Psilocybin desynchronizes the human brain.

A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.

The neural bases for timing of durations.

Durations are defined by a beginning and an end, and a major distinction is drawn between durations that start in the present and end in the future ('prospective timing') and durations that start in the past and end either in the past or the present ('retrospective timing'). Different psychological processes are thought to be engaged in each of these cases. The former is thought to engage a clock-like mechanism that accurately tracks the continuing passage of time, whereas the latter is thought to engage a reconstructive process that utilizes both temporal and non-temporal information from the memory of past events. We propose that, from a biological perspective, these two forms of duration estimation are supported by computational processes that are both reliant on population state dynamics but are nevertheless distinct. Prospective timing is effectively carried out in a single step where the ongoing dynamics of population activity directly serve as the computation of duration, whereas retrospective timing is carried out in two steps: the initial generation of population state dynamics through the process of event segmentation and the subsequent computation of duration utilizing the memory of those dynamics.

Ramping cells in the rodent medial prefrontal cortex encode time to past and future events via real Laplace transform.

In interval reproduction tasks, animals must remember the event starting the interval and anticipate the time of the planned response to terminate the interval. The interval reproduction task thus allows for studying both memory for the past and anticipation of the future. We analyzed previously published recordings from the rodent medial prefrontal cortex [J. Henke et al., eLife10, e71612 (2021)] during an interval reproduction task and identified two cell groups by modeling their temporal receptive fields using hierarchical Bayesian models. The firing in the "past cells" group peaked at the start of the interval and relaxed exponentially back to baseline. The firing in the "future cells" group increased exponentially and peaked right before the planned action at the end of the interval. Contrary to the previous assumption that timing information in the brain has one or two time scales for a given interval, we found strong evidence for a continuous distribution of the exponential rate constants for both past and future cell populations. The real Laplace transformation of time predicts exponential firing with a continuous distribution of rate constants across the population. Therefore, the firing pattern of the past cells can be identified with the Laplace transform of time since the past event while the firing pattern of the future cells can be identified with the Laplace transform of time until the planned future event.

Impaired perception of temporal contiguity between action and effect is associated with disorders of agency in schizophrenia.

Delusions of control in schizophrenia are characterized by the striking feeling that one's actions are controlled by external forces. We here tested qualitative predictions inspired by Bayesian causal inference models, which suggest that such misattributions of agency should lead to decreased intentional binding. Intentional binding refers to the phenomenon that subjects perceive a compression of time between their intentional actions and consequent sensory events. We demonstrate that patients with delusions of control perceived less self-agency in our intentional binding task. This effect was accompanied by significant reductions of intentional binding as compared to healthy controls and patients without delusions. Furthermore, the strength of delusions of control tightly correlated with decreases in intentional binding. Our study validated a critical prediction of Bayesian accounts of intentional binding, namely that a pathological reduction of the prior likelihood of a causal relation between one's actions and consequent sensory events-here captured by delusions of control-should lead to lesser intentional binding. Moreover, our study highlights the import of an intact perception of temporal contiguity between actions and their effects for the sense of agency.

When the Heart Meets the Mind: Exploring the Brain-Heart Interaction during Time Perception.

Recent studies suggest that time estimation relies on bodily rhythms and interoceptive signals. We provide the first direct electrophysiological evidence suggesting an association between the brain's processing of heartbeat and duration judgment. We examined heartbeat-evoked potential (HEP) and contingent negative variation (CNV) during an auditory duration-reproduction task and a control reaction-time task spanning 4, 8, and 12 s intervals, in both male and female participants. Interoceptive awareness was assessed with the Self-Awareness Questionnaire (SAQ) and interoceptive accuracy through the heartbeat-counting task (HCT). Results revealed that SAQ scores, but not the HCT, correlated with mean reproduced durations with higher SAQ scores associating with longer and more accurate duration reproductions. Notably, the HEP amplitude changes during the encoding phase of the timing task, particularly within 130-270 ms (HEP1) and 470-520 ms (HEP2) after the R-peak, demonstrated interval-specific modulations that did not emerge in the control task. A significant ramp-like increase in HEP2 amplitudes occurred during the duration-encoding phase of the timing but not during the control task. This increase within the reproduction phase of the timing task correlated significantly with the reproduced durations for the 8 s and the 4 s intervals. The larger the increase in HEP2, the greater the under-reproduction of the estimated duration. CNV components during the encoding phase of the timing task were more negative than those in the reaction-time task, suggesting greater executive resources orientation toward time. We conclude that interoceptive awareness (SAQ) and cortical responses to heartbeats (HEP) predict duration reproductions, emphasizing the embodied nature of time.

Differences in temporal processing speeds between the right and left auditory cortex reflect the strength of recurrent synaptic connectivity.

Brain asymmetry in the sensitivity to spectrotemporal modulation is an established functional feature that underlies the perception of speech and music. The left auditory cortex (ACx) is believed to specialize in processing fast temporal components of speech sounds, and the right ACx slower components. However, the circuit features and neural computations behind these lateralized spectrotemporal processes are poorly understood. To answer these mechanistic questions we use mice, an animal model that captures some relevant features of human communication systems. In this study, we screened for circuit features that could subserve temporal integration differences between the left and right ACx. We mapped excitatory input to principal neurons in all cortical layers and found significantly stronger recurrent connections in the superficial layers of the right ACx compared to the left. We hypothesized that the underlying recurrent neural dynamics would exhibit differential characteristic timescales corresponding to their hemispheric specialization. To investigate, we recorded spike trains from awake mice and estimated the network time constants using a statistical method to combine evidence from multiple weak signal-to-noise ratio neurons. We found longer temporal integration windows in the superficial layers of the right ACx compared to the left as predicted by stronger recurrent excitation. Our study shows substantial evidence linking stronger recurrent synaptic connections to longer network timescales. These findings support speech processing theories that purport asymmetry in temporal integration is a crucial feature of lateralization in auditory processing.

Neural mechanisms of sequential dependence in time perception: the impact of prior task and memory processing.

Our perception and decision-making are susceptible to prior context. Such sequential dependence has been extensively studied in the visual domain, but less is known about its impact on time perception. Moreover, there are ongoing debates about whether these sequential biases occur at the perceptual stage or during subsequent post-perceptual processing. Using functional magnetic resonance imaging, we investigated neural mechanisms underlying temporal sequential dependence and the role of action in time judgments across trials. Participants performed a timing task where they had to remember the duration of green coherent motion and were cued to either actively reproduce its duration or simply view it passively. We found that sequential biases in time perception were only evident when the preceding task involved active duration reproduction. Merely encoding a prior duration without reproduction failed to induce such biases. Neurally, we observed activation in networks associated with timing, such as striato-thalamo-cortical circuits, and performance monitoring networks, particularly when a "Response" trial was anticipated. Importantly, the hippocampus showed sensitivity to these sequential biases, and its activation negatively correlated with the individual's sequential bias following active reproduction trials. These findings highlight the significant role of memory networks in shaping time-related sequential biases at the post-perceptual stages.

Rodents monitor their error in self-generated duration on a single trial basis.

A fundamental question in neuroscience is what type of internal representation leads to complex, adaptive behavior. When faced with a deadline, individuals' behavior suggests that they represent the mean and the uncertainty of an internal timer to make near-optimal, time-dependent decisions. Whether this ability relies on simple trial-and-error adjustments or whether it involves richer representations is unknown. Richer representations suggest a possibility of error monitoring, that is, the ability for an individual to assess its internal representation of the world and estimate discrepancy in the absence of external feedback. While rodents show timing behavior, whether they can represent and report temporal errors in their own produced duration on a single-trial basis is unknown. We designed a paradigm requiring rats to produce a target time interval and, subsequently, evaluate its error. Rats received a reward in a given location depending on the magnitude of their timing errors. During the test trials, rats had to choose a port corresponding to the error magnitude of their just-produced duration to receive a reward. High-choice accuracy demonstrates that rats kept track of the values of the timing variables on which they based their decision. Additionally, the rats kept a representation of the mapping between those timing values and the target value, as well as the history of the reinforcements. These findings demonstrate error-monitoring abilities in evaluating self-generated timing in rodents. Together, these findings suggest an explicit representation of produced duration and the possibility to evaluate its relation to the desired target duration.

Alpha-band Brain Dynamics and Temporal Processing: An Introduction to the Special Focus.

For decades, the intriguing connection between the human alpha rhythm (an 8- to 13-Hz oscillation maximal over posterior cortex) and temporal processes in perception has furnished a rich landscape of proposals. The past decade, however, has seen a surge in interest in the topic, bringing new theoretical, analytic, and methodological developments alongside fresh controversies. This Special Focus on alpha-band dynamics and temporal processing provides an up-to-date snapshot of the playing field, with contributions from leading researchers in the field spanning original perspectives, new evidence, comprehensive reviews and meta-analyses, as well as discussion of ongoing controversies and paths forward. We hope that the perspectives captured here will help catalyze future research and shape the pathways toward a theoretically grounded and mechanistic account of the link between alpha dynamics and temporal properties of perception.

Alpha-Band Frequency and Temporal Windows in Perception: A Review and Living Meta-analysis of 27 Experiments (and Counting).

Temporal windows in perception refer to windows of time within which distinct stimuli interact to influence perception. A simple example is two temporally proximal stimuli fusing into a single percept. It has long been hypothesized that the human alpha rhythm (an 8- to 13-Hz neural oscillation maximal over posterior cortex) is linked to temporal windows, with higher frequencies corresponding to shorter windows and finer-grained temporal resolution. This hypothesis has garnered support from studies demonstrating a correlation between individual differences in alpha-band frequency (IAF) and behavioral measures of temporal processing. However, nonsignificant effects have also been reported. Here, we review and meta-analyze 27 experiments correlating IAF with measures of visual and audiovisual temporal processing. Our results estimate the true correlation in the population to be between .39 and .53, a medium-to-large effect. The effect held when considering visual or audiovisual experiments separately, when examining different IAF estimation protocols (i.e., eyes open and eyes closed), and when using analysis choices that favor a null result. Our review shows that (1) effects have been internally and independently replicated, (2) several positive effects are based on larger sample sizes than the null effects, and (3) many reported null effects are actually in the direction predicted by the hypothesis. A free interactive web app was developed to allow users to replicate our meta-analysis and change or update the study selection at will, making this a "living" meta-analysis (randfxmeta.streamlit.app). We discuss possible factors underlying null reports, design recommendations, and open questions for future research.

A Role for Bottom-Up Alpha Oscillations in Temporal Integration.

Neural oscillations in the 8-12 Hz alpha band are thought to represent top-down inhibitory control and to influence temporal resolution: Individuals with faster peak frequencies segregate stimuli appearing closer in time. Recently, this theory has been challenged. Here, we investigate a special case in which alpha does not correlate with temporal resolution: when stimuli are presented amidst strong visual drive. Based on findings regarding alpha rhythmogenesis and wave spatial propagation, we suggest that stimulus-induced, bottom-up alpha oscillations play a role in temporal integration. We propose a theoretical model, informed by visual persistence, lateral inhibition, and network refractory periods, and simulate physiologically plausible scenarios of the interaction between bottom-up alpha and the temporal segregation. Our simulations reveal that different features of oscillations, including frequency, phase, and power, can influence temporal perception and provide a theoretically informed starting point for future empirical studies.

Musical Expertise Influences the Processing of Short and Long Auditory Time Intervals: An Electroencephalography Study.

Musical expertise has been proven to be beneficial for time perception abilities, with musicians outperforming nonmusicians in several explicit timing tasks. However, it is unclear how musical expertise impacts implicit time perception. Twenty nonmusicians and 15 expert musicians participated in an EEG recording during a passive auditory oddball paradigm with 0.8- and 1.6-sec standard time intervals and deviant intervals that were either played earlier or delayed relative to the standard interval. We first confirmed that, as was the case for nonmusicians, musicians use different neurofunctional processes to support the perception of short (below 1.2 sec) and long (above 1.2 sec) time intervals: Whereas deviance detection for long intervals elicited a N1 component, P2 was associated with deviance detection for short time intervals. Interestingly, musicians did not elicit a contingent negative variation (CNV) for longer intervals but show additional components of deviance detection such as (i) an attention-related N1 component, even for deviants occurring during short intervals; (ii) a N2 component for above and below 1.2-sec deviance detection, and (iii) a P2 component for above 1.2-sec deviance detection. We propose that the N2 component is a marker of explicit deviance detection and acts as an inhibitory/conflict monitoring of the deviance. This hypothesis was supported by a positive correlation between CNV and N2 amplitudes: The CNV reflects the temporal accumulator and can predict explicit detection of the deviance. In expert musicians, a N2 component is observable without CNV, suggesting that deviance detection is optimized and does not require the temporal accumulator. Overall, this study suggests that musical expertise is associated with optimized implicit time perception.

Alpha Oscillations Create the Illusion of Time.

Recent neuroscience experiments have brought inconsistent findings to light about the influence of neural activity in the alpha-frequency band (at ≈10 Hz) on the temporal dynamics of visual perception. Whereas strong alpha effects were found when perception was more based on endogenous factors, there were null-effects for alpha when perception relied more on objective physical parameters. In this Perspective, I open up a new view on neural alpha activity that resolves some important aspects of this controversy by interpreting alpha not as temporal processing of sensory inputs per se but above all as the observer's internal processing dynamics, their so-called perception sets. Perception sets reflect internally stored knowledge for how to organize and build up perceptual processes. They result from previous sensory experiences, are under top-down control to support goal-directed behavior, and root in pre-established neural networks that communicate through alpha frequency channels. I present three example cases from the recent neuroscience literature that show an influence of alpha-driven perception sets on the observer's visual-temporal resolution, object processing, and the processing of behaviorally relevant image content. Because alpha-driven perception sets can structure perception from its high-level aspects, like categories, down to its basic building blocks, like objects and time samples, they may have a fundamental impact on our conscious experience of the sensory world, including our perception of time itself.

P1, N170, and N250 Event-related Potential Components Reflect Temporal Perception Processing in Face and Body Personal Identification.

Human faces and bodies represent various socially important signals. Although adults encounter numerous new people in daily life, they can recognize hundreds to thousands of different individuals. However, the neural mechanisms that differentiate one person from another person are unclear. This study aimed to clarify the temporal dynamics of the cognitive processes of face and body personal identification using face-sensitive ERP components (P1, N170, and N250). The present study performed three blocks (face-face, face-body, and body-body) of different ERP adaptation paradigms. Furthermore, in the above three blocks, ERP components were used to compare brain biomarkers under three conditions (same person, different person of the same sex, and different person of the opposite sex). The results showed that the P1 amplitude for the face-face block was significantly greater than that for the body-body block, that the N170 amplitude for a different person of the same sex condition was greater than that for the same person condition in the right hemisphere only, and that the N250 amplitude gradually increased as the degree of face and body sex-social categorization grew closer (i.e., same person condition > different person of the same sex condition > different person of the opposite sex condition). These results suggest that early processing of the face and body processes the face and body separately and that structural encoding and personal identification of the face and body process the face and body collaboratively.

Memory traces of duration and location in the right intraparietal sulcus.

Time and space form an integral part of every human experience, and for the neuronal representation of these perceptual dimensions, previous studies point to the involvement of the right-hemispheric intraparietal sulcus and structures in the medial temporal lobe. Here we used multi-voxel pattern analysis (MVPA) to investigate long-term memory traces for temporal and spatial stimulus features in those areas. Participants were trained on four images associated with short versus long durations and with left versus right locations. Our results demonstrate stable representations of both temporal and spatial information in the right posterior intraparietal sulcus. Building upon previous findings of stable neuronal codes for directly perceived durations and locations, these results show that the reactivation of long-term memory traces for temporal and spatial features can be decoded from neuronal activation patterns in the right parietal cortex.

Compression of time in double-step saccades.

Temporal intervals appear compressed at the time of saccades. Here, I asked if saccadic compression of time is related to motor planning or to saccade execution. To dissociate saccade motor planning from its execution, I used the double-step paradigm, in which subjects have to perform two horizontal saccades successively. At various times around the saccade sequence, I presented two large horizontal bars, which marked an interval lasting 100 ms. After 700 ms, a second temporal interval was presented, varying in duration across trials. Subjects were required to judge which interval appeared shorter. I found that during the first saccades in the double-step paradigm, temporal intervals were compressed. Maximum temporal compression coincided with saccade onset. Around the time of the second saccade, I found temporal compression as well, however, the time of maximum compression preceded saccade onset by about 70 ms. I compared the magnitude and time of temporal compression between double-step saccades and amplitude-matched single saccades, which I measured separately. Although I found no difference in time compression magnitude, the time when maximum compression occurred differed significantly. I conclude that the temporal shift of time compression in double-step saccades demonstrates the influence of saccade motor planning on time perception.NEW & NOTEWORTHY Visually defined temporal intervals appear compressed at the time of saccades. Here, I tested time perception during double-step saccades dissociating saccade planning from execution. Although around the time of the first saccade, peak compression was found at saccade onset, compression around the time of the second saccade peaked 70 ms before saccade onset. The results suggest that saccade motor planning influences time perception.

Spectral-temporal processing of naturalistic sounds in monkeys and humans.

Human speech and vocalizations in animals are rich in joint spectrotemporal (S-T) modulations, wherein acoustic changes in both frequency and time are functionally related. In principle, the primate auditory system could process these complex dynamic sounds based on either an inseparable representation of S-T features or, alternatively, a separable representation. The separability hypothesis implies an independent processing of spectral and temporal modulations. We collected comparative data on the S-T hearing sensitivity in humans and macaque monkeys to a wide range of broadband dynamic spectrotemporal ripple stimuli employing a yes-no signal-detection task. Ripples were systematically varied, as a function of density (spectral modulation frequency), velocity (temporal modulation frequency), or modulation depth, to cover a listener's full S-T modulation sensitivity, derived from a total of 87 psychometric ripple detection curves. Audiograms were measured to control for normal hearing. Determined were hearing thresholds, reaction time distributions, and S-T modulation transfer functions (MTFs), both at the ripple detection thresholds and at suprathreshold modulation depths. Our psychophysically derived MTFs are consistent with the hypothesis that both monkeys and humans employ analogous perceptual strategies: S-T acoustic information is primarily processed separable. Singular value decomposition (SVD), however, revealed a small, but consistent, inseparable spectral-temporal interaction. Finally, SVD analysis of the known visual spatiotemporal contrast sensitivity function (CSF) highlights that human vision is space-time inseparable to a much larger extent than is the case for S-T sensitivity in hearing. Thus, the specificity with which the primate brain encodes natural sounds appears to be less strict than is required to adequately deal with natural images.NEW & NOTEWORTHY We provide comparative data on primate audition of naturalistic sounds comprising hearing thresholds, reaction time distributions, and spectral-temporal modulation transfer functions. Our psychophysical experiments demonstrate that auditory information is primarily processed in a spectral-temporal-independent manner by both monkeys and humans. Singular value decomposition of known visual spatiotemporal contrast sensitivity, in comparison to our auditory spectral-temporal sensitivity, revealed a striking contrast in how the brain encodes natural sounds as opposed to natural images, as vision appears to be space-time inseparable.

Cerebellar Direct Current Stimulation Reveals the Causal Role of the Cerebellum in Temporal Prediction.

Temporal prediction (TP) influences our perception and cognition. The cerebellum could mediate this multi-level ability in a context-dependent manner. We tested whether a modulation of the cerebellar neural activity, induced by transcranial Direct Current Stimulation (tDCS), changed the TP ability according to the temporal features of the context and the duration of target interval. Fifteen healthy participants received anodal, cathodal, and sham tDCS (15 min × 2 mA intensity) over the right cerebellar hemisphere during a TP task. We recorded reaction times (RTs) to a target during the task in two contextual conditions of temporal anticipation: rhythmic (i.e., interstimulus intervals (ISIs) were constant) and single-interval condition (i.e., the estimation of the timing of the target was based on the prior exposure of the train of stimuli). Two ISIs durations were explored: 600 ms (short trials) and 900 ms (long trials). Cathodal tDCS improved the performance during the TP task (shorter RTs) specifically in the rhythmic condition only for the short trials and in the single-interval condition only for the long trials. Our results suggest that the inhibition of cerebellar activity induced a different improvement in the TP ability according to the temporal features of the context. In the rhythmic context, the cerebellum could integrate the temporal estimation with the anticipatory motor responses critically for the short target interval. In the single-interval context, for the long trials, the cerebellum could play a main role in integrating representation of time interval in memory with the elapsed time providing an accurate temporal prediction.

Mechanism of Duration Perception in Artificial Brains Suggests New Model of Attentional Entrainment.

While cognitive theory has advanced several candidate frameworks to explain attentional entrainment, the neural basis for the temporal allocation of attention is unknown. Here we present a new model of attentional entrainment guided by empirical evidence obtained using a cohort of 50 artificial brains. These brains were evolved in silico to perform a duration judgment task similar to one where human subjects perform duration judgments in auditory oddball paradigms. We found that the artificial brains display psychometric characteristics remarkably similar to those of human listeners and exhibit similar patterns of distortions of perception when presented with out-of-rhythm oddballs. A detailed analysis of mechanisms behind the duration distortion suggests that attention peaks at the end of the tone, which is inconsistent with previous attentional entrainment models. Instead, the new model of entrainment emphasizes increased attention to those aspects of the stimulus that the brain expects to be highly informative.

Surfacing of Latent Time Memories Supports the Representational Basis of Timing Behavior in Mice.

Animals can adapt their reward expectancy to changes in delays to reward availability. When temporal relations are altered, associative models of interval timing predict that the original time memory is lost due to the updating of the underlying associative weights, whereas the representational models render the preservation of the original time memory (as previously demonstrated in the extinction of conditioned fear). The current study presents the critical test of these theoretical accounts by training mice with two different intervals in a consecutive fashion (short → long or long → short) and then testing timing behaviors during extinction where neither temporal relation is in effect. Mice that were trained with the long interval first clustered their anticipatory responses around the average of two intervals (indirect higher-order manifestation of two memories in the form of temporal averaging), whereas mice trained with the short interval first clustered their responses either around the short or long interval (direct manifestation of memory representations by their independent indexing). We assert that the original memory representation formed during training with the long interval "metrically affords" the integration of subsequent experiences with a shorter interval, allowing their co-activation during extinction. The original memory representation formed during training with the short interval would not metrically afford such integration and thus result in the formation of a new (mutually exclusive) time memory representation, which does not afford their co-activation during extinction. Our results provide strong support for the representational account of interval timing. We provide a new theoretical account of these findings based on the "metric affordances" of the original memory representation formed during training with the original intervals.