Distinct encoding and post-encoding representational formats contribute to episodic sequence memory formation.

In episodic encoding, an unfolding experience is rapidly transformed into a memory representation that binds separate episodic elements into a memory form to be later recollected. However, it is unclear how brain activity changes over time to accommodate the encoding of incoming information. This study aimed to investigate the dynamics of the representational format that contributed to memory formation of sequential episodes. We combined representational similarity analysis and multivariate decoding approaches on EEG data to compare whether "category-level" or "item-level" representations supported memory formation during the online encoding of a picture triplet sequence and offline, in the period that immediately followed encoding. The findings revealed a gradual integration of category-level representation during the online encoding of the picture sequence and a rapid item-based neural reactivation of the encoded sequence at the episodic offset. However, we found that only memory reinstatement at episodic offset was associated with successful memory retrieval from long-term memory. These results suggest that post-encoding memory reinstatement is crucial for the rapid formation of unique memory for episodes that unfold over time. Overall, the study sheds light on the dynamics of representational format changes that take place during the formation of episodic memories.

Contextual incongruency triggers memory reinstatement and the disruption of neural stability.

Schemas, or internal representation models of the environment, are thought to be central in organising our everyday life behaviour by giving stability and predictiveness to the structure of the world. However, when an element from an unfolding event mismatches the schema-derived expectations, the coherent narrative is interrupted and an update to the current event model representation is required. Here, we asked whether the perceived incongruence of an item from an unfolding event and its impact on memory relied on the disruption of neural stability patterns preceded by the neural reactivation of the memory representations of the just-encoded event. Our study includes data from two different experiments whereby human participants (N = 33, 26 females and N = 18, 16 females, respectively) encoded images of objects preceded by trial-unique sequences of events depicting daily routine. We found that neural stability patterns gradually increased throughout the ongoing exposure to a schema-consistent episode, which was corroborated by the re-analysis of data from two other experiments, and that the brain stability pattern was interrupted when the encoding of an object of the event was incongruent with the ongoing schema. We found that the decrease in neural stability for low-congruence items was seen at ∼1000 ms from object encoding onset and that it was preceded by an enhanced N400 ERP and an increased degree of neural reactivation of the just-encoded episode. Current results offer new insights into the neural mechanisms and their temporal orchestration that are engaged during online encoding of schema-consistent episodic narratives and the detection of incongruencies.

Post-encoding Reactivation Is Related to Learning of Episodes in Humans.

Prior animal and human studies have shown that post-encoding reinstatement plays an important role in organizing the temporal sequence of unfolding episodes in memory. Here, we investigated whether post-encoding reinstatement serves to promote the encoding of "one-shot" episodic learning beyond the temporal structure in humans. In Experiment 1, participants encoded sequences of pictures depicting unique and meaningful episodic-like events. We used representational similarity analysis on scalp EEG recordings during encoding and found evidence of rapid picture-elicited EEG pattern reinstatement at episodic offset (around 500 msec post-episode). Memory reinstatement was not observed between successive elements within an episode, and the degree of memory reinstatement at episodic offset predicted later recall for that episode. In Experiment 2, participants encoded a shuffled version of the picture sequences from Experiment 1, rendering each episode meaningless to the participant but temporally structured as in Experiment 1, and we found no evidence of memory reinstatement at episodic offset. These results suggest that post-encoding memory reinstatement is akin to the rapid formation of unique and meaningful episodes that unfold over time.

Functional coupling between CA3 and laterobasal amygdala supports schema dependent memory formation.

The medial temporal lobe drives semantic congruence dependent memory formation. However, the exact roles of hippocampal subfields and surrounding brain regions remain unclear. Here, we used an established paradigm and high-resolution functional magnetic resonance imaging of the medial temporal lobe together with cytoarchitectonic probability estimates in healthy humans. Behaviorally, robust congruence effects emerged in young and older adults, indicating that schema dependent learning is unimpaired during healthy aging. Within the medial temporal lobe, semantic congruence was associated with hemodynamic activity in the subiculum, CA1, CA3 and dentate gyrus, as well as the entorhinal cortex and laterobasal amygdala. Importantly, a subsequent memory analysis showed increased activity for later remembered vs. later forgotten congruent items specifically within CA3, and this subfield showed enhanced functional connectivity to the laterobasal amygdala. As such, our findings extend current models on schema dependent learning by pinpointing the functional properties of subregions within the medial temporal lobe.

Theta rhythm supports hippocampus-dependent integrative encoding in schematic/semantic memory networks.

Integrating new information into existing schematic/semantic structures of knowledge is the basis of learning in our everyday life as it enables structured representation of information and goal-directed behaviour in an ever-changing environment. However, how schematic/semantic mnemonic structures aid the integration of novel elements remains poorly understood. Here, we showed that the ability to integrate novel picture information into learned structures of picture associations that overlapped by the same picture scene (i.e., simple network) or by a conceptually related picture scene (i.e., schematic/semantic network) is hippocampus-dependent, as patients with lesions at the medial temporal lobe (including the hippocampus) were impaired in inferring novel relations between pictures within these memory networks. We also found more persistent and widespread scalp EEG theta oscillations (3-5 Hz) while participants integrated novel pictures into schematic/semantic memory networks than into simple networks. On the other hand, greater neural similarity was observed between EEG patterns elicited by novel and related events within simple networks than between novel and related events within schematic/semantic memory networks. These findings have important implications for our understanding of the neural mechanisms that support the development and organization of structures of knowledge.

Rapid Memory Reactivation at Movie Event Boundaries Promotes Episodic Encoding.

Segmentation of continuous experience into discrete events is driven by rapid fluctuations in encoding stability at context shifts (i.e., event boundaries), yet the mechanisms underlying the online formation of event memories are poorly understood. We investigated the neural per-time point spatial similarity patterns of the scalp electrophysiological (EEG) activity of 30 human participants (male and female) watching a 50 min movie and found that event boundaries triggered the rapid reinstatement of the just-encoded movie event EEG patterns. We also found that the onset of memory reinstatement at boundary onset was accompanied by a left-lateralized anterior negative ERP effect, which likely reflects the detection of a shift in the narrative structure of the movie. A data-driven approach based on Hidden Markov modeling allowed us to detect event boundaries as shifts between stable patterns of brain EEG activity during encoding, and to identify their reactivation during a free recall task. These results provide the first neurophysiological underpinnings for how the memory systems segment a continuous long stream of experience into episodic events.SIGNIFICANCE OF STATEMENT Memory for specific episodic events are the building blocks of our autobiographical memory. However, it is still unclear how the memory systems structure the unfolding experience into discrete event units that can be understood and remembered at the long-term. Here, we show that the detection of context shifts, or event boundaries, during a 50 min movie viewing triggers the rapid memory reactivation of the just-encoded event to promote its successful encoding into long-term memory. By finding that memory reactivation, a neural mechanism critical for episodic memory formation and consolidation, takes place under these ecologically valid experimental circumstances, our results provide valuable insights into how the brain shapes the ongoing experience into episodic memories in the real-life.

Event conjunction: How the hippocampus integrates episodic memories across event boundaries.

Our lives are a continuous stream of experience. Our episodic memories on the other hand have a definitive beginning, middle, and end. Theories of event segmentation suggest that salient changes in our environment produce event boundaries which partition the past from the present and, as a result, produce discretized memories. However, event boundaries cannot completely discretize two memories; any shared conceptual link will lead to the rapid integration of these memories. Here, we present a new framework inspired by electrophysiological research that resolves this apparent contradiction. At its heart, the framework proposes that hippocampal theta-gamma coupling maintains a highly abstract model of an ongoing event and serves to encode this model as an episodic memory. When a second but related event begins, this theta-gamma model is rapidly reconstructed within the hippocampus where new details of the second event can be appended to the existing event model. The event conjunction framework is the first electrophysiological explanation of how event memories can be formed at, and integrated across, event boundaries.

Targeted Memory Reactivation during Sleep Adaptively Promotes the Strengthening or Weakening of Overlapping Memories.

System memory consolidation is conceptualized as an active process whereby newly encoded memory representations are strengthened through selective memory reactivation during sleep. However, our learning experience is highly overlapping in content (i.e., shares common elements), and memories of these events are organized in an intricate network of overlapping associated events. It remains to be explored whether and how selective memory reactivation during sleep has an impact on these overlapping memories acquired during awake time. Here, we test in a group of adult women and men the prediction that selective memory reactivation during sleep entails the reactivation of associated events and that this may lead the brain to adaptively regulate whether these associated memories are strengthened or pruned from memory networks on the basis of their relative associative strength with the shared element. Our findings demonstrate the existence of efficient regulatory neural mechanisms governing how complex memory networks are shaped during sleep as a function of their associative memory strength.SIGNIFICANCE STATEMENT Numerous studies have demonstrated that system memory consolidation is an active, selective, and sleep-dependent process in which only subsets of new memories become stabilized through their reactivation. However, the learning experience is highly overlapping in content and thus events are encoded in an intricate network of related memories. It remains to be explored whether and how memory reactivation has an impact on overlapping memories acquired during awake time. Here, we show that sleep memory reactivation promotes strengthening and weakening of overlapping memories based on their associative memory strength. These results suggest the existence of an efficient regulatory neural mechanism that avoids the formation of cluttered memory representation of multiple events and promotes stabilization of complex memory networks.

Semantic Congruence Accelerates the Onset of the Neural Signals of Successful Memory Encoding.

As the stream of experience unfolds, our memory system rapidly transforms current inputs into long-lasting meaningful memories. A putative neural mechanism that strongly influences how input elements are transformed into meaningful memory codes relies on the ability to integrate them with existing structures of knowledge or schemas. However, it is not yet clear whether schema-related integration neural mechanisms occur during online encoding. In the current investigation, we examined the encoding-dependent nature of this phenomenon in humans. We showed that actively integrating words with congruent semantic information provided by a category cue enhances memory for words and increases false recall. The memory effect of such active integration with congruent information was robust, even with an interference task occurring right after each encoding word list. In addition, via electroencephalography, we show in 2 separate studies that the onset of the neural signals of successful encoding appeared early (∼400 ms) during the encoding of congruent words. That the neural signals of successful encoding of congruent and incongruent information followed similarly ∼200 ms later suggests that this earlier neural response contributed to memory formation. We propose that the encoding of events that are congruent with readily available contextual semantics can trigger an accelerated onset of the neural mechanisms, supporting the integration of semantic information with the event input. This faster onset would result in a long-lasting and meaningful memory trace for the event but, at the same time, make it difficult to distinguish it from plausible but never encoded events (i.e., related false memories). SIGNIFICANCE STATEMENT: Conceptual or schema congruence has a strong influence on long-term memory. However, the question of whether schema-related integration neural mechanisms occur during online encoding has yet to be clarified. We investigated the neural mechanisms reflecting how the active integration of words with congruent semantic categories enhances memory for words and increases false recall of semantically related words. We analyzed event-related potentials during encoding and showed that the onset of the neural signals of successful encoding appeared early (∼400 ms) during the encoding of congruent words. Our findings indicate that congruent events can trigger an accelerated onset of neural encoding mechanisms supporting the integration of semantic information with the event input.

Theta-Alpha Oscillations Bind the Hippocampus, Prefrontal Cortex, and Striatum during Recollection: Evidence from Simultaneous EEG-fMRI.

Recollection of contextual information represents the core of human recognition memory. It has been associated with theta (4-8 Hz) power in electrophysiological recordings and, independently, with BOLD effects in a network including the hippocampus and frontal cortex. Although the notion of the hippocampus coordinating neocortical activity by synchronization in the theta range is common among theoretical models of recollection, direct evidence supporting this hypothesis is scarce. To address this apparent gap in our understanding of memory processes, we combined EEG and fMRI during a remember/know recognition task. We can show that recollection-specific theta-alpha (4-13 Hz) effects are correlated with increases in hippocampal connectivity with the PFC and, importantly, the striatum, areas that have been linked repeatedly to retrieval success. Together, our results provide compelling evidence that low-frequency oscillations in the theta and alpha range provide a mechanism to functionally bind the hippocampus, PFC, and striatum during successful recollection. SIGNIFICANCE STATEMENT: Low-frequency oscillations are supposed to drive the binding of information across a large-scale network centered on the hippocampus, which supports mnemonic functions. The electrophysiological means to investigate this phenomenon in humans (EEG/MEG), however, are inherently limited by their spatial resolution and therefore do not allow a precise localization of the brain regions involved. By combining EEG with BOLD-derived estimates of hippocampal connectivity during recognition, we can identify the striatum and specific areas in the medial and lateral PFC as part of a circuit linked to low-frequency oscillations (4-13 Hz) that promotes hippocampus-dependent context retrieval. Therefore, the current study closes an apparent gap in our understanding of the network dynamics of memory retrieval.

The right inferior frontal cortex in response inhibition: A tDCS-ERP co-registration study.

In any given common situation, when an individual controls him/herself or obeys and stops a current action when asked to do, it is because the brain executes an inhibitory process. This ability is essential for adaptive behaviour, and it is also a requirement for accurate performance in daily life. It has been suggested that there are two main inhibitory functions related to behaviour, as inhibition is observed to affect behaviour at different time intervals. Proactive inhibition permits the subject to control his behavioural response over time by creating a response tendency, while reactive inhibition is considered to be a process that usually inhibits an already initiated response. In this context, it has been established that inhibitory function is implemented by specific fronto-basal-ganglia circuits. In the present study, we investigated the role of the right inferior frontal cortex (rIFC) in response inhibition by combining into a single task the Go-NoGo task and the Stop-Signal task. Concurrently, we applied transcranial direct current stimulation (tDCS) over the IFC and recorded electroencephalography (EEG). Thus, we obtained online EEG measurements of the tDCS-induced modifications in the IFC together with the participant's performance in a response inhibition task. We found that applying bilateral tDCS on the IFC (right anodal/left cathodal) significantly increased proactive inhibition, although the behavioural parameters indicative of reactive inhibition were unaffected by the stimulation. Finally, the inhibitory-P3 component reflected a similar modulation under both inhibitory conditions induced by the stimulation. Our data indicates that an online tDCS-ERP approach is achievable, but that a tDCS bilateral montage may not be the most efficient one for modulating the rIFC.

Acetylcholine modulates human working memory and subsequent familiarity based recognition via alpha oscillations.

Working memory (WM) can be defined as the ability to maintain and process physically absent information for a short period of time. This vital cognitive function has been related to cholinergic neuromodulation and, in independent work, to theta (4-8Hz) and alpha (9-14Hz) band oscillations. However, the relationship between both aspects remains unclear. To fill this apparent gap, we used electroencephalography (EEG) and a within-subject design in healthy humans who either received the acetylcholinesterase inhibitor galantamine (8mg) or a placebo before they performed a Sternberg WM paradigm. Here, sequences of sample images were memorized for a delay of 5s in three different load conditions (two, four or six items). On the next day, long-term memory (LTM) for the images was tested according to a remember/know paradigm. As a main finding, we can show that both theta and alpha oscillations scale during WM maintenance as a function of WM load; this resembles the typical performance decrease. Importantly, cholinergic stimulation via galantamine administration slowed down retrieval speed during WM and reduced associated alpha but not theta power, suggesting a functional relationship between alpha oscillations and WM performance. At LTM, this pattern was accompanied by impaired familiarity based recognition. These findings show that stimulating the healthy cholinergic system impairs WM and subsequent recognition, which is in line with the notion of a quadratic relationship between acetylcholine levels and cognitive functions. Moreover, our data provide empirical evidence for a specific role of alpha oscillations in acetylcholine dependent WM and associated LTM formation.

Motivated encoding selectively promotes memory for future inconsequential semantically-related events.

Neurobiological models of long-term memory explain how memory for inconsequential events fades, unless these happen before or after other relevant (i.e., rewarding or aversive) or novel events. Recently, it has been shown in humans that retrospective and prospective memories are selectively enhanced if semantically related events are paired with aversive stimuli. However, it remains unclear whether motivating stimuli, as opposed to aversive, have the same effect in humans. Here, participants performed a three phase incidental encoding task where one semantic category was rewarded during the second phase. A memory test 24h after, but not immediately after encoding, revealed that memory for inconsequential items was selectively enhanced only if items from the same category had been previously, but not subsequently, paired with rewards. This result suggests that prospective memory enhancement of reward-related information requires, like previously reported for aversive memories, of a period of memory consolidation. The current findings provide the first empirical evidence in humans that the effects of motivated encoding are selectively and prospectively prolonged over time.

Replay of very early encoding representations during recollection.

Long-term memories are linked to cortical representations of perceived events, but it is unclear which types of representations can later be recollected. Using magnetoencephalography-based decoding, we examined which brain activity patterns elicited during encoding are later replayed during recollection in the human brain. The results show that the recollection of images depicting faces and scenes is associated with a replay of neural representations that are formed at very early (180 ms) stages of encoding. This replay occurs quite rapidly, ~500 ms after the onset of a cue that prompts recollection and correlates with source memory accuracy. Therefore, long-term memories are rapidly replayed during recollection and involve representations that were formed at very early stages of encoding. These findings indicate that very early representational information can be preserved in the memory engram and can be faithfully and rapidly reinstated during recollection. These novel insights into the nature of the memory engram provide constraints for mechanistic models of long-term memory function.

Dopaminergic stimulation facilitates working memory and differentially affects prefrontal low theta oscillations.

We used electroencephalography (EEG) together with psychopharmacological stimulation to investigate the role of dopamine in neural oscillations during working memory (WM). Following a within-subjects design, healthy humans either received the dopamine precursor L-Dopa (150 mg) or a placebo before they performed a Sternberg WM paradigm. Here, sequences of sample images had to be memorized for a delay of 5 s in three different load conditions (two, four or six items). On the next day, long-term memory (LTM) for the images was tested. Behaviorally, L-Dopa improved WM and LTM performance as a function of WM load. More precisely, there was a specific drug effect in the four-load condition with faster reaction times to the probe in the WM task and higher corrected hit-rates in the LTM task. During the maintenance period, there was a linear and quadratic effect of WM load on power in the high theta (5-8 Hz) and alpha (9-14 Hz) frequency range at frontal sensors. Importantly, a drug by load interaction--mimicking the behavioral results--was found only in low theta power (2-4 Hz). As such, our results indicate a specific link between prefrontal low theta oscillations, dopaminergic neuromodulation during WM and subsequent LTM performance.

Tracking explicit and implicit long-lasting traces of fearful memories in humans.

Recent accounts of Posttraumatic Stress Disorder (PTSD) suggest that the encoding of an episode within a fearful context generates different implicit and explicit memory representations. Whilst implicit memory traces include the associated emotional states, explicit traces include a recoding into an abstract or gist-based structural context of the episode. Theoretically, the long-term preservation of implicit memory traces may facilitate the often untreatable memory intrusions in PTSD. Here, we tracked in two experiments how implicit and explicit memory traces for fearful episodes dissociate and evolve over time. Subjects (N=86) were presented with semantically-related word-lists in a contextual fear paradigm and tested for explicit memories either immediately (i.e., 30 min) or after a delay (i.e., 1 or 2 weeks) with a verbal recognition task. Skin Conductance Response (SCR) was used to assess implicit memory responses. Subjects showed high memory accuracy for words when tested immediately after encoding. At test, SCR was higher during the presentation of verbatim but not gist-based words encoded in a fearful context, and remained unchanged after 2 weeks, despite subjects being unaware of words' encoding context. We found no clear evidence of accurate explicit memory traces for the fearful or neutral contexts of words presented during encoding, either 30 min or 2 weeks afterwards. These findings indicate that the implicit, but not the explicit, memory trace of a fearful context of an episode can be detected at long-term through SCR and is dissociated from the gist-based memory. They may have implicationstowards the understanding of how the processing of fearful memoriescould lead to PTSD.

Electrophysiological correlates of anticipating improbable but desired events.

Psychological studies have emphasized that motivation is regulated by the anticipation of the emotional impact from the possible occurrence of unexpected rewarding events. Here, we scrutinized the existence of a corresponding neural signal by means of event-related potentials (ERPs) and computational modeling. In the first experiment, we designed a task that manipulated the probability of gaining a monetary reward and measured ERPs during anticipation and at reward delivery. A sustained frontocentral neural activity (i.e., the stimulus preceding negativity, SPN) was evidenced during the anticipation period. Critically, the SPN was found to increase in amplitude as the reward became more unexpected. Changes in the SPN were found to be predictive of individual differences in risk seeking, suggesting that a greater risk attitude involved a greater motivational state for receiving an improbable reward. In the second experiment, SPN results associated with unexpected monetary gains were replicated in a condition in which participants avoided monetary losses and the occurrence of unexpected rewards was also associated with an increase in the amount of self-reported pleasure. These findings support the existence of a neural ERP signature that encodes the process of tuning our motivation to the possibility of receiving a desirable but improbable rewarding outcome.

Gamma amplitude is coupled to opposed hippocampal theta-phase states during the encoding and retrieval of episodic memories in humans.

Computational models and in vivo studies in rodents suggest that the emergence of gamma activity (40-140 Hz) during memory encoding and retrieval is coupled to opposed-phase states of the underlying hippocampal theta rhythm (4-9 Hz).1,2,3,4,5,6,7,8,9,10 However, direct evidence for whether human hippocampal gamma-modulated oscillatory activity in memory processes is coupled to opposed-phase states of the ongoing theta rhythm remains elusive. Here, we recorded local field potentials (LFPs) directly from the hippocampus of 10 patients with epilepsy, using depth electrodes. We used a memory encoding and retrieval task whereby trial unique sequences of pictures depicting real-life episodes were presented, and 24 h later, participants were asked to recall them upon the appearance of the first picture of the encoded episodic sequence. We found theta-to-gamma cross-frequency coupling that was specific to the hippocampus during both the encoding and retrieval of episodic memories. We also revealed that gamma was coupled to opposing theta phases during both encoding and recall processes. Additionally, we observed that the degree of theta-gamma phase opposition between encoding and recall was associated with participants' memory performance, so gamma power was modulated by theta phase for both remembered and forgotten trials, although only for remembered trials the dominant theta phase was different for encoding and recall trials. The current results offer direct empirical evidence in support of hippocampal theta-gamma phase opposition models in human long-term memory and provide fundamental insights into mechanistic predictions derived from computational and animal work, thereby contributing to establishing similarities and differences across species.

Hippocampal theta-phase modulation of replay correlates with configural-relational short-term memory performance.

There is now growing evidence that the hippocampus generates theta rhythms that can phase bias fast neural oscillations in the neocortex, allowing coordination of widespread fast oscillatory populations outside limbic areas. A recent magnetoencephalographic study showed that maintenance of configural-relational scene information in a delayed match-to-sample (DMS) task was associated with replay of that information during the delay period. The periodicity of the replay was coordinated by the phase of the ongoing theta rhythm, and the degree of theta coordination during the delay period was positively correlated with DMS performance. Here, we reanalyzed these data to investigate which brain regions were involved in generating the theta oscillations that coordinated the periodic replay of configural-relational information. We used a beamformer algorithm to produce estimates of regional theta rhythms and constructed volumetric images of the phase-locking between the local theta cycle and the instances of replay (in the 13-80 Hz band). We found that individual differences in DMS performance for configural-relational associations were related to the degree of phase coupling of instances of cortical reactivations to theta oscillations generated in the right posterior hippocampus and the right inferior frontal gyrus. This demonstrates that the timing of memory reactivations in humans is biased toward hippocampal theta phase.

Action dominates valence in anticipatory representations in the human striatum and dopaminergic midbrain.

The acquisition of reward and the avoidance of punishment could logically be contingent on either emitting or withholding particular actions. However, the separate pathways in the striatum for go and no-go appear to violate this independence, instead coupling affect and effect. Respect for this interdependence has biased many studies of reward and punishment, so potential action-outcome valence interactions during anticipatory phases remain unexplored. In a functional magnetic resonance imaging study with healthy human volunteers, we manipulated subjects' requirement to emit or withhold an action independent from subsequent receipt of reward or avoidance of punishment. During anticipation, in the striatum and a lateral region within the substantia nigra/ventral tegmental area (SN/VTA), action representations dominated over valence representations. Moreover, we did not observe any representation associated with different state values through accumulation of outcomes, challenging a conventional and dominant association between these areas and state value representations. In contrast, a more medial sector of the SN/VTA responded preferentially to valence, with opposite signs depending on whether action was anticipated to be emitted or withheld. This dominant influence of action requires an enriched notion of opponency between reward and punishment.