The hippocampus as the switchboard between perception and memory.

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.

Directional coupling of slow and fast hippocampal gamma with neocortical alpha/beta oscillations in human episodic memory.

Episodic memories hinge upon our ability to process a wide range of multisensory information and bind this information into a coherent, memorable representation. On a neural level, these 2 processes are thought to be supported by neocortical alpha/beta desynchronization and hippocampal theta/gamma synchronization, respectively. Intuitively, these 2 processes should couple to successfully create and retrieve episodic memories, yet this hypothesis has not been tested empirically. We address this by analyzing human intracranial electroencephalogram data recorded during 2 associative memory tasks. We find that neocortical alpha/beta (8 to 20 Hz) power decreases reliably precede and predict hippocampal "fast" gamma (60 to 80 Hz) power increases during episodic memory formation; during episodic memory retrieval, however, hippocampal "slow" gamma (40 to 50 Hz) power increases reliably precede and predict later neocortical alpha/beta power decreases. We speculate that this coupling reflects the flow of information from the neocortex to the hippocampus during memory formation, and hippocampal pattern completion inducing information reinstatement in the neocortex during memory retrieval.

Alpha Rhythms Reveal When and Where Item and Associative Memories Are Retrieved.

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.

Postretrieval Relearning Strengthens Hippocampal Memories via Destabilization and Reconsolidation.

Memory reconsolidation is hypothesized to be a mechanism by which memories can be updated with new information. Such updating has previously been shown to weaken memory expression or change the nature of the memory. Here we demonstrate that retrieval-induced memory destabilization also allows that memory to be strengthened by additional learning. We show that for rodent contextual fear memories, this retrieval conditioning effect is observed only when conditioning occurs within a specific temporal window opened by retrieval. Moreover, it necessitates hippocampal protein degradation at the proteasome and engages hippocampal Zif268 protein expression, both of which are established mechanisms of memory destabilization-reconsolidation. We also demonstrate a conceptually analogous pattern of results in human visual paired-associate learning. Retrieval-relearning strengthens memory performance, again only when relearning occurs within the temporal window of memory reconsolidation. These findings link retrieval-mediated learning in humans to the reconsolidation literature, and have potential implications both for the understanding of endogenous memory gains and strategies to boost weakly learned memories.SIGNIFICANCE STATEMENT Memory reconsolidation allows existing memories to be updated with new information. Previous research has demonstrated that reconsolidation can be manipulated pharmacologically and behaviorally to impair problematic memories. In this article, we show that reconsolidation can also be exploited to strengthen memory. This is shown both in rats, in a fear memory setting, and in a human declarative memory setting. For both, the behavioral conditions necessary to observe the memory strengthening match those that are required to trigger memory reconsolidation. There are several behavioral approaches that have previously been shown convincingly to strengthen memory. The present demonstration that reconsolidation can underpin long-lasting memory improvements may both provide an underlying mechanism for such approaches and provide new strategies to boost memories.

Perceived time and temporal structure: Neural entrainment to isochronous stimulation increases duration estimates.

Distortions of perceived duration can give crucial insights into the mechanisms that underlie the processing and representation of stimulus timing. One factor that affects duration estimates is the temporal structure of stimuli that fill an interval. For example, regular filling (isochronous interval) leads to an overestimation of perceived duration as compared to irregular filling (anisochronous interval). In the present article, we use electroencephalography (EEG) to investigate the neural basis of this subjective lengthening of perceived duration with isochrony. In a two-interval forced choice task, participants judged which of two intervals lasts longer - one always being isochronous, the other one anisochronous. Response proportions confirm the subjective overestimation of isochronous intervals. At the neural level, isochronous sequences are associated with enhanced pairwise phase consistency (PPC) at the stimulation frequency, reflecting the brain's entrainment to the regular stimulation. The PPC over the entrainment channels is further enhanced for isochronous intervals that are reported to be longer, and the magnitude of this PCC effect correlates with the amount of perceptual bias. Neural entrainment has been proposed as a mechanism of attentional selection, enabling increased neural responsiveness toward stimuli that arrive at an expected point in time. The present results support the proposed relationship between neural response magnitudes and temporal estimates: An increase in neural responsiveness leads to a more pronounced representation of the individual stimuli filling the interval and in turn to a subjective increase in duration.

Prefrontally driven downregulation of neural synchrony mediates goal-directed forgetting.

Neural synchronization between distant cell assemblies is crucial for the formation of new memories. To date, however, it remains unclear whether higher-order brain regions can adaptively regulate neural synchrony to control memory processing in humans. We explored this question in two experiments using a voluntary forgetting task. In the first experiment, we simultaneously recorded electroencephalography along with fMRI. The results show that a reduction in neural synchrony goes hand-in-hand with a BOLD signal increase in the left dorsolateral prefrontal cortex (dlPFC) when participants are cued to forget previously studied information. In the second experiment, we directly stimulated the left dlPFC with repetitive transcranial magnetic stimulation during the same task, and show that such stimulation specifically boosts the behavioral forgetting effect and induces a reduction in neural synchrony. These results suggest that prefrontally driven downregulation of long-range neural synchronization mediates goal-directed forgetting of long-term memories.

The relationship between level of processing and hippocampal-cortical functional connectivity during episodic memory formation in humans.

New episodic memory traces represent a record of the ongoing neocortical processing engaged during memory formation (encoding). Thus, during encoding, deep (semantic) processing typically establishes more distinctive and retrievable memory traces than does shallow (perceptual) processing, as assessed by later episodic memory tests. By contrast, the hippocampus appears to play a processing-independent role in encoding, because hippocampal lesions impair encoding regardless of level of processing. Here, we clarified the neural relationship between processing and encoding by examining hippocampal-cortical connectivity during deep and shallow encoding. Participants studied words during functional magnetic resonance imaging and freely recalled these words after distraction. Deep study processing led to better recall than shallow study processing. For both levels of processing, successful encoding elicited activations of bilateral hippocampus and left prefrontal cortex, and increased functional connectivity between left hippocampus and bilateral medial prefrontal, cingulate and extrastriate cortices. Successful encoding during deep processing was additionally associated with increased functional connectivity between left hippocampus and bilateral ventrolateral prefrontal cortex and right temporoparietal junction. In the shallow encoding condition, on the other hand, pronounced functional connectivity increases were observed between the right hippocampus and the frontoparietal attention network activated during shallow study processing. Our results further specify how the hippocampus coordinates recording of ongoing neocortical activity into long-term memory, and begin to provide a neural explanation for the typical advantage of deep over shallow study processing for later episodic memory.

The testing effect for visual materials depends on preexisting knowledge.

Remembering facilitates future remembering. This benefit of practicing by active retrieval, as compared to more passive relearning, is known as the testing effect and is one of the most robust findings in the memory literature. It has typically been assessed using verbal materials such as word pairs, sentences, or educational texts. We here investigate if memory for visual materials equally benefits from retrieval-mediated learning. Based on cognitive and neuroscientific theories, we hypothesize that testing effects will be limited to meaningful visual images that can be related to preexisting knowledge. In a series of four experiments, we systematically varied the type of material (meaningless "squiggle" shapes vs. meaningful object images) and the format of the test used to probe memory (a visually driven alternative forced-choice test vs. a remember/know recognition test). Within each experiment, we assessed the effects of practice type (retrieval or restudy) and the delay of the final test (immediate vs. 1 week) on the resulting practice benefits. Abstract shapes never showed a significant testing benefit, irrespective of test format. Meaningful object images did benefit from testing, particularly at long delays, and with a test format probing the recollective component of recognition memory. Together, our results indicate that retrieval can facilitate the recollection of visual images when they represent meaningful semantic units. This pattern of results is predicted by cognitive and neurobiologically motivated theories proposing that retrieval's benefits emerge through spreading activation in semantic networks, producing more easily accessible and longer-lasting memory traces. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Hippocampal neurons code individual episodic memories in humans.

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.

The relationship between brain oscillations and BOLD signal during memory formation: a combined EEG-fMRI study.

Previous studies demonstrated that increases in the theta frequency band with concomitant decreases in the alpha/beta frequency band indicate successful memory formation. However, little is known about the brain regions and the cognitive processes that underlie these encoding-related oscillatory memory effects. We investigated this relationship using simultaneous EEG-fMRI recordings in humans during long-term memory encoding. In line with prior studies, we demonstrate that a decrease in beta power and an increase in theta power positively predict subsequent recall. In fMRI, stronger activity in the left inferior prefrontal cortex and the right parahippocampal gyrus correlated with successful memory formation. EEG source localization revealed that the subsequent memory effect in the beta band was localized in the left inferior prefrontal cortex, whereas the effect in the theta band was localized in medial temporal lobe regions. Trial-by-trial correlations between EEG and BOLD activity showed that beta power correlated negatively with left inferior prefrontal cortex activity. This correlation was more pronounced for items that could later be successfully recalled compared to items later forgotten. Based on these findings, we suggest that beta oscillations in the left inferior prefrontal cortex indicate semantic encoding processes, whereas theta oscillations in the medial temporal lobe reflect the binding of an item to its spatiotemporal context.

Phase separation of competing memories along the human hippocampal theta rhythm.

Competition between overlapping memories is considered one of the major causes of forgetting, and it is still unknown how the human brain resolves such mnemonic conflict. In the present magnetoencephalography (MEG) study, we empirically tested a computational model that leverages an oscillating inhibition algorithm to minimise overlap between memories. We used a proactive interference task, where a reminder word could be associated with either a single image (non-competitive condition) or two competing images, and participants were asked to always recall the most recently learned word-image association. Time-resolved pattern classifiers were trained to detect the reactivated content of target and competitor memories from MEG sensor patterns, and the timing of these neural reactivations was analysed relative to the phase of the dominant hippocampal 3 Hz theta oscillation. In line with our pre-registered hypotheses, target and competitor reactivations locked to different phases of the hippocampal theta rhythm after several repeated recalls. Participants who behaviourally experienced lower levels of interference also showed larger phase separation between the two overlapping memories. The findings provide evidence that the temporal segregation of memories, orchestrated by slow oscillations, plays a functional role in resolving mnemonic competition by separating and prioritising relevant memories under conditions of high interference.

The brain time toolbox, a software library to retune electrophysiology data to brain dynamics.

Human thought is highly flexible, achieved by evolving patterns of brain activity across groups of cells. Neuroscience aims to understand cognition in the brain by analysing these intricate patterns. We argue that this goal is impeded by the time format of our data-clock time. The brain is a system with its own dynamics and regime of time, with no intrinsic concern for the human-invented second. Here, we present the Brain Time Toolbox, a software library that retunes electrophysiology data in line with oscillations that orchestrate neural patterns of cognition. These oscillations continually slow down, speed up and undergo abrupt changes, introducing a disharmony between the brain's internal regime and clock time. The toolbox overcomes this disharmony by warping the data to the dynamics of coordinating oscillations, setting oscillatory cycles as the data's new time axis. This enables the study of neural patterns as they unfold in the brain, aiding neuroscientific enquiry into dynamic cognition. In support of this, we demonstrate that the toolbox can reveal results that are absent in a default clock time format.

Oscillations support short latency co-firing of neurons during human episodic memory formation.

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.

Distinct frontoparietal networks set the stage for later perceptual identification priming and episodic recognition memory.

Recent imaging evidence suggests that a network of brain regions including the medial temporal lobe, ventrolateral prefrontal cortex, and dorsal posterior parietal cortex supports the successful encoding of long-term memories. Other areas, like the ventral posterior parietal and dorsolateral prefrontal cortices, have been associated with encoding failure rather than success. In line with the transfer-appropriate processing view, we hypothesized that distinct neural networks predict successful encoding depending on whether the later memory test draws primarily on perceptual or conceptual memory representations. Following an encoding phase, memory was assessed in a combined incidental perceptual identification and intentional recognition memory test. We found that during encoding, activation in ventral posterior parietal and dorsolateral prefrontal cortex predicted successful perceptual identification priming, whereas activation in ventrolateral prefrontal and dorsal posterior parietal cortex predicted successful recognition memory. Extending recent theories of attention to memory, the results suggest that ventral parietal regions support stimulus-driven attention to perceptual item features, forming memories accessed by later perceptual memory tests, whereas dorsal parietal regions support attention to meaningful item features, forming memories accessed by later conceptual memory tests.

Feature-specific reaction times reveal a semanticisation of memories over time and with repeated remembering.

Memories are thought to undergo an episodic-to-semantic transformation in the course of their consolidation. We here test if repeated recall induces a similar semanticisation, and if the resulting qualitative changes in memories can be measured using simple feature-specific reaction time probes. Participants studied associations between verbs and object images, and then repeatedly recalled the objects when cued with the verb, immediately and after a two-day delay. Reaction times during immediate recall demonstrate that conceptual features are accessed faster than perceptual features. Consistent with a semanticisation process, this perceptual-conceptual gap significantly increases across the delay. A significantly smaller perceptual-conceptual gap is found in the delayed recall data of a control group who repeatedly studied the verb-object pairings on the first day, instead of actively recalling them. Our findings suggest that wake recall and offline consolidation interact to transform memories over time, strengthening meaningful semantic information over perceptual detail.

Theta rhythmicity governs human behavior and hippocampal signals during memory-dependent tasks.

Memory formation and reinstatement are thought to lock to the hippocampal theta rhythm, predicting that encoding and retrieval processes appear rhythmic themselves. Here, we show that rhythmicity can be observed in behavioral responses from memory tasks, where participants indicate, using button presses, the timing of encoding and recall of cue-object associative memories. We find no evidence for rhythmicity in button presses for visual tasks using the same stimuli, or for questions about already retrieved objects. The oscillations for correctly remembered trials center in the slow theta frequency range (1-5 Hz). Using intracranial EEG recordings, we show that the memory task induces temporally extended phase consistency in hippocampal local field potentials at slow theta frequencies, but significantly more for remembered than forgotten trials, providing a potential mechanistic underpinning for the theta oscillations found in behavioral responses.

Neural markers of inhibition in human memory retrieval.

Retrieving particular information from memory facilitates the later retrieval of that information, but also impairs the later retrieval of related, interfering information. It has been theorized that this retrieval-induced forgetting reflects inhibition of interfering memory representations. We used event-related fMRI to investigate the functional neuroanatomy of this impaired retrieval, at the time the impairment is observed. Neural activity differences between impaired and facilitated information occurred in left ventrolateral prefrontal cortex (VLPFC, BA 45 and 47), precuneus (BA 7), and right inferior parietal lobule (IPL, BA 40). Activity in left anterior VLPFC (BA 47) and left posterior temporal cortex (BA 22), regions implicated in the controlled retrieval of weak semantic memory representations, predicted the degree of retrieval-induced forgetting. In contrast, activity in precuneus and right IPL predicted the degree of retrieval-induced facilitation. Our findings demonstrate that impairment of interfering memories and facilitation of practiced memories involve distinct neural processes, and suggest that the impairment reflects inhibition that weakens interfering memory representations.

A Neural Chronometry of Memory Recall.

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.

Evidence that neural information flow is reversed between object perception and object reconstruction from memory.

Remembering is a reconstructive process, yet little is known about how the reconstruction of a memory unfolds in time in the human brain. Here, we used reaction times and EEG time-series decoding to test the hypothesis that the information flow is reversed when an event is reconstructed from memory, compared to when the same event is initially being perceived. Across three experiments, we found highly consistent evidence supporting such a reversed stream. When seeing an object, low-level perceptual features were discriminated faster behaviourally, and could be decoded from brain activity earlier, than high-level conceptual features. This pattern reversed during associative memory recall, with reaction times and brain activity patterns now indicating that conceptual information was reconstructed more rapidly than perceptual details. Our findings support a neurobiologically plausible model of human memory, suggesting that memory retrieval is a hierarchical, multi-layered process that prioritises semantically meaningful information over perceptual details.

Alpha/beta power decreases track the fidelity of stimulus-specific information.

Massed synchronised neuronal firing is detrimental to information processing. When networks of task-irrelevant neurons fire in unison, they mask the signal generated by task-critical neurons. On a macroscopic level, such synchronisation can contribute to alpha/beta (8-30 Hz) oscillations. Reducing the amplitude of these oscillations, therefore, may enhance information processing. Here, we test this hypothesis. Twenty-one participants completed an associative memory task while undergoing simultaneous EEG-fMRI recordings. Using representational similarity analysis, we quantified the amount of stimulus-specific information represented within the BOLD signal on every trial. When correlating this metric with concurrently-recorded alpha/beta power, we found a significant negative correlation which indicated that as post-stimulus alpha/beta power decreased, stimulus-specific information increased. Critically, we found this effect in three unique tasks: visual perception, auditory perception, and visual memory retrieval, indicating that this phenomenon transcends both stimulus modality and cognitive task. These results indicate that alpha/beta power decreases parametrically track the fidelity of both externally-presented and internally-generated stimulus-specific information represented within the cortex.