial incongruency was generated by the location of the stimuli on the screen and one where it was generated by the location of the responses on the keyboard. While the first type of incongruency was visuo-spatial only, the second involved the motor system. Results showed stronger space-time congruency effects for the second type of incongruency (i.e., when the motor system was involved) than for the first type (visuo-spatial). Crucially, reading expertise, as measured by a standardized reading test, predicted the size of the space-time congruency effects. Altogether, these results reinforce the claim that the spatial representation of time is partially mediated by the motor system and partially grounded in spatially-directed movement, such as reading or writing.