The functions of sleep: A cognitive neuroscience perspective.

This Special Feature explores the various purposes served by sleep, describing current attempts to understand how the many functions of sleep are instantiated in neural circuits and cognitive structures. Our feature reflects current experts' opinions about, and insights into, the dynamic processes of sleep. In the last few decades, technological advances have supported the updated view that sleep plays an active role in both cognition and health. However, these roles are far from understood. This collection of articles evaluates the dynamic nature of sleep, how it evolves across the lifespan, becomes a competitive arena for memory systems through the influence of the autonomic system, supports the consolidation and integration of new memories, and how lucid dreams might originate. This set of papers highlights new approaches and insights that will lay the groundwork to eventually understand the full range of functions supported by sleep.

Diffusion MRI-guided theta burst stimulation enhances memory and functional connectivity along the inferior longitudinal fasciculus in mild cognitive impairment.

Mild cognitive impairment (MCI) during aging is often a harbinger of Alzheimer's disease, and, therefore, early intervention to preserve cognitive abilities before the MCI symptoms become medically refractory is particularly critical. Functional MRI­guided transcranial magnetic stimulation is a promising approach for modulating hippocampal functional connectivity and enhancing memory in healthy adults. Here, we extend these previous findings to individuals with MCI and leverage theta burst stimulation (TBS) and white matter tractography derived from diffusion-weighted MRI to target the hippocampus. Our preliminary findings suggested that TBS could be used to improve associative memory performance and increase resting-state functional connectivity of the hippocampus and other brain regions, including the occipital fusiform, frontal orbital cortex, putamen, posterior parahippocampal gyrus, and temporal pole, along the inferior longitudinal fasciculus in MCI. Although the sample size is small, these results shed light on how TBS propagates from the superficial cortex around the parietal lobe to the hippocampus.

Some implications of postnatal hippocampal development.

It is well established that in most species, the hippocampus shows extensive postnatal development. This delayed maturation has a number of implications, which can be thought of in three categories. First, the late maturation has the direct effect of depriving the developing organism of at least some of the functions of the hippocampus, in particular place learning, context coding and in humans, episodic memory. Second, such learning that does occur very early in life, prior to hippocampal maturation, will largely bear the imprint and properties of those brain systems that, unlike the hippocampus, are fully functional early in life. Third, the active state of development of hippocampus in the first weeks and months of life render this structure susceptible to disruption by environmental and/or chromosomal factors. In this article, I discuss my efforts, with many colleagues over the past 40 years, to understand each of these implications.

The hippocampal formation and action at a distance.

The question of why our conceptions of space and time are intertwined with memory in the hippocampal formation is at the forefront of much current theorizing about this brain system. In this article I argue that animals bridge spatial and temporal gaps through the creation of internal models that allow them to act on the basis of things that exist in a distant place and/or existed at a different time. The hippocampal formation plays a critical role in these processes by stitching together spatiotemporally disparate entities and events. It does this by 1) constructing cognitive maps that represent extended spatial contexts, incorporating and linking aspects of an environment that may never have been experienced together; 2) creating neural trajectories that link the parts of an event, whether they occur in close temporal proximity or not, enabling the construction of event representations even when elements of that event were experienced at quite different times; and 3) using these maps and trajectories to simulate possible futures. As a function of these hippocampally driven processes, our subjective sense of both space and time are interwoven constructions of the mind, much as the philosopher Immanuel Kant postulated.

The Continuity of Context: A Role for the Hippocampus.

Tracking moment-to-moment change in input and detecting change sufficient to require altering behavior is crucial to survival. Here, we discuss how the brain evaluates change over time, focusing on the hippocampus and its role in tracking context. We leverage the anatomy and physiology of the hippocampal longitudinal axis, re-entrant loops, and amorphous networks to account for stimulus equivalence and the updating of an organism's sense of its context. Place cells have a central role in tracking contextual continuities and discontinuities across multiple scales, a capacity beyond current models of pattern separation and completion. This perspective highlights the critical role of the hippocampus in both spatial cognition and episodic memory: tracking change and detecting boundaries separating one context, or episode, from another.

Parameters of Memory Reconsolidation: Learning Mode Influences Likelihood of Memory Modification.

When previously consolidated hippocampally dependent memory traces are reactivated they enter a vulnerable state in which they can be altered with new information, after which they must be re-consolidated in order to restabilize the trace. The existing body of literature on episodic reconsolidation largely focuses on the when and how of successful memory reactivation. What remains poorly understood is how the nature of newly presented information affects the likelihood of a vulnerable episodic memory being altered. We used our episodic memory reconsolidation paradigm to investigate if the intention to encode impacts what subsequently becomes attributed to an older, reactivated memory. Participants learned two lists of objects separated by 48 h. We integrated a modified item-list directed-forgetting paradigm into the encoding of the second object list by cueing participants to learn some of the objects intentionally (intentional learning), while other objects were presented without a cue (incidental learning). Under conditions of memory reactivation, subjects showed equal rates of memory modification for intentionally- and incidentally-learned objects. However, in the absence of reactivation we observed high misattribution rates of incidentally-learned objects. We consider two interpretations of these data, with contrasting implications for understanding the conditions that influence memory malleability, and suggest further work that should help decide between them.

Associations between sleep and episodic memory updating.

Prior research shows that contextual reminders can reactivate hippocampal links to previously consolidated memories, rendering them susceptible to being updated with new information which then is reconsolidated. Studies implicate sleep in the reconsolidation of reactivated memories, but it is unknown what role sleep plays in updating of a previously consolidated trace with new information. We tracked participants' sleep during an episodic reconsolidation paradigm, first with actigraphy (Experiment 1) then with polysomnography (Experiment 2). Our paradigm involved two learning sessions and a retrieval session, each separated by 48 hr. We reminded participants of the first learning experience immediately prior to the second, which led them to update the earlier memory with elements of the later experience. In Experiment 1, less sleep after Session 1 and more sleep after Session 2 are associated with increased updating. In Experiment 2, N2 sleep spindles (SSs) after the reminder and new learning are associated with more updating, but primarily when spindle activity after Session 1 is low. Thus, total sleep time and N2 SSs contribute to sleep-dependent updating of episodic memory. This outcome is consistent with other work connecting SS activity to the integration of novel information into existing knowledge structures, extended here with the study of how variations in sleep over successive nights contribute to this process. We discuss some possible roles of spindles in the decontextualization of hippocampal memory over time. Although much work addresses the role of sleep in the consolidation of new memories, this work uniquely addresses the contribution of sleep to the updating of a previously consolidated trace with new information.

Differential effects of unipolar versus bipolar depression on episodic memory updating.

Episodic memories, when reactivated, can be modified or updated by new learning. Since such dynamic memory processes remain largely unexplored in psychiatric disorders, we examined the impact of depression on episodic memory updating. Unipolar and bipolar depression patients, and age/education matched controls, first learned a set of objects (List-1). Two days later, participants in all three groups were either reminded of the first learning session or not followed by the learning of a new set of objects (List-2). Forty-eight hours later, List-1 recall was impaired in unipolar and bipolar patients compared to control participants. Further, as expected, control participants who received a reminder spontaneously recalled items from List-2 during recall of List-1, indicative of an updated List-1 memory. Such spontaneous intrusions were also seen in the unipolar and bipolar patients that received the reminder, suggesting that memory updating was unaffected in these two patient groups despite impaired recall of List 1. Unexpectedly, we observed a trend towards higher intrusions, albeit statistically insignificant, not only in the reminder but also in the no-reminder subgroups of bipolar patients. We probed this further in a second cohort by testing recall of List-2, which was also impaired in both depression groups. Again bipolar patients showed intrusions, but this time in the reverse order from List-1 into List-2, independent of a reminder. Taken together, despite impaired recall, updating of episodic memories was intact and unidirectional in unipolar depression. In contrast, indiscriminate updating, as evidenced by bidirectional interference between episodic memories, was seen in bipolar depression. These findings reveal a novel distinction between unipolar versus bipolar depression using a reactivation-dependent memory updating paradigm.

Curiosity-driven memory enhancement persists over time but does not benefit from post-learning sleep.

Sleep-dependent memory processing is dependent on several factors at learning, including emotion, encoding strength, and knowledge of future relevance. Recent work documents the role of curiosity on learning, showing that memory associated with high-curiosity encoding states is retained better and that this effect may be driven by activity within the dopaminergic circuit. Here, we examined whether this curiosity effect was enhanced by or dependent on sleep-related consolidation. Participants learned the answers to trivia questions that they had previously rated on a curiosity scale, and they were shown faces between each question and answer presentation. Memory for these answers and faces was tested either immediately or after a 12-hour delay containing sleep or wakefulness, and polysomnography data was collected for a subset of the sleep participants. Although the curiosity effect for both the answers and incidentally-learned faces was replicated in immediate tests and after the 12-hour delay, the effect was not impacted by the presence of sleep in either case, nor did the effect show a relationship with total sleep time or time in slow-wave sleep. This study suggests that curiosity may be a learning factor that is not subsequently affected by sleep-dependent memory consolidation, but more work ought to examine the role of sleep on curiosity-driven memory in other contexts.

Losing memories during sleep after targeted memory reactivation.

Targeting memories during sleep opens powerful and innovative ways to influence the mind. We used targeted memory reactivation (TMR), which to date has been shown to strengthen learned episodes, to instead induce forgetting (TMR-Forget). Participants were first trained to associate the act of forgetting with an auditory forget tone. In a second, separate, task they learned object-sound-location pairings. Shortly thereafter, some of the object sounds were played during slow wave sleep, paired with the forget tone to induce forgetting. One week later, participants demonstrated lower recall of reactivated versus non-reactivated objects and impaired recognition memory and lowered confidence for the spatial location of the reactivated objects they failed to spontaneously recall. The ability to target specific episodic memories for forgetting during sleep has implications for developing novel therapeutic techniques for psychological disorders such as PTSD and phobias.

Systems consolidation revisited, but not revised: The promise and limits of optogenetics in the study of memory.

Episodic memories (in humans) and event-like memories (in non-human animals) require the hippocampus for some time after acquisition, but at remote points seem to depend more on cortical areas instead. Systems consolidation refers to the process that promotes this reorganization of memory. Various theoretical frameworks accounting for this process have been proposed, but clear evidence favoring one or another of these positions has been lacking. Addressing this issue, a recent study deployed some of the most advanced neurobiological technologies - optogenetics and calcium imaging - and provided high resolution, precise observations regarding brain systems involved in recent and remote contextual fear memories. We critically review these findings within their historical context and conclude that they do not resolve the debate concerning systems consolidation. This is because the relevant question concerning the quality of memory at recent and remote time points has not been answered: Does the memory reorganization taking place during systems consolidation result in changes to the content of memory?

Publisher Correction: Viewpoints: how the hippocampus contributes to memory, navigation and cognition.

In the version of this article initially published, author Charan Ranganath's last name was misspelled Rangananth in the author list. Also, A. David Redish (redish@umn.edu) has been added as a corresponding author. The error has been corrected, and the corresponding author added, in the HTML and PDF versions of the article.

Brain correlates of memory reconsolidation: A role for the TPJ.

In this paper, we investigate the process by which new experiences reactivate and potentially update old memories. Such memory reconsolidation appears dependent on the extent to which current experience deviates from what is predicted by the reactivated memory (i.e. prediction error). If prediction error is low, the reactivated memory is likely to be updated with new information. If it is high, however, a new, separate, memory is more likely to be formed. The temporal parietal junction TPJ has been shown across a broad range of content areas (attention, social cognition, decision making and episodic memory) to be sensitive to the degree to which current information violates the observer's expectations - in other words, prediction error. In the current paper, we investigate whether the level of TPJ activation during encoding predicts if the encoded information will be used to form a new memory or update a previous memory. We find that high TPJ activation predicts new memory formation. In a secondary analysis, we examine whether reactivation strength - which we assume leads to a strong memory-based prediction - mediates the likelihood that a given individual will use new information to form a new memory rather than update a previous memory. Individuals who strongly reactivate previous memories are less likely to update them than individuals who weakly reactivate them. We interpret this outcome as indicating that strong predictions lead to high prediction error, which favors new memory formation rather than updating of a previous memory.

Sleep confers a benefit for retention of statistical language learning in 6.5month old infants.

Infants show robust ability to track transitional probabilities within language and can use this information to extract words from continuous speech. The degree to which infants remember these words across a delay is unknown. Given well-established benefits of sleep on long-term memory retention in adults, we examine whether sleep similarly facilitates memory in 6.5month olds. Infants listened to an artificial language for 7minutes, followed by a period of sleep or wakefulness. After a time-matched delay for sleep and wakefulness dyads, we measured retention using the head-turn-preference procedure. Infants who slept retained memory for the extracted words that was prone to interference during the test. Infants who remained awake showed no retention. Within the nap group, retention correlated with three electrophysiological measures (1) absolute theta across the brain, (2) absolute alpha across the brain, and (3) greater fronto-central slow wave activity (SWA).

Hippocampus at 25.

The journal Hippocampus has passed the milestone of 25 years of publications on the topic of a highly studied brain structure, and its closely associated brain areas. In a recent celebration of this event, a Boston memory group invited 16 speakers to address the question of progress in understanding the hippocampus that has been achieved. Here we present a summary of these talks organized as progress on four main themes: (1) Understanding the hippocampus in terms of its interactions with multiple cortical areas within the medial temporal lobe memory system, (2) understanding the relationship between memory and spatial information processing functions of the hippocampal region, (3) understanding the role of temporal organization in spatial and memory processing by the hippocampus, and (4) understanding how the hippocampus integrates related events into networks of memories. © 2016 Wiley Periodicals, Inc.

Behavioral and self-reported sensitivity to reward are linked to stress-related differences in positive affect.

Despite the high prevalence of stress exposure healthy adaptation or resilience is a common response. Theoretical work and recent empirical evidence suggest that a robust reward system, in part, supports healthy adaptation by preserving positive emotions even under exceptionally stressful circumstances. We tested this prediction by examining empirical relations among behavioral and self-reported measures of sensitivity to reward, trait resilience, and measures of affect in the context of experimentally induced stress. Using a quasi-experimental design we obtained measures of sensitivity to reward (self-report and behavioral), as well as affective and physiological responses to experimental psychosocial stress in a sample of 140 healthy college-age participants. We used regression-based moderation and mediational models to assess associations among sensitivity to reward, affect in the context of stress, and trait resilience and found that an interaction between exposure to experimental stress and self-reported sensitivity to reward predicted positive affect following experimental procedure. Participants with high sensitivity to reward reported higher positive affect following stress. Moreover, positive affect during or after stress mediated the relation between sensitivity to reward and trait resilience. Consistent with the prediction that a robust reward system serves as a protective factor against stress-related negative outcomes, our results found predictive associations among sensitivity to reward, positive affect, and resilience.

Episodic Memory and Beyond: The Hippocampus and Neocortex in Transformation.

The last decade has seen dramatic technological and conceptual changes in research on episodic memory and the brain. New technologies, and increased use of more naturalistic observations, have enabled investigators to delve deeply into the structures that mediate episodic memory, particularly the hippocampus, and to track functional and structural interactions among brain regions that support it. Conceptually, episodic memory is increasingly being viewed as subject to lifelong transformations that are reflected in the neural substrates that mediate it. In keeping with this dynamic perspective, research on episodic memory (and the hippocampus) has infiltrated domains, from perception to language and from empathy to problem solving, that were once considered outside its boundaries. Using the component process model as a framework, and focusing on the hippocampus, its subfields, and specialization along its longitudinal axis, along with its interaction with other brain regions, we consider these new developments and their implications for the organization of episodic memory and its contribution to functions in other domains.