Haunted by the past: old emotions remain salient in insomnia disorder.

Studies suggest that sleep supports persistent changes in the neuronal representation of emotional experiences such that they are remembered better and less distressful when recalled than when they were first experienced. It is conceivable that sleep fragmentation by arousals, a key characteristic of insomnia disorder, could hamper the downregulation of distress. In this study, we sought further support for the idea that insomnia disorder may involve a lasting deficiency to downregulate emotional distress. We used functional MRI in insomnia disorder (n = 27) and normal sleepers (n = 30) to identify how brain activation differs between novel and relived self-conscious emotions. We evaluated whether brain activity elicited by reliving emotional memories from the distant past resembles the activity elicited by novel emotional experiences more in insomnia disorder than in normal sleepers. Limbic areas were activated during novel shameful experiences as compared to neutral experiences in both normal sleepers and insomnia disorder. In normal sleepers, reliving of shameful experiences from the past did not elicit a limbic response. In contrast, participants with insomnia disorder recruited overlapping parts of the limbic circuit, in particular the dorsal anterior cingulate cortex, during both new and relived shameful experiences. The differential activity patterns with new and old emotions in normal sleepers suggest that reactivation of the long-term memory trace does not recruit the limbic circuit. The overlap of activations in insomnia disorder is in line with the hypothesis that the disorder involves a deficiency to dissociate the limbic circuit from the emotional memory trace. Moreover, the findings provide further support for a role of the anterior cingulate cortex in insomnia.

Slow dissolving of emotional distress contributes to hyperarousal.

The mechanisms underlying hyperarousal, the key symptom of insomnia, have remained elusive, hampering cause-targeted treatment. Recently, restless rapid-eye-movement (REM) sleep emerged as a robust signature of sleep in insomnia. Given the role of REM sleep in emotion regulation, we hypothesized that restless REM sleep could interfere with the overnight resolution of emotional distress, thus contributing to accumulation of arousal. Participants (n = 1,199) completed questionnaires on insomnia severity, hyperarousal, self-conscious emotional distress, and thought-like nocturnal mentation that was validated to be a specific proxy for restless REM sleep (selective fragmentation: R = 0.57, P < 0.001; eye movement density: R = 0.46, P < 0.01) in 32 polysomnographically assessed participants. The experience of distress lasting overnight increased with insomnia severity (ß = 0.29, P < 10(-23)), whereas short-lasting distress did not (ß = -0.02, P = 0.41). Insomnia severity was associated with hyperarousal (ß = 0.47, P < 10(-63)) and with the thought-like nocturnal mentation that is specifically associated with restless REM sleep (ß = 0.31, P < 10(-26)). Structural equation modeling showed that 62.4% of the association between these key characteristics of insomnia was mediated specifically by reduced overnight resolution of emotional distress. The model outperformed all alternative mediation pathways. The findings suggest that restless REM sleep reflects a process that interferes with the overnight resolution of distress. Its accumulation may promote the development of chronic hyperarousal, giving clinical relevance to the role of REM sleep in emotion regulation in insomnia, depression, and posttraumatic stress disorder.

Slow oscillations during sleep coordinate interregional communication in cortical networks.

Large-amplitude sleep slow oscillations group faster neuronal oscillations and are of functional relevance for memory performance. However, relatively little is known about the impact of slow oscillations on functionally coupled networks. Here, we provide a comprehensive view on how human slow oscillatory dynamics influence various measures of brain processing. We demonstrate that slow oscillations coordinate interregional cortical communication, as assessed by phase synchrony in the sleep spindle frequency range and cross-frequency coupling between spindle and beta activity. Furthermore, we show that the organizing role of slow oscillations is restricted to circumscribed topographical areas. These findings add importantly to our basic understanding of the orchestrating role of slow oscillations. In addition, they are of considerable relevance for accounts of sleep-dependent memory reprocessing and consolidation.

Neural mechanisms supporting the extraction of general knowledge across episodic memories.

General knowledge acquisition entails the extraction of statistical regularities from the environment. At high levels of complexity, this may involve the extraction, and consolidation, of associative regularities across event memories. The underlying neural mechanisms would likely involve a hippocampo-neocortical dialog, as proposed previously for system-level consolidation. To test these hypotheses, we assessed possible differences in consolidation between associative memories containing cross-episodic regularities and unique associative memories. Subjects learned face-location associations, half of which responded to complex regularities regarding the combination of facial features and locations, whereas the other half did not. Importantly, regularities could only be extracted over hippocampus-encoded, associative aspects of the items. Memory was assessed both immediately after encoding and 48 h later, under fMRI acquisition. Our results suggest that processes related to system-level reorganization occur preferentially for regular associations across episodes. Moreover, the build-up of general knowledge regarding regular associations appears to involve the coordinated activity of the hippocampus and mediofrontal regions. The putative cross-talk between these two regions might support a mechanism for regularity extraction. These findings suggest that the consolidation of cross-episodic regularities may be a key mechanism underlying general knowledge acquisition.

Local sleep spindle modulations in relation to specific memory cues.

Sleep spindles have been connected to memory processes in various ways. In addition, spindles appear to be modulated at the local cortical network level. We investigated whether cueing specific memories during sleep leads to localized spindle modulations in humans. During learning of word-location associations, words presented in the left and right visual hemifields were paired with different odors. By presenting a single odor during a subsequent nap, we aimed to selectively reactivate a subset of the studied material in sleeping subjects. During sleep, we observed topographically restricted spindle responses to memory cues, suggesting successful reactivation of specific memory traces. In particular, we found higher amplitude and greater incidence of fast spindles over posterior brain areas involved in visuospatial processing, contralateral to the visual field being cued. These results suggest that sleep spindles in different cortical areas reflect the reprocessing of specific memory traces.

Sensational Dreams: The Prevalence of Sensory Experiences in Dreaming.

Dreaming, a widely researched aspect of sleep, often mirrors waking-life experiences. Despite the prevalence of sensory perception during wakefulness, sensory experiences in dreams remain relatively unexplored. Free recall dream reports, where individuals describe their dreams freely, may not fully capture sensory dream experiences. In this study, we developed a dream diary with direct questions about sensory dream experiences. Participants reported sensory experiences in their dreams upon awakening, over multiple days, in a home-based setting (n = 3476 diaries). Our findings show that vision was the most common sensory dream experience, followed by audition and touch. Olfaction and gustation were reported at equally low rates. Multisensory dreams were far more prevalent than unisensory dreams. Additionally, the prevalence of sensory dream experiences varied across emotionally positive and negative dreams. A positive relationship was found between on the one hand sensory richness and, on the other emotional intensity of dreams and clarity of dream recall, for both positive and negative dreams. These results underscore the variety of dream experiences and suggest a link between sensory richness, emotional content and dream recall clarity. Systematic registration of sensory dream experiences offers valuable insights into dream manifestation, aiding the understanding of sleep-related memory consolidation and other aspects of sleep-related information processing.

Aging memories: differential decay of episodic memory components.

Some memories about events can persist for decades, even a lifetime. However, recent memories incorporate rich sensory information, including knowledge on the spatial and temporal ordering of event features, while old memories typically lack this "filmic" quality. We suggest that this apparent change in the nature of memories may reflect a preferential loss of hippocampus-dependent, configurational information over more cortically based memory components, including memory for individual objects. The current study systematically tests this hypothesis, using a new paradigm that allows the contemporaneous assessment of memory for objects, object pairings, and object-position conjunctions. Retention of each memory component was tested, at multiple intervals, up to 3 mo following encoding. The three memory subtasks adopted the same retrieval paradigm and were matched for initial difficulty. Results show differential decay of the tested episodic memory components, whereby memory for configurational aspects of a scene (objects' co-occurrence and object position) decays faster than memory for featured objects. Interestingly, memory requiring a visually detailed object representation decays at a similar rate as global object recognition, arguing against interpretations based on task difficulty and against the notion that (visual) detail is forgotten preferentially. These findings show that memories undergo qualitative changes as they age. More specifically, event memories become less configurational over time, preferentially losing some of the higher order associations that are dependent on the hippocampus for initial fast encoding. Implications for theories of long-term memory are discussed.

Involvement of spindles in memory consolidation is slow wave sleep-specific.

Both sleep spindles and slow oscillations have been implicated in sleep-dependent memory consolidation. Whereas spindles occur during both light and deep sleep, slow oscillations are restricted to deep sleep, raising the possibility of greater consolidation-related spindle involvement during deep sleep. We assessed declarative memory retention over an interval containing a nap and determined spindle density for light and deep sleep separately. In deep sleep, spindle density was considerably higher and showed a strong and robust positive correlation with retention. This relation was absent for light sleep, suggesting that the potentiating effects of spindles are tied to their co-occurrence with slow oscillations.

Closed-loop auditory stimulation of sleep slow oscillations: Basic principles and best practices.

Sleep is essential for our physical and mental well-being. During sleep, despite the paucity of overt behavior, our brain remains active and exhibits a wide range of coupled brain oscillations. In particular slow oscillations are characteristic for sleep, however whether they are directly involved in the functions of sleep, or are mere epiphenomena, is not yet fully understood. To disentangle the causality of these relationships, experiments utilizing techniques to detect and manipulate sleep oscillations in real-time are essential. In this review, we first overview the theoretical principles of closed-loop auditory stimulation (CLAS) as a method to study the role of slow oscillations in the functions of sleep. We then describe technical guidelines and best practices to perform CLAS and analyze results from such experiments. We further provide an overview of how CLAS has been used to investigate the causal role of slow oscillations in various sleep functions. We close by discussing important caveats, open questions, and potential topics for future research.

No evidence for a preferential role of sleep in episodic memory abstraction.

Substantial evidence suggests that sleep has a role in declarative memory consolidation. An influential notion holds that such sleep-related memory consolidation is associated with a process of abstraction. The neural underpinnings of this putative process are thought to involve a hippocampo-neocortical dialogue. Specifically, the idea is that, during sleep, the statistical contingencies across episodes are re-coded to a less hippocampus-dependent format, while at the same time losing configural information. Two previous studies from our lab, however, failed to show a preferential role of sleep in either episodic memory decontextualisation or the formation of abstract knowledge across episodic exemplars. Rather these processes occurred over sleep and wake time alike. Here, we present two experiments that replicate and extend these previous studies and exclude some alternative interpretations. The combined data show that sleep has no preferential function in this respect. Rather, hippocampus-dependent memories are generalised to an equal extent across both wake and sleep time. The one point on which sleep outperforms wake is actually the preservation of episodic detail of memories stored prior to sleep.

Sleep spindle dynamics suggest over-consolidation in post-traumatic stress disorder.

Devastating and persisting traumatic memories are a central symptom of post-traumatic stress disorder (PTSD). Sleep problems are highly co-occurrent with PTSD and intertwined with its etiology. Notably, sleep hosts memory consolidation processes, supported by sleep spindles (11-16 Hz). Here we assess the hypothesis that intrusive memory symptoms in PTSD may arise from excessive memory consolidation, reflected in exaggerated spindling. We use a newly developed spindle detection method, entailing minimal assumptions regarding spindle phenotype, to assess spindle activity in PTSD patients and traumatized controls. Our results show increased spindle activity in PTSD, which positively correlates with daytime intrusive memory symptoms. Together, these findings provide a putative mechanism through which the profound sleep disturbance in PTSD may contribute to memory problems. Due to its uniform and unbiased approach, the new, minimal assumption spindle analysis seems a promising tool to detect aberrant spindling in psychiatric disorders.

Shift from hippocampal to neocortical centered retrieval network with consolidation.

The standard model of system-level consolidation posits that the hippocampus is part of a retrieval network for recent memories. According to this theory, the memories are gradually transferred to neocortical circuits with consolidation, where the connections within this circuit grow stronger and reorganized so that redundant and/or contextual details may be lost. Thus, remote memories are based on neocortical networks and can be retrieved independently of the hippocampus. To test this model, we measured regional brain activity and connectivity during retrieval with functional magnetic resonance imaging. Subjects were trained on two sets of face-location association and were tested with two different delays, 15 min and 24 h including a whole night of sleep. We hypothesized that memory traces of the locations associated with specific faces will be linked through the hippocampus for the retrieval of recently learned association, but with consolidation, the activity and the functional connectivity between the neocortical areas will increase. We show that posterior hippocampal activity related to high-confidence retrieval decreased and neocortical activity increased with consolidation. Moreover, the connectivity between the hippocampus and the neocortical regions decreased and in turn, cortico-cortical connectivity between the representational areas increased. The results provide mechanistic support for a two-level process of the declarative memory system, involving initial representation of new associations in a network including the hippocampus and subsequent consolidation into a predominantly neocortical network.

The spectral fingerprint of sleep problems in post-traumatic stress disorder.

STUDY OBJECTIVES: Sleep problems are a core feature of post-traumatic stress disorder (PTSD). The aim of this study was to find a robust objective measure for the sleep disturbance in patients having PTSD. METHODS: The current study assessed EEG power across a wide frequency range and multiple scalp locations, in matched trauma-exposed individuals with and without PTSD, during rapid eye movement (REM) and non-REM (NREM) sleep. In addition, a full polysomnographical evaluation was performed, including sleep staging and assessment of respiratory function, limb movements, and heart rate. The occurrence of sleep disorders was also assessed. RESULTS: In patients having PTSD, NREM sleep shows a substantial loss of slow oscillation power and increased higher frequency activity compared with controls. The change is most pronounced over right-frontal sensors and correlates with insomnia. PTSD REM sleep shows a large power shift in the opposite direction, with increased slow oscillation power over occipital areas, which is strongly related to nightmare activity and to a lesser extent with insomnia. These pronounced spectral changes occur in the context of severe subjective sleep problems, increased occurrence of various sleep disorders and modest changes in sleep macrostructure. CONCLUSIONS: This is the first study to show pronounced changes in EEG spectral topologies during both NREM and REM sleep in PTSD. Importantly, the observed power changes reflect the hallmarks of PTSD sleep problems: insomnia and nightmares and may thus be specific for PTSD. A spectral index derived from these data distinguishes patients from controls with high effect size, bearing promise as a candidate biomarker.

Sleep directly following learning benefits consolidation of spatial associative memory.

The last decade has brought forth convincing evidence for a role of sleep in non-declarative memory. A similar function of sleep in episodic memory is supported by various correlational studies, but direct evidence is limited. Here we show that cued recall of face-location associations is significantly higher following a 12-h retention interval containing sleep than following an equally long period of waking. Furthermore, retention is significantly higher over a 24-h sleep-wake interval than over an equally long wake-sleep interval. This difference occurs because retention during sleep was significantly better when sleep followed learning directly, rather than after a day of waking. These data demonstrate a beneficial effect of sleep on memory that cannot be explained solely as a consequence of reduced interference. Rather, our findings suggest a competitive consolidation process, in which the fate of a memory depends, at least in part, on its relative stability at sleep onset: Strong memories tend to be preserved, while weaker memories erode still further. An important aspect of memory consolidation may thus result from the removal of irrelevant memory "debris."

Overnight worsening of emotional distress indicates maladaptive sleep in insomnia.

STUDY OBJECTIVES: Mechanisms underlying the distress of hyperarousal in people with insomnia remain enigmatic. We investigated whether insomnia impedes the overnight adaptation to emotional distress. METHODS: We induced the distressful self-conscious emotion of shame four times across three consecutive days by exposing 64 participants to their often embarrassingly out-of-tune singing, recorded earlier during a Karaoke session. Perceived physical, emotional, and social distress was assessed with the Experiential Shame Scale. RESULTS: Compared to exposures followed by wakefulness, exposures followed by sleep resulted in overnight relief of physical component of shame in normal sleepers, but in a striking opposite overnight worsening in people with insomnia. CONCLUSIONS: Our findings are the first to experimentally show that the benefits of sleep are not only lost when sleep is poor; people with insomnia experience a maladaptive type of sleep that actually aggravates physically perceived distress. Maladaptive sleep could shed new light on posttraumatic stress disorder (PTSD) and on diurnal mood fluctuation and the counterintuitive favorable effects of sleep deprivation in depression.

Reduced parahippocampal connectivity produces schizophrenia-like memory deficits in simulated neural circuits with reduced parahippocampal connectivity.

CONTEXT: Episodic memory impairments are well characterized in schizophrenia, but their neural origin is unclear. OBJECTIVE: To determine whether the episodic memory impairments in schizophrenia may originate from reduced parahippocampal connectivity. DESIGN: Experimental in silico model. SETTING: Department of Psychology, University of Amsterdam, Amsterdam, the Netherlands. INTERVENTIONS: A new, in silico medial temporal lobe model that simulates normal performance on a variety of episodic memory tasks was devised. The effects of reducing parahippocampal connectivity in the model (from perirhinal and parahippocampal cortex to entorhinal cortex and from entorhinal cortex to hippocampus) were evaluated and compared with findings in schizophrenic patients. Alternative in silico neuropathologies, increased noise and loss of hippocampal neurons, were also evaluated. RESULTS: In the model, parahippocampal processing subserves integration of different cortical inputs to the hippocampus and feature extraction during recall. Reduced connectivity in this area resulted in a pattern of deficits that closely mimicked the impairments in schizophrenia, including a mild recognition impairment and a more severe impairment in free recall. Furthermore, the schizophrenic model was not differentially sensitive to interference, also consistent with behavioral data. Notably, neither increased noise levels nor a reduction of hippocampal nodes in the model reproduced this characteristic memory profile. CONCLUSIONS: Taken together, these findings highlight the importance of parahippocampal neuropathology in schizophrenia, demonstrating that reduced connectivity in this region may underlie episodic memory problems associated with the disorder.

Recall of memory sequences by interaction of the dentate and CA3: a revised model of the phase precession.

Behavioral and electrophysiological evidence indicates that the hippocampus has a special role in the encoding and recall of memory sequences. Importantly, the hippocampal phase precession, a phenomenon recorded as a rat moves through place fields, can be interpreted as cued recall of the sequence of upcoming places. The phase precession can be recorded in all hippocampal regions, but the role of each region has been unclear. Here, we suggest how the dentate and CA3 regions can work together to learn sequences, recall sequences, and generate the phase precession. Our proposal is constrained by information regarding synaptic plasticity rules, network connectivity, timing delays and theta/gamma oscillations.

Generalization from episodic memories across time: a route for semantic knowledge acquisition.

The storage of input regularities, at all levels of processing complexity, is a fundamental property of the nervous system. At high levels of complexity, this may involve the extraction of associative regularities between higher order entities such as objects, concepts and environments across events that are separated in space and time. We propose that such a mechanism provides an important route towards the formation of higher order semantic knowledge. The present study assessed whether subjects were able to extract complex regularities from multiple associative memories and whether they could generalize this regularity knowledge to new items. We used a memory task in which subjects were required to learn face-location associations, but in which certain facial features were predictive of locations. We assessed generalization, as well as memory for arbitrary stimulus components, over a 4-h post-encoding consolidation period containing wakefulness or sleep. We also assessed the stability of regularity knowledge across a period of several weeks thereafter. We found that subjects were able to detect the regularity structure and use it in a generalization task. Interestingly, the performance on this task increased across the 4hr post-learning period. However, no differential effects of cerebral sleep and wake states during this interval were observed. Furthermore, it was found that regularity extraction hampered the storage of arbitrary facial features, resulting in an impoverished memory trace. Finally, across a period of several weeks, memory for the regularity structure appeared very robust whereas memory for arbitrary associations showed steep forgetting. The current findings improve our understanding of how regularities across memories impact memory (trans)formation.

Sound asleep: processing and retention of slow oscillation phase-targeted stimuli.

The sleeping brain retains some residual information processing capacity. Although direct evidence is scarce, a substantial literature suggests the phase of slow oscillations during deep sleep to be an important determinant for stimulus processing. Here, we introduce an algorithm for predicting slow oscillations in real-time. Using this approach to present stimuli directed at both oscillatory up and down states, we show neural stimulus processing depends importantly on the slow oscillation phase. During ensuing wakefulness, however, we did not observe differential brain or behavioral responses to these stimulus categories, suggesting no enduring memories were formed. We speculate that while simpler forms of learning may occur during sleep, neocortically based memories are not readily established during deep sleep.

Time, not sleep, unbinds contexts from item memory.

Contextual cues are known to benefit memory retrieval, but whether and how sleep affects this context effect remains unresolved. We manipulated contextual congruence during memory retrieval in human volunteers across 12 h and 24 h intervals beginning with either sleep or wakefulness. Our data suggest that whereas contextual cues lose their potency with time, sleep does not modulate this process. Furthermore, our results are consistent with the idea that sleep's beneficial effect on memory retention depends on the amount of waking time that has passed between encoding and sleep onset. The findings are discussed in the framework of competitive consolidation theory.