The first-night effect and the consistency of short sleep in insomnia disorder.

The nature and degree of objective sleep impairments in insomnia disorder remain unclear. This issue is complicated further by potential changes in sleep architecture on the first compared with subsequent nights in the laboratory. Evidence regarding differential first-night effects in people with insomnia disorder and controls is mixed. Here, we aimed to further characterize insomnia- and night-related differences in sleep architecture. A comprehensive set of 26 sleep variables was derived from two consecutive nights of polysomnography in 61 age-matched patients with insomnia and 61 good sleeper controls. People with insomnia expressed consistently poorer sleep than controls on several variables during both nights. While poorer sleep during the first night was observed in both groups, there were qualitative differences regarding the specific sleep variables expressing a first-night effect. Short sleep (total sleep time < 6 hr) was more likely during the first night and in insomnia, although approximately 40% of patients with insomnia presenting with short sleep on night 1 no longer met this criterion on night 2, which is important given the notion of short-sleeping insomnia as a robust subtype.

Emotional memories are enhanced when reactivated in slow wave sleep, but impaired when reactivated in REM.

Sleep supports memory consolidation. However, it is not completely clear how different sleep stages contribute to this process. While rapid eye movement sleep (REM) has traditionally been implicated in the processing of emotionally charged material, recent studies indicate a role for slow wave sleep (SWS) in strengthening emotional memories. Here, to directly examine which sleep stage is primarily involved in emotional memory consolidation, we used targeted memory reactivation (TMR) in REM and SWS during a daytime nap. Contrary to our hypothesis, reactivation of emotional stimuli during REM led to impaired memory. Consistent with this, REM% was correlated with worse recall in the group that took a nap without TMR. Meanwhile, cueing benefit in SWS was strongly correlated with the product of times spent in REM and SWS (SWS-REM product), and reactivation significantly enhanced memory in those with high SWS-REM product. Surprisingly, SWS-REM product was associated with better memory for reactivated items and poorer memory for non-reactivated items, suggesting that sleep both preserved and eliminated emotional memories, depending on whether they were reactivated. Notably, the emotional valence of cued items modulated both sleep spindles and delta/theta power. Finally, we found that emotional memories benefited from TMR more than did neutral ones. Our results suggest that emotional memories decay during REM, unless they are reactivated during prior SWS. Furthermore, we show that active forgetting complements memory consolidation, and both take place across SWS and REM. In addition, our findings expand upon recent evidence indicating a link between sleep spindles and emotional processing.

Actigraphy in studies on insomnia: Worth the effort?

In the past decades, actigraphy has emerged as a promising, cost-effective, and easy-to-use tool for ambulatory sleep recording. Polysomnography (PSG) validation studies showed that actigraphic sleep estimates fare relatively well in healthy sleepers. Additionally, round-the-clock actigraphy recording has been used to study circadian rhythms in various populations. To this date, however, there is little evidence that the diagnosis, monitoring, or treatment of insomnia can significantly benefit from actigraphy recordings. Using a case-control design, we therefore critically examined whether mean or within-subject variability of actigraphy sleep estimates or circadian patterns add to the understanding of sleep complaints in insomnia. We acquired actigraphy recordings and sleep diaries of 37 controls and 167 patients with varying degrees of insomnia severity for up to 9 consecutive days in their home environment. Additionally, the participants spent one night in the laboratory, where actigraphy was recorded alongside PSG to check whether sleep, in principle, is well estimated. Despite moderate to strong agreement between actigraphy and PSG sleep scoring in the laboratory, ambulatory actigraphic estimates of average sleep and circadian rhythm variables failed to successfully differentiate patients with insomnia from controls in the home environment. Only total sleep time differed between the groups. Additionally, within-subject variability of sleep efficiency and wake after sleep onset was higher in patients. Insomnia research may therefore benefit from shifting attention from average sleep variables to day-to-day variability or from the development of non-motor home-assessed indicators of sleep quality.

Dyscoordination of non-rapid eye movement sleep oscillations in autism spectrum disorder.

STUDY OBJECTIVES: Converging evidence from neuroimaging, sleep, and genetic studies suggest that dysregulation of thalamocortical interactions mediated by the thalamic reticular nucleus (TRN) contribute to autism spectrum disorder (ASD). Sleep spindles assay TRN function, and their coordination with cortical slow oscillations (SOs) indexes thalamocortical communication. These oscillations mediate memory consolidation during sleep. In the present study, we comprehensively characterized spindles and their coordination with SOs in relation to memory and age in children with ASD. METHODS: Nineteen children and adolescents with ASD, without intellectual disability, and 18 typically developing (TD) peers, aged 9-17, completed a home polysomnography study with testing on a spatial memory task before and after sleep. Spindles, SOs, and their coordination were characterized during stages 2 (N2) and 3 (N3) non-rapid eye movement sleep. RESULTS: ASD participants showed disrupted SO-spindle coordination during N2 sleep. Spindles peaked later in SO upstates and their timing was less consistent. They also showed a spindle density (#/min) deficit during N3 sleep. Both groups showed significant sleep-dependent memory consolidation, but their relations with spindle density differed. While TD participants showed the expected positive correlations, ASD participants showed the opposite. CONCLUSIONS: The disrupted SO-spindle coordination and spindle deficit provide further evidence of abnormal thalamocortical interactions and TRN dysfunction in ASD. The inverse relations of spindle density with memory suggest a different function for spindles in ASD than TD. We propose that abnormal sleep oscillations reflect genetically mediated disruptions of TRN-dependent thalamocortical circuit development that contribute to the manifestations of ASD and are potentially treatable.

Examining the effects of time of day and sleep on generalization.

Extracting shared structure across our experiences allows us to generalize our knowledge to novel contexts. How do different brain states influence this ability to generalize? Using a novel category learning paradigm, we assess the effect of both sleep and time of day on generalization that depends on the flexible integration of recent information. Counter to our expectations, we found no evidence that this form of generalization is better after a night of sleep relative to a day awake. Instead, we observed an effect of time of day, with better generalization in the morning than the evening. This effect also manifested as increased false memory for generalized information. In a nap experiment, we found that generalization did not benefit from having slept recently, suggesting a role for time of day apart from sleep. In follow-up experiments, we were unable to replicate the time of day effect for reasons that may relate to changes in category structure and task engagement. Despite this lack of consistency, we found a morning benefit for generalization when analyzing all the data from experiments with matched protocols (n = 136). We suggest that a state of lowered inhibition in the morning may facilitate spreading activation between otherwise separate memories, promoting this form of generalization.

Sharp Wave-Ripples in Human Amygdala and Their Coordination with Hippocampus during NREM Sleep.

Cooperative interactions between the amygdala and hippocampus are widely regarded as critical for overnight emotional processing of waking experiences, but direct support from the human brain for such a dialog is absent. Using overnight intracranial recordings in 4 presurgical epilepsy patients (3 female), we discovered ripples within human amygdala during nonrapid eye movement (NREM) sleep, a brain state known to contribute to affective processing. Like hippocampal ripples, amygdala ripples are associated with sharp waves, linked to sleep spindles, and tend to co-occur with their hippocampal counterparts. Moreover, sharp waves and ripples are temporally linked across the 2 brain structures, with amygdala ripples occurring during hippocampal sharp waves and vice versa. Combined with further evidence of interregional sharp-wave and spindle synchronization, these findings offer a potential physiological substrate for the NREM-sleep-dependent consolidation and regulation of emotional experiences.

The effects of eszopiclone on sleep spindles and memory consolidation in schizophrenia: a randomized clinical trial.

Sleep spindles, defining oscillations of stage 2 non-rapid eye movement sleep (N2), mediate memory consolidation. Schizophrenia is characterized by reduced spindle activity that correlates with impaired sleep-dependent memory consolidation. In a small, randomized, placebo-controlled pilot study of schizophrenia, eszopiclone (Lunesta®), a nonbenzodiazepine sedative hypnotic, increased N2 spindle density (number/minute) but did not significantly improve memory. This larger double-blind crossover study that included healthy controls investigated whether eszopiclone could both increase N2 spindle density and improve memory. Twenty-six medicated schizophrenia outpatients and 29 healthy controls were randomly assigned to have a placebo or eszopiclone (3 mg) sleep visit first. Each visit involved two consecutive nights of high density polysomnography with training on the Motor Sequence Task (MST) on the second night and testing the following morning. Patients showed a widespread reduction of spindle density and, in both groups, eszopiclone increased spindle density but failed to enhance sleep-dependent procedural memory consolidation. Follow-up analyses revealed that eszopiclone also affected cortical slow oscillations: it decreased their amplitude, increased their duration, and rendered their phase locking with spindles more variable. Regardless of group or visit, the density of coupled spindle-slow oscillation events predicted memory consolidation significantly better than spindle density alone, suggesting that they are a better biomarker of memory consolidation. In conclusion, sleep oscillations are promising targets for improving memory consolidation in schizophrenia, but enhancing spindles is not enough. Effective therapies also need to preserve or enhance cortical slow oscillations and their coordination with thalamic spindles, an interregional dialog that is necessary for sleep-dependent memory consolidation.

Analyzing human sleep EEG: A methodological primer with code implementation.

Recent years have witnessed a surge in human sleep electroencephalography (EEG) studies, employing increasingly sophisticated analysis strategies to relate electrophysiological activity to cognition and disease. However, properly calculating and interpreting metrics used in contemporary sleep EEG requires attention to numerous theoretical and practical signal-processing details that are not always obvious. Moreover, the vast number of outcome measures that can be derived from a single dataset inflates the risk of false positives and threatens replicability. We review several methodological issues related to 1) spectral analysis, 2) montage choice, 3) extraction of phase and amplitude information, 4) surrogate construction, and 5) minimizing false positives, illustrating both the impact of methodological choices on downstream results, and the importance of checking processing steps through visualization and simplified examples. By presenting these issues in non-mathematical form, with sleep-specific examples, and with code implementation, this paper aims to instill a deeper appreciation of methodological considerations in novice and non-technical audiences, and thereby help improve the quality of future sleep EEG studies.

Phase-based coordination of hippocampal and neocortical oscillations during human sleep.

During sleep, new memories undergo a gradual transfer from hippocampal (HPC) to neocortical (NC) sites. Precisely timed neural oscillations are thought to mediate this sleep-dependent memory consolidation, but exactly how sleep oscillations instantiate the HPC-NC dialog remains elusive. Employing overnight invasive electroencephalography in ten neurosurgical patients, we identified three broad classes of phase-based communication between HPC and lateral temporal NC. First, we observed interregional phase synchrony for non-rapid eye movement (NREM) spindles, and N2 and rapid eye movement (REM) theta activity. Second, we found asymmetrical N3 cross-frequency phase-amplitude coupling between HPC slow oscillations (SOs) and NC activity spanning the delta to high-gamma/ripple bands, but not in the opposite direction. Lastly, N2 theta and NREM spindle synchrony were themselves modulated by HPC SOs. These forms of interregional communication emphasize the role of HPC SOs in the HPC-NC dialog, and may offer a physiological basis for the sleep-dependent reorganization of mnemonic content.

No evidence for spontaneous cross-frequency phase-phase coupling in the human hippocampus.

Cross-frequency phase-phase coupling (PPC) has been suggested to play a role in cognitive processing and, in particular, in memory consolidation during sleep. Controversial results have been reported regarding the existence of spontaneous phase-phase coupling in the hippocampus. Here, we investigated this phenomenon in intracranial EEG recordings from the human hippocampus acquired during waking state and different sleep stages. We estimated the strength of interactions between different pairs of frequency bands and evaluated the statistical significance of findings using surrogates that build on different null hypotheses. Indications for spontaneous phase-phase coupling were only observed when testing with less rigorous surrogates. When requiring that all four surrogate tests be passed, however, there were no significant indications for phase-phase coupling. In conclusion, we did not detect evidence for spontaneous cross-frequency phase-phase coupling in the human hippocampus.

Effects of music on behavior and physiological stress response of domestic cats in a veterinary clinic.

OBJECTIVES: Our objective was to determine if feline-specific music played in a veterinary clinical setting would promote lower cat stress scores (CSSs), lower mean handling scale scores (HSs) and reduced neutrophil:lymphocyte ratios (NLRs) in cats during physical examinations. METHODS: Cats were exposed to one of three auditory stimuli tests - silence, classical music and cat-specific music - during three physical examinations 2 weeks apart. CSSs were recorded at pre- and post-auditory tests and during the examination period. The HSs were recorded at the physical examination period. The physiological stress was assessed via NLRs. RESULTS: The pre-auditory test showed no difference in CSS between cats listening to silence, classical music and cat music. CSSs for post-auditory tests and examination periods were not significantly different between silence and classical music; however, CSSs were significantly decreased in cats listening to cat music vs silence and in cats listening to cat music vs classical music. HSs were not different in cats listening to silence vs classical music, but were significantly lower in cats listening to cat music vs silence and classical music. No difference was found in NLRs among all three auditory stimuli tests. CONCLUSIONS AND RELEVANCE: Listening to cat-specific music prior to, and during, physical examination was associated with lower CSSs and lower HSs in cats, but had no effect on the physiological stress responses measured by NLRs. We conclude that cat-specific music may benefit cats by decreasing the stress levels and increasing the quality of care in veterinary clinical settings.

Heterogeneous profiles of coupled sleep oscillations in human hippocampus.

Cross-frequency coupling of sleep oscillations is thought to mediate memory consolidation. While the hippocampus is deemed central to this process, detailed knowledge of which oscillatory rhythms interact in the sleeping human hippocampus is lacking. Combining intracranial hippocampal and non-invasive electroencephalography from twelve neurosurgical patients, we characterized spectral power and coupling during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Hippocampal coupling was extensive, with the majority of channels expressing spectral interactions. NREM consistently showed delta-ripple coupling, but ripples were also modulated by slow oscillations (SOs) and sleep spindles. SO-delta and SO-theta coupling, as well as interactions between delta/theta and spindle/beta frequencies also occurred. During REM, limited interactions between delta/theta and beta frequencies emerged. Moreover, oscillatory organization differed substantially between i) hippocampus and scalp, ii) sites along the anterior-posterior hippocampal axis, and iii) individuals. Overall, these results extend and refine our understanding of hippocampal sleep oscillations.

Sleep selectively stabilizes contextual aspects of negative memories.

Sleep and emotion are both powerful modulators of the long-term stability of episodic memories, but precisely how these factors interact remains unresolved. We assessed changes in item recognition, contextual memory, and affective tone for negative and neutral memories across a 12 h interval containing sleep or wakefulness in 71 human volunteers. Our data indicate a sleep-dependent stabilization of negative contextual memories, in a way not seen for neutral memories, item recognition, or across wakefulness. Furthermore, retention of contextual memories was positively associated with the proportion of time spent in non-rapid eye movement sleep in a valence-independent manner. Finally, while affective responses to previously seen negative stimuli and to both old and new neutral stimuli decreased across an interval of sleep, effects for memorized items did not differ reliably between sleep and wake. These results add to our understanding of the complex interrelations among sleep, memory, and emotion.

Variability and stability of large-scale cortical oscillation patterns.

Individual differences in brain organization exist at many spatiotemporal scales and underlie the diversity of human thought and behavior. Oscillatory neural activity is crucial for these processes, but how such rhythms are expressed across the cortex within and across individuals is poorly understood. We conducted a systematic characterization of brain-wide activity across frequency bands and oscillatory features during rest and task execution. We found that oscillatory profiles exhibit sizable group-level similarities, indicating the presence of common templates of oscillatory organization. Nonetheless, well-defined subject-specific network profiles were discernible beyond the structure shared across individuals. These individualized patterns were sufficiently stable to recognize individuals several months later. Moreover, network structure of rhythmic activity varied considerably across distinct oscillatory frequencies and features, indicating the existence of several parallel information processing streams embedded in distributed electrophysiological activity. These findings suggest that network similarity analyses may be useful for understanding the role of large-scale brain oscillations in physiology and behavior.

Large-scale structure and individual fingerprints of locally coupled sleep oscillations.

Slow oscillations and sleep spindles, the canonical electrophysiological oscillations of nonrapid eye movement sleep, are thought to gate incoming sensory information, underlie processes of sleep-dependent memory consolidation, and are altered in various neuropsychiatric disorders. Accumulating evidence of the predominantly local expression of these individual oscillatory rhythms suggests that their cross-frequency interactions may have a similar local component. However, it is unclear whether locally coordinated sleep oscillations exist across the cortex, and whether and how these dynamics differ between fast and slow spindles, and sleep stages. Moreover, substantial individual variability in the expression of both spindles and slow oscillations raises the possibility that their temporal organization shows similar individual differences. Using two nights of multichannel electroencephalography recordings from 24 healthy individuals, we characterized the topography of slow oscillation-spindle coupling. We found that while slow oscillations are highly restricted in spatial extent, the phase of the local slow oscillation modulates local spindle activity at virtually every cortical site. However, coupling dynamics varied with spindle class, sleep stage, and cortical region. Moreover, the slow oscillation phase at which spindles were maximally expressed differed markedly across individuals while remaining stable across nights. These findings both add an important spatial aspect to our understanding of the temporal coupling of sleep oscillations and demonstrate the heterogeneity of coupling dynamics, which must be taken into account when formulating mechanistic accounts of sleep-related memory processing.

Individual Differences in Frequency and Topography of Slow and Fast Sleep Spindles.

Sleep spindles are transient oscillatory waveforms that occur during non-rapid eye movement (NREM) sleep across widespread cortical areas. In humans, spindles can be classified as either slow or fast, but large individual differences in spindle frequency as well as methodological difficulties have hindered progress towards understanding their function. Using two nights of high-density electroencephalography recordings from 28 healthy individuals, we first characterize the individual variability of NREM spectra and demonstrate the difficulty of determining subject-specific spindle frequencies. We then introduce a novel spatial filtering approach that can reliably separate subject-specific spindle activity into slow and fast components that are stable across nights and across N2 and N3 sleep. We then proceed to provide detailed analyses of the topographical expression of individualized slow and fast spindle activity. Group-level analyses conform to known spatial properties of spindles, but also uncover novel differences between sleep stages and spindle classes. Moreover, subject-specific examinations reveal that individual topographies show considerable variability that is stable across nights. Finally, we demonstrate that topographical maps depend nontrivially on the spindle metric employed. In sum, our findings indicate that group-level approaches mask substantial individual variability of spindle dynamics, in both the spectral and spatial domains. We suggest that leveraging, rather than ignoring, such differences may prove useful to further our understanding of the physiology and functional role of sleep spindles.

Coordination of Slow Waves With Sleep Spindles Predicts Sleep-Dependent Memory Consolidation in Schizophrenia.

Study Objectives: Schizophrenia patients have correlated deficits in sleep spindle density and sleep-dependent memory consolidation. In addition to spindle density, memory consolidation is thought to rely on the precise temporal coordination of spindles with slow waves (SWs). We investigated whether this coordination is intact in schizophrenia and its relation to motor procedural memory consolidation. Methods: Twenty-one chronic medicated schizophrenia patients and 17 demographically matched healthy controls underwent two nights of polysomnography, with training on the finger tapping motor sequence task (MST) on the second night and testing the following morning. We detected SWs (0.5-4 Hz) and spindles during non-rapid eye movement (NREM) sleep. We measured SW-spindle phase-amplitude coupling and its relation with overnight improvement in MST performance. Results: Patients did not differ from controls in the timing of SW-spindle coupling. In both the groups, spindles peaked during the SW upstate. For patients alone, the later in the SW upstate that spindles peaked and the more reliable this phase relationship, the greater the overnight MST improvement. Regression models that included both spindle density and SW-spindle coordination predicted overnight improvement significantly better than either parameter alone, suggesting that both contribute to memory consolidation. Conclusion: Schizophrenia patients show intact spindle-SW temporal coordination, and these timing relationships, together with spindle density, predict sleep-dependent memory consolidation. These relations were seen only in patients suggesting that their memory is more dependent on optimal spindle-SW timing, possibly due to reduced spindle density. Interventions to improve memory may need to increase spindle density while preserving or enhancing the coordination of NREM oscillations.

Phase-clustering bias in phase-amplitude cross-frequency coupling and its removal.

BACKGROUND: Cross-frequency coupling methods allow for the identification of non-linear interactions across frequency bands, which are thought to reflect a fundamental principle of how electrophysiological brain activity is temporally orchestrated. In this paper we uncover a heretofore unknown source of bias in a commonly used method that quantifies cross-frequency coupling (phase-amplitude-coupling, or PAC). NEW METHOD: We demonstrate that non-uniform phase angle distributions--a phenomenon that can readily occur in real data--can under some circumstances produce statistical errors and uninterpretable results when using PAC. We propose a novel debiasing procedure that, through a simple linear subtraction, effectively ameliorates this phase clustering bias. RESULTS: Simulations showed that debiased PAC (dPAC) accurately detected the presence of coupling. This was true even in the presence of moderate noise levels, which inflated the phase clustering bias. Finally, dPAC was applied to intracranial sleep recordings from a macaque monkey, and to hippocampal LFP data from a freely moving rat, revealing robust cross-frequency coupling in both data sets. COMPARISON WITH EXISTING METHODS: Compared to dPAC, regular PAC showed inflated or deflated estimations and statistically negative coupling values, depending on the strength of the bias and the angle of coupling. Noise increased these unwanted effects. Two other frequently used phase-amplitude coupling methods (the Modulation Index and Phase Locking Value) were also affected by the bias, though allowed for statistical inferences that were similar to dPAC. CONCLUSION: We conclude that dPAC provides a simple modification of PAC, and thereby offers a cleaner and possibly more sensitive alternative method, to more accurately assess phase-amplitude coupling.

Slow oscillations during sleep coordinate interregional communication in cortical networks.

Large-amplitude sleep slow oscillations group faster neuronal oscillations and are of functional relevance for memory performance. However, relatively little is known about the impact of slow oscillations on functionally coupled networks. Here, we provide a comprehensive view on how human slow oscillatory dynamics influence various measures of brain processing. We demonstrate that slow oscillations coordinate interregional cortical communication, as assessed by phase synchrony in the sleep spindle frequency range and cross-frequency coupling between spindle and beta activity. Furthermore, we show that the organizing role of slow oscillations is restricted to circumscribed topographical areas. These findings add importantly to our basic understanding of the orchestrating role of slow oscillations. In addition, they are of considerable relevance for accounts of sleep-dependent memory reprocessing and consolidation.