Offline Bi-Frontal Anodal Transcranial Direct Current Stimulation Decreases Total Sleep Time Without Disturbing Overnight Memory Consolidation.

OBJECTIVES: A proposed replay of memory traces between the hippocampus and frontal cortical brain areas during sleep is of high relevance for overnight memory consolidation. Recently, we demonstrated that bi-frontal anodal transcranial direct current stimulation (tDCS) prior to sleep increases waking EEG gamma power and decreases total sleep time during the night. It is unclear whether this effect on cortical excitability has an influence on overnight memory consolidation. We hypothesized that bi-frontal evening tDCS interferes with overnight memory consolidation with a polarity specific impairment following anodal tDCS. MATERIALS AND METHODS: Nineteen healthy participants underwent a within-subject, repeated-measures protocol in the sleep laboratory with bi-frontal tDCS applied prior to sleep according to the experimental protocol (anodal, cathodal, sham stimulation). Memory tasks for declarative and procedural memory were assessed prior to tDCS and on the following morning. RESULTS: No deterioration of overnight memory consolidation following evening offline bi-frontal tDCS could be detected. CONCLUSION(S): The application of tDCS can be considered safe regarding overnight memory consolidation and represents a promising treatment approach in conditions of decreased vigilance and arousal.

Brief periods of NREM sleep do not promote early offline gains but subsequent on-task performance in motor skill learning.

Sleep modulates motor learning, but its detailed impact on performance curves remains to be fully characterized. This study aimed to further determine the impact of brief daytime periods of NREM sleep on 'offline' (task discontinuation after initial training) and 'on-task' (performance within the test session) changes in motor skill performance (finger tapping task). In a mixed design (combined parallel group and repeated measures) sleep laboratory study (n=17 'active' wake vs. sleep, n=19 'passive' wake vs. sleep), performance curves were assessed prior to and after a 90min period containing either sleep, active or passive wakefulness. We observed a highly significant, but state- (that is, sleep/wake)-independent early offline gain and improved on-task performance after sleep in comparison to wakefulness. Exploratory curve fitting suggested that the observed sleep effect most likely emerged from an interaction of training-induced improvement and detrimental 'time-on-task' processes, such as fatigue. Our results indicate that brief periods of NREM sleep do not promote early offline gains but subsequent on-task performance in motor skill learning.

The effect of sleep-specific brain activity versus reduced stimulus interference on declarative memory consolidation.

Studies suggest that the consolidation of newly acquired memories and underlying long-term synaptic plasticity might represent a major function of sleep. In a combined repeated-measures and parallel-group sleep laboratory study (active waking versus sleep, passive waking versus sleep), we provide evidence that brief periods of daytime sleep (42.1 ± 8.9 min of non-rapid eye movement sleep) in healthy adolescents (16 years old, all female), compared with equal periods of waking, promote the consolidation of declarative memory (word-pairs) in participants with high power in the electroencephalographic sleep spindle (sigma) frequency range. This observation supports the notion that sleep-specific brain activity when reaching a critical dose, beyond a mere reduction of interference, promotes synaptic plasticity in a hippocampal-neocortical network that underlies the consolidation of declarative memory.

EEG Σ 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.

Effects of sleep deprivation on nocturnal cytokine concentrations in depressed patients and healthy control subjects.

Previous studies have reported alterations of cytokine and cytokine-receptor concentrations in psychiatric patient populations, including patients with major depressive disorder (MDD). However, study results are conflicting, and possible causes for these abnormalities are unknown. Since sleep deprivation may induce a rapid improvement of mood in depressed patients, the authors investigated the impact of total sleep deprivation (TSD) for one night, and subsequent recovery sleep, on nocturnal concentrations of interleukin-6 (IL-6), interleukin-1-receptor antagonist (IL-1RA), and soluble IL-2 receptor (sIL-2R) in 15 unmedicated patients with MDD and 16 healthy volunteers. Whereas IL-6 levels normalized again during the recovery night in depressed patients, they were still elevated in control subjects. Serum levels of IL-1RA were higher in depressed patients than in controls, but were not affected by TSD. During recovery sleep, IL-1RA levels increased as compared with the preceding TSD night only in controls. Responders (N=8) differed from nonresponders (N=7) to TSD with regard to IL-1RA, which increased significantly during TSD in responders only. Sleep deprivation therefore seems to significantly affect cytokine levels in both depressed patients and healthy subjects, but does so in different ways. Sleep disturbances in depressed patients could account for the increased levels of cytokines found in these patients in several previous studies. The interaction between antidepressant effects of TSD and alterations of cytokines warrants further investigation.

Modular-based psychotherapy (MoBa) versus cognitive-behavioural therapy (CBT) for patients with depression, comorbidities and a history of childhood maltreatment: study protocol for a randomised controlled feasibility trial.

INTRODUCTION: In depression treatment, most patients do not reach response or remission with current psychotherapeutic approaches. Major reasons for individual non-response are interindividual heterogeneity of etiological mechanisms and pathological forms, and a high rate of comorbid disorders. Personalised treatments targeting comorbidities as well as underlying transdiagnostic mechanisms and factors like early childhood maltreatment may lead to better outcomes. A modular-based psychotherapy (MoBa) approach provides a treatment model of independent and flexible therapy elements within a systematic treatment algorithm to combine and integrate existing evidence-based approaches. By optimally tailoring module selection and application to the specific needs of each patient, MoBa has great potential to improve the currently unsatisfying results of psychotherapy as a bridge between disorder-specific and personalised approaches. METHODS AND ANALYSIS: In a randomised controlled feasibility trial, N=70 outpatients with episodic or persistent major depression, comorbidity and childhood maltreatment are treated in 20 individual sessions with MoBa or standard cognitive-behavioural therapy for depression. The three modules of MoBa focus on deficits associated with early childhood maltreatment: the systems of negative valence, social processes and arousal. According to a specific questionnaire-based treatment algorithm, elements from cognitive behavioural analysis system of psychotherapy, mentalisation-based psychotherapy and/or mindfulness-based cognitive therapy are integrated for a personalised modular procedure.As a proof of concept, this trial will provide evidence for the feasibility and efficacy (post-treatment and 6-month follow-up) of a modular add-on approach for patients with depression, comorbidities and a history of childhood maltreatment. Crucial feasibility aspects include targeted psychopathological mechanisms, selection (treatment algorithm), sequence and application of modules, as well as training and supervision of the study therapists. ETHICS AND DISSEMINATION: This study obtained approval from the independent Ethics Committees of the University of Freiburg and the University of Heidelberg. All findings will be disseminated broadly via peer-reviewed articles in scientific journals and contributions to national and international conferences. TRIAL REGISTRATION NUMBER: DRKS00022093.

Effectiveness of Nature- and Animal Assisted Mindfulness for Relapse Prevention in Depressed Patients With a History of Childhood Maltreatment.

Background: For relapse prevention in depression, conventional mindfulness programs such as the mindfulness-based cognitive therapy proved to be useful. However, early life trauma is a risk factor for having adverse experiences during meditation. Thus, for this patient group mindfulness skills are often difficult to learn and may be facilitated by using animals and a nature setting. Methods: The aim of the study was to evaluate the preventative efficacy of a nature- and animal assisted mindfulness program (NAM) over the course of 1 year in unstable or partially remitted depressed patients with a history of early life trauma. NAM included 8 group sessions of 150 min each over 8 weeks plus one booster session. Sixty-seven participants were randomized to either NAM combined with treatment-as-usual (TAU; guideline oriented treatment) or TAU alone. The primary outcome was depression diagnosis over the course of 12 months after end of treatment. Secondary outcomes included clinician- and self-rated depressive symptoms, quality of life, mindfulness skills, and rumination post, and 12 months after the intervention. In addition, we evaluated the participants' satisfaction with the program. Results: Analyses revealed significant differences in relapse rates and number of weeks depressed throughout the course in favor of NAM. Furthermore, global quality of life improved significantly more in the NAM group. There was no significant difference for other secondary outcomes. Satisfaction with the program was high with a low drop-out rate of 6%. The vast majority of the participants felt safe practicing mindfulness in nature and found sheep for assistance helpful and motivating. Conclusions: A nature- and animal assisted mindfulness program proved to be feasible, highly acceptable, and more effective than standard treatment in preventing relapses in recurrently depressed patients with childhood maltreatment. Nature and animals can facilitate the engagement in the treatment process for individuals with a history of early trauma. However, further evidence in multicenter trials is necessary.

Sleep-related memory consolidation in primary insomnia.

It has been suggested that healthy sleep facilitates the consolidation of newly acquired memories and underlying brain plasticity. The authors tested the hypothesis that patients with primary insomnia (PI) would show deficits in sleep-related memory consolidation compared to good sleeper controls (GSC). The study used a four-group parallel design (n=86) to investigate the effects of 12 h of night-time, including polysomnographically monitored sleep ('sleep condition' in PI and GSC), versus 12 h of daytime wakefulness ('wake condition' in PI and GSC) on procedural (mirror tracing task) and declarative memory consolidation (visual and verbal learning task). Demographic characteristics and memory encoding did not differ between the groups at baseline. Polysomnography revealed a significantly disturbed sleep profile in PI compared to GSC in the sleep condition. Night-time periods including sleep in GSC were associated with (i) a significantly enhanced procedural and declarative verbal memory consolidation compared to equal periods of daytime wakefulness in GSC and (ii) a significantly enhanced procedural memory consolidation compared to equal periods of daytime wakefulness and night-time sleep in PI. Across retention intervals of daytime wakefulness, no differences between the experimental groups were observed. This pattern of results suggests that healthy sleep fosters the consolidation of new memories, and that this process is impaired for procedural memories in patients with PI. Future work is needed to investigate the impact of treatment on improving sleep and memory.

Sleep is more than rest for plasticity in the human cortex.

Sleep promotes adaptation of behavior and underlying neural plasticity in comparison to active wakefulness. However, the contribution of its two main characteristics, sleep-specific brain activity and reduced stimulus interference, remains unclear. We tested healthy humans on a texture discrimination task, a proxy for neural plasticity in primary visual cortex, in the morning and retested them in the afternoon after a period of daytime sleep, passive waking with maximally reduced interference, or active waking. Sleep restored performance in direct comparison to both passive and active waking, in which deterioration of performance across repeated within-day testing has been linked to synaptic saturation in the primary visual cortex. No difference between passive and active waking was observed. Control experiments indicated that deterioration across wakefulness was retinotopically specific to the trained visual field and not due to unspecific performance differences. The restorative effect of sleep correlated with time spent in NREM sleep and with electroencephalographic slow wave energy, which is thought to reflect renormalization of synaptic strength. The results indicate that sleep is more than a state of reduced stimulus interference, but that sleep-specific brain activity restores performance by actively refining cortical plasticity.

Differential effects of bifrontal tDCS on arousal and sleep duration in insomnia patients and healthy controls.

BACKGROUND: Arousal and sleep represent basic domains of behavior, and alterations are of high clinical importance. OBJECTIVE/HYPOTHESIS: The aim of this study was to further elucidate the neurobiology of insomnia disorder (ID) and the potential for new treatment developments, based on the modulation of cortical activity through the non-invasive brain stimulation technique transcranial direct current stimulation (tDCS). Specifically, we tested the hypotheses that bi-frontal anodal tDCS shortens and cathodal tDCS prolongs total sleep time in patients with ID, compared to sham stimulation. Furthermore, we tested for differences in indices of arousal between ID patients and healthy controls and explored their potential impact on tDCS effects. METHODS: Nineteen ID patients underwent a within-subject repeated-measures sleep laboratory study with adaptation, baseline and three experimental nights. Bifrontal anodal, cathodal and sham tDCS was delivered in a counterbalanced order immediately prior to sleep. Wake EEG was recorded prior to and after tDCS as well as on the following morning. Subsequently, we compared patients with ID to a healthy control group from an earlier dataset. RESULTS: Against our hypothesis, we did not observe any tDCS effects on sleep continuity or sleep architecture in patients with ID. Further analyses of nights without stimulation demonstrated significantly increased levels of arousal in ID patients compared to healthy controls, as indexed by subjective reports, reduced total sleep time, increased wake after sleep onset and increased high frequency EEG power during wakefulness and NREM sleep. Of note, indices of increased arousal predicted the lack of effect of tDCS in ID patients. CONCLUSIONS: Our study characterizes for the first time differential effects of tDCS on sleep in patients with ID and healthy controls, presumably related to persistent hyperarousal in ID. These findings suggest that adapted tDCS protocols need to be developed to modulate arousal and sleep dependent on baseline arousal levels.

Top-down control of arousal and sleep: Fundamentals and clinical implications.

Mammalian sleep emerges from attenuated activity in the ascending reticular arousal system (ARAS), the main arousal network of the brain. This system originates in the brainstem and activates the thalamus and cortex during wakefulness via a well-characterized 'bottom-up' pathway. Recent studies propose that a less investigated cortico-thalamic 'top-down' pathway also regulates sleep. The present work integrates the current evidence on sleep regulation with a focus on the 'top-down' pathway and explores the potential to translate this information into clinically relevant interventions. Specifically, we elaborate the concept that arousal and sleep continuity in humans can be modulated by non-invasive brain stimulation (NIBS) techniques that increase or decrease cortical excitability. Based on preclinical studies, the modulatory effects of the stimulation are thought to extend to subcortical arousal networks. Further exploration of the 'top-down' regulation of sleep and its modulation through non-invasive brain stimulation techniques may contribute to the development of novel treatments for clinical conditions of disrupted arousal and sleep, which are among the major health problems worldwide.

Modulation of Total Sleep Time by Transcranial Direct Current Stimulation (tDCS).

Arousal and sleep are fundamental physiological processes, and their modulation is of high clinical significance. This study tested the hypothesis that total sleep time (TST) in humans can be modulated by the non-invasive brain stimulation technique transcranial direct current stimulation (tDCS) targeting a 'top-down' cortico-thalamic pathway of sleep-wake regulation. Nineteen healthy participants underwent a within-subject, repeated-measures protocol across five nights in the sleep laboratory with polysomnographic monitoring (adaptation, baseline, three experimental nights). tDCS was delivered via bi-frontal target electrodes and bi-parietal return electrodes before sleep (anodal 'activation', cathodal 'deactivation', and sham stimulation). Bi-frontal anodal stimulation significantly decreased TST, compared with cathodal and sham stimulation. This effect was location specific. Bi-frontal cathodal stimulation did not significantly increase TST, potentially due to ceiling effects in good sleepers. Exploratory resting-state EEG analyses before and after the tDCS protocols were consistent with the notion of increased cortical arousal after anodal stimulation and decreased cortical arousal after cathodal stimulation. The study provides proof-of-concept that TST can be decreased by non-invasive bi-frontal anodal tDCS in healthy humans. Further elucidating the 'top-down' pathway of sleep-wake regulation is expected to increase knowledge on the fundamentals of sleep-wake regulation and to contribute to the development of novel treatments for clinical conditions of disturbed arousal and sleep.

Prolonged sleep under Stone Age conditions.

STUDY OBJECTIVES: We report on a unique experiment designed to investigate the impact of prehistoric living conditions on sleep-wake behavior. METHODS: A group of five healthy adults were assessed during life in a Stone Age-like settlement over two months. RESULTS: The most notable finding was that nocturnal time in bed and estimated sleep time, as measured by actigraphy, markedly increased during the experimental period compared to the periods prior to and following the experiment. These increases were primarily driven by a phase-advance shift of sleep onset. Subjective assessments of health and functioning did not reveal any relevant changes across the study. CONCLUSIONS: Our observations provide further evidence for the long-held belief that the absence of modern living conditions is associated with an earlier sleep phase and prolonged sleep duration. COMMENTARY: A commentary on this article appears in this issue on page 723.

The reorganisation of memory during sleep.

Sleep after learning promotes the quantitative strengthening of new memories. Less is known about the impact of sleep on the qualitative reorganisation of memory, which is the focus of this review. Studies have shown that, in the declarative system, sleep facilitates the abstraction of rules (schema formation), the integration of knowledge into existing schemas (schema integration) and creativity that requires the disbandment of existing patterns (schema disintegration). Schema formation and integration might primarily benefit from slow wave sleep, whereas the disintegration of a schema might be facilitated by rapid eye movement sleep. In the procedural system, sleep fosters the reorganisation of motor memory. The neural mechanisms of these processes remain to be determined. Notably, emotions have been shown to modulate the sleep-related reorganisation of memories. In the final section of this review, we propose that the sleep-related reorganisation of memories might be particularly relevant for mental disorders. Thus, sleep disruptions might contribute to disturbed memory reorganisation and to the development of mental disorders. Therefore, sleep-related interventions might modulate the reorganisation of memories and provide new inroads into treatment.

The impact of increasing sleep restriction on cortisol and daytime sleepiness in adolescents.

Sleep restriction is a widespread phenomenon, specifically in adolescents. This study investigated the impact of increasing sleep restriction in adolescents on cortisol levels and daytime sleepiness. Eighty-eight healthy adolescents were randomized to five sleep restriction protocols (four consecutive nights with 9, 8, 7, 6, or 5 h time in bed). Polysomnography (baseline and last experimental night) and multiple sleep latency test (day 6) data were obtained. Saliva cortisol levels were assessed half-hourly in the evening before and in the morning after the baseline and the last experimental night. Four nights of sleep restriction in healthy adolescents lead to a linear increase of objective sleepiness, but had no significant effect on evening or morning cortisol levels. The lack of detrimental effects of sleep restriction on cortisol levels might be due to compensation mechanisms during sleep.

Increased EEG sigma and beta power during NREM sleep in primary insomnia.

The hyperarousal model of primary insomnia suggests that a deficit of attenuating arousal during sleep might cause the experience of non-restorative sleep. In the current study, we examined EEG spectral power values for standard frequency bands as indices of cortical arousal and sleep protecting mechanisms during sleep in 25 patients with primary insomnia and 29 good sleeper controls. Patients with primary insomnia demonstrated significantly elevated spectral power values in the EEG beta and sigma frequency band during NREM stage 2 sleep. No differences were observed in other frequency bands or during REM sleep. Based on prior studies suggesting that EEG beta activity represents a marker of cortical arousal and EEG sleep spindle (sigma) activity is an index of sleep protective mechanisms, our findings may provide further evidence for the concept that a simultaneous activation of wake-promoting and sleep-protecting neural activity patterns contributes to the experience of non-restorative sleep in primary insomnia.

The timing of learning before night-time sleep differentially affects declarative and procedural long-term memory consolidation in adolescents.

Sleep after learning has been shown to foster the consolidation of new memories. However, fundamental questions on the best timing of learning before night-time sleep persist. We tested the hypothesis that learning directly prior to night-time sleep compared to 7.5 hrs prior to night-time sleep provides better conditions for the consolidation of declarative and procedural memories. Fifty healthy female adolescents (aged 16-17 years) were trained on a declarative word-pair and a procedural finger-tapping task at 3 pm (afternoon group, n = 25) or at 9 pm (evening group, n = 25), followed by a sleep laboratory night. Retrieval was assessed 24 hours and 7 days after initial training. Subjects trained in the afternoon showed a significantly elevated retention rate of word-pairs compared to subjects trained in the evening after 24 hours, but not after 7 days. In contrast, off-line gains in finger-tapping performance were significantly higher in subjects trained in the evening compared to those trained in the afternoon after both retention intervals. The observed enhanced consolidation of procedural memories after training in the evening fits to current models of sleep-related memory consolidation. In contrast, the higher retention of declarative memories after encoding in the afternoon is surprising, appeared to be less robust and needs further investigation.

Sleep restriction over several days does not affect long-term recall of declarative and procedural memories in adolescents.

OBJECTIVES: There is broad evidence that sleep as opposed to waking facilitates the consolidation of both declarative and procedural memory. The current study addressed the question whether different extents of sleep restriction after learning would impair long-term memory consolidation in adolescents. METHODS: Eighty-eight healthy adolescents were randomized to five different sleep protocols with 9, 8, 7, 6 or 5 h of time in bed for four consecutive nights under controlled conditions that excluded daytime sleep. Declarative (word-pair task) and procedural memory (mirror tracing task) encoding was assessed prior to the sleep restriction protocol. Recall was assessed after two recovery nights following the sleep protocol and 4 weeks later. RESULTS: Sleep diaries and actigraphy data demonstrated that the participants closely followed the sleep protocols. There were no differences in demographic parameters or memory encoding at baseline. In contrast to the initial prediction, restriction of nocturnal sleep over four consecutive nights had no significant impact on declarative or procedural memory consolidation. Polysomnographic monitoring after sleep restriction demonstrated a high preservation of the amount of slow wave sleep in the restricted conditions. CONCLUSIONS: The results suggest that adolescents show a high resilience of memory consolidation to substantial sleep curtailment across four nights that might be promoted by increased sleep intensity under conditions of sleep restriction.

Sleep and memory in healthy children and adolescents - a critical review.

There is mounting evidence that sleep is important for learning, memory and the underlying neural plasticity. This article aims to review published studies that evaluate the association between sleep, its distinct stages and memory systems in healthy children and adolescents. Furthermore it intends to suggest directions for future research. A computerised search of the literature for relevant articles published between 1966 and March 2008 was performed using the keywords "sleep", "memory", "learn", "child", "adolescents", "adolescence" and "teenager". Fifteen studies met the inclusion criteria. Published studies focused on the impact of sleep on working memory and memory consolidation. In summary, most studies support the hypothesis that sleep facilitates working memory as well as memory consolidation in children and adolescents. There is evidence that performance in abstract and complex tasks involving higher brain functions declines more strongly after sleep deprivation than the performance in simple memory tasks. Future studies are needed to better understand the impact of a variety of variables potentially modulating the interplay between sleep and memory, such as developmental stage, socioeconomic burden, circadian factors, or the level of post-learning sensory and motor activity (interference). This line of research can provide valuable input relevant to teaching, learning and public health policy.