Interactions between insomnia, sleep duration and emotional processes: An ecological momentary assessment of longitudinal influences combining self-report and physiological measures.

Previous studies indicated that further investigation is needed to understand how insomnia disorder interacts with emotional processes. The present study is an ecological momentary assessment evaluating the link between emotional and sleep alterations in patients with insomnia. Physiological (heart rate and heart rate variability) and subjective (sleep and emotions) indices were observed for 5 days in patients with insomnia disorder (n = 97), good sleepers under self-imposed sleep restriction (n = 41), and good sleepers with usual amount of sleep (n = 45). We evaluated differences in emotion regulation strategies and in valence and variability of emotional experiences. Over 5 days, patients with insomnia showed increased sleep and emotional difficulties compared with both control groups. Independent from group allocation, days with more negative emotions were associated with higher sleep alterations. Longer wake episodes at night and higher diurnal heart rate were associated with increased variations in emotion experienced during the day. Only in patients with insomnia, use of adaptive emotion regulation strategies was associated with higher sleep efficiency. Our data showed that alterations in sleep and emotional processes are closely linked. A combination of strategies targeting both sleep and emotional processes appears promising in the prevention and treatment of insomnia disorder.

Declarative virtual water maze learning and emotional fear conditioning in primary insomnia.

Healthy sleep restores the brain's ability to adapt to novel input through memory formation based on activity-dependent refinements of the strength of neural transmission across synapses (synaptic plasticity). In line with this framework, patients with primary insomnia often report subjective memory impairment. However, investigations of memory performance did not produce conclusive results. The aim of this study was to further investigate memory performance in patients with primary insomnia in comparison to healthy controls, using two well-characterized learning tasks, a declarative virtual water maze task and emotional fear conditioning. Twenty patients with primary insomnia according to DSM-IV criteria (17 females, three males, 43.5 ± 13.0 years) and 20 good sleeper controls (17 females, three males, 41.7 ± 12.8 years) were investigated in a parallel-group study. All participants completed a hippocampus-dependent virtual Morris water maze task and amygdala-dependent classical fear conditioning. Patients with insomnia showed significantly delayed memory acquisition in the virtual water maze task, but no significant difference in fear acquisition compared with controls. These findings are consistent with the notion that memory processes that emerge from synaptic refinements in a hippocampal-neocortical network are particularly sensitive to chronic disruptions of sleep, while those in a basic emotional amygdala-dependent network may be more resilient.

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.

REM sleep and memory reorganization: Potential relevance for psychiatry and psychotherapy.

Sleep can foster the reorganization of memory, i.e. the emergence of new memory content that has not directly been encoded. Current neurophysiological and behavioral evidence can be integrated into a model positing that REM sleep particularly promotes the disintegration of existing schemas and their recombination in the form of associative thinking, creativity and the shaping of emotional memory. Particularly, REM sleep related dreaming might represent a mentation correlate for the reconfiguration of memory. In a final section, the potential relevance for psychiatry and psychotherapy is discussed.

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.

Brain-derived neurotrophic factor genetic polymorphism rs6265 and creativity.

The protein brain-derived neurotrophic factor (BDNF) promotes neural plasticity of the central nervous system and plays an important role for learning and memory. A single nucleotide polymorphism (rs6265) at position 66 in the pro-region of the human BDNF gene, resulting in a substitution of the amino acid valine (val) with methionine (met), leads to attenuated BDNF secretion and has been associated with reduced neurocognitive function. Inhomogeneous results have been found regarding the effect of the BDNF genotype on behavior. We determined the BDNF genotype and performance on the Compound Remote Associate (CRA) task as a common measure of creativity in 76 healthy university students. In our main analyses, we did not find significant differences between met-carriers (n = 30) and non-met carriers (n = 46). In a secondary analysis, we found that met-carriers had a slower solution time (medium effect size) for items of medium difficulty. Our results suggest that met-carriers and non-met-carriers do not generally differ regarding their creativity, but non-met-carriers may have a certain advantage when it comes to moderately difficult problems. The wider literature suggests that both genetic variants come with advantages and disadvantages. Future research needs to sharpen our understanding of the disadvantages and, potentially, advantages met allele carriers may have.

Indices of cortical plasticity after therapeutic sleep deprivation in patients with major depressive disorder.

BACKGROUND: Therapeutic sleep deprivation (SD) presents a unique paradigm to study the neurobiology of major depressive disorder (MDD). However, the rapid antidepressant mechanism, which differs from today's slow first-line treatments, is not sufficiently understood. We recently integrated two prominent hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, into a synaptic plasticity model of therapeutic SD in MDD. Here, we further tested this model positing that homeostatically elevating net synaptic strength through therapeutic SD shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP)-like plasticity in patients with MDD into a more favorable window of associative plasticity. METHODS: We used paired associative stimulation (PAS), a transcranial magnetic stimulation protocol (TMS), to quantify cortical LTP-like plasticity after one night of therapeutic sleep deprivation in 28 patients with MDD. RESULTS: We demonstrate a significantly different inducibility of associative plasticity in clinical responders to therapeutic SD (> 50% improvement on the 6-item Hamilton-Rating-Scale for Depression, n=13) compared to non-responders (n=15), which was driven by a long-term depression (LTD)-like response in SD-non-responders. Indices of global net synaptic strength (wake EEG theta activity, intracortical inhibition and BDNF serum levels) were increased after SD in both groups, with responders showing a generally lower intracortical inhibition than non-responders. LIMITATIONS: Repetitive assessments prior to and after treatment would be needed to further determine potential mechanisms. CONCLUSION: After a night of therapeutic SD, clinical responders show a significantly higher inducibility of associative LTP-like plasticity than non-responders.

Sleep orchestrates indices of local plasticity and global network stability in the human cortex.

Animals and humans spend on average one third of their lives in sleep, but its functions remain to be specified. Distinct lines of research propose that sleep promotes local strengthening of information-bearing synapses (plasticity) and global downscaling of synaptic strength (stability) in neural networks-prerequisites for adaptive behavior in a changing environment. However, the potential orchestration of these processes, particularly in humans, needs to be further characterized. Here, we use electrophysiological, behavioral, and molecular indices to noninvasively study cortical plasticity and network stability in humans. We observe indices of local strengthening of prior induced long-term potentiation-like plasticity (paired associative stimulation induced change in motor-evoked potential) and global network stabilization (homeostatic regulation of wake EEG theta activity) after brief periods of nonrapid eye movement sleep compared with wakefulness. The interplay of local sleep slow oscillations and spindle activity, previously related to synaptic refinements during sleep, is identified as a potential mechanism. Our findings are consistent with the notion that sleep-specific brain activity patterns reduce the plasticity-stability dilemma by orchestrating local plasticity and global stability of neural assemblies in the human cortex. Future studies are needed to further decipher the neural mechanisms underlying our indirect observations.

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.

Sleep Strengthens but does Not Reorganize Memory Traces in a Verbal Creativity Task.

STUDY OBJECTIVES: Sleep after learning promotes the quantitative strengthening of new memories. Less is known about the impact of sleep on the qualitative reorganization of memory content. This study tested the hypothesis that sleep facilitates both memory strengthening and reorganization as indexed by a verbal creativity task. METHODS: Sixty healthy university students (30 female, 30 male, 20-30 years) were investigated in a randomized, controlled parallel-group study with three experimental groups (sleep, sleep deprivation, daytime wakefulness). At baseline, 60 items of the Compound Remote Associate (CRA) task were presented. At retest after the experimental conditions, the same items were presented again together with 20 new control items to disentangle off-line incubation from online performance effects. RESULTS: Sleep significantly strengthened formerly encoded memories in comparison to both wake conditions (improvement in speed of correctly resolved items). Offline reorganization was not enhanced following sleep, but was enhanced following sleep-deprivation in comparison to sleep and daytime wakefulness (solution time of previously incubated, newly solved items). Online performance did not differ between the groups (solution time of new control items). CONCLUSIONS: The results support the notion that sleep promotes the strengthening, but not the reorganization, of newly encoded memory traces in a verbal creativity task. Future studies are needed to further determine the impact of sleep on different types of memory reorganization, such as associative thinking, creativity and emotional memory processing, and potential clinical translations, such as the augmentation of psychotherapy through sleep interventions.

State-Dependent Partial Occlusion of Cortical LTP-Like Plasticity in Major Depression.

The synaptic plasticity hypothesis of major depressive disorder (MDD) posits that alterations in synaptic plasticity represent a final common pathway underlying the clinical symptoms of the disorder. This study tested the hypotheses that patients with MDD show an attenuation of cortical synaptic long-term potentiation (LTP)-like plasticity in comparison with healthy controls, and that this attenuation recovers after remission. Cortical synaptic LTP-like plasticity was measured using a transcranial magnetic stimulation protocol, ie, paired associative stimulation (PAS), in 27 in-patients with MDD according to ICD-10 criteria and 27 sex- and age-matched healthy controls. The amplitude of motor-evoked potentials was measured before and after PAS. Patients were assessed during the acute episode and at follow-up to determine the state- or trait-character of LTP-like changes. LTP-like plasticity, the PAS-induced increase in motor-evoked potential amplitudes, was significantly attenuated in patients with an acute episode of MDD compared with healthy controls. Patients with remission showed a restoration of synaptic plasticity, whereas the deficits persisted in patients without remission, indicative for a state-character of impaired LTP-like plasticity. The results provide first evidence for a state-dependent partial occlusion of cortical LTP-like plasticity in MDD. This further identifies impaired LTP-like plasticity as a potential pathomechanism and treatment target of the disorder.

Synaptic plasticity model of therapeutic sleep deprivation in major depression.

Therapeutic sleep deprivation (SD) is a rapid acting treatment for major depressive disorder (MDD). Within hours, SD leads to a dramatic decrease in depressive symptoms in 50-60% of patients with MDD. Scientifically, therapeutic SD presents a unique paradigm to study the neurobiology of MDD. Yet, up to now, the neurobiological basis of the antidepressant effect, which is most likely different from today's first-line treatments, is not sufficiently understood. This article puts the idea forward that sleep/wake-dependent shifts in synaptic plasticity, i.e., the neural basis of adaptive network function and behavior, represent a critical mechanism of therapeutic SD in MDD. Particularly, this article centers on two major hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, and on how they can be integrated into a novel synaptic plasticity model of therapeutic SD in MDD. As a major component, the model proposes that therapeutic SD, by homeostatically enhancing cortical synaptic strength, shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP) in patients with MDD in a more favorable window of associative plasticity. Research on the molecular effects of SD in animals and humans, including observations in the neurotrophic, adenosinergic, monoaminergic, and glutamatergic system, provides some support for the hypothesis of associative synaptic plasticity facilitation after therapeutic SD in MDD. The model proposes a novel framework for a mechanism of action of therapeutic SD that can be further tested in humans based on non-invasive indices and in animals based on direct studies of synaptic plasticity. Further determining the mechanisms of action of SD might contribute to the development of novel fast acting treatments for MDD, one of 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.

Sleep recalibrates homeostatic and associative synaptic plasticity in the human cortex.

Sleep is ubiquitous in animals and humans, but its function remains to be further determined. The synaptic homeostasis hypothesis of sleep-wake regulation proposes a homeostatic increase in net synaptic strength and cortical excitability along with decreased inducibility of associative synaptic long-term potentiation (LTP) due to saturation after sleep deprivation. Here we use electrophysiological, behavioural and molecular indices to non-invasively study net synaptic strength and LTP-like plasticity in humans after sleep and sleep deprivation. We demonstrate indices of increased net synaptic strength (TMS intensity to elicit a predefined amplitude of motor-evoked potential and EEG theta activity) and decreased LTP-like plasticity (paired associative stimulation induced change in motor-evoked potential and memory formation) after sleep deprivation. Changes in plasma BDNF are identified as a potential mechanism. Our study indicates that sleep recalibrates homeostatic and associative synaptic plasticity, believed to be the neural basis for adaptive behaviour, in humans.

Fear extinction as a model for synaptic plasticity in major depressive disorder.

BACKGROUND: The neuroplasticity hypothesis of major depressive disorder proposes that a dysfunction of synaptic plasticity represents a basic pathomechanism of the disorder. Animal models of depression indicate enhanced plasticity in a ventral emotional network, comprising the amygdala. Here, we investigated fear extinction learning as a non-invasive probe for amygdala-dependent synaptic plasticity in patients with major depressive disorder and healthy controls. METHODS: Differential fear conditioning was measured in 37 inpatients with severe unipolar depression (International Classification of Diseases, 10th revision, criteria) and 40 healthy controls. The eye-blink startle response, a subcortical output signal that is modulated by local synaptic plasticity in the amygdala in fear acquisition and extinction learning, was recorded as the primary outcome parameter. RESULTS: After robust and similar fear acquisition in both groups, patients with major depressive disorder showed significantly enhanced fear extinction learning in comparison to healthy controls, as indicated by startle responses to conditioned stimuli. The strength of extinction learning was positively correlated with the total illness duration. CONCLUSIONS: The finding of enhanced fear extinction learning in major depressive disorder is consistent with the concept that the disorder is characterized by enhanced synaptic plasticity in the amygdala and the ventral emotional network. Clinically, the observation emphasizes the potential of successful extinction learning, the basis of exposure therapy, in anxiety-related disorders despite the frequent comorbidity of major depressive disorder.

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.