European guideline for the diagnosis and treatment of insomnia

This European guideline for the diagnosis and treatment of insomnia was developed by a task force of the European Sleep Research Society, with the aim of providing clinical recommendations for the management of adult patients with insomnia. The guideline is based on a systematic review of relevant meta-analyses published till June 2016. The target audience for this guideline includes all clinicians involved in the management of insomnia, and the target patient population includes adults with chronic insomnia disorder. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to grade the evidence and guide recommendations. The diagnostic procedure for insomnia, and its co-morbidities, should include a clinical interview consisting of a sleep history (sleep habits, sleep environment, work schedules, circadian factors), the use of sleep questionnaires and sleep diaries, questions about somatic and mental health, a physical examination and additional measures if indicated (i.e. blood tests, electrocardiogram, electroencephalogram; strong recommendation, moderate- to high-quality evidence). Polysomnography can be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders), in treatment-resistant insomnia, for professional at-risk populations and when substantial sleep state misperception is suspected (strong recommendation, high-quality evidence). Cognitive behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (strong recommendation, high-quality evidence). A pharmacological intervention can be offered if cognitive behavioural therapy for insomnia is not sufficiently effective or not available. Benzodiazepines, benzodiazepine receptor agonists and some antidepressants are effective in the short-term treatment of insomnia (≤4 weeks; weak recommendation, moderate-quality evidence). Antihistamines, antipsychotics, melatonin and phytotherapeutics are not recommended for insomnia treatment (strong to weak recommendations, low- to very-low-quality evidence). Light therapy and exercise need to be further evaluated to judge their usefulness in the treatment of insomnia (weak recommendation, low-quality evidence). Complementary and alternative treatments (e.g. homeopathy, acupuncture) are not recommended for insomnia treatment (weak recommendation, very-low-quality evidence).

Relation between heart beat fluctuations and cyclic alternating pattern during sleep in insomnia patients.

Insomnia is a condition that affects the nervous and muscular system. Thirty percent of the population between 18 and 60 years suffers from insomnia. The effects of this disorder involve problems such as poor school or job performance and traffic accidents. In addition, patients with insomnia present changes in the cardiac function during sleep. Furthermore, the structure of electroencephalographic A-phases, which builds up the Cyclic Alternating Pattern during sleep, is related to the insomnia events. Therefore, the relationship between these brain activations (A-phases) and the autonomic nervous system would be of interest, revealing the interplay of central and autonomic activity during insomnia. With this goal, a study of the relationship between A-phases and heart rate fluctuations is presented. Polysomnography recording of five healthy subjects, five sleep misperception patients and five patients with psychophysiological insomnia were used in the study. Detrended Fluctuation Analysis (DFA) was used in order to evaluate the heart rate dynamics and this was correlated with the number of A-phases. The results suggest that pathological patients present changes in the dynamics of the heart rate. This is reflected in the modification of A-phases dynamics, which seems to modify of heart rate dynamics.

On separability of A-phases during the cyclic alternating pattern.

A statistical analysis of the separability of EEG A-phases, with respect to basal activity, is presented in this study. A-phases are short central events that build up the Cyclic Alternating Pattern (CAP) during sleep. The CAP is a brain phenomenon which is thought to be related to the construction, destruction and instability of sleep stages dynamics. From the EEG signals, segments obtained around the onset and offset of the A-phases were used to evaluate the separability between A-phases and basal sleep stage oscillations. In addition, a classifier was trained to separate the different A-phase types (A1, A2 and A3). Temporal, energy and complexity measures were used as descriptors for the classifier. The results show a percentage of separation between onset and preceding basal oscillations higher than 85 % for all A-phases types. For Offset separation from following baseline, the accuracy is higher than 80 % but specificity is around 75%. Concerning to A-phase type separation, A1-phase and A3-phase are well separated with accuracy higher than 80, while A1 and A2-phases show a separation lower than 50%. These results encourage the design of automatic classifiers for Onset detection and for separating among A-phases type A1 and A3. On the other hand, the A-phase Offsets present a smooth transition towards the basal sleep stage oscillations, and A2-phases are very similar to A1-phases, suggesting that a high uncertainty may exist during CAP annotation.

Characterization of the autonomic system during the cyclic alternating pattern of sleep.

Evaluation of the RR variability was carried out during the Cyclic Alternating Pattern (CAP) in sleep. CAP is a central phenomenon formed by short events called A-phases that break basal electroencephalogram (EEG) oscillations of the sleep stages. A-phases are classified in three types (A1, A2 and A3) based on the EEG desynchronization during A-phase. However, the relation of A-phases with other systems, such as cardiovascular system, is unclear and a deep analysis is required. For the study, six patients with Nocturnal Front Lobe Epilepsy (NFLE) and other six healthy controls patients underwent whole night polysomnographic recordings with CAP and hypnogram annotations. Amplitude reduction and time delay of the RR intervals minimum with respect to A-phases onset were computed. In addition, the same process was computed over randomly chosen RR interval segments during the NREM sleep for further comparison. The results suggest that the onset of the A-phases is correlated with a significative increase of the heart rate that peaks at around 4s after the Aphase onset, independently of the A-phase subtype.

Insomnia types and sleep microstructure dynamics.

This work aims to investigate sleep microstructure as expressed by Cyclic Alternating Pattern (CAP), and its possible alterations in pathological sleep. Three groups, of 10 subjects each, are considered: a) normal sleep, b) psychophysiological insomnia, and c) sleep misperception. One night sleep PSG and sleep macro- micro structure annotations were available per subject. The statistical properties and the dynamics of CAP events are in focus. Multiscale and non-linear methods are presented for the analysis of the microstructure event time series, applied for each type of CAP events, and their combination. The results suggest that a) both types of insomnia present CAP differences from normal sleep related to hyperarousal, b) sleep misperception presents more extensive differences from normal, potentially reflecting multiple sleep mechanisms, c) there are differences between the two types of insomnia as regard to the intertwining of events of different subtypes. The analysis constitutes a contribution towards new markers for the quantitative characterization of insomnia, and its subtypes.

Nonlinear analysis of the change points between A and B phases during the Cyclic Alternating Pattern under normal sleep.

This study analyzes the nonlinear properties of the EEG at transition points of the sequences that build the Cyclic Alternating Pattern (CAP). CAP is a sleep phenomenon built up by consecutive sequences of activations and non-activations observed during the sleep time. The sleep condition can be evaluated from the patterns formed by these sequences. Eleven recordings from healthy and good sleepers were included in this study. We investigated the complexity properties of the signal at the onset and offset of the activations. The results show that EEG signals present significant differences (p<0.05) between activations and non-activations in the Sample Entropy and Tsallis Entropy indices. These indices could be useful in the development of automatic methods for detecting the onset and offset of the activations, leading to significant savings of the physician's time by simplifying the manual inspection task.

A novel method to assist the detection of the Cyclic Alternating Pattern (CAP).

This study proposes a novel method to assist the detection of the components that build up the Cyclic Alternating Pattern (CAP). CAP is a sleep phenomenon formed by consecutive sequences of activations (A1, A2, A3) and non-activations during nonREM sleep. The main importance of CAP evaluation is the possibility of defining the sleep process more accurately. Ten recordings from healthy and good sleepers were included in this study. The method is based on inferential statistics to define the initial and ending points of the CAP components based only on an initialization point given by the expert. The results show concordance up to 95% for A1, 85% for A2 and 60% for A3, together with an overestimation of 1.5 s in A1, 1.3 s in A2 and 0 s in A3. The total CAP rate presents a total underestimation of 7 min. Those results suggest that the method is able to accurately detect the initial and ending points of the activations, and may be helpful for the physicians by reducing the time dedicated to the manual inspection task.

Predicting EEG complexity from sleep macro and microstructure.

This work investigates the relation between the complexity of electroencephalography (EEG) signal, as measured by fractal dimension (FD), and normal sleep structure in terms of its macrostructure and microstructure. Sleep features are defined, encoding sleep stage and cyclic alternating pattern (CAP) related information, both in short and long term. The relevance of each sleep feature to the EEG FD is investigated, and the most informative ones are depicted. In order to quantitatively assess the relation between sleep characteristics and EEG dynamics, a modeling approach is proposed which employs subsets of the sleep macrostructure and microstructure features as input variables and predicts EEG FD based on these features of sleep micro/macrostructure. Different sleep feature sets are investigated along with linear and nonlinear models. Findings suggest that the EEG FD time series is best predicted by a nonlinear support vector machine (SVM) model, employing both sleep stage/transitions and CAP features at different time scales depending on the EEG activation subtype. This combination of features suggests that short-term and long-term history of macro and micro sleep events interact in a complex manner toward generating the dynamics of sleep.

Sleep bruxism and sleep arousal: an experimental challenge to assess the role of cyclic alternating pattern.

Rhythmic masticatory muscle activity (RMMA) is the characteristic electromyographic pattern of sleep bruxism (SB), a sleep-related motor disorder associated with sleep arousal. Sleep arousals are generally organised in a clustered mode known as the cyclic alternating pattern (CAP). CAP is the expression of sleep instability between sleep maintaining processes (phase A1) and stronger arousal processes (phases A2 and A3). This study aimed to investigate the role of sleep instability on RMMA/SB occurrence by analysing CAP and electroencephalographic (EEG) activities. The analysis was performed on the sleep recordings of 8 SB subjects and 8 controls who received sensory stimulations during sleep. Baseline and experimental nights were compared for sleep variables, CAP, and EEG spectral analyses using repeated measure ANOVAs. Overall, no differences in sleep variables and EEG spectra were found between SB subjects and controls. However, SB subjects had higher sleep instability (more phase A3) than controls (P= 0·05). The frequency of phase A3 was higher in the pre-REM sleep periods (P < 0·001), where peaks in RMMA/SB activity were also observed (P = 0·05). When sleep instability was experimentally increased by sensory stimuli, both groups showed an enhancement in EEG theta and alpha power (P = 0·04 and 0·02, respectively) and significant increases in sleep arousal and all CAP variables. No change in RMMA/SB index was found within either groups (RMMA/SB occurred in all SB subjects and only one control during the experimental night). These findings suggest that CAP phase A3 may act as a permissive window rather than a generator of RMMA/SB activity in predisposed individuals.

Assessment of the EEG complexity during activations from sleep.

The present study quantitatively analyzes the EEG characteristics during activations (Act) that occur during NREM sleep, and constitute elements of sleep microstructure (i.e. the Cyclic Alternating Pattern). The fractal dimension (FD) and the sample entropy (SampEn) measures were used to study the different sleep stages and the Act that build up the sleep structure. Polysomnographic recordings from 10 good sleepers were analyzed. The complexity indexes of the Act were compared with the non-activation (NAct) periods during non-REM sleep. In addition, complexity measures among the different Act subtypes (A1, A2 and A3) were analyzed. A3 presented a quite similar complexity independently of the sleep stage, while A1 and A2 showed higher complexity in light sleep than during deep sleep. The current results suggest that Act present a hierarchic complexity between subtypes A3 (higher), A2 (intermediate) and A1 (lower) in all sleep stages.

CAP sleep in insomnia: new methodological aspects for sleep microstructure analysis.

This work aims to propose new methodologies for the quantitative characterization of insomnia. Sleep microstructure, as expressed by Cyclic Alternatic pattern (CAP) sleep, is studied and differences between normal sleepers and insomniacs are investigated. The dynamic in the structure of CAP activation events is studied by use of wavelet analysis and the content of events, i.e. EEG dynamics, is studied in terms of complexity analysis. Both in structure and content, features exhibiting statistically significant differences are proposed, opening new perspectives for the understanding and the quantitative characterization of sleep and its disorders.

EEG complexity during sleep: on the effect of micro and macro sleep structure.

This work investigates the relation between EEG complexity measures, in particular Fractal Dimension and Sample Entropy, and sleep structure, in terms of both macrostructure, i.e. sleep stages, and microstructure, i.e. phase A activation of CAP sleep. Activation phases are compared with the non-activation periods of non-REM sleep. The study suggests that complexity features can serve as consistent descriptors of sleep dynamics and can potentially assist in the classification of sleep stages.

Effects of zolpidem on cyclic alternating pattern, an objective marker of sleep instability, in Japanese patients with psychophysiological insomnia: a randomized crossover comparative study with placebo.

OBJECTIVE: A placebo-controlled randomized crossover study to investigate the effects of zolpidem on sleep stability in Japanese insomniac patients was performed using the cyclic alternating pattern (CAP) rate, a polysomnographic marker that reflects sleep instability. METHODS: Seventeen patients (5 M and 12 F, mean age: 40.4+/-13.6 years) who met the International Classification of Sleep Disorders (ICSD) criteria for psychophysiological insomnia were evaluated. During the first period, patients were administered the placebo on the first night, followed by either zolpidem or the placebo on the second night (treatment night). The second crossover period was conducted after a minimum 3-day observation. Improvement in the overnight CAP rate was the primary endpoint. Secondary endpoints included the CAP variables, conventional sleep variables, EEG arousals, subjective evaluation of sleep quality (measured by means of a visual analogue scale and the St. Mary's Hospital Sleep Questionnaire), and drug safety. RESULTS: Zolpidem significantly decreased the overnight CAP rate values (57.6 vs. 39.0%, p=0.009) and improved "sleep depth" (p=0.044) and "sleep quality" (p=0.023) subjective questionnaire scores. Zolpidem also significantly improved VAS (p=0.036). The amount of time spent in sleep stages 3+4 was significantly increased by zolpidem without affecting the amounts of stage 2 and rapid eye movement (REM) sleep. Significant negative correlations were found when the sleep quality score was matched to the CAP rate (p=0.022). No serious adverse events occurred during the study. DISCUSSION: In Japanese patients with psychophysiological insomnia, zolpidem increased sleep stability by significantly improving the overnight CAP rate. Zolpidem also improved sleep depth and sleep quality, both subjectively and objectively.

The challenge of chronic insomnia: is non-nightly hypnotic treatment a feasible alternative?

The adverse effects of insomnia on health and quality of life are matters receiving increasing attention. Yet, surveys have consistently shown that most people suffering from insomnia do not seek medical help, perhaps, in part, because of a concern of becoming dependent on hypnotic medication. The treatment of chronic insomnia poses a particular dilemma in that continuous hypnotic treatment is restricted in many countries to a maximum of 4 weeks, and behavioural treatment is not readily available. Non-nightly hypnotic treatment of chronic insomnia offers a promising alternative option for the many patients whose symptoms do not necessitate nightly drug intake, allaying fears of psychological dependence on medication and respecting regulatory constraints on hypnotic use while providing patients with adequate symptom relief. The practical feasibility and efficacy of this approach has been demonstrated with zolpidem using various treatment regimens and study designs. So far, six clinical trials have been completed on over 4000 patients. Published results show effective treatment of insomnia without any evidence of either adverse event associated with a discontinuous regimen or increased hypnotic use over the treatment period.

Spike-wave discharge and the microstructure of sleep-wake continuum in idiopathic generalised epilepsy.

This review summarises all the evidences about the influence of different vigilance states on the occurrence of spike wave discharge (SWD) in idiopathic generalised epilepsy (IGE) patients. Numerous converging observations showed that full REM-sleep and alert wakefulness exert strong inhibition. A critical zone of vigilance which is a transitional state between waking and non-REM (NREM) sleep, and NREM sleep and REM sleep, has a promoting effect on the absence type spike wave discharge. Spike wave discharges are associated with phasic arousals without awakening and are attached to oscillation son the microstructural level of sleep, perpetuated by cyclic arousal events known as 'cyclic alternating pattern' (CAP), especially within the critical zone, but also along the whole sleep process. More specifically SWD seems to be attached to the 'A-phase' of CAP which is a reactive one and reflects synchronised NREM sleep EEG elements, like K-complexes, spindles and delta groups. The more slow wave elements are found in phase A--like in subtype A1--the more the coincidence with SWD occurs, and the more it is characterised by fast rhythms--as in subtype A2 and A3--the less the association with SWD could be observed. Since subtype A1 is associated with the first sleep cycle and with the descending branches of cycles, it is concluded that SWD appear in those dynamic moments of vigilance level oscillations which were characterised by strong sleep-like answers to arousal influences in high sleep pressure periods of sleep cyclicity. These data harmonize with another line of evidence suggesting that SWD represent the epileptic variant of the complex thalamocortical system function which is the substrate of NREM sleep EEG phenomena. In idiopathic generalised epilepsy there is a growing body of evidence that--as it was assumed by Gloor--spindles transform to SWD pattern. These data explain why those dynamic changes which evoke sleep responses are promoting for the occurrence of SWD. Adapting these data we offer a new interpretation to explain the strong activation effect of sleep deprivation in this kind of epilepsy. We assume that it is mainly due to the forced vigilance level oscillations, especially in morning, when elevated sleep pressure and circadian wake promoting forces, representing opposite tendencies, increase the amount of oscillations.

Sleep in Lennox-Gastaut syndrome: the role of the cyclic alternating pattern (CAP) in the gate control of clinical seizures and generalized polyspikes.

Non-rapid eye movement (NREM) sleep contains periods of arousal instability (cyclic alternating pattern or CAP) and periods of arousal stability (non-CAP). During CAP, arousal oscillates between higher (phase A) and lower (phase B) levels of activation. We evaluated the relationship between CAP and the occurrence of epileptic events, i.e. clinical seizures and generalized interictal discharges, during sleep in 10 patients with Lennox-Gastaut syndrome (LGS). The macro- and microstructure of sleep of 10 attended overnight polysomnograms were analyzed. Compared with 10 age- and gender-matched controls, patients with LGS had significantly less stage 2 and REM sleep and higher amounts of CAP rate (68% vs. 33%; P<0.0001). The number of generalized polyspike bursts per hour of sleep was highest in slow wave sleep (226.5+/-57.6) and lowest in REM sleep (3.9+/-1.5). The polyspike burst frequency was significantly greater (P<0.017) during CAP (213.2+/-60.1) than during non-CAP (100.3+/-40), and within CAP, generalized polyspikes occurred more often (P=0.005) during phase A (461.1+/-127.2) than during phase B (6.1+/-1.9). The total amount of generalized polyspike bursts identified in NREM sleep correlated positively both with the number of A phases containing at least one generalized polyspike (P=0.005) and with the mean number of polyspikes within each of these A phases (P<0.0001). Nocturnal clinical seizures occurred in 8 of the 10 patients and showed a similar trend. We conclude from our results that CAP modulates the occurrence of both clinical seizures and generalized epileptic discharges in LGS by means of a gate-control mechanism: an independent spike generator is inhibited in phase B and non-CAP and bursts with its intrinsic activity in phase A.

Combined influence of cyclic arousability and EEG synchrony on generalized interictal discharges within the sleep cycle.

PURPOSE: to analyze the activating role of cyclic alternating pattern (CAP) and EEG synchrony on generalized interictal paroxysms in the first part of the night, when all sleep patterns are represented. METHODS: nocturnal polysomnographic investigation was accomplished on a randomized series of 18 subjects with an active form of primary generalized epilepsy (PGE), but only six patients showed a complete and regular profile of the first two sleep cycles (SCs). Completeness and regularity of the selected SCs consisted in the absence of intervening wakefulness, in the presence of all sleep stages, and in the identification of three main units, (a) a descending branch, dominated by the build-up of EEG synchrony in the transition from light to deep non-rapid eye movement (NREM) sleep; (b) a trough, where the magnitude of EEG synchrony is greatest and gives rise to stages 3 and 4; (c) an ascending branch characterized by a decrease of EEG synchrony preceding the onset of rapid eye movement (REM) sleep. Generalized paroxysms were evaluated in terms of discharge rates (number of interictal bursts per minute of sleep) and distribution within the investigated sleep parameters. RESULTS: the discharge rates decreased from SC1 to SC2, with higher values quantified during NREM sleep (mean, 2.8) compared with REM sleep (mean, 0.8). Both SCs showed a progressive decrease of activation across the three units, from the highest discharge rates reached during the descending branches (mean, 3.6) to the more attenuated discharge rates during the troughs (mean, 2.4) down to the lowest rates during the ascending limbs (mean, 1.1). The magnitude of activation during the descending branches was closely related to the CAP condition (mean, 5.2) and to the powerful effect of phase A (mean, 13.9). The great majority (82%) of EEG discharges occurring in phase A were distributed within the A1 subtypes (identified by sequences of k-complexes or delta bursts). CONCLUSIONS: within the first two SCs, the features of NREM sleep endowed with the major activating power on generalized bursts are represented by the rise of EEG synchrony (descending branch) and by the A phases of CAP involved in the regulation of its build-up.

[Neurophysiological basis of insomnia: role of cyclic alternating patterns]. / Les bases neurophysiologiques de l'insomnie: le rôle des tracés alternant cycliques (CAP).

During non-REM (NREM) sleep it is possible to identify two complementary conditions of arousal stability and arousal instability. Unstable sleep, which can be detected in all stages, is expressed by the recurrence of arousal complexes (sequences of K-complexes, delta bursts, K-alpha, conventional arousals), which translate a brief (10-15 s) activation of the sleeping brain. These repetitive arousal complexes compose the cyclic alternating pattern (CAP). During stable NREM sleep, arousal complexes are rare or absent and the EEG lacks any cyclic pattern (non-CAP). CAP is a spontaneous feature of normal sleep as it is typically involved in stage changes and nocturnal motor activity. The physiological amount of CAP rate (ratio of CAP time to NREM sleep time) varies with age according to a U-shape curve. Within these ranges, sleep is perceived as continuous and restorative. Conversely, an excess of CAP rate fragments sleep and impairs its quality. Polysomnographic investigation reveals that untreated insomniac patients exhibit significantly higher values of CAP rate compared to healthy sleepers. Effective hypnotic treatment restores physiological amounts of CAP rate, with specific differences between the administered drugs. The sensitivity of CAP parameters to drug manipulation can provide circumscribed information on the hypnotic properties of active compounds.