Human Episodic Memory Research Articles

Using fast visual rhythmic stimulation to control inter-hemispheric phase offsets in visual areas

Spike timing dependent plasticity (STDP) is believed to be important for neural communication and plasticity in human episodic memory, but causal evidence is lacking due to technical challenges. Rhythmic sensory stimulation that has been used to investigate causal relations between oscillations and cognition may be able to address this question. The challenge, however, is that the frequency corresponding to the critical time window for STDP is gamma (~40 Hz), yet the application of rhythmic sensory stimulation has been limited primarily to lower frequencies (<30 Hz). It remains unknown whether this method can be applied to precisely control the activation time delay between distant groups of neurons at a millisecond scale. To answer this question and examine the role of STDP in human episodic memory, we simulated the STDP function by controlling the activation time delay between the left and right visual cortices during memory encoding. This was achieved by presenting flickering (37.5 Hz) movie pairs in the left and right visual fields with a phase lag of either 0, 90, 180 or 270°. Participants were asked to memorize the two movies within each pair and the association was later tested. Behavioral results revealed no significant difference in memory performance across conditions with different degrees of gamma phase synchrony. Yet importantly, our study showed for the first time, that oscillatory activity can be driven with a precision of 6.67 ms delay between neuronal groups. Our method hereby provides an approach to investigate relations between precise neuronal timing and cognitive functions.

Gene-expression correlates of the oscillatory signatures supporting human episodic memory encoding.

In humans, brain oscillations support critical features of memory formation. However, understanding the molecular mechanisms underlying this activity remains a major challenge. We measured memory-sensitive oscillations using intracranial electroencephalography recordings from the temporal cortex of patients performing an episodic memory task. When these patients undergo resection subsequently, we employ transcriptomics on the temporal cortex to link gene expression with brain oscillations, identifying genes correlated with oscillatory signatures of memory formation across six frequency bands. A co-expression analysis isolated oscillatory signature-specific modules associated with neuropsychiatric disorders as well as ion channel activity, with highly correlated genes exhibiting strong connectivity within these modules. Using single-nuclei transcriptomics, we further revealed that these modules are enriched for specific classes of both excitatory and inhibitory neurons, and immunohistochemistry confirmed expression of highly correlated genes. This unprecedented dataset of patient-specific brain oscillations coupled to genomics unlocks new insights into the genetic mechanisms that support memory encoding.

Examining the effects of transcranial direct current stimulation on human episodic memory with machine learning.

We aimed to replicate a published effect of transcranial direct-current stimulation (tDCS)-induced recognition enhancement over the human ventrolateral prefrontal cortex (VLPFC) and analyse the data with machine learning. We investigated effects over an adjacent region, the dorsolateral prefrontal cortex (DLPFC). In total, we analyzed data from 97 participants after exclusions. We found weak or absent effects over the VLPFC and DLPFC. We conducted machine learning studies to examine the effects of semantic and phonetic features on memorization, which revealed no effect of VLPFC tDCS on the original dataset or the current data. The highest contributing factor to memory performance was individual differences in memory not explained by word features, tDCS group, or sample size, while semantic, phonetic, and orthographic word characteristics did not contribute significantly. To our knowledge, this is the first tDCS study to investigate cognitive effects with machine learning, and future studies may benefit from studying physiological as well as cognitive effects with data-driven approaches and computational models.

Engrams of Fast Learning.

Fast learning designates the behavioral and neuronal mechanisms underlying the acquisition of a long-term memory trace after a unique and brief experience. As such it is opposed to incremental, slower reinforcement or procedural learning requiring repetitive training. This learning process, found in most animal species, exists in a large spectrum of natural behaviors, such as one-shot associative, spatial, or perceptual learning, and is a core principle of human episodic memory. We review here the neuronal and synaptic long-term changes associated with fast learning in mammals and discuss some hypotheses related to their underlying mechanisms. We first describe the variety of behavioral paradigms used to test fast learning memories: those preferentially involve a single and brief (from few hundred milliseconds to few minutes) exposures to salient stimuli, sufficient to trigger a long-lasting memory trace and new adaptive responses. We then focus on neuronal activity patterns observed during fast learning and the emergence of long-term selective responses, before documenting the physiological correlates of fast learning. In the search for the engrams of fast learning, a growing body of evidence highlights long-term changes in gene expression, structural, intrinsic, and synaptic plasticities. Finally, we discuss the potential role of the sparse and bursting nature of neuronal activity observed during the fast learning, especially in the induction plasticity mechanisms leading to the rapid establishment of long-term synaptic modifications. We conclude with more theoretical perspectives on network dynamics that could enable fast learning, with an overview of some theoretical approaches in cognitive neuroscience and artificial intelligence.

Amnesia for context fear is caused by widespread disruption of hippocampal activity

The hippocampus plays an essential role in the formation and retrieval of episodic memories in humans and contextual memories in animals. However, amnesia is not always observed when this structure is compromised. To determine why this is the case, we compared the effects of several different circuit manipulations on memory retrieval and hippocampal activity. Mice were first trained on context fear conditioning and then optogenetic and chemogenetic tools were used to alter activity during memory retrieval. We found that retrieval was only impaired when manipulations caused widespread changes (increases or decreases) in hippocampal activity. Widespread increases occurred when pyramidal cells were excited and widespread decreases were found when GABAergic neurons were stimulated. Direct hyperpolarization of excitatory neurons only moderately reduced activity and did not produce amnesia. Surprisingly, widespread decreases in hippocampal activity did not prevent retrieval if they occurred gradually prior to testing. This suggests that intact brain regions can express contextual memories if they are given adequate time to compensate for the loss of the hippocampus.

Behavioral evidence for pattern separation in human episodic memory.

An essential feature of episodic memory is the ability to recall the multiple elements relating to one event from the multitude of elements relating to other, potentially similar events. Hippocampal pattern separation is thought to play a fundamental role in this process, by orthogonalizing the representations of overlapping events during encoding, to reduce interference between them during the process of pattern completion by which one or other is recalled. We introduce a new paradigm to test the hypothesis that similar memories, but not unrelated memories, are actively separated at encoding. Participants memorized events which were either unique or shared a common element with another event (paired “overlapping” events). We used a measure of dependency, originally devised to measure pattern completion, to quantify how much the probability of successfully retrieving associations from one event depends on successful retrieval of associations from the same event, an unrelated event or the overlapping event. In two experiments, we saw that within event retrievals were highly dependent, indicating pattern completion; retrievals from unrelated events were independent; and retrievals from overlapping events were antidependent (i.e., less than independent), indicating pattern separation. This suggests that representations of similar (overlapping) memories are actively separated, resulting in lowered dependency of retrieval performance between them, as would be predicted by the pattern separation account.

Distance- rather than location-based temporal judgments are more accurate during episodic recall in a real-world task

ABSTRACT Definitions of episodic memory typically emphasise the importance of spatiotemporal frameworks in the contextual reconstruction of episodic retrieval. However, our ability to retrieve specific temporal contexts of experienced episodes is poor. This has bearing on the prominence of temporal context in the definition and evaluation of episodic memory, particularly among non-human animals. Studies demonstrating that rats rely on elapsed time (distance) rather than specific timestamps (location) to disambiguate events have been used to suggest that human episodic memory is qualitatively different to other species. We examined whether humans were more accurate using a distance- or location-based method for judging when an event happened. Participants (n = 57) were exposed to a series of events and then asked either when (e.g., 1:03 pm) or how long ago (HLA; e.g., 33 min) a specific event took place. HLA judgements were significantly more accurate, particularly for the most recently experienced episode. Additionally, a significantly higher proportion of participants making HLA judgements accurately recalled non-temporal episodic features across all episodes. Finally, for participants given the choice of methods for making temporal judgements, a significantly higher proportion chose to use HLA judgements. These findings suggest that human and non-human temporal judgements are not qualitatively different.

Generalising reconsolidation: Spatial context and prediction error

Activating a previously consolidated memory trace brings it back into a labile state where it must then undergo a re-stabilisation process known as reconsolidation. During this process memories are susceptible to interference and may be updated with new information. In the studies showing this effect in human episodic memory, the reconsolidation process has been triggered primarily using spatial context or prediction error manipulations to reactivate an established memory. However, these studies have produced conflicting results, showing both that spatial context is necessary and sufficient to trigger reconsolidation and that prediction error is necessary and sufficient to trigger the process. We examined this conflict in two experiments, one investigating the role of context cues and another investigating the role of prediction error. In Experiment 1, spatial context triggered a reconsolidation process and prediction error was irrelevant. In Experiment 2, prediction error triggered reconsolidation, and spatial context cues were irrelevant. These findings replicate prior research but add to the puzzle concerning the roles of these two means of triggering reconsolidation.

Longitudinal Differences in Human Hippocampal Connectivity During Episodic Memory Processing.

The question of longitudinal hippocampal functional specialization is critical to human episodic memory because an accurate understanding of this phenomenon would impact theories of mnemonic function and entail practical consequences for the clinical management of patients undergoing temporal lobe surgery. The implementation of the robotically assisted stereo electroencephalography technique for seizure mapping has provided our group with the opportunity to obtain recordings simultaneously from the anterior and posterior human hippocampus, allowing us to create an unparalleled data set of human subjects with simultaneous anterior and posterior hippocampal recordings along with several cortical regions. Using these data, we address several key questions governing functional hippocampal connectivity in human memory. First, we ask whether functional networks during episodic memory encoding and retrieval are significantly different for the anterior versus posterior hippocampus (PH). We also examine how connections differ across the 2–5 Hz versus 4–9 Hz theta frequency ranges, directly addressing the relative contribution of each of these separate bands in hippocampal–cortical interactions. While we report some overlapping connections, we observe evidence of distinct anterior versus posterior hippocampal networks during memory encoding related to frontal and parietal connectivity as well as hemispheric differences in aggregate connectivity. We frame these findings in light of the proposed AT/PM memory systems. We also observe distinct encoding versus retrieval connectivity patterns between anterior and posterior hippocampal networks, we find that overall connectivity is greater for the PH in the right hemisphere, and further that these networks significantly differ in terms of frontal and parietal connectivity. We place these findings in the context of existing theoretical treatments of human memory systems, especially the proposed AT/PM system. During memory retrieval, we observe significant differences between slow-theta (2–5 Hz) and fast-theta (4–9 Hz) connectivity between the cortex and hippocampus. Taken together, our findings describe mnemonically relevant functional connectivity differences along the longitudinal axis of the human hippocampus that will inform interpretation of models of hippocampal function that seek to integrate rodent and human data.

Electrophysiological signatures of memory reactivation in humans.

The reactivation of neural activity that was present during the encoding of an event is assumed to be essential for human episodic memory retrieval and the consolidation of memories during sleep. Pioneering animal work has already established a crucial role of memory reactivation to prepare and guide behaviour. Research in humans is now delineating the neural processes involved in memory reactivation during both wakefulness and sleep as well as their functional significance. Focusing on the electrophysiological signatures of memory reactivation in humans during both memory retrieval and sleep-related consolidation, this review provides an overview of the state of the art in the field. We outline recent advances, methodological developments and open questions and specifically highlight commonalities and differences in the neuronal signatures of memory reactivation during the states of wakefulness and sleep.This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.

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.

Young and Older Adults Benefit From Sleep, but Not From Active Wakefulness for Memory Consolidation of What-Where-When Naturalistic Events.

An extensive psychological literature shows that sleep actively promotes human episodic memory (EM) consolidation in younger adults. However, evidence for the benefit of sleep for EM consolidation in aging is still elusive. In addition, most of the previous studies used EM assessments that are very different from everyday life conditions and are far from considering all the hallmarks of this memory system. In this study, the effect of an extended period of sleep was compared to the effect of an extended period of active wakefulness on the EM consolidation of naturalistic events, using a novel (What-Where-When) EM task, rich in perceptual details and spatio-temporal context, presented in a virtual environment. We investigated the long-term What-Where-When and Details binding performances of young and elderly people before and after an interval of sleep or active wakefulness. Although we found a noticeable age-related decline in EM, both age groups benefited from sleep, but not from active wakefulness. In younger adults, only the period of sleep significantly enhanced the capacity to associate different components of EM (binding performance) and more specifically the free recall of what-when information. Interestingly, in the elderly, sleep significantly enhanced not only the recall of factual elements but also associated details and contextual information as well as the amount of high feature binding (i.e., What-Where-When and Details). Thus, this study evidences the benefit of sleep, and the detrimental effect of active wakefulness, on long-term feature binding, which is one of the core characteristics of EM, and its effectiveness in normal aging. However, further research should investigate whether this benefit is specific to sleep or more generally results from the effect of a post-learning period of reduced interference, which could also concern quiet wakefulness.

Flexible network community organization during the encoding and retrieval of spatiotemporal episodic memories.

Memory encoding and retrieval involve distinct interactions between multiple brain areas, yet the flexible structure of corresponding large-scale networks during such memory processing remains unclear. Using functional magnetic resonance imaging, we employed a spatiotemporal encoding and retrieval task, detecting functional community structure across the multiple components of our task. Consistent with past work, we identified a set of stable subnetworks, mostly belonging to primary motor and sensory cortices but also identified a subset of flexible hubs, mostly belonging to higher association areas. These “mover” hubs changed connectivity patterns across spatial and temporal memory encoding and retrieval, engaging in an integrative role within the network. Global encoding network and subnetwork dissimilarity predicted retrieval performance. Together, our findings emphasize the importance of flexible network allegiance among some hubs and the importance of network reconfiguration to human episodic memory.

Memory entrainment by visually evoked theta-gamma coupling

The wake human brain constantly encodes novel information and integrates them into existing neuronal representations. It is posited that the formation of new memory traces is orchestrated by the synchronization of neuronal activity in the theta rhythm (3–8 Hz), theta coupled gamma activity (40–120 Hz), and decreases in the alpha rhythm (8–12 Hz). Critically, given the correlative nature of neurophysiological recordings, the functional relevance of oscillatory processes is not well understood. Here, we experimentally enhanced memory formation processes by a rhythmic visual stimulation at an individual theta frequency, in contrast to the stimulation at an individual alpha frequency. This memory entrainment effect was not explained by theta power per se, but was driven by a visually evoked theta-gamma coupling pattern. This underlines the functional role of the theta rhythm and the theta-gamma neuronal code in human episodic memory. The entrainment of mnemonic network mechanisms by a visual stimulation technique provides a proof of concept that visual pacemakers can entrain complex cognitive processes in the wake human brain.

Contiguity in episodic memory.

Contiguity is one of the major predictors of recall dynamics in human episodic memory. But there are many competing theories of how the memory system gives rise to contiguity. Here we provide a set of benchmark findings for which any such theory should account. These benchmarks are drawn from a review of the existing literature as well as analyses of both new and archival data. They include 34 distinct findings on how various factors including individual and group differences, task parameters, and type of stimuli influence the magnitude of the contiguity effect. We will see that contiguity is observed in a range of tasks including recognition, paired associates, and autobiographical recall and across a range of time scales including minutes, days, weeks, and years. The broad pattern of data point toward a theory in which contiguity arises from fundamental memory mechanisms that encode and search an approximately time scale invariant representation of temporal distance.

The effects of post-encoding stress and glucocorticoids on episodic memory in humans and rodents

It is now well established that acute stress shortly after encoding (i.e., post-encoding stress) can benefit episodic memory. In the current paper, we briefly review the human literature examining the effects of post-encoding stress on episodic memory, and we relate that literature to studies of post-encoding manipulations of cortisol in humans, as well as studies of post-encoding stress and administration of corticosterone on analogous memory tasks in rodents. An examination of the literature reveals several important gaps in our understanding of stress and memory. For example, although the human literature shows that post-encoding stress generally improves memory, these effects are not observed if stress occurs in a different context from learning. Moreover, the rodent literature shows that post-encoding stress generally impairs memory instead of improving it, and these effects depend on whether the animal is habituated to the learning context prior to encoding. Although many aspects of the results support a cellular consolidation account of post-encoding stress, we present possible modifications, such as a network reset, to better account for the data. We also suggest that it is important to incorporate ideas of contextual binding in order to understanding the effects of post-encoding stress and glucocorticoids on memory.

Changes in patterns of neural activity underlie a time-dependent transformation of memory in rats and humans.

The dynamic process of memory consolidation involves a reorganization of brain regions that support a memory trace over time, but exactly how the network reorganizes as the memory changes remains unclear. We present novel converging evidence from studies of animals (rats) and humans for the time-dependent reorganization and transformation of different types of memory as measured both by behavior and brain activation. We find that context-specific memories in rats, and naturalistic episodic memories in humans, lose precision over time and activity in the hippocampus decreases. If, however, the retrieved memories retain contextual or perceptual detail, the hippocampus is engaged similarly at recent and remote timepoints. As the interval between the timepoint increases, the medial prefrontal cortex is engaged increasingly during memory retrieval, regardless of the context or the amount of retrieved detail. Moreover, these hippocampal-frontal shifts are accompanied by corresponding changes in a network of cortical structures mediating perceptually-detailed as well as less precise, schematic memories. These findings provide cross-species evidence for the crucial interplay between hippocampus and neocortex that reflects changes in memory representation over time and underlies systems consolidation.

Time, memory, and the legacy of Howard Eichenbaum.

Over the past 15 years, there has been an explosion of new research on the role of the hippocampus in the representation of information about time in memory. Much of this work was inspired by the ideas and research of Howard Eichenbaum, who made major contributions to our understanding of the neurobiology of episodic memory and the neural representation of time. In this article, I will review evidence regarding the role of time in understanding hippocampal function. This review will cover a broad range of evidence from studies of humans and nonhuman animals with a narrative arc that follows Howard's major discoveries. These studies demonstrate that the hippocampus encodes information in relation to an episodic context, and that time, as well as space, serves to define these contexts. Moreover, the research has shown that the hippocampus can encode temporal, spatial, and situational information in parallel. Building on this work, I present a new framework for understanding temporal structure in human episodic memory. I conclude by outlining current controversies and new questions that must be addressed by the field in the years to come.

Theta band network supporting human episodic memory is not activated in the seizure onset zone

Episodic memory, everyday memory for events, is frequently impaired in patients with epilepsy. We tested patients undergoing intracranial electroencephalography (intracranial EEG) monitoring for the treatment of medically-refractory epilepsy on a well-characterized paradigm that requires episodic memory. We report that an anatomically diffuse network characterized by theta-band (4–7 Hz) coherence is activated at the time of target selection in a task that requires episodic memory. This distinct network of oscillatory activity is absent when episodic memory is not required. Further, the theta band synchronous network was absent in electrodes within the patient's seizure onset zone (SOZ). Our data provide novel empirical evidence for a set of brain areas that supports episodic memory in humans, and it provides a pathophysiologic mechanism for the memory deficits observed in patients with epilepsy.

For distinguished contributions to psychophysiology: Margaret M. Bradley

For distinguished contributions to psychophysiology: Margaret M. Bradley