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Learning never stops. As we navigate life, we continuously acquire and update knowledge to optimize memory-guided action, with a gradual shift from the former to the latter as we master our environment. How are these learning dynamics expressed in the brain and in behavioral patterns? Here, we devised a spatiotemporal image learning task ("Memory Arena") in which participants learn a set of 50 items to criterion across repeated exposure blocks. Critically, brief task-free periods between successive image presentations allowed us to assess multivariate electroencephalogram (EEG) patterns representing the previous and/or upcoming image identity, as well as anticipatory eye movements toward the upcoming image location. As expected, participants eventually met the performance criterion, albeit with different learning rates. During task-free periods, we were able to readily decode representations of both previous and upcoming image identities. Importantly though, decoding strength followed opposing slopes for previous vs. upcoming images across time, with a gradual decline of evidence for the previous image and a gradual increase of evidence for the upcoming image. Moreover, the ratio of upcoming vs. previous image evidence directly followed behavioral learning rates. Finally, eye movement data revealed that participants increasingly used the task-free period to anticipate upcoming image locations, with target-precision slopes paralleling both behavioral performance measures as well as EEG decodability of the upcoming image across time. Together, these results unveil the neural and behavioral dynamics underlying the gradual transition from learning to memory-guided action., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

How do passing moments turn into lasting memories? Sheltered from external tasks and distractions, sleep constitutes an optimal state for the brain to reprocess and consolidate previous experiences. Recent work suggests that consolidation is governed by the intricate interaction of slow oscillations (SOs), spindles, and ripples - electrophysiological sleep rhythms that orchestrate neuronal processing and communication within and across memory circuits. This review describes how sequential SO-spindle-ripple coupling provides a temporally and spatially fine-tuned mechanism to selectively strengthen target memories across hippocampal and cortical networks. Coupled sleep rhythms might be harnessed not only to enhance overnight memory retention, but also to combat memory decline associated with healthy ageing and neurodegenerative diseases., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Associative memory enables the encoding and retrieval of relations between different stimuli. To better understand its neural basis, we investigated whether associative memory involves temporally correlated spiking of medial temporal lobe (MTL) neurons that exhibit stimulus-specific tuning. Using single-neuron recordings from patients with epilepsy performing an associative object-location memory task, we identified the object-specific and place-specific neurons that represented the separate elements of each memory. When patients encoded and retrieved particular memories, the relevant object-specific and place-specific neurons activated together during hippocampal ripples. This ripple-locked coactivity of stimulus-specific neurons emerged over time as the patients' associative learning progressed. Between encoding and retrieval, the ripple-locked timing of coactivity shifted, suggesting flexibility in the interaction between MTL neurons and hippocampal ripples according to behavioral demands. Our results are consistent with a cellular account of associative memory, in which hippocampal ripples coordinate the activity of specialized cellular populations to facilitate links between stimuli., (© 2024. The Author(s).)

The beneficial effect of sleep on memory consolidation relies on the precise interplay of slow oscillations and spindles. However, whether these rhythms are orchestrated by an underlying pacemaker has remained elusive. Here, we tested the relationship between respiration, which has been shown to impact brain rhythms and cognition during wake, sleep-related oscillations and memory reactivation in humans. We re-analysed an existing dataset, where scalp electroencephalography and respiration were recorded throughout an experiment in which participants (N = 20) acquired associative memories before taking a nap. Our results reveal that respiration modulates the emergence of sleep oscillations. Specifically, slow oscillations, spindles as well as their interplay (i.e., slow-oscillation_spindle complexes) systematically increase towards inhalation peaks. Moreover, the strength of respiration - slow-oscillation_spindle coupling is linked to the extent of memory reactivation (i.e., classifier evidence in favour of the previously learned stimulus category) during slow-oscillation_spindles. Our results identify a clear association between respiration and memory consolidation in humans and highlight the role of brain-body interactions during sleep., (© 2023. The Author(s).)

The hippocampus is an essential hub for episodic memory processing. However, how human hippocampal single neurons code multi-element associations remains unknown. In particular, it is debated whether each hippocampal neuron represents an invariant element within an episode or whether single neurons bind together all the elements of a discrete episodic memory. Here we provide evidence for the latter hypothesis. Using single-neuron recordings from a total of 30 participants, we show that individual neurons, which we term episode-specific neurons, code discrete episodic memories using either a rate code or a temporal firing code. These neurons were observed exclusively in the hippocampus. Importantly, these episode-specific neurons do not reflect the coding of a particular element in the episode (that is, concept or time). Instead, they code for the conjunction of the different elements that make up the episode., (© 2023. The Author(s).)

While the benefits of sleep for associative memory are well established, it is unclear whether single-item memories profit from overnight consolidation to the same extent. We addressed this question in a preregistered, online study and also investigated how the temporal proximity between learning and sleep influences overnight retention. Sleep relative to wakefulness improved retention of item and associative memories to similar extents irrespective of whether sleep occurred soon after learning or following a prolonged waking interval. Our findings highlight the far-reaching influences of sleep on memory that can arise even after substantial periods of wakefulness., (© 2023 Petzka et al.; Published by Cold Spring Harbor Laboratory Press.)

Learning and plasticity rely on fine-tuned regulation of neuronal circuits during offline periods. An unresolved puzzle is how the sleeping brain, in the absence of external stimulation or conscious effort, coordinates neuronal firing rates (FRs) and communication within and across circuits to support synaptic and systems consolidation. Using intracranial electroencephalography combined with multiunit activity recordings from the human hippocampus and surrounding medial temporal lobe (MTL) areas, we show that, governed by slow oscillation (SO) up-states, sleep spindles set a timeframe for ripples to occur. This sequential coupling leads to a stepwise increase in (1) neuronal FRs, (2) short-latency cross-correlations among local neuronal assemblies and (3) cross-regional MTL interactions. Triggered by SOs and spindles, ripples thus establish optimal conditions for spike-timing-dependent plasticity and systems consolidation. These results unveil how the sequential coupling of specific sleep rhythms orchestrates neuronal processing and communication during human sleep., (© 2023. The Author(s).)

Theta and gamma oscillations in the medial temporal lobe are suggested to play a critical role for human memory formation via establishing synchrony in neural assemblies. Arguably, such synchrony facilitates efficient information transfer between neurons and enhances synaptic plasticity, both of which benefit episodic memory formation. However, to date little evidence exists from humans that would provide direct evidence for such a specific role of theta and gamma oscillations for episodic memory formation. Here, we investigate how oscillations shape the temporal structure of neural firing during memory formation in the medial temporal lobe. We measured neural firing and local field potentials in human epilepsy patients via micro-wire electrode recordings to analyze whether brain oscillations are related to co-incidences of firing between neurons during successful and unsuccessful encoding of episodic memories. The results show that phase-coupling of neurons to faster theta and gamma oscillations correlates with co-firing at short latencies (~20-30 ms) and occurs during successful memory formation. Phase-coupling at slower oscillations in these same frequency bands, in contrast, correlates with longer co-firing latencies and occurs during memory failure. Thus, our findings suggest that neural oscillations play a role for the synchronization of neural firing in the medial temporal lobe during the encoding of episodic memories., Competing Interests: FR, GP, RC, DR, VS, HH, SG, GK, Mt, LK, BS, MW, MS, SH No competing interests declared, (© 2022, Roux et al.)

Sleep constitutes a privileged state for new memories to reactivate and consolidate. Previous work has demonstrated that consolidation can be bolstered experimentally either via delivery of reminder cues (targeted memory reactivation [TMR]) or via noninvasive brain stimulation geared toward enhancing endogenous sleep rhythms. Here, we combined both approaches, controlling the timing of TMR cues with respect to ongoing slow-oscillation (SO) phases. Prior to sleep, participants learned associations between unique words and a set of repeating images (e.g., car) while hearing a prototypical image sound (e.g., engine starting). Memory performance on an immediate test vs. a test the next morning quantified overnight memory consolidation. Importantly, two image sounds were designated as TMR cues, with one cue delivered at SO UP states and the other delivered at SO DOWN states. A novel sound was used as a TMR control condition. Behavioral results revealed a significant reduction of overnight forgetting for words associated with UP-state TMR compared with words associated with DOWN-state TMR. Electrophysiological results showed that UP-state cueing led to enhancement of the ongoing UP state and was followed by greater spindle power than DOWN-state cueing. Moreover, UP-state (and not DOWN-state) cueing led to reinstatement of target image representations. Together, these results unveil the behavioral and mechanistic effects of delivering reminder cues at specific phases of endogenous sleep rhythms and mark an important step for the endeavor to experimentally modulate memories during sleep.

Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations. We argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery., (© 2022. The Author(s).)

Stress may shift behavioural control from a goal-directed system that encodes action-outcome relationships to a habitual system that learns stimulus-response associations. Although this shift to habits is highly relevant for stress-related psychopathologies, limitations of existing behavioural paradigms hinder research from answering the fundamental question of whether the stress-induced bias to habits is due to reduced outcome processing or enhanced response processing at the time of stimulus presentation, or both. Here, we used EEG-based multivariate pattern analysis to decode neural outcome representations crucial for goal-directed control, as well as response representations during instrumental learning. We show that stress reduced outcome representations but enhanced response representations. Both were directly associated with a behavioural index of habitual responding. Furthermore, changes in outcome and response representations were uncorrelated, suggesting that these may reflect distinct processes. Our findings indicate that habitual behaviour under stress may be the result of both enhanced stimulus-response processing and diminished outcome processing., Competing Interests: JM, BS, LS No competing interests declared, (© 2022, Meier et al.)

Our ability to recall memories is improved when sleep follows learning, suggesting that sleep facilitates memory consolidation. A number of factors are thought to influence the impact of sleep on newly learned information, such as whether or not we rehearse that information (e.g. via restudy or retrieval practice), or the extent to which the information is consistent with our pre-existing schematic knowledge. In this pre-registered, online study, we examined the effects of both rehearsal and schematic congruency on overnight consolidation. Participants learned noun-colour pairings (e.g. elephant-red) and rated each pairing as plausible or implausible before completing a baseline memory assessment. Afterwards, participants engaged in a period of restudy or retrieval practice for the pairings, and then entered a 12 h retention interval of overnight sleep or daytime wakefulness. Follow-up assessments were completed immediately after sleep or wake, and again 24 h after learning. Our data indicated that overnight consolidation was amplified for restudied relative to retested noun-colour pairings, but only when sleep occurred soon after learning. Furthermore, whereas plausible (i.e. schematically congruent) pairings were generally better remembered than implausible (i.e. schematically incongruent) pairings, the benefits of sleep were stronger for implausible relative to plausible memories. These findings challenge the notion that schema-conformant memories are preferentially strengthened during post-learning sleep., Competing Interests: The authors have declared that no competing interests exist.

Memory consolidation-the transformation of labile memory traces into stable long-term representations-is facilitated by post-learning sleep. Computational and biophysical models suggest that sleep spindles may play a key mechanistic role for consolidation, igniting structural changes at cortical sites involved in prior learning. Here, we tested the resulting prediction that spindles are most pronounced over learning-related cortical areas and that the extent of this learning-spindle overlap predicts behavioral measures of memory consolidation. Using high-density scalp electroencephalography (EEG) and polysomnography (PSG) in healthy volunteers, we first identified cortical areas engaged during a temporospatial associative memory task (power decreases in the alpha/beta frequency range, 6-20 Hz). Critically, we found that participant-specific topographies (i.e., spatial distributions) of post-learning sleep spindle amplitude correlated with participant-specific learning topographies. Importantly, the extent to which spindles tracked learning patterns further predicted memory consolidation across participants. Our results provide empirical evidence for a role of post-learning sleep spindles in tracking learning networks, thereby facilitating memory consolidation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

How does the human brain manage multiple bits of information to guide goal-directed behavior? Successful working memory (WM) functioning has consistently been linked to oscillatory power in the theta frequency band (4-8 Hz) over fronto-medial cortex (fronto-medial theta [FMT]). Specifically, FMT is thought to reflect the mechanism of an executive sub-system that coordinates maintenance of memory contents in posterior regions. However, direct evidence for the role of FMT in controlling specific WM content is lacking. Here, we collected high-density electroencephalography (EEG) data while participants engaged in WM-dependent tasks and then used multivariate decoding methods to examine WM content during the maintenance period. Engagement of WM was accompanied by a focal increase in FMT. Importantly, decoding of WM content was driven by posterior sites, which, in turn, showed increased functional theta coupling with fronto-medial channels. Finally, we observed a significant slowing of FMT frequency with increasing WM load, consistent with the hypothesized broadening of a theta "duty cycle" to accommodate additional WM items. Together, these findings demonstrate that frontal theta orchestrates posterior maintenance of WM content. Moreover, the observed frequency slowing elucidates the function of FMT oscillations by specifically supporting phase-coding accounts of WM., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Adaptive memory recall requires a rapid and flexible switch from external perceptual reminders to internal mnemonic representations. However, owing to the limited temporal or spatial resolution of brain imaging modalities used in isolation, the hippocampal-cortical dynamics supporting this process remain unknown. We thus employed an object-scene cued recall paradigm across two studies, including intracranial electroencephalography (iEEG) and high-density scalp EEG. First, a sustained increase in hippocampal high gamma power (55 to 110 Hz) emerged 500 ms after cue onset and distinguished successful vs. unsuccessful recall. This increase in gamma power for successful recall was followed by a decrease in hippocampal alpha power (8 to 12 Hz). Intriguingly, the hippocampal gamma power increase marked the moment at which extrahippocampal activation patterns shifted from perceptual cue toward mnemonic target representations. In parallel, source-localized EEG alpha power revealed that the recall signal progresses from hippocampus to posterior parietal cortex and then to medial prefrontal cortex. Together, these results identify the hippocampus as the switchboard between perception and memory and elucidate the ensuing hippocampal-cortical dynamics supporting the recall process., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

To form an episodic memory, we must first process a vast amount of sensory information about the to-be-encoded event and then bind these sensory representations together to form a coherent memory trace. While these two cognitive capabilities are thought to have two distinct neural origins, with neocortical alpha/beta oscillations supporting information representation and hippocampal theta-gamma phase-amplitude coupling supporting mnemonic binding, evidence for a dissociation between these two neural markers is conspicuously absent. To address this, seventeen human participants completed an associative memory task that first involved processing information about three sequentially-presented stimuli, and then binding these stimuli together into a coherent memory trace, all the while undergoing MEG recordings. We found that decreases in neocortical alpha/beta power during sequence perception, but not mnemonic binding, correlated with enhanced memory performance. Hippocampal theta/gamma phase-amplitude coupling, however, showed the opposite pattern; increases during mnemonic binding (but not sequence perception) correlated with enhanced memory performance. These results demonstrate that memory-related decreases in neocortical alpha/beta power and memory-related increases in hippocampal theta/gamma phase-amplitude coupling arise at distinct stages of the memory formation process. We speculate that this temporal dissociation reflects a functional dissociation in which neocortical alpha/beta oscillations could support the processing of incoming information relevant to the memory, while hippocampal theta-gamma phase-amplitude coupling could support the binding of this information into a coherent memory trace., (Copyright © 2021. Published by Elsevier Inc.)

Spatial navigation and memory rely on neural systems that encode places, distances, and directions in relation to the external world or relative to the navigating organism. Place, grid, and head-direction cells form key units of world-referenced, allocentric cognitive maps, but the neural basis of self-centered, egocentric representations remains poorly understood. Here, we used human single-neuron recordings during virtual spatial navigation tasks to identify neurons providing a neural code for egocentric spatial maps in the human brain. Consistent with previous observations in rodents, these neurons represented egocentric bearings toward reference points positioned throughout the environment. Egocentric bearing cells were abundant in the parahippocampal cortex and supported vectorial representations of egocentric space by also encoding distances toward reference points. Beyond navigation, the observed neurons showed activity increases during spatial and episodic memory recall, suggesting that egocentric bearing cells are not only relevant for navigation but also play a role in human memory., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sleep is thought to support memory consolidation via reactivation of prior experiences, with particular electrophysiological sleep signatures (slow oscillations (SOs) and sleep spindles) gating the information flow between relevant brain areas. However, empirical evidence for a role of endogenous memory reactivation (i.e., without experimentally delivered memory cues) for consolidation in humans is lacking. Here, we devised a paradigm in which participants acquired associative memories before taking a nap. Multivariate decoding was then used to capture endogenous memory reactivation during non-rapid eye movement (NREM) sleep in surface EEG recordings. Our results reveal reactivation of learning material during SO-spindle complexes, with the precision of SO-spindle coupling predicting reactivation strength. Critically, reactivation strength (i.e. classifier evidence in favor of the previously studied stimulus category) in turn predicts the level of consolidation across participants. These results elucidate the memory function of sleep in humans and emphasize the importance of SOs and spindles in clocking endogenous consolidation processes.

Auditory beats are amplitude-modulated signals (monaural beats) or signals that subjectively cause the perception of an amplitude modulation (binaural beats). We investigated the effects of monaural and binaural 5 Hz beat stimulation on neural activity and memory performance in neurosurgical patients performing an associative recognition task. Previously, we had reported that these beat stimulation conditions modulated memory performance in opposite directions. Here, we analyzed data from a patient subgroup, in which microwires were implanted in the amygdala, hippocampus, entorhinal cortex and parahippocampal cortex. We identified neurons responding with firing rate changes to binaural versus monaural 5 Hz beat stimulation. In these neurons, we correlated the differences in firing rates for binaural versus monaural beats to the memory-related differences for remembered versus forgotten items and associations. In the left hemisphere, we detected statistically significant negative correlations between firing rate differences for binaural versus monaural beats and remembered versus forgotten items/associations. Importantly, such negative correlations were also observed between beat stimulation-related firing rate differences in the pre-stimulus window and memory-related firing rate differences in the post-stimulus windows. In line with concepts of homeostatic plasticity, our findings suggest that beat stimulation is linked to memory performance via shifting baseline firing levels.

Episodic memory retrieval is characterised by the vivid reinstatement of information about a personally-experienced event. Growing evidence suggests that this reinstatement is supported by reductions in the spectral power of alpha/beta activity. Given that the amount of information that can be recalled depends on the amount of information that was originally encoded, information-based accounts of alpha/beta activity would suggest that retrieval-related alpha/beta power decreases similarly depend upon decreases in alpha/beta power during encoding. To test this hypothesis, seventeen human participants completed a sequence-learning task while undergoing concurrent MEG recordings. Regression-based analyses were then used to estimate how alpha/beta power decreases during encoding predicted alpha/beta power decreases during retrieval on a trial-by-trial basis. When subjecting these parameter estimates to group-level analysis, we find evidence to suggest that retrieval-related alpha/beta (7-15Hz) power decreases fluctuate as a function of encoding-related alpha/beta power decreases. These results suggest that retrieval-related alpha/beta power decreases are contingent on the decrease in alpha/beta power that arose during encoding. Subsequent analysis uncovered no evidence to suggest that these alpha/beta power decreases reflect stimulus identity, indicating that the contingency between encoding- and retrieval-related alpha/beta power reflects the reinstatement of a neurophysiological operation, rather than neural representation, during episodic memory retrieval., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Sleep stabilizes newly acquired memories, a process referred to as memory consolidation. According to recent studies, sleep-dependent consolidation processes might be deployed to different extents for different types of memories. In particular, weaker memories might benefit greater from post-learning sleep than stronger memories. However, under standard testing conditions, sleep-dependent consolidation effects for stronger memories might be obscured by ceiling effects. To test this possibility, we devised a new memory paradigm (Memory Arena) in which participants learned temporospatial arrangements of objects. Prior to a delay period spent either awake or asleep, training thresholds were controlled to yield relatively weak or relatively strong memories. After the delay period, retrieval difficulty was controlled via the presence or absence of a retroactive interference task. Under standard testing conditions (no interference), a sleep-dependent consolidation effect was indeed observed for weaker memories only. Critically though, with increased retrieval demands, sleep-dependent consolidation effects were seen for both weaker and stronger memories. These results suggest that all memories are consolidated during sleep, but that memories of different strengths require different testing conditions to unveil their benefit from post-learning sleep., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Electrophysiological activity in medial temporal lobe (MTL) structures is pivotal for declarative long-term memory. Single-neuron and microcircuit findings capitalizing on human microwire recordings from the medial temporal lobe are still fragmentary. In particular, it is an open question whether identical or different groups of neurons participate in different memory functions. Here, we investigated category-specific responses in the human MTL based on single-neuron recordings in presurgical epilepsy patients performing an associative long-term memory task. Additionally, auditory beat stimuli were presented during encoding and retrieval to modulate memory performance. We describe the proportion of neurons in amygdala, entorhinal cortex, hippocampus and parahippocampal cortex belonging to different response classes. These entail neurons coding stimulus-familiarity, neurons coding successful item memory, and neurons coding associated source memory, as well as the overlap between these classes. As major results we demonstrate that neurons responding to stimulus familiarity (old/new effect) can be identified in the MTL even when using previously known rather than entirely novel stimulus material (words). We observed a significant overlap between familiarity-related neurons and neurons coding item retrieval (remembered/forgotten effect). The largest fraction of familiarity-related neurons was found in the parahippocampal cortex, and a considerable fraction of all parahippocampal neurons was related to successful item retrieval. Neurons related to successful source retrieval were different from the neurons coding the associated information. Most importantly, there was no overlap between neurons coding item memory and those coding associated source memory strongly suggesting that these functions are facilitated by different sets of neurons., Competing Interests: Declaration of competing interest The authors declare that no financial or non-financial competing interests exist., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

During sleep, new memories undergo a gradual transfer from hippocampal (HPC) to neocortical (NC) sites. Precisely timed neural oscillations are thought to mediate this sleep-dependent memory consolidation, but exactly how sleep oscillations instantiate the HPC-NC dialog remains elusive. Employing overnight invasive electroencephalography in ten neurosurgical patients, we identified three broad classes of phase-based communication between HPC and lateral temporal NC. First, we observed interregional phase synchrony for non-rapid eye movement (NREM) spindles, and N2 and rapid eye movement (REM) theta activity. Second, we found asymmetrical N3 cross-frequency phase-amplitude coupling between HPC slow oscillations (SOs) and NC activity spanning the delta to high-gamma/ripple bands, but not in the opposite direction. Lastly, N2 theta and NREM spindle synchrony were themselves modulated by HPC SOs. These forms of interregional communication emphasize the role of HPC SOs in the HPC-NC dialog, and may offer a physiological basis for the sleep-dependent reorganization of mnemonic content.

Memories for past experiences can range from vague recognition to full-blown recall of associated details. Electroencephalography has shown that recall signals unfold a few hundred milliseconds after simple recognition, but has only provided limited insights into the underlying brain networks. Functional magnetic resonance imaging (fMRI) has revealed a "core recollection network" (CRN) centered on posterior parietal and medial temporal lobe regions, but the temporal dynamics of these regions during retrieval remain largely unknown. Here we used Magnetoencephalography in a memory paradigm assessing correct rejection (CR) of lures, item recognition (IR) and associative recall (AR) in human participants of both sexes. We found that power decreases in the alpha frequency band (10-12 Hz) systematically track different mnemonic outcomes in both time and space: Over left posterior sensors, alpha power decreased in a stepwise fashion from 500 ms onward, first from CR to IR and then from IR to AR. When projecting alpha power into source space, the CRN known from fMRI studies emerged, including posterior parietal cortex (PPC) and hippocampus. While PPC showed a monotonic change across conditions, hippocampal effects were specific to recall. These region-specific effects were corroborated by a separate fMRI dataset. Importantly, alpha power time courses revealed a temporal dissociation between item and associative memory in hippocampus and PPC, with earlier AR effects in hippocampus. Our data thus link engagement of the CRN to the temporal dynamics of episodic memory and highlight the role of alpha rhythms in revealing when and where different types of memories are retrieved. SIGNIFICANCE STATEMENT Our ability to remember ranges from the vague feeling of familiarity to vivid recollection of associated details. Scientific understanding of episodic memory thus far relied upon separate lines of research focusing on either temporal (via electroencephalography) or spatial (via functional magnetic resonance imaging) dimensions. However, both techniques have limitations that have hindered understanding of when and where memories are retrieved. Capitalizing on the enhanced temporal and spatial resolution of magnetoencephalography, we show that changes in alpha power reveal both when and where different types of memory are retrieved. Having access to the temporal and spatial characteristics of successful retrieval provided new insights into the cross-regional dynamics in the hippocampus and parietal cortex., (Copyright © 2020 Martín-Buro et al.)

Cooperative interactions between the amygdala and hippocampus are widely regarded as critical for overnight emotional processing of waking experiences, but direct support from the human brain for such a dialog is absent. Using overnight intracranial recordings in 4 presurgical epilepsy patients (3 female), we discovered ripples within human amygdala during nonrapid eye movement (NREM) sleep, a brain state known to contribute to affective processing. Like hippocampal ripples, amygdala ripples are associated with sharp waves, linked to sleep spindles, and tend to co-occur with their hippocampal counterparts. Moreover, sharp waves and ripples are temporally linked across the 2 brain structures, with amygdala ripples occurring during hippocampal sharp waves and vice versa . Combined with further evidence of interregional sharp-wave and spindle synchronization, these findings offer a potential physiological substrate for the NREM-sleep-dependent consolidation and regulation of emotional experiences., (© The Author(s) 2020. Published by Oxford University Press.)

Episodic memory allows us to mentally travel through time. How does the brain convert a simple reminder cue into a full-blown memory of past events and experiences? In this review, we integrate recent developments in the cognitive neuroscience of human memory retrieval, pinpointing the neural chronometry underlying successful recall. Electrophysiological recordings suggest that sensory cues proceed into the medial temporal lobe within the first 500 ms. At this point, a hippocampal process sets in, geared toward internal pattern completion and coordination of cortical memory reinstatement between 500 and 1500 ms. We further highlight the dynamic principles governing the recall process, which include a reversal of perceptual information flows, temporal compression, and theta clocking., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cross-frequency coupling of sleep oscillations is thought to mediate memory consolidation. While the hippocampus is deemed central to this process, detailed knowledge of which oscillatory rhythms interact in the sleeping human hippocampus is lacking. Combining intracranial hippocampal and non-invasive electroencephalography from twelve neurosurgical patients, we characterized spectral power and coupling during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Hippocampal coupling was extensive, with the majority of channels expressing spectral interactions. NREM consistently showed delta-ripple coupling, but ripples were also modulated by slow oscillations (SOs) and sleep spindles. SO-delta and SO-theta coupling, as well as interactions between delta/theta and spindle/beta frequencies also occurred. During REM, limited interactions between delta/theta and beta frequencies emerged. Moreover, oscillatory organization differed substantially between i) hippocampus and scalp, ii) sites along the anterior-posterior hippocampal axis, and iii) individuals. Overall, these results extend and refine our understanding of hippocampal sleep oscillations., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

How do we recall vivid details from our past based only on sparse cues? Research suggests that the phenomenological reinstatement of past experiences is accompanied by neural reinstatement of the original percept. This process critically depends on the medial temporal lobe (MTL). Within the MTL, perirhinal cortex (PRC) and parahippocampal cortex (PHC) are thought to support encoding and recall of objects and scenes, respectively, with the hippocampus (HC) serving as a content-independent hub. If the fidelity of recall indeed arises from neural reinstatement of perceptual activity, then successful recall should preferentially draw upon those neural populations within content-sensitive MTL cortex that are tuned to the same content during perception. We tested this hypothesis by having eighteen human participants undergo functional MRI (fMRI) while they encoded and recalled objects and scenes paired with words. Critically, recall was cued with the words only. While HC distinguished successful from unsuccessful recall of both objects and scenes, PRC and PHC were preferentially engaged during successful versus unsuccessful object and scene recall, respectively. Importantly, within PRC and PHC, this content-sensitive recall was predicted by content tuning during perception: Across PRC voxels, we observed a positive relationship between object tuning during perception and successful object recall, while across PHC voxels, we observed a positive relationship between scene tuning during perception and successful scene recall. Our results thus highlight content-based roles of MTL cortical regions for episodic memory and reveal a direct mapping between content-specific tuning during perception and successful recall., (Copyright © 2019 Schultz et al.)

Imagine how flicking through your photo album and seeing a picture of a beach sunset brings back fond memories of a tasty cocktail you had that night. Computational models suggest that upon receiving a partial memory cue ('beach'), neurons in the hippocampus coordinate reinstatement of associated memories ('cocktail') in cortical target sites. Here, using human single neuron recordings, we show that hippocampal firing rates are elevated from ~ 500-1500 ms after cue onset during successful associative retrieval. Concurrently, the retrieved target object can be decoded from population spike patterns in adjacent entorhinal cortex (EC), with hippocampal firing preceding EC spikes and predicting the fidelity of EC object reinstatement. Prior to orchestrating reinstatement, a separate population of hippocampal neurons distinguishes different scene cues (buildings vs. landscapes). These results elucidate the hippocampal-entorhinal circuit dynamics for memory recall and reconcile disparate views on the role of the hippocampus in scene processing vs. associative memory.

It has been known for centuries that gentle rocking promotes sleep. Two new studies now shed light on the underlying mechanism in both humans and mice., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

We propose a framework for the memory function of spindle oscillations during sleep. In this framework, memories are reinstated by spindle events and further reprocessed during subsequent spindle refractory periods. We posit that spindle refractoriness is crucial for protecting memory reprocessing from interference. We further argue that temporally-coordinated spindle refractory periods across local networks facilitate the consolidation of rich, multimodal representations, and that localized spindle refractoriness optimizes oscillatory interactions that support systems consolidation in the sleeping brain., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Auditory beat stimulation is an upcoming technique for non-invasive brain stimulation. Its influence on mediotemporal regions and memory processes has not yet been thoroughly investigated. A recent study suggests that auditory beats are able to alter intracranial EEG (iEEG) power and phase synchronization. 5 Hz binaural beat stimulation increased temporo-lateral phase synchronization, while 5 Hz monaural beat stimulation decreased mediotemporal synchronization. Based on the relevance of phase synchronization for memory operations, we hypothesized that 5 Hz binaural beat stimulation enhances, while 5 Hz monaural beat stimulation decreases long-term memory performance. We analyzed data from presurgical epilepsy patients with implanted depth electrodes in the hippocampus and rhinal cortex. 5 Hz monaural and binaural beat vs. control stimulation was applied while patients performed an associative learning task involving item and source recognition. We evaluated behavioral effects for item (hits minus false alarms) and source memory (correct minus incorrect) and the impact of auditory beats on iEEG power, rhinal-hippocampal phase synchronization and inter-trial phase locking. A three-way repeated measures ANOVA (encoding/retrieval, item/source, monaural/binaural/control) revealed a main effect of stimulation ( p = 0.03) and a linear effect in the expected direction: binaural > control > monaural ( p = 0.036). Both monaural and binaural stimulation were associated with increased phase locking of 5 Hz oscillations within rhinal cortex. These phase locking increases, however, corresponded to reverse phase shifts. Our data suggest that binaural vs. monaural 5 Hz stimulation increases vs. decreases long-term memory performance. These behavioral effects appear to be related to reverse phase shifts within rhinal cortex.

Events that violate predictions are thought to not only modulate activity within the hippocampus and PFC but also enhance communication between the two regions. Scalp and intracranial EEG studies have shown that oscillations in the theta frequency band are enhanced during processing of contextually unexpected information. Some theories suggest that the hippocampus and PFC interact during processing of unexpected events, and it is possible that theta oscillations may mediate these interactions. Here, we had the rare opportunity to conduct simultaneous electrophysiological recordings from the human hippocampus and PFC from two patients undergoing presurgical evaluation for pharmacoresistant epilepsy. Recordings were conducted during a task that involved encoding of contextually expected and unexpected visual stimuli. Across both patients, hippocampal-prefrontal theta phase synchronization was significantly higher during encoding of contextually unexpected study items, relative to contextually expected study items. Furthermore, the hippocampal-prefrontal theta phase synchronization was larger for contextually unexpected items that were later remembered compared with later forgotten items. Moreover, we did not find increased theta synchronization between the PFC and rhinal cortex, suggesting that the observed effects were specific to prefrontal-hippocampal interactions. Our findings are consistent with the idea that theta oscillations orchestrate communication between the hippocampus and PFC in support of enhanced encoding of contextually deviant information.

How are brief encounters transformed into lasting memories? Previous research has established the role of non-rapid eye movement (NREM) sleep, along with its electrophysiological signatures of slow oscillations (SOs) and spindles, for memory consolidation [1-4]. In related work, experimental manipulations have demonstrated that NREM sleep provides a window of opportunity to selectively strengthen particular memory traces via the delivery of auditory cues [5-10], a procedure known as targeted memory reactivation (TMR). It has remained unclear, however, whether TMR triggers the brain's endogenous consolidation mechanisms (linked to SOs and/or spindles) and whether those mechanisms in turn mediate effective processing of mnemonic information. We devised a novel paradigm in which associative memories (adjective-object and adjective-scene pairs) were selectively cued during a post-learning nap, successfully stabilizing next-day retention relative to non-cued memories. First, we found that, compared to novel control adjectives, memory cues evoked an increase in fast spindles. Critically, during the time window of cue-induced spindle activity, the memory category linked to the verbal cue (object or scene) could be reliably decoded, with the fidelity of this decoding predicting the behavioral consolidation benefits of TMR. These results provide correlative evidence for an information processing role of sleep spindles in service of memory consolidation., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A region of the brain called the putamen has a central role in procedural memory consolidation during sleep.

How do we retrieve vivid memories upon encountering a simple cue? Computational models suggest that this feat is accomplished by pattern completion processes involving the hippocampus. However, empirical evidence for hippocampal pattern completion and its underlying mechanisms has remained elusive. Here, we recorded direct intracranial EEG as human participants performed an associative memory task. For each study (encoding) and test (retrieval) event, we derived time-frequency resolved representational patterns in the hippocampus and compared the extent of pattern reinstatement for different mnemonic outcomes. Results show that successful associative recognition (AR) yields enhanced event-specific reinstatement of encoding patterns compared to non-associative item recognition (IR). Moreover, we found that gamma power (50-90 Hz) increases - in conjunction with alpha power (8-12 Hz) decreases not only distinguish AR from IR, but also correlate with the level of hippocampal reinstatement. These results link single-shot hippocampal pattern completion to episodic recollection and reveal how oscillatory dynamics in the gamma and alpha bands orchestrate these mnemonic processes.

Brain oscillations are one of the core mechanisms underlying episodic memory. However, while some studies highlight the role of synchronized oscillatory activity, others highlight the role of desynchronized activity. We here describe a framework to resolve this conundrum and integrate these two opposing oscillatory behaviors. Specifically, we argue that the synchronization and desynchronization reflect a division of labor between a hippocampal and a neocortical system, respectively. We describe a novel oscillatory framework that integrates synchronization and desynchronization mechanisms to explain how the two systems interact in the service of episodic memory., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

During systems-level consolidation, mnemonic representations initially reliant on the hippocampus are thought to migrate to neocortical sites for more permanent storage, with an eminent role of sleep for facilitating this information transfer. Mechanistically, consolidation processes have been hypothesized to rely on systematic interactions between the three cardinal neuronal oscillations characterizing non-rapid eye movement (NREM) sleep. Under global control of de- and hyperpolarizing slow oscillations (SOs), sleep spindles may cluster hippocampal ripples for a precisely timed transfer of local information to the neocortex. We used direct intracranial electroencephalogram recordings from human epilepsy patients during natural sleep to test the assumption that SOs, spindles and ripples are functionally coupled in the hippocampus. Employing cross-frequency phase-amplitude coupling analyses, we found that spindles were modulated by the up-state of SOs. Notably, spindles were found to in turn cluster ripples in their troughs, providing fine-tuned temporal frames for the hypothesized transfer of hippocampal memory traces.

The ability to remember life's events, and to leverage memory to guide behavior, defines who we are and is critical for everyday functioning. The neural mechanisms supporting such mnemonic experiences are multiprocess and multinetwork in nature, which creates challenges for studying them in humans and animals. Advances in noninvasive neuroimaging techniques have enabled the investigation of how specific neural structures and networks contribute to human memory at its many cognitive and mechanistic levels. In this review, we discuss how functional and anatomical imaging has provided novel insights into the types of information represented in, and the computations performed by, specific medial temporal lobe (MTL) regions, and we consider how interactions between the MTL and other cortical and subcortical structures influence what we learn and remember. By leveraging imaging, researchers have markedly advanced understanding of how the MTL subserves declarative memory and enables navigation of our physical and mental worlds., (Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.)

Neural representations of specific stimuli rely on activity patterns in distributed neural assemblies [1-4]. According to one influential view, these assemblies are characterized by synchronized gamma-band activity (GBA) [5-11] that reflects stimulus-specific representations [12-14]. However, recent studies have shown that GBA is closely correlated with the overall amount of cellular activity and may be detrimental for precise representations of specific stimuli [15, 16]. Until now, the role of GBA for the formation of dynamically changing representations has been unknown. Here, we applied representational similarity analysis (RSA) [17] to intracranial electroencephalogram (iEEG) data from ten presurgical epilepsy patients to identify stimulus-specific neural representations. Patients first learned and then retrieved their paths through virtual houses. Dynamic representations were identified by the rapidly changing distributions of frequency-specific global (spatial) activity patterns across the brain. We found that GBA patterns during successful (but not unsuccessful) retrieval of one sequence were more similar to activity during encoding of that same sequence compared to other sequences. The contribution of individual electrodes to these global representations was correlated with local similarity in individual electrodes (i.e., with RSA across time). Moreover, time-resolved RSA values were negatively correlated with the magnitude of iEEG gamma power: RSA values were higher at time points when gamma power was reduced. Both global and local representations relied on a small proportion of electrodes. These results show that behaviorally relevant neural representations of specific dynamically changing stimuli can be tracked by iEEG recordings and that they are associated with reductions of gamma power., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

How are new experiences transformed into memories? Recent findings have shown that activation in brain regions involved in the initial task performance reemerges during postlearning rest, suggesting that "offline activity" might be important for this transformation. It is unclear, however, whether such offline activity indeed reflects reactivation of individual learning experiences, whether the amount of event-specific reactivation is directly related to later memory performance, and what brain regions support such event-specific reactivation. Here, we used functional magnetic resonance imaging to assess whether event-specific reactivation occurs spontaneously during an active, postlearning delay period in the human brain. Applying representational similarity analysis, we found that successful recall of individual study events was predicted by the degree of their endogenous reactivation during the delay period. Within the medial temporal lobe, this reactivation was observed in the entorhinal cortex. Beyond the medial temporal lobe, event-specific reactivation was found in the retrosplenial cortex. Controlling for the levels of blood oxygen level-dependent activation and the serial position during encoding, the data suggest that offline reactivation might be a key mechanism for bolstering episodic memory beyond initial study processes. These results open a unique avenue for the systematic investigation of reactivation and consolidation of episodic memories in humans.

A simple cue can be sufficient to elicit vivid recollection of a past episode. Theoretical models suggest that upon perceiving such a cue, disparate episodic elements held in neocortex are retrieved through hippocampal pattern completion. We tested this fundamental assumption by applying functional magnetic resonance imaging (fMRI) while objects or scenes were used to cue participants' recall of previously paired scenes or objects, respectively. We first demonstrate functional segregation within the medial temporal lobe (MTL), showing domain specificity in perirhinal and parahippocampal cortices (for object-processing vs scene-processing, respectively), but domain generality in the hippocampus (retrieval of both stimulus types). Critically, using fMRI latency analysis and dynamic causal modeling, we go on to demonstrate functional integration between these MTL regions during successful memory retrieval, with reversible signal flow from the cue region to the target region via the hippocampus. This supports the claim that the human hippocampus provides the vital associative link that integrates information held in different parts of cortex.

Zero-lag phase synchronization of EEG activity has been reported to be a central mechanism accompanying long-term memory formation. In this pilot study, we examined the effects of synchronous low-amplitude stimulation of the rhinal cortex and the hippocampus in eleven temporal lobe epilepsy patients. The impact of in-phase stimulation (zero lag) on long-term memory encoding of words was contrasted with anti-phase (180° phase lag) and sham stimulation. We hypothesized more correctly remembered words for the in-phase compared to the sham condition and fewer correctly remembered words for the anti-phase vs. the sham condition. Indeed, we observed a trend for a linear condition effect for correctly remembered words, which is in accordance to our prediction (in-phase > sham > anti-phase). This finding suggests that even weak synchronous deep brain stimulation of rhinal cortex and hippocampus may modulate memory performance, while clear evidence for an enhancement of memory by this kind of deep brain simulation is still lacking., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A recurring issue in neuroscience concerns evidence as to whether two or more brain regions implement qualitatively different functions. Here we introduce the application of state-trace analysis to measures of neural activity, illustrating how this analysis can furnish compelling evidence for qualitatively different functions, even when the precise "neurometric" mapping between function and brain measure is unknown. In doing so, we address a long-standing debate about the brain systems supporting human memory: whether the hippocampus and the perirhinal cortex, two key components of the medial temporal lobe memory system, provide qualitatively different contributions to recognition memory. An alternative account has been that both regions support a single shared function, such as memory strength, with the apparent dissociations obtained by previous neuroimaging studies merely reflecting different, nonlinear neurometric mappings across regions. To adjudicate between these scenarios, we analyze intracranial electroencephalographic data obtained directly from human hippocampus and perirhinal cortex during a recognition paradigm and apply state-trace analysis to responses evoked by the retrieval cue as a function of different types of memory judgment. Assuming only that the neurometric mapping in each region is monotonic, any unidimensional theory (such as the memory-strength account) will produce a monotonic state trace. Critically, results showed a nonmonotonic state trace; that is, activity levels in the two regions did not show the same relative ordering across memory conditions. This nonmonotonic state trace demonstrates that there are at least two different functions implemented across the hippocampus and perirhinal cortex, allowing formal rejection of a single-process account of medial temporal lobe contributions to recognition memory.

The essence of episodic memory is our ability to reexperience past events in great detail, even in the absence of external stimulus cues. Does the phenomenological reinstatement of past experiences go along with reinstating unique neural representations in the brain? And if so, how is this accomplished by the medial temporal lobe (MTL), a brain region intimately linked to episodic memory? Computational models suggest that such reinstatement (also termed "pattern completion") in cortical regions is mediated by the hippocampus, a key region of the MTL. Although recent functional magnetic resonance imaging studies demonstrated reinstatement of coarse item properties like stimulus category or task context across different brain regions, it has not yet been shown whether reinstatement can be observed at the level of individual, discrete events-arguably the defining feature of episodic memory-nor whether MTL structures like the hippocampus support this "true episodic" reinstatement. Here we show that neural activity patterns for unique word-scene combinations encountered during encoding are reinstated in human parahippocampal cortex (PhC) during retrieval. Critically, this reinstatement occurs when word-scene combinations are successfully recollected (even though the original scene is not visually presented) and does not encompass other stimulus domains (such as word-color associations). Finally, the degree of PhC reinstatement across retrieval events correlated with hippocampal activity, consistent with a role of the hippocampus in coordinating pattern completion in cortical regions.

In the endeavor to understand how our brains enable our multifaceted memories, much controversy surrounds the contributions of the hippocampus and perirhinal cortex (PrC). We recorded functional magnetic resonance imaging (fMRI) in healthy controls and intracranial electroencephalography (EEG) in patients during a recognition memory task. Although conventional fMRI analysis showed indistinguishable roles of the hippocampus and PrC in familiarity-based item recognition and recollection-based source retrieval, event-related fMRI and EEG time courses revealed a clear temporal dissociation of memory signals in and across these regions. An early source retrieval effect was followed by a late, post-decision item novelty effect in hippocampus, whereas an early item novelty effect was followed by a sustained source retrieval effect in PrC. Although factors such as memory strength were not experimentally controlled, the temporal pattern across regions suggests that a rapid item recognition signal in PrC triggers a source retrieval process in the hippocampus, which in turn recruits PrC representations and/or mechanisms, evidenced here by increased hippocampal-PrC coupling during source recognition.