Impaired memory consolidation during sleep in patients with functional memory disorder

Functional memory disorder (FMD) is characterized by mnestic and attentional deficits without symptoms of mild cognitive impairment or dementia. FMD usually develops in subjects with high psychosocial stress level and is classified to the somatoform disorders. We assessed memory performance (procedural mirror tracing task, declarative visual and verbal memory task) and other cognitive functions before and after one night of sleep in 12 FMD patients (mean age: 51.7 yrs, 7 females) and 12 healthy subjects matched for age, gender and IQ. Memory performance and other neurocognitive tasks did not differ between the groups at baseline. After one night of sleep, FMD patients showed an impairment of declarative memory consolidation compared to healthy subjects (visual task: p = 0.004; verbal task: p = 0.039). Spectral analysis of sleep-EEG indicated an increased cortical excitation in FMD. We hypothesize that a hyperarousal state in FMD might contribute to sleep disturbance implicating negative effects on declarative memory consolidation.     

The effect of daytime napping and full‐night sleep on the consolidation of declarative and procedural information

Many studies investigating sleep and memory consolidation have evaluated full‐night sleep rather than alternative sleep periods such as daytime naps. This multi‐centre study followed up on, and was compared with, an earlier full‐night study (Schabus et al., 2004) investigating the relevance of daytime naps for the consolidation of declarative and procedural memory. Seventy‐six participants were randomly assigned to a nap or wake group, and performed a declarative word‐pair association or procedural mirror‐tracing task. Performance changes from before to after a 90‐min retention interval filled with sleep or quiet wakefulness were evaluated between groups. Associations between performance changes, sleep architecture, spindles, and slow oscillations were investigated. For the declarative task we observed a trend towards stronger forgetting across a wake period compared with a nap period, and a trend towards memory increase over the full‐night. For the procedural task, accuracy was significantly decreased following daytime wakefulness, showed a trend to increase with a daytime nap, and significantly increased across full‐night sleep. For the nap protocol, neither sleep stages, spindles, nor slow oscillations predicted performance changes. A direct comparison of day and nighttime sleep revealed that daytime naps are characterized by significantly lower spindle density, but higher spindle activity and amplitude compared with full‐night sleep. In summary, data indicate that daytime naps protect procedural memories from deterioration, whereas full‐night sleep improves performance. Given behavioural and physiological differences between day and nighttime sleep, future studies should try to characterize potential differential effects of full‐night and daytime sleep with regard to sleep‐dependent memory consolidation.     

Hippocampal and medial prefrontal cortical volume is associated with overnight declarative memory consolidation independent of specific sleep oscillations

The current study was designed to further clarify the influence of brain morphology, sleep oscillatory activity and age on memory consolidation. Specifically, we hypothesized, that a smaller volume of hippocampus, parahippocampal and medial prefrontal cortex negatively impacts declarative, but not procedural, memory consolidation. Explorative analyses were conducted to demonstrate whether a decrease in slow‐wave activity negatively impacts declarative memory consolidation, and whether these factors mediate age effects on memory consolidation. Thirty‐eight healthy participants underwent an acquisition session in the evening and a retrieval session in the morning after night‐time sleep with polysomnographic monitoring. Declarative memory was assessed with the paired‐associate word list task, while procedural memory was tested using the mirror‐tracing task. All participants underwent high‐resolution magnetic resonance imaging. Participants with smaller hippocampal, parahippocampal and medial prefrontal cortex volumes displayed a reduced overnight declarative, but not procedural memory consolidation. Mediation analyses showed significant age effects on overnight declarative memory consolidation, but no significant mediation effects of brain morphology on this association. Further mediation analyses showed that the effects of age and brain morphology on overnight declarative memory consolidation were not mediated by polysomnographic variables or sleep electroencephalogram spectral power variables. Thus, the results suggest that the association between age, specific brain area volume and overnight memory consolidation is highly relevant, but does not necessarily depend on slow‐wave sleep as previously conceptualized.     

Offline consolidation of procedural skill learning is enhanced by negative emotional content

It is now well established that both procedural skills and episodic memories consolidate across periods of offline retention, and most particularly across periods of sleep. Such consolidation has been demonstrated to be more marked for emotional than for neutral episodes, but the interaction between emotionality and the offline consolidation of procedural skills has yet to be investigated. Here, we address this issue by examining the impact of an emotional background context at encoding upon the subsequent consolidation of mirror tracing, a well-studied procedural skill. We also consider the importance of sleep for such consolidation by manipulating the retention interval (over a day, overnight, or over 24 h containing normal sleep). Our data show significantly greater offline improvements in the accuracy of mirror tracing when negative emotional content is present during the training phase when compared to when neutral or positive content is present. Furthermore, consolidation across a night of sleep is associated with faster and more accurate performance than consolidation across a day of wakefulness. These novel findings show that the emotional context in which a procedural skill is learned can impact upon subsequent offline consolidation.     

Phase‐amplitude coupling of sleep slow oscillatory and spindle activity correlates with overnight memory consolidation

Initially independent lines of research suggest that sleep‐specific brain activity patterns, observed as electroencephalographic slow oscillatory and sleep spindle activity, promote memory consolidation and underlying synaptic refinements. Here, we further tested the emerging concept that specifically the coordinated interplay of slow oscillations and spindle activity (phase‐amplitude coupling) support memory consolidation. Particularly, we associated indices of the interplay between slow oscillatory (0.16–1.25 Hz) and spindle activity (12–16 Hz) during non‐rapid eye movement sleep (strength [modulation index] and phase degree of coupling) in 20 healthy adults with parameters of overnight declarative (word‐list task) and procedural (mirror‐tracing task) memory consolidation. The pattern of results supports the notion that the interplay between oscillations facilitates memory consolidation. The coincidence of the spindle amplitude maximum with the up‐state of the slow oscillation (phase degree) was significantly associated with declarative memory consolidation (r = .65, p = .013), whereas the overall strength of coupling (modulation index) correlated with procedural memory consolidation (r = .45, p = .04). Future studies are needed to test for potential causal effects of the observed association between neural oscillations during sleep and memory consolidation, and to elucidate ways of modulating these processes, for instance through non‐invasive brain‐stimulation techniques.     

Sleep-related attentional bias in patients with primary insomnia compared with sleep experts and healthy controls

Sleep-related attentional bias has been proposed to be an important factor in the development and maintenance of primary insomnia. In this study, a newly introduced mixed modality (visual auditory) task and an emotional Stroop task were used to investigate attentional processes in patients with primary insomnia, sleep experts and healthy controls (n = 20 per group). The sleep expert group served as second control group to control for effects of frequency of concept usage (FOCU). The results of the emotional Stroop task showed a sleep-related attentional bias in the insomnia group in comparison with the expert group. However, no significant differences were detected in the other group comparisons and in the mixed modality task. The difference between insomnia patients and sleep experts in the emotional Stroop task indicates that FOCU is not the underlying process of sleep-related attentional bias. Insomnia patients seem to be more emotionally, cognitively or procedurally affected by sleep-related stimuli than sleep experts. The findings suggest that a desensitization of sleep-related stimuli might be used therapeutically, thus extending the current cognitive behavioral treatments for primary insomnia.     

Schlaf, Plastizität und Gedächtnis

A compelling line of evidence – from the molecular to the behavioural level – indicates that healthy sleep facilitates neural plasticity and related declarative and procedural memory consolidation. This review provides an overview of the current basic research and clinical findings. Emerging insights into the interplay between sleep and memory have the potential to be informative for fundamental processes of brain plasticity. From a clinical perspective, new findings of disrupted sleep-related memory under conditions of disturbed sleep, such as in primary insomnia or many mental illnesses, may contribute to a more complete understanding of the disorders. The long-term goal of this research includes recommendations on healthy behavioural patterns and the development of novel interventional strategies for patients with disturbed sleep or reduced memory function.     

Sleep loss affects vigilance: effects of chronic insomnia and sleep therapy

Although complaints of impaired daytime functioning are essential to the diagnosis of primary insomnia, objective evidence for cognitive dysfunction has been hard to establish. A prerequisite for understanding the neurocognitive consequences of primary insomnia is to establish task paradigms that robustly differentiate insomniacs from well-sleeping subjects. We hypothesized that the decline in performance that typically occurs with an increasing cognitive demand would provide a more sensitive measure than performance on a single task version. The hypothesis was tested, first, by assessing the performance on two vigilance tasks with different cognitive demands in 25 elderly patients with primary insomnia and 13 healthy well-sleeping age-matched subjects. Secondly, we investigated the performance response to sleep therapy using a waiting-list controlled design. Sleep therapy consisted of a multi-component intervention including sleep restriction, cognitive behavioral therapy, bright-light therapy, structured physical activity and body temperature manipulations. The results show that insomniacs differed markedly from controls in their reaction times across tasks with different cognitive demands: patients responded faster on the 'simple' vigilance task, yet slower on the 'complex' vigilance task. Sleep therapy effectively restored normal performance: patients became significantly slower on the 'simple' task and faster on the 'complex' task, returning to the performance levels of control subjects. These findings indicate that the performance decline associated with increasing cognitive demands is possibly the first sensitive and robust measure of the neurocognitive sequelae of insomnia. We suggest that future studies on cognition in primary insomnia should apply a design that varies task demands.     

EEG sigma and slow‐wave activity during NREM sleep correlate with overnight declarative and procedural memory consolidation

Previous studies suggest that sleep‐specific brain activity patterns such as sleep spindles and electroencephalographic slow‐wave activity contribute to the consolidation of novel memories. The generation of both sleep spindles and slow‐wave activity relies on synchronized oscillations in a thalamo‐cortical network that might be implicated in synaptic strengthening (spindles) and downscaling (slow‐wave activity) during sleep. This study further examined the association between electroencephalographic power during non‐rapid eye movement sleep in the spindle (sigma, 12–16 Hz) and slow‐wave frequency range (0.1–3.5 Hz) and overnight memory consolidation in 20 healthy subjects (10 men, 27.1 ± 4.6 years). We found that both electroencephalographic sigma power and slow‐wave activity were positively correlated with the pre–post‐sleep consolidation of declarative (word list) and procedural (mirror‐tracing) memories. These results, although only correlative in nature, are consistent with the view that processes of synaptic strengthening (sleep spindles) and synaptic downscaling (slow‐wave activity) might act in concert to promote synaptic plasticity and the consolidation of both declarative and procedural memories during sleep.     

Long-term nightly treatment with indiplon in adults with primary insomnia: results of a double-blind, placebo-controlled, 3-month study

OBJECTIVES: To evaluate the efficacy and safety of indiplon in primary insomnia. DESIGN: Randomized, double-blind, placebo-controlled, 3-month study. SETTING: Multi-center outpatient setting. PATIENTS: N=702 (61% female; mean age 46 years) who met DSM-IV criteria for primary insomnia of at least 3 months' duration. Interventions: Indiplon 10 mg (n=236), indiplon 20 mg (n=233), or placebo (n=233). MEASUREMENTS: Subjective assessment of each of the following: latency to sleep onset (sLSO), total sleep time (sTST), number of awakenings after sleep onset (sNAASO), wake time after sleep onset (sWASO), sleep quality, Insomnia Severity Index (ISI), and global improvement. RESULTS: Treatment with indiplon resulted in significant improvement relative to placebo at all time points for the primary endpoint, sLSO. Mean sLSO at Month 1 for each treatment group was: 10 mg (34.0 +/- 1.3 mins), 20 mg (33.0 +/- 1.3 mins), and placebo (48.7 +/- 1.9 mins; P <0.0001 for both comparisons); efficacy was sustained through Month 3. Both doses of indiplon resulted in significant improvement in sleep maintenance and duration endpoints, sTST and sWASO, as well as sleep quality, ISI, and global improvement at all assessment time points. CONCLUSIONS: In patients with chronic insomnia, long-term nightly treatment with 10 mg and 20 mg doses of indiplon resulted in significant and sustained efficacy in sleep onset, maintenance, and duration, and significant associated improvement in both daytime functioning and quality of life.     

The Impact of Sleep-Related Attentional Bias on Polysomnographically Measured Sleep in Primary Insomnia

Study Objectives:

Although sleep-related attentional bias has been shown to be evident in primary insomnia, the association with objectively measured sleep has not been investigated. In the present study, we used polysomnography (PSG) to fill this void.

Design:

Patients with primary insomnia and healthy controls were studied using a visual dot probe task (VDP) and an emotional Stroop task (EST). Additionally, polysomnography was carried out in a sub-sample (n = 22) of patients in the subsequent night.

Setting:

Department of Psychiatry and Psychotherapy of the University of Freiburg Medical Center.

Participants:

Thirty patients with primary insomnia and 30 matched healthy controls.

Interventions:

N/A

Measurements and Results:

Patients with primary insomnia demonstrated a significant sleep-related attentional bias compared to controls in the EST but no significant group effects were found for the VDP. VDP attentional bias scores were positively correlated with measures of sleep pressure, including total sleep time, sleep efficiency, and the amount of slow wave sleep. EST attentional bias scores were not correlated with subsequent PSG parameters, and we did not observe a correlation between attentional bias scores on the two tasks.

Conclusions:

The unexpected relationship between increased attentional bias, in the VDP task, and improved markers of sleep duration and continuity, may be indicative of a homeostatic craving for sleep in those with high attentional bias. This awaits further testing in multiple night studies, to shed light on the mechanisms and implications of sleep-related attentional bias.

Citation:

Spiegelhalder K; Kyle SD; Feige B; Prem M; Nissen C; Espie CA; Riemann D. The impact of sleep-related attentional bias on polysomnographically measured sleep in primary insomnia. SLEEP 2010;33(1):107-112.     

Sleep microstructure around sleep onset differentiates major depressive insomnia from primary insomnia

In the present study we investigate whether alterations of sleep propensity or of wake propensity are implicated in sleep initiation disturbances encountered in major depressive insomnia and in primary insomnia. For this purpose, the time course of electroencephalogram (EEG) power density during the period preceding sleep onset and during the first non-rapid eye movement (REM) period was examined in three age and gender matched groups of 10 women and 11 men (healthy controls, primary insomniacs and depressive insomniacs). In contrast to healthy controls and depressive insomniacs, patients with primary insomnia did not experience a gradual decrease of their alpha and beta1 power during the sleep onset period and had a lower delta activity in the 5 min preceding sleep onset. Compared with the two other groups, depressive patients exhibit less dynamic changes in slow wave activity during the first non-REM period. The present results suggest that hyperarousal (high 'Process W') may mainly be implicated in the sleep initiation difficulties of primary insomniacs whereas the homeostatic sleep regulation process seems to be partially maintained. In our major depressed patients, the sleep initiation disturbances appeared to relate to a lower sleep pressure (low 'Process S') rather than to hyperarousal. This study supports the idea that different mechanisms are implicated in sleep disturbances experienced by primary insomniacs and major depressive insomniacs.     

Procedural memory consolidation is associated with heart rate variability and sleep spindles

Sleep and memory studies often focus on overnight rather than long‐term memory changes, traditionally associating overnight memory change (OMC) with sleep architecture and sleep patterns such as spindles. In addition, (para‐)sympathetic innervation has been associated with OMC after a daytime nap using heart rate variability (HRV). In this study we investigated overnight and long‐term performance changes for procedural memory and evaluated associations with sleep architecture, spindle activity (SpA) and HRV measures (R‐R interval [RRI], standard deviation of R‐R intervals [SDNN], as well as spectral power for low [LF] and high frequencies [HF]). All participants (N = 20, M_age = 23.40 ± 2.78 years) were trained on a mirror‐tracing task and completed a control (normal vision) and learning (mirrored vision) condition. Performance was evaluated after training (R1), after a full‐night sleep (R2) and 7 days thereafter (R3). Overnight changes (R2‐R1) indicated significantly higher accuracy after sleep, whereas a significant long‐term (R3‐R2) improvement was only observed for tracing speed. Sleep architecture measures were not associated with OMC after correcting for multiple comparisons. However, individual SpA change from the control to the learning night indicated that only “SpA enhancers” exhibited overnight improvements for accuracy and long‐term improvements for speed. HRV analyses revealed that lower SDNN and LF power was associated with better OMC for the procedural speed measure. Altogether, this study indicates that overnight improvement for procedural memory is specific for spindle enhancers, and is associated with HRV during sleep following procedural learning.     

Sleep and time course of consolidation of visual discrimination skills in patients with narcolepsy–cataplexy

The level of procedural skills improves in normal individuals when the acquisition is followed by a period of sleep rather than wake. If sleep plays an important role in the consolidation process the advantage it provides should be reduced or delayed when its organization is altered, as in patients with chronic sleep disorders. To test this prediction in patients with narcolepsy–cataplexy (NC), who usually have a more fragmented organization of sleep than normals, we compared the initial, intermediate and delayed level of consolidation of visual skills . Twenty-two drug-naive NC patients and 22 individually-matched controls underwent training at a texture discrimination task (TDT) and were re-tested on the next morning (after a night spent in laboratory with polysomnography) and after another six nights (spent at home). TDT performance was worse in patients than controls at training and at both retrieval sessions and the time course of consolidation was different in NC patients (who improved mainly from next-day to 7th-day retrieval session) compared with controls. Moreover, the less-improving patients at next-day retrieval had a wider disorganization of sleep, probably because of an episode of rapid eye movement (REM) sleep at sleep onset REM, on post-training night more frequently than more-improving patients. These findings suggest that the time course of the consolidation process of procedural skills may be widely influenced by the characteristics of sleep organization (varying night-by-night much more in NC patients than controls) during post-training night.     

Different criteria of sleep latency and the effect of melatonin on sleep consolidation

OBJECTIVES: Since there is no consensus definition of sleep onset, we studied different aspects of initial sleep periods in healthy volunteers taking melatonin. Two criteria for sleep latency were used: 10 minutes of uninterrupted sleep and 1.5 minutes of stage 1 sleep. PARTICIPANTS: Forty healthy male volunteers (mean age 28 +/- 5 years) were assigned to 2 groups: 30 ingested melatonin and 10 placebo. DESIGN: All volunteers underwent an initial polysomnogram (baseline) after a 1-night adaptation period. The next day, the placebo or a 10-mg dose of melatonin was administered for 28 days, 1 hour before sleep time, in double-blind fashion. The second polysomnogram was recorded on day 14. SETTING: Sleep laboratory RESULTS: Chronic melatonin administration led to a significant reduction in sleep latency, using only the criterion 10 minutes of uninterrupted sleep. This effect suggests that melatonin may have a hypnotic effect, and the use of melatonin may lead to better sleep consolidation. CONCLUSIONS: These results show differences that have clinical implications, since the criteria used to diagnose initial insomnia were based on sleep onset.     

Manifestations of Insomnia in Sleep Apnea: Implications for Screening and Treatment

The aims of this study were to examine the presence, type, and severity of insomnia complaints in obstructive sleep apnea (OSA) patients and to assess the utility of the Sleep Symptom Checklist (SSC) for case identification in primary care. Participants were 88 OSA patients, 57 cognitive-behavioral therapy for insomnia (CBT-I) patients, and 14 healthy controls (Ctrl). Each completed a sleep questionnaire as well as the SSC, which includes insomnia, daytime functioning, psychological, and sleep disorder subscales. Results showed that OSA patients could be grouped according to 3 insomnia patterns: no insomnia (OSA), n = 21; insomnia (OSA-I), n = 30, with a subjective complaint and disrupted sleep; and noncomplaining poor sleepers (OSA-I-NC), n = 37. Comparisons among the OSA, CBT-I, and Ctrl groups demonstrate distinct profiles on the SSC subscales, indicating its potential utility for both case identification and treatment planning.     

Patients with primary insomnia in the sleep laboratory: do they present with typical nights of sleep?

The validity of sleep laboratory investigations in patients with insomnia is important for researchers and clinicians. The objective of this study was to examine the first‐night effect and the reverse first‐night effect in patients with chronic primary insomnia compared with good sleeper controls. A retrospective comparison of a well‐characterised sample of 50 patients with primary insomnia and 50 good sleeper controls was conducted with respect to 2 nights of polysomnography, and subjective sleep parameters in the sleep laboratory and the home setting. When comparing the first and second sleep laboratory night, a significant first‐night effect was observed across both groups in the great majority of the investigated polysomnographic and subjective variables. However, patients with primary insomnia and good sleeper controls did not differ with respect to this effect. Regarding the comparison between the sleep laboratory nights and the home setting, unlike good sleeper controls, patients with primary insomnia reported an increased subjective sleep efficiency on both nights (in part due to a reduced bed time) and an increased subjective total sleep time on the second night. These results suggest that even the second sleep laboratory night does not necessarily provide clinicians and researchers with a representative insight into the sleep perception of patients with primary insomnia. Future studies should investigate whether these findings also hold for other patient populations.     

Sleep slow oscillations favour local cortical plasticity underlying the consolidation of reinforced procedural learning in human sleep

We investigated changes of slow‐wave activity and sleep slow oscillations in the night following procedural learning boosted by reinforcement learning, and how these changes correlate with behavioural output. In the Task session, participants had to reach a visual target adapting cursor's movements to compensate an angular deviation introduced experimentally, while in the Control session no deviation was applied. The task was repeated at 13:00 hours, 17:00 hours and 23:00 hours before sleep, and at 08:00 hours after sleep. The deviation angle was set at 15° (13:00 hours and 17:00 hours) and increased to 45° (reinforcement) at 23:00 hours and 08:00 hours. Both for Task and Control nights, high‐density electroencephalogram sleep recordings were carried out (23:30?19:30 hours). The Task night as compared with the Control night showed increases of: (a) slow‐wave activity (absolute power) over the whole scalp; (b) slow‐wave activity (relative power) in left centro‐parietal areas; (c) sleep slow oscillations rate in sensorimotor and premotor areas; (d) amplitude of pre‐down and up states in premotor regions, left sensorimotor and right parietal regions; (e) sigma crowning the up state in right parietal regions. After Task night, we found an improvement of task performance showing correlations with sleep slow oscillations rate in right premotor, sensorimotor and parietal regions. These findings suggest a key role of sleep slow oscillations in procedural memories consolidation. The diverse components of sleep slow oscillations selectively reflect the network activations related to the reinforced learning of a procedural visuomotor task. Indeed, areas specifically involved in the task stand out as those with a significant association between sleep slow oscillations rate and overnight improvement in task performance.     

Effect of short-term treatment with gaboxadol on sleep maintenance and initiation in patients with primary insomnia

STUDY OBJECTIVE: To perform an early evaluation of the efficacy and safety of gaboxadol in the treatment of primary insomnia. METHODS: 26 adults (18-65 years) with DSM-IV criteria for primary insomnia were randomly assigned gaboxadol (5 mg, 15 mg) or placebo in a double-blind, crossover study. After a 3-night polysomnographic (PSG) screen, treatment was administered 30 min before bedtime on 2 consecutive nights during 3 separate sessions including PSG. Efficacy analyses (n = 23) were based on the average of Nights 1 and 2, and compared gaboxadol versus placebo. Baseline was the average of Nights 2 and 3 of the screening session. Both gaboxadol doses significantly (P < 0.05) improved mean total sleep time (mean +/- SD: baseline = 368.0 +/- 51.1 min, 15 mg = 420.3 +/- 24.5 min, 5 mg = 419.8 +/- 20.4 min, placebo = 408.7 +/- 30.4 min). Both gaboxadol doses reduced mean wake after sleep onset, although statistical significance was only achieved with 5 mg (baseline = 61.6 +/- 35.4 min, 15 mg = 38.0 +/- 21.1 min, 5 mg = 34.6 +/- 14.3 min, placebo = 43.4 +/- 22.9 min). Gaboxadol 15 mg also significantly reduced mean latency to persistent sleep (baseline = 55.6 +/- 27.0 min, 15 mg = 23.6 +/- 15.1 min, placebo = 30.0 +/- 19.1 min) and enhanced slow wave duration (baseline = 72.4 +/- 20.8 min, 15 mg = 114.0 +/- 37.5 min, placebo = 93.9 +/- 31.3 min) with no significant effects on REM sleep duration. Patient reports (Leeds Sleep Evaluation Questionnaire) of reduced time to sleep and increased sleep quality showed significant improvement with gaboxadol 15 mg. No next-day residual effects were observed with either dose of gaboxadol (assessed 2 h and 9 h after lights on). All adverse events were mild or moderate. CONCLUSION: Gaboxadol 15 mg was effective and generally well tolerated in the short-term treatment of patients with primary insomnia. Gaboxadol also enhanced slow wave sleep duration and had no significant effects on REM sleep duration. These findings suggest that gaboxadol may be a useful treatment for insomnia.