Interobserver reliability of ICSD-R criteria for REM sleep behaviour disorder

We estimated the interobserver reliability (IR) of the diagnosis of rapid eye movement (REM) Sleep Behaviour Disorder (RBD) among trained neurologists, with the application of International Classification of Sleep Disorders Revised (ICSD-R), by means of videotaped interviews of people with motor sleep behaviour disorders of different nature. IR of clinical judgement for the diagnosis of RBD was "substantial" (Kappa 0.65); nevertheless, some criteria ('limb or body movement associated with dream mentation', criterion B, and 'sleep behaviours (that) disrupt sleep continuity', criterion C3) showed a 'moderate' IR, resulting from the intrinsic limitations of the patient report and terminological ambiguity. Further clarification of terminology of the ICSD-R criteria would be useful to improve the reliability.     

Effects of exogenous melatonin on sleep and circadian rhythms in women with premenstrual dysphoric disorder

We previously found normal polysomnographic (PSG) sleep efficiency, increased slow-wave sleep (SWS), and a blunted melatonin secretion in women with premenstrual dysphoric disorder (PMDD) compared to controls. Here, we investigated the effects of exogenous melatonin in five patients previously studied. They took 2 mg of slow-release melatonin 1 h before bedtime during their luteal phase (LP) for three menstrual cycles. At baseline, patients spent every third night throughout one menstrual cycle sleeping in the laboratory. Measures included morning urinary 6-sulfatoxymelatonin (aMt6), PSG sleep, nocturnal core body temperature (CBT), visual analog scale for mood (VAS-Mood), Prospective Record of the Impact and Severity of Menstrual Symptoms (PRISM), and ovarian plasma hormones. Participants also underwent two 24-hour intensive physiological monitoring (during the follicular phase and LP) in time-isolation/constant conditions to determine 24-hour plasma melatonin and CBT rhythms. The same measures were repeated during their third menstrual cycle of melatonin administration. In the intervention condition compared to baseline, we found increased urinary aMt6 (p < 0.001), reduced objective sleep onset latency (p = 0.01), reduced SWS (p < 0.001), and increased Stage 2 sleep (p < 0.001). Increased urinary aMt6 was correlated with reduced SWS (r = −0.51, p < 0.001). Circadian parameters derived from 24-hour plasma melatonin and CBT did not differ between conditions, except for an increased melatonin mesor in the intervention condition (p = 0.01). Ovarian hormones were comparable between the conditions (p ≥ 0.28). Symptoms improved in the intervention condition, as measured by the VAS-Mood (p = 0.02) and the PRISM (p < 0.001). These findings support a role for disturbed melatonergic system in PMDD that can be partially corrected by exogenous melatonin.     

Evidence that non‐dreamers do dream: a REM sleep behaviour disorder model

To determine whether non‐dreamers do not produce dreams or do not recall them, subjects were identified with no dream recall with dreamlike behaviours during rapid eye movement sleep behaviour disorder, which is typically characterised by dream‐enacting behaviours congruent with sleep mentation. All consecutive patients with idiopathic rapid eye movement sleep behaviour disorder or rapid eye movement sleep behaviour disorder associated with Parkinson's disease who underwent a video‐polysomnography were interviewed regarding the presence or absence of dream recall, retrospectively or upon spontaneous arousals. The patients with no dream recall for at least 10 years, and never‐ever recallers were compared with dream recallers with rapid eye movement sleep behaviour disorder regarding their clinical, cognitive and sleep features. Of the 289 patients with rapid eye movement sleep behaviour disorder, eight (2.8%) patients had no dream recall, including four (1.4%) patients who had never ever recalled dreams, and four patients who had no dream recall for 10–56 years. All non‐recallers exhibited, daily or almost nightly, several complex, scenic and dreamlike behaviours and speeches, which were also observed during rapid eye movement sleep on video‐polysomnography (arguing, fighting and speaking). They did not recall a dream following sudden awakenings from rapid eye movement sleep. These eight non‐recallers with rapid eye movement sleep behaviour disorder did not differ in terms of cognition, clinical, treatment or sleep measures from the 17 dreamers with rapid eye movement sleep behaviour disorder matched for age, sex and disease. The scenic dreamlike behaviours reported and observed during rapid eye movement sleep in the rare non‐recallers with rapid eye movement sleep behaviour disorder (even in the never‐ever recallers) provide strong evidence that non‐recallers produce dreams, but do not recall them. Rapid eye movement sleep behaviour disorder provides a new model to evaluate cognitive processing during dreaming and subsequent recall.     

123I-MIBG cardiac scintigraphy provides clues to the underlying neurodegenerative disorder in idiopathic REM sleep behavior disorder

OBJECTIVE: RBD is considered to be a manifestation of an evolving synucleinopathy, such as Parkinson disease (PD), dementia of Lewy bodies (DLB), and multiple system atrophy (MSA). We tested whether the degree of accumulation of cardiac 123I-MIBG scintigraphy can distinguish the clinical syndromes associated with Lewy body-related disease from the syndrome of PSP (a tauopathy) and MSA. DESIGN: Cross-sectional. SETTING: University-based sleep disorders laboratory. PATIENTS: Subjects comprised 95 patients (31, idiopathic RBD; 26, PD; 10, MSA; 6, DLB; 13, progressive supranuclear palsy [PSP]) and 9 control subjects. INTERVENTION: To compare tracer uptake of cardiac 123I-MIBG between idiopathic RBD, PD, MSA, DLB, and PSP and control subjects. MEASUREMENTS AND RESULTS: Cardiac 123I-MIBG accumulation was evaluated by the heart/mediastinum (H/M) ratio. Mean value of the H/M ratio (early, delayed) was significantly reduced in patients with idiopathic RBD compared to MSA patients, PSP patients, control subjects (P < 0.001 in each group) and PD patients in early images (P < 0.05). There was a correlation between the H/M ratio and disease duration in the idiopathic RBD group. ROC analysis revealed that an H/M cut-off value of 1.9 was useful for differentiating RBD from MSA and PSP as well as distinguishing control subjects from those with RBD in both early and delayed images. CONCLUSION: Cardiac 123I-MIBG findings are similar among idiopathic RBD and the syndromes of PD and DLB, but differ from those of PSP and MSA.     

Effect of clonazepam and clonidine on primary sleep bruxism: a double‐blind,crossover, placebo‐controlled trial

The aim of this study was to assess the acute effects of clonazepam and clonidine on rhythmic masticatory muscle activity in young adults with primary sleep bruxism, as well as accompanying effects on sleep architecture and cardiac activity. This study used a double‐blind, crossover, placebo‐controlled design. Polysomnography was performed on 19 subjects [nine men and 10 women; mean age (±SE): 25.4 ± 2.7 years] for 5 nights. The first 2 nights were used for the habituation and diagnosis of sleep bruxism. The other 3 nights were randomly assigned for clonazepam (1.0 mg), clonidine (0.15 mg) or placebo (all administered 30 min before bedtime). Sleep, oromotor activity and cardiac activity variables were assessed and compared among the three drug conditions. Clonidine significantly reduced the median percentage of time spent in the rapid eye movement sleep stage compared with placebo and clonazepam. The number of rhythmic masticatory muscle activity episodes was reduced with clonidine by >30% compared with placebo and clonazepam. The reduction of rhythmic masticatory muscle activity index by clonidine was associated with an increase of mean RR intervals (slower heart rate) during quiet sleep periods and during a 70‐s period before the onset of rhythmic masticatory muscle activity episodes. However, no changes in cardiac activity variables were observed for clonazepam. In young adults with primary sleep bruxism, clonidine was significantly more effective in suppressing sleep bruxism than clonazepam. The acute effects of clonidine on rhythmic masticatory muscle activity episodes may be mediated by suppression of autonomic nervous system activity and non‐rapid eye movement–rapid eye movement sleep processes.     

Cognitive dysfunction and REM sleep behavior disorder: Key findings in the literature and preliminary longitudinal findings

A considerable proportion of subjects initially diagnosed with idiopathic REM sleep behavior disorder (iRBD) are reported to convert to a neurodegenerative disorder, mainly synucleinopathies.     

Modafinil in the treatment of idiopathic hypersomnia without long sleep time—a randomized,double‐blind,placebo‐controlled study

In 2010 the European Medicines Agency withdrew the indication of modafinil for the treatment of obstructive sleep apnea, shift work sleep disorder and for idiopathic hypersomnia (IH). In uncontrolled studies, modafinil has been reported to be efficacious in the treatment of sleep disorders. We therefore performed a randomized, placebo‐controlled study with the aim of proving the efficacy of modafinil treatment in these patients. Drug‐free IH patients without long sleep according to ICSD2 criteria, age >18 years and disease duration >2 years were included. After a washout phase, patients at baseline received placebo or 100 mg modafinil in the morning and at noon over 3 weeks, followed by 1 week without medication. At each visit the Epworth Sleepiness Scale (ESS) and Clinical Global Impression (CGI) rating scale were performed. At baseline and on days 8 and 21 four Maintenance of Wakefulness Tests (MWTs)/day or per day were performed. Patients kept a sleep–wake diary throughout the study. Between 2009 and 2011 three sleep centres recruited 33 participants. Compared to placebo, modafinil decreased sleepiness significantly and improved mean sleep latency in the MWT non‐significantly. The CGI improved significantly from baseline to the last visit on treatment. The most frequent adverse events were headaches and gastrointestinal disorders; skin and psychiatric reactions were not reported. The number of reported naps and duration of daytime sleepiness decreased significantly. Total sleep time of nocturnal sleep was slightly reduced. The sleep diaries showed increases in feeling refreshed in the morning; the diurnal diaries showed significant improvement of performance and of exhaustion. Modafinil is an effective and safe medication in the treatment of IH. Adverse events are mild to moderate.     

Quantitative electroencephalography during rapid eye movement (REM) and non‐REM sleep in combat‐exposed veterans with and without post‐traumatic stress disorder

Sleep disturbances are a hallmark feature of post‐traumatic stress disorder (PTSD), and associated with poor clinical outcomes. Few studies have examined sleep quantitative electroencephalography (qEEG), a technique able to detect subtle differences that polysomnography does not capture. We hypothesized that greater high‐frequency qEEG would reflect ‘hyperarousal’ in combat veterans with PTSD (n = 16) compared to veterans without PTSD (n = 13). EEG power in traditional EEG frequency bands was computed for artifact‐free sleep epochs across an entire night. Correlations were performed between qEEG and ratings of PTSD symptoms and combat exposure. The groups did not differ significantly in whole‐night qEEG measures for either rapid eye movement (REM) or non‐REM (NREM) sleep. Non‐significant medium effect sizes suggest less REM beta (opposite to our hypothesis), less REM and NREM sigma and more NREM gamma in combat veterans with PTSD. Positive correlations were found between combat exposure and NREM beta (PTSD group only), and REM and NREM sigma (non‐PTSD group only). Results did not support global hyperarousal in PTSD as indexed by increased beta qEEG activity. The correlation of sigma activity with combat exposure in those without PTSD and the non‐significant trend towards less sigma activity during both REM and NREM sleep in combat veterans with PTSD suggests that differential information processing during sleep may characterize combat‐exposed military veterans with and without PTSD.     

Lack of effects of pramipexole on REM sleep behavior disorder in Parkinson disease

STUDY OBJECTIVES: REM sleep behavior disorder (RBD) is a common manifestation of Parkinson disease (PD) which is characterized by dream-enacting behaviors, unpleasant dreams, and loss of muscle atonia during REM sleep. Dopaminergic mechanisms are thought to play a role in RBD pathogenesis. To further asses such a role, we have evaluated the effect of pramipexole, a dopamine receptor agonist, on RBD features in PD patients. SETTING: University hospital sleep disorder center. PARTICIPANTS: Eleven PD patients with untreated RBD. interventions: Not applicable. MEASUREMENTS AND RESULTS: In a prospective study, 11 consecutive PD patients with untreated RBD on levodopa monotherapy were placed on pramipexole to further ameliorate their parkinsonism. The effects on RBD were evaluated before and 3 months after stable pramipexole therapy through patient and bed partner interviews and blind assessment of video-polysomnographic measures. Pramipexole improved parkinsonism in all patients. Patients and bed partners reported no significant changes in frequency and severity of the abnormal RBD related motor and vocal sleep behaviors or the frequency of unpleasant dreams. Video-polysomnography analyses showed no differences in RBD related sleep measures including tonic submental electromyographic activity, phasic submental electromyographic activity, percentage of REM sleep time spent with abnormal behaviors, and severity of the abnormal behaviors detected on the videotapes. CONCLUSION: In PD, pramipexole improved parkinsonism but did not modify RBD related symptoms and objective video-polysomnographic abnormalities. This observation suggests that in PD, dopamine mechanisms do not play a central role in the pathogenesis of RBD.     

Body temperature,activity and melatonin profiles in adults with attention‐deficit/hyperactivity disorder and delayed sleep: a case–control study

Irregular sleep–wake patterns and delayed sleep times are common in adults with attention‐deficit/hyperactivity disorder, but mechanisms underlying these problems are unknown. The present case–control study examined whether circadian abnormalities underlie these sleep problems in a naturalistic home setting. We included 12 medication‐naïve patients with attention‐deficit/hyperactivity disorder and delayed sleep phase syndrome, and 12 matched healthy controls. We examined associations between sleep/wake rhythm in attention‐deficit/hyperactivity disorder and circadian parameters (i.e. salivary melatonin concentrations, core and skin temperatures, and activity patterns) of the patients and controls during five consecutive days and nights. Daily bedtimes were more variable within patients compared with controls (F = 8.19, P < 0.001), but melatonin profiles were equally stable within individuals. Dim‐light melatonin onset was about 1.5 h later in the patient group (U = 771, Z = ?4.63, P < 0.001). Patients slept about 1 h less on nights before work days compared with controls (F = 11.21, P = 0.002). The interval between dim‐light melatonin onset and sleep onset was on average 1 h longer in patients compared with controls (U = 1117, Z = ?2.62, P = 0.009). This interval was even longer in patients with extremely late chronotype. Melatonin, activity and body temperatures were delayed to comparable degrees in patients. Overall temperatures were lower in patients than controls. Sleep‐onset difficulties correlated with greater distal–proximal temperature gradient (DPG; i.e. colder hands, r² = ?0.32, P = 0.028) in patients. Observed day‐to‐day bedtime variability of individuals with attention‐deficit/hyperactivity disorder and delayed sleep phase syndrome were not reflected in their melatonin profiles. Irregular sleep–wake patterns and delayed sleep in individuals with attention‐deficit/hyperactivity disorder and delayed sleep phase syndrome are associated with delays and dysregulations of the core and skin temperatures.     

Objective measures of sleep and dim light melatonin onset in adolescents and young adults with delayed sleep phase disorder compared to healthy controls

Delayed sleep phase disorder is characterized by a delay in the timing of the major sleep period relative to conventional norms. The sleep period itself has traditionally been described as normal. Nevertheless, it is possible that sleep regulatory mechanism disturbances associated with the disorder may affect sleep duration and/or architecture. Polysomnographic data that may shed light on the issue are scarce. Hence, the aim of this study was to examine polysomnographic measures of sleep in adolescents and young adults with delayed sleep phase disorder, and to compare findings to that of healthy controls. A second aim was to estimate dim light melatonin onset as a marker of circadian rhythm and to investigate the phase angle relationship (time interval) between dim light melatonin onset and the sleep period. Data from 54 adolescents and young adults were analysed, 35 diagnosed with delayed sleep phase disorder and 19 healthy controls. Results show delayed timing of sleep in participants with delayed sleep phase disorder, but once sleep was initiated no group differences in sleep parameters were observed. Dim light melatonin onset was delayed in participants with delayed sleep phase disorder, but no difference in phase angle was observed between the groups. In conclusion, both sleep and dim light melatonin onset were delayed in participants with delayed sleep phase disorder. The sleep period appeared to occur at the same circadian phase in both groups, and once sleep was initiated no differences in sleep parameters were observed.     

Rapid eye movement fragmentation,not slow‐wave sleep,predicts neutral declarative memory consolidation in posttraumatic stress disorder

Individuals diagnosed with posttraumatic stress disorder (PTSD) experience disruption at both slow‐wave sleep (SWS) and rapid‐eye movement (REM) sleep stages and demonstrate marked memory impairment. A small group of studies suggests that, within the disorder, there is a mechanistic relation between these sleep and memory impairments. This study sought to extend that literature by examining whether, in PTSD‐diagnosed individuals, memory‐retention deficits are present after a sleep‐filled (but not after a wake‐filled) delay (i.e., whether memory deficits can be traced to interruptions of sleep‐dependent memory consolidation). Moreover, we investigated whether SWS‐ or REM‐based disturbances, or both, contribute to retention deficits. We recruited participants into three groups: PTSD (n = 21), trauma‐exposed non‐PTSD (TE; n = 19) and healthy control (HC; n = 20). Using a crossover design, we assessed memory recall before and after an 8‐hr period of polysomnography‐monitored sleep and an 8‐hr period of regular waking activity. PTSD‐diagnosed participants retained less information than controls over the sleep‐filled (but not wake‐filled) delay. Furthermore, increased REM fragmentation predicted postsleep memory retention in PTSD‐diagnosed individuals only. No SWS parameter was associated with or predictive of the amount of information retained postsleep. We conclude that specific REM‐related changes in PTSD‐diagnosed individuals affected sleep‐dependent neutral declarative memory consolidation. Generally, these findings extend the literature suggesting that the co‐occurrence of sleep and memory difficulties in PTSD is not accidental, but that these two symptom clusters are meaningfully related. Specifically, the study illustrates that subtle REM‐related disruptions contribute most strongly to memory impairment in PTSD.     

The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis

Study Objectives:

To perform a meta-analysis of the efficacy and safety of exogenous melatonin in advancing sleep-wake rhythm in patients with delayed sleep phase disorder.

Design:

Meta analysis of papers indexed for PubMed, Embase, and the abstracts of sleep and chronobiologic societies (1990–2009).

Patients:

Individuals with delayed sleep phase disorder.

Interventions:

Administration of melatonin.

Measurements and Results:

A meta-analysis of data of randomized controlled trials involving individuals with delayed sleep phase disorder that were published in English, compared melatonin with placebo, and reported 1 or more of the following: endogenous melatonin onset, clock hour of sleep onset, wake-up time, sleep-onset latency, and total sleep time. The 5 trials including 91 adults and 4 trials including 226 children showed that melatonin treatment advanced mean endogenous melatonin onset by 1.18 hours (95% confidence interval [CI]: 0.89–1.48 h) and clock hour of sleep onset by 0.67 hours (95% CI: 0.45–0.89 h). Melatonin decreased sleep-onset latency by 23.27 minutes (95% CI: 4.83 –41.72 min). The wake-up time and total sleep time did not change significantly.

Conclusions:

Melatonin is effective in advancing sleep-wake rhythm and endogenous melatonin rhythm in delayed sleep phase disorder.

Citation:

van Geijlswijk IM; Korzilius HPLM; Smits MG. The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis. SLEEP 2010;33(12):1605-1614.     

A quantitative statistical analysis of the submentalis muscle EMG amplitude during sleep in normal controls and patients with REM sleep behavior disorder

The aim of this study was to evaluate quantitatively the amplitude of the submentalis muscle EMG activity during sleep in controls and in patients with idiopathic REM sleep behavior disorder (RBD) or with RBD and multiple system atrophy (MSA). We recruited 21 patients with idiopathic RBD, 10 with MSA, 10 age-matched and 24 young normal controls. The average amplitude of the rectified submentalis muscle EMG signal was used for the assessment of atonia and a Sleep Atonia Index was developed; moreover, also chin muscle activations were detected and their duration and interval analyzed. The Sleep Atonia Index was able to distinguish clearly REM from NREM sleep in normal controls with values very close to 1 in young normal subjects and only slightly (but significantly) lower in old controls. Idiopathic RBD patients showed a further significant decrease of this index; MSA patients showed the lowest values of REM Sleep Atonia Index, which were very well distinguishable from those of normal controls and of idiopathic RBD patients. The distribution of the duration of chin activations was monomodal in all groups, with idiopathic RBD patients showing the highest levels. This study is a really quantitative attempt to provide practical indices for the objective evaluation of EMG atonia during REM sleep and of EMG activations. Our proposed Sleep Atonia Index can have a practical application in the clinical evaluations of patients and represents an additional useful parameters to be used in conjunction with the other criteria for the diagnosis of this sleep motor disorder.     

A randomized,double‐blind,placebo‐controlled,dose‐finding trial with Lolium perenne peptide immunotherapy

Background

A novel subcutaneous allergen immunotherapy formulation (gpASIT+?) containing Lolium perenne peptides (LPP) and having a short up‐dosing phase has been developed to treat grass pollen–induced seasonal allergic rhinoconjunctivitis. We investigated peptide immunotherapy containing the hydrolysate from perennial ryegrass allergens for the optimum dose in terms of clinical efficacy, immunogenicity and safety.

Methods

This prospective, double‐blind, placebo‐controlled, phase IIb, parallel, four‐arm, dose‐finding study randomized 198 grass pollen–allergic adults to receive placebo or cumulative doses of 70, 170 or 370 μg LPP. All patients received weekly subcutaneous injections, with the active treatment groups reaching assigned doses within 2, 3 and 4 weeks, respectively. Efficacy was assessed by comparing conjunctival provocation test (CPT) reactions at baseline, after 4 weeks and after completion. Grass pollen–specific immunoglobulins were analysed before and after treatment.

Results

Conjunctival provocation test (CPT) response thresholds improved from baseline to V7 by at least one concentration step in 51.2% (170 μg; P = .023), 46.3% (370 μg), and 38.6% (70 μg) of patients receiving LPP vs 25.6% of patients receiving placebo (modified per‐protocol set). Also, 39% of patients in the 170‐μg group became nonreactive to CPT vs 18% in the placebo group. Facilitated allergen‐binding assays revealed a highly significant (P < .001) dose‐dependent reduction in IgE allergen binding across all treatment groups (70 μg: 17.1%; 170 μg: 18.8%; 370 μg: 26.4%). Specific IgG₄ levels increased to 1.6‐fold (70 μg), 3.1‐fold (170 μg) and 3.9‐fold (370 μg) (mPP).

Conclusion

Three‐week immunotherapy with 170 μg LPP reduced CPT reactivity significantly and increased protective specific antibodies.

     

Symposium: Normal and abnormal REM sleep regulation: REM sleep behaviour disorder: an update on a series of 96 patients and a review of the world literature

REM sleep behaviour disorder (RBD) is an injurious clinical disorder of attempted dream-enactment ('oneirism') in humans which has a corresponding experimental animal model involving dorsolateral pontine tegmental lesions in cats. To date, our sleep disorders centre has collected data on 96 chronic RBD cases which can be compared with pooled data on 70 chronic RBD cases from other centres contained in 26 reports published in the world literature since 1985, when our initial cases were first reported. The data from our centre and from other centres demonstrate a male predominance in RBD (87.5% vs 63.5%); indicate a similar mean age of RBD onset (52.4 y vs 55.9 y); contain substantial numbers of diverse central nervous system disorders causally associated with RBD (47.9% vs 60.0%); and identify clonazepam treatment as being very effective in controlling both the (violent) dream and sleep behavioural disturbances of RBD. Our centre's data additionally reveal an 80% prevalence of elevated stage 3/4 (slow-wave) sleep% for age in RBD, and reveal a frequent presence of periodic and aperiodic limb movements during NREM sleep. Thus, RBD in humans is a complex syndrome in which there is generalized REM and NREM sleep motor dyscontrol, as was originally observed in the animal RBD model by Jouvet and Delorme in 1965.     

Japanese sake yeast supplementation improves the quality of sleep: a double‐blind randomised controlled clinical trial

Activation of adenosine A_2a receptors in cerebral neurons induces sleep in various mammals. It was previously found that Japanese sake yeast enriched in adenosine analogues activates A_2a receptors in vitro and induces sleep in mice. Here it is reported that sake yeast activated A_2a receptors in a cultured human cell line and improved human sleep quality in a clinical trial. Sake yeast activated A_2a receptors in HEK cells in a dose‐dependent manner with an EC₅₀ of 40 μg mL^?1, and the activation was attenuated almost completely by the A_2a receptor antagonist ZM241385 with an IC₅₀ of 73 nm . In a double‐blind placebo‐controlled crossover clinical study, 68 healthy participants ingested tablets containing either 500 mg of sake yeast powder or a placebo (cellulose) 1 h before sleep for 4 days. Electroencephalograms were recorded during sleep at home with a portable device for 4 week days. Electroencephalogram analyses revealed that sake yeast supplementation significantly (P = 0.03) increased delta power during the first cycle of slow‐wave sleep by 110%, without changing other sleep parameters. Sake yeast supplementation also significantly increased growth hormone secretion in the urine on awakening by 137% from 3.17 ± 0.41 (placebo) to 4.33 ± 0.62 (sake yeast) pg mg^?1 creatinine (P = 0.03). Subjective sleepiness (P = 0.02) and fatigue (P = 0.06) in the morning were improved by sake yeast. Given these benefits and the absence of adverse effects during the study period, it was concluded that sake yeast supplementation is an effective and safe way to support daily high‐quality, deep sleep.     

Twenty‐four‐hour motor activity and body temperature patterns suggest altered central circadian timekeeping in Smith–Magenis syndrome,a neurodevelopmental disorder

Smith–Magenis syndrome (SMS) is a contiguous gene syndrome linked to interstitial microdeletion, or mutation of RAI1, within chromosome 17p11.2. Key behavioral features of SMS include intellectual disability, sleep‐disturbances, maladaptive, aggressive and self‐injurious behaviors, hyperactivity, and sudden changes in mood. A distinguishing feature of this syndrome is an inverted pattern of melatonin characterized by elevated daytime and low nighttime melatonin levels. As the central circadian clock controls the 24‐hr rhythm of melatonin, we hypothesized that the clock itself may contribute to the disrupted pattern of melatonin and sleep. In this report, 24‐hr patterns of body temperature, a surrogate marker of clock‐timing, and continuous wrist activity were collected to examine the links between body temperature, sleep behavior, and the circadian clock. In addition, age‐dependent changes in sleep behavior were explored. Actigraphy‐estimated sleep time for SMS was 1 hr less than expected across all ages studied. The timing of the 24‐hr body temperature (Tb‐24) rhythm was phase advanced, but not inverted. Compared to sibling (SIB) controls, the SMS group had less total night sleep, lower sleep efficiency, earlier sleep onset, earlier final awake times, increased waking after sleep onset (WASO), and increased daytime nap duration. The timing of wake onset varied with age, providing evidence of ongoing developmental sleep changes from childhood through adolescence. Clarification of the circadian and developmental factors that contribute to the disrupted and variable sleep patterns in this syndrome will be helpful in identifying more effective individualized treatments.     

Controlled‐release melatonin,singly and combined with cognitive behavioural therapy,for persistent insomnia in children with autism spectrum disorders: a randomized placebo‐controlled trial

Although melatonin and cognitive–behavioural therapy have shown efficacy in treating sleep disorders in children with autism spectrum disorders, little is known about their relative or combined efficacy. One hundred and sixty children with autism spectrum disorders, aged 4–10 years, suffering from sleep onset insomnia and impaired sleep maintenance, were assigned randomly to either (1) combination of controlled‐release melatonin and cognitive–behavioural therapy; (2) controlled‐release melatonin; (3) four sessions of cognitive–behavioural therapy; or (4) placebo drug treatment condition for 12 weeks in a 1 : 1 : 1 : 1 ratio. Children were studied at baseline and after 12 weeks of treatment. Treatment response was assessed with 1‐week actigraphic monitoring, sleep diary and sleep questionnaire. Main outcome measures, derived actigraphically, were sleep latency, total sleep time, wake after sleep onset and number of awakenings. The active treatment groups all resulted in improvements across all outcome measures, with moderate‐to‐large effect sizes from baseline to a 12‐week assessment. Melatonin treatment was mainly effective in reducing insomnia symptoms, while cognitive–behavioural therapy had a light positive impact mainly on sleep latency, suggesting that some behavioural aspects might play a role in determining initial insomnia. The combination treatment group showed a trend to outperform other active treatment groups, with fewer dropouts and a greater proportion of treatment responders achieving clinically significant changes (63.38% normative sleep efficiency criterion of >85% and 84.62%, sleep onset latency <30 min). This study demonstrates that adding behavioural intervention to melatonin treatment seems to result in a better treatment response, at least in the short term.