A mechanistic study on the tolerance of PAM distal end mismatch by SpCas9.

The therapeutic application of CRISPR-Cas9 is limited due to its off-target activity. To have a better understanding of this off-target effect, we focused on its mismatch-prone PAM distal end. The off-target activity of SpCas9 depends directly on the nature of mismatches, which in turn results in deviation of the active site of SpCas9 due to structural instability in the RNA-DNA duplex strand. In order to test the hypothesis, we designed an array of mismatched target sites at the PAM distal end and performed in vitro and cell line-based experiments, which showed a strong correlation for Cas9 activity. We found that target sites having multiple mismatches in the 18th to 15th position upstream of the PAM showed no to little activity. For further mechanistic validation, Molecular Dynamics simulations were performed, which revealed that certain mismatches showed elevated root mean square deviation values that can be attributed to conformational instability within the RNA-DNA duplex. Therefore, for successful prediction of the off-target effect of SpCas9, along with complementation-derived energy, the RNA-DNA duplex stability should be taken into account.

Stability of sensorimotor network sculpts the dynamic repertoire of resting state over lifespan.

Temporally stable patterns of neural coordination among distributed brain regions are crucial for survival. Recently, many studies highlight association between healthy aging and modifications in organization of functional brain networks, across various time-scales. Nonetheless, quantitative characterization of temporal stability of functional brain networks across healthy aging remains unexplored. This study introduces a data-driven unsupervised approach to capture high-dimensional dynamic functional connectivity (dFC) via low-dimensional patterns and subsequent estimation of temporal stability using quantitative metrics. Healthy aging related changes in temporal stability of dFC were characterized across resting-state, movie-viewing, and sensorimotor tasks (SMT) on a large (n = 645) healthy aging dataset (18-88 years). Prominent results reveal that (1) whole-brain temporal dynamics of dFC movie-watching task is closer to resting-state than to SMT with an overall trend of highest temporal stability observed during SMT followed by movie-watching and resting-state, invariant across lifespan aging, (2) in both tasks conditions stability of neurocognitive networks in young adults is higher than older adults, and (3) temporal stability of whole brain resting-state follows a U-shaped curve along lifespan-a pattern shared by sensorimotor network stability indicating their deeper relationship. Overall, the results can be applied generally for studying cohorts of neurological disorders using neuroimaging tools.

Emotion dynamics as hierarchical Bayesian inference in time.

What fundamental property of our environment would be most valuable and optimal in characterizing the emotional dynamics we experience in daily life? Empirical work has shown that an accurate estimation of uncertainty is necessary for our optimal perception, learning, and decision-making. However, the role of this uncertainty in governing our affective dynamics remains unexplored. Using Bayesian encoding, decoding and computational modeling, on a large-scale neuroimaging and behavioral data on a passive movie-watching task, we showed that emotions naturally arise due to ongoing uncertainty estimations about future outcomes in a hierarchical neural architecture. Several prefrontal subregions hierarchically encoded a lower-dimensional signal that highly correlated with the evolving uncertainty. Crucially, the lateral orbitofrontal cortex (lOFC) tracked the temporal fluctuations of this uncertainty and was predictive of the participants' predisposition to anxiety. Furthermore, we observed a distinct functional double-dissociation within OFC with increased connectivity between medial OFC and DMN, while with that of lOFC and FPN in response to the evolving affect. Finally, we uncovered a temporally predictive code updating an individual's beliefs spontaneously with fluctuating outcome uncertainty in the lOFC. A biologically relevant and computationally crucial parameter in the theories of brain function, we propose uncertainty to be central to the definition of complex emotions.

Reconfiguration of Directed Functional Connectivity Among Neurocognitive Networks with Aging: Considering the Role of Thalamo-Cortical Interactions.

A complete picture of how subcortical nodes, such as the thalamus, exert directional influence on large-scale brain network interactions across age remains elusive. Using directed functional connectivity and weighted net causal outflow on resting-state fMRI data, we provide evidence of a comprehensive reorganization within and between neurocognitive networks (default mode: DMN, salience: SN, and central executive: CEN) associated with age and thalamocortical interactions. We hypothesize that thalamus subserves both modality-specific and integrative hub role in organizing causal weighted outflow among large-scale neurocognitive networks. To this end, we observe that within-network directed functional connectivity is driven by thalamus and progressively weakens with age. Secondly, we find that age-associated increase in between CEN- and DMN-directed functional connectivity is driven by both the SN and the thalamus. Furthermore, left and right thalami act as a causal integrative hub exhibiting substantial interactions with neurocognitive networks with aging and play a crucial role in reconfiguring network outflow. Notably, these results were largely replicated on an independent dataset of matched young and old individuals. Our findings strengthen the hypothesis that the thalamus is a key causal hub balancing both within- and between-network connectivity associated with age and maintenance of cognitive functioning with aging.

Organization of directed functional connectivity among nodes of ventral attention network reveals the common network mechanisms underlying saliency processing across distinct spatial and spatio-temporal scales.

Previous neuroimaging studies have extensively evaluated the structural and functional connectivity of the Ventral Attention Network (VAN) and its role in reorienting attention in the presence of a salient (pop-out) stimulus. However, a detailed understanding of the "directed" functional connectivity within the VAN during the process of reorientation remains elusive. Functional magnetic resonance imaging (fMRI) studies have not adequately addressed this issue due to a lack of appropriate temporal resolution required to capture this dynamic process. The present study investigates the neural changes associated with processing salient distractors operating at a slow and a fast time scale using custom-designed experiment involving visual search on static images and dynamic motion tracking, respectively. We recorded high-density scalp electroencephalography (EEG) from healthy human volunteers, obtained saliency-specific behavioral and spectral changes during the tasks, localized the sources underlying the spectral power modulations with individual-specific structural MRI scans, reconstructed the waveforms of the sources and finally, investigated the causal relationships between the sources using spectral Granger-Geweke Causality (GGC). We found that salient stimuli processing, across tasks with varying spatio-temporal complexities, involves a characteristic modulation in the alpha frequency band which is executed primarily by the nodes of the VAN constituting the temporo-parietal junction (TPJ), the insula and the lateral prefrontal cortex (lPFC). The directed functional connectivity results further revealed the presence of bidirectional interactions among prominent nodes of right-lateralized VAN, corresponding only to the trials with saliency. Thus, our study elucidates the invariant network mechanisms for processing saliency in visual attention tasks across diverse time-scales.

Large-scale Functional Integration, Rather than Functional Dissociation along Dorsal and Ventral Streams, Underlies Visual Perception and Action.

Visual dual-stream theory posits that two distinct neural pathways of specific functional significance originate from primary visual areas and reach the inferior temporal (ventral) and posterior parietal areas (dorsal). However, there are several unresolved questions concerning the fundamental aspects of this theory. For example, is the functional dissociation between ventral and dorsal stream driven by features in input stimuli or is it driven by categorical differences between visuoperceptual and visuomotor functions? Is the dual stream rigid or flexible? What is the nature of the interactions between the two streams? We addressed these questions using fMRI recordings on healthy human volunteers and employing stimuli and tasks that can tease out the divergence between visuoperceptual and visuomotor variants of dual-stream theory. fMRI scans were repeated after seven practice sessions that were conducted in a non-MRI environment to investigate the effects of neuroplasticity. Brain activation analysis supports an input-based functional dissociation and existence of context-dependent neuroplasticity in dual-stream areas. Intriguingly, premotor cortex activation was observed in the position perception task and distributed deactivated regions were observed in all perception tasks, thus warranting a network-level analysis. Dynamic causal modeling analysis incorporating activated and deactivated brain areas during perception tasks indicates that the brain dynamics during visual perception and actions could be interpreted within the framework of predictive coding. Effectively, the network-level findings point toward the existence of more intricate context-driven functional networks selective of "what" and "where" information rather than segregated streams of processing along ventral and dorsal brain regions.

Lifespan associated global patterns of coherent neural communication.

Healthy ageing is accompanied by changes to spontaneous electromagnetic oscillations. At the macroscopic scale, previous studies have quantified the basic features, e.g., power and frequencies in rhythms of interest from the perspective of attention, perception, learning and memory. On the other hand, signatures and modes of neural communication have recently been argued to be identifiable from global measures applied on neuro-electromagnetic data such as global coherence that quantifies the degree of togetherness of distributed neural oscillations and metastability that parametrizes the transient dynamics of the network switching between successive stable states. Here, we demonstrate that global coherence and metastability can be informative measures to track healthy ageing dynamics over lifespan and together with the traditional spectral measures provides an attractive explanation of neuronal information processing. Finding normative patterns of brain rhythms in resting state MEG would naturally pave the way for tracking task relevant metrics that could crucially determine cognitive flexibility and performance. While previously reported observations of a reduction in peak alpha frequency and increased beta power in older adults are reflective of changes at individual sensors (during rest and task), global coherence and metastability pinpoint the underlying coordination dynamics over multiple brain areas across the entire lifespan. In addition to replication of the previous observations in a substantially larger lifespan cohort than what was previously reported, we also demonstrate, for the first time to the best of our knowledge, age related changes in coherence and metastability in signals over time scales of neuronal processing. Furthermore, we observed a marked frequency dependence in changes in global coordination dynamics, which, coupled with the long-held view of specific frequency bands subserving different aspects of cognition, hints at differential functional processing roles for slower and faster brain dynamics.

Biophysical mechanisms governing large-scale brain network dynamics underlying individual-specific variability of perception.

Perception necessitates interaction among neuronal ensembles, the dynamics of which can be conceptualized as the emergent behavior of coupled dynamical systems. Here, we propose a detailed neurobiologically realistic model that captures the neural mechanisms of inter-individual variability observed in cross-modal speech perception. From raw EEG signals recorded from human participants when they were presented with speech vocalizations of McGurk-incongruent and congruent audio-visual (AV) stimuli, we computed the global coherence metric to capture the neural variability of large-scale networks. We identified that participants' McGurk susceptibility was negatively correlated to their alpha band global coherence. The proposed biophysical model conceptualized the global coherence dynamics emerge from coupling between the interacting neural masses-representing the sensory-specific auditory/visual areas and modality nonspecific associative/integrative regions. Subsequently, we could predict that an extremely weak direct AV coupling results in a decrease in alpha band global coherence-mimicking the cortical dynamics of participants with higher McGurk susceptibility. Source connectivity analysis also showed decreased connectivity between sensory-specific regions in participants more susceptible to McGurk effect, thus establishing an empirical validation to the prediction. Overall, our study provides an outline to link variability in structural and functional connectivity metrics to variability of performance that can be useful for several perception and action task paradigms.

Resting state dynamics meets anatomical structure: Temporal multiple kernel learning (tMKL) model.

Over the last decade there has been growing interest in understanding the brain activity, in the absence of any task or stimulus, captured by the resting-state functional magnetic resonance imaging (rsfMRI). The resting state patterns have been observed to be exhibiting complex spatio-temporal dynamics and substantial effort has been made to characterize the dynamic functional connectivity (dFC) configurations. However, the dynamics governing the state transitions that the brain undergoes and their relationship to stationary functional connectivity still remains an open problem. One class of approaches attempts to characterize the dynamics in terms of finite number of latent brain states, however, such attempts are yet to amalgamate the underlying anatomical structural connectivity (SC) with the dynamics. Another class of methods links individual dynamic FCs with the underlying SC but does not characterize the temporal evolution of FC. Further, the latent states discovered by previous approaches could not be directly linked to the SC, thereby motivating us to discover the underlying lower-dimensional manifold that represents the temporal structure. In the proposed approach, the discovered manifold is further parameterized as a set of local density distributions, or latent transient states. We propose an innovative method that learns parameters specific to the latent states using a graph-theoretic model (temporal Multiple Kernel Learning, tMKL) that inherently links dynamics to the structure and finally predicts the grand average FC of the test subjects by leveraging a state transition Markov model. The proposed solution does not make strong assumptions about the underlying data and is generally applicable to resting or task data for learning subject-specific state transitions and for successfully characterizing SC-dFC-FC relationship through a unifying framework. Training and testing were done using the rs-fMRI data of 46 healthy participants. tMKL model performs significantly better than the existing models for predicting resting state functional connectivity based on whole-brain dynamic mean-field model (DMF), single diffusion kernel (SDK) model and multiple kernel learning (MKL) model. Further, the learned model was tested on an independent cohort of 100 young, healthy participants from the Human Connectome Project (HCP) and the results establish the generalizability of the proposed solution. More importantly, the model retains sensitivity toward subject-specific anatomy, a unique contribution towards a holistic approach for SC-FC characterization.

Does the regulation of local excitation-inhibition balance aid in recovery of functional connectivity? A computational account.

Computational modeling of the spontaneous dynamics over the whole brain provides critical insight into the spatiotemporal organization of brain dynamics at multiple resolutions and their alteration to changes in brain structure (e.g. in diseased states, aging, across individuals). Recent experimental evidence further suggests that the adverse effect of lesions is visible on spontaneous dynamics characterized by changes in resting state functional connectivity and its graph theoretical properties (e.g. modularity). These changes originate from altered neural dynamics in individual brain areas that are otherwise poised towards a homeostatic equilibrium to maintain a stable excitatory and inhibitory activity. In this work, we employ a homeostatic inhibitory mechanism, balancing excitation and inhibition in the local brain areas of the entire cortex under neurological impairments like lesions to understand global functional recovery (across brain networks and individuals). Previous computational and empirical studies have demonstrated that the resting state functional connectivity varies primarily due to the location and specific topological characteristics of the lesion. We show that local homeostatic balance provides a functional recovery by re-establishing excitation-inhibition balance in all areas that are affected by lesion. We systematically compare the extent of recovery in the primary hub areas (e.g. default mode network (DMN), medial temporal lobe, medial prefrontal cortex) as well as other sensory areas like primary motor area, supplementary motor area, fronto-parietal and temporo-parietal networks. Our findings suggest that stability and richness similar to the normal brain dynamics at rest are achievable by re-establishment of balance.

Brain state dependent postinhibitory rebound in entorhinal cortex interneurons.

Postinhibitory rebound (PIR) is believed to play an important role in the genesis and maintenance of biological rhythms. While it has been demonstrated during several in vitro studies, in vivo evidence for PIR remains scarce. Here, we report that PIR can be observed in the dorsomedial entorhinal cortex of anesthetized rats, mostly between putatively connected GABAergic interneurons, and that it is more prevalent during the theta (4-6 Hz) oscillation state than the slow (0.5-2 Hz) oscillation state. Functional inhibition was also found to be brain state and postsynaptic cell type dependent but that alone could not explain this brain state dependence of PIR. A theoretical analysis, using two Fitzhugh-Nagumo neurons coupled to an external periodic drive, predicted that the modulation of a faster spiking rate by the slower periodic drive could account for the brain state dependence of PIR. Model predictions were verified experimentally. We conclude that PIR is cell type and brain state dependent and propose that this could impact network synchrony and rhythmogenesis.

Altered global modular organization of intrinsic functional connectivity in autism arises from atypical node-level processing.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by restricted interests and repetitive behaviors as well as social-communication deficits. These traits are associated with atypicality of functional brain networks. Modular organization in the brain plays a crucial role in network stability and adaptability for neurodevelopment. Previous neuroimaging research demonstrates discrepancies in studies of functional brain modular organization in ASD. These discrepancies result from the examination of mixed age groups. Furthermore, recent findings suggest that while much attention has been given to deriving atlases and measuring the connections between nodes, within node information may also be crucial in determining altered modular organization in ASD compared with typical development (TD). However, altered modular organization originating from systematic nodal changes are yet to be explored in younger children with ASD. Here, we used graph-theoretical measures to fill this knowledge gap. To this end, we utilized multicenter resting-state fMRI data collected from 5 to 10-year-old children-34 ASD and 40 TD obtained from the Autism Brain Image Data Exchange (ABIDE) I and II. We demonstrate that alterations in topological roles and modular cohesiveness are the two key properties of brain regions anchored in default mode, sensorimotor, and salience networks, and primarily relate to social and sensory deficits in children with ASD. These results demonstrate that atypical global network organization in children with ASD arises from nodal role changes, and contribute to the growing body of literature suggesting that there is interesting information within nodes providing critical markers of functional brain networks in autistic children.

Effective networks mediate right hemispheric dominance of human 40 Hz auditory steady-state response.

Auditory steady-state responses (ASSR) are induced from the brainstem to the neocortex when humans hear periodic amplitude-modulated tonal signals. ASSRs have been argued to be a key marker of auditory temporal processing and pathological reorganization of ASSR - a biomarker of neurodegenerative disorders. However, most of the earlier studies reporting the neural basis of ASSRs were focused on looking at individual brain regions. Here, we seek to characterize the large-scale directed information flow among cortical sources of ASSR entrained by 40 Hz external signals. Entrained brain rhythms with power peaking at 40 Hz were generated using both monaural and binaural tonal stimulation. First, we confirm the presence of ASSRs and their well-known right hemispheric dominance during binaural and both monaural conditions. Thereafter, reconstruction of source activity employing individual anatomy of the participant and subsequent network analysis revealed that while the sources are common among different stimulation conditions, differential levels of source activation and differential patterns of directed information flow among sources underlie processing of binaurally and monaurally presented tones. Particularly, we show bidirectional interactions involving the right superior temporal gyrus and inferior frontal gyrus underlie right hemispheric dominance of 40 Hz ASSR during both monaural and binaural conditions. On the other hand, for monaural conditions, the strength of inter-hemispheric flow from left primary auditory areas to right superior temporal areas followed a pattern that comply with the generally observed contralateral dominance of sensory signal processing.

Structural-and-dynamical similarity predicts compensatory brain areas driving the post-lesion functional recovery mechanism.

The focal lesion alters the excitation-inhibition (E-I) balance and healthy functional connectivity patterns, which may recover over time. One possible mechanism for the brain to counter the insult is global reshaping functional connectivity alterations. However, the operational principles by which this can be achieved remain unknown. We propose a novel equivalence principle based on structural and dynamic similarity analysis to predict whether specific compensatory areas initiate lost E-I regulation after lesion. We hypothesize that similar structural areas (SSAs) and dynamically similar areas (DSAs) corresponding to a lesioned site are the crucial dynamical units to restore lost homeostatic balance within the surviving cortical brain regions. SSAs and DSAs are independent measures, one based on structural similarity properties measured by Jaccard Index and the other based on post-lesion recovery time. We unravel the relationship between SSA and DSA by simulating a whole brain mean field model deployed on top of a virtually lesioned structural connectome from human neuroimaging data to characterize global brain dynamics and functional connectivity at the level of individual subjects. Our results suggest that wiring proximity and similarity are the 2 major guiding principles of compensation-related utilization of hemisphere in the post-lesion functional connectivity re-organization process.

A Decomposition Analysis to Understand the Wealth-Based Inequalities in Child Vaccination in Rural Southern Assam: A Cross-Sectional Study.

Background: The socio-environmental aspects of southern Assam reflect a general pattern of backwardness. Moreover, child healthcare resources in the region are inadequately used, leading to low vaccination coverage. Given this background, this paper attempted to comprehend wealth-based inequality in full vaccination in rural areas of southern Assam. Methodology: Based on a multistage cluster sampling approach, 360 children of 12-23 months were selected from the study area. To identify the predictors of a child, a non-linear model was estimated by using the generalized linear model (GLM) approach followed by Erreygers decomposition technique to quantify the wealth inequality in the obtained predictors in explaining the disparity in full vaccination. Result: The Bacillus Calmette-Guérin (BCG) vaccination recorded the highest vaccination coverage, at nearly 90% and the lowest was observed for the measles vaccine, around 61 percent. Slightly more than half of the eligible children (54 percent) were vaccinated against all the Universal Immunization Programme (UIP)-recommended vaccines. The decomposition analysis revealed that the occupation of the child's father, maternal age, birth order of the child, and health-seeking behavior such as antenatal care (ANC) were the prime factors related to inequality in full vaccination in the region. Conclusion: Vaccination coverage in the region has improved over time, however, full vaccination is concentrated towards the economically advantaged section of the society in rural southern Assam. Targeted, context-specific, and expanded government initiatives could aid in addressing the overall wealth-related full vaccination inequalities in the valley.

Whole-Brain Network Models: From Physics to Bedside.

Computational neuroscience has come a long way from its humble origins in the pioneering work of Hodgkin and Huxley. Contemporary computational models of the brain span multiple spatiotemporal scales, from single neuronal compartments to models of social cognition. Each spatial scale comes with its own unique set of promises and challenges. Here, we review models of large-scale neural communication facilitated by white matter tracts, also known as whole-brain models (WBMs). Whole-brain approaches employ inputs from neuroimaging data and insights from graph theory and non-linear systems theory to model brain-wide dynamics. Over the years, WBM models have shown promise in providing predictive insights into various facets of neuropathologies such as Alzheimer's disease, Schizophrenia, Epilepsy, Traumatic brain injury, while also offering mechanistic insights into large-scale cortical communication. First, we briefly trace the history of WBMs, leading up to the state-of-the-art. We discuss various methodological considerations for implementing a whole-brain modeling pipeline, such as choice of node dynamics, model fitting and appropriate parcellations. We then demonstrate the applicability of WBMs toward understanding various neuropathologies. We conclude by discussing ways of augmenting the biological and clinical validity of whole-brain models.

Biophysical mechanism underlying compensatory preservation of neural synchrony over the adult lifespan.

We propose that the preservation of functional integration, estimated from measures of neural synchrony, is a key objective of neurocompensatory mechanisms associated with healthy human ageing. To support this proposal, we demonstrate how phase-locking at the peak alpha frequency in Magnetoencephalography recordings remains invariant over the lifespan in a large cohort of human participants, aged 18-88 years. Using empirically derived connection topologies from diffusion tensor imaging data, we create an in-silico model of whole-brain alpha dynamics. We show that enhancing inter-areal coupling can cancel the effect of increased axonal transmission delays associated with age-related degeneration of white matter tracts, albeit at slower network frequencies. By deriving analytical solutions for simplified connection topologies, we further establish the theoretical principles underlying compensatory network re-organization. Our findings suggest that frequency slowing with age- frequently observed in the alpha band in diverse populations- may be viewed as an epiphenomenon of the underlying compensatory mechanism.

Hippocampus Maintains a Coherent Map Under Reward Feature-Landmark Cue Conflict.

Animals predominantly use salient visual cues (landmarks) for efficient navigation. When the relative position of the visual cues is altered, the hippocampal population exhibits heterogeneous responses and constructs context-specific spatial maps. Another critical factor that can strongly modulate spatial representation is the presence of reward. Reward features can drive behavior and are known to bias spatial attention. However, it is unclear whether reward features are used for spatial reference in the presence of distal cues and how the hippocampus population dynamics changes when the association between reward features and distal cues is altered. We systematically investigated these questions by recording place cells from the CA1 in different sets of experiments while the rats ran in an environment with the conflicting association between reward features and distal cues. We report that, when rewards features were only used as local cues, the hippocampal place fields exhibited coherent and dynamical orientation across sessions, suggesting the use of a single coherent spatial map. We found that place cells maintained their spatial offset in the cue conflict conditions, thus showing a robust spatial coupling featuring an attractor-like property in the CA1. These results indicate that reward features may control the place field orientation but may not cause sufficient input difference to create context-specific spatial maps in the CA1.

Atypical core-periphery brain dynamics in autism.

The intrinsic function of the human brain is dynamic, giving rise to numerous behavioral subtypes that fluctuate distinctively at multiple timescales. One of the key dynamical processes that takes place in the brain is the interaction between core-periphery brain regions, which undergoes constant fluctuations associated with developmental time frames. Core-periphery dynamical changes associated with macroscale brain network dynamics span multiple timescales and may lead to atypical behavior and clinical symptoms. For example, recent evidence suggests that brain regions with shorter intrinsic timescales are located at the periphery of brain networks (e.g., sensorimotor hand, face areas) and are implicated in perception and movement. On the contrary, brain regions with longer timescales are core hub regions. These hubs are important for regulating interactions between the brain and the body during self-related cognition and emotion. In this review, we summarize a large body of converging evidence derived from time-resolved fMRI studies in autism to characterize atypical core-periphery brain dynamics and how they relate to core and contextual sensory and cognitive profiles.

Contextual prediction errors reorganize naturalistic episodic memories in time.

Episodic memories are contextual experiences ordered in time. This is underpinned by associative binding between events within the same contexts. The role of prediction errors in declarative memory is well established but has not been investigated in the time dimension of complex episodic memories. Here we combine these two properties of episodic memory, extend them into the temporal domain and demonstrate that prediction errors in different naturalistic contexts lead to changes in the temporal ordering of event structures in them. The wrongly predicted older sequences were weakened despite their reactivation. Interestingly the newly encoded sequences with prediction errors, seen once, showed accuracy as high as control sequences which were viewed repeatedly without change. Drift-diffusion modelling revealed a lower decision threshold for the newer sequences than older sequences, reflected by their faster recall. Moreover, participants' adjustments to their decision threshold significantly correlated with their relative speed of sequence memory recall. These results suggest a temporally distinct and adaptive role for prediction errors in learning and reorganizing episodic temporal sequences.