The European Insomnia Guideline: An update on the diagnosis and treatment of insomnia 2023.

Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential-diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders, etc.), treatment-resistant insomnia (A) and for other indications (B). Cognitive-behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in-person or digitally (A). When cognitive-behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤ 4 weeks). Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged-release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive-behavioural therapy for insomnia (B).

From dawn to dusk-mimicking natural daylight exposure improves circadian rhythm entrainment in patients with severe brain injury.

STUDY OBJECTIVES: While light therapy has proven effective in re-entraining circadian rhythms, the potential of such an intervention has not been evaluated systematically in post-comatose patients with disorders of consciousness (DOC), who often have strongly altered circadian rhythms. METHODS: We recorded skin temperature over 7-8 days in patients with DOC in each of two conditions: habitual light (HL), and dynamic daylight (DDL) condition. While patients were in a room with usual clinic lighting in the HL condition, they were in an otherwise comparable room with biodynamic lighting (i.e. higher illuminance and dynamic changes in spectral characteristics during the day) in the DDL condition. To detect rhythmicity in the patients' temperature data, we computed Lomb-Scargle periodograms and analyzed normalized power, and peak period. Furthermore, we computed interdaily stability and intradaily variability, which provide information about rhythm entrainment and fragmentation. RESULTS: We analyzed data from 17 patients with DOC (i.e. unresponsive wakefulness syndrome [n = 15] and minimally conscious state [n = 2]). The period length of the patients' temperature rhythms was closer to 24 h in the DDL as compared to the HL condition (median median deviation from 24 h: DDL = 0.52 h, HL = 3.62 h). Specifically, in 11/17 (65%) patients the period length was closer to 24 h in the DDL condition. Furthermore, the patients' rhythm was more pronounced, more stable, and less variable in the DDL condition. CONCLUSIONS: Our results indicate that DDL stimulation entrains and stabilizes circadian rhythms. This highlights the importance of adequate room lighting as an adjunct therapeutic approach for improving circadian rhythms in severely brain-injured patients. TRIAL REGISTRATION INFORMATION: German Clinical Trials Register (DRKS00016041); registration: 18.01.2019; recording start: 04.06.2019 https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016041.

The Brain Selectively Tunes to Unfamiliar Voices during Sleep.

The brain continues to respond selectively to environmental stimuli during sleep. However, the functional role of such responses, and whether they reflect information processing or rather sensory inhibition, is not fully understood. Here, we present 17 human sleepers (14 females) with their own name and two unfamiliar first names, spoken by either a familiar voice (FV) or an unfamiliar voice (UFV), while recording polysomnography during a full night of sleep. We detect K-complexes, sleep spindles, and microarousals, and assess event-related and frequency responses as well as intertrial phase synchronization to the different stimuli presented during nonrapid eye movement (NREM) sleep. We show that UFVs evoke more K-complexes and microarousals than FVs. When both stimuli evoke a K-complex, we observe larger evoked potentials, more precise time-locking of brain responses in the delta band (1-4 Hz), and stronger activity in the high frequency (>16 Hz) range, in response to UFVs relative to FVs. Crucially, these differences in brain responses disappear completely when no K-complexes are evoked by the auditory stimuli. Our findings highlight discrepancies in brain responses to auditory stimuli based on their relevance to the sleeper and propose a key role for K-complexes in the modulation of sensory processing during sleep. We argue that such content-specific, dynamic reactivity to external sensory information enables the brain to enter a sentinel processing mode in which it engages in the important internal processes that are ongoing during sleep while still maintaining the ability to process vital external sensory information.SIGNIFICANCE STATEMENT Previous research has shown that sensory processing continues during sleep. Here, we studied the capacity of the sleeping brain to extract and process relevant sensory information. We presented sleepers with their own names and unfamiliar names spoken by either an FV or a UFV. During NREM sleep, UFVs elicited more K-complexes and microarousals than FVs. By contrasting stimuli that evoked K-complexes, we demonstrate that UFVs evoked larger, more synchronized brain responses as well as stronger power at high frequencies (>16 Hz) relative to FVs. These differences in brain responses disappeared when no K-complexes were evoked. Our results suggest a pivotal role for K-complexes in the selective processing of relevant information during NREM sleep.

Consensus on the reporting and experimental design of clinical and cognitive-behavioural neurofeedback studies (CRED-nf checklist).

Neurofeedback has begun to attract the attention and scrutiny of the scientific and medical mainstream. Here, neurofeedback researchers present a consensus-derived checklist that aims to improve the reporting and experimental design standards in the field.

Standing sentinel during human sleep: Continued evaluation of environmental stimuli in the absence of consciousness.

While it is a well-established finding that subjects' own names (SON) and familiar voices are salient during wakefulness, we here investigated processing of environmental stimuli during sleep including deep N3 and REM sleep. Besides the effects of sleep depth we investigated how sleep-specific EEG patterns (i.e. sleep spindles and slow oscillations [SOs]) relate to stimulus processing. Using 256-channel EEG we studied processing of auditory stimuli by means of event-related oscillatory responses (de-/synchronisation, ERD/ERS) and potentials (ERPs) in N = 17 healthy sleepers. We varied stimulus salience by manipulating subjective (SON vs. unfamiliar name) and paralinguistic emotional relevance (familiar vs. unfamiliar voice, FV/UFV). Results reveal that evaluation of voice familiarity continues during all NREM sleep stages and even REM sleep suggesting a 'sentinel processing mode' of the human brain in the absence of wake-like consciousness. Especially UFV stimuli elicit larger responses in a 1-15 Hz range suggesting they continue being salient. Beyond this, we find that sleep spindles and the negative slope of SOs attenuate information processing. However, unlike previously suggested they do not uniformly inhibit information processing, but inhibition seems to be scaled to stimulus salience.

Significance of circadian rhythms in severely brain-injured patients: A clue to consciousness?

OBJECTIVE: To investigate the relationship between the presence of a circadian body temperature rhythm and behaviorally assessed consciousness levels in patients with disorders of consciousness (DOC; i.e., vegetative state/unresponsive wakefulness syndrome or minimally conscious state). METHODS: In a cross-sectional study, we investigated the presence of circadian temperature rhythms across 6 to 7 days using external skin temperature sensors in 18 patients with DOC. Beyond this, we examined the relationship between behaviorally assessed consciousness levels and circadian rhythmicity. RESULTS: Analyses with Lomb-Scargle periodograms revealed significant circadian rhythmicity in all patients (range 23.5-26.3 hours). We found that especially scores on the arousal subscale of the Coma Recovery Scale-Revised were closely linked to the integrity of circadian variations in body temperature. Finally, we piloted whether bright light stimulation could boost circadian rhythmicity and found positive evidence in 2 out of 8 patients. CONCLUSION: The study provides evidence for an association between circadian body temperature rhythms and arousal as a necessary precondition for consciousness. Our findings also make a case for circadian rhythms as a target for treatment as well as the application of diagnostic and therapeutic means at times when cognitive performance is expected to peak.

Better than sham? A double-blind placebo-controlled neurofeedback study in primary insomnia.

See Thibault et al. (doi:10.1093/awx033) for a scientific commentary on this article.Neurofeedback training builds upon the simple concept of instrumental conditioning, i.e. behaviour that is rewarded is more likely to reoccur, an effect Thorndike referred to as the 'law of effect'. In the case of neurofeedback, information about specific electroencephalographic activity is fed back to the participant who is rewarded whenever the desired electroencephalography pattern is generated. If some kind of hyperarousal needs to be addressed, the neurofeedback community considers sensorimotor rhythm neurofeedback as the gold standard. Earlier treatment approaches using sensorimotor-rhythm neurofeedback indicated that training to increase 12-15 Hz sensorimotor rhythm over the sensorimotor cortex during wakefulness could reduce attention-deficit/hyperactivity disorder and epilepsy symptoms and even improve sleep quality by enhancing sleep spindle activity (lying in the same frequency range). In the present study we sought to critically test whether earlier findings on the positive effect of sensorimotor rhythm neurofeedback on sleep quality and memory could also be replicated in a double-blind placebo-controlled study on 25 patients with insomnia. Patients spent nine polysomnography nights and 12 sessions of neurofeedback and 12 sessions of placebo-feedback training (sham) in our laboratory. Crucially, we found both neurofeedback and placebo feedback to be equally effective as reflected in subjective measures of sleep complaints suggesting that the observed improvements were due to unspecific factors such as experiencing trust and receiving care and empathy from experimenters. In addition, these improvements were not reflected in objective electroencephalographic-derived measures of sleep quality. Furthermore, objective electroencephalographic measures that potentially reflected mechanisms underlying the efficacy of neurofeedback such as spectral electroencephalographic measures and sleep spindle parameters remained unchanged following 12 training sessions. A stratification into 'true' insomnia patients and 'insomnia misperceivers' (subjective, but no objective sleep problems) did not alter the results. Based on this comprehensive and well-controlled study, we conclude that for the treatment of primary insomnia, neurofeedback does not have a specific efficacy beyond unspecific placebo effects. Importantly, we do not find an advantage of neurofeedback over placebo feedback, therefore it cannot be recommended as an alternative to cognitive behavioural therapy for insomnia, the current (non-pharmacological) standard-of-care treatment. In addition, our study may foster a critical discussion that generally questions the effectiveness of neurofeedback, and emphasizes the importance of demonstrating neurofeedback efficacy in other study samples and disorders using truly placebo and double-blind controlled trials.

Preferential processing of emotionally and self-relevant stimuli persists in unconscious N2 sleep.

Information processing has been suggested to depend on the current state of the brain as well as stimulus characteristics (e.g. salience). We compared processing of salient stimuli (subject's own names [SONs] and angry voice [AV] stimuli) to processing of unfamiliar names (UNs) and neutral voice (NV) stimuli across different vigilance stages (i.e. wakefulness as well as sleep stages N1 and N2) by means of event-related oscillatory responses during wakefulness and a subsequent afternoon nap. Our findings suggest that emotional prosody and self-relevance drew more attentional resources during wakefulness with specifically AV stimuli being processed more strongly. During N1, SONs were more arousing than UNs irrespective of prosody. Moreover, emotional and self-relevant stimuli evoked stronger responses also during N2 sleep suggesting a 'sentinel processing mode' of the brain during this state of naturally occurring unconsciousness. Finally, this initial preferential processing of salient stimuli during N2 sleep seems to be followed by an inhibitory sleep-protecting process, which is reflected by a K-complex-like response.

Can self-relevant stimuli help assessing patients with disorders of consciousness?

Emotional and self-relevant stimuli are able to automatically attract attention and their use in patients suffering from disorders of consciousness (DOC) might help detecting otherwise hidden signs of cognition. We here recorded EEG in three Locked-in syndrome (LIS) and four Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) patients while they listened to the voice of a family member or an unfamiliar voice during a passive. Data indicate that, in a passive listening condition, the familiar voice induces stronger alpha desynchronization than the unfamiliar one. In an active condition, the target evoked stronger alpha desynchronization in controls, two LIS patients and one VS/UWS patient. Results suggest that self-relevant familiar voice stimuli can engage additional attentional resources and might allow the detection of otherwise hidden signs of instruction-following and thus residual awareness. Further studies are necessary to find sensitive paradigms that are suited to find subtle signs of cognition and awareness in DOC patients.

Event-related EEG power modulations and phase connectivity indicate the focus of attention in an auditory own name paradigm.

Estimating cognitive abilities in patients suffering from Disorders of Consciousness remains challenging. One cognitive task to address this issue is the so-called own name paradigm, in which subjects are presented with first names including the own name. In the active condition, a specific target name has to be silently counted. We recorded EEG during this task in 24 healthy controls, 8 patients suffering from Unresponsive Wakefulness Syndrome (UWS) and 7 minimally conscious (MCS) patients. EEG was analysed with respect to amplitude as well as phase modulations and connectivity. Results showed that general reactivity in the delta, theta and alpha frequency (event-related de-synchronisation, ERS/ERD, and phase locking between trials and electrodes) toward auditory stimulation was higher in controls than in patients. In controls, delta ERS and lower alpha ERD indexed the focus of attention in both conditions, late theta ERS only in the active condition. Additionally, phase locking between trials and delta phase connectivity was highest for own names in the passive and targets in the active condition. In patients, clear stimulus-specific differences could not be detected. However, MCS patients could reliably be differentiated from UWS patients based on their general event-related delta and theta increase independent of the type of stimulus. In conclusion, the EEG signature of the active own name paradigm revealed instruction-following in healthy participants. On the other hand, DOC patients did not show clear stimulus-specific processing. General reactivity toward any auditory input, however, allowed for a reliable differentiation between MCS and UWS patients.

EEG entropy measures indicate decrease of cortical information processing in Disorders of Consciousness.

OBJECTIVE: Clinical assessments that rely on behavioral responses to differentiate Disorders of Consciousness are at times inapt because of some patients' motor disabilities. To objectify patients' conditions of reduced consciousness the present study evaluated the use of electroencephalography to measure residual brain activity. METHODS: We analyzed entropy values of 18 scalp EEG channels of 15 severely brain-damaged patients with clinically diagnosed Minimally-Conscious-State (MCS) or Unresponsive-Wakefulness-Syndrome (UWS) and compared the results to a sample of 24 control subjects. Permutation entropy (PeEn) and symbolic transfer entropy (STEn), reflecting information processes in the EEG, were calculated for all subjects. Participants were tested on a modified active own-name paradigm to identify correlates of active instruction following. RESULTS: PeEn showed reduced local information content in the EEG in patients, that was most pronounced in UWS. STEn analysis revealed altered directed information flow in the EEG of patients, indicating impaired feed-backward connectivity. Responses to auditory stimulation yielded differences in entropy measures, indicating reduced information processing in MCS and UWS. CONCLUSIONS: Local EEG information content and information flow are affected in Disorders of Consciousness. This suggests local cortical information capacity and feedback information transfer as neural correlates of consciousness. SIGNIFICANCE: The utilized EEG entropy analyses were able to relate to patient groups with different Disorders of Consciousness.

Oscillatory brain responses to own names uttered by unfamiliar and familiar voices.

Among auditory stimuli, the own name is one of the most powerful and it is able to automatically capture attention and elicit a robust electrophysiological response. The subject's own name (SON) is preferentially processed in the right hemisphere, mainly because of its self-relevance and emotional content, together with other personally relevant information such as the voice of a familiar person. Whether emotional and self-relevant information are able to attract attention and can be, in future, introduced in clinical studies remains unclear. In the present study we used EEG and asked participants to count a target name (active condition) or to just listen to the SON or other unfamiliar names uttered by a familiar or unfamiliar voice (passive condition). Data reveals that the target name elicits a strong alpha event related desynchronization with respect to non-target names and triggers in addition a left lateralized theta synchronization as well as delta synchronization. In the passive condition alpha desynchronization was observed for familiar voice and SON stimuli in the right hemisphere. Altogether we speculate that participants engage additional attentional resources when counting a target name or when listening to personally relevant stimuli which is indexed by alpha desynchronization whereas left lateralized theta synchronization may be related to verbal working memory load. After validating the present protocol in healthy volunteers it is suggested to move one step further and apply the protocol to patients with disorders of consciousness in which the degree of residual cognitive processing and self-awareness is still insufficiently understood.

Enhancing sleep quality and memory in insomnia using instrumental sensorimotor rhythm conditioning.

EEG recordings over the sensorimotor cortex show a prominent oscillatory pattern in a frequency range between 12 and 15 Hz (sensorimotor rhythm, SMR) under quiet but alert wakefulness. This frequency range is also abundant during sleep, and overlaps with the sleep spindle frequency band. In the present pilot study we tested whether instrumental conditioning of SMR during wakefulness can enhance sleep and cognitive performance in insomnia. Twenty-four subjects with clinical symptoms of primary insomnia were tested in a counterbalanced within-subjects-design. Each patient participated in a SMR- as well as a sham-conditioning training block. Polysomnographic sleep recordings were scheduled before and after the training blocks. Results indicate a significant increase of 12-15 Hz activity over the course of ten SMR training sessions. Concomitantly, the number of awakenings decreased and slow-wave sleep as well as subjective sleep quality increased. Interestingly, SMR-training enhancement was also found to be associated with overnight memory consolidation and sleep spindle changes indicating a beneficial cognitive effect of the SMR training protocol for SMR "responders" (16 out of 24 participants). Although results are promising it has to be concluded that current results are of a preliminary nature and await further proof before SMR-training can be promoted as a non-pharmacological approach for improving sleep quality and memory performance.

Mirroring of a simple motor behavior in disorders of consciousness.

OBJECTIVE: In patients suffering from Disorders of Consciousness (DOC) electrophysiological recordings at bedside could serve as a complimentary and economical tool to improve diagnosis. We utilized a motor observation and imagination paradigm to gain new insights on preserved cognitive processing in DOC. METHODS: EEG brain oscillations were analyzed in 10 VS/UWS (Vegetative State/Unresponsive Wakefulness Syndrome) patients and 7 MCS (Minimally Conscious State) patients and 21 controls during observation and imagination of a grasping movement and group statistics were conducted. RESULTS: While control subjects showed a typical desynchronization at 8-15Hz during observation of a movement, MCS patients presented an analogue response at 8-10Hz, but exhibited a synchronization at 12-15Hz. The VS group did not show a systematic response. Imagery-related activation was only sustained for 1500ms even in control subjects, therefore, limiting conclusions regarding the ability to follow an instruction. Furthermore, a clinically diagnosed VS patient exhibited EEG responses indicative for MCS. CONCLUSION: Results indicate that MCS patients are still able to process an observed motor behavior on a basic sensory and perhaps even pre-motoric level, but seem not to be capable of "mirroring" the movement like healthy participants. SIGNIFICANCE: "Real-world" tasks as presented here carry the potential to identify residual cognitive functioning in DOC patients and may ultimately help to lower misdiagnosis rates.

Homeostatic sleep pressure and responses to sustained attention in the suprachiasmatic area.

Throughout the day, cognitive performance is under the combined influence of circadian processes and homeostatic sleep pressure. Some people perform best in the morning, whereas others are more alert in the evening. These chronotypes provide a unique way to study the effects of sleep-wake regulation on the cerebral mechanisms supporting cognition. Using functional magnetic resonance imaging in extreme chronotypes, we found that maintaining attention in the evening was associated with higher activity in evening than morning chronotypes in a region of the locus coeruleus and in a suprachiasmatic area (SCA) including the circadian master clock. Activity in the SCA decreased with increasing homeostatic sleep pressure. This result shows the direct influence of the homeostatic and circadian interaction on the neural activity underpinning human behavior.

Theta coupling in the human electroencephalogram during a working memory task.

The role of coupling between prefrontal and temporo-parietal brain areas within the theta frequency range of the human electroencephalogram was explored in a working memory task. During encoding of visual information higher theta amplitudes were observed in the right compared to the left hemisphere. Retrieval of visuospatial and verbal information elicited a more bilateral activation pattern. These effects were accompanied by theta coupling between dorsolateral prefrontal and right posterior temporal electrode sites during encoding. During retrieval prefrontal and bilateral temporo-parietal brain areas were coupled. These results support the idea of working memory functions being dependent on distributed prefrontal-temporal networks.