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.

Sleep fragmentation and lucid dreaming.

Lucid dreaming-the phenomenon of experiencing waking levels of self-reflection within one's dreams-is associated with more wake-like levels of neural activation in prefrontal brain regions. In addition, alternating periods of wakefulness and sleep might increase the likelihood of experiencing a lucid dream. Here we investigate the association between sleep fragmentation and lucid dreaming, with a multi-centre study encompassing four different investigations into subjective and objective measures of sleep fragmentation, nocturnal awakenings, sleep quality and polyphasic sleep schedules. Results across these four studies provide a more nuanced picture into the purported connection between sleep fragmentation and lucid dreaming: While self-assessed numbers of awakenings, polyphasic sleep and physiologically validated wake-REM sleep transitions were associated with lucid dreaming, neither self-assessed sleep quality, nor physiologically validated numbers of awakenings were. We discuss these results, and their underlying neural mechanisms, within the general question of whether sleep fragmentation and lucid dreaming share a causal link.

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.

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.

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.

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.

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.

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.

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.

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.

Sleeping worries away or worrying away sleep? Physiological evidence on sleep-emotion interactions.

Recent findings suggest that sleep might serve a role in emotional coping. However, most findings are based on subjective reports of sleep quality, while the relation with underlying sleep physiology is still largely unknown. In this study, the impact of an emotionally distressing experience on the EEG correlates of sleep was assessed. In addition, the association between sleep physiological parameters and the extent of emotional attenuation over sleep was determined. The experimental set up involved presentation of an emotionally neutral or distressing film fragment in the evening, followed by polysomnographic registration of undisturbed, whole-night sleep and assessment of emotional reactivity to film cues on the next evening. We found that emotional distress induced mild sleep deterioration, but also an increase in the proportion of slow wave sleep (SWS) and altered patterning of rapid eye movement (REM) sleep. Indeed, while REM sleep occurrence normally increases over the course of the night, emotional distress flattened this distribution and correlated with an increased number of REM periods. While sleep deterioration was negatively associated to emotional attenuation over sleep, the SWS response was positively related to such attenuation and may form part of a compensatory response to the stressor. Interestingly, trait-like SWS characteristics also correlated positively with the extent of emotion attenuation over sleep. The combined results provide strong evidence for an intimate reciprocal relation between sleep physiology and emotional processing. Moreover, individual differences in subjects' emotional and sleep responses suggest there may be a coupling of certain emotion and sleep traits into distinct emotional sleep types.

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.

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.

Facilitation of memory by contextual cues in patients with diencephalic or medial temporal lobe dysfunction.

Item-context binding is crucial for successful episodic memory formation, and binding deficits have been suggested to underlie episodic-memory deficits. Here, our research investigated the facilitation of cued recall and recognition memory by contextual cues in 20 patients with Korsakoff's amnesia, 20 unilateral medial-temporal lobectomy (MTL) patients and 36 healthy controls. In a computerized task participants had to learn 40 nouns that were randomly combined with a photograph of an everyday scene. Korsakoff patients showed a general memory deficit in both the cued recall and the recognition condition. A less severe memory impairment was found in the patients with medial-temporal lobectomy. Contextual cues facilitated cued recall to an equal extent in unilateral temporal lobectomy patients and healthy controls. However, no facilitation was observed in Korsakoff patients, suggesting an impairment in item-context binding during cued recall tasks. In contrast to the presumed exclusive dependency of recognition memory on item information, all groups equally profited from the contextual cues in recognition tasks. Our findings show that unilateral lesions as with MTL result in normal binding of context and item information, while bilateral dysfunction of the hippocampal-diencephalic system results in impaired context and item binding.