Cortical hyperarousal in individuals with frequent nightmares.

Nightmares are common among the general population and psychiatric patients and have been associated with signs of nocturnal arousal such as increased heart rate or increased high-frequency electroencephalographic (EEG) activity. However, it is still unclear, whether these characteristics are more of a trait occurring in people with frequent nightmares or rather indicators of the nightmare state. We compared participants with frequent nightmares (NM group; n = 30) and healthy controls (controls; n = 27) who spent 4 nights in the sleep laboratory over the course of 8 weeks. The NM group received six sessions of imagery rehearsal therapy (IRT), the 'gold standard' of cognitive-behavioural therapy for nightmares, between the second and the third night. Sleep architecture and spectral power were compared between groups, and between nights of nightmare occurrence and nights without nightmare occurrence in the NM group. Additionally, changes before and after therapy were recorded. The NM group showed increased beta (16.25-31 Hz) and low gamma (31.25-35 Hz) power during the entire night compared to the controls, but not when comparing nights of nightmare occurrence to those without. Moreover, low gamma activity in rapid eye movement sleep was reduced after therapy in the NM group. Our findings indicate, cortical hyperarousal is more of a trait in people with frequent nightmares within a network of other symptoms, but also malleable by therapy. This is not only a new finding for IRT but could also lead to improved treatment options in the future that directly target high-frequency EEG activity.

To sleep or not to sleep, that is the question: A systematic review and meta-analysis on the effect of post-trauma sleep on intrusive memories of analog trauma.

Distressing intrusive memories of a traumatic event are one of the hallmark symptoms of posttraumatic stress disorder. Thus, it is crucial to identify early interventions that prevent the occurrence of intrusive memories. Both, sleep and sleep deprivation have been discussed as such interventions, yet previous studies yielded contradicting effects. Our systematic review aims at evaluating existing evidence by means of traditional and individual participant data (IPD) meta-analyses to overcome power issues of sleep research. Until May 16th, 2022, six databases were searched for experimental analog studies examining the effect of post-trauma sleep versus wakefulness on intrusive memories. Nine studies were included in our traditional meta-analysis (8 in the IPD meta-analysis). Our analysis provided evidence for a small effect favoring sleep over wakefulness, log-ROM = 0.25, p < .001, suggesting that sleep is associated with a lower number of intrusions but unrelated to the occurrence of any versus no intrusions. We found no evidence for an effect of sleep on intrusion distress. Heterogeneity was low and certainty of evidence for our primary analysis was moderate. Our findings suggest that post-trauma sleep has the potential to be protective by reducing intrusion frequency. More research is needed to determine the impact following real-world trauma and the potential clinical significance.

The circadian neurobiology of reward.

Circadian clocks are important regulators of physiology and behavior. In the brain, circadian clocks have been described in many centers of the central reward system. They affect neurotransmitter signaling, neuroendocrine circuits, and the sensitivity to external stimulation. Circadian disruption affects reward signaling, promoting the development of behavioral and substance use disorders. In this review, we summarize our current knowledge of circadian clock-reward crosstalk. We show how chronodisruption affects reward signaling in different animal models. We then translate these findings to circadian aspects of human reward (dys-) function and its clinical implications. Finally, we devise approaches to and challenges in implementing the concepts of circadian medicine in the therapy of substance use disorders.

Sleep's role in updating aversive autobiographical memories.

Aversive autobiographical memories play a key role in the development and maintenance of many mental disorders. Imagery rescripting is a well-established psychotherapeutic intervention aiming to create a more adaptive version of an aversive memory by modifying its interpretation. Sleep has been shown to support reconsolidation of updated neutral memories. Here, we investigated in healthy participants whether a 90-min nap compared to wake supports the adaptive reconsolidation of autobiographical memories. Forty-four university students received a single 50-min imagery rescripting session. Thereafter, half of the participants took a 90-min nap, whereas the other half stayed awake. Subjective (arousal ratings, reports of emotions and dysfunctional cognitions) and heart rate (HR) responses to individual memory scripts were measured before the intervention (pre), after the 90-min retention interval (post 1) and 7 days later (post 2). Results demonstrate a significant decrease in distress of aversive memories pre to post imagery rescripting. The nap group showed less distressing dysfunctional cognitions along with a lower HR in response to the negative memory script as compared to the wake group at post 1. These differences were no longer evident 1 week later (post 2). Central sleep spindle density during the nap was correlated with the reduction in HR in response to the negative memory script from pre to post 1. Our results provide first evidence for sleep benefitting adaptive reconsolidation of aversive autobiographical memories. Future research should expand this approach to clinical populations and investigate precise conditions under which sleep may benefit psychotherapeutic interventions utilizing reconsolidation mechanisms.

Investigating the effect of a nap following experimental trauma on analogue PTSD symptoms.

Cognitive models assume that the incomplete integration of a traumatic experience into the autobiographical memory results in typical symptoms associated with post-traumatic stress disorder (PTSD) such as intrusive re-experiencing. Sleep supports the integration of new experiences into existing memory networks through memory consolidation. In fifty-six females, we investigated whether a 90-min daytime nap (n = 33) compared to a wake period (n = 23) after being exposed to an experimental trauma (i.e. a trauma film) prevents PTSD analogue symptoms. Intrusive memories were recorded for seven days using a diary, overall PTSD symptoms were assessed using the Impact of Event Scale (IES-R) and affective response to trauma cues were measured one week after experimental trauma. The two groups did not differ in any of the analogue PTSD symptoms. However, participants obtaining rapid eye movement (REM) sleep in the nap experienced less distressing intrusive memories. Moreover, the duration of REM sleep and slow wave activity was negatively correlated with analogue PTSD symptoms. Our findings suggest that even a short sleep period after experimental trauma can play a protective role in trauma memory formation but only if the nap contains REM sleep. Our data provide additional evidence for a critical role of REM sleep in PTSD development.

Sleep-dependent memory consolidation in children with self-limited focal epilepsies.

OBJECTIVE: Children with self-limited focal epilepsies of childhood (SLFE) are known to show impaired memory functions, particularly in the verbal domain. Interictal epileptiform discharges (IED) in these epilepsies are more pronounced in nonrapid eye movement (NREM) sleep. Nonrapid eye movement sleep is crucial for consolidation of newly-encoded memories. Therefore, we hypothesize that sleep-dependent memory consolidation is altered in relation to IED in children with SLFE. METHODS: We conducted a prospective case-control study. We applied a verbal (word pair) and a visuospatial (two-dimensional [2D] object location) learning task, both previously shown to benefit from sleep in terms of memory consolidation. Learning took place in the evening, and retrieval was tested in the morning after a night of sleep. Electroencephalogram (EEG) was recorded across night. After sleep-stage scoring, the spike-wave index (SWI) was assessed at the beginning and the end of sleep. Fourteen patients with SLFE (age: 5.5 to 11.6 years) were compared with 15 healthy controls (age: 6.8 to 9.1 years) examined in a previous study. RESULTS: In contrast to healthy controls (mean: +12.9% recalled word pairs, p = .003, standard deviation (SD) = 12.4%), patients did not show overnight performance gains in the verbal memory task (mean: +6.4% recalled word pairs, p > .05, SD = 17.3) Neither patients nor controls showed significant overnight changes in visuospatial task performance. Spike-wave index was negatively correlated with recall performance in the verbal but not in the visuospatial task. SIGNIFICANCE: We found evidence for impaired overnight improvement of performance in children with SLFE in a verbal learning task, with high SWI rates predicting low recall performance. We speculate that spike-waves hamper long-term memory consolidation by interfering with NREM sleep.

Selective suppression of rapid eye movement sleep increases next-day negative affect and amygdala responses to social exclusion.

Healthy sleep, positive general affect, and the ability to regulate emotional experiences are fundamental for well-being. In contrast, various mental disorders are associated with altered rapid eye movement (REM) sleep, negative affect, and diminished emotion regulation abilities. However, the neural processes mediating the relationship between these different phenomena are still not fully understood. In the present study of 42 healthy volunteers, we investigated the effects of selective REM sleep suppression (REMS) on general affect, as well as on feelings of social exclusion, cognitive reappraisal (CRA) of emotions, and their neural underpinnings. Using functional magnetic resonance imaging we show that, on the morning following sleep suppression, REMS increases general negative affect, enhances amygdala responses and alters its functional connectivity with anterior cingulate cortex during passively experienced experimental social exclusion. However, we did not find effects of REMS on subjective emotional ratings in response to social exclusion, their regulation using CRA, nor on functional amygdala connectivity while participants employed CRA. Our study supports the notion that REM sleep is important for affective processes, but emphasizes the need for future research to systematically investigate how REMS impacts different domains of affective experience and their neural correlates, in both healthy and (sub-)clinical populations.

No effect of targeted memory reactivation during sleep on retention of vocabulary in adolescents.

Re-exposure of newly acquired vocabulary during sleep improves later memory recall in healthy adults. The success of targeted memory reactivation (TMR) during sleep presumably depends on the presence of slow oscillations (i.e., EEG activity at a frequency of about 0.75 Hz). As slow oscillating activity is at its maximum during adolescence, we hypothesized that TMR is even more beneficial at this developmental stage. In the present study, adolescents aged 11 to 13 learnt Dutch vocabulary in the evening and were tested on recall performance the next morning. Half of the words were presented via loudspeakers during post-learning periods of NREM (Non Rapid Eye Movement) sleep in order to stimulate memory reactivation. Unexpectedly, TMR during sleep did not improve memory on the behavioral level in adolescents. On the oscillatory level, successful reactivation during sleep resulted in the characteristic increase in theta power over frontal brain regions, as reported in adults. However, we observed no increase in spindle power during successful reactivation. Possible factors that may explain the lacking effect of TMR in adolescents in this study such as differences in learning abilities and pre-sleep performance levels are discussed.

The Sleeping Infant Brain Anticipates Development.

From the age of 3 months, infants learn relations between objects and co-occurring words [1]. These very first representations of object-word pairings in infant memory are considered as non-symbolic proto-words comprising specific visual-auditory associations that can already be formed in the first months of life [2-5]. Genuine words that refer to semantic long-term memory have not been evidenced prior to 9 months of age [6-9]. Sleep is known to facilitate the reorganization of memories [9-14], but its impact on the perceptual-to-semantic trend in early development is unknown. Here we explored the formation of word meanings in 6- to 8-month-old infants and its reorganization during the course of sleep. Infants were exposed to new words as labels for new object categories. In the memory test about an hour later, generalization to novel category exemplars was tested. In infants who took a short nap during the retention period, a brain response of 3-month-olds [1] was observed, indicating generalizations based on early developing perceptual-associative memory. In those infants who napped longer, a semantic priming effect [15, 16] usually found later in development [17-19] revealed the formation of genuine words. The perceptual-to-semantic shift in memory was related to the duration of sleep stage 2 and to locally increased sleep spindle activity. The finding that, after the massed presentation of several labeled category exemplars, sleep enabled even 6-month-olds to create semantic long-term memory clearly challenges the notion that immature brain structures are responsible for the typically slower lexical development.

Intranasal insulin decreases circulating cortisol concentrations during early sleep in elderly humans.

Aging is associated with increases in hypothalamic-pituitary-adrenal (HPA) axis activity that can predispose to metabolic and cognitive impairments. We investigated in elderly and young subjects whether intranasal insulin administration to the human brain reduces early-sleep nadir concentrations of adrenocorticotropin and cortisol, that is, indicators of baseline HPA axis activity. In within-subject comparisons, intranasal insulin (160 IU) or placebo was administered to 14 elderly (mean age 70.0 years) and 30 young (23.6 years) healthy subjects before bedtime. Sleep was polysomnographically assessed and blood samples were repeatedly collected. Elderly compared with young participants displayed increased early-sleep cortisol concentrations (p < 0.04) and reductions in slow wave and REM sleep (p < 0.001). Insulin administration reduced cortisol levels between 2300 hours and 0020 hours in the elderly (p = 0.03) but not young participants (p = 0.56; p = 0.003 for interaction). Findings indicate that central nervous insulin acts as an inhibitory signal in basal HPA axis activity regulation and suggest that intranasal insulin may normalize sleep-associated stress axis activity in older age.

Targeted Reactivation during Sleep Differentially Affects Negative Memories in Socially Anxious and Healthy Children and Adolescents.

Cognitive models propose a negative memory bias as one key factor contributing to the emergence and maintenance of social anxiety disorder (SAD). The long-term consolidation of memories relies on memory reactivations during sleep. We investigated in SAD patients and healthy controls the role of memory reactivations during sleep in the long-term consolidation of positive and negative information. Socially anxious and healthy children and adolescents learnt associations between pictures showing ambiguous situations and positive or negative words defining the situations' outcome. Half of the words were re-presented during postlearning sleep (i.e., they were cued). Recall of picture-word associations and subjective ratings of pleasantness and arousal in response to the pictures was tested for cued and uncued stimuli. In the morning after cueing, cueing facilitated retention of positive and negative memories equally well in SAD patients and healthy controls. One week later, cueing led to reduced ratings of pleasantness of negative information in SAD but not in healthy controls. Coincidental to these findings was more pronounced EEG theta activity over frontal, temporal and parietal regions in response to negative stimuli in SAD patients. Our findings suggest that the preferential abstraction of negative emotional information during sleep might represent one factor underlying the negative memory bias in SAD.SIGNIFICANCE STATEMENT We aim to uncover mechanisms underlying the characteristic negative memory bias in social anxiety disorder (SAD). The formation of long-lasting memories-a process referred to as memory consolidation-depends on the reactivation of newly acquired memories during sleep. We demonstrated that experimentally induced memory reactivation during sleep renders long-term memories of negative experiences more negative in SAD patients but not in healthy controls. We also found in SAD patients that the reactivation of negative experiences coincided with more pronounced oscillatory theta activity. These results provide first evidence that memory reactivation during sleep might contribute to the negative memory bias in SAD.

Widespread reduction in sleep spindle activity in socially anxious children and adolescents.

Social anxiety disorder (SAD) is one of the most prevalent psychiatric diseases typically emerging during childhood and adolescence. Biological vulnerabilities such as a protracted maturation of prefrontal cortex functioning together with heightened reactivity of the limbic system leading to increased emotional reactivity are discussed as factors contributing to the emergence and maintenance of SAD. Sleep slow wave activity (SWA, 0.75-4.5 Hz) and sleep spindle activity (9-16 Hz) reflect processes of brain maturation and emotion regulation. We used high-density electroencephalography to characterize sleep SWA and spindle activity and their relationship to emotional reactivity in children and adolescents suffering from SAD and healthy controls (HC). Subjectively rated arousal was assessed using an emotional picture-word association task. SWA did not differ between socially anxious and healthy participants. We found a widespread reduction in fast spindle activity (13-16 Hz) in SAD patients compared to HC. SAD patients rated negative stimuli to be more arousing and these arousal ratings were negatively correlated with fast spindle activity. These results suggest electrophysiological alterations that are evident at an early stage of psychopathology and that are closely linked to one core symptom of anxiety disorders such as increased emotional reactivity. The role of disturbed GABAergic neurotransmission is discussed as an underlying factor.

Prior knowledge is essential for the beneficial effect of targeted memory reactivation during sleep.

Prior knowledge speeds up system consolidation and accelerates integration of newly acquired memories into existing neocortical knowledge networks. By using targeted memory reactivations, we demonstrate that prior knowledge is also essential for successful reactivation and consolidation of memories during sleep, both on the behavioral and oscillatory level (i.e., theta and fast spindle activity). Thus, prior knowledge is a prerequisite for new memories to enter processes of system consolidation during sleep.

Children's initial sleep-associated changes in motor skill are unrelated to long-term skill levels.

Sleep is considered to support the formation of skill memory. In juvenile but not adult song birds learning a tutor's song, a stronger initial deterioration of song performance over night-sleep predicts better song performance in the long run. This and similar observations have stimulated the view of sleep supporting skill formation during development in an unsupervised off-line learning process that, in the absence of external feedback, can initially also enhance inaccuracies in skill performance. Here we explored whether in children learning a motor sequence task, as in song-learning juvenile birds, changes across sleep after initial practice predict performance levels achieved in the long run. The task was a serial reaction time task (SRTT) where subjects had to press buttons which were lighted up in a repeating eight-element sequence as fast as possible. Twenty-five children (8-12 years) practised the task in the evening before nocturnal sleep which was recorded polysomnographically. Retrieval was tested on the following morning and again 1 week later after daily training on the SRTT. As expected, changes in response speed over the initial night of sleep were negatively correlated with final performance speed after the 1-week training. However, unlike in song birds, this correlation was driven by the baseline speed level achieved before sleep. Baseline-corrected changes in speed or variability over the initial sleep period did not predict final performance on the trained SRTT sequence, or on different sequences introduced to assess generalization of the trained behaviour. The lack of correlation between initial sleep-dependent changes and long-term performance might reflect that the children were too experienced for the simple SRTT, possibly also favouring ceiling effects in performance. A consistent association found between sleep spindle activity and explicit sequence knowledge alternatively suggests that the expected correlation was masked by explicit memory systems interacting with skill memory formation.

Memory cueing during sleep modifies the interpretation of ambiguous scenes in adolescents and adults.

The individual tendency to interpret ambiguous situations negatively is associated with mental disorders. Interpretation biases are already evident during adolescence and due to the greater plasticity of the developing brain it may be easier to change biases during this time. We investigated in healthy adolescents and adults whether stabilizing memories of positive or negative scenes modulates the later interpretation of similar scenes. In the evening, participants learnt associations between ambiguous pictures and words that disambiguate the valence of the pictures in a positive or negative direction. Half of the words were acoustically presented (i.e. cued) during post-learning sleep which is known to benefit memory consolidation by inducing reactivation of learned information. Cued compared to un-cued stimuli were remembered better the next morning. Importantly, cueing positively disambiguated pictures resulted in more positive interpretations whereas cueing negatively disambiguated pictures led to less positive interpretations of new ambiguous pictures with similar contents the next morning. These effects were not modulated by participants' age indicating that memory cueing was as efficient in adolescents as in adults. Our findings suggest that memory cueing during sleep can modify interpretation biases by benefitting memory stabilization and generalization. Implications for clinical settings are discussed.

Generalization of word meanings during infant sleep.

Sleep consolidates memory and promotes generalization in adults, but it is still unknown to what extent the rapidly growing infant memory benefits from sleep. Here we show that during sleep the infant brain reorganizes recent memories and creates semantic knowledge from individual episodic experiences. Infants aged between 9 and 16 months were given the opportunity to encode both objects as specific word meanings and categories as general word meanings. Event-related potentials indicate that, initially, infants acquire only the specific but not the general word meanings. About 1.5 h later, infants who napped during the retention period, but not infants who stayed awake, remember the specific word meanings and, moreover, successfully generalize words to novel category exemplars. Independently of age, the semantic generalization effect is correlated with sleep spindle activity during the nap, suggesting that sleep spindles are involved in infant sleep-dependent brain plasticity.

Sleep slow-wave activity reveals developmental changes in experience-dependent plasticity.

Experience-dependent plasticity, the ability of the brain to constantly adapt to an ever-changing environment, has been suggested to be highest during childhood and to decline thereafter. However, empirical evidence for this is rather scarce. Slow-wave activity (SWA; EEG activity of 1-4.5 Hz) during deep sleep can be used as a marker of experience-dependent plasticity. For example, performing a visuomotor adaptation task in adults increased SWA during subsequent sleep over a locally restricted region of the right parietal cortex, which is known to be involved in visuomotor adaptation. Here, we investigated whether local experience-dependent changes in SWA vary as a function of brain maturation. Three age groups (children, adolescents, and adults) participated in a high-density EEG study with two conditions (baseline and adaptation) of a visuomotor learning task. Compared with the baseline condition, sleep SWA was increased after visuomotor adaptation in a cluster of eight electrodes over the right parietal cortex. The local boost in SWA was highest in children. Baseline SWA in the parietal cluster and right parietal gray matter volume, which both indicate region-specific maturation, were significantly correlated with the local increase in SWA. Our findings indicate that processes of brain maturation favor experience-dependent plasticity and determine how sensitive a specific brain region is for learning experiences. Moreover, our data confirm that SWA is a highly sensitive tool to map maturational differences in experience-dependent plasticity.

Transcranial oscillatory direct current stimulation during sleep improves declarative memory consolidation in children with attention-deficit/hyperactivity disorder to a level comparable to healthy controls.

BACKGROUND: Slow oscillations (<1 Hz) during slow wave sleep (SWS) promote the consolidation of declarative memory. Children with attention-deficit/hyperactivity disorder (ADHD) have been shown to display deficits in sleep-dependent consolidation of declarative memory supposedly due to dysfunctional slow brain rhythms during SWS. OBJECTIVE: Using transcranial oscillating direct current stimulation (toDCS) at 0.75 Hz, we investigated whether an externally triggered increase in slow oscillations during early SWS elevates memory performance in children with ADHD. METHODS: 12 children with ADHD underwent a toDCS and a sham condition in a double-blind crossover study design conducted in a sleep laboratory. Memory was tested using a 2D object-location task. In addition, 12 healthy children performed the same memory task in their home environment. RESULTS: Stimulation enhanced slow oscillation power in children with ADHD and boosted memory performance to the same level as in healthy children. CONCLUSION: These data indicate that increasing slow oscillation power during sleep by toDCS can alleviate declarative memory deficits in children with ADHD.

Sleep improves prospective remembering by facilitating spontaneous-associative retrieval processes.

Memories are of the past but for the future, enabling individuals to implement intended plans and actions at the appropriate time. Prospective memory is the specific ability to remember and execute an intended behavior at some designated point in the future. Although sleep is well-known to benefit the consolidation of memories for past events, its role for prospective memory is still not well understood. Here, we show that sleep as compared to wakefulness after prospective memory instruction enhanced the successful execution of prospective memories two days later. We further show that sleep benefited both components of prospective memory, i.e. to remember that something has to be done (prospective component) and to remember what has to be done (retrospective component). Finally, sleep enhanced prospective remembering particularly when attentional resources were reduced during task execution, suggesting that subjects after sleep were able to recruit additional spontaneous-associative retrieval processes to remember intentions successfully. Our findings indicate that sleep supports the maintenance of prospective memory over time by strengthening intentional memory representations, thus favoring the spontaneous retrieval of the intended action at the appropriate time.

Slow wave sleep induced by GABA agonist tiagabine fails to benefit memory consolidation.

STUDY OBJECTIVES: Slow wave sleep (SWS) plays a pivotal role in consolidating memories. Tiagabine has been shown to increase SWS in favor of REM sleep without impacting subjective sleep. However, it is unknown whether this effect is paralleled by an improved sleep-dependent consolidation of memory. DESIGN: This double-blind within-subject crossover study tested sensitivity of overnight retention of declarative neutral and emotional materials (word pairs, pictures) as well as a procedural memory task (sequence finger tapping) to oral administration of placebo or 10 mg tiagabine (at 22:30). PARTICIPANTS: Fourteen healthy young men aged 21.9 years (range 18-28 years). MEASUREMENTS AND RESULTS: Tiagabine significantly increased the time spent in SWS and decreased REM sleep compared to placebo. Tiagabine also enhanced slow wave activity (0.5-4.0 Hz) and density of < 1 Hz slow oscillations during NREM sleep. Fast (12-15 Hz) and slow (9-12 Hz) spindle activity, in particular that occurring phase-locked to the slow oscillation cycle, was decreased following tiagabine. Despite signs of deeper and more SWS, overnight retention of memory tested after sleep the next evening (19:30) was generally not improved after tiagabine, but on average even lower than after placebo, with this impairing effect reaching significance for procedural sequence finger tapping. CONCLUSIONS: Our data show that increasing slow wave sleep with tiagabine does not improve memory consolidation. Possibly this is due to functional differences from normal slow wave sleep, i.e., the concurrent suppressive influence of tiagabine on phase-locked spindle activity.