Neuroimaging Signatures of Metacognitive Improvement in Sensorimotor Timing.

Error monitoring is an essential human ability underlying learning and metacognition. In the time domain, humans possess a remarkable ability to learn and adapt to temporal intervals, yet the neural mechanisms underlying this are not clear. Recently, we demonstrated that humans improve sensorimotor time estimates when given the chance to incorporate previous trial feedback ( Bader and Wiener, 2021), suggesting that humans are metacognitively aware of their own timing errors. To test the neural basis of this metacognitive ability, human participants of both sexes underwent fMRI while they performed a visual temporal reproduction task with randomized supra-second intervals (1.5-6 s). Crucially, each trial was repeated following feedback, allowing a "re-do" to learn from the successes or errors in the initial trial. Behaviorally, we replicated our previous finding of improved re-do trial performance despite temporally uninformative (i.e., early or late) feedback. For neuroimaging, we observed a dissociation between estimating and reproducing time intervals. Estimation engaged the default mode network (DMN), including the superior frontal gyri, precuneus, and posterior cingulate, whereas reproduction activated regions associated traditionally with the "timing network" (TN), including the supplementary motor area (SMA), precentral gyrus, and right supramarginal gyrus. Notably, greater and more extensive DMN involvement was observed in re-do trials, whereas for the TN, it was more constrained. Task-based connectivity between these networks demonstrated higher inter-network correlation primarily when estimating initial trials, while re-do trial communication was higher during reproduction. Overall, these results suggest that the DMN and TN jointly mediate subjective self-awareness to improve timing performance.

Separable Representations for Duration and Distance in Virtual Movements.

To navigate through the environment, humans must be able to measure both the distance traveled in space, and the interval elapsed in time. Yet, how the brain holds both of these metrics simultaneously is less well known. One possibility is that participants measure how far and how long they have traveled relative to a known reference point. To measure this, we had human participants (n = 24) perform a distance estimation task in a virtual environment in which they were cued to attend to either the spatial or temporal interval traveled while responses were measured with multiband fMRI. We observed that both dimensions evoked similar frontoparietal networks, yet with a striking rostrocaudal dissociation between temporal and spatial estimation. Multivariate classifiers trained on each dimension were further able to predict the temporal or spatial interval traveled, with centers of activation within the SMA and retrosplenial cortex for time and space, respectively. Furthermore, a cross-classification approach revealed the right supramarginal gyrus and occipital place area as regions capable of decoding the general magnitude of the traveled distance. Altogether, our findings suggest the brain uses separate systems for tracking spatial and temporal distances, which are combined together along with dimension-nonspecific estimates.

Coordinate-Based Meta-Analyses of the Time Perception Network.

The study of time perception has advanced over the past three decades to include numerous neuroimaging studies, most notably including the use of functional Magnetic Resonance Imaging (fMRI). Yet, with this increase in studies, there comes the desire to draw broader conclusions across datasets about the nature and instantiation of time in the human brain. In the absence of collating individual studies together, the field has employed the use of Coordinate-Based Meta-Analyses (CBMA), in which foci from individual studies are modeled as probability distributions within the brain, from which common areas of activation-likelihood are determined. This chapter provides an overview of these CBMA studies, the methods they employ, the conclusions drawn by them, and where future areas of inquiry lie. The result of this survey suggests the existence of a domain-general "timing network" that can be used both as a guide for individual neuroimaging studies and as a template for future meta-analyses.

The role of consciously timed movements in shaping and improving auditory timing.

Our subjective sense of time is intertwined with a plethora of perceptual, cognitive and motor functions, and likewise, the brain is equipped to expertly filter, weight and combine these signals for seamless interactions with a dynamic world. Until relatively recently, the literature on time perception has excluded the influence of simultaneous motor activity, yet it has been found that motor circuits in the brain are at the core of most timing functions. Several studies have now identified that concurrent movements exert robust effects on perceptual timing estimates, but critically have not assessed how humans consciously judge the duration of their own movements. This creates a gap in our understanding of the mechanisms driving movement-related effects on sensory timing. We sought to address this gap by administering a sensorimotor timing task in which we explicitly compared the timing of isolated auditory tones and arm movements, or both simultaneously. We contextualized our findings within a Bayesian cue combination framework, in which separate sources of temporal information are weighted by their reliability and integrated into a unitary time estimate that is more precise than either unisensory estimate. Our results revealed differences in accuracy between auditory, movement and combined trials, and (crucially) that combined trials were the most accurately timed. Under the Bayesian framework, we found that participants' combined estimates were more precise than isolated estimates, yet were sub-optimal when compared with the model's prediction, on average. These findings elucidate previously unknown qualities of conscious motor timing and propose computational mechanisms that can describe how movements combine with perceptual signals to create unified, multimodal experiences of time.

Gradient Organization of Space, Time, and Numbers in the Brain: A Meta-analysis of Neuroimaging Studies.

In this study, we ran a meta-analysis of neuroimaging studies to pinpoint the neural regions that are commonly activated across space, time, and numerosity, and we tested the existence of gradient transitions among these magnitude representations in the brain. Following PRISMA guidelines, we included in the meta-analysis 112 experiments (for space domain), 114 experiments (time domain), and 115 experiments (numerosity domain), and we used the activation likelihood estimation method. We found a system of brain regions that was commonly recruited in all the three magnitudes, which included bilateral insula, the supplementary motor area (SMA), the right inferior frontal gyrus, and bilateral intraparietal sulci. Gradiental transitions between different magnitudes were found along all these regions but insulae, with space and numbers leading to gradients mainly over parietal regions (and SMA) whereas time and numbers mainly over frontal regions. These findings provide evidence for the GradiATOM theory (Gradient Theory of Magnitude), suggesting that spatial proximity given by overlapping activations and gradients is a key aspect for efficient interactions and integrations among magnitudes.

Awareness of errors and feedback in human time estimation.

Behavioral and electrophysiology studies have shown that humans possess a certain self-awareness of their individual timing ability. However, conflicting reports raise concerns about whether humans can discern the direction of their timing error, calling into question the extent of this timing awareness. To understand the depth of this ability, the impact of nondirectional feedback and reinforcement learning on time perception were examined in a unique temporal reproduction paradigm that involved a mixed set of interval durations and the opportunity to repeat every trial immediately after receiving feedback, essentially allowing a "redo." Within this task, we tested two groups of participants on versions where nondirectional feedback was provided after every response, or not provided at all. Participants in both groups demonstrated reduced central tendency and exhibited significantly greater accuracy in the redo trial temporal estimates, showcasing metacognitive ability, and an inherent capacity to adjust temporal responses despite the lack of directional information or any feedback at all. Additionally, the feedback group also exhibited an increase in the precision of responses on the redo trials, an effect not observed in the no-feedback group, suggesting that feedback may specifically reduce noise when making a temporal estimate. These findings enhance our understanding of timing self-awareness and can provide insight into what may transpire when this is disrupted.

Dissociable neural indices for time and space estimates during virtual distance reproduction.

The perception and measurement of spatial and temporal dimensions have been widely studied. Yet, whether these two dimensions are processed independently is still being debated. Additionally, whether EEG components are uniquely associated with time or space, or whether they reflect a more general measure of magnitude quantity remains unknown. While undergoing EEG, subjects performed a virtual distance reproduction task, in which they were required to first walk forward for an unknown distance or time, and then reproduce that distance or time. Walking speed was varied between estimation and reproduction phases, to prevent interference between distance or time in each estimate. Behaviorally, subject performance was more variable when reproducing time than when reproducing distance, but with similar patterns of accuracy. During estimation, EEG data revealed the contingent negative variation (CNV), a measure previously associated with timing and expectation, tracked the probability of the upcoming interval, for both time and distance. However, during reproduction, the CNV exclusively oriented to the upcoming temporal interval at the start of reproduction, with no change across spatial distances. Our findings indicate that time and space are neurally separable dimensions, with the CNV both serving a supramodal role in temporal and spatial expectation, yet an exclusive role in preparing duration reproduction.

From ATOM to GradiATOM: Cortical gradients support time and space processing as revealed by a meta-analysis of neuroimaging studies.

According to the ATOM (A Theory Of Magnitude), formulated by Walsh more than fifteen years ago, there is a general system of magnitude in the brain that comprises regions, such as the parietal cortex, shared by space, time and other magnitudes. The present meta-analysis of neuroimaging studies used the Activation Likelihood Estimation (ALE) method in order to determine the set of regions commonly activated in space and time processing and to establish the neural activations specific to each magnitude domain. Following PRISMA guidelines, we included in the analysis a total of 112 and 114 experiments, exploring space and time processing, respectively. We clearly identified the presence of a system of brain regions commonly recruited in both space and time that includes: bilateral insula, the pre-supplementary motor area (pre-SMA), the right frontal operculum and the intraparietal sulci. These regions might be the best candidates to form the core magnitude neural system. Surprisingly, along each of these regions but the insula, ALE values progressed in a cortical gradient from time to space. The SMA exhibited an anterior-posterior gradient, with space activating more-anterior regions (i.e., pre-SMA) and time activating more-posterior regions (i.e., SMA-proper). Frontal and parietal regions showed a dorsal-ventral gradient: space is mediated by dorsal frontal and parietal regions, and time recruits ventral frontal and parietal regions. Our study supports but also expands the ATOM theory. Therefore, we here re-named it the 'GradiATOM' theory (Gradient Theory of Magnitude), proposing that gradient organization can facilitate the transformations and integrations of magnitude representations by allowing space- and time-related neural populations to interact with each other over minimal distances.

Functional correlates of likelihood and prior representations in a virtual distance task.

Spatial navigation is an imperative cognitive function, in which individuals must interact with their environment in order to accurately reach a destination. Previous research has demonstrated that, when traveling a predetermined distance, humans must balance between noise in the measurement process and the prior history of traveled distances. This tradeoff has recently been formally described using Bayesian estimation; however, the neural correlates of Bayesian estimation during distance reproduction have yet to be investigated. Here, human subjects performed a virtual reality distance reproduction task during functional Magnetic Resonance Imaging (fMRI), in which they were required to reproduce various traveled distances in the absence of overt navigational cues. As previously demonstrated, subjects exhibited a central tendency effect, wherein reproduced distances gravitated to the mean of the stimulus set. fMRI activity during this task revealed distance-sensitive activity in a network of regions, including prefrontal and hippocampal regions. Using a computational index of central tendency, we found that activity in the retrosplenial cortex, a region highly implicated in spatial navigation, negatively covaried between subjects with the degree of central tendency observed; conversely, we found that activity in the anterior hippocampus/amygdala complex was positively correlated with the central tendency effect of gravitating to the average reproduced distance. These findings suggest dissociable roles for the retrosplenial cortex and hippocampal complex during distance reproduction, with both regions coordinating with the prefrontal cortex the influence of prior history of the environment with present experience. Hum Brain Mapp 37:3172-3187, 2016. © 2016 Wiley Periodicals, Inc.

Repetition enhancement and memory effects for duration.

A remarkable aspect of conscious perception is that moments carryover from one to the next, also known as temporal continuity. This ability is thus crucial for detecting regularities, such as in speech and music, and may rely on an accurate perception of time. Investigations of human time perception have detailed two electroencephalographic (EEG) components associated with timing, the contingent negative variation (CNV) and late positive component of timing (LPCt); however, the precise roles of these components in timing remain elusive. Recently, we demonstrated that the perception of duration is influenced by durations presented on prior trials, which we explained by the creation of an implicit memory standard that adapts to local changes in sequence presentation. Here, we turn to the neural basis of this effect. Human participants performed a temporal bisection task in which they were required to classify the duration of auditory stimuli into short and long duration categories; crucially, the presentation order was first-order counterbalanced, allowing us to measure the effect of each presented duration on the next. EEG recordings revealed that the CNV and LPCt signals both covaried with the duration presented on the current trial, with CNV predicting reaction time and LPCt predicting choice. Additionally, both signals covaried with the duration presented in the prior trial but in different ways, with the CNV amplitude reflecting the change in the memory standard and the LPCt reflecting decision uncertainty. Furthermore, we observed a repetition enhancement effect of duration only for the CNV, suggesting that this signal additionally indexes the similarity of successive durations. These findings demonstrate dissociable roles for the CNV and LPCt, and demonstrate that both signals are continuously updated on a trial-by-trial basis that reflects shifts in temporal decisions.

Individual differences in the morphometry and activation of time perception networks are influenced by dopamine genotype.

Individual participants vary greatly in their ability to estimate and discriminate intervals of time. This heterogeneity of performance may be caused by reliance on different time perception networks as well as individual differences in the activation of brain structures utilized for timing within those networks. To address these possibilities we utilized event-related functional magnetic resonance imaging (fMRI) while human participants (n=25) performed a temporal or color discrimination task. Additionally, based on our previous research, we genotyped participants for DRD2/ANKK1-Taq1a, a single-nucleotide polymorphism associated with a 30-40% reduction in striatal D2 density and associated with poorer timing performance. Similar to previous reports, a wide range of performance was found across our sample; crucially, better performance on the timing versus color task was associated with greater activation in prefrontal and sub-cortical regions previously associated with timing. Furthermore, better timing performance also correlated with increased volume of the right lateral cerebellum, as demonstrated by voxel-based morphometry. Our analysis also revealed that A1 carriers of the Taq1a polymorphism exhibited relatively worse performance on temporal, but not color discrimination, but greater activation in the striatum and right dorsolateral prefrontal cortex, as well as reduced volume in the cerebellar cluster. These results point to the neural bases for heterogeneous timing performance in humans, and suggest that differences in performance on a temporal discrimination task are, in part, attributable to the DRD2/ANKK1 genotype.

Memorability shapes perceived time (and vice versa).

Visual stimuli are known to vary in their perceived duration. Some visual stimuli are also known to linger for longer in memory. Yet, whether these two features of visual processing are linked is unknown. Despite early assumptions that time is an extracted or higher-order feature of perception, more recent work over the past two decades has demonstrated that timing may be instantiated within sensory modality circuits. A primary location for many of these studies is the visual system, where duration-sensitive responses have been demonstrated. Furthermore, visual stimulus features have been observed to shift perceived duration. These findings suggest that visual circuits mediate or construct perceived time. Here we present evidence across a series of experiments that perceived time is affected by the image properties of scene size, clutter and memorability. More specifically, we observe that scene size and memorability dilate time, whereas clutter contracts it. Furthermore, the durations of more memorable images are also perceived more precisely. Conversely, the longer the perceived duration of an image, the more memorable it is. To explain these findings, we applied a recurrent convolutional neural network model of the ventral visual system, in which images are progressively processed over time. We find that more memorable images are processed faster, and that this increase in processing speed predicts both the lengthening and the increased precision of perceived durations. These findings provide evidence for a link between image features, time perception and memory that can be further explored with models of visual processing.

Parietal influence on temporal encoding indexed by simultaneous transcranial magnetic stimulation and electroencephalography.

Previous studies have suggested that contingent negative variation (CNV), as recorded by electroencaphalography (EEG), may serve as an index of temporal encoding. The interpretation of these studies is complicated by the fact that, in a majority of studies, the CNV signal was obtained at a time when subjects were not only registering stimulus duration but also making decisions and preparing to act. Previously, we demonstrated that repetitive transcranial magnetic stimulation (rTMS) of the right supramarginal gyrus (rSMG) in humans lengthened the perceived duration of a visual stimulus (Wiener et al., 2010a), suggesting the rSMG is involved in basic encoding processes. Here, we report a replication of this effect with simultaneous EEG recordings during the encoding of stimulus duration. Stimulation of the rSMG led to an increase in perceived duration and the amplitude of N1 and CNV components recorded from frontocentral sites. Furthermore, the size of the CNV amplitude, but not N1, positively correlated with the size of the rTMS effect but negatively correlated with bias (the baseline tendency to report a comparison stimulus as shorter), suggesting that the CNV indexes stimulus duration. These results suggest that a feedforward mechanism from parietal to prefrontal regions mediates temporal encoding and demonstrate a dissociation between early and late phases of encoding processes.

Minimizing within-experiment and within-group effects in Activation Likelihood Estimation meta-analyses.

Activation Likelihood Estimation (ALE) is an objective, quantitative technique for coordinate-based meta-analysis (CBMA) of neuroimaging results that has been validated for a variety of uses. Stepwise modifications have improved ALE's theoretical and statistical rigor since its introduction. Here, we evaluate two avenues to further optimize ALE. First, we demonstrate that the maximum contribution of an experiment makes to an ALE map is related to the number of foci it reports and their proximity. We present a modified ALE algorithm that eliminates these within-experiment effects. However, we show that these effects only account for 2-3% of cumulative ALE values, and removing them has little impact on thresholded ALE maps. Next, we present an alternate organizational approach to datasets that prevents subject groups with multiple experiments in a dataset from influencing ALE values more than others. This modification decreases cumulative ALE values by 7-9%, changes the relative magnitude of some clusters, and reduces cluster extents. Overall, differences between results of the standard approach and these new methods were small. This finding validates previous ALE reports against concerns that they were driven by within-experiment or within-group effects. We suggest that the modified ALE algorithm is theoretically advantageous compared with the current algorithm, and that the alternate organization of datasets is the most conservative approach for typical ALE analyses and other CBMA methods. Combining the two modifications minimizes both within-experiment and within-group effects, optimizing the degree to which ALE values represent concordance of findings across independent reports.

Selectivity of timing: A meta-analysis of temporal processing in neuroimaging studies using activation likelihood estimation and reverse inference.

Over the last few decades, many researchers have investigated time perception and how it is processed in the brain. Past studies have identified cortical and subcortical regions that play an important role in implicit and/or explicit timing tasks. In regard to timing, different regions appear to have roles of varying importance depending on the duration (sub-second vs. supra-second), type of task (such as involving motor responses or passively observing stimuli), and modality (such as auditory, visual, and sensorimotor) resulting in the literature reporting divergent results that are contingent on the specifics of the task. This meta-analysis aims at identifying regions that show activation only for explicit timing tasks through reverse inference. As such, two datasets (the first including studies that involved explicit timing tasks while the second did not) were compared using the activation likelihood estimation (ALE) algorithm. Reverse inference was implemented through Bayes factor modeling, which allowed for the comparison of the activated regions between the two ALE-maps. Results showed a constellation of regions that exhibited selective activation likelihood in explicit timing tasks with the largest posterior probability of activation resulting in the left supplementary motor area (SMA) and the bilateral insula. Some areas that have been dubbed critical for time perception in past studies (i.e., the cerebellum) did not exhibit prevalent activation after analyses.

Dissociable effects of emotional stimuli on electrophysiological indices of time and decision-making.

Previous research has demonstrated that emotional faces affect time perception, however, the underlying mechanisms are not fully understood. Earlier attempts focus on effects at the different stages of the pacemaker-accumulator model (clock, memory, and/or decision-making) including, an increase in pacemaker rate or accumulation rate via arousal or attention, respectively, or by biasing decision-making. A visual temporal bisection task with sub-second intervals was conducted in two groups to further investigate these effects; one group was strictly behavioral whereas the second included a 64-channel electroencephalogram (EEG). To separate the influence of face and timing responses, participants timed a visual stimulus, temporally flanked (before and after) by two faces, either negative or neutral, creating three trial-types: Neg→Neut, Neut→Neg, or Neut→Neut. We found a leftward shift in bisection point (BP) in Neg→Neut relative to Neut→Neut suggests an overestimation of the temporal stimulus when preceded by a negative face. Neurally, we found the face-responsive N170 was larger for negative faces and the N1 and contingent negative variation (CNV) were larger when the temporal stimulus was preceded by a negative face. Additionally, there was an interaction effect between condition and response for the late positive component of timing (LPCt) and a significant difference between response (short/long) in the neutral condition. We concluded that a preceding negative face affects the clock stage leading to more pulses being accumulated, either through attention or arousal, as indexed by a larger N1, CNV, and N170; whereas viewing a negative face after impacted decision-making mechanisms, as evidenced by the LPCt.

Double dissociation of dopamine genes and timing in humans.

A number of lines of evidence implicate dopamine in timing [Rammsayer, T. H. Neuropharmacological approaches to human timing. In S. Grondin (Ed.), Psychology of time (pp. 295-320). Bingley, UK: Emerald, 2008; Meck, W. H. Neuropharmacology of timing and time perception. Brain Research, Cognitive Brain Research, 3, 227-242, 1996]. Two human genetic polymorphisms are known to modulate dopaminergic activity. DRD2/ANKK1-Taq1a is a D(2) receptor polymorphism associated with decreased D(2) density in the striatum [Jönsson, E. G., Nothen, M. M., Grunhage, F., Farde, L., Nakashima, Y., Propping, P., et al. Polymorphisms in the dopamine D(2) receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Molecular Psychiatry, 4, 290-296, 1999]; COMT Val158Met is a functional polymorphism associated with increased activity of the COMT enzyme such that catabolism of synaptic dopamine is greater in pFC [Meyer-Lindenberg, A., Kohn, P. D., Kolachana, B., Kippenhan, S., McInerney-Leo, A., Nussbaum, R., et al. Midbrain dopamine and prefrontal function in humans: Interaction and modulation by COMT genotype. Nature Neuroscience, 8, 594-596, 2005]. To investigate the role of dopamine in timing, we genotyped 65 individuals for DRD2/ANKK1-Taq1a, COMT Val158Met, and a third polymorphism, BDNF Val66Met, a functional polymorphism affecting the expression of brain-derived neurotrophic factor [Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., Bertolino, A., et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112, 257-269, 2003]. Subjects were tested on a temporal discrimination task with sub- and supra-second intervals (500- and 2000-msec standards) as well as a spontaneous motor tempo task. We found a double dissociation for temporal discrimination: the DRD2/ANKK1-Taq1a polymorphism (A1+ allele) was associated with significantly greater variability for the 500-msec duration only, whereas the COMT Val158Met polymorphism (Val/Val homozygotes) was associated with significantly greater variability for the 2000-msec duration only. No differences were detected for the BDNF Vall66Met variant. Additionally, the DRD2/ANKK1-Taq1a polymorphism was associated with a significantly slower preferred motor tempo. These data provide a potential biological basis for the distinctions between sub- and supra-second timing and suggest that BG are integral for the former whereas pFC is implicated in the latter.

Slowing the body slows down time perception.

Interval timing is a fundamental component of action and is susceptible to motor-related temporal distortions. Previous studies have shown that concurrent movement biases temporal estimates, but have primarily considered self-modulated movement only. However, real-world encounters often include situations in which movement is restricted or perturbed by environmental factors. In the following experiments, we introduced viscous movement environments to externally modulate movement and investigated the resulting effects on temporal perception. In two separate tasks, participants timed auditory intervals while moving a robotic arm that randomly applied four levels of viscosity. Results demonstrated that higher viscosity led to shorter perceived durations. Using a drift-diffusion model and a Bayesian observer model, we confirmed these biasing effects arose from perceptual mechanisms, instead of biases in decision making. These findings suggest that environmental perturbations are an important factor in movement-related temporal distortions, and enhance the current understanding of the interactions of motor activity and cognitive processes.

How movements shape the perception of time.

In order to keep up with a changing environment, mobile organisms must be capable of deciding both where and when to move. This precision necessitates a strong sense of time, as otherwise we would fail in many of our movement goals. Yet, despite this intrinsic link, only recently have researchers begun to understand how these two features interact. Primarily, two effects have been observed: movements can bias time estimates, but they can also make them more precise. Here we review this literature and propose that both effects can be explained by a Bayesian cue combination framework, in which movement itself affords the most precise representation of time, which can influence perception in either feedforward or active sensing modes.

Fast forward: supramarginal gyrus stimulation alters time measurement.

The neural basis of temporal processing is unclear. We addressed this important issue by performing two experiments in which repetitive transcranial magnetic stimulation (rTMS) was administered in different sessions to the left or right supramarginal gyrus (SMG) or vertex; in both tasks, two visual stimuli were presented serially and subjects were asked to judge if the second stimulus was longer than the first (standard) stimulus. rTMS was presented on 50% of trials. Consistent with a previous literature demonstrating the effect of auditory clicks on temporal judgment, rTMS was associated with a tendency to perceive the paired visual stimulus as longer in all conditions. Crucially, rTMS to the right SMG was associated with a significantly greater subjective prolongation of the associated visual stimulus in both experiments. These findings demonstrate that the right SMG is an important element of the neural system underlying temporal processing and, as discussed, have implications for neural and cognitive models of temporal perception and attention.